Brain Embolism

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Brain Embolism

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NEUROLOGICAL DISEASE AND THERAPY Advisory Board Gordon H. Baltuch, M.D., Ph.D. Department of Neurosurgery University of Pennsylvania Philadelphia, Pennsylvania, U.S.A.

Cheryl Bushnell, M.D., M.H.S. Duke Center for Cerebrovascular Disease Department of Medicine, Division of Neurology Duke University Medical Center Durham, North Carolina, U.S.A.

Louis R. Caplan, M.D. Professor of Neurology Harvard University School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A.

Mark A. Stacy, M.D. Movement Disorder Center Duke University Medical Center Durham, North Carolina, U.S.A.

Mark H. Tuszynski, M.D., Ph.D. Professor of Neurosciences Director, Center for Neural Repair University of California—San Diego La Jolla, California, U.S.A.

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1. Handbook of Parkinson’s Disease, edited by William C. Koller 2. Medical Therapy of Acute Stroke, edited by Mark Fisher 3. Familial Alzheimer’s Disease: Molecular Genetics and Clinical Perspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner 4. Alzheimer’s Disease: Treatment and Long-Term Management, edited by Jeffrey L. Cummings and Bruce L. Miller 5. Therapy of Parkinson’s Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by Michael J. Thorpy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L. Schraeder 8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice, edited by Takehiko Yanagihara and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, Walter H. Moos, and Elkan R. Gamzu 12. Handbook of Amyotrophic Lateral Sclerosis, edited by Richard Alan Smith 13. Handbook of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller 14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Fereydoun Dehkharghani 15. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders, edited by Roger Kurlan 16. Handbook of Cerebellar Diseases, edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr. 18. Parkinsonian Syndromes, edited by Matthew B. Stern and William C. Koller 19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robert A. Morantz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa B. H. Youdim, and Keith Tipton 22. Handbook of Dementing Illnesses, edited by John C. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak 24. Handbook of Neurorehabilitation, edited by David C. Good and James R. Couch, Jr. 25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett 26. Principles of Neurotoxicology, edited by Louis W. Chang 27. Handbook of Neurovirology, edited by Robert R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology, edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by Philip B. Gorelick and Milton Alter 30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller

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31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management, edited by Ronald J. Tusa and Steven A. Newman 32. Handbook of Olfaction and Gustation, edited by Richard L. Doty 33. Handbook of Neurological Speech and Language Disorders, edited by Howard S. Kirshner 34. Therapy of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson 35. Evaluation and Management of Gait Disorders, edited by Barney S. Spivack 36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S. Dyer 37. Neurological Complications of Cancer, edited by Ronald G. Wiley 38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn 39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B. Calne 40. Etiology of Parkinson’s Disease, edited by Jonas H. Ellenberg, William C. Koller and J. William Langston 41. Practical Neurology of the Elderly, edited by Jacob I. Sage and Margery H. Mark 42. Handbook of Muscle Disease, edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded, edited by Stuart D. Cook 44. Central Nervous System Infectious Diseases and Therapy, edited by Karen L. Roos 45. Subarachnoid Hemorrhage: Clinical Management, edited by Takehiko Yanagihara, David G. Piepgras, and John L. D. Atkinson 46. Neurology Practice Guidelines, edited by Richard Lechtenberg and Henry S. Schutta 47. Spinal Cord Diseases: Diagnosis and Treatment, edited by Gordon L. Engler, Jonathan Cole, and W. Louis Merton 48. Management of Acute Stroke, edited by Ashfaq Shuaib and Larry B. Goldstein 49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras 50. Handbook of Ataxia Disorders, edited by Thomas Klockgether 51. The Autonomic Nervous System in Health and Disease, David S. Goldstein 52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. Ingoglia and Marion Murray 53. Handbook of Multiple Sclerosis: Third Edition, edited by Stuart D. Cook 54. Long-Term Effects of Stroke, edited by Julien Bogousslavsky 55. Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefano Govoni 56. Dopamine Receptors and Transporters: Function, Imaging, and Clinical Implication, Second Edition, edited by Anita Sidhu, Marc Laruelle, and Philippe Vernier 57. Handbook of Olfaction and Gustation: Second Edition, Revised and Expanded, edited by Richard L. Doty 58. Handbook of Stereotactic and Functional Neurosurgery, edited by Michael Schulder 59. Handbook of Parkinson’s Disease: Third Edition, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller

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60. Clinical Neurovirology, edited by Avindra Nath and Joseph R. Berger 61. Neuromuscular Junction Disorders: Diagnosis and Treatment, Matthew N. Meriggioli, James F. Howard, Jr., and C. Michel Harper 62. Drug-Induced Movement Disorders, edited by Kapil D. Sethi 63. Therapy of Parkinson’s Disease: Third Edition, Revised and Expanded, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 64. Epilepsy: Scientific Foundations of Clinical Practice, edited by Jong M. Rho, Raman Sankar, and José E. Cavazos 65. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders: Second Edition, edited by Roger Kurlan 66. Handbook of Cerebrovascular Diseases: Second Edition, Revised and Expanded, edited by Harold P. Adams, Jr. 67. Emerging Neurological Infections, edited by Christopher Power and Richard T. Johnson 68. Treatment of Pediatric Neurologic Disorders, edited by Harvey S. Singer, Eric H. Kossoff, Adam L. Hartman, and Thomas O. Crawford 69. Synaptic Plasticity : Basic Mechanisms to Clinical Applications, edited by Michel Baudry, Xiaoning Bi, and Steven S. Schreiber 70. Handbook of Essential Tremor and Other Tremor Disorders, edited by Kelly E. Lyons and Rajesh Pahwa 71. Handbook of Peripheral Neuropathy, edited by Mark B. Bromberg and A. Gordon Smith 72. Carotid Artery Stenosis: Current and Emerging Treatments, edited by Seemant Chaturvedi and Peter M. Rothwell 73. Gait Disorders: Evaluation and Management, edited by Jeffrey M. Hausdorff and Neil B. Alexander 74. Surgical Management of Movement Disorders (HBK), edited by Gordon H. Baltuch and Matthew B. Stern 75. Neurogenetics: Scientific and Clinical Advances, edited by David R. Lynch 76. Epilepsy Surgery: Principles and Controversies, edited by John W. Miller and Daniel L. Silbergeld 77. Clinician's Guide To Sleep Disorders, edited by Nathaniel F. Watson and Bradley Vaughn 78. Amyotrophic Lateral Sclerosis, edited by Hiroshi Mitsumoto, Serge Przedborski and Paul H. Gordon 79. Duchenne Muscular Dystrophy: Advances in Therapeutics, edited by Jeffrey S. Chamberlain and Thomas A. Rando 80. Handbook of Multiple Sclerosis, Fourth Edition, edited by Stuart D. Cook 81. Brain Embolism, edited by Louis R. Caplan and Warren J. Manning 82. Handbook of Secondary Dementias, edited by Roger Kurlan 83. Parkinson's Disease: Genetics and Pathogenesis, edited by Ted M. Dawson 84. Migraine, Russell Lane and Paul Davies 85. Migraine and Other Headache Disorders, edited by Richard B. Lipton and Marcelo Bigal 86. Restless Leg Syndrome, edited by William G. Ondo 87. Handbook of Dementing Illnesses, Second Edition, edited by John C. Morris, James E. Galvin, and David M. Holtzman

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Brain Embolism

edited by

Louis R. Caplan Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A.

Warren J. Manning Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A.

New York London

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-2929-3 (Hardcover) International Standard Book Number-13: 978-0-8247-2929-5 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

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Preface

In medicine, as in other areas of life, interest and emphasis on various topics go through periods of ups and downs. Brain embolism was defined by most physicians during the middle years of the twentieth century as embolism to the brain arising from clots, bacteria, and other substances that came from the heart. During the last three decades, technology has been introduced that can show brain infarction during life and can detect embolic particles passing through arteries that supply the brain. These more recent brain and vascular studies showed that the great majority of brain ischemic events are caused by embolism. However, not all of the embolic particles arise from the heart. Many come from the aorta, from systemic veins, and from the cervico-cranial arteries. This knowledge has led to a return to the original definition of embolism, that is, blockage of an artery by material originating from a distant site. The process of brain embolism is complex. There are a variety of donor sites and sources of embolic material. The particles that embolize also vary greatly. Emboli travel to many different recipient sites. Whether or not the emboli cause brain infarction is also complex and depends on other factors, including the vascular endothelium at the recipient site and the blood together with its constituents. No prior monographs have covered the complex topic of brain embolism in depth, stimulating us to try and fill this gap in the literature. Drs. Willis Hurst, Marc Chimowitz, and Caplan authored a monograph nearly a decade ago entitled Clinical Neurocardiology that contained a single chapter on brain embolism. The time has come for an updated review of this important topic. To ensure a thorough review of the topic, we recruited experts in areas of knowledge that we believed would enhance the monograph. Dr. Warren Manning, a cardiologist, contributed chapters related to cardiac origin and therapy for cardiac lesions that can lead to brain embolism. We also enlisted the help of experts in neck and transcranial ultrasound technology (Professor Michael Hennerici and his colleagues at the University of Heidelberg in Germany, and Dr. Carlos Molina (Barcelona, Spain) and Dr. Alexei Alexandrov (Houston, Texas, U.S.A.). Dr. Gregory del Zoppo added his considerable expertise about blood and endothelial factors that contribute to thromboembolism. The first part of the book begins with a historical review of the subject. Knowing where a topic has been is key to recognizing where it now is and where it is most likely headed in the future. This is followed by an overview that introduces the three main dramatists personae in the theatre of brain embolism—donor sites, embolic substances, and recipient sites. Pathological, clinical, and diagnostic aspects related to the recipient sites of brain emboli are explored in detail, followed by detailed analyses of the donor iii

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source of emboli—the heart, aorta, and cervico-cranial brain supply arteries. Next, the pathophysiology of embolism and the role of the blood, vascular endothelium, and neurovascular unit are explored. The nature of embolic substances is discussed, including their usual sources and clinical features. The monograph also reviews therapeutics and analyzes the effectiveness and risks of the various treatments employed. Finally, we look to the future. Louis R. Caplan Warren J. Manning Boston 2006

Contents Preface . . . . iii Contributors . . . . xi

Part I: Historical Background and Overview 1. Historical Background: Development of Ideas and Knowledge about Stroke and Brain Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Louis R. Caplan Early Writers—Description of Apoplexy and Interest in Anatomy . . . . 1 The 18th Century: Morgagni—The Beginning of Modern Pathology . . . . 3 The First Half of the 19th Century—Recognition of Brain Infarction and a Relationship with Heart Disease . . . . 4 The Second Half of the 19th Century—Cardiac Embolism Becomes an Established Clinical Entity . . . . 7 The First Half of the 20th Century—An Emphasis on Vascular Anatomy . . . . 8 Data Banks and Stroke Registries . . . . 13 New Technology and Further Studies Clarify More Potential Donor Sources of Emboli . . . . 17 Brain and Vascular Investigations Bring Embolism to the Forefront as the Major Cause of Brain Infarction . . . . 18 References . . . . 19

1

2. Overview: The Major Components of Brain Embolism . . . . . . . . . . . . . . . 25 Louis R. Caplan The Recipient Arteries . . . . 25 The Embolic Material . . . . 27 The Donor Source . . . . 28 References . . . . 29

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Part II: Recipient Arteries and Brain Ischemia 3. Recipient Artery: Anatomy and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . 31 Louis R. Caplan Examining Recipient Arteries to Separate Embolism and Thrombosis . . . . 31 Hemorrhagic Infarction . . . . 33 Location, Types, and Size of Embolic Brain Infarcts . . . . 36 References . . . . 58 4. Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Louis R. Caplan General Clinical Features and Diagnosis . . . . 61 Anterior Carotid Artery Circulation Embolism . . . . 67 Posterior Circulation Vertebro-Basilar Arteries Embolism . . . . 70 References . . . . 77 5. The Eye as the Recipient Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Louis R. Caplan Anatomy of the Arteries that Supply the Eye . . . . 81 Clinical Symptoms and Signs of Eye Ischemia . . . . 83 Methods of Investigating the Eye as a Recipient Site of Embolism . . . . 87 Differential Diagnosis of Retinal Embolism . . . . 88 Usual Sources of Retinal Embolism . . . . 89 Treatment . . . . 90 References . . . . 90 6. Imaging Evaluation: Recipient Artery Sites . . . . . . . . . . . . . . . . . . . . . . . . 93 Louis R. Caplan Brain Neuroimaging . . . . 93 Intracranial Vascular Imaging . . . . 97 Magnetic Resonance Perfusion Imaging and Complete Magnetic Resonance Protocols . . . . 101 Computed Tomography Perfusion and Complete Computed Tomography Protocols . . . . 104 Other Techniques for Studying Perfusion . . . . 106 References . . . . 109 7. Transcranial Doppler Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Carlos A. Molina and Andrei V. Alexandrov Introduction . . . . 113 TCD Diagnosis of Arterial Occlusions . . . . 114 TCD Monitoring During Thrombolysis . . . . 117 Detection of Intracranial Artery Stenosis and Artery-to-Artery Embolism . . . . 121 Emboli Monitoring . . . . 122 Detection of Right-to-Left Shunts . . . . 123 References . . . . 124

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Part III: Donor Sources—Nature, Frequency, Recognition 8. Cardiac Sources of Embolism: The Usual Suspects . . . . . . . . . . . . . . . . . 129 Louis R. Caplan and Warren J. Manning Arrhythmias . . . . 130 Cardiac Valve Disease . . . . 131 Aortic Valve Disease . . . . 132 Infective Endocarditis . . . . 137 Noninfective Fibrous and Fibrinous Endocardial Lesions (Including Valve Strands) . . . . 139 Myocardial and Cardiac Chamber Lesions . . . . 144 Cardiac Myxomas and Other Tumors . . . . 147 Paradoxical Embolism and Cardiac Septal Lesions . . . . 148 References . . . . 151

9. Cardiac Source of Embolism: Pathophysiology and Identification . . . . . . 161 Warren J. Manning Major Sources of Emboli . . . . 161 Left Atrial Anatomy and Imaging . . . . 161 Left Atrial Thrombi . . . . 162 Mitral Stenosis . . . . 163 Atrial Fibrillation . . . . 165 Left Ventricular Thrombi . . . . 169 Myocardial Infarction . . . . 170 Dilated Cardiomyopathy . . . . 171 Prosthetic Valve Thrombi . . . . 171 Aortic Atherosclerosis . . . . 171 Infective Endocarditis . . . . 172 Valvular Calcification . . . . 173 Valve Excrescences . . . . 173 Mitral Annular Calcification . . . . 174 Intracardiac Tumors . . . . 174 Left Atrial Spontaneous Echo Contrast . . . . 175 Abnormalities of the Interatrial Septum . . . . 176 Imaging Procedures . . . . 179 Summary and Recommendations . . . . 179 References . . . . 180

10. The Aorta as a Donor Source of Brain Embolism . . . . . . . . . . . . . . . . . . . 187 Louis R. Caplan Early Pathology-Based Reports of Embolism from the Aorta . . . . 187 Aortic Atherosclerosis . . . . 187 Heart Surgery and Aortic Atherosclerosis . . . . 191 Encephalopathy, Cognitive, and Neurobehavioral Abnormalities After Heart Surgery . . . . 194 Imaging of the Proximal Aorta . . . . 196 References . . . . 198

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11. Arterial Sources of Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Louis R. Caplan Diseases, Pathology, and Pathophysiology . . . . 203 Atherosclerosis . . . . 203 Arterial Dissections . . . . 205 Fibromuscular Dysplasia . . . . 205 Arterial Aneurysms and Dolichoectatic Arteries . . . . 208 Distribution of Arterial Lesions . . . . 209 Relation of Symptoms to Severity of Atherosclerotic Arterial Stenosis . . . . 213 Imaging and Laboratory Evaluation of Potential Donor Sources of Embolism . . . . 216 References . . . . 219 12. Ultrasound of Cervical Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Michael Hennerici, Hansjoerg Baezner, and Michael Daffertshofer Intima – Media Thickness: The Initial Stage of Arterial Disease . . . . 223 Plaque Development: The Intermediate Stage of Arterial Disease . . . . 226 Plaque Development: The Final Stage . . . . 234 References . . . . 236

Part IV: Pathophysiology 13. Vascular Hemostasis and Brain Embolism . . . . . . . . . . . . . . . . . . . . . . . . 243 Gregory J. del Zoppo Thrombosis and the Pathophysiology of Brain Ischemia . . . . 244 Cerebrovascular Thrombosis . . . . 245 Hemorrhagic Transformation . . . . 247 Stroke and Consumptive Coagulopathy . . . . 248 Platelet Activation . . . . 249 Thrombin Generation . . . . 249 Fibrin Degradation . . . . 249 Endogenous Protective Mechanisms . . . . 250 Cerebrovascular Reservoir . . . . 250 Collateral Circuits . . . . 250 Microvessel-Associated Protection . . . . 250 Endogenous Thrombus Lysis . . . . 251 Vascular Matrix Degradation . . . . 251 Modulation of Thrombin Activity . . . . 252 Microvessel Integrity, Hemostasis, and Selective Neuron Vulnerability . . . . 253 Summary . . . . 253 References . . . . 254

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Part V: Embolic Materials 14. Embolic Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Louis R. Caplan Cardiac-Origin Substances . . . . 259 Arterial Origin Sources . . . . 264 Substances that Originate from Outside the Cardiovascular Systems . . . . 264 Fat Embolism . . . . 264 Air Embolism . . . . 268 Tumor Embolism . . . . 269 Foreign Body Embolism . . . . 270 References . . . . 271 Part VI: Treatment 15. Treatment of the Acute Embolic Event . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Louis R. Caplan Reperfusion . . . . 277 Anticoagulation . . . . 282 Neuroprotective Agents . . . . 283 Managing Brain Edema and Mass Effect . . . . 284 References . . . . 284 16. Cardiac Source of Embolism: Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 289 Warren J. Manning Atrial Fibrillation . . . . 289 New Onset Atrial Fibrillation . . . . 289 Recurrent or Persistent Atrial Fibrillation . . . . 297 Atrial Fibrillation Risk Profile . . . . 298 Combination Therapy . . . . 300 Abnormalities of the Interatrial Septum . . . . 309 References . . . . 311 17. Treatment of Aortic and Arterial Sources . . . . . . . . . . . . . . . . . . . . . . . . 319 Louis R. Caplan Treatment of Aortic Atheromatosis . . . . 319 Treatment of Arterial Source Emboli . . . . 320 Substances that Alter Fibrinogen Concentrations . . . . 323 Anticoagulants . . . . 324 Surgical and Interventional Treatments . . . . 326 References . . . . 328 Part VII: The Future 18. A Look Towards the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Louis R. Caplan and Warren J. Manning Diagnostic Advances . . . . 335

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Therapeutic Advances . . . . 338 Thrombolysis . . . . 338 Mechanical Devices . . . . 338 Antiplatelet Agents . . . . 339 Anticoagulants . . . . 339 Neuroprotectants . . . . 340 Personnel and Systems of Care . . . . 340 Index . . . . 341

Contributors

Andrei V. Alexandrov Departments of Neurology and Radiology, University of Texas Health Sciences Center, Houston, Texas, U.S.A. Hansjoerg Baezner Department of Neurology, University of Heidelberg, Universita¨tsklinikum Mannheim, Mannheim, Germany Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A. Michael Daffertshofer Department of Neurology, University of Heidelberg, Universita¨tsklinikum Mannheim, Mannheim, Germany Michael Hennerici Department of Neurology, University of Heidelberg, Universita¨tsklinikum Mannheim, Mannheim, Germany Warren J. Manning Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A. Carlos A. Molina Neurovascular Unit, Vall d’Hebron Hospital, University of Barcelona, Barcelona, Spain Gregory J. del Zoppo Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, U.S.A.

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PART I:

HISTORICAL BACKGROUND AND OVERVIEW

1 Historical Background: Development of Ideas and Knowledge about Stroke and Brain Embolism Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

In order to know where we are now and where we are headed in the future, we must know where we and our predecessors have been. History adds a broadening dimension to knowledge. For this reason, I begin this monograph on brain embolism with a historical chapter that briefly reviews the development of ideas about embolism and stroke. Clearly, recognition of the clinical entity “stroke” preceded thought and data about stroke mechanisms, so that the history of stroke is indelibly interwoven into the history of brain embolism.

EARLY WRITERS—DESCRIPTION OF APOPLEXY AND INTEREST IN ANATOMY The earliest physicians described clinical phenomenology to give a reasonable prognosis about the outcome in individual patients. Hippocrates (circa 400 B.C.E. ) was probably the first to write about the medical aspects of stroke (1 –5). Hippocrates and his followers were mostly interested in predicting the outcome of an illness for the patient and his family. Hippocrates was a keen observer, who urged for a careful observation and recording of phenomenology. Hippocrates wrote in his aphorisms on apoplexy, “persons are most subject to apoplexy between the ages of forty and sixty,” and attacks of numbness might reflect “impending apoplexy” (1,5). In reference to an apoplectic attack, Hippocrates wrote, “During the spasms the loss of speech for a long time is unfortunate; if present for a short time it proclaims a paralysis of the tongue, of the arm, or of parts on the right side.” Hippocrates also noted some anatomical features. He observed that there were many blood vessels connected to the brain, most of which were “thin,” but two (the carotid arteries) were stout. The Greeks recognized that interruption of these blood vessels to the brain could cause loss of consciousness; so they named the arteries carotid, from the Greek word Karos, meaning “deep sleep” (1 – 5). Centuries after Hippocrates, a Greek physician Claudius Galenus, usually referred to as Galen of Pergamon (130 – 199 C.E. ), described the anatomy of the brain and its 1

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blood vessels from dissections of animals. Galen’s early writings emphasized observation and experimentation, but later works combined theorizing and speculation, in which he attributed disease to disequilibrium between various putative body humors and secretions, such as water, blood, phlegm, bile, and so forth (4). Galen and his extensive writings dominated the 1300 years following his death. During the ensuing Dark and Middle ages, persons claiming to be physicians gained knowledge solely from studying the Galenic texts, considered at the time to be the epitome of all medical wisdom. Andreas Vesalius (1514 – 1564) challenged the Galenic tradition by dissecting humans and relying on his own personal observations, instead of on Galen’s writings (2 – 4,6). Vesalius’s dissections were published in a volume entitled De Humani Corpis Fabrica (usually referred to as the Fabrica), which contained the detailed drawings that his collaborator and young artist Jan Kalkar reproduced as woodcuts and copper plates. The seventh book of the Fabrica contains 15 diagrams of the brain. These were the most detailed neuroanatomical studies upto that point. During the last half of the seventeenth century, two physicians, Johann Jakob Wepfer (1620 –1695) and Thomas Willis (1621 – 1675), made important anatomical and clinical observations. Wepfer wrote a popular treatise on apoplexy, that was originally published in 1658 and had five subsequent editions (7,8). Wepfer performed meticulous examinations of the brains of patients dying of apoplexy. He described the carotid siphon and the course of the middle cerebral artery. He recognized that the carotid and vertebral arteries could become hard and obstructed and speculated that the blockage could prevent sufficient nutrition from reaching the brain (7,8). Wepfer was the first to show clearly that bleeding in the brain was an important cause of apoplexy. Sir Thomas Willis (Fig. 1) was born shortly after the deaths of Queen Elizabeth and William Shakespeare. Willis was a successful practicing physician and a very

Figure 1 Sir Thomas Willis. Source: From Ref. 145.

Development of Ideas and Knowledge about Stroke and Brain Embolism

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accomplished organizer, researcher, and teacher. He performed autopsies on his patients and did extensive anatomical dissections, especially on the brain (9,10). Sir Christopher Wrenn, the renowned architect and artist, worked with him and was responsible for the engraved plates in Willis’ Cerebri Anatome (9 –11). Willis became the Sedleian Professor of Natural Philosophy at Oxford University. His anatomy book contains very detailed descriptions of the brain stem, cerebellum, cerebral hemispheres, and the ventricles of the brain. Willis recognized transient ischemic attacks and described cases in which “both carotid arteries were choked up so that not the least drop of blood could pass through either of them” (9 – 11).

THE 18TH CENTURY: MORGAGNI—THE BEGINNING OF MODERN PATHOLOGY During the eighteenth century, one of the true giants of medical history, Giovanni Battista Morgagni (1682 – 1771), focused his attention on pathology and the cause of diseases (2,4). Until then, anatomy and prognosis were emphasized. Morgagni, a distinguished professor of anatomy at the University of Padua, had a vision that the key to understanding disease was to perform thorough necropsies on humans with illnesses and to correlate the pathological findings with the symptoms during life. Although the clinicopathological method is now taken for granted, this was a new approach for eighteenth-century physicians. Morgagni labored many years to meticulously collect material for his epic work, De Sedibus et Causis Morborum per Anatomen Indagatis, which was published when he was 79 years old (2,4,12). De Sedibus is a five-volume work organized in the form of 70 letters to a young man, describing the cases collected. The first volume of De Sedibus was entitled Disease of the Head. Morgagni’s clinical descriptions of patients were detailed in the book, but it contained no formal physical or neurological examinations, because these were not performed during his time. Chapter two in this volume was titled Of the Apoplexy in General, and succeeding chapters were on serous and sanguineous apoplexy. He recognized that the causes of apoplexy were heterogeneous. “Of the many who died of apoplexy in the same month, or even in the same day, all did by no means discover the same injuries to the brain; but some of these appearances were widely different from others, and proceeded from different causes” (12). Morgagni was the first to separate intracerebral hemorrhage from cases of apoplexy in which there was no bleeding. However, he did not clearly describe brain infarcts but continued to refer to an excess of fluid (“serum”) in the cranial cavity (serous apoplexy). Morgagni described cases of intracerebral hemorrhage and recognized that paralysis was on the side of the body opposite the brain lesion. The first volume also contains clear descriptions of vascular lesions. In one patient, who died suddenly and who had preceding attacks of vertigo, Morgagni noted, “In the left vertebral artery, very near to its anastamosis with the other arteries, were thin small plates, some resembling a tendinous, some a cartilaginous, and others a bony consistency” (12). Commenting on a diseased artery in another patient, Morgagni wrote, “I opened both of these arteries, and on their internal surfaces I found a little white body, thickish, somewhat hard and even almost cartilaginous; and it could not but happen that they must, in some measure stop up the cavity as they protruded internally” (12). Morgagni also noted heart disease in many patients, although he did not posit embolism. “In the pericardium was a proper quantity of water, with a flaccid heart. . . . A heart of this kind, indeed, does not seem to have been able to propel the blood” (12).

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Morgagni’s work shifted the emphasis of physicians from anatomy alone to inquiry about diseases and their pathology, causes, and clinical manifestations during life. The way was prepared for clinicians and pathologists to further their knowledge about stroke.

THE FIRST HALF OF THE 19TH CENTURY—RECOGNITION OF BRAIN INFARCTION AND A RELATIONSHIP WITH HEART DISEASE During the early years of the nineteenth century, physicians began to recognize the occurrence of brain infarction and observed that heart disease was common in patients with apoplexy. A very influential treatise on apoplexy was written by a prominent Irish physician John Cheyne (1777 – 1836). Cheyne’s book, which appeared in 1812, was titled Cases of Apoplexy and Lethargy with Observations upon the Comatose Diseases (2,3,13). Cheyne separated the phenomenology of lethargy and coma from apoplexy. Cheyne’s description of the neurological abnormalities was more detailed than those of his predecessors, and the “morbid appearances” of the patients’ brains were emphasized, following the example of Morgagni. The pathological findings included descriptions of brain softening and intracerebral and subarachnoid hemorrhages. Cheyne wrote that sanguineous apoplexies were much more common than serous, and he noted, “The causes of serous apoplexy are involved in great obscurity” (13). Cheyne also wrote, “Inordinate contractions of the heart have been mentioned as a cause of apoplexy. They have preceded apoplexy, and are probably connected to the disease . . . they may prove the immediate cause of the fit, by throwing blood with violence upon the brain” (13). Remember that at that time there was no method of measuring blood pressure, and physicians posited increased circulation as a potential cause of intracranial hemorrhage. John Cooke (1756 – 1838), a physician at the London Hospital, summarized the history of neurological thought concerning apoplexy in his Croonian lecture in 1819 (3,14). John Abercrombie (1780 – 1844) contributed a more detailed clinical classification of apoplexy in his general neurology text published in 1828 (15). He used the presence of headache, stupor, paralysis, and outcome to separate apoplectics into different clinical groups. He also described brain infarcts more clearly than his predecessors and speculated about their cause. Abercrombie described infarcts (referred to as ramollissements, a French term meaning softening) as follows: “a peculiar softening of the brain . . . it consists in a part of the cerebral substance being broken down in a soft pulpy mass, retaining its natural color, but having lost its cohesion and consistence” (15). Later in the text, he wrote, “This peculiar softening of the cerebral matter is analogous to gangrene in other parts of the body . . . like gangrene it may arise from inflammation and failure of the circulation from disease of the arteries” (15). George Burrows (1801 –1881) a physician at St. Bartholomew’s Hospital in London published a monograph in 1846 that emphasized brain – heart relationships (16). He entitled the book On Disorders of the Cerebral Circulation and on the connection between Affections of the Brain and Diseases of the Heart. Burrows, a general physician, noted “the full extent of the influence of diseases of the heart in disturbing the functions, or producing actual structural changes in other organs, and especially of the brain, has not been thoroughly estimated” (16). He analyzed 132 examples of apoplexy and sudden hemiplegia and noted that about three-fifth had unequivocal signs of cardiac disease—either hypertrophy, dilatation, valvular disease, or some combination of these lesions” (16). William S. Kirkes was one of the first physicians to emphasize the relationship of endocarditis to brain infarcts (17). In 1852, he described three patients. The first was a

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woman of 34, who had a loud systolic murmur and suddenly became speechless and hemiplegic. At necropsy, the mitral valve contained large excrescences, and the middle cerebral artery was occluded by a firm fibrinous plug. The brain beyond the occlusion and the spleen and kidney were also infarcted, and an iliac artery was also occluded by embolic material. The other two patients had cardiac valvular vegetations and brain infarcts and died of endocarditis (17). Kirkes concluded that the vegetative materials must have mixed with the circulating blood to disseminate into the brain and visceral arteries. During the middle years of the nineteenth century, dissemination of knowledge about the pathology of neurological diseases and stroke came with the publication of four atlases, each containing plates of brain and vascular lesions. Hooper’s atlas, published in 1828, clearly illustrated pontine and putaminal hemorrhages (18). Cruveilher (1835 – 1842) (19), Carswell (1838) (20), and Bright (1831) (21) also published atlases containing lithographs of systemic and neuropathological lesions. Richard Bright, better known for his work on nephritis, collected more than 200 neuropathological cases and specimens (2) and presented illustrations of 25 nervous-system specimens, including cerebrovascular cases, in his volume on nervous-system disorders (2,21). Bright illustrated the external aspect and a coronal section of the brain in a patient who died of an acute large brain infarct, involving most of the territory of the middle cerebral artery. In 1836, Bright published a paper on the clinical and necropsy findings in patients with abnormalities of the arteries of the brain (22). Clinicians of this era recognized that arteries and veins could become occluded, but the cause of the occlusions and their relationship to brain and other organ softening was not clarified. Thrombi and coagula in the vascular system were discovered at necropsy, but observers debated whether or not these formed postmortem or during life. During the late 18th and early 19th centuries, two major figures, John Hunter (1728 –1793) in England and Cruveilhier in France, thought that coagula were caused by inflammation in the veins (23). Hunter, an English surgeon, writing in 1793 noted the frequency of vein inflammation after surgery and after phlebotomies and postulated that venous thrombi formed as exudates from the walls of blood vessels (24). If adhesions did not form in the vessels, the clots could be swept into the general circulation. Cruveilhier wrote that coagulation in veins was the earliest sign of phlebitis. He even stated that “phlebitis dominates all pathology” (19). Thrombi within arteries and the heart were attributed at that time to a similar inflammatory arteritis. Inflammation was considered the cause of thrombosis. Virchow Defines and Describes Embolism Rudolph Virchow (1821 – 1902) (Fig. 2) deserves the major credit for describing the process of in situ antimortem thrombosis with subsequent embolism. In a remarkable series of observations and experiments, he analyzed the relationship between thrombi and infarction, locally and at a distance (25). Among 76 necropsies performed in 1847, he found thrombi in the veins of the extremities in 18 patients and within the pulmonary arteries in 11 patients (23,25). He reasoned that the bloodstream emanating from these veins must have been the conduit for transportation of these thrombi to such distant sites as the lung arteries. He then experimented on animals to study the fate of foreign materials placed in veins. He then sought and found obstruction of brain, splenic, renal, and limb arteries at necropsy in patients who had cardiac valve disease and left atrial thrombi. He thus systematically proved that in situ thrombosis and embolism were the causes of infarction and that the process was not dependent on inflammation. Within the period of two years, he established that blood clots need not form at the sites where

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Figure 2 Rudolph Ludwig Carl Virchow. Source: From Ref. 146.

they were discovered at necropsy but could be carried by the blood stream from peripheral veins to the pulmonary arteries and from the left atrium to the brain and other peripheral arteries. Virchow also was the first to introduce the name fibrinogen into clinical medicine. Johannes Mu¨ller in 1832 introduced the term fibrin to describe the insoluble substance within thrombi. Fibrinogen was used by Virchow to name the soluble plasma precursor to fibrin.

Arterial Occlusion and Embolism as the Cause of Infarction Present day physicians now take for granted the concept that infarction is due to lack of blood supply and nutrition caused by blockage of arteries supplying areas of ischemia. But early observers referred to focal necrotic regions using nonspecific descriptive terms, such as softenings, ramollissements, and encephalomalacia. These brain softenings were not clearly attributed to ischemia until the middle years of the 19th century (23). Rene Laennec (1781 – 1826), the French physician who introduced the stethoscope into clinical medicine, was probably the first to use the word infarction for the process in the lungs, which had been called pulmonary apoplexy (4,23,26). Physicians did not appreciate the clinical features of coronary thrombosis and myocardial infarction until the report of James Herrick in 1912 (27), and cardiologists did not clarify the relationship between angina pectoris, coronary artery occlusion, and myocardial infarction until the 1940s (28). Interest in the causes of brain ischemia probably began with Wepfer, who recognized that, at necropsy, there often was an obstruction of blood flow caused by the disease of arterial walls (7). Abercrombie had likened brain softening to gangrene in other organs (15). Cruveilhier and Carswell documented arterial obliterations at necropsy in cases of peripheral gangrene (23). Virchow discussed the clotting of blood within vessels and emphasized that local factors within arterial walls could promote clotting as well as general thrombosis diffusely

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within small vessels. He introduced the terms thrombus, thrombosis, embolus, and embolism (23). In his summary of the medical literature, Virchow cited 11 examples of published cases of embolic disease although in none was the fundamental process appreciated, the embolic plugs usually being attributed to arterial inflammation (23,25).

THE SECOND HALF OF THE 19TH CENTURY—CARDIAC EMBOLISM BECOMES AN ESTABLISHED CLINICAL ENTITY John Lidell wrote an influential monograph on apoplexy that was published in 1873 (29). He gave his book the long title A Treatise on Apoplexy, cerebral hemorrhage, cerebral embolism, cerebral gout, cerebral rheumatism, and epidemic cerebro-spinal meningitis (29). He clearly stated, “cerebral anemia, for example, from embolism of the cerebral arteries, often induces the symptoms of apoplexy” (29). He noted that the term embolism was derived from the Greek word 1mbolo6 meaning a plug. An artery becomes “plugged up with a clot of blood, or a concretion of fibrin, or a fragment of broken-down tissue which has been brought by the circulating blood from some distant part” (29). He cited the paper by William Kirkes (17) and summarized three of Kirkes’s cases, all of whom had large brain infarcts and diseased mitral valves at necropsy. He commented, “It is plain that embolism produced by dislodgement of matter from the mitral valve was the cause of the brain symptoms” (29). Sir William Osler (Fig. 3) in his popular textbook of medicine noted that embolism “in the great majority of cases comes from the left heart and is either a vegetation or, more commonly of a recurrent endocarditis.” Rheumatic mitral stenosis, thrombi within the left auricular appendage, and aortic atheromas were also mentioned by Osler as sources

Figure 3

Sir William Osler. Source: From Ref. 147.

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of emboli (30). In his Gulstonian lectures, Osler defined the clinical findings in patients with endocarditis and emphasized the neurological sequelae (31). Neurological texts, for example, the popular monograph of William Gowers, also discussed brain embolism related to cardiac valve disease (32). Gowers notes, “the source of the plug must be somewhere between the lungs and the brain—in the pulmonary veins, the left side of the heart, the commencement of the aorta, or the large arteries of the neck” (32). Charles Dana authored the other popular neurology text at the turn of the century (33). Dana noted that the usual source was acute or recurrent endocarditis. “The embolic plug cuts off the blood supply from a certain area of brain tissue” (33). He described red and white softening. By the start of the twentieth century, the phenomenology of brain embolism from rheumatic mitral stenosis and from infective endocarditis was very well known.

THE FIRST HALF OF THE 20TH CENTURY—AN EMPHASIS ON VASCULAR ANATOMY Anatomists and researchers during the early years of the 20th century became very interested in the blood vessels that supply blood to the brain, including the cerebral hemispheres, basal ganglia, brainstem, and cerebellum. Duret (34,35), working in the laboratory of Charcot in France, and Stopford (36) in England meticulously dissected the arteries that supply blood to the brainstem. Charles Foix (1882 – 1927) (Fig. 4), who worked in the clinics and pathology laboratories at the Salpetriere Hospital in Paris, gave a better picture of arterial anatomy (37). Foix and his colleagues defined the distribution and localization of brain infarcts (“ramollissements”) and the neurological abnormalities present during life. In addition, they clarified and illustrated the anatomical

Figure 4 Charles Foix.

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distribution of the main intracranial arteries and their usual branches and regions of supply (37 –45). They studied, analyzed, reported, and illustrated their findings in both the anterior and posterior circulations in detail. During the four short years, between 1923 and 1927, Foix et al. (37 – 45) defined the arterial distribution of the brain. Charles Foix and Colleagues Examined the Arteries that Supplied Brain Infarcts The early writings of Foix, his students, and colleagues were concerned mostly with vascular anatomy, distribution of infarcts, and clinical –anatomical correlation. Only a few weeks before his premature death, Foix, along with Hillemand and Ley, presented a preliminary report to the Medical Society of the hospitals of Paris on the vascular pathology found in arteries supplying regions of brain softening (46). They carefully examined the arteries that their anatomical researches had shown, that supplied the regions of brain infarction. Until that time, although clinicians recognized that extracranial and intracranial arteries were often diseased at necropsy, there was little interest in the mechanism of occlusion because no treatment was available and there was no way of imaging the arteries or the brain during life. Among the 56 necropsied patients, the artery supplying the infarct was completely occluded in only 12 patients, subtotally, and incompletely occluded in 14, but in 30, the supply artery was widely patent (46). Foix et al. (46) proposed four possible explanations for the frequent lack of arterial occlusion at necropsy: (i) the occlusion might follow brain softening and might have developed later, (ii) embolism with passage of embolic material by the time of autopsy, (iii) insufficiency (“l’insuffisance cardio-arterielle”), that is, more proximally located circulatory failure, and (iv) vasospasm (“spasme arterielle”). This paper, which now would qualify as only an abstract, opened the door for inquiry about the mechanisms of brain infarction. Kubik and Adams—Occlusion of the Basilar Artery: Separating Thrombosis In Situ from Embolism Certainly, one of the most important and influential reports in the field of cerebrovascular disease was the report on basilar artery occlusion by Charles Kubik and Raymond Adams (Fig. 5) published in 1946 (47). This report was one of the most complete and most detailed clinical-pathological studies of any vascular syndrome. This was not the first publication about occlusion of the basilar artery; there had been prior reports of single or a few cases (48). Pines and Gilinsky had described a patient with a likely embolic occlusion of the rostral basilar artery (48,49). The report of Kubik and Adams (47) was distinguished because of the large number of patients (18 patients), the meticulous dissection and illustration of the brain lesions at the various brainstem levels, delineation of the nature of the vascular occlusion, a discussion of separation of in situ thrombosis from embolism, and the detailed descriptions of the clinical symptoms and signs. At the time of their report, the authors were both neuropathologists working in the necropsy laboratories at the Massachusetts General Hospital and the Boston City Hospital in Boston. They examined some of the patients during life and later reviewed their clinical charts. The extent and location of the thrombosis correlated well with the areas of brainstem infarction, and usually only a portion of the basilar artery was occluded (47). They attributed 11 of the basilar artery occlusions to in situ thrombosis engrafted upon arteriostenosis. Seven occlusions were considered embolic on the basis of the location, morphology, and appearance of the thrombi found at postmortem. In all the cases

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Figure 5 Raymond Adams.

attributed to in situ thrombosis, there was extensive underlying arteriostenosis of the basilar artery with severe luminal narrowing by plaque. The occlusion always involved at least two segments of the basilar artery. The thrombosed portion of the basilar artery in these cases was “distended, firm, and rigid and the thrombus could not be displaced by pressure” (47). In some cases, microscopic analysis of the thrombus revealed that different portions of the clot must have formed at different times. In cases attributed to embolism to the basilar artery, the clot was usually lodged in the distal portion of the basilar artery at its bifurcation. Embolic plugs occasionally lodged in the regions of the basilar artery that were narrowed by atheromatous plaques. Therefore, the presence of plaques alone did not separate thrombosis from embolism. Focal regions of layered thrombi could be superimposed on the firm nonadherent emboli. All of the infarcts were grossly “pale” and “anemic,” but some contained petechial hemorrhages visible under the microscope within zones of infarcted tissue (47). The symptoms in most patients began abruptly, and all the cases were fatal (otherwise, the patient would not have reached their pathology laboratory). Recognition of the clinical signs should allow for accurate antemortem diagnosis of basilar artery occlusion. In fact, at the end of the article, the author reported the clinical findings that led them to suspect basilar artery thrombosis in seven patients who were still alive (47). Unfortunately, with the limited technology available at the time, there was no safe way during life to document the nature of the vascular lesion. Miller Fisher—Carotid Artery Disease, Transient Ischemic Attacks, and Artery-to-Artery Embolism During the first half of the 20th century and before that time, brain infarcts were usually attributed to occlusion of intracranial arteries. In the reports of Kubik and Adams, the

Development of Ideas and Knowledge about Stroke and Brain Embolism

Figure 6

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C. Miller Fisher and Louis R. Caplan.

occlusion involved the basilar artery, an important intracranial artery. Most anterior circulation infarcts were attributed to occlusion of the middle cerebral artery. As in the report (47), clinicians of that era thought that strokes generally came abruptly without warning but often progressed after the onset of ischemia. Shortly after the second world war, Miller Fisher (Fig. 6), a clinician and neuropathologist who worked first in Canada and later at the Massachusetts General Hospital with Dr. Adams, turned his attention to carotid artery disease. Fisher’s first paper on occlusion of the internal carotid artery appeared in 1951 (50), just five years after the report of Kubik and Adams. Several years later, he published a second paper on carotid artery disease that amplified the findings of the initial report (51). He made four key observations that had an important influence on the approach of clinicians to patients with brain ischemia: warning spells preceded strokes, occlusive disease was often in the neck, eye ischemia was a frequent type of warning, and the mechanism of brain infarction was artery-toartery embolism from the internal carotid artery into its intracranial artery branches. He noted the very frequent occurrence of temporary warning episodes in his patients with carotid artery disease, which he dubbed transient ischemic attacks (TIAs), that preceded and presaged later strokes. Prior to Fisher, a few scattered mentions of transient warning spells can be found in the literature, but practicing physicians in 1950 were generally unaware of their existence. The occlusive disease was in the internal carotid artery in the neck where it was potentially reachable by surgery. This was the first emphasis on occlusive disease in the neck. J. Ramsey Hunt had previously published a report on the role of the carotid artery in causing brain ischemia in 1914 (52). Hunt wrote, “The object of the present study is to emphasize the importance of obstructive lesions of the main arteries of the neck in the causation of softening of the brain” (52). In this paper, he mentioned attacks of transient hemiplegia, but this report had not received much attention before Fisher. Several years after Fisher’s report, Hutchinson and Yates began to systematically dissect and

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examine the cervicocranial arteries in the neck (53,54). They found a high frequency of occlusive disease in the cervical vertebral arteries near their origins from the subclavian arteries. Vertebral artery occlusive disease in the neck seemed to parallel carotid occlusive disease, leading Hutchinson and Yates to coin the term “carotico-vertebral” stenosis (54). These reports alerted physicians that brain ischemia was often caused by disease in the neck, a location more accessible than the intracranial arteries. Fisher’s reports on carotid artery occlusion emphasized the occurrence of intraarterial embolism, arising from proximal arterial occlusive lesions, as a very important cause of ischemic stroke (50,51). Chiari in 1896 described a patient with an apparent cerebral embolus in whom no cardiac source could be found at necropsy. He opened the carotid artery in its entire length and found thrombus deposited upon an atherosclerotic lesion in the proximal internal carotid artery (55). Chiari then studied 400 cases and in seven cases found thrombus within the carotid artery in the neck, and in four cases cerebral embolism had occurred. He emphasized that embolism from the carotid artery in the neck was an important source of brain embolism. The reports of Chiari and Hunt went unnoticed until Fisher’s landmark paper. Before Fisher’s papers, in the early 1950s, brain embolism was invariably attributed to a cardiac source. Torvik and Jorgenson (56 – 59) published extensive reports that analyzed necropsy findings in relation to carotid artery occlusions and brain infarcts found among 994 patients that came to autopsy in Oslo, Norway. They reported the vascular and brain findings and accompanying clinical course in patients with brain infarcts and vascular lesions. The internal carotid artery in the neck and head were about equally involved. They attempted to separate those cases caused by primarily arterial thrombosis and intra-arterial embolism from those related to cardiac origin embolism (56 – 59). In 1986, Fisher and his neurosurgical colleague Robert Ojemann published a detailed report on the gross and microscopic findings within surgical specimens of the carotid artery (60). This information was also the main topic of Fisher’s Willis lecture at an American Heart Association International Stroke meeting. The specimens clearly showed thrombi within the artery that were the source of artery-to-artery embolism. Fisher noted that some of the patients who developed carotid artery occlusion and brain infarcts had previous attacks of transient monocular visual loss on the side ipsilateral to the carotid occlusion and on the opposite side of the hemiparesis (50,51). He later published an article that described and illustrated the findings in the retina seen with an opthalmoscope in patients who had transient visual loss (61).

Fisher and Adams and Hemorrhagic Brain Infarcts Both Fisher and Adams were experienced neuropathologists. They began to notice that in some patients with hemorrhagic brain infarcts, careful dissection of the supply arteries at necropsy failed to show an arterial occlusion proximal to the hemorrhagic changes in the brain. They then systematically and extensively studied their necropsy material to define the mechanism of hemorrhagic infarction in the brain (62,63). They found that embolism was the major cause of hemorrhagic infarction. Obstruction of a brain-supplying artery caused ischemia to neurons and ischemic damage to blood vessels within the area of ischemia. When the obstructing embolus moved distally, the previously ischemic region was reperfused with blood. The damaged capillaries and arterioles within that region were no longer competent, and blood leaked into the surrounding infarcted tissue. Figure 3 in Chapter 3 shows an illustrative case from the report of Fisher and Adams.

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Fisher reviewed the past literature on hemorrhagic infarction and brain embolism (23). On the basis of these ideas, Fisher and Adams were able to posit that the essential cause of hemorrhagic infarction was reperfusion of the previous ischemic tissue. The other mechanism that caused hemorrhagic infarction besides embolism was systemic hypoperfusion. After cardiac arrest or shock, the reinstitution of effective circulation after a prolonged period of brain hypoperfusion can lead to hemorrhage within borderzone infarcts. These hemorrhagic changes were bilateral and scattered, as opposed to the hemorrhagic changes in brain embolism that were within discrete unilateral infarcts. These observations emphasized to clinicians the importance of brain embolism as a cause of stroke and that hemorrhagic changes were a reliable sign of embolism.

DATA BANKS AND STROKE REGISTRIES During the middle years of the twentieth century, clinicians had become very interested in clinical phenomenology by personally studying and describing small groups of patients. A major focal point was the clinical differentiation between brain hemorrhage and brain infarction and characterizing the differential diagnostic features found among the various mechanisms of brain infarction. In 1935, Charles Aring and Houston Meritt performed necropsies in a group of patients at the Boston City Hospital, in order to clarify the differential diagnostic features between brain hemorrhages and infarcts (64). Of the 245 cases, 15% had hemorrhages (intracerebral or subarachnoid), 82% had ischemic infarcts called “thrombotic,” and only 3% were considered to have embolic brain infarcts (64). Aring and Meritt used the term “embolic” to mean cardiac-origin embolism. They classified patients’ infarcts and strokes as embolic only if there was a recognized cardiac source. Furthermore, at that time, the only accepted cardiac sources were rheumatic mitral valve stenosis with atrial fibrillation and recent myocardial infarction. This cardiogenic definition of embolism endured during the next 40 years. During the middle decades of the twentieth century, many of the mechanisms and subtypes of brain infarction and hemorrhage were further clarified. Lacunar infarcts, internal carotid artery stenosis and occlusion, intracranial artery occlusive disease, and other conditions were studied, and their clinical and pathological findings were reported. As more and more sophisticated technology able to effectively image brain and vascular structures became available, clinical diagnosis of these stroke subtypes was greatly facilitated. During the 1970s and 1980s, these technological advances made it possible to define clinical, imaging, and laboratory findings in patients with nonfatal, even minor strokes, transient ischemic attacks, and prestroke vascular lesions. With more advanced knowledge of clinical and morphological features, clinicians sought more quantitative data. How often did lacunar infarcts, cardio-embolic brain infarcts, and intracerebral hemorrhages occur? How often did each of many clinical symptoms and signs occur in each subtype of stroke? Clinicians realized that valid statistically meaningful data could not be collected unless large number of patients with a wide spectrum of representative cases were studied and analyzed. The advent of computers in medicine in the 1970s greatly facilitated the storage and analysis of the large quantities of complex data. Collection of data on large number of stroke patients began with the series of surveys conducted by Dalsgaard-Nielsen in Scandinavia (65) and with retrospective reviews of series of patients seen by clinicians at the Mayo Clinic in Rochester, Minnesota (66,67). These early databases recorded a relatively high rate of brain infarcts versus hemorrhages (.4/1). Embolism was infrequently diagnosed with ranges of 3% to 8%

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of strokes. These studies were based on chart reviews and preceded computed tomography (CT) scanning and modern cardiac technological evaluation. The Harvard Cooperative Stroke Registry (HSR) in the early 1970s was the first computer-based registry of prospectively studied stroke patients (68). My colleagues and I adopted a different approach to the diagnosis of brain embolism. Diagnostic criteria in the HSR emphasized the recipient artery and not the source. Embolism was diagnosed when there was a sudden obstruction of a large intracranial artery or one of its branches. The embolus could arise from any source but predominantly the heart or one of the cervico-cranial arteries that supply the brain. A sudden onset neurologic deficit and an arteriogram that showed blockage of an intracranial artery not due to local atherosclerosis were the most common evidence for embolism. Echocardiography was not available at that time, and only about half the patients had cranial CT. Angiography, when performed within 48 hours, often showed an abrupt cut-off of an intracranial artery supplying the region of infarction. Some of the patients had cardiac disease, especially atrial fibrillation. Others had proximal arterial lesions that were presumed to be the donor source of arteryto-artery embolism. In the HSR, using this approach, 31% of patients were classified as having strokes due to brain embolism. During the 1970s and 1980s, a number of other hospital-based stroke registries and databases also provided quantitative information about clinical and laboratory phenomena and diagnoses (69 – 73). Community-based studies in South Alabama (74); Framingham, Massachusetts (75); Oxfordshire in Great Britain (76); the Lehigh Valley in Pennsylvania (77), and various regions in North Carolina, Oregon, and New York (78) generated important epidemiological data. In general, there was less technological evaluation in these community-based patients compared to the hospital-based registries. During the 1990s, a number of other hospital-based registries were able to take advantage of modern technology to clarify stroke subtypes (79 – 84). The hospital-based registries that followed the HSR and all of the modern registries found a relatively high rate of brain embolism varying between 22% and 46% (84,85). The frequency of the various stroke subtypes is noted in Table 1. Stroke registries and data banks have undoubtedly assisted collection and analysis of a wide variety of clinical, radiological, laboratory, pathological, and epidemiological information (86,87). Technological Advances Allow More Accurate Diagnosis of Stroke Subtypes and Cardiac and Vascular Lesions Egas Moniz introduced dye contrast angiography into clinical medicine in 1927 (88,89). His early studies used contrast agents later shown to be quite hazardous. Moreover, cutdowns were needed to introduce the contrast. Moniz (88) illustrated examples of occlusive lesions of neck arteries in his monograph on cerebral angiography and in a monograph on carotid artery occlusion (90,91). When I was a stroke fellow in 1969, the favored technique for angiography was direct puncture of the neck arteries. Contrast was hand-injected, and films were hand-pulled either rapidly or slowly depending on the estimated rapidity of the brain circulation. Only one plane, anteroposterior or lateral posterior, could be filmed after each contrast injection. Complication rates were relatively high. An advance was made when Seldinger, in 1953 (92), described catheter-based angiography, but the Seldinger technique of opacifying cervico-cranial arteries by introducing a catheter into the femoral artery and directing it into the neck arteries, and then introducing contrast did not become widespread until the 1970s. Until the mid-1970s, there was no method of imaging the brain other than pneumoencephalography, in which air introduced by lumbar puncture opacified the cerebral

1988– 96 407 63% 60.5 100% 40% 24% 32% 14% 100%

Years N % Men Mean age % Ischemic Embolism Cardiac Large artery Penetrating artery % Infarcts p circ

1972– 76 694 53% 64.4 83.4% 31% 19% 40% 23% 37% of LA

HSR

24% 14% NS

1978– 81 1158 56% 63 80% 28%

PSDB 1983– 86 1805 47% 65 68% 39%a 20% 9% 27% NS

SDB 1982– 87 1000 61.5% 60.8 82% 36%b 18% 25.5% 15% 26%

LSR

23% 38% NS

1979– 82 540 52% 63 78% 22%

MRSR

8% 32% 23% 11.5%

1972– 80 673 57% 64.8 94%

Austin SR 1987– 94 2500 57% 68 84% 46%b 31% 15.5% 10% 26.7%

BSR 1992– 97 1042 58% 70.2 85% 46% 38% 9% 20% 29%

Athens SR

25.6% 20.9% 20.5% NS

1998 –99 5017 57.6% 65.9 100%

GSDB

28% 17% 15% NS

1993– 95 555 56% 75.4 86%

Arcadia SR

b

Embolism recalculated using HSR criteria (85). Cardiac þ large artery without stenosis. Abbreviations: Arcadia SR, Arcadia Stroke Registry (101); Athens SR, Athens Stroke Registry (95); Austin SR, Austin Stroke Registry (116); BSR, Besancon Stroke Registry (94,100); GSDB, German Stroke Data Bank (102); HSR, Harvard Stroke Registry (89); LA, large artery; LSR, Lausanne Stroke Registry (92); MRSR, Michael Reese Stroke Registry (90); N, number of cases; NEMCPCR, New England Medical Center Posterior Circulation Registry; NS, not stated; p circ, posterior circulation; PSDB, Pilot Stroke Data Bank (99); SDB, Stroke Data Bank (91); SR, Stroke Registry.

a

NEMCPCR

Registry

Table 1 Relative Frequencies of the Various Stroke Subtypes in Published Stroke Registries

Development of Ideas and Knowledge about Stroke and Brain Embolism 15

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ventricles and the cisterns but did not show brain tissue. Hounsfield, working at the research laboratories of EMI in Britain, originated the concept of CT (3,93). The instrument was first tried at the Atkinson-Morley’s Hospital in London (3). CT scanners were first introduced into North America in 1973. Films from first-generation scanners were quite primitive, but by the late 1970s, third-generation scanners had made CT a very clinically useful, almost indispensable, diagnostic technique. By the mid-1980s, CT was readily available throughout North America and most of the Western Europe. CT allowed clear distinction between brain ischemia and hemorrhage and allowed definition of the size and location of most brain infarcts and hemorrhages. The advent of magnetic resonance imaging (MRI) into clinical medicine in the mid-1980s was a further major advance (93). MRI proved superior to CT in imaging lesions abutting on bony surfaces, posterior fossa lesions, showing old hemosiderincontaining hemorrhages, and imaging vascular malformations. MRI also made it possible to visualize lesions in different planes by providing sagittal, coronal, and horizontal sections. More recently, improved filming techniques have made it possible to image the brain vasculature through the techniques of magnetic resonance angiography (MRA) (94) and CT angiography (CTA) (95). Ultrasound was introduced into clinical medicine in 1961 by Franklin et al. (96), who used Doppler shifts of ultrasound to study blood flow in canine blood vessels (96). B-mode ultrasound was used to show images of the extracranial carotid arteries noninvasively. By the early 1980s, B-mode, continuous-wave, and pulsed-Doppler technology could reliably detect severe extracranial vascular occlusive disease in the carotid and vertebral arteries in the neck. Sequential ultrasound studies allowed physicians to learn the natural history of the development and progression of plaques and occlusive lesions and to correlate the occurrence and severity of disease and of the thickness of the intimal and medial coats of the arteries with stroke risk factors, symptoms, and treatment. In 1982, Aaslid et al. (97) introduced a high-energy bidirectional pulsed-Doppler system that used low frequencies to study intracranial arteries, transcranial Doppler ultrasound (TCD). TCD made noninvasive detection of severe occlusive disease in the major intracranial arteries possible during life, as well as sequential study of the lesions (98). TCD made it possible to estimate the effect of neck occlusive disease on intracranial perfusion (98). In 1990, Spencer et al. (99) described that Doppler signals felt to represent solid material emboli were released from carotid artery plaques during carotid artery surgery. Later experimental and clinical studies showed that intracranial arteries could be monitored using TCD to detect microembolic signals (100,101). In this technique, transcranial Doppler probes are positioned over brain arteries, most often the middle and posterior cerebral arteries on each side. When particles pass through the arteries being monitored, they produce an audible chirping noise and high-intensity transient signals visible on an oscilloscope. The signal character depends on the nature of the particles (gas, thrombus, calcium, cholesterol crystal etc.), particle size, and particle transit time. Preliminary studies showed that patients with cardiac lesions and those with symptomatic occlusive lesions in the neck had a relatively high frequency of intracranial microembolic signals. Introduction of echocardiography and ambulatory cardiac rhythm monitoring in the 1970s and 1980s greatly improved cardiac diagnoses and detection of potential cardiogenic sources of embolism. By the early 1990s, clinicians could safely define the nature, extent, and location of most important brain, cardiac, and vascular lesions in stroke patients. Accurate diagnosis using modern technology facilitated clinical-imaging correlations in patients with TIAs and strokes, and this paved the way for monitoring the effects of various treatments. Patients with vascular risk factors could be studied and lesions found by imaging could be potentially treated to prevent cerebrovascular events.

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By the end of the twentieth century, advanced brain imaging with CT, MRI, and newer magnetic resonance (MR) modalities, including fluid attenuating inversion recovery (FLAIR) images, diffusion-weighted images (DWI), perfusion-weighted images (PWI), susceptibility-weighted (also called T
2 ) images, functional MRI (fMRI), and MR spectroscopy (MRS), were able to show clinicians the location, severity, and potential reversibility of brain ischemia. Vascular lesions could be quickly and safely defined using CT angiography, MR angiography, and extracranial and transcranial ultrasound.

NEW TECHNOLOGY AND FURTHER STUDIES CLARIFY MORE POTENTIAL DONOR SOURCES OF EMBOLI At the time of Aring and Meritt (64), the only heart disorders accepted as sources of embolism were rheumatic valve disease with atrial fibrillation, bacterial endocarditis, prosthetic heart valves (although their use was not common), myxomas and other cardiac tumors, and acute myocardial infarction. The advent of better diagnostic technology to investigate cardiac and vascular lesions led to the recognition of many conditions that previously were not known to be important donor sources of embolism. Fisher was among the first to warn the general medical community about the embologenic potential of atrial fibrillation (102,103). Fisher et al. performed necropsy examinations on 333 patients with atrial fibrillation and 58 patients with ischemic heart disease without known atrial fibrillation. Among the atrial fibrillation patients, embolism was found in 41% of those with mitral valve disease, 35% of those with ischemic heart disease, 35% of those with both mitral valve and ischemic heart disease, and in 17% of those with other heart disease, whereas only 7% of the nonfibrillators had embolism (102). The authors concluded, “these findings suggest a high risk of embolism from atrial fibrillation of any origin” (102). Fisher later urged anticoagulation of patients with atrial fibrillation warning that the first stroke was often devastating (103). At first cardiologists did not accept the idea that such a common disorder could be a frequent cause of brain infarction. Epidemiological studies from Framingham (104,105) and elsewhere (106) showed definitively that atrial fibrillation was not only a definite embolic source, in fact, it was probably the commonest cardiac condition leading to brain embolism. Other cardiac conditions are now known commonly or occasionally to provide the source for embolization to systemic arteries and the brain. The sick-sinus syndrome, like atrial fibrillation, can be associated with poor atrial contraction and clot formation in the left atrium (107). Swirling echo dense particles (often referred to as smoke), when seen in the heart on echocardiography, for example in patients with atrial fibrillation, often foretell a risk of embolism (108). Although rheumatic and infective valvular lesions were long considered to be potentially embologenic, echocardiography and clinical studies soon implicated mitral valve prolapse with myxomatous degeneration of the valve (109), mitral annulus calcification (110), and fibrotic valve disease associated with systemic lupus erythematosis (Libman-Sacks endocarditis), the antiphospholipid antibody syndrome (111,112) and cancer (nonbacterial thrombotic endocarditis) as important potential sources of embolism. Even fibrotic valve strands were potentially embolic (113,114). Imaging of patients with coronary artery disease showed that many had ventricular aneurysms or hypokinetic, or akinetic, segments that harbored thrombi (115,116). Echocardiography also showed that atrial septal dysfunction in the form of atrial septal defects, patent foramen ovale, and atrial septal aneurysms were more frequent than previously thought and that these lesions were very common in patients with strokes of uncertain cause (117,118).

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Although it was widely known that the aorta was very often the seat of severe atherosclerosis, the role of aortic plaques as donor sources of brain embolism was only recently emphasized. Tunick et al. (119,120) were among the first to report cases of brain embolism that arose from protruding aortic atheromas. Pierre Amarenco and his clinical and pathology colleagues (121), working in Paris, then systematically showed that ulcerated atheromas in the aorta at necropsy and protruding atheromas found during transesophageal echocardiography (122) were prevalent in stroke patients, especially those in whom no other cause was found. Further echocardiographic studies in New York (123) and France (124) confirmed the importance of protruding mobile aortic atheromatous plaques as a donor source of brain embolism. Since Fisher’s reports on carotid artery disease in the early 1950s (50,51), the medical community knew that carotid artery disease was an important cause of stroke but the mechanism was not clear—hypoperfusion and/or embolism. Pessin et al. (125) in 1980 showed that clinical findings differed depending on the appearance of the carotid artery lesion on angiography (125). Certain appearances favored embolism. Studies of specimens of the carotid artery removed surgically (60,126) and at necropsy (127) showed that stenotic ulcerated plaques often with plaque ruptures, which brought the content of the plaque into contact with the luminal contents, had precipitated the formation of red-erythrocyte thrombi often engrafted upon white platelet – fibrin thrombi. Most patients with severe stenosis had mural thrombi or platelet-fibrin aggregates within arterial ulcerations, irregularities, and crevices. These thrombi then often embolized into systemic and brain arteries. Ultrasound studies of carotid plaque morphology confirmed the morphological data (128,129). Michael Hennerici and I then postulated that hyperperfusion and embolism were complementary in causing brain infarction as decreased perfusion led to diminished washout and clearance of emboli (130). Extracranial arterial occlusion caused transient hypoperfusion and transient brain ischemia or minor infarction, whereas major deficits and sizable brain infarction were always explained by intracranial arterial embolism. Carotid (131) and vertebral artery dissections (132,133) were also recognized as important sources of artery-to-artery embolism.

BRAIN AND VASCULAR INVESTIGATIONS BRING EMBOLISM TO THE FOREFRONT AS THE MAJOR CAUSE OF BRAIN INFARCTION Only very recently have studies documented the great importance and ubiquity of intracranial embolism, arising from the heart, the aorta, and the cervico-cranial arteries as the cause of transient brain ischemia and infarction. In the Harvard Stroke Registry, cerebral angiography performed within 48 hours after the onset of the symptoms of ischemic stroke showed a high incidence of intracranial arterial occlusion, whereas studies after 48 hours were often normal (69). Ringelstein et al. (134) studied the pathogenesis of brain infarcts in 107 patients with cervical internal carotid artery occlusions. Angiography in 15 of 21 patients (71%) showed an “occlusio supra occlusionem,” that is, artery-to-artery emboli that arose from the carotid artery occlusion blocking intracranial arteries (134). Fieschi et al. (135) performed angiography within six hours of the onset of the symptoms of brain ischemia and showed complete arterial occlusions by thrombi in 76% of patients; most of the occlusions (66%) were intracranial. In a trial of patients screened for acute treatment with intravenous recombinant tissue plasminogen activator (rtPA), 112 of 139 patients (80%) had arterial occlusions on angiography performed within eight hours of the onset of symptom (136,137). In a study of thrombolytic treatment of patients with

Development of Ideas and Knowledge about Stroke and Brain Embolism

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acute brainstem ischemia, a high proportion had occlusions within the intracranial posterior circulation (138). Monitoring of the intracranial arteries of patients using TCD has shown a very high frequency of intracranial embolism in patients with potential donor sources of embolic materials (139 –144).

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105. Wolf PA, Dawber TR, Thomas HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978; 28:973 – 977. 106. Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991; 84:469 – 481. 107. Fairfax AJ, Lambert CD, Leatham A. Systemic embolism in chronic sinoatrial disorder. N Engl J Med 1976; 295:190 – 192. 108. Beppu S, Nimura Y, Sakakibara H. Smoke-like echo in the left atrial cavity in mitral valve disease: its features and significance. J Am Coll Cardiol 1985; 6:744– 749. 109. Barnett HJM, Jones MW, Boughner DR, Kostuk WJ. Cerebral ischemic events associated with prolapsing mitral valve. Arch Neurol 1976; 33:777– 782. 110. DeBono D, Warlow C. Mitral annulus calcification and cerebral or retinal ischemia. Lancet 1979; 2:383 – 385. 111. Brenner B, Blumenfeld Z, Markiewicz W, Reisner SA. Cardiac involvement in patients with primary antiphospholipid syndrome. J Am Coll Cardiol 1991; 18:931 –936. 112. Barbut D, Borer J, Wallerson D, Ameisen O, Lockshin M. Anticardiolipin antibody and stroke: possible relation of valvular heart disease and embolic events. Cardiology 1991; 79:99– 109. 113. Nighoghossian N, Derex L, Loire R, et al. Giant Lambl excrescences: an unusual source of cerebral embolism. Arch Neurol 1997; 54:41– 44. 114. Roberts JK, Omarali I, Di Tullio MR, et al. Valvular strands and cerebral ischemia: effect of demographics and strand characteristics. Stroke 1997; 28:2185 – 2188. 115. Reeder GS, Lengyei M, Tajik AJ, et al. Mural thrombus in left ventricular aneurysm: incidence, role of angiography, and relation between anticoagulation and embolism. Mayo Clin Proceed 1981; 56:77 – 81. 116. Cabin HS, Roberts WC. Left ventricular aneurysm, intra-aneurysmal thrombus and systemic embolus in coronary heart disease. Chest 1980; 77:586 –590. 117. Di Tullio M, Sacco RL, Gopal A, Mohr JP, Homma S. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Int Med 1992; 117:461– 465. 118. Petty GW, Khanderia BK, Chu C-P, Sicks JD, Whisnant JP. Patent foramen ovale in patients with cerebral infarction. A transesophageal echocardiographic study. Arch Neurol 1997; 54:819 – 822. 119. Tunick PA, Kronzon I. Protruding atherosclerotic plaque in the aortic arch of patients with systemic embolization: a new finding seen by transesophageal echocardiography. Am Heart J 1990; 120:658– 660. 120. Tunick PA, Perez JL, Kronzon I. Protruding atheromas in the thoracic aorta and systemic embolization. Ann Int Med 1991; 115:423– 427. 121. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221 – 225. 122. Amarenco P, Cohen A, Baudrimont M, Bousser M-G. Transesophageal echocardiographic detection of aortic arch disease in patients with cerebral infarction. Stroke 1992; 23: 1005– 1009. 123. Di Tullio MR, Sacco RL, Gersony D, et al. Aortic atheromas and acute ischemic stroke: a transesophageal echocardiographic study in an ethnically mixed population. Neurology 1996; 46:1560 – 1566. 124. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216– 1221. 125. Pessin M, Duncan G, Davis K, et al. Angiographic appearance of carotid occlusion in acute stroke. Stroke 1980; 11:485 – 487. 126. Torvik A, Svindland A, Lindboe CF. Pathogenesis of carotid thrombosis. Stroke 1989; 20:1477 – 1483. 127. Ogata J, Masuda J, Yutani C, Yamaguchi T. Rupture of atheromatous plaque as a cause of thrombotic occlusion of stenotic internal carotid artery. Stroke 1990; 21:1740 – 1745. 128. European Carotid Plaque Study Group. Carotid artery plaque composition: relationship to clinical presentation and ultrasound B-mode imaging. Eur J Vasc Endovac Surg 1995; 10:23 – 30.

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129. Geroulakos G, Ramaswami G, Nicolaides A, et al. Characterization of symptomatic and asymptomatic carotid plaques using high-resolution real-time ultrasonography. Br J Surg 1993; 80:1274 – 1277. 130. Caplan LR, Hennerici M. Hypothesis: impaired clearance of emboli (washout) is an important link between hypoperfusion, embolis, and ischemic stroke. Arch Neurol 1998; 55:1475 – 1482. 131. Fisher CM, Ojemann R, Roberson G. Spontaneous dissection of cervicocerebral arteries. Can J Neuro Sci 1978; 5:9 –19. 132. Caplan LR, Zarins CK, Hemmati M. Spontaneous dissection of the extracranial vertebral arteries, Stroke 1985; 16:1030 – 1038. 133. Caplan LR, Baquis GD, Pessin MS, D’Alton J, Adelman LS, DeWitt LD Ho K, Izukawa D, Kwan ES. Dissection of the intracranial vertebral artery. Neurology 1988; 38:868 – 877. 134. Ringelstein EB, Zeumer H, Angelou D. The pathogenesis of strokes from internal carotid artery occlusion: diagnostic and therapeutical implications. Stroke 1983; 14:867 – 875. 135. Fieschi C, Argentino C, Lenzi GL, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci 1989; 91:311– 321. 136. Wolpert SM, Bruchman H, Greenlee R, et al. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. AJNR 1993; 14:333– 347. 137. del Zoppo GJ, Poeck K, Pessin MS and 16 co-authors of the rtPA acute stroke study group. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992; 32:78– 86. 138. Bruchman H, Ferbert A, del Zoppo GJ, Hacke W, Zeumer H. Acute vertebral basilar thrombosis; angiologic-clinical comparison and therapeutic implications. Acta Radiol 1987; 369(suppl):38 – 42. 139. Markus HS. Transcranial Doppler detection of circulating cerebral emboli, a review. Stroke 1993; 24:1246 – 1250. 140. Markus HS, Harrison MJ. Microembolic signal detection using ultrasound. Stroke 1995; 26:1517 – 1519. 141. Tong DC, Albers GW. Transcranial Doppler-detected microemboli in patients with acute stroke. Stroke 1995; 26:1588 – 1592. 142. Sliwka U, Job F-P, Wissuwa D, et al. Occurrence of transcranial Doppler high-intensity transient signals in patients with potential cardiac sources of embolism: a prospective study. Stroke 1995; 26:2067 – 2070. 143. Daffertshofer M, Ries S, Schminke U, Hennerici M. High-intensity transient signals in patients with cerebral ischemia. Stroke 1996; 27:1844 – 1849. 144. Sliwka U, Lingnau A, Stohlmann W-D, et al. Prevalence and time course of microembolic signals in patients with acute strokes, a prospective study. Stroke 1997; 28:358 – 363. 145. McHenry L. Introduction to Willis T. The Anatomy of the Brain and Nerves. Birmingham: The Classics of Neurology and Neurosurgery Library, 1965. 146. Haymaker W, ed. The Founders of Neurology. Springfield, Ilinois: Charles C Thomas, 1953. 147. Roland CG. Introduction to Osler W. The Cerebral Palsies of Children and On Chorea and Choreiform Affections. Birmingham: The Classics of Neurology and Neurosurgery Library, 1986.

2 Overview: The Major Components of Brain Embolism Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

There are three important actors, dramatis personae, in the drama of brain embolism: the recipient artery that catches and receives the embolic material, even temporarily; the embolic material itself—the stuff that makes up the emboli; and the donor source from which the embolic material originates (Fig. 1). I find it useful to think of the brain embolism triad as birds and nests. The bird (embolic material) arises from a nest (donor source) and often flies from the nest to rest on a distant tree branch or other destination (recipient artery) (Fig. 2) (1). All of the actors in the drama play important roles, but each role has its own unique character and significance in the play. Of course, there are many nests, many birds, and many different destinations to which they fly.

THE RECIPIENT ARTERIES The recipient artery determines to a large extent the clinical symptoms and signs. When a recipient extracranial or intracranial artery is blocked, blood flow to that area of the brain, which is supplied by the blocked artery, suddenly becomes insufficient. Less fuel in the form of oxygen and sugar reaches the brain. The lack of energy causes the brain region to interrupt its normal functioning. The neurological symptoms that result from the arterial blockage depends on the area of brain that is underperfused. If an embolus blocks a posterior cerebral artery (PCA) supplying the visual cortex, loss of vision in the opposite visual field might result. If an embolus blocks the left middle cerebral artery (MCA), the right limbs might become weak and numb, and the patient might not be able to speak normally. An embolus to an intracranial vertebral artery (ICVA) might cause loss of function of the cerebellum with resultant loss of the ability to walk normally. The symptoms do not depend on the nature of the embolic material. Of course, the recipient artery cannot tell what is blocking it. The brain region supplied only knows that it is not getting enough energy to continue to function as before. Whether the symptoms are transient or persist depends very much on the fate of the embolus. Angiographic and ultrasound studies confirm that emboli move (2 – 6). An embolus very often moves through a recipient artery so quickly that either no obstruction 25

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Figure 1 Drawing showing the major players: the donor sources, including the heart, aorta, cervico-cranial arteries, embolus, and recipient artery. a, cardiac wall; b, atrial septal abnormality; c, internal carotid artery; d, anterior cerebral artery embolus. Source: From Ref. 11.

or a very transient obstruction occurs. These transient passing emboli can be identified as high-intensity transient signals (HITS) that pass quickly under an ultrasound probe monitoring an intracranial artery. No symptoms result. Alternatively, depending on the size and nature of the embolic material, the embolus could rest long enough to interrupt function and cause brain ischemia but short enough that when the embolus passes no permanent infarction has developed. The temporary symptoms that result would be classified as a transient ischemic attack (TIA). If the embolus stays long enough, infarction occurs, in which case the symptoms and signs may or may not persist, depending on the location and size of the brain infarct. The great majority of emboli that go into an internal carotid artery (ICA) from the heart or aorta, or arise from the ICA, go into the ipsilateral middle cerebral artery (MCA). The embolus might rest first within the ICA in the neck or the ICA intracranially and then go into the proximal MCA or the superior or inferior division of the MCA or into one of the smaller (MCA) cortical branches (7,8). Occasionally, the embolus might go into other branches of the intracranial ICA, the ipsilateral anterior cerebral artery (ACA) or the anterior choroidal artery (AChA). If an embolus goes into a vertebral artery in the neck or arises from an extracranial vertebral artery (ECVA), most often it will travel rostrally into the ipsilateral intracranial vertebral artery (ICVA), or go even further to reach the basilar artery bifurcation or one or both PCAs or the superior cerebellar arteries (SCAs) located at the top of the

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Figure 2

27

A bird leaving its nest.

basilar artery (9,10). If the embolus is large enough, it could obstruct the basilar artery itself leading to severe brainstem ischemia or infarction. At times, a number of different arteries are blocked.

THE EMBOLIC MATERIAL Like nests, birds that occupy the nests are also heterogeneous. The nature of the embolic material determines the most likely prophylaxis and treatment. Emboli that arise from the heart often consist of red erythrocyte –fibrin thrombi that form in inefficiently beating atria or on the surface of myocardial infarcts or within ventricular aneurysms. Figure 3 shows a red thrombus that embolized to an MCA. White platelet –fibrin thrombi form along irregular valvular surfaces and prosthetic valves. Often, white thrombi form the nidus for a superimposed red thrombus so that both are involved in the thromboembolism. Calcium present in calcific aortic valves and in mitral annuli calcifications can break loose and embolize. Bacteria and fungi engrafted upon valves in patients with infective endocarditis can travel into the bloodstream and into the brain and systemic arteries. Tumor tissues from cardiac myxomas and fibroelastomas can form the matter of emboli. Similarly, emboli arising from the aorta consist of very different substances. White platelet –fibrin thrombi form in crevices and irregular surfaces. These white clots activate the coagulation cascade and promote red thrombi, which form on their surface. Red thrombi often form within ulcers or regions of plaque rupture. Red and white thrombi often break off and reach the brain. Cholesterol crystals within aortic plaques or

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Figure 3 An embolus within the middle cerebral artery at necropsy. The inset shows the clot removed from the artery.

complex plaques themselves can travel to the brain. Calcium may also be a component of aortogenic emboli. Artery-to-artery emboli have the same basic components as those that arise from the aorta: calcium, cholesterol fragments, red and white clots, and so forth. Occasionally, air, fat, and foreign materials enter the blood stream and embolize to the brain and other viscera. Acute treatment should consider the nature of the embolic material—the stuff. Thrombolytic drugs, such as recombinant tissue plasminogen activator (rt-PA), can lyse red clots but are ineffective against white clots. On the other hand, glycoprotein IIB/IIIA inhibitors that are active against platelet-fibrin bridges can potentially lyse white clots. These treatments are likely to be ineffective against calcium, cholesterol crystals, tumor fragments, infective agents, and foreign matter. A mechanical method of retrieving emboli might be able to snare a number of different materials. Similarly, prophylaxis against re-embolization, secondary prevention, must consider the nature of the embolic material. The most effective prophylaxis against embolism in patients with infective endocarditis is antibacterial and antifungal agents.

THE DONOR SOURCE The preceding sections have already enumerated the usual nests— the heart, the aorta, and the extracranial and intracranial arteries. Secondary prevention also depends on the nature of the donor sources. Atrial fibrillation might respond to antiarrythmics. Intra-atrial septal abnormalities and defects can be repaired. Ventricular aneurysms can be resected. Abnormal valves can be repaired or replaced by prosthetic valves. Cardiac tumors can be removed. Surgeons have operated on protruding aortic atheromas and, in the future, these lesions might be dealt with using endovascular techniques. Clearly arterial lesions

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are often repaired surgically or using endovascular technology in the form of angioplasty and/or stenting. In the ensuing chapters of this book, I and others describe and elaborate on these three major components of the brain embolism triad. We describe their nature in much more detail and the related symptoms and signs, diagnosis, prognosis, outcomes, and treatments. All too long, clinicians have focused on the nests and have lost sight of the birds and their customary destinations and habits. Clinicians must refocus on all three characters or else they will be unable to understand the drama of embolism. REFERENCES 1. Caplan LR. Of birds, and nests, and brain emboli. Rev Neurol 1991; 147:265 – 273. 2. Dalal P, Shah P, Sheth S, et al. Cerebral embolism: angiographic observations on spontaneous clot lysis. Lancet 1965; 1:61 –64. 3. Liebeskind A, Chinichian A, Schechter M. The moving embolus seen during cerebral angiography. Stroke 1971; 2:440 – 443. 4. Caplan LR, Allam GJ, Teal PA. The moving embolus. J Neuroimag 1993; 3:195– 197. 5. Daffertshofer M, Ries S, Schminke U, Hennerici M. High-intensity transient signals in patients with cerebral ischemia. Stroke 1996; 27:1844 –1849. 6. Sliwka U, Lingnau A, Stohlmann W-D, et al. Prevalence and time course of microembolic signals in patients with acute strokes, a prospective study. Stroke 1997; 28:358 – 363. 7. Gacs G, Merer FT, Bodosi M. Balloon catheter as a model of cerebral emboli in humans. Stroke 1982; 13:39 – 42. 8. Helgason C. Cardioembolic stroke topography and pathogenesis. Cerebrovasc Brain Metab Rev 1992; 4:28 – 58. 9. Caplan LR. Top of the basilar syndrome: selected clinical aspects. Neurology 1980; 30:72– 79. 10. Caplan LR. Posterior circulation disease: clinical findings, diagnosis, and management. Boston: Blackwell Science, 1996. 11. Caplan LR. Caplan’s Stroke: A Clinical Approach. 3rd ed. Boston: Butterworth-Heinemann, 2000:19, figure 2.2.

PART II:

RECIPIENT ARTERIES AND BRAIN ISCHEMIA

3 Recipient Artery: Anatomy and Pathology Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

EXAMINING RECIPIENT ARTERIES TO SEPARATE EMBOLISM AND THROMBOSIS Examination of the recipient artery and any blood coagulation material within the artery has often been used to separate in situ thrombosis from embolism. Figure 1 shows an artery distended with an embolus, and Figure 2 shows the embolic clot that was removed from the artery. Kubik and Adams (1), in their classic report on basilar artery thrombosis published in 1946, paid particular attention to distinguishing embolism and thrombosis at necropsy. “Thrombosis of the basilar artery could usually be recognized at a glance. The thrombosed portion of the vessel was distended, firm, and rigid and the thrombus could not be displaced by pressure. . . . In embolism, the embolus was usually lodged in the distal portion of the artery.” In all cases attributed to in situ thrombosis, there was extensive underlying atherostenosis of the basilar artery with severe luminal narrowing by plaque. In some patients, microscopic analysis of thrombi revealed that different portions of the clots must have formed at different times. Embolic plugs occasionally lodged in regions of the artery that were narrowed by atheromatous plaques. The presence of plaques alone did not separate thrombosis from embolism. Focal regions of layered thrombi could be superimposed on firm nonadherent emboli (1). Torvik and Jorgenson (2) commented in 1969 on the morphology within recipient arteries. “The diagnosis of thrombosis (in situ) was based on the demonstration of a red, laminated intravascular plug which was firmly and extensively attached to the vessel wall. Sharply-delimited plugs which were only loosely attached to the arterial wall were rated as embolic. In occlusions more than a few days old, invasion of the plug by fibroblasts and capillaries over a wide segment of the arterial wall was considered to be diagnostic of a thrombus. Organization from only a small segment of the vessel wall in occlusions which were more than a few days old was regarded as an indication of embolism.” Torvik and Jorgenson (2) also commented on materials found within small vessels beyond the region of transient or persistent occlusion. Fibrin-rich masses were often found in distal arteries in patients with brain embolism, whereas platelet aggregates were more often found in patients with presumed in situ occlusions. “Platelet aggregates were frequently found in both arteries and veins within the infarcted tissue, in the adjacent area, and the overlying or more distant leptomeninges. Many of the aggregates were completely 31

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Figure 1 A clot distending an intracranial artery (black arrow) at an arterial bifurcation photographed at necropsy.

occluding the vessel; others appeared to have been floating free or else they formed mural thrombi showing a limited contact with the inner lining of the vessel. All stages in the transformation of platelet aggregates to fibrin-rich masses were represented but most of the aggregates appeared fresh with little or no fibrin” (2). Emboli often distend the recipient artery but are not adherent to the arterial wall. They tend to lodge at bifurcations of arteries. Most often, there is an absence of severe atherosclerosis in the region of the recipient artery where the embolus lodges. The presence of cardiac, aortic, and proximal arterial lesions at necropsy is also helpful in attempting to distinguish embolic from thrombotic occlusions. The location, size, and nature of the resulting brain infarct too can give clues to the embolic nature of the vascular occlusive process.

Figure 2 The clot removed from the artery.

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HEMORRHAGIC INFARCTION When embolism causes brain infarction, the infarcts often become hemorrhagic. Miller Fisher and Raymond Adams (3 – 5) extensively studied their necropsy material to define the mechanism of hemorrhagic brain infarction. Obstruction of a brain-supplying artery causes ischemia to neurons and also leads to ischemic damage to the capillaries and small blood vessels within the area of ischemia. When the obstructing embolus moves distally, at least partially recanalizing the previously blocked artery, the region that was previously ischemic becomes reperfused with blood, often under normal arterial pressure. The damaged capillaries and arterioles within that region are no longer competent, and blood leaks into the surrounding infarcted tissue. An example of this mechanism is shown in Figures 3A and B from the Fisher and Adams study (4,5). An embolus must have initially blocked the main stem middle cerebral artery (MCA) in this patient, before the origin of the lenticulostriate branches, causing ischemia to the basal ganglia, internal capsule, and the superficial cortical territories supplied by the MCA. The embolus then must have moved distally and at necropsy had passed beyond the lenticulostriate branches but continued to obstruct the MCA more distally (Fig. 3B). The reperfused deep basal ganglionic region was hemorrhagic at necropsy, whereas the superficial territory of the MCA, which was never reperfused, showed a bland infarct (Fig. 3A) (3 – 5). The essential cause of hemorrhagic infarction is reperfusion of previously ischemic tissue. Reperfusion occurs most often after passage of emboli and recanalization of the recipient artery. Sometimes, collateral vascular channels can provide enough reperfusion to cause bleeding into infarcts (6). Most often, petechial hemorrhages and stippling within areas of brain necrosis are found. In the great majority of patients, hemorrhagic infarction consists of diapedesis of red blood cells into infarcted tissue. Often the appearance is that of randomly scattered petechial hemorrhages or a confluent purpuric pattern spread throughout the infarct (7). Figures 4 and 5 show well-defined hemorrhagic infarcts caused by emboli to MCA branches. In Figure 4, an embolus has blocked an anterior branch of the superior division of the MCA, whereas in Figure 5 a more posterior superior division MCA branch was the recipient artery. In some brain infarcts, especially large ones involving more than one lobe, localized homogeneous collections of blood (intracerebral hematomas) can develop within regions of hemorrhagic infarction. In most patients with hemorrhagic infarcts, the hemorrhagic transformation does not cause worsening of the clinical symptoms and signs. The hemorrhagic changes are usually found on routine follow-up especially when T2 -weighted magnetic resonance imaging (MRI) scans are performed. Bleeding into dead tissue does not alter clinical findings unless a large spacetaking hematoma develops. The other cerebrovascular condition that often causes hemorrhagic infarction besides embolism is systemic hypoperfusion. After cardiac arrest or shock, the reinstitution of effective circulation after a prolonged period of decreased blood pressure and blood flow severe enough to have caused hypoperfusion of the brain can lead to hemorrhage within border-zone infarcts. Hemorrhagic regions within brain infarcts are quite commonly found in patients with brain embolism. In two series, the investigators prospectively studied the frequency of hemorrhagic infarction on sequential planned brainimaging scans. Yamaguchi et al. (8) compared the findings on computed tomography (CT) scans performed three to 10 days after stroke in 120 patients who had embolic brain infarcts with 109 patients whose infarcts were considered due to thrombosis that had formed locally, in situ within the intracranial arteries. Hemorrhagic infarcts were found in 45 patients (40%) who had embolic infarcts, compared to 2 (1.8%) patients with local thrombosis-related infarcts (8). Okada et al. (9) studied 160 patients who had

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Figure 3 (A) Coronal section of the brain at necropsy showing a hemorrhagic infarction on the right involving the caudate nucleus and putamen, regions supplied by the lenticulostriate branches of the right middle cerebral artery. (B) Drawing of the intracranial internal carotid artery and its branches at necropsy. An embolus (hatched region) was found in the distal portion of the mainstem middle cerebral artery beyond the lenticulostriate branches that supply the caudate nucleus and putamen. This embolus, at one time, must have blocked these penetrating branches and then moved more distally in the artery. Abbreviations: Antr CA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; P. Comm, posterior communicating arteries. Source: From Ref. 5.

brain infarcts presumed to be caused by embolism by performing CT scans every 10 days during hospitalization. Hemorrhagic infarction was found on the CT scan at some time during the course in 65 (40.6%) patients. Hemorrhagic changes were found on the initial CT scan performed during the first four days in only 10 patients (6%), while the remainder of the hemorrhagic infarcts were found on follow-up CT scans (9). Studies using CT scans at the New England Medical Center in Boston showed that all the cerebral (10) and cerebellar (11) hemorrhagic infarcts that were studied and reported in patients

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Figure 4 A hemorrhagic infarct (white arrow) involves the territory of an anterior branch of the superior division of the middle cerebral artery at necropsy. There is also a small region of hemorrhagic infarction in the basal ganglia (small black arrow).

were attributable to brain embolism. MRI is more sensitive than CT in detecting small hemorrhages and hemorrhagic infarction, so that sequential MRI would most likely show a frequency of .50% for hemorrhagic changes in patients with embolic brain infarcts.

Figure 5 Cut section of the posterior portion of the brain at necropsy. A very wellcircumscribed, triangular-shaped, very hemorrhagic infarct is seen within the parietal lobe on the left of the picture (white arrow). This infarct was the result of an embolus to a posterior branch of the superior division of the middle cerebral artery. Source: From Ref. 5.

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When studied, anticoagulation of patients with hemorrhagic infarction due to brain embolism did not cause an increase in bleeding (10). Physicians are accustomed to treating patients with hemoptysis caused by pulmonary embolism with heparin followed by coumadin. Patients with pulmonary embolism-related hemoptysis have beefy, hemorrhagic lung infarcts and yet heparin does not seem to create a major risk for further symptomatic lung bleeding. The situation is similar within the brain. Recent studies have shown that anticoagulation of patients with hemorrhagic infarcts in the brain caused by dural venous sinus occlusions have better outcomes if treated with anticoagulants (12 – 14). However, anticoagulation, especially using an intravenous bolus dose of heparin does carry a risk of hematoma formation in patients with large brain infarcts, even when hemorrhagic changes are not present on the acute brain-imaging scans.

LOCATION, TYPES, AND SIZE OF EMBOLIC BRAIN INFARCTS Anterior Vs. Posterior Circulation Localization About 80% of emboli that arise from the heart go into the anterior (carotid artery) circulation, equally divided between the left and right sides. The remaining 20% of emboli go into the posterior (vertebral and basilar arteries) circulation, a rate roughly equal to the proportion of the blood supply that goes into the vertebrobasilar arteries. In the Harvard Stroke Registry (15), 78% of emboli caused clinical anterior circulation ischemia, whereas the frequency of anterior circulation embolism was 85% in the Michael Reese Stroke Registry (16), 70% in the Lausanne Stroke Registry (17), 73% in the Besancon Stroke Registry (18,19), and 71% in the Athens Stroke Registry (20). The average of the frequencies of anterior circulation localization approximates about 80%, which is the expected frequency according to the proportion of blood flow. The recipient artery destination depends on the size and nature of the particles and their origin. Calcific particles from heart valves or mitral annular calcifications are less mobile and adapt less well to the shape of their recipient artery resting place than red (erythrocyte-fibrin) and white (platelet-fibrin) thrombi. The circulating blood stream seems to be able to somehow bypass obstructing cholesterol crystal emboli, especially in the retinal arteries. Emboli that originate in patients with patent foramen ovale and atrial septal defects more often than expected reach locations within the posterior circulation (21,22). Among one large series, 42.7% of strokes were located within the posterior circulation in patients with patent foramen ovale, atrial septal aneurysm, or both, compared to 35.4% of posterior circulation location in patients without cardiac atrial septal abnormalities (21). In another series, among patients with large patent foramen ovales, 8 of 14 strokes involved the posterior circulation (22). Posterior circulation symptoms and infarcts are also found more commonly than expected after cardiac catheterization with or without coronary angiography (23,24). In one series 6 of 10 ischemic events that followed cardiac catheterization could be localized to the posterior circulation (23). In another series, among 37 ischemic events complicating cardiac catheterization, 20 (54%) had a vertebro-basilar territory localization (24).

Anterior Circulation Sites and Types of Embolic Infarcts Within the anterior and posterior circulations there are predilection sites for the destination of embolic particles. Large emboli entering a common carotid artery (CCA) could become lodged in the common or internal carotid artery (ICA), especially if atheromatous

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plaques had already narrowed the lumens of these arteries. Only large emboli are likely to be able to block the carotid arteries in the neck. Torvik and Jorgenson in their study of autopsy material identified patients who had embolism to the carotid arteries (2,25). In India, in years past it was customary in patients with embolism arising from rheumatic mitral stenosis to surgically remove large emboli from the recipient carotid arteries in the neck. If emboli are able to pass through the carotid arteries in the neck, the next potential lodging place is the intracranial ICAs (top-of-the carotid or carotid T portion) at their bifurcation into the anterior cerebral (ACA) and middle cerebral (MCA) arteries. Figure 6 is a drawing of the ICA showing the major intracranial branches. Bifurcations are frequent resting places for emboli. Emboli that pass through the carotid intracranial bifurcations most often go into the MCAs and their branches. Gacs et al. (26) showed that balloon emboli placed in the circulation nearly always followed the same pathway and ended up in the MCAs and their branches. Embolism in experimental animals, produced by the introduction of silicone cylinders or spheres, elastic cylinders, and autologous blood clots, also showed a very high incidence of MCA territory localization (27). Emboli often pass into the superior and inferior divisions of the MCA and the cortical branches of these divisions. The superior division supplies the cortex and white matter above the sylvian fissure, including the frontal and superior parietal lobes. The inferior division supplies the area below the sylvian fissure, including the temporal and inferior parietal lobes. Figure 7 is a drawing of the convexal surface of the brain that shows the divisions of the MCA and their main branches. Figure 8 is a drawing of a cut section of the brain showing the supply zones of the different cerebral arteries. The MCA supplies

Figure 6 Anteroposterior views of branches of the internal carotid artery. Abbreviations: ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery. Source: From Ref. 14.

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Figure 7 Drawing of the lateral surface of the brain showing the superior and inferior trunk divisions of the middle cerebral artery and their branches. Drawn by Dr. Juan Sanchez Ramos. Abbreviations: MCA, middle cerebral artery. Source: From Ref. 5.

most of the convexal surface of the brain and the basal ganglia. The ACA supplies the paramedian frontal lobe. Emboli seldom go into the penetrating artery (lenticulostriate arteries) branches of the MCAs or the penetrators from the ACAs because these vessels originate at an angle of about 908 from the parent arteries.

Figure 8 Artist’s drawing of the blood supplies of the various cerebral arteries. Coronal view: The right side depicts territories supplied by the anterior cerebral artery, middle cerebral artery (MCA), posterior cerebral artery (PCA), and anterior choroidal artery (AChA). The left side depicts individual vessels: (a) basilar artery; (b) thalamoperforators that originate in the PCA; (c) AChA; (d) MCA; (e) lenticulostriate arteries. Abbreviations: ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; AChA, anterior choroidal artery. Source: From Ref. 14.

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Figure 9 Drawings from computed tomography scans of patients with embolic brain infarcts in the middle cerebral artery distribution. (A) Striatocapsular infarct; (B,C) Deep basal ganglioniccapsular and superficial territory infarcts (D,I) Entire middle cerebral artery territory infarcts; (E,F,G) Right side: superior division infarcts; (H) Left side: inferior division infarcts; (G) Left side: (H) Right side: small cortical branch territory infarcts. Source: From Ref. 5.

Embolism into the MCAs can cause a variety of different patterns of infarction. Figure 9 shows drawings of CT scans of nine patients with MCA embolic infarcts, and Figures 10– 18 are imaging scans of patients with embolism involving the MCA territory. It is essential for clinicians to be able to recognize the various patterns of infarction. Blockage of the mainstem MCA before the lenticulostriate branches can cause a large infarct that encompasses the entire MCA territory, including the deep basal ganglia and internal capsule as well as the cerebral cortex and subcortical white matter of both the suprasylvian and infrasylvian MCA territories (Figs. 9D and 9I). Sometimes, the cortical territory of the MCA is infarcted, but the deep basal ganglionic and internal capsule is relatively spared (Fig. 10). In some patients, an embolus blocks the ICA, causing infarction of the ACA territory as well as the entire MCA territory (Fig. 11).

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Figure 10 Computed tomography scan showing large infarct on the right of the figure (black arrow) in the nearly entire cortical and subcortical territory of the middle cerebral artery. The caudate nucleus and basal ganglia are relatively spared.

Figure 11 Computed tomography scan showing a large infarct (black arrow) involving the anterior cerebral artery territory (double arrows) as well as the entire middle cerebral artery territory on the right of the figure. Source: From Ref. 5.

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Figure 12 Magnetic resonance imaging showing a striatocapsular infarct that involves the caudate nucleus, internal capsule, and putamen on the right of the figure (arrowhead ).

In young patients, when the mainstem MCA is blocked, the rapid development of collateral circulation over the convexity of the brain often leads to the superficial territory of the MCA being spared. The clot in the mainstem MCA blocks the lenticulostriate branches, and collateral circulation to the deep MCA territory is poor. The resultant

Figure 13 Magnetic resonance imaging scan, T2 weighted, showing a small superior division middle cerebral artery territory infarct on the right of the figure (white arrow). Source: From Ref. 5.

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Figure 14 Computed tomography scan showing bilateral superior division middle cerebral artery (MCA) territory embolic infarcts. The deep MCA territories are also infarcted.

infarct is limited to the basal ganglia and surrounding cerebral white matter and is usually referred to as a striatocapsular infarct (Fig. 9A; 12). Passage of an embolus into the superior division of the MCA leads to a cortical/subcortical infarct in the region of the suprasylvian convexity [Fig. 9E, F, G, H (right side); 13]. Figure 14 shows a CT scan

Figure 15 Magnetic resonance imaging T2-weighted image showing a small inferior division infarct on the right of the figure (white arrows). Source: From Ref. 5.

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Figure 16 Superficial and deep infarcts. (A) computed tomography scan showing deep striatocapsular infarct (arrowhead) and inferior division middle cerebral artery (MCA) territory infarct (small black arrow). (B) Diffusion-weighted magnetic resonance imaging scans at different levels showing large striatocapsular infarct in the figure on the left and small infarcts in the cortical branches of the territories of superior and inferior division MCA territory in the figure on the right.

from an unfortunate patient who has had embolic infarctions of the superior divisions of both MCAs. Embolism in the inferior division leads to an infarct limited to the temporal and inferior parietal lobes below the sylvian fissure [Fig. 9H (left side), 15]. When an embolus rests first in the mainstem MCA and then travels to one of the divisional branches, infarction involves the deep territory and cortex above or below the sylvian fissure (Fig. 9B, C; Fig. 6A, B). Small emboli block cortical branches and cause small cortical/subcortical infarcts involving one or several gyri [Fig. 9G (left side); Fig. 16B; 17; 18]. Occasionally, emboli block the ACA or its distal branches. This causes an infarct in the paramedian area of one frontal lobe. Figure 19A is a necropsy specimen of an embolic infarct involving ACA territory and Figure 19B is an MRI scan showing a typical ACA territory infarct due to embolism.

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Figure 17 Magnetic resonance imaging fluid-attenuated inversion recovery image showing a middle cerebral artery pial territory gyral infarct.

Posterior Circulation Sites Figure 20 is a drawing of the arteries that compose the posterior circulation and the brainstem and cerebellar areas that they supply. Figure 21 is a drawing that shows common locations where emboli block recipient arteries within the posterior circulation. Emboli that enter the posterior circulation can block the vertebral arteries in the neck or intracranially. Emboli that are able to pass through the intracranial vertebral arteries (ICVAs) will usually be able to pass through the proximal and middle portions of the basilar artery, which has a larger diameter than the ICVAs. The basilar artery becomes narrower as it courses craniad. Emboli often block the distal basilar artery bifurcation (“top of the basilar”) or one of its branches (28,29). The main branches of the basilar artery bifurcation are arteries penetrating to the medial portions of the thalami and midbrain, the superior cerebellar artery (SCA), which supplies the upper surface of the cerebellum, and the

Figure 18 Magnetic resonance imaging diffusion-weighted scans at different levels showing multiple small middle cerebral artery pial territory infarcts.

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Figure 19 Anterior cerebral artery territory infarcts. (A) Figure 6.14 postmortem necropsy coronal slice of brain showing a large anterior cerebral artery (ACA)-territory infarct above the very enlarged left lateral ventricle. The corpus callosum is necrotic, and the infarct extends toward the right cingulate gyrus. (B) Magnetic resonance imaging, T2 weighted, showing a paramedian ACA territory infarct. Source: From Ref. 45.

posterior cerebral arteries (PCAs), which supply the lateral portions of the thalami and the temporal and occipital lobe territories of the PCAs. Figure 22 is an MRI that shows an occipital and medial temporal lobe embolic infarct in the distribution of one PCA. Figure 23 is a necropsy specimen that shows a hemorrhagic infarct in the territory of the bilateral PCAs that resulted from an embolus to the rostral basilar artery bifurcation. Figure 24 consists of two views of an embolic infarct to one SCA, whereas the MRIs in Figure 25 show embolic infarcts involving the bilateral SCAs. Sometimes, infarcts are limited to one branch of an artery that penetrates into the midbrain or thalamus

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Figure 20 Drawing of the arterial supply of the brainstem and cerebellum. Abbreviations: ASA, anterior spinal artery; VA, intracranial vertebral artery; BA, basilar artery; PICA, posterior inferior cerebellar artery; AICA, anterior inferior cerebellar artery; SCA, superior cerebellar artery; PCA, posterior cerebral artery. Source: From Ref. 30.

Figure 21 Drawing of the base of the brain showing the most frequent sites of embolism within the posterior circulation. The black clots are located within the left intracranial vertebral artery and in the distal basilar artery and its left superior cerebellar and posterior cerebral artery branches. The left temporal lobe and left cerebellum are shaded gray to show infarction. Drawn by Dari Paquette. Source: From Ref. 30.

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Figure 22 Magnetic resonance imaging of T2-weighted axial section showing a large left occipital lobe infarct on the right of the figure. Source: From Ref. 30.

(Fig. 26). Figure 27A is a CT scan that shows bilateral infarcts in the territory of the thalamo-perforating arteries that emanate from the basilar artery bifurcation; Figure 28 is a necropsy specimen showing a typical bilateral “butterfly-shaped” infarct in the paramedian thalamus due to a “top-of-the-basilar” embolus. At times, rostral basilar artery emboli cause infarcts in both thalami and both occipital lobes (Fig. 29).

Figure 23 Cut section of the posterior portion of the brain at necropsy showing a bilateral hemorrhagic infarct within the territories of the posterior cerebral arteries (PCA) (white arrows). The black stippled areas within the infarct represent small hemorrhages. These infarcts are a result of a single embolus temporarily blocking the distal bifurcation of the basilar artery impeding flow to the left and right PCA. Source: From Ref. 5.

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Figure 24 Magnetic resonance imaging T2-weighted scans showing a unilateral infarct within the territory of the medial branch of the superior cerebellar artery. (A) Sagittal section showing the infarct (black arrow). (B) Coronal section. The black arrow points to the infarct involving the superior vermis and medial portion of the cerebellar hemisphere. Source: From Ref. 30.

Some emboli stop at the level of one ICVA. The most frequent brain area infarcted is the posterior inferior portion of the cerebellum in the territory of the posterior inferior cerebellar artery (PICA) branch of the ICVA (Fig. 30A, B). At times, an embolus will stop at the level of one ICVA causing a PICA territory infarct, and then the embolus or a portion of it passes distally, causing an infarct in SCA territory on one or the other side (30). Figure 31 is an MRI that shows a PICA territory infarct on the right of the figure and

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Figure 25 Magnetic resonance imaging T2-weighted scans showing bilateral superior cerebellar artery territory infarcts. (A) Coronal section: the arrowhead points to the infarcts. (B) Axial section showing the infarcts. Source: From Ref. 30.

an SCA territory infarct on the left side of the figure that resulted from a cardiogenic embolus.

Angiographic Sites of Recipient Artery Occlusions Cerebral angiography was used for diagnosis in the Harvard Stroke Registry (HSR), as many patients were seen before CT scans were available (15). Table 1 shows the frequency of embolic occlusions among the various intracranial arteries based on angiography in the HSR. The MCAs were involved in 80% of patients; the mainstem MCA and superior division branches were the regions within the MCAs that were most often occluded (15).

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Figure 26 Necropsy specimen showing a unilateral midbrain infarct (large black arrow) in the territory of a penetrating artery branch of the distal basilar artery.

In the Lausanne Stroke Registry (LSR), the distribution of infarcts in patients with potential cardiac sources of emboli was based on brain imaging, using either a CT scan or an MRI (31). Among 1311 patients who were tabulated in the LSR, 305 (23%) had potential cardiac sources of emboli. Table 2 shows the distribution of brain infarcts among these 305 patients (31).

Figure 27 Computed tomography scan showing bilateral large nearly symmetrical posterior medial thalamic infarcts (white arrow) due to embolism to the “top of the basilar artery.” Source: From Ref. 30.

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Figure 28 Bilateral, paramedian, thalamic – subthalamic artery territory butterfly-shaped infarct (white arrows) abutting the third ventricle due to embolism to the “top of the basilar artery.” Source: From Ref. 30.

Multiple Emboli Another important feature of cardiac origin embolism is development of multiple cortical/ subcortical infarcts in multiple vascular territories within both anterior circulations and the posterior circulation, especially in the absence of severe proximal arterial occlusive lesions. Emboli arising from the aorta probably share the same patterns of infarction as that found in cardiac-origin embolism, although recipient sites of aortic-origin emboli

Figure 29 Computed tomography scan illustrating a devastating “top of the basilar artery” embolus. The bilateral occipital lobes in the territory of the posterior cerebral arteries (small black arrows) and the right thalamus (white arrow) are infarcted.

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Figure 30 Posterior inferior cerebellar artery (PICA) territory infarcts. (A) Magnetic resonance imaging (MRI), T2-weighted, axial-section scan showing a very large infarct (white arrows) involving the brainstem and cerebellum on one side caused by embolism to the right intracranial vertebral artery. (B) MRI, T2-weighted, sagittal-section scan showing a PICA territory infarct (white arrow). Source: From Ref. 30.

have not been extensively studied. Figure 32 is a CT scan that shows multiple brain infarcts in a patient with cardiac valve disease.

Intra-arterial Emboli Vs. Cardiogenic Emboli Emboli that arise from proximal arteries go only into branches of that artery. Repeated embolism going into one MCA suggests an intrinsic lesion of the carotid artery on that side. The distal termination sites within the anterior and posterior circulations are the same as that described in cardiac origin embolism. Proximal arterial disease often

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Figure 31 Magnetic resonance imaging of a T1-weighted, coronal section showing a left posterior inferior cerebellar artery territory infarct (white arrow) and a right superior cerebellar artery territory infarct (black arrow) caused by an embolus to the left intracranial vertebral artery that later passed distally.

induces circulatory changes with increased collateral circulation. The preexistence of collateral circulation might limit the size of intra-arterial embolic infarcts when compared to cardiac and aortic origin embolism, in which there is no such pre-event adaptation. The distribution of infarcts according to superficial and deep intracranial territories also probably differs between patients with cardiac and intra-arterial sources of embolism. Table 3 shows the distribution of infarcts in the Stroke Data Bank (32). Superficial and deep infarcts were much more often found in patients with cardiac sources of embolism (32). Large emboli more often block the mainstem MCAs and PCAs before their penetrating artery branches, leading to infarcts that are both deep and superficial. In contrast purely

Table 1 Vascular Recipient Arteries in the Harvard Stroke Registry Based on Cerebral Angiography Anterior cerebral artery Middle cerebral artery Main stem Superior division Superior division branch Inferior division Inferior division branch Multiple branches Posterior cerebral artery Basilar artery Source: From Ref. 12.

3 75 26 9 22 8 1 9 11 5

(3%) (80%)

(12%) (5%)

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Table 2 Topography of Infarcts in the Lausanne Stroke Registry in Patients with Potential Cardiac Sources of Embolism Anterior circulation Global MCA Superior division MCA Inferior division MCA Deep subcortical ACA ACA and MCA together Posterior circulation Brainstem Thalamus (deep PCA) Superficial PCA Superficial and deep PCA Cerebellum

213 33 60 54 56 9 1 69 18 12 21 3 10

(70%) (11%) (20%) (18%) (18%) (3%) (0.3%) (23%) (6%) (4%) (7%) (1%) (3%)

Abbreviations: MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery. Source: From Ref. 27.

superficial infarcts were more common in patients with intra-arterial embolism in the Stroke Data Bank (32). Size of Infarcts Emboli of cardiac origin are often larger than those that originate in the proximal arteries and so the infarcts that result are, on average, larger than artery-to-artery infarcts (32 – 34).

Figure 32 Computed tomography scan showing five brain infarcts (black arrows) located in the basal ganglia and temporal lobes bilaterally. Source: From Ref. 5.

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Distribution of Infarcts in the Stroke Data Bank

Infarct type Superficial infarcts Deep small infarct Deep large infarcts Superficial and deep infarcts

Cardiac-origin embolism (%)

Intra-arterial embolism (%)

24 13 9 53

61 10 16 13

Source: From Ref. 28.

In the Stroke Data Bank, the medium volume of infarction on CT scans in patients with cardiac origin embolism was 2.4 times that found in patients with intra-arterial embolism, a highly significant difference (P , 0.01) (32). In a study that included more than 2000 stroke patients, the average size of brain infarcts that causes seizures mostly due to cardiac origin embolism was 73.7 cm3 versus 48.9 cm3 for nonembolic infarcts (35). The presence of proximal arterial occlusion and the gradual pace of in situ arterial narrowing and occlusion allow time for collateral circulation to develop and thus likely limit the size of the infarction. In contrast, embolic occlusion of recipient arteries from a cardiac source occurs abruptly. A decreased level of consciousness early during the course of a stroke, a finding likely related to the size of infarction among other factors, was also significantly more common among Stroke Data Bank patients with cardiogenic embolism compared to those who had intra-arterial embolism (29.8% vs. 6.1%, P , 0.01) (32). Edema and Brain Shifts in Patients with Large Embolic Brain Infarcts Because embolic brain infarcts, especially those caused by cardiac origin embolism, are often large, brain swelling and mass effect often develop. Patients with very large infarcts often worsen during the first 24 to 48 hours after their initial symptoms. The most common infarcts that create major pressure effects are: large MCA territory infarcts [so-called malignant MCA infarcts (36)], large infarcts caused by carotid artery occlusion that include the MCA and also the ACA and sometimes Anterior Choroidal Artery territories, and large cerebellar infarcts especially involving PICA cerebellum and SCA supplied cerebellum. Probably at least 1/3 of the cerebellum on one side must be infarcted to be likely to cause major tumoral effects (37). These large cerebellar infarcts can compress the brainstem and the fourth ventricle leading to death if not decompressed surgically (38 –41). Most often, pressure effects caused by swelling of large cerebral hemisphere infarcts result in a shift of the midline without herniation of brain contents. The brain is compartmentalized by bony fortresses (anterior, middle, and posterior fossas) and by dural structures (falx cerebri and tentorium cerebelli), which, under normal circumstances, contain their usual contents. When mass effects are very severe, brain tissue bulges or spills out of its usual abode into a different compartment; this is called “herniation” (42,43). Brain shifts and herniations and their effects are depicted in Figure 33. The most common are: 1. 2.

compression of the lateral ventricle with a shift in midline structures (Fig. 33A); herniation of the temporal lobe through the tentorial notch, to compress the midbrain (Fig. 33B);

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Figure 33 Drawings of brain shifts and herniations: Displacement of brain tissues due to massproducing strokes is illustrated in patients with large infarcts. (A) Hemisphere infarct causes compression of the ipsilateral lateral ventricle and shift of the midline to the opposite side. (B) Large hemisphere infarct causes uncal herniation. The medial temporal lobe exerts pressure on the upper brainstem. (C) Frontal lobe large infarct causes herniations of the cingulum under the falx cerebri. (D) Cerebellum infarct causes increased posterior fossa pressure with compression of the brainstem and herniation of the cerebellum through the foramen magnum.These patterns are also illustrated on the larger figure to the left. Source: From Ref. 14.

3. 4. 5. 6.

herniation of the cingulate gyrus under the falx, allowing it to reach the contralateral side (Fig. 33C); symmetrical, downward pressure by the swollen cerebral hemispheres on the rostral brainstem, causing elongation; herniation of the cerebellum upward through the tentorial notch, to compress the brainstem (Fig. 33D); and downward herniation of the cerebellar tonsils through the foramen magnum, compressing the medulla and upper cervical spinal cord (Fig. 33D).

Shifts in brain contents can also lead to compression or stretch of arteries and infarction in areas of supply and also to secondary hemorrhages. The most common locations of secondary vascular changes leading to infarction involve the PCAs where they pass between the tentorium and the medial temporal lobe and the ACAs adjacent to the falx. Distortion of the upper brainstem at the tentorial opening often leads to secondary hemorrhages in the brainstem. These usually involve the midline and paramedian vessels and are called “Du¨ret hemorrhages,” after the French clinician and researcher, Henri Du¨ret, who first described them (44). Examples of Du¨ret hemorrhages are shown in Figures 34A and B. The ventricular system may also be compressed at various sites. Large cerebral infarcts can compress the ipsilateral lateral ventricles and may cause blockage of the foramen of Monro, leading to enlargement of the contralateral lateral ventricle. Large cerebellar infarcts can compress the fourth ventricle or cerebral aqueduct, leading to obstructive hydrocephalus of the third and lateral ventricles (Fig. 35). Shifts in brain contents, herniations, and secondary infarctions, as well as Du¨ret hemorrhages and hydrocephalus, all cause clinical worsening of signs and symptoms and often lead to fatal outcomes.

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Figure 34 Du¨ret hemorrhages. (A) Midline hemorrhage (black) due to compression from a cerebral hemisphere lesion on the left side of the figure. (B) Large midline hemorrhage (black) in the midbrain extending into the left tegmentum. There are smaller hemorrhages in the cerebral peduncles on both sides.

Figure 35 Computed tomography scan showing a large right cerebellar infarct (black arrow) compressing the brainstem. The cisterns around the brainstem are compressed and are obliterated on the scan. The temporal horns of the lateral ventricles are dilated (white arrows).

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REFERENCES 1. Kubik CS, Adams RD. Occlusion of the basilar artery: a clinical and pathological study. Brain 1946; 69:73 – 121. 2. Torvik A, Jorgenson L. Ischemic cerebrovascular diseases in an autopsy series. Part 2. Prevalence, location, pathogenesis, and clinical course of cerebral infarcts. J Neurol Sci 1969; 9:285 – 320. 3. Fisher CM, Adams RD. Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1951; 10:92 – 94. 4. Fisher CM, Adams RD. Observations on brain embolism with special reference to hemorrhagic infarction. In: Furlan AJ, ed. The Heart and Stroke. London: Springer-Verlag, 1987:17 –36. 5. Caplan LR. Brain embolism. In: Caplan LR, Hurst WH, Chimowitz MB, eds. Clinical Neurocardiology. New York: Marcel Dekker, 1999. 6. Ogata J, Yutani C, Imakita M, et al. Hemorrhagic infarct of the brain without a reopening of the occluded arteries in cardioembolic stroke. Stroke 1989; 20:876– 883. 7. Garcia J, Ho K-L, Caccamo DV. Intracerebral hemorrhage:pathology of selected topics. In: Kase CS, Caplan LR, eds. Intracerebral Hemorrhage. Boston: Butterworth-Heinemann, 1994:45 – 72. 8. Yamaguchi T, Minematsu K, Choki JI, Ikeda M. Clinical and neuroradiological analysis of thrombotic and embolic cerebral infarction. Jpn Circ 1984; 48:50 – 58. 9. Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic transformation in cerebral embolism. Stroke 1989; 20:598 – 603. 10. Pessin MS, Estol C, Lafranchise F, Caplan LR. Safety of anticoagulation after hemorrhagic infarction. Neurology 1993; 43:1298 – 1303. 11. Chaves CJ, Pessin MS, Caplan LR, et al. Cerebellar hemorrhagic infarction. Neurology 1996; 46:346 – 349. 12. Einhaupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597 –600. 13. Caplan LR. Venous and Dural Sinus Thrombosis in Posterior Circulation Ischemia: Clinical Findings, Diagnosis, and Management. Boston: Blackwell Science, 1996:569 – 592. 14. Caplan LR. Cerebral Venous Thrombosis in Caplan LR Stroke: A Clinical Approach. 3rd ed. Boston: Butterworth-Heinemann, 2000. 15. Mohr JP, Caplan LR, Melski JW, et al. The Harvard Cooperative Stroke Registry: a prospective registry. Neurology 1978; 28:754 –762. 16. Caplan LR, Hier DB, D’Cruz I. Cerebral embolism in the Michael Reese Stroke Registry. Stroke 1983; 14:530 – 536. 17. Bogousslavsky J, van Melle G, Regli F. The Lausanne Stroke Registry: Analysis of 1000 consecutive patients with first stroke. Stroke 1988; 19:1083– 1092. 18. Moulin T, Tatu L, Crepin-Leblond T, Chavot D, Berges S, Rumbach L. The Besancon Stroke Registry: an acute stroke registry of 2500 consecutive patients. Eur Neurol 1997; 38:10– 20. 19. Moulin T, Tatu L, Vuillier F, Berger E, Chavot D, Rumbach L. Role of a stroke data bank in evaluating cerebral infarction subtypes: patterns and outcome of 1776 consecutive patients from the Besancon Stroke Registry. Cerebrovasc Dis 2000; 10:261 – 271. 20. Vemmos K, Takis C, Georgilis K, Zakopoulos N, Lekakis J, Papamichael CM, Zis V, Stamatelopoulos S. The Athens Stroke Registry: results of a five-year hospital-based study. Cerebrovasc Dis 2000; 10:133 – 141. 21. Mas J-L, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740 – 1746. 22. Steiner MM, DiTullio MR, Runsek T, et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998; 29:944–948. 23. Dawson DM, Fischer EG. Neurologic complications of cardiac catheterization. Neurology 1977; 27:496 – 497. 24. Lockwood KI, Capraro J, Hanson M, Conomy J. Neurologic complications of cardiac catheterization. Neurology 1983; 33(suppl 2):143.

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25. Torvik A, Jorgenson L. Thrombotic and embolic occlusions of the carotid arteries in an autopsy material. Part l. Prevalence, location, and associated diseases. J Neurol Sci 1964; 1:24 – 39. 26. Gacs G, Merer FT, Bodosi M. Balloon catheter as a model of cerebral emboli in humans. Stroke 1982; 13:39 – 42. 27. Helgason C. Cardioembolic stroke topography and pathogenesis. Cerebrovasc Brain Metab Rev 1992; 4:28 – 58. 28. Caplan LR. Top of the basilar syndrome: selected clinical aspects. Neurology 1980; 30:72– 79. 29. Mehler MF. The rostral basilar artery syndrome: diagnosis, etiology, prognosis. Neurology 1989; 39:9 – 16. 30. Caplan LR. Posterior Circulation Disease: Clinical Findings, Diagnosis, and Management. Boston: Blackwell Science, 1996. 31. Bogousslavsky J, Cachin C, Regli F, et al. Cardiac sources of embolism and cerebral infarction. Clinical consequences and vascular concomitants. Neurology 1991; 41:855 – 859. 32. Timsit SG, Sacco RL, Mohr JP, et al. Brain infarction severity differs according to cardiac or arterial embolic source. Neurology 1993; 43:728– 733. 33. Lodder J, Krijne-Kubat B, Broekman J. Cerebral hemorrhagic infarction at autopsy: cardiac embolic cause and the relationship to the cause of death. Stroke 1986; 17:626 – 629. 34. Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 1986; 17:586 – 589. 35. Bladin CF, Seizures of the stroke MD thesis. University of Melbourne, Australia, 1997. 36. Hacke W, Scwab S, et al. Malignant MCA infarcts. Arch Neurol 1996; 53:309 – 315. 37. Amarenco P. Cerebellar stroke syndromes. In: Bogousslavsky J, Caplan LR, eds. Stroke Syndromes. Cambridge: Cambridge University Press, 1996:344 – 357. 38. Hornig CR, Rust DS, Busse O, et al. Space-occupying cerebellar infarction. Clinical course and prognosis. Stroke 1994; 25:372– 374. 39. Rieke K, Krieger D, Adams H-P, et al. Therapeutic strategies in space-occupying cerebellar infarction based on clinical, neuroradiological and neurophysiological data. Cerebrovasc Dis 1993; 3:45 – 55. 40. Krieger D, Busse O, Schramm J, et al. German-Austrian Space Occupying Cerebellar Infarction Study (GASCIS): study design, methods, patients’ characteristics. J Neurol 1992; 239:183 – 185. 41. Musselmann, Busse O, Jaucz M, et al. German-Austrian Space Occupying Cerebellar Stroke Study (GASCIS): a multicenter trial about space occupying cerebellar strokes. Cerebrovasc Dis 1995; 5:240. 42. Ropper AH. Lateral displacement of brain and level of consciousness in patients with acute hemispheral mass. N Engl J Med 1986; 314:53– 958. 43. Ropper AH. A preliminary MRI study of the geometry of brain displacement and level of consciousness with acute intracranial masses. Neurology 1989; 39:622 – 627. 44. Duret H. Traumatismes Cranio-cerebaux. Paris: Librarie Felix Alcan, 1919. 45. Caplan LR. Large Artery Occlusive Disease of the Anterior Circulation in Caplan’s Stroke: A Clinical Approach. Boston: Butterworth-Heinemann, 2000:165 –198.

4 Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Nearly always, the clinical presentation in patients with brain embolism relates to the recipient artery. Blockage of a recipient artery causes brain symptoms that can be persistent or transient. Factors that affect the outcome of the ischemic brain include: the size and nature of the embolic material; any proximal circulatory insufficiency (washout) (1); fragmentation and passage of the embolic material distally; resistance or susceptibility to ischemia of the brain tissue deprived of blood flow; collateral circulation; and perhaps other factors not well understood now.

GENERAL CLINICAL FEATURES AND DIAGNOSIS Early Clinical Course The most common and characteristic time course in patients with embolism to brain arteries is the very sudden onset of neurologic symptoms and signs that are maximal at onset. After an embolus blocks a recipient artery, collateral circulation begins to develop and some improvement may occur. The breakup and distal movement of an embolus strongly affect the subsequent clinical course. Movement of emboli is most common during the first 48 hours after the onset of symptom. In the Harvard Stroke Registry (HSR), angiography performed after 48 hours in patients with clinical brain embolism was often normal, but immediate angiography performed within hours after the onset of symptom nearly always showed embolic intracranial occlusions (2). Others have also shown a very high rate of angiographic detection of emboli when studies are performed within eight hours after the onset of stroke (3 –5). Transcranial Doppler monitoring of intracranial arteries after the onset of embolic strokes also shows a high frequency of the passage of emboli (6,7). Movement of emboli before the development of irreversible brain damage allows reperfusion of previously ischemic brain tissue and is often accompanied by clinical improvement in the symptoms and signs. However, in some patients, the embolus or its fragments block an important distal branch leading to further ischemia and worsening of symptoms. For example, a patient with an embolus to the left main-stem middle 61

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cerebral artery (MCA) might develop the sudden onset of right hemiplegia, hemisensory loss, and aphasia. When the embolus passes and the lenticulostriate arteries supplying the internal capsule and basal ganglia regions are reperfused, the right limb weakness might improve. Improved cortical blood flow might be accompanied by improvement in speech. However, if the embolus then passed into the superior division of the MCA or one of its branches, the hemiparesis and speech deficit could worsen. The weakness might be limited to the hand and face controlled by the precentral gyrus motor cortex regions supplied by cortical branches of the superior division of the MCA. If the embolus had passed instead into the inferior division of the MCA supplying the temporal lobe and occluded it or one of its branches, the patient might then have developed a fluent Wernicke-type aphasia. When worsening develops after initial clinical improvement in patients with brain embolism, it usually occurs in a single step and nearly always occurs during the first 48 hours. Multiple stepwise worsening, gradual smooth worsening, and delayed worsening are unusual. Late worsening after 48 hours should raise suspicion of hemorrhage into the area of infarction as hemorrhagic transformation often occurs between two and seven days after the onset of stroke. In patients with large brain infarcts, peri-infarct edema can lead to worsening. Edema usually becomes clinically apparent from two to four days after the onset. Table 1 shows the course of deficit in various stroke registries comparing patients with embolism and in situ thrombosis (2,8,9). Another pattern quite characteristic of brain embolism has been called “spectacular shrinking deficit” by Mohr (10). This term describes sudden, complete, or nearly complete clearing of a sudden onset of severe neurologic deficit. Most often, the patient has had a main-stem MCA or basilar artery embolus that rapidly passed. An example of each situation from my own personal experience will illustrate this syndrome, which is diagnostic of brain embolism. One evening, an 82-year old woman sneezed and suddenly became unresponsive. She was comatose when brought to the hospital. Her pupils were small and did not react to light. Her eyes were deviated down and inward. She did not respond to stimuli. Her electrocardiogram showed atrial fibrillation. The family was called and told that the situation was ominous and that she might be in a terminal coma and to prepare for the worst. Family members came to the hospital, witnessed her coma, and then went home. Computed tomography (CT) scan was performed and was normal. The next morning, the patient called home and requested her clothes and her toothbrush and berated the family for not bringing these things with them.

Table 1 Early Course of Deficit in Patients with In Situ Thrombosis Versus Embolism in Various Stroke Registries Thrombosis

Embolism

Course

HSR

MRSR

LSR

HSR

MRSR

LSR

Maximal at onset Stepwise/stuttering Progressive Gradual smooth Fluctuating

40% 34%

45% 30%

66%

79% 11%

89% 10%

82%

13% 13%

14% 11%

5% 5%

1%

27% 7%

13% 5%

Note: In the LSR, gradual smooth and stepwise/stuttering are considered as progressive. Abbreviations: HSR, Harvard Stroke Registry (2); MRSR, Michael Reese Stroke Registry (8); LSR, Lausanne Stroke Registry (9).

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A 65-year old man, while eating lunch, suddenly collapsed and was brought to the hospital. Examination showed a sleepy man who could be aroused. His eyes were conjugately deviated to the left. He did not speak; his right limbs were quite weak, and he did not respond to pin or pinch on his right limbs and body. He did not respond to or look at stimuli on his right side. CT scan was negative but transcranial Doppler ultrasound (TCD) showed no blood flow signal in the left MCA. The family saw his poor condition and was told that the outlook was grim. Suddenly, within an hour, the patient began to speak and move the right limbs, and he quickly returned almost to normal. Repeat TCD now showed normal left MCA blood flow velocities. Subsequent transesophageal echocardiography evaluation showed a thrombus within the left ventricle. The first patient had a “top of the basilar” artery embolus with temporary midbrain and thalamic stunning (11 – 13). The coma and abnormal pupillary responses and eye movement abnormalities were explained by ischemia within the rostral brainstem tegmentum. CT confirmed that the upper brainstem dysfunction was not caused by pressure from a large hemispheric lesion with herniation and that there was no infarction in the upper brainstem. The embolus passed sometimes during the night. The second patient had a main stem left MCA embolus, which caused severe but transient dysfunction of the supply zone of that artery. The TCD confirmed blockage of the MCA, but CT showed no infarction. The left hemisphere was temporarily stunned, that is, not receiving enough blood containing oxygen and sugar to function normally, but was not sufficiently deprived of fuel to develop irreversible damage. Passage of the embolus allowed rapid recovery of left cerebral hemisphere brain function. In one clinical study from Japan, among 118 patients who had the abrupt onset of neurological signs, 14 had rapid clearing of their signs within 24 hours, and in 10, the deficit cleared within four hours (14). All the 14 patients, who had spectacular shrinking deficits, had cardiogenic embolism. Angiography in this series showed migration of emboli in the patients with these shrinking deficits (14). Transient Ischemic Attacks Temporary deficits that qualify as transient ischemic attacks (TIAs) do occur in some patients with brain embolism. In patients with arterial sources of emboli, the attacks are always in the supply territory of the affected artery. For example, a patient with severe atherosclerotic stenosis of the right internal carotid artery (ICA) might have attacks of right monocular visual loss and/or spells of numbness or weakness of the left arm, hand, face, or leg. A patient with right vertebral artery stenosis might have attacks of double vision, dizziness, and staggering. In patients with cardiogenic or aortic origin embolism, when attacks occur, they are random and involve different vascular territories. One of my patients awakened one night to urinate, and after urinating developed weakness and numbness of his left arm and leg. By the next morning, the symptoms had cleared and he was able to use his left limbs normally. He did not tell his wife or a doctor. He had been feeling poorly for weeks with night sweats and fever, symptoms that he also concealed from others. The very next night, he again arose to urinate and now found that his right hand was weak. His wife heard him return to bed and noted that his voice was slurred and his speech did not make good sense. By the next morning, when she brought him to the doctor, he had almost returned to normal. CT scan showed a small left precentral gyrus infarct. The doctor was unsure whether the patient might have been confused about the side involved in the first occurrence and ordered noninvasive vascular studies of the extracranial and intracranial carotid and vertebral artery circulations, which were normal. Subsequent testing showed that the patient

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had bacterial endocarditis and probably had two emboli, one to the right and the other to the left cerebral hemispheres. The definition of a TIA, usually cited, is that of a transient focal deficit that clears within 24 hours. This definition is quite arbitrary, and, in fact, most TIAs clear within one hour (15 – 20). Despite the fact that the symptoms are transient, CT and magnetic resonance imaging (MRI) often show infarcts in regions of the brain appropriate to the symptoms (15 – 18). The longer that symptoms last, the more likely that a brain infarct will be present on CT or MRI scanning (17). Patients with transient focal symptoms and patients with symptoms that persist have potentially serious cerebrovascular, cardiac, or hematological conditions and are at risk for further strokes. Brain ischemia deserves a thorough evaluation irrespective of the timing of clinical symptoms (15,18 –20). Activity at the Onset of Symptoms In the past, clinicians thought that strokes due to in situ thrombosis usually developed upon arising from sleep or after a nap, thrombosis having occurred while the circulation is most sluggish. In contrast, strokes related to hemorrhage and embolism were posited to occur during vigorous activity. Activity is thought to provoke leakage of blood from fragile vessels and vessels damaged by hypertension and to “shake loose” potential emboli from their nests. Studies, however, show that most strokes develop during the morning hours between 10 am and noon, after awakening, and after daily activities have begun, and not during sleep (21). In various stroke registries, activity at the onset was not helpful in differentiating between the various stroke mechanisms (2,8). Most strokes occurred during daily activities. In the Michael Reese Stroke Registry (MRSR) only 5% of emboli and 1% of thrombotic and lacunar strokes began during vigorous physical activity or stress (8). Occasionally, a vigorous sneeze or cough or sudden strong body movement precipitates embolism, although the frequency of this occurrence is relatively low. Emboli also seem to occur more often than chance after awakening at night to urinate, a so-called “matutinal” (morning) embolus. Systemic Embolism Necropsy studies of patients with cardiac origin brain embolism nearly always show embolic infarcts in other systemic organs, especially the spleen and kidneys (22). In contrast, the frequency of clinical recognition of systemic embolism is quite low. In various stroke registries, the frequency of diagnosis of systemic embolism was: 2% HSR (2), 2.3% MRSR (8), 3.6% Stroke Data Bank (SDB) (23), 3% Lausanne Stroke Registry (LSR) (9). The highest frequency of systemic embolism, 8%, was found in a study of 60 patients who had cardiogenic brain embolism, in which two patients had kidney and three had peripheral limb embolism (24). Embolism to the brain that causes ischemia almost invariably leads to transient or persistent symptoms. The brain is like litmus paper, very sensitive to perturbations. Systemic embolism also causes ischemia, but the symptoms are much less specific. Embolism to a limb might cause arm pain, a leg cramp, or other transient discomfort, symptoms that are very common and usually are explained by activity, positioning of the limb, or some other banal everyday occurrence. Similarly, embolism to the intestinal tract might cause stomach cramps, bowel irregularity, a bellyache—rather common and nonspecific symptoms. Embolism to the kidneys or spleen causes flank or abdominal discomfort rarely diagnosed as due to systemic embolism. Hematuria and the sudden

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onset of severe limb ischemia are probably the only two occurrences that usually lead to recognition of systemic embolism, especially in patients with known heart disease. Headache Headache is an extremely common symptom among stroke patients. Although brain tissue contains no pain sensitive afferent nerve fibers, the vessel walls and meninges contain many pain-sensitive nerve endings. Stretching and dilatation of arteries on the brain surface and in the neck often cause head and neck discomfort and headache. The frequency and causes of headache vary depending on the stroke mechanism. Some headaches are caused by mass effect caused by large brain infarcts with surrounding brain edema or by hemorrhages within the brain parenchyma. Irritation of the meninges by blood causes headache in patients with subarachnoid hemorrhage (SAH). In embolism related to bacterial endocarditis, meningeal seeding by bacteria can be the cause of headache. In patients, who have intracranial large artery occlusions, headache may be due to distention of occluded arteries by clot, dilatation of collateral arteries, and tears within arterial walls. Table 2 lists the frequencies of headache at or near the onset of stroke in various stroke registries and series (2,8,9,25,26). Headache is most frequently reported in patients with intracerebral hemorrhage. Patients with brain embolism have headache more often than patients with lacunar infarcts caused by penetrating artery disease but less often than patients with occlusive disease of large extracranial and intracranial arteries. Patients with SAH may have episodes in which a small amount of blood leaks into the subarachnoid space causing what has been referred to as a “sentinel” headache. Frequent dull or throbbing headaches are often present in the days or weeks before ischemic stroke in patients with large artery thrombosis. These are due to distention of occluded arteries as well as dilated collateral arteries. Headaches are rarely noted before brain embolism except when the donor source is a large extracranial artery. Seizures Seizures at or near the onset of stroke are very uncommon in patients with ischemic strokes irrespective of cause. Seizures are more common in patients with intracerebral and subarachnoid hemorrhages than in patients with ischemic strokes, irrespective of the mechanism of the brain ischemia. In the HSR, 4% of patients with brain embolism had seizures early in their clinical course, as compared to 0.3% of patients with large artery in situ occlusions (2). No patient with lacunar infarction in the HSR had an early seizure, an

Table 2 Headache At or Near the Time of Onset Among Various Stroke Types in Various Stroke Registries

Registry Harvard (2) Lausanne (9) Stroke Data Bank (25) Michael Reese – Illinois (8,26) Note: % of patients.

Large artery thrombosis

Embolism

Lacunar infarction

Intracerebral hemorrhage

12% 17% 11% 26%

9% 18% 10% 14%

3% 7% 5% 6%

33% 40% 41% 55%

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expected finding because lacunes are, by definition, small and deep and not likely to cause cortical irritation (2). In the SDB, only 3.1% of patients with cardiac-origin embolism had seizures during the acute hospitalization (27), and no patient with presumed brain embolism in the LSR had early seizures (9). In a thesis that analyzed the development of seizures among 770 patients with firstever symptomatic supratentorial brain infarcts in the Maastricht stroke registry, the presence of cardiac-origin embolism meant that the patient had a relative risk of 5.14 of developing an early-onset seizure, compared to patients without cardiogenic embolism (28). Among 2000 stroke patients in another large series, patients with hemorrhagic infarcts and large infarcts were most likely to have seizures. The average size of infarcts in patients with seizures was 76.7 cm3 versus 45.6 cm3 in patients who did not have seizures (29). In this series, 40% of the seizures in stroke patients occurred during the first day and 51% during the first week; 96% of poststroke seizures occurred during the first year after stroke (29). Seizures near the time of the onset of stroke symptoms are probably more common in patients with embolism than in nonembolic causes of ischemic stroke. However, seizures are too infrequent in any subtype of ischemic stroke to be of much help in differential diagnosis.

Decreased Level of Consciousness Early decrease in the level of consciousness in ischemic stroke patients is most often due to acute brainstem tegmental ischemia related to embolism to the basilar artery (11 – 13). Decreased consciousness can also result from major hemispheral ischemia caused by sudden occlusion of the major blood supply of either hemisphere. Later in the course, during days 3 –7, persistent loss of consciousness is usually explained by brain edema and the mass effect of large cerebellar and cerebral infarcts. Transient loss of consciousness is most often seizure related or due to a cardiac arrhythmia. Few studies have analyzed the frequency of loss of consciousness at or near the time of stroke. In the SDB, decreased consciousness early in the stroke was present in 29.8% of patients with embolism of cardiac origin, compared to a 6.1% frequency in patients with artery-to-artery brain embolism (27). Decreased consciousness at or near the time of stroke is more common in patients with embolic occlusions than in other causes of ischemic stroke and is more common in patients with cardiac origin embolism than in those with proximal arterial sources. The larger size of emboli of cardiac origin, as compared with emboli of arterial origin, is the probable explanation for the difference.

Clinical Patterns of Neurologic Symptoms Neurological diagnoses are often made by pattern matching. Clinicians match the findings in any given patient with those usually found in patients with lesions affecting certain anatomical regions. Lesions in specific anatomical loci, in turn, are associated with occlusions of the various feeding arteries. Table 3 shows the most common brain and vascular locations of cardio-embolic infarcts in the LSR (30). Each of these locations has characteristic clinical findings. Because the findings in patients with posterior circulation embolism are less well known, I will devote more discussion to the symptoms and signs in the vertebro-basilar territory. Some necropsy specimens and imaging scans of infarcts in various vascular territories preferentially affected by embolism have been shown in Chapter 3. Please refer to these as the various syndromes discussed.

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Table 3 Topography of Infarcts in the Lausanne Stroke Registry in Patients with Potential Cardiac Sources of Embolism Anterior circulation Global MCA Superior division MCA Inferior division MCA Deep subcortical ACA ACA and MCA together Posterior circulation Brainstem Thalamus (deep PCA) Superficial PCA Superficial and deep PCA Cerebellum

213 (70%) 33 (11%) 60 (20%) 54 (18%) 56 (18%) 9 (3%) 1 (0.3%) 69 (23%) 18 (6%) 12 (4%) 21 (7%) 3 (1%) 10 (3%)

Abbreviations: MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral arteries.

ANTERIOR CAROTID ARTERY CIRCULATION EMBOLISM Main-Stem MCA Territory Ischemia and Infarcts Among all series, the great majority of emboli are found within the MCAs and their branches. Large emboli may block the main-stem MCA near its origin, leading to infarction of the entire territory of the cerebral hemisphere supplied by the MCA. This includes the basal ganglia (caudate and putamen) and the frontal, temporal, and parietal lobar white and gray matter supplied by the MCA. The clinical deficits in these patients are very severe, and most patients die. Rarely, patients survive but remain severely and permanently disabled. These very large infarcts are often referred to as malignant MCA territory infarcts. Consciousness is reduced. The eyes usually rest conjugately towards the side of the infarct. The contralateral limbs are paralyzed and insensitive to pin stimulation or pinch. Although the patient may attend to voices, visual objects, and people situated on the same side of space as the brain infarct, they often will ignore identical stimuli on the contralateral side of space. When the left MCA is occluded, patients do not speak or heed directions or queries. Within the first 24 to 48 hours, stupor deepens, then coma develops, and the patient often dies without decompressive surgery. Occasionally, patients with main-stem MCA emboli who have very severe clinical signs, rapidly, almost miraculously, recover (14). This, so-called “spectacular shrinking deficit” is due to reperfusion of brain that was reversibly ischemic (“stunned”). CT and MRI brain scans and vascular imaging tests can be helpful in predicting the prognosis for recovery. The presence of early signs of infarction bodes poorly for recovery. When the CT or MRI scan are normal initially, the prognosis is more hopeful. Occlusion of the MCA proximal to the lenticulostriate branches sometimes produces an infarct that includes the deep basal ganglionic and capsular territory as well as superficial MCA territory. This pattern of infarction, involvement of superficial and deep MCA territory, was found in more than half of the patients in the SDB series with cardiac-origin embolism (27). These patients with large superficial and deep MCA territory infarcts invariably have a hemiparesis involving the face, arm, and leg on the side contralateral to the lesion. They also usually have some degree of hemisensory loss. Conjugate eye deviation and inattention to the contralateral side of visual space are variable findings

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that depend on the size of the infarct and its distribution in the white matter and cerebral cortex. Cortical function abnormalities, such as aphasia, abnormal drawing and copying, visual neglect, and lack of awareness of the neurological deficit, depend on the location and extent of cortical infarction and whether the left or the right cerebral hemisphere is involved. Striatocapsular (Deep MCA Territory) Ischemia Basal ganglia and internal capsule infarction is usually due to embolic occlusion of the main-stem MCA before its lenticulostriate branches. There is excellent potential for collateral circulation over the convexities but poor collateral circulation in the deep basal gray nuclei and the internal capsule. For this reason, some patients with MCA occlusion have selective ischemia of the deep lenticulostriate territory (“striatocapsular infarcts”) (31). Patients with striatocapsular ischemia are invariably hemiparetic, but the distribution of weakness in face, arm, and leg varies. Sensory loss is usually minor, because the posterior portion of the internal capsule is spared. When the lesion is in the left hemisphere, after a short period of temporary mutism, speech is sparse and dysarthric, but repetition of spoken language is preserved. Comprehension of spoken and written language depends on both the size and the anteroposterior extent of the lesion. When the right hemisphere is involved, there often is neglect of contralateral visual and tactile stimuli, usually more transient than with parietal lobe cortical infarction. Superior Division MCA Ischemia The superior trunk of the MCA supplies the frontal and superior parietal lobes. Ischemia is most often due to embolism to the superior division but in situ narrowing does occasionally occur. The neurological signs include hemiplegia, more severe in the face and hand and upper extremity, with relative sparing of the lower extremity; hemisensory loss, usually including decreased pinprick and position sense, sometimes sparing the leg; conjugate eye deviation, the eyes resting toward the side of the brain lesion; and neglect of the contralateral side of space, especially to visual stimuli. Visual neglect is usually more severe in patients with right-hemisphere lesions. When the lesion is in the left, dominant hemisphere, there is invariably an accompanying aphasia. Verbal output is sparse, and the patients do not do what they are asked with either hand, although they may follow whole-body commands. They may nod appropriately to “yes/no” questions asked verbally, but comprehension of written material is poor. With time, a pattern of Broca’s aphasia evolves, with sparse, effortful speech, poor pronunciation of syllables, and omission of small words (such as prepositions) but preserved comprehension of spoken language. This type of speech has been called “telegraphic,” as small words were often omitted in telegrams for economy. In superior-division right-hemisphere MCA infarcts, patients frequently seem unaware of their deficit (anosognosia) and may not admit that they are hemiplegic or impaired in any way. Some patients are also “impersistent” (32,33), performing requested tasks quickly but terminating them prematurely. They may also fail to detect “body signals” repetitive speech intonations, and accents and so do not pick up the mood and tone of verbal communications (33,34). These nonlinguistic aspects of speech are often referred to as “prosody.” Inferior Divison of the MCA Ischemia Ischemia is almost entirely due to embolism to this arterial territory. In contrast to patients with lesions of the superior division, these patients usually have no elementary motor or

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sensory signs. They often have visual field defects, either hemianopia or upperquadrantanopia, affecting the contralateral visual field. When the left hemisphere is involved, patients have a Wernicke-type aphasia. Speech is fluent and syllables are well pronounced, but patients use wrong or nonexistent words, and what is said makes little sense. Comprehension and repetition of spoken language are poor. There may be relative sparing of written comprehension, with the patient preferring that words be written. When the right hemisphere is affected, patients draw and copy poorly and may have difficulty finding their way about or reading maps (33). Behavioral abnormalities often accompany temporal-lobe infarctions. Patients with Wernicke’s aphasia are often irascible, paranoid, and may become aggressive. Patients with right temporal infarcts often have an agitated hyperactive state resembling delirium tremens. The key findings in patients with right inferior MCA division infarcts are a left visual-field defect, poor drawing and copying, and agitation and restlessness (35). Anterior Cerebral Artery Ischemia Intrinsic occlusive disease of the anterior cerebral artery (ACA) is unusual. Most ACA territory infarcts are caused by embolism from the heart or the ipsilateral ICA. Most patients with intrinsic disease of the ACA also have extensive ICA and MCA disease, often with multiple infarcts. Some ACA-territory infarcts are due to occlusive disease of the ICA and others are caused by vasospasm-related ischemia in patients with SAH due to anterior communicating artery aneurysms. The single most important clue to an ACA-territory infarct is the distribution of motor weakness (36). Paralysis is usually greatest in the contralateral foot but is also severe in the proximal thigh. Shoulder shrug is weak on the involved side, but the hand and face are usually normal if the deep ACA territory is spared. Some patients with anterior or large ACA territory infarcts have a hemiplegia. Cortical sensory loss is also present in the weak limbs but is usually slight. A grasp refex is often present in the hand contralateral to the infarct. When the infarct involves the left ACA territory and the supplementary motor cortex, a transcortical motor and sensory aphasia often results. These patients have limited spontaneous speech and may have poor comprehension but retain the ability to repeat spoken words and phrases. Occasionally, patients have the sudden development of bilateral ACA territory infarction explained by hypoplasia or absence of the A1 segment of the ACA on one side. In that circumstance, the territories of the ACA on both sides are supplied by one ACA. Occlusion of the ICA or ACA supplying both sides leads to bilateral frontal-lobe infarction. The resulting clinical picture is that of sudden apathy, abulia, and incontinence. Patients may become relatively motionless and mute. When the paracentral lobule is involved, there is weakness on one or both sides, predominantly affecting the lower extremities. Anterior Choroidal Artery Territory Ischemia Many patients with anterior choroidal artery (AChA) territory infarcts are diabetic or hypertensive. Most often, infarction in AChA territory is due to occlusion of the AChA. Carotid artery occlusion, vasospasm in patients with carotid artery aneurysms, and carotid artery-origin and cardiac-origin embolism occasionally cause AChA teritory infarction, often coupled with MCA territory infarcts. The syndrome of the AChA includes: (i) hemiparesis affecting face, arm, and leg, (ii) prominent hemisensory loss, which is often temporary, (iii) homonymous hemianopia, (iv) when the lateral geniculate body is infarcted, an unusual hemianopia occurs, with sparing of a beak-shaped tongue of

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vision within the center of the hemianopic visual field, and (v) absence of important persistent neglect, aphasia, or other higher cortical-function abnormalities (37,38). Hemiparesis is the most consistent finding. Dysarthria and hemisensory abnormalities are less often present and usually do not persist. Hemianopia is the least common sign. Some patients with bilateral AChA territory capsular infarcts have severe dysarthria and may even become mute. POSTERIOR CIRCULATION VERTEBRO-BASILAR ARTERIES EMBOLISM About one-fifth of emboli go into one of the vertebral arteries and enter the intracranial posterior circulation arteries. The most common clinical patterns of symptoms occur in patients with posterior cerebral arteries (PCA), cerebellar, and top of the basilar territory infarctions (11 – 13). Emboli most often go to the most distal portion of the vertebro-basilar system. Emboli may block one of the intracranial vertebral arteries (ICVAs), causing infarction in the posterior undersurface of the cerebellum in the territory of the posterior inferior cerebellar artery (PICA) branch of the ICVA. As the basilar artery is wider at its origin, having been formed by the confluence of the smaller ICVAs, emboli that pass through the vertebral arteries do not usually become lodged until they reach the distal end of the basilar artery and its branches. The resulting infarcts can be localized to: (i) a unilateral PCA territory in the occipital and temporal lobes, (ii) bilateral PCA territory, (iii) superior cerebellar artery (SCA) territory, (iv) midbrain and thalamic territories supplied by penetrating branches arising from the rostral basilar artery, or (v) combinations of (i) to (iv). Posterior Cerebral Artery Territory Infarcts The most common finding in patients with unilateral PCA territory infarction is a hemianopia (39,40). Hemianopia is due to infarction of the striate visual cortex on the banks of the calcarine fissure, a region supplied by the calcarine branch of the PCA, or is explained by interruption of the geniculocalcarine tract as it courses toward the visual cortex. 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 lobe cortex, patients are fully aware of the visual defect. Usually described as a void, a blackness, or limited vision to one side, patients usually recognize that they must give 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—a so-called macular sparing. Optokinetic nystagmus is normal. Although they accurately report motion or the presence of objects in their hemianopic field, some patients cannot identify the nature, location, or color of that object. When the full PCA territory is involved, visual neglect can accompany the hemianopia. Some patients with PCA territory embolic infarcts also have sensory symptoms on the same side of the body as the visual field defect. This is explained by ischemia to the major somatosensory relay nuclei, the ventral posteromedial and -lateral (VPM and VPL)

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nuclei that are located in the ventrolateral portion of the thalamus. Occlusion of the proximal PCA interupts flows to this portion of the thalamus supplied by the thalamogeniculate branches (41). Ischemia to these nuclei or to the white matter tracts carrying fibers from the thalamus to somatosensory cortex (postcentral gyrus and the Sensory 2 region in the parietal operculum) produces changes in sensation, usually without paralysis. Patients report paresthesias or numbness in the face, limbs, and the trunk. On examination, their touch, pinprick, and position senses are 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. Rarely, occlusion of the proximal portion of the PCA can cause a hemiplegia (13,42). Penetrating branches from the most proximal portion of the PCA penetrate into the midbrain to supply the cerebral peduncle. Proximal PCA occlusions cause hemiplegia because of midbrain peduncular infarction, accompanied by a hemisensory loss owing to lateral thalamic infarction and hemianopia owing to occipital lobe infarction. The resultant neurological deficit is not easily distinguished clinically from MCA and AChA territory infarcts, but separation is made readily by CT and MRI results. When the left PCA territory is infarcted, several additional findings may occur (13,43 –45). Alexia Without Agraphia Infarction of the left occipital lobe and splenium of the corpus callosum are associated with a remarkable clinical syndrome first described by Dejerine in 1892 (46). Because the left visual cortex is infarcted, patients see with their right occipital lobe and their left visual field. In order to name what they see, the information must be communicated from the right occipital cortex to the language region in the left temporal and parietal lobes. Infarction of the corpus callosum or adjacent white matter pathways interrupts communication between the right occipital cerebral visual cortex and the left cerebral hemisphere. Patients have difficulty naming what they see. The most obvious abnormality is in reading. Although usually able to name individual letters or numbers, patients cannot read words or phrases. Because the speech cortex is normal, they retain the ability to speak, repeat speech, and write. They can spell words aloud and name words spelled to them. Although they are able to write a paragraph, they often cannot read it back moments later. Usually accompanying the dyslexia is a defect in naming colors. Patients can match colors and shades, proving that their perception of colors is normal. They can also describe the usual color of familiar objects and can even color correctly when given an array of crayons. Nonetheless, when shown a colored object, they cannot name the color (13,44,46 –48). Anomic and Transcortical Sensory Aphasia Some patients with left PCA-territory infarction have difficulty naming objects that they recognize and can identify their use and others can repeat but not understand spoken language (13,44,49). Gerstmann’s Syndrome PCA-territory infarction can undercut the angular gyrus, leading to a number of diverse findings, usually lumped together as Gerstmann’s syndrome. These abnormalities include difficulty in distinguishing right from left; difficulty in naming digits on their own or on others’ hands; difficulty in drawing objects from memory; agraphia; and

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difficulty in calculating. In any single patient, all features may appear together or one or more may occur in isolation (13). Altered Memory A defect in acquisition of new memories is common when both medial temporal lobes are damaged and also occurs in lesions limited to the left temporal lobe (13,47,48,50,51). The memory deficit in patients who have unilateral temporal lobe lesions is usually not permanent but has lasted up to six 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 a few minutes before. Other Deficits Some patients with left PCA-territory infarction have difficulty in understanding the nature and use of objects presented visually. They can trace with their fingers and copy objects, showing that visual perception is preserved. They can often name objects if the objects are presented in their hand exploring by touch or when described verbally, despite not being able to name or identify objects that they see. The explanation is similar to that of alexia without agraphia. The patients cannot get the visual information to the speech cortex (13,44,48). Infarcts of the right PCA territory are often accompanied by prosopagnosia, difficulty in recognizing familiar faces (13,44,52). At times, patients cannot recognize their own spouses, their children, or even their own images in a mirror. Disorientation to place and an inability to recall routes or to read or revisualize the location of places on maps are also found in some in patients with right PCA-territory infarcts (13,44,53). Patients with infarcts that involve the right occipital and temporal lobes also may have difficulty revisualizing a given object or a person. Dreams may also be devoid of visual imagery. Neglect of visual objects located in the opposite side of space is much more common after lesions of the right than of the left PCA territory. When the PCA territory is infarcted bilaterally, the commonest findings are cortical blindness, amnesia, and agitated delirium (13,44). Most often, bilateral PCA territory infarction is due to embolism, with blockage of the distal basilar artery bifurcation. Cortically blind patients cannot see or identify objects in either visual field but have preserved pupillary light reflexes. Some patients with cortical blindness do not volunteer or admit that they cannot see and seem to avoid barriers in their way. Amnesia due to bilateral medial temporal-lobe infarction may be permanent and closely resembles Korsakoff’s syndrome. Also, infarcting the hippocampus, fusiform, and lingual gyri, usually bilaterally, leads to an agitated hyperactive state that can be confused with delirium tremens (13,54). When infarction is limited to the lower banks of the calcarine fissures bilaterally, the major findings are prosopagnosia and defective color vision (13,44,55,56). “Top-Of-The-Basilar” Ischemia 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. In most patients, infarction is limited to either brainstem or hemispheral structures. The major abnormalities associated with rostral brainstem infarction relate to abnormalities of alertness, behavior, memory, and oculomotor and pupillary functions (11– 13).

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The most common abnormalities of eye position and movement involve vertical gaze and convergence. Patients may be unable to look up and down. Voluntary eye movements in the vertical plane are generated by simultaneous activation of the cerebral hemispheral gaze centers. Vertical gaze pathways converge on the periaqueductal gray region of the midbrain that contains a group of nerve cells referred to as the rostral interstitial nucleus of the medial longitudinal fasciculus (RIMLF). In some patients, who cannot look up or down on command, vertical eye movements can be obtained by passive movement of the neck up and down or by simultaneous instillation of warm or cold water into both ear canals. The pathways that control up and down gaze are not identical. Either up gaze or down gaze can be selectively involved, but in most patients, both directions of vertical gaze are involved together. Occasionally, only one eye fails to move up and/or down. Asymetric or unilateral lesions in the midbrain tegmentum and posterior thalami can cause ocular tilt reactions that are contraversive, that is, the contralateral eye and ear are displaced below their opposite counterparts. The abnormalities include skew deviation, ocular torsion, and abnormalities of the estimation of the visual vertical (57 –59). At times, very small amplitude lightening-like movements occur spontaneously and on attempted horizontal and vertical gaze. Convergence abnormalities are also very common in patients with rostral midbrain lesions. Usually, one or both eyes are hyperconverged, as if there was increased tone or overactivity of structures that control the coordination of bilateral ocular adduction that we call convergence. The hyperconvergence may be unilateral or bilateral, so that one or both eyes may rest inward or down and inward at rest. When patients tried to gaze up, their eyes may show adductor contractions causing convergence movements. Asking patients to peer inward at the tip of their nose or at the examiner’s finger placed at a near fixation site often leads to a further increase in the convergence and may provoke some bilateral synchronous adductor movements of the eyes. Having the patient watch an upwardly directed optokinetic striped tape also stimulates convergence movements. Some call the bilateral convergence movements “retractory nystagmus,” but the movements are not true nystagmus and do not usually cause significant retraction of the globe, although observation of the eyes superficially gives that impression. The increased tone and activity of adductor movements are probably responsible for the so-called pseudosixth phenomenon (11,13,43). This term has been used to describe failure of full abduction on lateral gaze in patients with upper brainstem lesions in the absence of a lesion that could affect the sixth nerve whose nucleus and fibers are located much lower in the brainstem in the pons. Pseudosixth palsy can be unilateral or bilateral. A close inspection of the eye movements in the abducting eye shows that there are often inward-directed small movements of the eye as it abducts. Often the contralateral eye is hyperadducted. Covering the contralateral hyperadducted eye and asking the patient to look further laterally sometimes enable further abduction excursion of the open eye. There are two different phenomena that explain the failure of the ocular abduction in this syndrome: (i) dysconjugate gaze with fixation by the hyperadducted eye. When the patient looks laterally, they first fixate with the hyperadducted eye. This fixation will stop any further lateral eye movement as the patient has already fixated on the object with the adducted eye. Covering the hyperadducted eye then encourages fixation with the abducting eye. And (ii) convergence vectors counter and neutralize the lateral excursion of the eye. The sum of the laterally directed gaze vector and the inwardly directed convergence vector is less than full abduction. 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

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posterior commissure (60). In some patients, both lids are retracted but one side 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 nuclei. A combination of diencephalic and midbrain lesions cause midposition fixed pupils. In midbrain lesions, the pupil may become eccentric (“corectopia”) (11,13,61) or assume an oval position (11,13,62). Eccentricity can be transient and fluctuate from minute to minute. Abnormalities of alertness and behavior are common in patients with rostral brainstem infarcts. Lesions that include the reticular activating system in the rostral brainstem most often produce hypersomnolence rather than coma. The reticular-activating system courses through the tegmental regions on both sides of the sylvan aqueduct and the banks of the third ventricle. This region is perfused by the thalamic subthalamic arteries (also called the thalamoperforating arteries) and the paramedian mesencephalic arteries that branch from the apex of the basilar artery and the initial portion of the basilarcommunicating artery (mesencephalic artery). Butterfly-shaped bilateral rostral midbrain periaqueductal lesions as shown in Fig. 28 in Chapter 3 caused by the top-of-the-basilar artery embolism can cause both prolonged hypersomnolence and third nerve palsies (11,13,63,64). Apathy and inertia are also commonly found (65). Some patients show very little spontaneity and activity. Abnormal reports and hallucinations probably relate to the altered sleep – wake dreaming cycle present in patients with rostral basilar artery territory infarction (11,13). Reports often consist of replies to queries that have no relation to reality. The patients may mislocate themselves, giving the names of distant geographical locations, and in the personal time dimension, saying that they were presently performing activities that they only had done in their childhood, adolescence, or much earlier in their adult life. Some patients act as if they are performing an activity, for example, talking on the telephone when there is no phone nearby. These reports and behaviors probably represent what they were daydreaming about at the time. Some may recall nocturnal dreaming. The reticular activating system and the neural substrates that control the sleep –wake cycle and dreaming are all intimately related. Clouding of the distinction between dreams and reality may explain some of the unusual reports and behaviors in patients with rostral brainstem infarction. So-called peduncular hallucinations have long been recognized and described in patients with rostral brainstem lesions (11,13). The term pedonculaire was used by the French to refer to the general region of the midbrain and not just the cerebral peduncle. Hallucinations can also occur in patients with thalamic lesions. The hallucinations are predominantly visual but there may be some minor tactile and auditory components. The visual hallucinations are often quite vivid and contain multiple colors, objects, and scenes. The hallucinations occur predominantly after sundown and are sometimes quite frightening to the patient. Some patients with rostral 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 nonverbal memory. Amnesia has developed in patients with infarction in the antero-lateral thalamic territory supplied by the polar (tubero-thalamic) artery as well as in the territory of the thalamicsubthalamic artery (13,36,66,67). Patients with left thalamic infarcts may have more difficulty with memory for language-related activities, whereas patients with right thalamic lesions may have more difficulty with visual-spatial memory tasks. In patients with top-ofthe-basilar embolism, both territories in the medial thalamus are often infarcted. Patients

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with polar territory infarcts show more decrease in spontaneity and abulia. They have difficulty generating lists of common objects, for example, colors, items of clothing, fruits, vegetables, cities in their state, etc. Patients with infarction of the thalamic-subthalamic artery territory, especially when bilateral, have severe deficits in anterograde memory formation and some retrograde amnesia. Sensory and motor abnormalities are usually absent in patients with top-of-thebasilar territory infarction unless the proximal PCAs are also occluded. Movement disorders, especially, hemiballism have been described in some patients with small infarcts and hemorrhages involving the subthalamic nuclei, but hemiballism is extremely rare in patients with well documented top-of-the-basilar territory infarcts.

Cerebellar Infarcts Large cerebellar infarcts are predominantly caused by embolism. Emboli often reach the SCA, which lies very near the top-of-the-basilar artery. These emboli arise from the heart, aorta, or the extracranial or ICVAs. Emboli from the heart, aorta, and vertebral artery in the neck often block the intracranial vertebral artery leading to an infarct in the territory of the PICA, which is the largest branch of the intracranial vertebral artery on each side. Occasional patients have both PICA and SCA territory cerebellar infarcts, an embolus having rested first at the level of the intracranial vertebral artery, causing a PICA territory infarct, and then traveled distally to the SCA. Alternatively, a thrombus or occlusive lesion in the intracranial vertebral artery could have caused the PICA territory infarct and then been the donor source of an SCA embolus.

Superior Cerebellar Artery Territory Infarction Isolated SCA territory infarcts are not common; 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. The symptoms and signs in patients with partial SCA territory infarcts are less severe and disabling than those in other cerebellar artery territories and can easily be overlooked clinically. The classic SCA syndrome is said to consist of: ipsilateral limb ataxia; ipsilateral Horner’s syndrome; contralateral loss of pain and temperature sensibility of the face, arm, leg, and trunk; contralateral fourth nerve palsy (13,68 –70). Abnormal spontaneous involuntary movements of the limbs on the ipsilateral side also occur. The classic syndrome is present when the pontine and midbrain tegmentum and superior cerebellar surface are both infarcted. The full syndrome is rare. Some patients with SCA territory cerebellar infarcts have relatively minor symptoms of sudden onset with rapid improvement. 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 PICA territory cerebellar infarcts. The lateral cerebellar hemispheres are related predominantly to limb movements under voluntary control, whereas the vermis relates more to posture, stance, trunk movements, and gait. The dentate nucleus is the major outflow tract of the cerebellum for modulating voluntary limb movements. The dentate nucleus and surrounding cerebellar white matter are supplied by SCA branches. SCA territory infarcts may involve the superior vermis and a sizable portion of the hemisphere, in addition to the dentate nuclei explaining the frequent occurrence of both limb and gait ataxia in patients with SCA territory infarcts.

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SCA territory infarcts can involve the entire SCA territory, including the rostral pontine and midbrain tegmentum and the SCA supplied cerebellum, or can involve the full cerebellar territory but spare the brain stem or be limited to territory supplied by the medial (mSCA) or lateral (lSCA) branches of the SCA. The bilateral SCA territories may be involved. SCA territory infarcts are often accompanied by PCA and midbrain and thalamic infarcts in territories supplied by other branches of the rostral basilar artery. Branch infarcts are much more common than full SCA territory infarcts (69 –72). The clinical findings depend very much on whether the brainstem territory of the SCA is involved and whether infarction is limited to SCA teritory or also includes structures supplied by other rostral basilar artery branches. Large, full SCA cerebellar infarcts can produce a pseudotumoral syndrome but do so less often than full PICA territory infarcts. Stupor and symptoms of hydrocephalus are only rarely found in patients with infarcts limited to the SCA cerebellar territory. Branch infarcts have been less often analyzed in the SCA territory, compared to PICA territory. Isolated lSCA territory infarcts are located predominantly in the rostral anterior cerebellum and sometimes include the dorsolateral pontine tegmentum. Nearly all patients have prominent limb ataxia, varying from slight clumsiness to severe incoordination and dysmetria (68). Dysarthria is also a frequent and prominent finding. Cerebellar gait ataxia and severe veering and pulling of the trunk to the ipsilateral side, so-called axial lateropulsion, also occur. Axial lateropulsion can be the only main finding in patients with lSCA territory infarction. Edema and mass effect do not occur, and recovery is usually excellent. Infarcts limited to the mSCA territory are less frequent than lSCA territory infarction. One patient with an isolated paravermal infarct in the territory of the mSCA had atrial fibrillation and presented with the acute onset of severe isolated dysarthria (68).

Cerebellar Infarction in PICA Distribution PICA cerebellar infarcts can be divided into: (i) infarction in the territory of the mPICA, affecting mostly the inferior cerebellar vermis, (ii) infarction limited to the lPICA, affecting mostly the lateral surface of the posterior inferior cerebellar hemisphere, and (iii) full PICA territory infarcts, involving both the mPICA and lPICA territories (13,69 –73). Full PICA territory infarcts are often accompanied by edema formation and mass effect— so-called pseudotumoral cerebellar infarcts. About one fifth of PICA territory cerebellar infarcts are accompanied by infarction in the dorsal or dorsolateral medulla (13). The combination of lateral medullary and PICA territory cerebellar infarction occurs when the ICVA is occluded and blocks the orifice of both PICA, and the lateral medullary penetrators. PICA usually originates more caudally, but in some patients, these branches arise near each other. Most often, mPICA territory infarcts are accompanied by dorsal medullary infarcts as the mPICA branch has some supply to the dorsal medulla. Infarcts in the cerebellum limited to lPICA distribution are rarely accompanied by medullary infarction. Infarcts limited to the medial vermis in the territory of mPICA usually cause a vertiginous labyrithian syndrome that closely mimics a peripheral vestibulopathy (13, 69 –73). Severe vertigo with prominent nystagmus is the major finding. 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

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but without vertigo or dysarthria. Body sway towards the side of the lesion, ipsilateral limb ataxia, and abnormal rapid alternating movements are also common. 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 lying more ipsilaterally. Vomiting, gait ataxia, truncal lateropulsion, and limb incoordination are other common findings. The truncal dysfunction is similar to that found in the lateral medullary syndrome; 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 as would be found in the involvement of the dentate nucleus or its superior cerebellar peduncle efferent pathways. The syndrome of pseudotumoral cerebellar infarction is most often found in patients with large full PICA territory infarcts. 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 early signs of cerebellar mass effect. Most characteristic of large cerebellar space taking infarcts are the oculomotor abnormalities, which develop because of brainstem compression. Most common are 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 is followed by deep coma when the oculomotor abnormalities become bilateral. Once coma has intervened, the mortality rate is extremely high. Neuroimaging tests help confirm the compression of the posterior fossa cisterns and the fourth ventricle and the development of hydrocephalus.

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5 The Eye as the Recipient Artery Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Readers might ask why include the eye in a monograph about brain embolism. Many reasons come to mind. The eye is really an outpouching from the brain, and the optic nerve is really a brain tract. The eye is fed, like the brain, by the carotid arteries. The eye is delivered and uses more blood than is accounted for by its size and many emboli headed cranially wind up in the arteries that supply the eye. The human brain is dominated by visual functions—looking, seeing, and revisualizing things, scenes, and people in our mind’s eye. The visual loss related to eye ischemia is quite different than that related to brain ischemia. The two syndromes are different, and it is important that they are separated. Clinicians should become aware of the signs and symptoms related to embolism to the eye.

ANATOMY OF THE ARTERIES THAT SUPPLY THE EYE The eyes are supplied by the ophthalmic artery branches of the internal carotid arteries (ICAs). The ophthalmic arteries originate just after the ICAs penetrate the dura to enter the cranial cavity; occasionally, they arise from the ICA within the cavernous sinus before dural penetration. Rarely, the ophthalmic artery arises from the middle meningeal branch of the external carotid artery or the middle cerebral or posterior communicating artery branches of the ICA. After a very short course within the cranial cavity (2 – 7 mm in length), the ophthalmic arteries again penetrate through the dura and enter the optic canals where the arteries run alongside the optic nerves. Just before the ophthalmic arteries cross the optic nerves, the central retinal arteries branch out. The central retinal arteries penetrate the optic nerve, enter the globe, and then divide into superior and inferior branches that supply the inner two-thirds of the retina (1,2). Whereas the central retinal arteries supply the major blood flow to the retina, the posterior ciliary arteries provide the major blood supply to the optic nerves. Two or three short posterior ciliary arteries originate from the ophthalmic arteries when the latter cross the optic nerves about 15– 20 mm behind the globes. One or two long posterior ciliary arteries originate from the proximal ophthalmic artery to supply the inferior portion 81

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of the choroidal supply, whereas the superior ciliary arteries arise more distally from the ophthalmic artery and supply the superior portion of the choroidal supply (3). The short posterior ciliary artery branches penetrate the sclera of the eye where the dural sheath of the optic nerve joins the globe. The major portions of the anterior optic nerve receive their blood supply from these ciliary arteries. One short posterior ciliary artery supplies the superior portion of the optic nerve, and another short ciliary artery supplies the inferior portion of the nerve (1 – 4). This anatomical supply explains the altitudinal nature of visual field defects related to optic nerve infarction. The posterior ciliary arteries also supply the choroid, a portion of the retina, and structures within the anterior segment of the eye. The arterial supply of the eye is shown in Figure 1.

Figure 1 Blood vessels of the orbit. Source: From Ref. 1.

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CLINICAL SYMPTOMS AND SIGNS OF EYE ISCHEMIA There are four major syndromes of acute eye ischemia. Embolism to the eye most often causes temporary loss of vision. This syndrome has been variously referred to as transient monocular blindness (TMB), transient monocular visual loss (TMVL), and amaurosis fugax (AF). Because the visual symptoms are often partial and do not qualify as blindness, and because AF is used variously to incorporate bilateral visual loss and loss of vision related to brain lesions, I prefer to use TMVL. Persistent loss of vision in one eye is usually caused by a central retinal artery occlusion (CRAO). When an embolus blocks a branch of a retinal artery, the term central retinal artery branch occlusions (CRABO) is most often used. Transient Monocular Visual Loss The clinical importance of monocular visual loss was described in detail by Miller Fisher (5 –7), who emphasized that transient visual loss in one eye often provided a clue to the presence of severe occlusive disease of the ipsilateral ICA in the neck, especially if patients with attacks of monocular visual loss also had transient attacks of dysfunction of the contralateral limbs. Fisher also described and illustrated the fundoscopic findings in a patient that he observed during an attack of TMVL (8). The visual loss is usually described by the patient as a graying, blurring, darkening, fogging, obscuring, or dimming of vision in one eye. It can involve the entire field of vision in that eye, or an altitudinal, or lateral, or central sector of vision can be obscured during the attack. Some patients describe a shade, blind, or curtain that descends quickly over the eye. The arteries that supply the inferior retina are more tortuous, have smaller diameters, and take a longer course, so that the inferior segments are more vulnerable to ischemia—explaining why the shade usually descends rather than ascends (3). Occasionally, the curtain ascends or is drawn laterally across the eye. Sometimes, the curtain creates a uniform line across the vision, and in other patients there is a step in the middle. At times, patients with retinal ischemia describe positive phenomena, including scintillations: bright, often colored, visual displays, and streaks, lines, and shimmers (9). Miller Fisher’s original patient, who was examined during an attack of TMVL, “likened the failure of vision to the snowing up of a television screen . . . colorless snowflakes were bright, shining, and jumping. As the cloud took form he could still see through it, but as the cloud became more dense, a total blackout occurred” (8). Attacks most often last a few minutes but can range from seconds to hours. In some patients, the attacks are repeated and can occur from many a day to widely spaced episodes during a period of months. Pain in and around the eye is rare in patients with TMVL arising from embolism but is more common in patients with migraine-related TMVL and when carotid dissection provided the donor source of embolism. Some patients have ipsilateral facial paresthesias accompanying the visual loss (10). A warm flush, tingling, and a sensation as if the eye were twitching can be reported to involve the eye, the eyelid, the periorbital region, or the cheek. The paresthesias may precede, coincide, or follow the visual loss. Some patients who have attacks of TMVL also have separate attacks of weakness of the contralateral limbs or other signs of ischemia affecting the cerebral hemisphere on the same side as the affected eye (2,11). The most important and common ophthalmoscopic finding in patients with TMVL is the presence of embolic particles within retinal arteries (12). The most frequently detected particles are cholesterol crystals, often called Hollenhorst plaques after the

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Figure 2 A photograph of the ocular fundus in a patient with two visible “Hollenhorst plaques.” The arrows point to the crystals at arterial bifurcations.

ophthalmologist who first described them (13,14) (Figs. 2 and 3). Hollenhorst recognized that patients with these plaques often had carotid artery disease (13,14). These cholesterol crystal emboli are white but may appear bright, often glinting, and yellow-orange. They are usually small (10 –250 mm in diameter), most often lodge at bifurcations of retinal

Figure 3 An ocular fundus photograph. The arrow points to a large cholesterol crystal blocking a central retinal artery branch. A white fluffy retinal infarct can be seen in the retina beyond the branch.

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Figure 4 An ocular fundus photograph showing a long partially fragmented white platelet-fibrin thrombus (arrows).

arteries, and usually do not block blood flow. They can move or disappear rapidly but may injure the vascular wall leading to sheathing of the artery. Compressing the orbit may cause crystals to move, flip over, or “flash,” making them more visible with the ophthalmoscope. Fluorescein angiograms, even when crystals are no longer seen through an ophthalmoscope, may show hyperfluorescent crystals or leakage of dye in regions of arteries damaged by the crystal emboli. Platelet-fibrin emboli (“white clots”), in contrast to cholesterol crystal emboli, form longer gray-white columns that gradually progress through small retinal arteries with distal fragments breaking off as the column moves (Fig. 4). Fisher described and drew these white clots as they traversed the retina in a patient with episodes of TMVL (8). Sometimes, the pale plugs are made of fibrin, especially following heart surgery and in those patients with cardiac donor sources of emboli (15). The third type of embolic material consists of calcium fragments, which appear chalky white and usually remain in one location obstructing blood flow. These emboli do not scintillate and are characteristically somewhat wider than the blood stream (15). These particles can be dislodged from the aorta and cardiac valves during surgery or spontaneously embolize from regions of mitral annulus and valvular calcifications. Talc, cornstarch, and other foreign body emboli have been described in retinal arteries of patients who inject intravenously mashed up pills intended for oral use after dissolving the tablets in water (16 – 18). Central Retinal Artery Occlusion Most patients with CRAO develop persistent painless blindness in one eye. Von Graefe is usually credited with the first description of this condition. He noted attenuated arteries and veins, a pale optic disc, clouding of the retina, and a cherry red spot in the macula (19). In blind patients, the pupil fails to react to light. At times, perception of hand

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Figure 5 An ocular fundus photograph showing a central retinal artery occlusion. The veins are visible, but no retinal arteries are seen. The retina is beginning to become edematous and white regions can be seen along the veins.

movements and light can be retained in portions of the visual field in that eye because the posterior ciliary arterial system supplies a portion of the retina. If the ophthalmoscopic examination is performed soon after onset of blindness, the most striking findings relate to slowing of the retinal circulation (20). Segmentation of the blood column with slow streaming of flow is seen in the veins. The segmentation has been referred to as box car – like, resembling the cars that are present on the end of trains that carry cargo. The blood in the arteries appears dark, and a few areas show segmentation; the segmentation appears as clear areas alternating with regions where the cells seem clumped together. The segmentation is always more obvious in the veins than in the retinal arteries. Sometimes, when the changes in the vessels are not obvious, gentle pressure on the globe during ophthalmoscopy can produce segmentation of the blood column, indicating a very low central retinal artery pressure. If CRAO lasts more than an hour, the retina becomes infarcted. Cloudy swelling of the ganglion cells causes them to become less transparent, and the retina develops a milky-white appearance, especially near the macula (20). The cherry red appearance of the macula is related to accentuation of the normal fovea through which the choroid coat appears red. Later optic atrophy is evident, and the optic disc appears chalk white. Figure 5 shows the fundus oculi in a patient with a CRAO. Central Retinal Artery Branch Occlusions In patients with central retinal artery branch occlusions (CRABO), branches of the central retinal artery are occluded. The visual loss is focal and corresponds to the portion of the retina that is ischemic. The visual defects are usually lateral or altitudinal or form a scotoma. The ischemic portion of the retina often has a ground glass – like appearance due to ischemic edema (1). Later, well-delineated retinal infarcts and focal cotton-wool spots called cytoid bodies that represent retinal microinfarcts are often seen.

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Blockage of the retinal artery branch is often visible with the ophthalmoscope, especially if ophthalmoscopy is performed relatively soon after the onset of visual loss. Diagnosis is facilitated with fluorescein angiography that shows a lack of perfusion of the fluorescein-containing blood in the region of retinal ischemia. The point of occlusion can often be clarified using fluorescein angiography (21).

Anterior Ischemic Optic Neuropathy Patients with anterior ischemic optic neuropathy (AION) usually develop painless monocular visual loss. Most often, the visual loss is noted on awakening in the morning, and it usually does not worsen later. The severity of the visual loss varies but is usually not complete. The visual loss is often altitudinal. AION is caused by ischemia to the optic nerve, usually in the anterior portion of the nerve. The major blood supply of the optic nerve comes from the posterior ciliary arteries. Ophthalmoscopy soon after symptom onset usually shows edema of the optic disc, and, at times, small splinter hemorrhages are seen at the margins of the optic disc (22). Optic atrophy develops later. When the ischemia is in the posterior portion of the optic nerve, the fundus can look normal. Unlike the other syndromes described earlier (TMVL, CRAO, and CRABO), which are caused predominantly by embolism, AION is thought to be due most often to hypoperfusion of the optic nerve head. Occasionally, infarction of the optic nerve can accompany ipsilateral cerebral hemisphere infarction. When this occurs, the usual cause is occlusion of the ICA, with thrombus extension to the carotid siphon blocking flow in the ophthalmic artery and its branches (23). Carotid dissection can also cause blockage of ophthalmic artery flow, with resultant hemiparesis and ipsilateral visual loss (24).

METHODS OF INVESTIGATING THE EYE AS A RECIPIENT SITE OF EMBOLISM Careful and thorough ophthalmoscopy using either a direct or an indirect ophthalmoscope is the most important diagnostic maneuver. Often the pupil must be dilated to obtain an optimal view of the fundus oculi. Embolic particles seen within the eye are tangible evidence of embolism. Emboli are seen in 11–40% of patients with CRAO and 60 – 70% of patients with CRABO (1,25,26). In population-based studies, when ophthalmoscopy is performed by experienced observers, retinal emboli are found in about 1.4% of patients (27). About one-fifth of patients with acute strokes in the carotid artery territory have visible emboli in the ipsilateral eye; these are predominantly cholesterol crystal emboli (27). Often, fluorescein angiography can clarify the presence, location, and nature of the retinal artery block. Several techniques have been used in the past to measure retinal artery pressure and blood flow, but these instrumentations are seldom used clinically today. Ophthalmodynamometry (ODM) is performed using a handheld instrument that looks much like the gauge that measures pressure in car tires. Pressure is applied to the globe during ophthalmoscopy. The pressure used to provoke pulsations in retinal arteries is equal to the diastolic pressure in the central retinal artery (CRA); obliteration of arterial flow occurs at systolic pressure. Oculoplethysmography (OPG) measures the ocular pulse that can be used to calculate the systolic pressure of the retinal artery. It is measured by using air-filled cups that are applied laterally to the sclerae of both eyes. A partial vacuum is applied to the cups to raise

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intraocular pressure. The vacuum is slowly released until a measurable pulse amplitude appears (1,28). Transcranial Doppler (TCD) ultrasound has virtually replaced ODM and OPG. TCD probes placed over the orbit can measure blood flow velocities in the intracranial ICA and ophthalmic arteries. TCD also allows emboli monitoring. TCD will be discussed thoroughly in chapter 7. Color Doppler imaging of the orbit now allows visualization of the ophthalmic, central retinal, and posterior ciliary arteries. The corresponding veins can also be imaged. The blood-flow velocities in the arteries supplying the eye can be quantified using spectral analysis, and a B-mode image is produced that can show occlusion of the ophthalmic and/or CRA and calcific and other emboli within the major arteries (1,29 – 32). Techniques used to study the arteries within the cranium (computed tomograph angiography, magnetic resonance angiography, digital subtraction dye angiography) can also be used to study the ophthalmic artery but the resolution is not good and branches are not shown very well.

DIFFERENTIAL DIAGNOSIS OF RETINAL EMBOLISM Intrinsic disease of the ophthalmic artery can cause TMVL as well as retinal and optic nerve infarction with persistent monocular visual loss. Atheromatous disease of the ophthalmic and/or CRA is rare but occasionally occurs in diabetics (33). Severe occlusive disease of the ICA in the siphon proximal to or at the origin of the ophthalmic artery can also cause hemodynamic-related monocular visual loss. Sometimes the cause is an aneurysm that harbors a clot. The aneurysm may lie within the cavernous sinus and cause cranial nerve signs. Most patients with carotid artery siphon stenosis and those with aneurysms have a high frequency of hypertension. Giant cell (temporal) arteritis is probably the most frequent cause of ophthalmic artery disease. Persistent visual loss in one eye followed by visual loss in the other eye is the commonest clinical pattern in patients with temporal arteritis. TMVL is much less common. Occasionally, patients with migraine have attacks of monocular visual loss. These are usually described as greying or blurring of vision; sometimes a grey or white curtain covers vision. Descriptions of the visual loss are similar to those used by patients with carotid artery occlusive disease and eye embolism and are quite distinct from the bright scintillations of occipital migraine (34 –36). Some have had aching or discomfort in the eye during attacks. Migrainous vasospastic TMB is most common in relatively young women but also occurs in men. In some migraine patients, attacks are frequent and occur more than once a day. Ophthalmoscopy in patients with vasospastic TMVL usually shows constricted retinal arteries and rouleaux formation in veins in relation to slowed blood flow. The arteries may appear threadlike, and the optic disc often appears pale (34 – 36). Hypercalcemia caused by hyperparathyroidism and ingestion of large amounts of licorice can provoke retinal artery vasospasm and cause transient visual dysfunction in one or both eyes (37). Conditions that increase intracranial or intraocular pressure can also cause TMVL. Patients with pseudotumor cerebri (benign intracranial hypertension) have transient visual obscurations (38). These are often monocular but can be binocular. The episodes of visual loss are usually very brief and often are precipitated by coughing, straining, or other maneuvers that elevate intracranial pressure. The mechanism is presumed to be insufficient arterial perfusion to surmount the increased intracranial pressure that causes

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increased pressure in retinal veins. The same mechanism probably occurs in patients with glaucoma and cavernous sinus arteriovenous fistulas. Systemic disorders that cause hypercoagulability and hyperviscosity, such as polycythemia vera, thrombocytosis, and Waldenstrom’s macroglobulinemia, can cause sluggish retinal artery blood flow that can give symptomatic transient visual loss. Detachment of the retina presents rarely as transient loss of vision. Intrinsic disease of arteries within the eye, including preretinal arterial loops, can cause repeated episodes of TMVL. These loops arise from the CRA and are often kinked, causing flow to become temporarily or persistently diminished within the loop, causing transient loss of a portion of monocular vision (39).

USUAL SOURCES OF RETINAL EMBOLISM The most important cause of TMVL, CRAO, and CRABO is occlusive disease of the ICA in the neck. Patients with severe internal carotid occlusive disease with ,1 mm residual lumen (90% stenosis) often have relatively frequent brief attacks of dimming of vision in the entire visual field of the eye. Patients with plaque disease that causes less severe stenosis more often have isolated, infrequent episodes of loss of vision in a part of the visual field correlated with emboli to branch retinal arteries. When the ICA becomes completely occluded, patients may show periodic dimming of vision when exposed to bright light. Occasionally, patients with bilateral internal carotid occlusive disease have had bilateral dimming of vision on bright light exposure. Some patients who have had attacks of TMVL when their ICAs were severely stenotic stop having TMVL when the ICAs fully occlude. Monitoring of the ipsilateral middle cerebral artery using TCD ultrasound in patients with TMVL related to severe carotid stenosis shows many high intensity transient signals (HITS) that represent microemboli emanating from carotid plaques (40 –42). After the ICA occludes, microemboli diminish and soon are no longer detectable by TCD. These same patients with carotid artery occlusion may have a recurrence of their TMVL when the ipsilateral external carotid artery, which provides the main collateral artery supply of the eye, becomes stenotic or occluded. Wijman and colleagues used TCD-monitoring to study 45 patients. Thirty-seven had TMVL, including seven who also had episodes of cerebral ischemia, and seven had retinal infarcts (CRA or CRABO) (42). Microembolic signals (MES) were detected in 40% of the patients with retinal ischemia and were more commonly detected when monitoring was done soon after symptoms manifested. The frequency of signals correlated with ICA disease in this study, in which cardiac origin embolic sources were excluded. Severe ICA stenosis or occlusion was present in 33 of 45 (73%) patients (42). Most patients with retinal strokes (CRAO and CRABO) have embolic occlusions emanating from the ICA (1,43). Branch retinal artery occlusions are more often attributable to severe ICA disease than CRAOs (1,25,43 –47). In a series of patients with CRAO and CRABO, 29 of 34 patients (85%) had abnormal ICAs on angiography; among these 12 had ICA occlusion or severe stenosis, and 17 had plaques, ulcers, or moderate stenosis (43). The aorta can also be an important source of cholesterol crystal embolism. Cardiac conditions that promote systemic and brain embolism also cause retinal infarcts and TMVL. Cardiac-origin embolic sources were found in 29 of 103 (28%) patients with retinal artery occlusions in one series (26). In this same series, among 18 patients who had angiography, 12 had ICA stenosis or irregularity (26). Repeated attacks of TMVL are very rarely attributable to cardiac-origin embolism.

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TREATMENT Treatment depends very much on the cause. Ocular massage, carbon dioxide inhalation, acetazolamide, inhaled isuprel, and sublingual nitroglycerine all have been advocated with variable success. In some patients with ophthalmic artery occlusion, intra-arterial thrombolysis has been used. REFERENCES 1. Hedges TR Jr. Ocular ischemia. In: Caplan LR, ed. Brain Ischemia: Basic Concepts and Clinical Relevance. London: Springer-Verlag, 1995:61 – 73. 2. Hayreh SS. Arteries of the orbit in the human being. Br J Surg 1963; 50:938– 953. 3. Liebeskind DS, Weigele JB, Hurst RW. Anatomical substrates of the descending shade in amaurosis fugax. Stroke 2004; 35:260. 4. Oliver JM, Spalton DJ, McCartney ACE. Microvascular study of the retrolaminar optic nerve in man: the possible significance in anterior ischemic optic neuropathy. Eye 1990; 4:7– 24. 5. Fisher CM. Occlusion of the ICA. Arch Neurol 1951; 65:346 –377. 6. Fisher CM. Transient monocular blindness associated with hemiplegia. American Arch Ophthalmol 1952; 47:167 – 203. 7. Fisher M. Occlusion of the carotid arteries. Arch Neurol Psychiatry 1954; 72:187– 204. 8. Fisher CM. Observations of the fundus oculi in transient monocular blindness. Neurology 1959; 9:333 – 347. 9. Goodwin JA, Gorelick PB, Helgason C. Symptoms of amaurosis fugax in atherosclerotic carotid artery disease. Neurology 1987; 37:829– 832. 10. Ropper AH. Transient ipsilateral paresthesias (TIPs) with transient monocular blindness. Arch Neurol 1985; 42:295. 11. Pessin MS, Duncan GW, Mohr JP, et al. Clinical and angiographic features of carotid transient ischemic attacks. N Engl J Med 1977; 296:358 – 362. 12. Hedges TR. Opthalmoscopic findings in ICA occlusion. Am J Ophthalmol 1963; 55: 1007– 1012. 13. Hollenhorst RW. The ocular manifestation of internal carotid arterial thrombosis. Med Clin North Am 1960; 44:897 – 908. 14. Hollenhorst RW. Significance of bright plaques in the retinal arterioles. JAMA 1961; 178: 123– 129. 15. Wray SH. Visual aspects of extracranial ICA disease. In: Bernstein EF, ed. Amaurosis Fugax. New York: Springer-Verlag, 1988:72– 80. 16. Atlee W. Talc and cornstarch emboli in the eyes of drug abusers. JAMA 1972; 219:49 – 51. 17. Caplan LR, Thomas C, Banks G. Central nervous system complications of “Ts and blues” addiction. Neurology 1982; 32:623– 628. 18. Caplan LR, Hier DB, Banks G. Stroke and drug abuse. Curr Concepts Cerebrovasc Dis (Stroke) 1982; 27:9 – 13. 19. Von Graefe A. Uber embolie der arteria centralis retinae als ursache plotzlicher erblindung. Arch Clin Exp Opthalmol 1859; 5:136– 140. 20. Wray S. Occlusion of the central retinal artery. In: Bernstein EF, ed. Amaurosis Fugax. New York: Springer-Verlag, 1988:81– 89. 21. Michaelson JB, Friedlander MH. Angiography of retinal and choroidal vascular disease. In: Bernstein EF, ed. Amaurosis Fugax. New York: Springer-Verlag, 1988:51 – 71. 22. Hayreh SS. Acute ischemia of the optic nerve. In: Bernstein EF, ed. Amaurosis Fugax. New York: Springer-Verlag, 1988:93– 113. 23. Bogousslavsky J, Regli F, Zografos L, Uske A. Opticocerebral syndrome: simultaneous hemodynamic infarction of optic nerve and brain. Neurology 1987; 37:263 – 268. 24. Biousse V, Schaison M, Touboul P-J, D’Anglejan-Chatillon J, Bousser M-G. Ischemic optic neuropathy associated with ICA dissection. Arch Neurol 1998; 55:715 – 719.

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25. Savino PJ, Glaser JS, Cassady J. Retinal stroke: is the patient at risk? Arch Opthalmol 1977; 95:1185 – 1189. 26. Wilson LA, Warlow CP, Ross-Russell RW. Cardiovascular disease in patients with retinal artery occlusion. Lancet 1979; 1:292– 294. 27. Egan RA, Lutsep HL, Clark WM. The prevalence of retinal embolic events at the time of acute ischemic stroke. Stroke 2004:267. 28. Gee W, Oller DW, Wiley J. Noninvaive diagnosis of carotid occlusion by ocular plethysmography. Stroke 1976; 7:18 – 21. 29. Erickson SJ, Hendrix LE, Massaro BM, et al. Color Doppler flow imaging of the normal and abnormal orbit. Radiology 1989; 173:511 – 516. 30. Lieb WE, Cohen SM, Merton DA, Shields JA, Mitchell DG, Goldberg BB. Color Doppler imaging of the eye and orbit: technique and normal vascular anatomy. Arch Opthalmol 1991; 109:527 – 531. 31. Lieb WE, Flaharty PM, Sergott RC, Medlock RD, Brown GC, Bosley T, Savino PJ. Color Doppler imaging provides accurate assessment of orbital blood flow in occlusive carotid artery disease. Ophthalmology 1991; 98:548– 552. 32. Hedges TR, Reichel E, Duker JS, Pulafito CA, Heggerick PA. Color Doppler imaging identifies different mechanisms of central retinal artery occlusion. Invest Opthalmol Visual Sci 1993; 34:842. 33. Nakajima M, Kimura K, Minematsu K, Saito K, Takada T, Tanaka M. A case of frequently recurring amaurosis fugax with atherothrombotic ophthalmic artery occlusion. Neurology 2004; 62:117 – 118. 34. Burger SK, Saul RF, Selhorst JB, Thurston SE. Transient monocular blindness caused by vasospasm. N Engl J Med 1991; 325:870– 873. 35. Winterkorn JM, Teman AJ. Recurrent attacks of amaurosis fugax treated with calcium channel blockers. Ann Neurol 1991; 30:423– 425. 36. Winterkorn JM, Kupersmith M, Wirtschafter JD, Forman S. Brief report: Treatment of vasospastic amaurosis fugax with calcium channel blockers. N Engl J Med 1993; 329:396– 398. 37. Dobbins KR, Saul RF. Transient visual loss after licorice ingestion. J Neuroophthalmol 2000; 20:38 – 41. 38. Merle H, Smadja D, Ayeboua L, Cabre P, Gerard M, Alliot E, Rapoport P, Jallot-Sainte-Rose N, Richer R, Poman G. Benign intracranial hypertension. Retrospective study of 20 cases. J French Ophthalmol 1998; 21:42 – 50. 39. Reichel E, Duker JS, Puliafito CA, Hedges TR, Caplan LR. Branch retinal arterial occlusion caused by a preretinal loop. Neurology 1994; 44:1181 – 1183. 40. Sitzer M, Siebler M, Steinmetz H. Silent emboli and their relation to clinical symptoms in extracranial carotid artery disease. Cerebrovasc Dis 1995; 5:121 –123. 41. Droste DW, Dittrich R, Kemeny V, Schulte-Altedorneburg G, Ringelstein EB. Prevalence and frequency of microembolic signals in 105 patients with extracranial carotid artery occlusive disease. J Neurol. Neurosurg. Psychiatr 1999; 67:525– 528. 42. Wijman AC, Babikian VL, Majucha CA, Koleini B, Hyde C, Winter MR, Pochay VE. Cerebral microembolism in patients with retinal ischemia. Stroke 1998; 29:1139 – 1143. 43. Merchut MP, Gupta SR, Naheedy MH. The relation of retinal artery occlusion and carotid artery stenosis. Stroke 1988; 19:1239 –1242. 44. Lorentzen SE. Occlusion of the central retinal artery. Acta Opthalmol 1969; 47:690 –703. 45. Kollarits CR, Lubow M, Hissong SL. Retinal strokes: 1 Incidence of carotid atheromata. JAMA 1972; 222:1273 – 1275. 46. Appen RE, Wray SH, Cogan DC. Central retinal artery occlusion. Am J Opthalmol 1975; 79:374 – 381. 47. Chawluk JB, Kushner MJ, Bank WJ, et al. Atherosclerotic carotid artery disease in patients with retinal ischemic syndromes. Neurology 1988; 38:858– 863.

6 Imaging Evaluation: Recipient Artery Sites Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Brain imaging and vascular investigations play a very important role in the diagnosis and management of patients suspected of having brain embolism. This chapter concentrates on the recipient artery and its brain supply and covers donor arterial sites as well. The key questions that physicians should ask are enumerated in Table 1. The essential issues are whether or not the patient has a brain infarct, and if so, where, how large, and whether or not intracranial arteries are occluded by emboli. The advent of thrombolytic treatment and the potential for mechanical opening of occluded arteries have made it very important to obtain accurate diagnoses quickly and safely in patients seen soon after the onset of symptom.

BRAIN NEUROIMAGING Computed tomography (CT) and magnetic resonance imaging (MRI) are indispensable in the diagnosis of brain embolism. The first question to be answered is: is there a lesion caused by cerebrovascular disease present, and if so, is the lesion an infarct or a hemorrhage? Brain neuroimaging tests are now able to answer this query very well. CT and MRI are able to separate brain infarcts from hemorrhages. CT scans have been traditionally used to exclude hemorrhage as hematomas are nearly always visible immediately after the onset of stroke and are easily seen as hyperdense, well-circumscribed lesions on the CT. In rare instances, CT scans fail to show hemorrhages, especially, if the hemorrhagic lesions are near the bony surfaces, for example in the orbital frontal region, or if the patient is severely anemic (1 – 3). T2-weighted (also called susceptibility-weighted images) MRI scans also can detect hemorrhages early after the onset of symptom (4 – 7). Figure 1 shows CT and T2-weighted MRI scans on the same patient with a putaminal hemorrhage. MRI can also show tiny old hemorrhages, usually called “micro-bleeds,” that represent a risk for treatment with thrombolytic and anticoagulant drugs (8 –11). Subarachnoid hemorrhages can also be detected on MRI scans if proper techniques are performed (6,12). Recent studies have shown that these MRI studies can show hemorrhages even earlier and better than CT scans (13,14). CT scans are not good at detecting very early acute brain infarcts, whereas MRI is more sensitive in detecting early infarction, especially if diffusion-weighted scans are 93

94 Table 1

Caplan Questions to Be Answered by Imaging

1. Is there a nonischemic process present in the brain, such as a brain hemorrhage, brain tumor, subdural hematoma, etc.? 2. Is a brain infarct present? If so, where is it? How large is it? What is the arterial supply of the infarcted brain region? 3. Are there other older infarcts visible? If so, are they in the same vascular territory or in other supply zones? 4. Is the intracranial artery supplying the infarcted zone patent or occluded? Are other intracranial arteries occluded? 5. Are there brain regions that are underperfused and ischemic but not yet infarcted?

performed. Diffusion-weighted (DWI) MRI scans show regions of increased brain water content that usually represent regions that will become infarcted. MRI is clearly superior to CT in detecting and showing infarcts in the cerebellum, brainstem, and inferior temporal lobes. When infarcts are present, their location, size, and multiplicity can help predict the mechanism of infarction (15). As described in chapter 3, infarcts caused by embolism are most likely to be cortical, or subcortical and cortical (Fig. 9 of chap. 3). Embolic infarcts are often confined to a pial arterial branch territory or to the upper or lower division of one middle cerebral artery (MCA). Infarcts that involve the territories of the superior cerebellar, posterior cerebral, and posterior inferior cerebellar arteries are most often embolic—either cardiogenic or intra-arterial, especially if the infarcts are large (15 –17). Infarcts that are supplied by the arteries emanating from the distal basilar artery (“top-of-the-basilar”) are also predominantly embolic (15 – 20). Large infarcts (as shown in Figs. 10 and 11 of chap. 3) are most often caused by embolism, and cardiac-origin emboli usually produce larger infarcts than artery-to-artery emboli. Infarcts that are initially hemorrhagic or later become hemorrhagic are most often attributable to embolism. Multiple superficial infarcts, especially in different arterial territories, are also usually explained by multiple emboli of cardiac or aortic origin. The presence of multiple infarcts in one vascular territory, such as the right internal carotid artery (ICA) territory, most often indicates disease in that artery, in this case the right ICA or MCA. The mechanism of these infarcts is artery-to-artery emboli often admixed with hypoperfusion (21). Infarcts that are very small and deep and conform to the territory of one penetrating artery are rarely embolic. CT and MRI brain imaging are useful even when the neurological symptoms reported by the patient or the family are transient. Scans in that circumstance may show unexpected infarcts despite the negativity of the history and neurological examinations. Such so-called “silent infarcts” are common. Neurological symptoms may have been present but forgotten by the patient. In other instances, the symptoms may have been trivial, for example, the patient may ignore a temporary limp, a short period of less precise articulation, or word-finding difficulty, or transient numbness in a limb. Often the neurological symptoms are misinterpreted as representing transient compression of a nerve in a limb or other relatively minor nonstroke causes. Careful inspection of CT scans performed soon after the onset of stroke sometimes shows subtle signs of early infarction. These so-called early signs are listed in Table 2. Loss of definition of the gray – white matter junction in ischemic regions, edema that causes effacement of sulci in one cerebral hemisphere or one arterial vascular territory, and loss of definition of the basal ganglia and the insular region are all early signs of infarction. Frank hypodensity usually indicates an established brain infarct. Another

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Figure 1 A patient with a recent left putaminal hemorrhage: (A) Computed tomography scan. The hemorrhage on the right of the figure is shown as a well-demarcated white lesion. (B) T2-weighted magnetic resonance imaging scan of the same patient showing the hemorrhage as a black lesion.

common finding on noncontrast CT scans is opacification of the middle cerebral or other arteries—the so-called hyperdense MCA sign. Figure 2 shows two examples of this sign. The hyperdensity is caused by a thrombus or very slow flow within the artery. Sometimes hyperdense intracranial internal carotid, basilar, and posterior cerebral arteries are found in

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Table 2 Early Computed Tomography Signs of Infarction 1. Loss of definition of the basal ganglia-lenticular nucleus. 2. Loss of definition of the insular ribbon. 3. Poor demarcation of the gray-white cortical ribbon. 4. Effacement of gyral markings. 5. Low-density areas. 6. Hyperdense arteries, especially, the MCA. Abbreviation: MCA, middle cerebral artery.

Figure 2 Computed tomography scans showing hyperdense middle cerebral artery (MCA). (A) Double-white arrows point to white curvilinear vascular structures, representing the left internal carotid artery, anterior cerebral artery, and MCA. (B) A black arrow points to a hyperdense left MCA.

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patients with ischemia in those vascular territories. Hyperdense arteries on noncontrast scans were found in 10% of acute strokes in one study (22), in 21% (23) and 22% (24) of acute embolic MCA occlusions in other studies, and in 31% of acute anterior circulation brain infarcts in another study (25). The hyperdense MCA sign has a relatively low sensitivity (about 50%) but a very high specificity (about 90%). Occasionally, a hypodense artery that appears black on CT scans can indicate a fat embolus within an intracranial artery (26). Occasionally, CT and MRI can show arterial lesions that can be the source of arteryto-artery embolism. Aneurysms, either dolichoectatic fusiform expansions, or large berrytype aneurysms can harbor clots and cause ischemia by embolization of clot material or blockage of branches by thrombus that remains within the aneurysm. Fusiform and large berry-type aneurysms are often visible on enhanced CT scans and on MRI. The appearance of the aneurysm on MRI with heterogeneous shadows can suggest the presence of thrombus within the lumen. The absence of normal vascular flow voids on MRI scans can also suggest the presence of occlusive arterial lesions. On gradient echo T2-weighted MRI scans (also referred to as susceptibility images), thrombosed arteries and veins can sometimes be seen as dark, hypodense, and curvilinear vascular structures (27,28). Dissected arteries, another important source of artery-to-artery embolism, often have a characteristic appearance on MRI. Dissection of an artery can be detected on MRI by the presence of intramural blood. The clot within the vascular wall has the same characteristics as hematomas. Typically, the intramural thrombus appears highly intense on an axial T1-weighted image and remains hyperintense on a T2-weighted image. Figure 3 illustrates two examples of vertebral artery dissections shown by MRI. Often, the lumen of the artery is eccentrically narrowed and may be thrombosed. CT and MRI can also be useful in helping to decide on treatment and in rendering a prognosis. Patients who have embolic brain ischemia are candidates for thrombolytic treatment if seen early enough in their course. If a patient with a suspected MCA territory embolus has a large infarct already visible on CT or MRI at the time that thrombolytic treatment is considered, the likelihood of a good outcome would be small as much brain was likely to have been infarcted already and would be unlikely to recover after reperfusion. The risk of hemorrhage after thrombolytic treatment is also considerably higher when sizable infarction is present before treatment (29). Decisions on the timing of anticoagulation also depend on the imaging results. When large infarcts are present, the risk of hemorrhage after heparin anticoagulation is higher.

INTRACRANIAL VASCULAR IMAGING Dye Contrast Catheter Angiography Vascular studies have a dual purpose: to define the lesion within recipient arteries and to image any possible arterial sources of embolism. As angiography was the first vascular imaging test used to detect emboli and to define vascular lesions, knowledge of the diagnostic angiographic findings will help physicians interpret the results of less invasive vascular tests. Angiographic findings that suggest embolism are enumerated in Table 3. The presence of blocked superficial branches of intracranial arteries is highly suggestive of embolism as atherosclerosis rarely affects branch arteries but is much more common in the major extracranial and basal intracranial arteries. The absence of any vascular occlusive lesion in the artery supplying an infarcted zone usually means that an embolus has temporarily blocked that artery and then passed. For example, if a patient has a sizable acute right MCA territory infarct and the right ICA and MCA are normal angiographically,

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Figure 3 Vertebral artery dissections. (A) Axial T1-weighted magnetic resonance imaging (MRI) showing hyperdense arterial expanded wall (black arrows) on the right of the figure. The lumen is narrowed compared to the contralateral vertebral artery. (B) Axial T1-weighted MRI scans showing a right vertebral artery dissection. The image on the left shows a hyperintense hematoma within the wall of the artery with an eccentric compromised lumen. In the right, more rostral figure of the medulla, the black lumenal flow void, is larger and the wall is the normal size.

Table 3

Angiographic Signs Indicating Embolism

1. Blockage of superficial branches of intracranial arteries. 2. Absence of any vascular occlusive lesion in the artery, supplying a cortical or subcortical/cortical infarct. 3. Movement or disappearance of a vascular obstructing lesion on sequential angiographic films. 4. Sudden sharply demarcated occlusion of major intracranial arteries, especially the MCAs, PCAs, and cerebellar arteries in the absence of atherosclerosis in those vessels. 5. A filling defect within a symptomatic intracranial artery. Abbreviations: MCA, middle cerebral artery; PCA, posterior cerebral artery.

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then one can conclude that there must have been temporary blockage of the right MCA by an embolus that remained long enough to cause infarction and later passed. Movement or disappearance of a vascular obstructing lesion on sequential angiographic films is diagnostic of embolism, as in situ occlusions are adherent and do not move quickly. Emboli usually produce sudden sharply demarcated occlusions of major intracranial arteries, especially, the MCAs, posterior cerebral arteries (PCAs), and cerebellar arteries in the absence of atherosclerosis in those vessels. Patients who have in situ thrombi formed at the sites of previous atherosclerosis usually have had prior transient ischemic attacks, and the occlusion is tapered. The in situ –occluded artery shows some signs of prior atherosclerotic stenosis. A filling defect within a symptomatic intracranial artery is also highly suggestive of embolism. Angiography also gives information about possible proximal arterial sources of embolism. In a patient with a right MCA territory infarct, severe stenosis of the right ICA in the neck is highly suggestive of intra-arterial embolism arising from the right ICA. Newer, less-invasive vascular imaging tests are now used instead of angiography in most patients. CT angiography (CTA), magnetic resonance angiography (MRA), and transcranial Doppler ultrasound are excellent screening tests that often give enough information to guide treatment, although their accuracy is less than catheter dye angiography. Noninvasive imaging should always precede angiography, even when it has already been decided that angiography is needed (30). The results of noninvasive vascular tests can help better target angiography and limit the number of arteries that require study, thus reducing the amount of contrast media needed and the length of the procedure. CTA and MRA can generate accurate images of the major extracranial and intracranial arteries but do not show branches very well. Clinicians should view MRA and CTA, using the same criteria for embolism that were discussed for catheter dye contrast angiography.

Magnetic Resonance Angiography MRA is a very important investigation that promises to yield a great deal of information about vascular occlusive lesions. MRA can be performed at the same time that MRI brain images are generated. MRA does not require injection of any substance, although gadolinium injection can yield better images of the arteries in some patients with reduced flow. It is noninvasive and quite safe. MRA can be performed using a variety of different techniques including, two-dimentional and three-dimensional time-of-flight and phase contrast imaging (31 – 34). MRA is a functional technique that creates an image of flow in the artery. Unlike the contrast injection angiograms, the images do not reflect anatomy. The changing angles and curvature of the ICA in the siphon often makes interpretation of this region more difficult as compared to the straight portions of the artery. The horizontal segment of the MCA is usually well shown. The intracranial vertebral, basilar, and posterior cerebral arteries are also imaged quite well with MRA. MRA is not as accurate as digital subtraction catheter angiography in estimating the severity of arterial stenosis, but complete occlusions of large arteries are usually well shown.

Computed Tomography Angiography Infusions and bolus injections of contrast in conjunction with CT scanning yield diagnostic images of neck and intracranial arteries. CTA can be performed at the same time as CT

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brain images. The development of more rapid spiral (helical) CT scanners has enabled the development of CTA. This technique involves intravenous injection of a bolus of dye followed by helical scanning. Volumetric data acquisition and improved computerized image manipulation have improved the CTA image display into three-dimensional reformations. CTA is based on anatomical imaging, and, when blood flow is severely reduced, CTA has theoretical advantages over MRA, which is a functional imaging technique. CTA provides useful images of intracranial arteries and can show regions of extracranial and intracranial stenosis, dolichoectasia, and aneurysms (35 – 39). Figure 4 is a CTA that shows a vertebral-posterior inferior cerebellar artery aneurysm. In one study, among 40 patients who were considered potential candidates for thrombolytic therapy, CTA showed that 34 had a recent arterial occlusion (40). Interobserver variability for both CTA and MRA are good, but different observers interpret CTA more variably than MRA (41). Arterial enhancement of branches beyond the occluded arteries can give information about collateral blood supply to ischemic regions (38). Bolus injection of contrast followed by sequential imaging at specific time intervals (“triphasic perfusion computed tomography”) using helical CT can yield rapid information about regions of brain ischemia and blockage of intracranial arteries (42,43). The technique involves giving a bolus injection using a power injector of contrast into an antecubital vein after a noncontrast CT has been performed. Early, middle, and late phase images are obtained 18, 30, and 80 seconds, respectively, after the contrast has been injected (42,43). Occlusion of the MCA or its branches can be detected from the images even without reformation, allowing rapid decision about thrombolysis. However, only limited CT scan cuts, usually taken along the plane of the MCAs, are

Figure 4 Computed tomography angiography showing a large aneurysm at the junction of the right vertebral and posterior inferior cerebellar arteries.

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Figure 5 Triphasic computed tomography (CT) perfusion scans in a patient with a right middle cerebral artery (MCA) occlusion. The four images on the left of each row are from the CT study, whereas the five images in each row are from diffusion-weighted magnetic resonance imaging scans at the same levels. The top row represents scans taken 18 seconds after a bolus injection of contrast. The white arrow in the fourth image in that row points to the failure of filling of the right MCA. In the second row are scans taken 30 seconds after contrast injection. The right MCA territory is darker than the left and has much less vascularity indicating less dye delivery. In the third row are scans taken 80 seconds after contrast injection. Now, the right MCA territory hypoperfusion is very well delineated. Source: Photo courtesy of Dr. Soo Joo Lee and his colleagues from the Samsung Medical Center in Seoul, Korea.

imaged. The contrast dye infusion, also enhances the brain CT images, yielding a perfusion CT scan, which is somewhat comparable to a perfusion image MR scan. Figure 5 is an example of a triphasic CT perfusion study in a patient with a right MCA occlusion.

MAGNETIC RESONANCE PERFUSION IMAGING AND COMPLETE MAGNETIC RESONANCE PROTOCOLS Brain perfusion can also be imaged using dynamic contrast-enhanced MR scans (31,44 –47). Ultrafast imaging after Gd-DTPA injection is used to calculate regional cerebral blood volume (rCBV) and regional cerebral blood flow (rCBF) and to produce the so-called perfusion-weighted images (31,44 – 49). These images show regions of reduced blood flow when compared to comparable portions of the brain. Perfusion is however quite complex. There are multiple possible measurements, such as the relative

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Figure 6 Perfusion magnetic resonance imaging, using bolus tracking of contrast in a patient with an acute right middle cerebral artery territory infarct. (A) Four T2-weighted images are shown selected from 40 images acquired every two seconds (s). The seconds after injection are noted above the images. The contrast agent arrives about 20 seconds after the beginning of the series and causes a transient decrease in the signal. The graph shows the signal drop during time in the various regions labeled 1, 2, and 3 in the figure on the left. 1 is in normal brain, 2 is in hypoperfused but not infracted brain, and 3 is in the core of the infarct. The signal decrease is more pronounced in normal brain. No signal decrease is seen in the core of the infarct. The signal drop is delayed in underperfused tissue. (B) The images were processed pixel by pixel and time to peak, mean transit time, relative cerebral blood flow, and relative cerebral blood volume maps were generated. The diffusion-weighted scan is on the left for comparison. Abbreviations: DWI, diffusion-weighted; MTT, mean transit time; rCBF, relative cerebral blood flow; rCBV, relative cerebral blood volume; TTP, time to peak. Source: From Ref. 49.

mean transit time that analyzes the rate of passage of the bolus of gadolinium through the ischemic region, the time to peak, that is, the time it takes for the maximum perfusion, and the relative cerebral blood flow and cerebral blood volumes in the ischemic area. Figure 6 (49) shows data available from DWI and perfusion MRI. The various blood flow measurements sometimes vary; some may be abnormal, whereas other measurements are within the normal range (49). Within an ischemic zone, perfusion may be quite heterogeneous, showing severe hypoperfusion in one area and minor hypoperfusion in another region (50,51). In some centers, it takes additional time to calculate and display perfusion scans, delaying comparison of the diffusion-weighted scan abnormalities with the perfusion scan. Perhaps, just as useful information can be gleaned from the diffusion-weighted scan and the MRA, as in most patients, prediction of the hypoperfused region can be estimated by the severity of the clinical signs and the location of the occluded artery. Comparison of the region of probable infarction on diffusion-weighted scans with the region of reduced perfusion (either from perfusion-weighted scans or estimated by

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Figure 7 A drawing showing information obtained using stroke magnetic resonance imaging (MRI) protocols. The upper left image is an magnetic resonance angiography, showing no flow in the left middle cerebral artery. The adjacent figure in the upper row is a diffusionweighted scan showing the area of infarction. The figure just below it is a perfusion scan that shows the region of reduced perfusion. In the right figure, the area of cell damage (infarction) is subtracted from the area of underperfusion to yield a zone of at risk tissue. The figure on the lower left is a brain tumor studied by MRI. Source: Courtesy of Dr. Peter Schellinger of Heidelberg, Germany.

the MRA results) gives an indication of the part of the brain that is underperfused but not yet infarcted (the presumed ischemic penumbra) (47,48). When the region of reduced perfusion matches the zone of infarction, progression of infarction and progression of neurological signs are rare. When this information is supplemented by vascular imaging, usually MRA, which is acquired at the same time as the diffusion-weighted and perfusion MRI scans, the treating physician has all the useful information needed to assess brain perfusion and to allow a logical decision about the likely utility of acute treatments such as thrombolysis. The drawing in Figure 7 illustrates the information gained from the MRI protocols often used to evaluate acute stroke patients. A patient with an occluded MCA shown by MRA who has a large zone of reduced perfusion within the MCA territory shown by perfusion MRI, and a relatively small region of infarction shown by DWI MRI represents the ideal candidate for thrombolysis. On the other hand, a large zone of infarction on DWI MRI, open ICA and MCA on MRA, and perfusion deficits that match or are less than the zone of infarction on diffusion-weighted scans are characteristics of candidates in whom thrombolysis has little likely utility. In patients who show a large perfusion greater than diffusion mismatch, in whom MRA shows that the artery supplying the ischemia zone is occluded, the infarct invariably enlarges if the artery is not opened quickly (48). When MRA shows patency of the intracranial artery leading to an ischemic zone, usually, no added infarction occurs (48). All of these clinically relevant data can be acquired rapidly without risk on one machine, making modern MRI imaging using the new technology far and away the best method for studying acute stroke patients. Figures 8 – 10 show results of acute MRI stroke protocols to illustrate their utility. Figure 11 shows MRI studies before and after tissue

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Figure 8 Acute magnetic resonance imaging stroke protocol in a patient with an internal carotid artery occlusion. Diffusion-weighted (DWI) scan in the upper left shows a striato-capsular zone of hyperdensity representing infarction. This area of abnormality is faintly shown on the T2-weighted image below. The upper right image is a perfusion scan showing a large area of hypoperfusion (B), larger than the infarct shown on DWI. The lower right magnetic resonance angiography image shows an occlusion of the right internal carotid artery (C arrow). Abbreviation: MRA, magnetic resonance angiography.

plaminogen activator (tPA) thrombolysis in a patient with an acute embolic occlusion of the MCA.

COMPUTED TOMOGRAPHY PERFUSION AND COMPLETE COMPUTED TOMOGRAPHY PROTOCOLS Brain perfusion can also be studied using contrast-enhanced CT techniques (52 –55). CT perfusion involves continuous CT acquisition, using a helical scanner during the

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Figure 9 Acute magnetic resonance imaging stroke protocol in a patient with a vertebral artery occlusion. The sagittal and axial diffusion-weighted sections in the upper row show a small right medullary infarct. The T2-weighted image below taken at the same time is normal. The right intracranial vertebral artery is not seen on the magnetic resonance angiography below (white arrow). Abbreviations: DWI, diffussion-weighted; MRA, magnetic resonance angiography.

administration of iodinated dye. The dye increases the intensity in brain regions that are normally perfused but is not as visible in regions that are underperfused. Transit times, cerebral blood flow, and cerebral blood volumes can be calculated using relevant software. The contrast enhancement in each pixel is compared to the contralateral mirror cerebral region. The values for mean transit time (MTT), rCBF, and rCBV are compared to normal values and known ischemic thresholds, and are used to characterize hypoperfused brain regions as being in the core of an infarct and penumbra (51). Within an established infarct (usually the core of an infarct), both rCBF and rCBV are reduced; within penumbral zones, vascular dilatation usually leads to an increase in rCBV so that rCBF is decreased but rCBV is increased (53). When perfusion CT is combined with CTA and noncontrast CT scans, comparable information to MRI protocols can be obtained (52 –55). Figure 12 (53) shows an acute and delayed stroke CT perfusion protocol in a patient with a persistent MCA occlusion. The penumbral zone in the initial scan progressed to infarction during the 28 hours between scans because the MCA did not open. The major difference between acute CT and MRI

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Figure 10 Acute magnetic resonance imaging stroke protocol in a patient with a posterior cerebral artery occlusion. The upper row shows axial and sagittal diffusion-weighted sections showing a left occipital infarct. The T2-weighted image at the same time is normal. The magnetic resonance angiography shows an embolic occlusion of the left posterior cerebral artery (white arrow). Abbreviations: DWI, diffusion-weighted; MRA, magnetic resonance angiography.

protocols is that CT does not show the acute area of infarction as well as DWI MRI. A limited number of CT sections can be shown so that some underperfused regions not included in the sections taken are missed, whereas MRI is able to show a much larger area of the brain. Posterior circulation thromboembolism is presently not well studied by CT perfusion protocols.

OTHER TECHNIQUES FOR STUDYING PERFUSION Inhalation of xenon, an inert gas that is not metabolized, has been used for decades to study cerebral blood flow. The development of xenon inhalation combined with CT scanning (XeCT) has allowed the imaging of rCBF changes on sequential standard CT slices (56,57). Xenon enhances or modifies the images, allowing visualization of relative

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Figure 11 Magnetic resonance imaging stroke protocol in a patient with an embolic occlusion of the left middle cerebral artery (MCA) given tissue plasminogen activator (tPA) 130 minutes after the onset of symptom. In the upper row, the diffusion-weighted (DWI) shows a faint left capsular infarct, and the magnetic resonance angiography shows the left MCA occlusion (small white arrow). The bottom row of scan images is taken 18 hours after tPA. The infarct (identical to that in the upper row) is shown now in both the DWI and T2-weighted images. The left MCA is partially reperfused, but there is still a region of underperfusion seen on the perfusion image on the bottom right. Abbreviations: MRA, magnetic resonance angiography; DWI, diffusion-weighted; PI, perfusion image; tPA, tissue plasminogen activator.

rCBF in regions of interest. This technique facilitates comparison of the zone of infarction on CT with regions of reduced cerebral blood flow (CBF). Single photon emission computed tomography (SPECT) uses ordinary radionuclear camera equipment and does not require a cyclotron to generate radionuclides. The most common radioisotopes used now are Technetium-99M-labeled hexamethylpropylene amineoxime and Technetium-99m labeled ethyl cysteinate dimer (Tc ECD) (58,59). Regional radiotracer uptake can be imaged in three planes. The isotopes measure rCBF rather than metabolic activity. SPECT and XeCT contain no important metabolic information. A major advantage of SPECT scanning is that imaging does not have to be performed immediately after the injection of the radionuclide. The findings on SPECT imaging represent those that were present at the time of injection. Acute treatment could be initiated immediately after the injection, even before imaging. SPECT does not show the region of infarction but can be used with CT, and can be helpful in the diagnosis and management of stroke patients, when the proper questions are asked (60,61). Positron-emission tomography (PET scanning) uses rapidly metabolized radioisotopes and is not practical in the management of patients with acute stroke.

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Figure 12 Computed tomography (CT) perfusion scans in a patient with a persistent left middle cerebral artery (MCA) occlusion taken seven hours (left column) and 35 hours (right column) after the onset of symptom. The upper row shows native CT scans before contrast that show an old right frontal infarct. A new left parasylvian infarct is visible after 35 hours. The mean transit time maps are shown in the second row. The dark area of prolonged transit times has enlarged between the scans. Similarly, the regional cerebral blood flow maps in row 3 and the regional cerebral blood volume maps in row 4 were also changed during the 28 hours between scans. In the fifth row on the left is a prognostic map that shows the area of infarction in darker grey and the area of penumbra (at-risk, underperfused but not yet infarcted brain in lighter grey). On the right in the fifth row, the previously lighter grey area is now darker, indicating an increase in the area of infarction (as mirrored in the native CT scan taken at that time). In the bottom row are CT angiography films that show the persistent MCA occlusion (white arrows). Source: From Ref. 53.

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24. Moulin T, Cattin F, Crepin-Leblond T, et al. Early CT signs in acute middle cerebral artery infarction: predictive value for subsequent infarct location and outcome. Neurology 1996; 47:366 – 375. 25. Argentino C, De Michele M, Fiorelli M, et al. Posterior circulation infarcts simulating anterior circulation stroke: perspective of the acute phase. Stroke 1996; 27:1306– 1309. 26. Lee TC, Bartlett ES, Fox A, Symons SP. The hypodense artery sign. AJNR 2005; 26: 2027– 2029. 27. Chalela JA, Haymore JB, Ezzedine MA, Daavis LA, Warach S. The hypointense MCA sign. Neurology 2002; 58:1470. 28. 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. 29. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274:1017 – 1025. 30. Caplan LR, Wolpert SM. Angiography in patients with occlusive cerebrovascular disease: a stroke neurologist and a neuroradiologist’s views. AJNR 1991; 12:593– 601. 31. Warach S, Li W, Ronthal M, Edelman R. Acute cerebral ischemia: evaluation with dynamic contrast-enhanced MR imaging and MR angiography. Radiology 1992; 182:41– 47. 32. Johnson BA, Heiserman JE, Drayer BP, Keller PJ. Intracranial MR angiography: its role in the integrated approach to brain infarction. AJNR 1994; 15:901– 908. 33. Gillard JH, Oliverio PJ, Barker PB, Oppenheimer SM, Bryan RN. MR angiography in acute cerebral ischemia of the anterior circulation: a preliminary report. AJNR 1997; 18:343 – 350. 34. Ruggieri PM, Masaryk T, Ross JS. Magnetic resonance angiography: cerebrovascular applications. Stroke 1992; 23:774– 780. 35. Wong KS, Liang EY, Lam WWM, Huang YN, Kay R. Spiral computed tomography angiography in the assessment of middle cerebral artery occlusive disease. J Neurol Neurosurg Psychiatry 1995; 59:537 –539. 36. von Kummer R, Weber J. Brain and vascular imaging in acute ischemic stroke: the potential of computed tomography. Neurology 1997; 49(suppl 4):S52– S55. 37. Alberico RA, Patel M, Casey S, et al. Evaluation of the circle of Willis with threedimensional CT angiography in patients with suspected—intracranial aneurysms. AJNR 1995; 16:1571 – 1578. 38. Knauth M, von Kummer R, Jansen O, et al. Potential of CT angiography in acute ischemic stroke AJNR 1997; 18:1001 – 1010. 39. Skutta B, Furst G, Eilers J, Ferbert A, Kuhn F-P. Intracranial stenoocclusive disease: doubledetector helical CT angiography versus digital subtraction angiography. AJNR 1999; 20:791 – 799. 40. Wildermuth S, Knauth M, Brandt T, et al. Role of CT angiography in patient selection for thrombolytic therapy in acute hemispheric stroke. Stroke 1998; 29:935 – 938. 41. Wong KS, Lam WWM, Liang E, et al. Variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis. Stroke 1996; 27:1084 – 1087. 42. Na DG, Byun HS, Lee KH, et al. Acute occlusion of the middle cerebral artery: early evaluation with triphasic helical CT-preliminary results. Radiology 1998; 207:113 – 122. 43. Lee KH, Cho S-J, Byun HS, et al. Triphasic perfusion computed tomography in acute middle cerebral artery stroke: a correlation with angiographic findings. Arch Neurol 2000; 57:990 – 999. 44. Fisher M, Prichard JW, Warach S. New magnetic resonance techniques for acute ischemic stroke. JAMA 1995; 274:908 – 911. 45. Rother J, Guckel F, Neff W, Schwartz A, Hennerici M. Assessment of regional cerebral blood flow volume in acute human stroke by use of a single-slice dynamic susceptibility contrastenhanced magnetic resonance imaging. Stroke 1996; 27:1088– 1093.

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46. Sorensen AG, Buonanno F, Gonzalez RG, et al. Hyperacute stroke: evaluation with combined multisection diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology 1996; 199:391 – 401. 47. Schlaug G, Benfield A, Baird AE, et al. The ischemic penumbra operationally defined by diffusion and perfusion MRI. Neurology 1999; 53:1528– 1537. 48. Staroselskaya I, 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. 49. Neumann-Haefelin T, Moseley ME, Albers GW. New magnetic resonance imaging methods for cerebrovascular disease: emerging clinical applications. Ann Neurol 2000; 47:559 – 570. 50. Ostergaard L, Sorensen AG, Chesler DA, et al. Combined diffusion-weighted and perfusionweighted flow heterogeneity magnetic resonance imaging in acute stroke. Stroke 2000; 31:1097 – 1103. 51. Chaves C, Silver B. Staroselskaya, Baird A, Caplan LR, Warach S. Relation of perfusionweighted magnetic resonance imaging (MRI) and clinical outcome in patients with ischemic stroke. Cerebrovasc Dis 1999; 9(suppl 1):56. 52. von Kummer R, Weber J. Brain and vascular imaging in acute ischemic stroke: the potential of computed tomography. Neurology 1997; 49(suppl 4):S52– S55. 53. Wintermark M, Reichhart M, Thiran J-P, et al. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol 2002; 51:417– 432. 54. Nabavi DG, Kloska SP, Nam E-M, et al. MOSAIC: multimodal stroke assessment using computed tomography: novel diagnostic approach for the prediction of infarction size and clinical outcome. Stroke 2002; 33:2819 – 2826. 55. Koroshetz W. Contrast computed tomography scan in acute stroke: “You can’t always get what you want but . . . you get what you need.” Ann Neurol 2002; 51:415 – 416. 56. Yonas H, Wolfson SK, Gur D, et al. Clinical experience with the use of xenon-enhanced CT blood flow mapping in cerebral vascular disease. Stroke 1984; 15:443 – 450. 57. Yonas H, Darby JM, Marks EC, Durham SR, Maxwell C. CBF measured by Xe-CT: approach to analysis and normal values. J Cereb Blood Flow Metab 1991; 11:716– 725. 58. Therapeutics and Technology Subcommittee of the Amerrican Academy of Neurology. Assessment of brain SPECT. Neurology 1996; 46:278 – 285. 59. Masdeu JC, Brass LM. SPECT imaging of stroke. J Neuroimag 1995; 5:514 – 522. 60. Caplan LR. Question-driven technology assessment: SPECT as an example. Neurology 1991; 41:187 – 191. 61. Fayad P, Brass LM. Single photon emission computed tomography in cerebrovascular disease. Stroke 1991; 22:950 – 954.

7 Transcranial Doppler Ultrasound Carlos A. Molina Neurovascular Unit, Vall d’Hebron Hospital, University of Barcelona, Barcelona, Spain

Andrei V. Alexandrov Departments of Neurology and Radiology, University of Texas Health Sciences Center, Houston, Texas, U.S.A.

INTRODUCTION Ultrasound offers a clinical tool that can detect embolism in real time (1), particularly in the form of transcranial Doppler (TCD); it can localize embolic occlusion, detect recanalization or continuing embolization, and define potential sources or pathways of embolization (2). Given the great heterogeneity in the pathophysiology of ischemic stroke, emergent noninvasive neurovascular imaging is essential for timely initiation of established therapies and development of new treatment strategies to prevent reversal of brain ischemia. Rapid identification of the location and severity of arterial obstruction can aid triage of acute stroke patients (1). Systemic thrombolysis is now increasingly used worldwide for the treatment of acute stroke. The rationale for thrombolysis in acute ischemic stroke is recanalization of an occluded artery to reestablish brain function by saving tissues at risk. Because “time is brain,” it is crucial to rapidly identify patients who will benefit from thrombolityc therapy, likely those who have embolic or atherothrombotic arterial occlusions, before lytic drug administration (3,4). Detection of an intracranial artery occlusion in patients with acute ischemic stroke depends mainly on the stroke subtype and on the time elapsed from stroke onset to the initial neurovascular evaluation. Angiography shows intracranial large artery occlusions of mostly embolic origin from cardiac or proximal arterial sources in up to 75 – 80% of acute stroke patients (5 –9). If left untreated, an acute occlusion slowly resolves over time, being no longer evident on subsequent angiographic studies or at autopsy. In one study, during the first week after stroke, the main-stem middle cerebral artery (MCA) occlusion spontaneously disappeared in 44% of cases, whereas distal MCA occlusions were no longer present in 67% of patients (10). These observations indicate that spontaneous recanalization is common after acute stroke but unfortunately often occurs too late to rescue ischemic brain tissue. The idea that early spontaneous recanalization infrequently occurs during the first few hours of acute stroke is supported by data from the placebo arm of the intra-arterial thrombolysis trials (11,12). If the first diagnostic 113

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angiogram was performed 5 hours and the second one 2 hours later, early spontaneous arterial reopening was seen in no more than 14% of patients on the second angiogram (12). Although catheter cerebral angiography is the gold standard for diagnosis of arterial occlusion, it is a costly and invasive procedure not suited for screening unselected patients for acute arterial lesions or monitoring spontaneous or therapeutically driven recanalization. In contrast, TCD is a rapid, noninvasive, and inexpensive technique that provides information about the presence and location of arterial occlusion and recanalization in real-time and at the patient’s bedside. Several studies have evaluated digital subtraction angiography (DSA), contrast-enhanced CT angiography (CTA), magnetic resonance angiography (MRA), and ultrasound in the acute stroke setting (13 –17). In one study, DSA showed complete arterial occlusions in 76% of acute stroke patients within six hours of symptom onset, of which 66% were intracranial (13). Noncontrast-enhanced TCD, in one study, had a sensitivity of 80% and a specificity of 90%, compared with DSA in patients presenting within five hours of MCA-territory stroke (17). TCD may be used as a screening test to determine the need for further angiographic studies. The bedside availability, convenience to the patient, and continuous monitoring option make TCD particularly suitable for emergency evaluations. TCD also allows real-time assessment of blood flow velocity, pulsatility, and embolization of cerebral vessels, which is not available with angiography. This chapter reviews current diagnostic criteria and clinical applications of TCD in patients with brain embolization.

TCD DIAGNOSIS OF ARTERIAL OCCLUSIONS TCD can identify isolated and tandem occlusions in the intracranial circulation. TCD is highly sensitive for residual flow surrounding an acute occlusion of a major cerebral artery. Flow patterns of occlusion on TCD are based on the relative relationship between thrombus location and arterial segment insonated (Fig. 1). Zanette et al. (10,18) first noted the different patterns of intracranial artery occlusion on TCD. A proximal MCA occlusion was defined as the absence of flow or a minimal flow signal throughout the MCA at an insonation depth between 45 and 65 mm accompanied by flow diversion in the ipsilateral anterior (ACA) and posterior cerebral arteries (PCA). A diffuse dampening of mean flow velocity in the affected MCA .21% versus unaffected MCA is regarded as distal MCA occlusion. Recanalization on follow-up TCD is diagnosed when dampened flow appears in a previously demonstrated proximal MCA occlusion (partial recanalization) or when a previous absent, minimal, or dampened flow comes within the normal range (complete recanalization). No change in the abnormal waveforms indicates that no recanalization has occurred. Using these patterns Toni et al. (19) showed that a normal TCD examination within the first six hours of stroke onset independently predicted spontaneous neurological improvement and good long-term outcome. Conversely, persistent occlusion at six hours was an independent predictor of early neurological worsening and poor clinical outcome. TCD patterns of occlusion and recanalization described by Zanette et al. (20 – 23) have been further refined for use in patients undergoing thrombolysis. The thrombolysis in brain ischemia (TIBI) grading system addresses the dynamic nature of acute occlusion and recanalization processes (21). This grading system had a good correlation with angiography with a sensitivity and specificity values .90% for the MCA territory and .86% for the vertebrobasilar territory (22,23).

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Figure 1 Embolic MCA occlusion. Angiography shows an acute embolic occlusion of the MCA with residual flow around a “sausage-shaped” thrombus. The drawing shows representative abnormal thrombolysis in brain ischemia waveforms that can be obtained along the middle cerebral artery stem obstructed by an embolus. Abbreviations: MCA, middle cerebral artery; TIBI, thrombolysis in brain ischemia.

Complete MCA occlusion is defined by absent (TIBI 0) or minimal (TIBI 1) signals (Fig. 2) at one or more depths (range, 40 –65 mm). MCA occlusion is often accompanied by flow diversion to the ACA or PCA (mean flow velocity ACA . contralateral MCA, or PCA . contralateral MCA). Detection of a short systolic spike with no end-diastolic flow is regarded as a minimal flow signal. In this case, either terminal internal carotid artery (ICA) or PCA flow signals had to be identified from the ipsilateral temporal window to exclude suboptimal ultrasound penetration through the bone. Absent or minimal flow signals may be confirmed by insonation from the contra-lateral temporal window. Partial MCA occlusion is diagnosed when blunted (TIBI 2) or dampened (TIBI 3) signals (Fig. 2) at 40 –65 mm depths with potential flow diversion signs to the ACA or

Figure 2

The TIBI flow grades. Abbreviation: TIBI, thrombolysis in brain ischemia.

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PCA. A blunted flow signal is characterized by delayed (0.2 seconds) systolic flow acceleration with a pulsatility index (PI) ,1.2. The PI [Gosling-King] is determined by the formula peak systolic velocity-end diastolic velocity/mean flow velocity. A PI ,1.2 indicates low-resistance flow diversion to branching vessels or a residual positive enddiastolic flow at the site of occlusion MCA. A dampened (TIBI 3) flow signal is identified when normal systolic flow acceleration is present in the pulsatile MCA waveform with mean flow velocities ,70% of the contralateral MCA and positive end-diastolic flow with variable PI values. Complete recanalization is diagnosed if low-resistance stenotic (TIBI 4) or normal (TIBI 5) signals appear throughout the MCA stem (depths 40 to 65 mm), with no other signs of persisting distal occlusion (i.e., dampened distal signal or flow diversion). In cases with residual stenosis on TCD, low-resistance flow indicates patency and perfusion of the distal vasculature. The TIBI flow grading system has a good correlation with the thrombolysis in myocardial infarction (TIMI) criteria (24). The TIMI score is an angiography-based grading system, that was originally developed and used to describe flow in the coronary arteries (24). Its clinical use has been extended to the cerebral circulation (12). TIMI is based on the degree of opacification of the distal vessels on DSA. Complete occlusion (TIMI grade 0 or I) is defined as no or minimal perfusion with no opacification of the distal vessels on DSA and no reconstitution of distal flow on MRA or CTA. Partial occlusion (TIMI grade II) is defined as an obstruction that results in delayed opacification of the distal vessels on DSA and appearance of distal slow-flow filling of decreased intensity on MRA or CTA. Complete recanalization (TIMI grade III) is defined as unimpeded perfusion of the distal vasculature regardless of whether a residual stenosis or a focal flow gap is present. However, the TIMI grading system has limitations when applied to assess recanalization of intracranial arteries. The TIMI system evaluates local recanalization, and, therefore, it does not accurately reflect the dynamic nature of the recanalization process during stroke thrombolysis. For instance, the phenomenon of proximal clot fragmentation, followed by downstream embolization occluding smaller arteries, cannot be adequately represented by the TIMI system. Identification of a severe carotid obstruction ipsilateral to an MCA occlusion, the so-called tandem ICA/MCA occlusion, requires a battery of flow findings on TCD. This battery was described by Wilterdink et al. and further expanded by Christou et al. (25,26). A broad TCD battery includes three major and three minor criteria (26). Major criteria are: 1. 2. 3.

Collateral flow signals (anterior, posterior communicating, or ophthalmic arteries). Abnormal ICA siphon or terminal ICA signals (absent, minimal, blunted, dampened, or stenotic waveforms). Delayed systolic flow acceleration in the MCA (arrival of maximum frequencies in late systole)

Minor criteria are: 1. 2. 3.

Decreased pulsatility index (0.6 or interhemispheric difference .30%). Flow diversion signs (velocity: PCA . MCA, PCA . ICA, and contralateral ACA . MCA). Compensatory velocity increase (.20% increase in the contralateral hemispheric vessels or vertebrobasilar arteries).

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In acute stroke patients, this broad TCD battery has shown a sensitivity of 79% and specificity of 86% against angiography to detect severe ICA stenoses or occlusion (26). Acute tandem ICA/MCA occlusion is diagnosed with TCD if abnormal TIBI MCA waveforms or an asonic MCA segment is present with one major or two minor findings according to the broad TCD battery for an ICA obstruction (27). In other words, an abnormal TIBI waveform indicates the presence of an MCA occlusion, whereas an additional finding of at least one collateral channel indicates a proximal hemodynamically significant lesion in the feeding vessel. TCD can identify not only residual flow signals in the acutely occluded artery but also major collateral channels in both the anterior and posterior circulations. In patients with tandem ICA/MCA occlusions, the number and extent of collateral flow through the ipsilateral ACA and PCA are associated with less severe stroke symptoms as measured by the National Institute of Health Stroke Scale (NIHSS) score (27). In fact, fluctuations of neurological signs in the absence of recanalization or reocclusion on TCD may reflect changes in perfusion through collateral channels. Similarly, in patients with basilar artery occlusion, the presence of a reversed flow in the distal basilar artery has been shown to be associated with a lower NIHSS score and good short- and long-term outcome (28).

TCD MONITORING DURING THROMBOLYSIS The National Institutes of Neurological Disorders (NINDS) rtPA stroke study showed a beneficial effect of intravenous recombinant tissue plasminogen activator (tPA), when given ,3 hours after symptom onset (29). However, the NINDS trial, like other randomized clinical trials of intravenous thrombolysis, did not monitor presence and location of arterial occlusion and recanalization at different times after stroke (30 – 34). General agreement exists that clinical benefit of tPA in ischemic stroke is linked to accelerated clot lysis and early recanalization (29,30). However, trials of intravenous thromblytic therapies did not evaluate whether clinical efficacy was dependent on the presence of arterial occlusion and whether clinical improvement was linked to subsequent recanalization after thrombolytic therapy or to spontaneous recanalization in patients receiving placebo (29 – 34). Nonrandomized angiographic studies with intravenous tPA showed recanalization rates of 25 –50% (11,35,36). Overall, the rate of early tPAinduced recanalization (partial or complete) on repeat TCD examinations within the first six hours of symptom was as high as 66 – 70% (37,38) compared with only 13– 14% of spontaneous recanalization rates on TCD and angiography (12,13,37). In continuous TCD-monitoring studies, when intravenous tPA was given within ,3 hours of stroke onset, the rate of complete and partial recanalization within two hours after tPA bolus was 30% and 40%, respectively (38). Moreover, a case-control TCD study in patients with cardioembolic strokes showed that intravenous tPA increased the rates of complete and partial recanalization 8-fold and 3-fold within six hours of symptom onset (37). The timing of arterial recanalization after tPA therapy, as determined by TCD, correlates with clinical recovery from stroke. Christou et al. (39) studied 40 stroke patients who were continuously monitored with TCD for one hour after tPA bolus. In this study, recanalization on TCD occurred at the mean time of 251 + 171 minutes after stroke onset, and within 60 minutes of tPA bolus in 75% of patients who were recanalized. Moreover, the timing of artery reopening inversely correlated with early improvement in the NIHSS scores within the next hour as well as at 24 hours. Importantly, this study showed the existence of a 300-minute-after-symptom-onset window for arterial

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recanalization to achieve early complete clinical recovery in human stroke. These findings parallel animal models of cerebral ischemia, suggesting an S-shaped relationship between the duration of ischemia and the reversibility of paralysis with subsequent brain infarction (39,40). During the last few years, mounting evidence from continuous TCD-monitoring studies confirmed initial clinical observations in stroke patients, suggesting that spontaneous embolus migration with brain reperfusion may lead to a spectacular shrinking deficit in patients with cardioembolic stroke (41 –43). The dynamic process of thrombus dissolution during fibrinolytic therapy may be accurately delineated by continuous TCD monitoring (43). Shortly after tPA administration, TCD can show in real-time the beginning, duration, amount, and time to maximum completeness of recanalization and characteristic embolic signals indicating thrombus fragmentation or the presence of emboligenic surface (43,44) (Fig. 3). Alexandrov et al. (43) developed a sonographic classification to assess the speed of intracranial clot lysis during continuous TCD monitoring (43). The beginning and continuation of recanalization was determined when one of the following flow signal changes is detected on TCD (Fig. 3): 1. 2. 3. 4. 5.

Waveform change by one TIBI residual flow grade (for example, absent to minimal, minimal to blunted, and minimal to normal). Appearance of embolic signals (transient high-intensity signals of variable duration). Flow velocity improvement by 30% at a constant angle of insonation. Signal intensity and velocity improvement of variable duration at constant gain/ sample volume/scale settings. Appearance of flow signals with variable (.30%) pulsatility indexes and amplitude of systolic peaks.

The speed of clot lysis during continuous TCD monitoring was categorized into sudden (abrupt appearance of a normal or low-resistance signal), stepwise (gradual flow improvement over 1 –29 minutes), or slow (flow improvement in 30 minutes) recanalization (43). Sudden recanalization reflects rapid and complete restoration of flow; stepwise and slow recanalizations indicate proximal clot fragmentation, downstream embolization, and continued clot migration (Fig. 4). These patterns may represent a surrogate measurement of the efficacy of thrombolytic therapy. Although sudden recanalization was observed in only 8– 12% of patients treated with intravenous tPA, this pattern has been associated with a higher degree of neurological improvement and better long-term outcome than stepwise and slow recanalization, presumably due to faster and more complete embolus dissolution that occurred closer to stroke symptoms onset (43,45). Moreover, the speed of clot dissolution on TCD predicts the evolution of the ischemic brain tissue on diffusion-weighted imaging (DWI) (46). Molina et al. (46) showed that sudden clot lysis produced slower lesion growth on DWI and greater likelihood of DWI lesion reversal at 48-hour MRI than slower clot lysis. Although treatment with tPA is effective across different stroke mechanisms (29), response to tPA varies, depending on the size, composition, and source of the offending thrombus. Specific structural aspects of thrombi have received attention with respect to lytic susceptibility and penetration of thrombolytic agents. Old, platelet-rich, and wellorganized thrombi formed under flow conditions are more resistant to thrombolysis than fresh, fibrin- and red-cell rich clots formed under conditions of stasis (47 –49). Moreover, physical structure and biochemical and cellular composition of brain emboli may differ,

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Figure 3 Signs of the beginning and continuation of arterial recanalization. (1) Waveform improvement by one or more TIBI residual flow grade: the first set illustrates flow changes from a minimal to blunted waveform (appearance of positive end-diastolic flow and rounded systolic complex); (2) Appearance of embolic signals: the second set of waveforms illustrate dampened and normal flow signals with multiple transient high intensity signals of variable duration with characteristic chirp or poplike sounds (arrows); (3,4) Flow velocity improvement by 30% or more and the signal intensity or improvement: this set shows flow tracing obtained at a constant angle of insonation with mean flow velocity improvement from 15 cm to 30 cm, preceded by the improvement in the strength (brightness) of the residual flow signal (middle set); (5) Appearance of flow signals with variable (.30%) amplitude of systolic peaks and pulsatility: a turbulent high frequency, high resistance stenotic flow signal (bottom left); variable velocities with transient appearance of flow in a branching vessel below the baseline (arrow, bottom right). Abbreviation: TIBI, thrombolysis in brain ischemia. Source: From Ref. 43.

depending on whether the embolic source is a thrombus engrafted in a proximal atherosclerotic lesion or a clot formed in cardiac cavities. In a recent study of patients with proximal MCA occlusion treated with intravenous tPA, early recanalization was shown to be more frequent, faster, and more complete in cardioembolic strokes as compared with other stroke subtypes (45). Moreover, cardiac

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Figure 4 Duration of arterial recanalization. (I) Sudden (abrupt appearance of a normal or stenotic low resistance signal). (a) TCD shows a minimal signal in the MCA at the time of tPA bolus. (b) At 31 minutes after bolus the first improvement in signal intensity was noticed and marked as “beginning” of recanalization. (c) In less than five seconds, the first low resistance signal was detected with normal waveform. (d) After 30 seconds, a strong normal flow velocity signal was detected. Recanalization started at 31 minutes after tPA bolus, its duration was 35 seconds, and timing of complete recanalization of the distal M1 MCA segment (TIBI grade III equivalent) was 32 minutes after tPA bolus. (II) Stepwise (flow improvement over 1–29 minutes). (a) TCD shows a minimal signal in the mid-to-distal M1 MCA at the time of tPA bolus. (b) After nine minutes, TCD shows the first improvement in the amplitude of systolic velocities (beginning of recanalization). The absence of end-diastolic velocities still indicates minimal TIBI flow signal and persisting occlusion. (c) At 14 minutes, positive end-diastolic flow is detected with rounded systolic shape of the waveform (TIBI blunted signal) with flow improvement by TIBI-1 grade. Note high-intensity bruits during each cardiac cycle with possible embolic signals. (d) At 16 minutes, TCD shows high resistance turbulent stenotic signals with elevated and variable systolic velocities, which are replaced by normal waveforms at 18 minutes. (e) At this point, TCD findings indicate that the M1 MCA patency at the site of insonation is restored. Further improvement in flow velocity, pulsatility, and strength of the signal was detected 18–20 minutes after bolus (f) indicating continuous flow recovery presumably due to distal clot migration beyond M2 MCA, bifurcation TCD shows the beginning of recanalization at nine minutes, duration of 11 minutes, and timing of complete (TIMI grade III equivalent) recanalization at 20 minutes after tPA bolus. (III) Slow (30–60 minutes). (a) At the time of tPA bolus, TCD shows a minimal flow signal at the M1 MCA origin (above baseline) and a flow signal below baseline from the proximal A1 ACA with mean flow velocity of 24 cm. (b) At 12 minutes after bolus, slow positive end-diastolic flow appears in the proximal M1 MCA indicating the beginning of recanalization. A decrease in the ACA flow signal may indicate clot movement or breakup at its proximal part. Variable M1 MCA and A1 ACA flow velocities with dampened TIBI flow grade are seen during the next 40 minutes (c) with arrival of the dampened flow signal with the highest mean flow velocity of 28 cm and improved A1 ACA velocities of 54 cm at 54 minutes after tPA bolus. (d) TCD findings indicate the beginning of recanalization at 12 minutes, duration of 42 minutes, and timing of partial (TIBI grade II equivalent) recanalization with continuing flow diversion to ACA at 54 minutes after tPA bolus. Abbreviations: TCD, transcranial doppler; MCA, middle cerebral artery; tPA, tissue plasminogen activator; ACA, anterior cerebral artery. Source: From Ref. 43.

sources of emboli were identified in 81% of patients who showed a sudden clot breakup during tPA infusion (45). On the other hand, the presence of concomitant ipsilateral severe ICA disease was associated with lower MCA recanalization rates and poorer clinical outcomes, as shown in another study (50).

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Faster recanalization rates point to the likelihood that cardioembolic strokes may be caused by emboli that are more uniform fibrin-rich red clots (45). Given the high binding affinity of tPA for fibrin, tPA penetrates and distributes more homogeneously in fibrin-rich clots, leading to more rapid and complete clot dissolution (greater likelihood of sudden and stepwise recanalizations). In contrast, in well-organized and platelet-rich clots, penetration and distribution of tPA are limited, which may result in nonuniform clot softening and degradation, mostly from the outside of the clot. As a result, the clot shrinks and moves distally, lodging in smaller arteries, which can prolong ischemia (tendency to slow and frequently incomplete recanalizations). This may explain the observation that slower speed of recanalization is associated with less neurological improvement and worse long-term outcomes compared to faster recanalizations after initiation of tPA therapy (43,45). Slow and incomplete recanalization is often reflected by dampened flow signals (TIBI grade III). This waveform indicates embolus location in the distal branches and increased resistance to flow in the distal circulatory bed affected by ischemia (21). This hemodynamic observation reflects impaired ability to washout or clear embolic debris through the circulatory bed. Caplan and Hennerici (51) posit that impaired washout intertwines embolization with delayed emboli clearance in hypoperfused brain tissues and the two together (emboli and hypoperfusion) contribute to the development of brain infarction. On TCD, this impaired washout of proximal emboli is also reflected by abnormal TIBI waveforms (0 – 2) that indicate persistent proximal arterial occlusion. Large emboli can cause hypoperfusion that is strongly linked to brain ischemia and infarction as there is a close correlation of (i) the severity of arterial stenosis with brain infarction, (ii) impaired functional blood flow reserve in patients with carotid artery disease and subsequent brain infarction, (iii) reduced collateral blood flow with poor prognosis after thrombolysis, and (iv) stroke-related neurologic deficits after cardiac and carotid surgery to hypoperfusion during surgery (51). Furthermore, microembolization is common in patients with severe symptomatic carotid artery stenosis and during and after cardiac/carotid surgery. All these factors predispose to decreased ability of brain circulation to effectively clear emboli. Ultrasound testing can directly identify severe stenoses, impaired vasomotor reactivity, poor collaterals, and hypoperfusion states (2,21,52). Continuous TCD monitoring also shows the dynamic process of brain embolization and its impact on flow waveforms and velocities in real time (53).

DETECTION OF INTRACRANIAL ARTERY STENOSIS AND ARTERY-TO-ARTERY EMBOLISM Intracranial atherosclerosis is the leading cause of approximately 8% of all strokes in Caucasian patients and is the most commonly found vascular lesion in Asian stroke patients (54,55). The traditional dependence on invasive vascular-imaging techniques to diagnose intracranial artery stenosis has probably underestimated its real prevalence. TCD represents a reliable noninvasive tool for the diagnosis and follow-up of intracranial stenosis (2,51 –61). TCD criteria for intracranial stenosis have been validated with conventional angiography. Sensitivity and specificity values vary depending on the intracranial artery studied, severity of arterial stenosis, and arterial segment insonated. The highest sensitivity and specificity values correspond to moderate and severe stenosis located in the proximal MCA, PCA, and basilar artery.

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TCD diagnosis of intracranial stenoses is based on the following criteria (49): (i) local flow acceleration, (ii) disturbed flow with spectral broadening in the region of stenosis, and (iii) reduced maximum and mean flow velocities distal to the stenosis (49). MCA stenosis is diagnosed if the mean blood flow velocity (MFV) exceeds 100 cm/s or peak systolic flow velocities exceed 140– 160 cm/s, with side-to-side differences more than 30%. In a study with angiographic control, MFV threshold of 100 cm/s is better differentiated (50%) than MCA stenosis (,50%) with sensitivity 100%, specificity 98%, positive predictive value (PPV) 88%, and negative predictive value (NPV) 95% (60). Regardless of using peak or mean velocities for the maximum flow acceleration thresholds, the ratio to a nonaffected MCA should be used to decide on the severity of the stenosis. Mild (,50%) lesions will produce normal stenotic flow velocity ratio 1:,2, moderate (50 –69%) lesions have 1:2, and severe (.70%) lesions have 1:3 ratios (60,62). Increasing velocity is associated with stenosis progression that occurs more frequently in symptomatic patients (55,63). Intracranial arterial stenoses may have emboligenic surfaces, and TCD can detect embolic signals originating in the M1 MCA and insonation along the distal artery can show artery-to-artery embolization from isolated intracranial lesions (63 – 66). These emboli, which appear in clusters or even individually, may change the flow velocity, indicating that their size is comparable to the residual lumen (65,66). TCD detection of embolic signals has been shown to be linked to MCA stenoses with higher stroke recurrence (63 –67a).

EMBOLI MONITORING Detection of emboli with TCD is based on the definition of microembolic signals (MES) provided by the International Cerebral Hemodynamics Society consensus (67). MES, as shown in Figure 3, have the following characteristics on spectral Doppler analysis: (i) random occurrence during the cardiac cycle, (ii) brief duration (usually ,0.1 sec), (iii) high intensity (.3 dB over background), (iv) primarily unidirectional signals (if fast Fourier transformation is used), and (v) audible component (chirp, pop). The power motion-mode Doppler adds extra dimensions to the process of emboli detection (68). It shows tracks of emboli in time and space and provides simultaneous real-time assessment of emboli passing through different vessels (Fig. 5), thereby increasing the yield of emboli detection with a single transducer (68 – 70). A new definition is proposed to identify emboli using power m-mode Doppler that takes into account embolus motion in one direction on m-mode display at a minimum spatial extent of 7.5 mm and temporal extent of 30 ms (70). Practically all MES detected by TCD are asymptomatic as the size of the particles producing them is usually comparable to or even smaller than the diameter of brain capillaries (71). However, their cumulative count is related to the incidence of neuropsychological deficits after cardiopulmonary bypass and (72,73), stroke after carotid endarterectomy (52,74 – 77). The significance of MES as a risk factor for ischemic stroke and parameter platelet inhibition efficacy is emerging (78). Strict standards should be followed when an interpreter documents and reports microemboli on TCD (78). The gold standard for MES identification still remains the on- or off-line interpretation of real-time, videotaped, or digitally taped flow signals (78 –80). If spectral TCD is used, recordings should be obtained with minimal gain at a fixed angle of insonation with a small (,10 mm) sample volume. The probe should be maintained with a fixation device for at least 0.5– 1 hour while monitoring for detection of spontaneous embolization. Prolonged monitoring times, two-channel simultaneous

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Figure 5 Power m-mode display of embolic signals. (A) A single embolus (arrow) originating in a dissolving thrombus in the MCA in an acute stroke patient treated with intravenous tPA for a cardioembolic MCA occlusion. Note that m-mode tracks embolic path in time and space along the distal M1 segment. (B) Bilateral simultaneous insonation of both MCAs in a patient undergoing cardiothoracic surgery experiencing massive air embolization due to perforated pulmonary artery. (C) Positive “bubble” testing for the right-to-left shunt in a patient with paradoxical embolism due to deep venous thrombosis and a large and functional patent foramen ovale. Abbreviations: MCA, middle cerebral artery; tPA, tissue plasminogen activator.

registration, and the use of power m-mode can improve the yield of emboli detection. Differentiation of embolic signals from artifacts is possible with commercially available software.

DETECTION OF RIGHT-TO-LEFT SHUNTS Testing for right-to-left shunt is essential in patients with stroke or transient ischemic attack due to suspected paradoxical embolism (81). Although TCD cannot localize the shunt, that is, patent foramen ovale (PFO) or anterior septal defect, it provides complementary information to transesophageal echocardiography (TEE). For instance, “bubble” testing with TCD can be done in a matter of minutes at the bedside with minimal or no discomfort to the patient. TCD can offer results of shunt detection with accuracy equal to TEE for detection of functional PFO’s and detect shunt presence even after TEE is negative, that is, in case of pulmonary arteriovenous malformation or inability of patient to perform Valsalva maneuver during TEE (82,83). To optimize TCD performance, the following protocol should be followed: 1.

The patient is in the supine position, and an 18-gauge needle is inserted into the cubital vein.

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2. 3. 4. 5. 6. 7.

8.

A 3-way stop-cock connector with two 10 mL syringes is connected to iv access. Nine milliliter of isotonic (preferably bacteriostatic) saline is forcefully mixed with 1 cc of air. Less than 1 mL of the patient’s blood may be suctioned into the syringe for better bubble formation with agitation. At least one MCA is monitored with TCD. The first bolus injection of agitated saline is made with the patient breathing normally. A second bolus injection of similarly prepared agitated saline is made with 10 sec Valsalva maneuver initiated five seconds after beginning of saline injection. If negative, TCD-monitoring is extended up to one minute in order to detect potentially late-arriving bubbles, suggesting a pulmonary arteriovenous shunt.

At times, a so-called curtain of almost continuous signals develops. A four-level categorization is proposed by the International Consensus criteria (83): 1. 2. 3. 4.

No microembolic signals were detected (negative “bubble” test). From one to ten MES detected (positive “bubble” test). More than 10 MES detected with no curtain. A curtain test indicates the presence of a large and functional shunt (Fig. 5).

The report of the findings should comment on whether or not MES or bubbles were detected at rest or provoked by Valsalva maneuver. If few single bubbles were detected at rest and curtain appeared with Valsalva, this also needs to be reflected in the report. Interest in shunt-testing with TCD is increasing. Besides stroke with paradoxical embolism, functional PFO may play a significant negative role in altitude decompression of patients undergoing hip replacement and patients who have migraine with aura (84 – 87). Noninvasive shunt detection, functional assessment, and percutaneous closure open new possibilities in management of these patients.

REFERENCES 1. Grotta JC. Ultrasound: a clinician’s perspective. In: Alexandrov AV, ed. Cerebrovascular Ultrasound in Stroke Prevention and Treatment. New York: Futura Blackwell Publishing, 2003. 2. Sloan MA et al. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004; 62:1468 – 1481. 3. Caplan LR, Mohr JP, Kistler JP, Koroshetz W. Should thrombolytic therapy be the first-line treatment for acute ischemic stroke? Thrombolysis—not a panacea for ischemic stroke. N Engl J Med 1997; 337:1309 – 1310. 4. Grotta JC. t-PA—the best current option for most patients. N Engl J Med 1997; 337: 1310– 1312. 5. Bladin PF. A radiologic and pathologic study of embolism of the internal carotid-middle cerebral arterial axis. Radiology 1964; 82:615 – 624. 6. Fieschi C, Bozzao L. Transient embolic occlusion of the middle cerebral and internal arteries in cerebral apoplexy. J Neurol Neurosurg Psychiatry 1969; 32:236– 240. 7. Dalal PM, Shah PM, Sheth SC, Deshpande CK. Cerebral embolism: angiographic observation on spontaneous clot lysis. Lancet 1965; 9:61– 64.

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27. El-Mitwalli A, Saad M, Christou I, Malkoff M, Alexandrov AV. Clinical and sonographic pattern of tandem internal carotid artery/middle cerebral artery occlusion in tissue plasminogen activator-treated patients. Stroke 2002; 33:99– 102. 28. Ribo M, Garami Z, Uchino K, Song J, Molina CA, Alexandrov AV. Detection of reversed basilar flow with power-motion Doppler after acute occlusion predicts favorable outcome. Stroke 2004; 35:79 – 82. 29. The National Institutes of Neurological Disorders, and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581 – 1587. 30. Hacke W, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). J Am Med Assoc 1995; 274:1017– 1025. 31. MAST-E. Thrombolytic therapy with streptokinase in acute ischemic stroke: the Multicenter Acute Stroke Trial: European Study group. N Engl J Med 1996; 335:145– 150. 32. MAST-I. Randomised controlled trial of streptokinase, aspirin and combination of both in treatment of acute ischemic stroke: Multicenter Acute Stroke Trial-Italy (MAST-I) Group. Lancet 1995; 346:1509 – 1514. 33. Hacke W et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet 1998; 352:1245– 1251. 34. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS study: a randomized controlled trial: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. J Am Med Assoc 1999; 282:2019 – 2026. 35. Del Zoppo GJ et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992; 32:78– 86. 36. von Kummer R, Holle R, Rosin L, Forsting M, Hacke W. Does arterial recanalization improve outcome in carotid territory stroke? Stroke 1995; 26:581– 587. 37. Molina CA, Montaner J, Abilleira S, Arenillas JF, Ribo M, Huertas R, Romero F, AlvarezSabin J. Time course of tissue plasminogen activator – induced recanalization in acute cardioembolic stroke: a case-control study. Stroke 2001; 32:2821 – 2827. 38. Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber P, Burgin WS, Malkoff M, Wojner AW, Grotta JC. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuous monitored with 2-MHz transcranial Doppler monitoring. Stroke 2000; 31:610 – 614. 39. Christou I, Alexandrov AV, Burgin WS, Wojner AW, Felberg RA, Malkoff M, Grotta JC. Timing of recanalization after tissue plasminogen activator therapy determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000; 31:1812 – 1816. 40. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981; 54:773 – 782. 41. Minematsu K, Yamaguchi T, Omae T. “Spectacular shrinking deficit”: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology 1992; 42:157 –162. 42. Baird AE, Donnan GA, Austin MC, McKay WJ. Early reperfusion in the “spectacular shrinking deficit” demonstrated by single-photon emission computed tomography. Neurology 1995; 45:1335 – 1339. 43. Alexandrov AV, Burgin SW, 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. 44. Alexandrov AV, Demchuk AM, Felberg RA, Grotta JC, Krieger D. Intracranial clot dissolution is associated with embolic signals on transcranial Doppler. J Neuroimaging 2000; 10:27– 32. 45. Molina CA, Montaner J, Arenillas JF, Ribo M, Rubiera M, Alvarez-Sabı´n J. Differential pattern of tissue plasminogen activator – induced proximal middle cerebral artery recanalization among stroke subtypes. Stroke 2004; 35:486– 490. 46. Molina CA, Rovira A, Arenillas JF, Grive E, Montaner J, Ribo´ M, Sanchez E, Alvarez-Sabı´n J. Speed of tPA-induced clot dissolution predicts the evolution of diffusion-weighted imaging lesion in hyperacute stroke. Stroke 2004; 35:237. [Abstract].

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68. Moehhring MA, Spencer MP. Power M-mode transcranial Doppler ultrasound and simultaneous single gate spectrogram. Ultrasound Med Biol 2002; 28:49 –57. 69. Alexandrov AV, Demchuk AM, Burgin WS. Insonation method and diagnostic flow signatures for transcranial power motion (M-mode) Doppler. J Neuroimaging 2002; 12:236 – 244. 70. Saqqur M, Dean N, Schebel M, Hill MD, Salam A, Shuaib A, Demchuk AM. Improved detection of microbubble signals using power M-mode Doppler. Stroke 2004; 35:14 – 17. 71. Brucher R, Russel D. Background and principles. In: Tegeler CH, Babikian VL, Gomez CR, eds. Neurosonology. St Louis: Mosby, 1996:231 – 234. 72. Clark RE, Brillman J, Davis DA, Lovell MR, Price TR, Magovern GJ. Microemboli during coronary artery bypass grafting. Genesis and effect on outcome. J Thorac Cardiovasc Surg 1995; 109(2):249– 257. 73. Diegeler A, Hirsch R, Schneider F, Schilling LO, Falk V, Rauch T, Mohr FW. Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation. Ann Thorac Surg 2000; 69(4):1162– 1166. 74. Jansen C, Moll FL, Vermeulen FE, van Haelst JM, Ackerstaff RG. Continuous transcranial Doppler ultrasonography and electroencephalography during carotid endarterectomy: a multimodal monitoring system to detect intraoperative ischemia. Ann Vasc Surg 1993; 7(1): 95 – 101. 75. Ackerstaff RG, Jansen C, Moll FL, Vermeulen FE, Hamerlijnck RP, Mauser HW. The significance of microemboli detection by means of transcranial Doppler ultrasonography monitoring in carotid endarterectomy. J Vasc Surg 1995; 21(6):963 –969. 76. Ackerstaff RG, Moons KG, van de Vlasakker CJ, Moll FL, Vermeulen FE, Algra A, Spencer MP. Association of intraoperative transcranial doppler monitoring variables with stroke from carotid endarterectomy. Stroke 2000; 31(8):1817 –1823. 77. Kaposzta Z, Clifton A, Molloy J, Martin JF, Markus HS. S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty. Circulation 2002; 106(24):3057– 3062. 78. Ringelstein EB, Droste DW, Babikian VL, Evans DH, Grosset DG, Kaps M, Markus HS, Russell D, Siebler M. Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection. Stroke 1998; 29:725 –729. 79. Cullinane M et al. Evaluation of new online automated embolic signal detection algorithm, including comparison with panel of international experts. Stroke 2000; 31(6):1335 –1341. 80. Markus HS. Transcranial Doppler ultrasound. Br Med Bull 2000; 56(2):378 –388. 81. Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, Drobinski G, Thomas D, Grosgogeat Y. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148 – 1152. 82. Zanette EM, Mancini G, De Castro S, Solaro M, Cartoni D, Chiarotti F. Patent foramen ovale and transcranial Doppler: Comparison of different procedures. Stroke 1996; 27:2251– 2255. 83. Jauss M, Zanette E. Detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography. Cerebrovasc Dis 2000; 10:490 – 496. 84. Foster PP, Boriek AM, Butler BD, Gernhardt ML, Bove AA. Patent foramen ovale and paradoxical systemic embolism: a bibliographic review. Aviat Space Environ Med 2003; 74(6 Pt 2):B1 – B64. 85. Colonna DM, Kilgus D, Brown W, Challa V, Stump DA, Moody DM. Acute brain fat embolization occurring after total hip arthroplasty in the absence of a patent foramen ovale. Anesthesiology 2002; 96(4):1027– 1029. 86. Anzola GP, Magoni M, Guindani M, Rozzini L, Dalla Volta G. Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study. Neurology 1999; 52(8): 1622– 1625. 87. Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 2000; 356:1648 – 1651.

PART III:

DONOR SOURCES—NATURE, FREQUENCY, RECOGNITION

8 Cardiac Sources of Embolism: The Usual Suspects Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Warren J. Manning Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Our understanding of cardiac sources of embolism has expanded greatly over the past 50 years. During the 1950s, the only two cardiac disorders that were accepted as risk factors for embolism were rheumatic mitral stenosis in combination with atrial fibrillation and recent myocardial infarction. We now know that many cardiac conditions increase risk of cardiac thrombosis and embolism (1,2). Advances in cardiac imaging [echocardiography and, more recently, cardiovascular magnetic resonance and cardiac computed tomography (CT)] and the expanding data derived from large epidemiologic studies (e.g., the Framingham Heart Study) and large prospective clinical trials have made it possible during the past three decades to noninvasively diagnose cardiac disorders more definitively and to attempt to estimate the risk of embolism and benefit of specific therapies. Cardiac disorders that carry a risk of brain embolism can be divided into seven groups: (i) arrhythmias, especially atrial fibrillation and atrial flutter, (ii) valvular heart diseases, including mitral stenosis, prosthetic heart valves, infective endocarditis, and marantic endocarditis, (iii) ventricular myocardial abnormalities leading to dilated ventricles, especially those related to coronary artery disease, and myocarditis, (iv) intracardiac masses, especially tumors, such as myxomas and thrombi, (v) intracardiac shunts, especially intra-atrial septal defects and patent foramen ovale (PFO), that allow emboli forming in the peripheral veins to gain access to the systemic circulation (rather than being filtered by the lungs) leading to so-called paradoxical embolism, (vi) atrial lesions, such as dilated atria, thrombi, tumors (e.g., myxomas and fibroelastomas), and atrial septal aneurysms, and (vii) aortic lesions, such as aortic atherosclerosis. In 1856, Virchow (3,4) described three requirements for the development of thrombi: a region of circulatory stasis, injury to endothelial surfaces, and increased blood coagulability. In areas of stasis, a low shear rate and other factors activate the classical coagulation cascade, leading to the formation of erythrocyte-fibrin thrombi. Stasis occurs most often in the atria and atrial appendages in patients with atrial 129

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fibrillation and dilated cardiomyopathy, in the ventricular chambers in patients with global dysfunction, and in regions of akinesis, dyskinesis, and aneurysm. Abnormal myocardial endothelium occurs in patients with myocardial infarcts, ventricular aneurysms, and inflammatory and other myocardopathies and endocardial disorders. Valvular endothelium can be damaged by many different conditions. Loss of a protective endothelial surface exposes circulating blood to the underlying tissues and causes platelet activation, adhesion, and secretion, and also activates the coagulation cascade (4,5). Recent studies have shown increased platelet activation and blood coagulability in patients with cardiac-origin embolism (6,7). In this chapter, we describe the cardiac disorders known to predispose patients to brain embolism. We emphasize some of the sources that are less well known. In the succeeding chapters, we will discuss diagnosis and treatment.

ARRHYTHMIAS Atrial Fibrillation Atrial fibrillation is characterized by disorganized atrial electrical activation, and, as a result, atrial contractions are disorganized and ineffective (8). Atrial fibrillation is the most common arrhythmia, afflicting more than 2.5 million (about 0.4% of the adult population) in the United States alone. Atrial fibrillation becomes much more common after 60 years of age. An analysis of the Framingham Heart Study population showed that at age 40 the lifetime risk of developing atrial fibrillation was 26% for men and 23% for women (9). It is estimated that almost six million adults will have atrial fibrillation in the year 2050 (10). Perhaps as many as 5% of individuals over age 60 have atrial fibrillation (8 – 11). Epidemiological studies during the past three decades have firmly established that atrial fibrillation is a major risk factor in stroke, that strokes in patients with atrial fibrillation are most often due to cardiogenic embolism, and that in moderate- and high-risk patients, antithrombotic treatment substantially reduces the frequency of clinical brain embolism in these patients (8 – 12). The etiology of atrial fibrillation and associated cardiac and other medical factors affect the risk of stroke in patients with atrial fibrillation. In the Framingham Heart Study, rheumatic heart disease and atrial fibrillation conveyed a 17.6-fold increased risk of clinical stroke compared with subjects with no history of atrial fibrillation (12). For those patients who do not have valve disease, atrial fibrillation increases the risk 5.6-fold compared with nonfibrillation (12). Other clinical risk factors that increase risk of embolism in the atrial fibrillation population include advanced age, congestive heart failure, a history of systemic hypertension, and prior thromboembolism (13,14). In patients with atrial fibrillation who do not have valvular disease, thrombi often form in the left atrial appendage, whereas patients with atrial fibrillation and valvular disease have thrombi in the left atrial appendage and the body of the left atrium (15,16). Figure 1 shows a thrombus in the left atrial appendage. Echocardiographic findings that identify patients at increased risk for embolism include left atrial enlargement (17,18), abnormal left atrial appendage function (15,19 – 21), mitral annulus calcification (MAC), and left ventricular dysfunction (15,18). For the atrial fibrillation population, mitral regurgitation appears to be somewhat protective against clinical thromboembolism (22). After atrial thrombus, transesophageal echocardiography (TEE) evidence of spontaneous echo contrast (also called “smoke”) is the most important factor that predicts the likelihood of cardiogenic embolism in patients with atrial fibrillation. First described in patients with mitral valve disease (23), spontaneous echo contrast refers to swirling hazes of echogenicity within the atria and in left ventricular aneurysms. Spontaneous

Cardiac Sources of Embolism: The Usual Suspects

Figure 1

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A thrombus in the left atrial appendage (black arrows) in a patient with atrial fibrillation.

echo contrast can vary from a faint, cloudlike appearance to bright contrast that often may make it difficult to exclude an atrial thrombus. Spontaneous echo contrast is probably due to the interaction between plasma proteins and erythrocytes at low shear rates (15,24). The major determinants of spontaneous echogenicity are the fibrinogen levels and slow intracardiac flow (25). Antithrombotic therapy has no impact on the severity of spontaneous echo contrast. Atrial Flutter Knowledge of the clinical risk attributable to atrial flutter is far less than its more common cousin, atrial fibrillation. This is because atrial flutter is far less common in the general population and often degenerates to atrial fibrillation or patients have periods of both atrial fibrillation and atrial flutter (26). For this reason, many epidemiologic and clinical studies of patients with atrial fibrillation have included patients with atrial flutter. Although atrial flutter is associated with a more organized atrial contraction pattern, atrial appendage function is depressed and spontaneous echo contrast may be found. Clinical and echocardiographic risk factors for embolism in atrial flutter are not well defined but are presumed to be similar to atrial fibrillation (27). CARDIAC VALVE DISEASE Cardioembolic strokes are common among those with valvular heart disease (28). Abnormalities of valve surfaces and changes in valve function and cardiac physiology that result from valve disease promote the formation of both white platelet – fibrin thrombi and red clots on valve surfaces and in the adjacent cardiac chambers. Pieces of calcium associated with chronic valvular disease may also embolize. Stenotic valves have decreased pliability and irregular surfaces; progressive commisural adhesions and valve leaflet dystrophic calcifications develop, leading to progressive narrowing of the cross-sectional area of valve orifices. Valvular outlet obstruction causes increased turbulence of blood flow. The intensity of turbulence is markedly increased in the jet stream of blood distal to stenotic valves (29). Platelets are activated in regions of increased turbulence; the amount of thrombus formed is directly related to valve orifice turbulence (30).

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Distal to stenotic valves, blood flow consists of a central jet stream surrounded by annular eddies that course between the outflow tract walls and the mainstream (31). These eddies permit blood to remain more in close contact with the irregular valve surfaces than in regions of normal laminar flow. Platelets activated by the turbulent jet stream have prolonged contact with dystrophic irregular valve surfaces, causing adhesion of platelet-fibrin thrombi to valve surfaces, further platelet activation, and formation of thrombi. Valve incompetence prolongs the time that blood is in contact with abnormal valve surfaces and also promotes thrombus formation. Valve disease often leads to atrial and ventricular cavity enlargement. Left atrial enlargement is especially common in patients with mitral stenosis and mitral insufficiency. In patients with mitral stenosis, enlargement of the left atrium is associated with stasis and thrombus formation when atrial fibrillation develops, but thromboembolic risk among those with mitral stenosis is increased even in the absence of atrial fibrillation. Rheumatic Mitral Valve Disease Although the incidence of rheumatic fever and rheumatic heart disease has dramatically declined during the past decades, rheumatic heart disease is still an important cause of brain embolism worldwide. The mitral valve is most often involved in women, whereas the aortic valve is more commonly involved in men. Second in frequency is involvement of both the mitral and aortic valves. The pulmonic and tricuspid valves are seldom the site of important clinical rheumatic valvulitis. Clinicians have long emphasized that embolization, especially to the brain, may be the earliest clinical indication of rheumatic mitral stenosis. Harris and Levine (33,34) commented in 1941, “It seemed that the typical case was one in which paralysis occurred suddenly at a time when there was no complaint of dyspnea and the patient was able to lie flat in bed and had been ambulatory” (32). They studied 72 patients with mitral stenosis and brain embolism. In 17 (24%) patients, the heart rhythm was regular at the time of the brain embolism, and, as far as could be ascertained, the patients never had atrial fibrillation (32). Atrial fibrillation was present in 55 (76%) patients. The initial stroke was often very severe, leading to persistent hemiplegia. The case fatality rate was high: 24 (33%) patients died within a few days or a few weeks after their cardioembolic stroke (32). The frequency of clinical embolism in patients with mitral stenosis ranges in various series between 10% (34) and 20% (35,36) and is likely skewed by referral bias. Fifty to seventy-five percent of clinical emboli involve the brain. Although embolism does occur in patients with mitral stenosis who are in normal sinus rhythm, the development of atrial fibrillation greatly increases the risk. In a large study of 754 patients with chronic rheumatic heart disease followed for more than 5000 patient-years, the incidence of embolism was 1.5% per patient-year (34). The incidence of embolism was seven times higher in patients with atrial fibrillation than in those who had sinus rhythm. One-third of recurrences of embolism occurred during the first month and two-thirds during the first year after the onset of atrial fibrillation (34). Rheumatic mitral regurgitation is a less frequent cause of brain embolism than mitral stenosis. Among individuals with embolism in one series, 93% had predominant mitral stenosis, and only 7% had mitral insufficiency (37). Mitral insufficiency is often accompanied by progressive left ventricular hypertrophy. AORTIC VALVE DISEASE Progressive calcific aortic stenosis and/or aortic regurgitation often develop between the ages of 20 and 60 in patients with congenital bicuspid aortic valves and can also follow

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rheumatic valvulitis. Calcific degenerative changes usually are well developed during the fourth and fifth decades of life in patients with bicuspid valves, whereas idiopathic calcific aortic stenosis is more prevalent in the sixth through eighth decades (38). Some observers believe that idiopathic calcific aortic valve disease of the elderly is due to inflammation and atherosclerosis, but proof of this hypothesis is not yet available. Microthrombi with evidence of organization have been found at necropsy in 53% of stenotic aortic valves (39). Changes in the aortic valve are progressive. Thickening of previously diseased valves is thought to result from the deposition of fibrin. Fibrin deposits become organized and calcified with resultant distortion of the normal valve architecture. Bicuspid and calcific aortic valves are not able to open freely. Narrowing and irregularity of the valve orifice contributes to turbulent blood flow. Eddies form in the region of the sinus of Valsalva and also adjacent to any regurgitant jet stream that flows into the left ventricle (40). Abnormal flow and abnormal valve surfaces activate platelets and induce fibrin deposition, accounting for the prevalence of microthrombi along valve surfaces. Embolism has been considered a much less common occurrence in patients with aortic valve disease when compared to those with mitral valve disease. Pleet et al. (41) reported four patients who had bicuspid aortic valves and cerebrovascular events: three had sudden onset strokes, and the other patient had recurrent stereotyped transient neurological symptoms. Full evaluation showed no cause for the brain infarcts except for the bicuspid valve, and the authors attributed the strokes to brain embolism from the congenitally abnormal valves. The fourth patient, who had repeated transient ischemic events, had a chronic hematological disorder and may not have had brain embolism. Others have reported instances of spontaneous brain embolism from calcific aortic valves (42 –44). In each patient the calcific embolus was seen on noncontrast CT as a dense calcified region, and vascular studies showed that the calcific density was within intracranial arteries. Clinical and necropsy studies show that embolism from calcific aortic valves is probably not rare. Soulie et al. (45) found emboli in 33% of 81 patients with calcific aortic stenosis. Holley et al. (46) in another autopsy study, found calcific emboli in 37 of 165 (22%) patients with calcific aortic stenosis. Thirty-two emboli were found in the coronary arteries, eleven in the renal vessels, one in the central retinal artery, and one in the middle cerebral artery (MCA) (46). Although the MCA was occluded by a calcific embolus in one patient, no neurologic signs were recorded and no infarct was found (46). During life, calcific emboli have often been identified in the eye because of their typical morphology on fundoscopic examination of the retina (47,48). Calcific retinal emboli appear as white, irregular, immovable densities and are usually distinguishable from bright cholesterol crystals and fibrin-platelet plugs. Among 103 patients with retinal artery occlusions and cardiovascular disease, aortic stenosis was present in 11 patients and was the most common cardiac lesion (48). In all clinical studies, symptoms that reflect embolization occur more often after cardiac procedures (catheterization and surgery) than occur spontaneously. Kapila and Hart (49) described a patient with calcific aortic stenosis who developed a left hemiparesis two days after cardiac catheterization, and a calcific embolus was seen on CT scan occluding the right MCA. The risk of stroke from cardiac catheterization among patients with aortic stenosis is likely underestimated. Omran et al. (50) reported on 152 patients with aortic valve stenosis referred for cardiac catheterization. Among the 101 patients randomized to retrograde crossing of the aortic valve, three (3%) patients had a clinical stroke, and an additional 19% had evidence of silent brain infarcts when comparing head MRI performed prior to and 48 hours after catheterization. This compared with no clinical or silent events among patients who did not have catheter crossing of their valve. Aortic valve surgery is especially associated with a high frequency of embolism.

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Holley et al. (51) found 82 instances of embolization among 38 of the 62 patients (61%) who had closed valvulotomy or aortic valve replacement and died at various intervals after surgery. As might be expected, embolization is even more common in patients with endocarditis superimposed upon bicuspid or calcific aortic valves than it is in noninfected valves. The discrepancy between the relatively high frequency of calcific emboli found at necropsy and in the eye and the low frequency of clinically symptomatic brain and visceral organ ischemic events may be explained by the small size of the embolic particles and the fact that visceral emboli are much harder to diagnose than brain emboli. Not much data are available regarding embolism in patients with isolated aortic insufficiency. Aortic regurgitation is caused by the dysfunction of the aortic valve leaflets or aortic root dilation. Bicuspid aortic valve, rheumatic valvulitis, and infective endocarditis are probably the most common causes of aortic leaflet disease, whereas Marfans, aortic dissection, and annulo-aortic ectasia due to hypertension are the common causes of aortic root dilation (38). Syphillis leading to aortic root dilation was formerly a common cause of aortic valve insufficiency, but it is now quite rare. Mitral Valve Prolapse The topic of embolism in patients with mitral valve prolapse (MVP) has always been controversial. Barlow and Bosman (52), in an early report of the mid-systolic click-MVP syndrome, described a 23-year-old woman who had transient left-arm weakness, and evaluation showed MVP. No details of the neurological symptoms or signs were included and the relationship of the neurological event to her heart condition was not considered (52,53). Subsequent reports of a possible relation between MVP and brain ischemia by Barnett et al. (53 –56) occurred during 1974– 1980. The initial report was of four patients, but Barnett et al. (54,57) later expanded the number of cases to 14 patients. All patients were relatively young (10 – 48 year), and none had cardiovascular risk factors or occlusive vascular lesions. Since then, a number of case-control and necropsy studies have shown that patients with MVP do have cardiogenic embolism but not very often. Cerebrovascular events in patients with MVP have a relatively low recurrence rate even without treatment and with no attributable risk for those under the age of 45 years (58). MVP is a common cardiac valvular abnormality among young and middle-aged adults (59). Estimates of prevalence range from ,1% in men to up to 5% in women (60). Systolic prolapse of the posterior leaflet is most common but can be bileaflet or rarely isolated anterior leaflet prolapse. The pathological process is the disruption of collagen and infiltration by a myxomatous substance rich in mucopolysaccharide. The mitral valve leaflets are often thickened. The chordae tendinae and the mitral annulus may also contain myxomatous deposits with elongation of the chordae, which sometimes rupture, and dilatation of the mitral valve annulus (61). Mitral regurgitation develops when the mitral leaflets fail to coapt. At necropsy, thrombi have been found, especially in the angle between the posterior leaflet of the mitral valve and the left atrial wall (57,62). The development of an adherent thrombus in the cul-de-sac created between the prolapsing posterior mitral valve leaflet and the atrial wall may be attributed to an irregular surface caused by a jet of mitral regurgitant (53). A friable, granular, yellow thrombus composed of fibrin and platelets was found at necropsy in a 21-year-old patient who died after the sudden onset of a left hemiplegia (63). Fibrin emboli were found in the coronary and renal arteries as well as in the frontal MCA branches in the brain (63). MVP is diagnosed by echocardiography when there is abnormal posterior systolic motion of the coapted posterior and/or anterior leaflets of at least 2 mm in the parasternal, long-axis view (59). Mitral valve thickening and redundancy and the presence of mitral

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regurgitation, especially late systolic mitral regurgitation, are important additional criteria for the presence of important myxomatous mitral valve changes (64–66). About 8% of patients with MVP develop severe mitral regurgitation, leading to congestive heart failure and necessitating mitral valve replacement. Atrial fibrillation can occur at any time but is more common in older patients, especially those with mitral regurgitation and large left atria. Myxomatous valves can become infected during bacteremia. Antibiotic prophylaxis is indicated in the presence of mitral regurgitation, but the frequency of infective endocarditis is quite low (67). MVP most often occurs in isolation but is more common in patients with inherited connective tissue disorders, such as Marfans, Ehlers-Danlos, osteogenesis imperfecta and bicuspid aortic valves (56). Abnormalities of platelet function have been shown in patients with MVP and thromboembolism. Shortened platelet survival time, an increase in circulating platelet aggregates, and increased levels of b-thromboglobulin and platelet factor-4 have been reported in patients with MVP (53). Interaction of circulating platelets with abnormal endocardial and valve structures found in patients with myxomatous valve degeneration causes increased platelet aggregation, adhesion, and secretion. Platelet fibrin aggregates adhere to abnormal valve surfaces and later embolize or promote formation of erythrocyte-fibrin clots. Mitral Annulus Calcification Mitral Annulus Calcification (MAC) is a degenerative disorder of the fibrous support structure of the mitral valve that occurs rather commonly in the elderly, especially in women. MAC is also associated with hypertension, coronary atherosclerotic heart disease, and occlusive cerebrovascular disease. Posterior mitral annular calcification is most common and is easily recognized on transthoracic echocardiography. McKeown (53,68) found MAC at necropsy in 27% of 100 elderly patients. Among 5694 individuals in the Framingham Heart Study, 2.8% had posterior submitral calcification; 95% of those patients who had MAC came from the 40% of subjects who were more than 59 years of age, and twice as many women as men had MAC (69). In the original autopsy description of MAC, which appeared in the New England Journal of Medicine in 1962, four of the 14 patients described by Korn et al. (70) had brain infarcts, multiple in three. The first important clinical premortem description of MAC as a potential cause of stroke was in 1979 by DeBono and Warlow (71), who studied 151 consecutive patients with retinal or brain ischemia. They found MAC in eight patients, compared to no instances of MAC in ageand sex-matched controls who did not have brain or eye ischemia (71). Perhaps, the best epidemiological study of the relationship of MAC with stroke was the Framingham Heart Study (72). Between 1979 and 1981, 426 men and 733 women in the Framingham Heart Study cohort (average age of 70) who had no prior clinical strokes had m-mode echocardiograms. Among these 1159 patients, 44 (10.3%) men and 116 (15.8%) women had MAC. During eighth year of follow-up, 51 (5.1%) patients without MAC had strokes compared with 22 (13.8%) patients with MAC; MAC was associated with a 2.10 relative risk of stroke (95% confidence interval 1.24 –3.57, P ¼ 0.006) (72). There was a continuous relation in this study between frequency of stroke and severity of MAC; each millimeter of thickening on the M-mode echocardiogram represented a relative risk of stroke of 1.24. Even when patients with atherosclerotic heart disease and congestive heart failure were excluded, patients with MAC still had twice the stroke risk as those without MAC (72). Pathological data is more convincing, in our opinion, in linking MAC to brain embolism. Korn et al. (70) reported the clinical and necropsy data on 14 patients with MAC. They noted that calcification has a predilection for the posterior portion of the mitral

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annulus ring. Calcific masses often projected superiorly toward the atrium and centrally into the cavity of the left ventricle (70). Pomerance later noted ulceration and extrusion of the calcium through the overlying cusp into the ventricular cavity in some patients with MAC studied at necropsy, and thrombi were attached to the ulcerated regions in four patients (73). The embolic material can be either calcium (as has also been shown in calcific aortic stenosis) or thrombus. Thrombi attached to calcified mitral annuli have also been shown by echocardiography. Stein and Soble (74) reported two such patients. TEE showed a 2 mm mobile thrombus attached to the atrial surface of the calcified posterior portion of the mitral annulus in a 74-year-old woman who had developed a sudden onset right hemiparesis and aphasia. There were no other cardiac sources of emboli. In a second patient who had a parietal lobe brain infarct, TEE showed a 5 mm mobile thrombus attached to an 8 mm calcified nodule on the posterior mitral valve leaflet (74). Eicher et al. (75) reported on ten patients with MAC who underwent TEE in which thombus assocated with MAC was identified in three (30%) patients. Thrombus resolved with antithrombotic therapy. Prosthetic Cardiac Valves Advances in cardiac diagnosis and cardiac surgery have led to increasingly frequent replacement of heart valves. More than 60,000 valve replacements are performed annually in the United States alone (76). Mechanical valves are made primarily with metal and carbon alloys and are inherently quite thrombogenic. Thrombogenic potential is highest with caged-ball prostheses (e.g., Starr-Edwards valve), lowest in individuals with bileaflet-tilting-disk prostheses (e.g., St. Jude Medical), and intermediate with single-tiltingdisk valves (e.g., Bjork-Shiley) (76). Bioprosthetic valves are most commonly heterografts derived from pig or cow pericardial or valve tissues mounted on metal supports and are currently the most common choice for valvular prosthesis, especially among older patients. Homografts in the form of preserved human cadaveric valves are occasionally used for valve replacements in middle-aged adults. Bioprosthetic valves have low thrombogenic tendencies (but still higher than native valves), and so long-term anticoagulation is ordinarily not prescribed. Older bioprosthetic valves were less durable than mechanical valves, but newer valves demonstrate excellent durability (76). Valve thrombosis and endocarditis are important complications in patients with mechanical and occasionally bioprosthetic valve prostheses. Important valve thrombosis causes pulmonary congestion, reduced cardiac output, and brain and systemic embolism. The frequency of prosthetic-valve thrombosis is estimated to be between 0.1% and 5.7% per year (77,78). Alteration of blood flow related to mechanical valves, as well as the inherent thrombogenicity of the materials used, promote thrombosis and thromboembolism. Flow velocity studies show turbulent flow patterns that contribute to vascular stasis and thrombus formation around mechanical valve prostheses (79). Hematological studies in patients with mechanical valves show elevation of platelet-specific proteins that indicate platelet activation and decreased platelet survival in patients with artificial heart valves (80 – 82). The pathophysiological events that promote thromboembolism begin during heart surgery. Prosthetic materials and injured perivalvular tissues cause platelet activation as soon as circulation is restored. Dacron sewing rings common to all prosthetic valves form a fertile nidus for platelet activation and adhesion (2). Prosthetic materials also activate the intrinsic pathway of the coagulation cascade (83). Both platelet activation and activation of the coagulation cascade promote the formation of red erythrocyte-fibrin thrombi. Degenerative changes in bioprosthetic valves also can lead to the deposition of

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white platelet-fibrin thrombi (84). Late thrombosis has also been shown in the cusp sinuses of bioprosthetic mitral valves that have undergone fibrosis and calcification (85,86). Embolism is an important complication in patients with both mechanical and bioprosthetic valves. Most symptomatic emboli go to the brain. Patients with mitral mechanical valves have a higher frequency of embolization than those with aortic valves, especially patients with coexistant atrial fibrillation. This is probably related to the lower velocities across the mitral valve and large left atria in patients with mitral valve prostheses. INFECTIVE ENDOCARDITIS Although neurological complications of infective endocarditis have been well recognized since the time of Osler (87), the clinical spectrum of endocarditis has changed dramatically during the past decades. Compared with endocarditis patients three decades ago, present day series of patients with infective endocarditis are on average older, use illicit drugs more often, more commonly are on hemodialysis, more often have tricuspid and prosthetic valve infections, and have more infections with staphylococcus aureus (88 –90). Valvular vegetations in patients with infective endocarditis are composed of platelets, fibrin, erythrocytes, and inflammatory cells attached to the damaged endothelium of native and prosthetic valves. Organisms are enmeshed, often deep within the fibrinous material, explaining why antibiotics may have difficulty sterilizing the lesions. Vegetations range in size from a few millimeters to several centimeters, and their potential for embolization is directly related to size, mobility, and friability (91). Larger vegetations are seen among those with staphylococcus aureus and fungal endocarditis. Figure 2 shows vegetations in a patient with infective endocarditis. Salgado et al. (92) compared valve involvement in patients with and without neurologic complications of endocarditis. Aortic valve disease was present in 38 (59.4%) of 64 patients with neurologic complications, as compared to 65 (59.6%) of 111 patients without neurologic complications. Mitral involvement ocurred in 22 (34.4%) of 64 patients with neurologic complications, as compared to 34 (31.5%) who

Figure 2 Bacterial vegetations (black arrows) found at necropsy in a patient with infective endocarditis.

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did not have neurologic problems (92). The frequency of tricuspid valve endocarditis is quite variable, possibly related to the underlying population served by the facility (e.g., intravenous drug abusers). Although the predominant underlying valve disease was formerly rheumatic, now calcified valves, MVP, and prosthetic valves make up a higher proportion of endocarditis cases than in the past. In the Salgado et al. (92) series, among patients with prosthetic valve infections, mechanical valve endocarditis was more often associated with neurologic complications than bioprosthetic valve endocarditis. In 1969, Mayo Clinic neurologists reported their experience accumulated during the period 1950 – 1964 (93). Among 385 patients with endocarditis, 110 (29%) patients had neurologic complications, including 55 (50%) with cerebrovascular disease. Forty-four (80%) of the 55 individuals with cerebrovascular complications had brain infarcts (38 carotid system, 6 vertebrobasilar). Among the 11 patients with brain hemorrhages, eight hemorrhages were into the brain substance (intracerebral), and three were subarachnoid (93). Twenty-one patients in the Mayo Clinic series had acute encephalopathy and seven had meningitis. These syndromes, brain ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, encephalopathy, and meningitis, remain the major neurological complications found in recent series of patients with both native valve and prosthetic valve endocarditis (92,94 – 97). Brain ischemia in patients with endocarditis is invariably due to embolism. Ischemia can take the form of transient ischemic attacks that involve the brain or the retina. About one-fifth of patients with endocarditis develop brain infarcts: Brain ischemia is reported in 17% (92), 19% (94), and 15% (97) of patients in various infective endocarditis series. At necropsy, small cortical or subcortical bland infarcts are found, usually multiple. In one series, 19 (58%) of 33 infarcts were small, 11 (33%) were moderate in size, and three (9%) were large (94). Larger infarcts were found in patients with staphylococcus aureus endocarditis. In another series, among 133 episodes of endocarditis, three patients had transient monocular visual loss, and one patient had a retinal infarct (95). Brain ischemia may be the presenting sign of endocarditis and is most common early in the course of the disease. Ischemic strokes can also occur in the days after antibiotic treatment is begun. Transcranial Doppler monitoring of patients with endocarditis shows that microemboli continue to occur even after antibiotic treatment, although more emboli are detected before and early after antibiotics are initiated. Brain hemorrhage is much less frequent than ischemia, but the effects of hemorrhage can be devastating or mortal. Some patients have bleeding into bland infarcts. This usually takes the form of hemorrhagic infarction—petechial and larger hemorhagic mottling within the infarct without formation of a frank discrete hematoma. In some patients, large hematomas develop. Hematomas are often found in patients with mechanical valves treated with warfarin anticoagulation. In other patients, intracerebral hemorrhage results from rupture of a septic arteritis caused by the embolization of infective material to the artery with necrosis of the arterial wall (98,99). In a small minority of cases, intracerebral hemorrhage is due to rupture of a mycotic aneurysm into the brain substance. Mycotic aneurysms are caused by the embolization of infected material into the wall and adventitia of brain arteries. The aneurysms usually occur distally along arteries and tend to be multiple. The location of aneurysms in patients with infective endocarditis is similar to those found in patients with atrial myxomas, probably because of similar embolic etiologies. In contrast, ordinary saccular “berry” aneurysms occur proximally along the basal arteries of the circle of Willis. Angiography of patients without brain hemorrhage seldom shows mycotic aneurysms. Many patients who develop brain hemorrhage have had an attack of transient or persistent brain ischemia in the hours or days before the hemorrhage. This prodromal ischemia is explained by an arterial embolus

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causing brain infarction. Hemorrhage into an infarct or rupture of the artery that received the infected embolus causes the hemorrhage that often proves fatal (98,99). Diffuse brain-related symptoms, usually referred to as encephalopathy, are very common in patients with endocarditis. Symptoms include lethargy and decreased level of consciousness, confusion, agitation, poor concentration, and poor memory. Encephalopathy has different explanations. Often the encephalopathy is metabolic and is explained by systemic factors, such as azotemia, pulmonary dysfunction, hyponatremia, and so on. In other patients, the encephalopathy is a toxic effect related to fever and to the acute infection. Patients with staphylococcus aureus endocarditis are more often encephalopathic than in endocarditis caused by other organisms. Necropsy and CT/magnetic resonance imaging studies of patients with encephalopathy often reveal multiple small, scattered brain infarcts, and/or microabscesses (95,100). Encephalopathy usually develops during uncontrolled infection, with more virulent organisms supporting the role of microscopic sized septic emboli as the cause (95,101). Though reported, meningitis is rare in patients with endocarditis. The presentation is often headache with fever. Meningeal infection is caused by the embolization of infected vegetations to meningeal arteries. The infecting organisms have changed during the years; staphylococcus aureus endocarditis has become more frequent and the cause of increased morbidity (90). Patients with staphylococcus aureus endocarditis have larger and more multiple brain infarcts (94), encephalopathy (95), and intracerebral hemorrhages (92). Laboratory studies are very helpful in diagnosing endocarditis, but the clinical findings remain most important for recognition. The disease should be suspected in any patient with unexplained fever and a new heart murmur. Multiple blood cultures should be obtained prior to the initiation of antibiotics. The spinal fluid in patients with clinical findings suspicious but not diagnostic of endocarditis can be helpful. The cerebrospinal fluid may be normal or contain slightly increased protein levels and increased numbers of erythrocytes and leukocytes. Usually, the pleocytosis is moderate (,300 cells/cc) and may be predominantly lymphocytic or polymorphonuclear, unless a clinical picture of meningitis is present, in which case there may be more white blood cells. The most important treatment is the rapid introduction of antimicrobial therapy. Most neurologic complications occur before or soon after the initiation of antibiotic treatment. Recurrent strokes do occur after bacteriologic cure but rarely. In one series, among 147 patients discharged from the hospital after treatment of infective endocarditis, 15 developed strokes after discharge; all except one of the stroke patients had prosthetic valve endocarditis (92). Strokes in this series occurred long after discharge (median 22 months) and were better explained by recurrence of endocarditis, complications of anticoagulants, or to noninfective disease of the prosthetic valves, than to cerebrovascular complications of the original endocarditic episode (92).

NONINFECTIVE FIBROUS AND FIBRINOUS ENDOCARDIAL LESIONS (INCLUDING VALVE STRANDS) Fibrous valve thickening, often with grossly visible vegetations that contain mixtures of blood, platelets, and fibrin are sometimes found on the heart valves and adjacent endocardium in patients who have no evidence of either rheumatic fever or bacterial endocarditis. The first detailed description of such lesions was in 1924 by Emanuel Libman and Benjamin Sacks (102), who reported four patients studied clinically and pathologically of an “atypical verrucous endocarditis.” These patients included three young women and one 19-year-old man. Necropsy showed fibrous thickening of valves with vegetations,

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especially along the closure lines of the valves and on the valve leaflets. The vegetations extended to the papillary muscles and ventricular endocardium. The histopathology was thought to be unique by the authors. In one patient: “In the mitral valve, there was a deposit of agglutinated blood platelets over large flat areas, beneath which the endocardial tissues were densely infiltrated with polymorphonuclear leukocytes and round cells . . . The valve itself was enormously thickened owing to an old chronic inflammatory process . . . The blood platelet masses showed a tendency in places to fibroblastic invasion. The inflammatory process extended throughout the entire thickness of the valve, and the vegetative deposit was therefore present on both the auricular and the ventricular aspects of the valve” (102). Figure 3 is a drawing from the Libman and Sacks paper illustrating the findings at autopsy in one of their patients. Fibrinous pericarditis was present in three of the patients, and a skin rash, bleeding, arthritis, anemia, and glomerulonephritis were common clinical features. The fouth patient was the only one who had prominent clinical neurological abnormalities that consisted of a unilateral paralysis and seizures that developed shortly before death. The authors speculated that the neurological findings in this patient might be caused by emboli from the valvular vegetations (the brain was not available for examination in this patient). Libman and Sacks were uncertain of the diagnosis but noted that the clinical picture resembled some of the erythematous diseases that Osler had mentioned in his textbook of medicine (102). Baehr et al. (103) published a series of 23 patients who had acute

Figure 3 Drawing of a heart at necropsy. The left side of the heart shows a verrucous vegetations along the line of closure of the mitral valve extending in places to the free edge. There are areas of endocarditis on the papillary endocardium and adjacent mural endocardium and an isolated patch of mural endocarditis in the region of the apex of the ventricle. A healing fibrinous pericarditis is also present. Source: From Ref. 102.

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disseminated lupus erythematosis, among whom 13 had a nonrheumatic verrucous endocarditis similar to that described earlier by Libman and Sacks. Pollack et al. (104) reported the pathological findings in disseminated lupus erythematosis in 1941. These clinical and pathological reports brought the disease lupus erythematosis, known previously as predominantly a skin disorder, to the attention of the medical community as an acute disseminated systemic disease. Gross, a younger colleague of Libman and Sacks at Mt. Sinai Hospital in New York, reported a detailed study of 27 hearts, 23 of whom were fatal cases of acute lupus erythematosis (105). Gross pointed out that the patients in the original Mt. Sinai Hospital report had the typical clinical findings of lupus erythematosis, and Gross suggested that the endocarditic lesions be named after Libman –Sacks and that the verrucous endocardial lesions were disgnostic of lupus erythematosis (105). Libman and Sacks (102), and Gross (105) knew that similar endocarditic lesions also occurred in terminal or cachectic diseases, such as carcinoma, tuberculosis and leukemia, and had usually been called nonbacterial thrombotic endocarditis (NBTE). Since these early reports, we now know that similar lesions of the cardiac valves and endocardium occur in patients with systemic lupus erythematosis (SLE), the antiphospholipid antibody (APlA) syndrome, and marantic NBTE. Presumably all have a similar pathogenesis. Echocardiographic studies have attempted to define the frequency and importance of noninfective endocarditic lesions in series of patients with SLE (106 –108). Galve et al. (106) performed transthoracic echocardiography on 74 patients with SLE on two occasions approximately five year apart. Clinically important valve disease was found in 18% of patients, including seven with vegetations mostly on the mitral and aortic valves. Nine patients had leaflet thickening and stiffness, causing stenosis or regurgitation in six and calcification in two. Six of the 74 patients required valve surgery during the five year of follow-up and one developed vegetations not present five year previously (106). Roldan et al. (107) performed two TEE studies (29 months apart) on 69 SLE patients. Valvular abnormalities were found on the initial TEE in 61% of patients, including valve thickening (61%), vegetations (43%), valve regurgitation (25%), and stenosis (4%). Involvement of the mitral valve was found with involvement of the aortic valve; tricuspid valve disease occurred occasionally, but pulmonic valve involvement was rare. The second TEE demonstrated valvular disease in 53% of patients (107). The combined incidence of stroke, peripheral embolism, heart failure, and superimposed infective endocarditis was 22% in those with valvular disease on TEE (107). Crozier et al. (108) found a high frequency of mitral regurgitation (46%) among 50 Chinese women with SLE. Stroke and microinfarcts were most often attributable to brain embolism from valvular lesions or coagulopathy. The presence of coagulopathy and thrombocytopenia in SLE probably correlates with the presence of valvular disease, although this relationship has not been well reported. The APlA syndrome has become recognized within the past two decades as a prothrombotic syndrome separate from the SLE. The APlA syndrome is characterized by frequent fetal loss, strokes, myocardial infarctions, thrombophlebitis, pulmonary embolism, and thrombocytopenia. Serological testing reveals positive assays for the lupus anticoagulant and/or anticardiolipin antibodies. Echocardiographic studies have shown that there is a relatively high frequency of valvular cardiac lesions in patients with this syndrome and that the valve lesions are indistinguishable from those found in patients with SLE. Brenner et al. (109) studied 34 patients with the APlA syndrome using transthoracic echocardiography. Fourteen (41%) patients had arterial thromboembolism, 6 (18%) had venous thrombosis, and 14 (41%) had recurrent fetal loss. Valvular lesions (mostly mitral and aortic thickening and vegetations) were found in

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11 (32%) patients, including 9 (64%) of the 14 with arterial thromboembolism (109). Barbut et al. (110) studied the prevalence of APlA syndrome among patients in whom echocardiography showed mitral and/or aortic regurgitation. Among 87 consecutive patients with these valve dysfunctions, 26 (30%) had immunoglobulin G or M anticardiolipin antibodies. Focal cerebral ischemic events occurred in eight (30%) of these patients (seven judged embolic), including 7 of the IgG anticardiolipin positive patients (110). Barbut et al. (111) studied 21 patients with APlA antibodies who had focal cerebral ischemic events. Twelve (86%) of fourteen stroke patients, and 3 (42%) of seven nonstroke lesion patients had echocardiographic evidence of mitral or aortic valve abnormalities. Eight (38%) of 21 patients with APlAs had SLE (111). In a cooperative study performed by the APlAs in Stroke Study Group, among 128 patients who had brain or ocular ischemia and were APlA positive and had echocardiography, 16 (22.2%) had mitral valve abnormalities, and 2 (1.6%) had aortic valve abnormalities (112). Figure 4 contains an echocardiogram that shows a vegetation on the mitral valve in a patient with multiple brain emboli and APlAs and the appearance of the mitral valve removed at surgery. Phospholipids are important constituents of cardiac valve endothelium, blood platelets, vascular endothelium, and coagulation proteins. At present, assays for APlAs only include testing for lupus anticoagulant and anticardiolipin antibodies. Some patients with the clinical features of the APlA syndrome have negative antibody assays. Some of these patients also have prominent valve vegetations and cardiogenic brain embolism. Both hypercoagulability and NBTE have long been recognized to occur in patients with cancer and other debilitating chronic diseases. Most often the cancers are mucinous adenocarcinomas (113). In one study, among 20 cancer patients who had thromboembolic disease of the brain and other organs, 16 (80%) had NBTE at necropsy (114). Among those with NBTE, valvular involvement was mitral in eight (50%) patients, aortic in four (25%), combined mitral and aortic in three (19%), and tricuspid in one (6%) patients. Large vessel occlusive emboli and multiple infarcts and microvascular occlusions were found in the brains of these patients (114). In another study, among 18 patients with cancer and NBTE, 8 (44%) developed a stroke, and in 5 patients, stroke was the initial clinical manifestation of cancer (115). Edoute et al. (116) performed prospective echocardiograms on 200 cancer patients and found a 19% frequency of NBTE. The valve lesions equally involved the mitral and aortic valves, and elevated plasma D-dimer levels, a marker for hypercoagulability was also often found in the cancer patients with clinical thromboembolism (116). NBTE is characterized by friable white or tan vegetations, usually along lines of valve closure. The vegetations can be large. Microscopy usually shows degenerating platelets interwoven with strands of fibrin and some leukocytes forming eosinophilic masses of tissue. All three conditions—SLE, APlA syndrome, and NBTE—are associated with hypercoagulability, strokes, and platelet abnormalities. The cardiac valve and endothelial lesions in these three conditions are very similar and probably indistinguishable grossly and microscopically. Platelet deposition, incorporation of fibrin, and the formation of platelet thrombi on valve and endocardial surfaces are common to all three conditions. Noninfective NBTE valve lesions are also found in patients with carcinoid tumors (probably causally related to elevated serotonin levels in the blood), and after the use of some drugs (ergotamine, methysergide, dexfenfluramine, and the combination fenfluramine and phentermine) (117). The valve and endocardial lesions that result are similar to each other morphologically and consist of fibrotic thickening of the valves with reduced pliability. To date, embolism has not been reported as a consequence of this type of valve disease.

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Figure 4 Mitral valve vegetations in a patient with antiphospholipid antibody (APlA) syndrome and multiple brain emboli. (A) Echocardiography showing a pedunculated, mobile lesion on the mitral valve (white arrows). (B) Mitral valve removed surgically showing vegetations. Abbreviations: LA, left atrium; LV, left ventricle; AO, aorta. Source: From Ref. 1.

TEE in older individuals often show strands of mobile tissue attached to valve surfaces. The cause and significance of these strands remain uncertain. Lambl (118) had originally described such filamentous outgrowths from the ventricular surfaces of the aortic valves sometimes found at necropsy, and, therefore, these fibrous strandlike lesions have often been called Lambl excrescences. Later Magarey (119) found similar filiform strands on the atrial surface of mitral valves. The strands, which were composed of a cellular connective tissue core covered by endothelium, were usually ,1 mm thick and ranged in length from 1 to 10 mm. Magarey (119) related the strands to mitral valve thickening and posited that they originated from fibrinous deposits on the valve

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surface. Freedberg et al. (120) reviewed retrospectively an unselected series of 1559 patients who had undergone TEEs during a two year period and found mitral valve strands in 63 (4%) and aortic valve strands in 26 (1.7%) patients. Strands were found in 10.6% of patients referred because of suspected recent embolic events, compared to only 2.3% of those referred for other indications (120). In another TEE study, Tice et al. (121) prospectively sought mitral valve strands among all patients who had echocardiography during a two-year period at their hospital. Among 968 patients, 22 (2.3%) had mitral valve strands, including 20 (91%) patients who had TEE because of brain ischemic events. Overall, 20 (6.3%) of 318 patients having TEE because of brain ischemia had strands, compared with only two (0.3%) of 650 patients having TEE for other indications (121). Nighoghossian et al. (122) reported three patients who had brain ischemic events presumably related to mitral valve strands who had cardiac surgery. Extensive evaluation including cerebral angiography and serological testing showed no cause for stroke other than the valve lesions. The valve lesions were described as: a floating mass 6 mm thick on the ventricular surface of the mitral valve, a 6 mm lesion on the anterior mitral valve leaflet, and a sessile 5 mm lesion on the anterior mitral valve leaflet (122). One patient had immediate cardiac surgery when the valve lesion was found; the other two patients had surgery when they had subsequent strokes despite anticoagulant therapy. Histopathological examinations showed that the lesions were composed of an acellular fibrous core with rings of granular material and endothelial cells. In two patients, thrombi were attached to the lesions (122). Roberts et al. (123) compared the frequency of strands among patients referred for TEE because of brain ischemia and those referred for other indications. An association between brain ischemia and strands was found (odds ratio 4.4, 95% confidence interval 2.0 – 9.6). The association was maintained for men and women and all racial groups and was strongest for younger patients and those with both mitral and aortic valve strands. The effect of strands did not depend on valve thickness (123). Cohen et al. (124) studied 338 patients referred to their echocardiographic labratory because of brain ischemia and compared the findings to 276 patients who had no history of brain ischemia. Strands were found in 22.5% of brain ischemia patients, compared with only 12.1% of controls (crude odds ratio of 2.1– 95% confidence interval 1.3– 3.4, P , 0.005). Strands were often found in patients with mitral valve thickening (124). Homma et al. (125) performed echocardiography on 619 stroke patients and found strands in 244 (39%), 36 (6%) aortic, 172 (28%) mitral, and 36 (6%) aortic and mitral. These observations and the pathological studies of Magarey (119) suggest that strands probably most often are formed because of a degenerative process that causes fibrinous deposits on valve surfaces. Emboli can arise from the abnormal valves, or, on occasion, from the strands, or from thrombi formed on the surface of the valve or on the strands. Strands may share a pathogenesis with valve lesions found in some patients with SLE, APlA syndrome, and cancer. Some patients with strands have APlAs (126).

MYOCARDIAL AND CARDIAC CHAMBER LESIONS Myocardial Infarction Myocardial Infarction and Coronary Artery Disease Systemic embolism is apparent clinically in about 3% (range 0.6 – 6.4%) of patients with acute myocardial infarction with large anteroapical infarctions with aneurysm formation

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Figure 5 The heart at necropsy in a patient with a massive brain embolus. A large thrombus is seen overlying a recent myocardial infarct. Source: From Ref. 2.

conveying the highest risk (127 –132). Most clinically symptomatic emboli are those that involve the brain and present as acute strokes. Most strokes that occur in patients with acute myocardial infarcts are caused by embolization of thrombi formed in the left ventricle but some strokes are related to left atrial thrombi and extracranial occlusive vascular disease. Figure 5 shows a large mural thrombus at necropsy in a patient with a recent myocardial infarction who died of brain embolism. Vascular occlusions, including coronary artery thrombosis, are followed by an increase in acute phase reactants, including serine protease coagulation proteins. Venous thromboses and occlusion of atherostenotic craniocervical arteries may occur in the days and weeks after myocardial infarction because of this hypercoagulability. Left ventricular thrombi have been described in up to 20 –40% of patients with acute anteroapical myocardial infarcts but are unusual in patients with inferior infarction (129,133,134). Most thrombi form on the apical wall of the left ventricle probably in relation to regions of reduced ventricular contractility. Mural thrombi are more likely to form in patients with transmural and large anterior myocardial infarcts than in those with small infarcts. Areas of decreased ventricular contractility, low ejection fraction, and development of a left ventricular aneurysm predispose to thrombus formation. Large thrombi most often occur within the first three days after myocardial infarction especially in those patients with large infarcts that carry a poor prognosis (135,136). Systemic embolization occurs on average 14 days after myocardial infarction and is unusual

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after four to six weeks (137). Pedunculated, mobile thrombi that project into the left ventricular cavity pose the greatest risks for embolization. Regions of akinesis and dyskinesis and frank ventricular aneurysms often persist after acute myocardial infarction. In the Coronary Artery Surgery Study, 7.6% of patients had angiographically defined left ventricular aneurysms (138). Aneurysms are usually anterior, apical, or anteroapical; posterior aneurysms involving the diaphragmatic wall occur but are rare. Although aneurysms are relatively common and mural thrombi often form within aneurysms, the risk of stroke is relatively low, about 5% (137,139). Posited reasons for a rather low rate of embolization despite aneurysm formation include: mural thrombi become organized and adherent to the aneurysm walls, thrombi often have a relatively small area of contact with blood flow in the ventricle, and there is a loss of systolic force generated by the underlying adjacent myocardium (86,140). Considering all patients who have recovered after myocardial infarction, the risk of stroke in patients with impaired left ventricular function after myocardial infarction is substantial. Among 2,231 patients with left ventricular dysfunction after acute myocardial infarction who were followed for an average of 42 months, 103 (4.6%) patients developed strokes (141). The estimated five-year stroke rate was 8.1%, and the actual stroke rate was 1.5% per year of follow-up (141). Large size of myocardial infarcts and reduced left ventricular ejection fraction were the two most important predictors of the development of stroke in this study. Patients with ejection fractions of ,30 were at highest risk, and for every absolute decrease of 5% in the left ventricular ejection fraction, the risk of stroke increased by 18% (141). In the Survival and Ventricular Enlargement trial, the beneficial effects of anticoagulation in preventing stroke were found in patients with moderate to severe decreases in left ventricular ejection fraction and also in patients with better preserved function (ejection fractions .35%) (141). Some patients with brain embolism are unexpectedly found to have left ventricular thrombi (142,143). Some of these patients do not have a history of acute myocardial infarction, and the cardiac cavity lesions are often first thought to represent myxomas or other cardiac tumors. Sequential echocardiography shows that these thrombi can gradually regress or suddenly disappear (143 – 145) sometimes without development of neurological or systemic organ symptoms or signs of embolism. Thrombus formation and spontaneous endogenous fibrinolysis and fragmentation of thrombi are dynamic processes. Nonischemic Cardiomyopathies Conditions that affect the endocardium and underlying myocardium can promote the formation of intracavitary mural thrombi and resultant systemic and brain embolism. Probably, the three most important factors that determine thrombus formation are extent of involvement of the endocardial surface, underlying ventricular contractility within the ventricles, and activation of platelets and the coagulation system. Among the three categories of cardiomyopathies—dilated, restrictive, and hypertrophic—mural thrombus formation and embolism are most common among the dilated cardiomyopathies. Intraventricular thrombus formation is enhanced by stasis of blood and by the loss of normal subendocardial trabeculation. The network of subendocardial trabeculae can act as many small compartments that produce high levels of force within the ventricle propelling blood away from the endocardial surface (146). As the left ventricle dilates and systolic function deteriorates (left ventricular ejection fraction ,40%), thrombi are more likely to form, and patients have an increased risk of thromboembolism (146). In one study of patients with idiopathic dilated cardiomyopathy, 60% had mural thrombi defined by echocardiography, and even more had clinical or necropsy evidence

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of systemic embolism (147). Conditions as diverse as muscular dystrophies (148,149), cardiac amyloidosis (150), peripartum cardiomyopathy (151,152), cocaine-related cardiomyopathy (153) noncompaction of the myocardium (154), and cardiac sarcoidosis (155) have all been reported to cause thromboembolism. Mural thrombi form mostly within the trabeculae carnae near the cardiac apex. Atrial fibrillation further increases the frequency of embolism in these groups. Embolism is unusual in patients with hypertrophic cardiomyopathies unless they develop atrial fibrillation or end-stage dilated cardiomyopathy.

CARDIAC MYXOMAS AND OTHER TUMORS Although cardiac tumors are rare, they are an important cause of embolism and are very important to diagnose. The cells of origin for myxomas are endocardial and arise from multipotential mesenchymal cells that persist as embryonal remnants during septation of the heart (156). About 75% form in the left atrium and 15 –20% in the right atrium, and the rest are located in the ventricles and very rarely (,2%) on a heart valve (156,157). Most myxomas originate from the interatrial septum at the edge of the fossa ovalis, but some originate from the posterior or anterior atrial walls or the auricular appendage (156,157). Myxomas project from their endocardial attachments into cardiac chambers. Myxomas are most often found in patients between the ages of 30 and 60; women are slightly more often affected than men, and 5 –10% of patients have a familial myxoma syndrome in which multiple myxomas are more common. Embolism is estimated to occur in 30– 50% of patients with cardiac myxomas and may be the presenting manifestation (156,158 – 160). Most emboli arise from the left atrium and go to the brain or systemic organs. Occasional cases of right atrial myxomas with systemic embolism have been reported in the presence of a PFO (161 –163). The most common recognized site of embolism is to the brain, embolism to the eye can cause transient or persistent visual loss, and embolism to the spinal cord has also been reported (156,164,165). Most often, patients with brain embolism present with a sudden onset focal neurologic deficit. Transient neurological deficits sometimes occur. Often there has been more than one brain embolism before atrial myxomas are diagnosed. Patients may also present with systemic symptoms (e.g., low grade fever, myalgia, night sweats) or with syncope/presyncope if the myxoma is large enough to obstruct mitral inflow. Usually the diagnosis of myxomas is made when the patient is referred for an echocardiogram to evaluate a suspected cardiac source of embolism. Transthoracic echocardiography is very sensitive for the detection of myxomas, although the frequency of detection is likely related to tumor size and to residual tumor for those who present with an acute neurologic event (166). Mobile myxomas on a stalk are more likely to embolise than sessile tumors with a broad base of attachment. Embolic material may be tumor fragments and/or overlying thrombus. Patients with progressive dementia caused by multiple small brain infarcts (167), and sudden coma due to a shower of tumor emboli to multiple brain arteries have been reported (168). Occasional patients with brain emboli from myxomas have subarachnoid or intracerebral hemorrhage. Bleeding is related to the development of hemorrhagic infarction or rupture of aneurysms. Embolism of myxoma tissue to the wall of brain arteries causes aneurysms that are similar to mycotic aneurysms found in patients with bacterial endocarditis. Usually, the aneurysms are relatively small, multiple, and on peripheral branches of brain arteries. Some aneurysms are quite large. The peripheral location of aneurysms in patients with myxomas and endocarditis differs from that usually found in patients with saccular (berry) aneurysms. Delayed progressive brain ischemia and

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enlargement of aneurysms can develop after the initial embolic event (169). Although delayed growth and rupture of aneurysms, and metastatic tumor growth do occur, their frequency is very low. In a review of 35 patients with atrial myxomas followed at the Mayo Clinic, none had subsequent delayed neurological events attributable to their myxomas (170). Recurrent cardiac tumors after surgery can be the result of incomplete excision or reucurrent primary tumor as in the familial myxoma syndrome. Papillary fibroelastomas are another primary cardiac tumor associated with brain embolism (171,172). The lesions consist of multiple papillary fronds that radiate from an avascular fibrocollagenous core attached by a short pedicle to the endothelium. They most often arise from the valves with a slight predisposition for the aortic valve (173). Angina and coronary ischemia may be caused by embolism to the coronary arteries or transient obstruction of flow into the coronary ostia. Multiple brain infarcts usually occur before the diagnosis is made by echocardiography. Other cardiac tumors are more rare and also rarely present with neurologic symptoms. Rhabdomyomas are often multiple, arise from the ventricular myocardium, and project into the ventricular cavity (173). Tuberose sclerosis is present in about 33% of patients with rhabdomyomas (173). Other cardiac tumors include lipomas, which often involve the interatrial septum and can arise from the mitral or aortic valves, rhabdomyosarcomas, angiosarcomas, and metastatic tumors. These rarely have been associated with brain embolism. Patients with neurofibromatosis may develop rhabdomyosarcomas that have been reported to cause brain emboli (174).

PARADOXICAL EMBOLISM AND CARDIAC SEPTAL LESIONS Although once considered to be rare, emboli entering the systemic circulation through right-to-left communication of blood are becoming more frequently recognized with the advent of newer diagnostic technologies. By far, the most common potential intracardiac shunt is a PFO. Because the nomenclature is confusing, it is worthwhile to review the embryology of the division of the common atrium into left and right atria. The interatrial septum begins to form during the fifth week of uterine life (175). The septum primum grows caudally from the superior portion of the single atrium and fuses with the endocardial cushion, closing the defect called the ostium primum. Another potential defect forms from partial resorption of the septum primum and is called the ostium secundum. A second septum, the septum secundum, arises from the superior portion of the atrium and descends on the right side of the septum primum to cover the ostium secundum. The ostium secundum is not covered completely because of the presence of the foramen ovale. The foramen ovale consists of the septum primum and septum secundum, which are joined parallel to a slitlike valve. This valve allows oxygenated blood to bypass the pulmonary circulation of the fetus during intrauterine life (175). In a significant number of individuals the foramen ovale remains somewhat patent during adult life. The relatively high frequency of PFOs in the normal adult population has made it difficult to be certain in an individual stroke patient with a PFO as to whether paradoxical embolism through the PFO was the cause of their stroke or whether the PFO was merely an incidental finding. Autopsy series have shown that about 30% of adults have a PFO (176). Hagen et al. (176) studied 956 patients with clinically and pathologically normal hearts and found a PFO in 27.3%. The frequency of PFOs declined with age: 34% during the first three decades of life, 25% during the fourth to eighth decades, and 20% during the 9th and 10th decades. The average diameter of PFOs was 4.9 mm, and the size tended to increase with age (176).

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Echocardiographic studies have shown that PFOs are more commonly found in younger (,45 –55 year) patients with stroke than in controls, and PFOs are more common in patients with an undetermined cause of stroke (“cryptogenic stroke”) than in those in whom another etiology has been defined (177). Lechat et al. (178) examined 60 adults ,55 years old with stroke and 100 controls, using transthoracic echocardiography with injections of agitated saline to identify PFOs. The frequency of PFOs was higher in the stroke group (40%) than in controls (10%). Among patients with an identifiable stroke cause 21% had PFOs, whereas 40% of patients with possible risk factors for stroke, such as migraine, mitral valve prolapse, or use of oral contraceptives, had PFOs. The frequency of PFO detection was highest (54%) in those patients with no identifiable risk factor or cause of stroke (178). DiTullio et al. (179) studied 146 patients among whom 31% had no known cause of stroke and 69% had identifiable causes other than paradoxical embolism. Among the total group of patients, 26 (18%) patients had PFOs. Patients with cryptogenic stroke had a higher prevalence of PFOs than those with identifiable causes both in the group ,55 years (48% compared to 4%) and those .55 years (38% vs. 8%) (179). A meta-analysis showed that among nine case-control studies involving 566 stroke patients and 458 control nonstroke patients, young stroke patients had an odds ratio of 3.1 for having a PFO (180). Review of series of patients with paradoxical embolism (181 – 183) through a PFO and our own experience allows us to arrive at five criteria that, when four or more are met, establishes with a high degree of certainty the presence of paradoxical embolism. The findings are: (i) a situation that promotes thrombosis of leg or pelvic veins, for example long sitting in one position, recent surgery, and so on, (ii) increased coagulability, for example the use of oral contraceptives, presence of factor V Leiden with resistance to activated protein C, dehydration, (iii) the sudden onset of stroke during sexual intercourse, straining during bowel movements, coughing or other activity that includes a Valsalva maneuver or that promotes right-to-left shunting of blood, (iv) pulmonary embolism within a short time before or after the neurological ischemic event, and (v) the absence of other putative causes of stroke after thorough evaluation. The most common territory of stroke is the MCA, but the vertebrobasilar territory is involved more than explained by chance (183,184). The 37.5% of posterior circulation infarction in one study (182) is more than expected, as only 20% of blood flow to the brain goes through the posterior circulation. Paradoxical embolism has also been described through ventricular septal defects (VSDs) (185), atrial septal defects (ASDs) (186), and pulmonary arteriovenous fistulas (187). Among these, atrial septal defects are the most important and most frequent sites after PFOs among patients with paradoxical embolism. There are three types of atrial septal defects: primum ASDs (about 15% of ASDs) when the septum primum does not fuse with the endocardial cushion leaving a defect; secundum ASDs (about 75% of ASDs) when the fossa ovalis is not completely covered by the septum secundum; and Sinus Venosus ASDs (5 –10% of ASDs) when there is an abnormal insertion of the superior or inferior vena cava that overrides the interatrial septum leaving a defect at the mouth of the vein insertion (175). Venous thrombosis can be detected if studies are performed early in the course (188). Some venous thrombi involve the pelvic veins and might be detected by abdominal and pelvic imaging techniques (189). Predictors for the likelihood of paradoxical embolism through PFOs have been sought using TEE (179,190 –192). In one study, the presence of an atrial septal aneurysm accompanying the PFO was an important finding favoring the presence of paradoxical embolism (190). In another study, PFOs were significantly larger (2.1 þ 1.7 vs. 0.6 þ 0.8 mm), and there were more microbubbles (14 + 11 vs. 1.6 + 0.8 per mm3) in

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patients with cryptogenic stroke than in those with identified causes of stroke (191). Occasionally a thrombus can be seen during echocardiography traversing the foramen ovale (193). Figure 6 from (193) shows such an embolus intransit through a PFO. Atrial septal aneurysms have recently received increased attention in relation to their possible role in contributing to brain embolism (177,194). Fusion of the septum primum closes the foramen ovale and leads to a depression on the right side of the interatrial septal wall. Bulging of the septum primum tissue of the atrial septum through the fossa ovalis into either the right or the left atrial cavity is called an atrial septal aneurysm. Atrial septal aneurysms were first reported in 1934 (195); they were found in 1% of necropsies by Silver and Dorsey (196) and were found in 3 –4% of TEEs (197). The majority of

Figure 6 Thrombus traversing a patent foramen ovale (PFO). (A) An echocardiographic image of the heart in the oblique plane (508) at the level of the aortic root. A large thrombus is in transit from the right atrium to the left atrium through a PFO. (B) The large 13 by 1.5 cm thrombus removed at surgery. Abbreviations: T, thrombus; RA, right atrium; LA, left atrium; AO, aorta; IAS, intraatrial septum; TV, tricuspid valve. Source: From Ref. 193.

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patients with an atrial septal aneurysm have a PFO, and there is a strong association between atrial septal aneurysms and interatrial shunts. The presence of either atrial septal aneurysms and/or PFOs is strongly associated with the presence of cryptogenic stroke especially among young stroke patients (177,194,197 –199). The exact independent mechanism by which atrial septal aneurysms may contribute to brain embolism has not been clarified. The atrial septal aneurysm might alter flow through the PFO or serve as a nidus for local thrombosis due to abnormal endothelial surface (177). Thrombus has been reported within the neck of an atrial septal aneurysm in one patient (200) and has been found within the base of atrial septal aneurysms at necropsy (198).

REFERENCES 1. Caplan LR. Brain embolism in Caplan LR, Hurst JW, Chimowitz MI. Clinical Neurocardiology. New York: Marcel Dekker, 1999:35 – 185. 2. Caplan LR. Caplan’s Stroke a clinical approach 3rd ed. Boston: Butterworth-Heinemann, 2000:247 – 282. 3. Virchow R. Gesammelte abhandlungen zur wissenschaftlichenmedtezin. Frankfurt, Meidinger Sohn, 1856:219 – 732. 4. Hanna JP, Furlan AJ. Cardiac disease and embolic sources. In: Caplan LR, ed. Brain Ischemia. London: Springer-Verlag, 1995:299 –315. 5. Baumgartner HR, Haudenschild C. Adhesion of platelets to subendothelium. Ann New York Acad Sci 1972; 201:22 – 36. 6. Gustafsson C, Blomback M, Britton M, Hamsten A, Svensson J. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke 1990; 21:47 – 51. 7. Kumagai K, Fukunami M, Ohmori M, Kitabatake A, Kamada T, Hoki N. Increased intracardiovascular clotting in patients with chronic atrial fibrillation. J Am Coll Cardiol 1990; 16:377 –380. 8. Kay GN, Plumb VJ. Atrial fibrillation, atrial flutter, and atrial tachycardia. In: Fuster V, Alexander RW, O’Rourke RA, eds. Hurst’s The Heart. 11th ed. New York: McGraw Hill, 2004:825 – 853. 9. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk of atrial fibrillation: the Framingham heart Study. Circulation 2004; 110:1042 –1046. 10. Go AS, Hylek EM, Phillips KA. Prevalence of diagnosed atrial fibrillation in adults. JAMA 2001; 285:2370 – 2375. 11. Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991; 84:469– 481. 12. Wolf PA, Dawber TR, Thomas HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham Study. Neurology 1978; 28:973 –977. 13. Dunn MJ, Alexander R, DeSilva F, Hildner. Antithrombotic therapy in atrial fibrillation. Chest 1989; 95:118S – 127S. 14. The Stroke Prevention in Atrial Fibrillation Investigators: Predictors of thromboembolism in atrial fibrillation: 1. clinical features of patients at risk. Ann Intern Med 1992; 116:1 –5. 15. DiPasquale G, Urbinati S, Pinelli G. New echocardiographic markers of embolic risk in atrial fibrillation. Cerebrovasc Dis 1995; 5:315– 322. 16. Black IW, Hopkins AP, Lee LCL, Walsh WF. Evaluation of transesophageal echocardiography before cardioversion of atrial fibrillation and flutter in nonanticoagulated patients. Am Heart J 1993; 126:375 – 381. 17. Caplan LR, D’Cruz I, Hier DB, Reddy H, Shah S. Atrial size, atrial fibrillation, and stroke. Ann Neurol 1986; 19:158– 161. 18. The Stroke Prevention in Atrial Fibrillation Investigators: Predictors of thromboembolism in atrial fibrillation: 11. echocardiographic features of patients at risk. Ann Intern Med 1992; 116:6 –12.

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9 Cardiac Source of Embolism: Pathophysiology and Identification Warren J. Manning Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Cardiac sources of cerebrovascular ischemic events are increasingly being recognized and may account for 20– 30% of the 500,000 strokes that occur annually in the United States (1). Conventional transthoracic echocardiography (TTE) remains the cornerstone of noninvasive cardiac imaging and has been extensively used in numerous studies during the past three decades to identify both clinical and imaging risk factors for cardiogenic thromboembolism. Subsequently, moderately invasive transesophageal echocardiography (TEE) has been shown to be a superior method for the identification of most cardiac sources of emboli (2,3) and to be more cost effective (4). Clinical paradigms for the use of these primary imaging modalities continue to evolve. In addition, preliminary data suggest that newer imaging methods, such as magnetic resonance imaging (MRI), may also have an important role in identifying cardiogenic sources of embolism, but the impact of these newer imaging methods on treatment and prognosis remains to be defined. MAJOR SOURCES OF EMBOLI Potential cardiac sources of thromboembolism are summarized in Table 1 and can be broadly categorized into masses (e.g., thrombi, aortic atherosclerotic plaques, valvular vegetations, and intracardiac tumors) that migrate/embolize, an increased propensity for thrombus formation identified on imaging studies [e.g., left atrial (LA) spontaneous echo contrast, prominent mitral annular calcification, left ventricular (LV) aneurysms], and “passageways” for paradoxical thromboembolism, for example, patent foramen ovale (PFO) and atrial septal defects, often accompanied by atrial septal aneurysms (ASAs). The most common cardiac sources are LA thrombi, LV thrombi, aortic atherosclerosis, and PFO. LEFT ATRIAL ANATOMY AND IMAGING The body of the left atrium is a thin-walled, ovoid chamber that lies immediately posterior to the ascending aorta. The endocardial surface of the LA is generally smooth and continuous, 161

162 Table 1

Manning Sources of Cardioembolic Thromboembolism

Masses Left atrial thrombi Rheumatic mitral stenosis Atrial fibrillation Left atrial tumors Intracardiac tumors, e.g., myxoma, fibroelastoma Left ventricular thrombi Anteroapical infarction/aneurysm Aortic atherosclerosis Hypertension Hypercholesterolemia Valvular heart disease Endocarditis Calcific aortic stenosis Dysfunctional prosthetic valve Propensity for thrombus formation Spontaneous echo contrast Left ventricular cavity enlargement/systolic dysfunction Interatrial septal aneurysm “Passageways” for paradoxical embolism Patent foramen ovale Atrial septal defect

as it developed from the fetal common pulmonary vein (5). Gender-specific and body-size normograms for transthoracic LA measurements have been published, but absolute LA dimension and length value are reported by most clinical echocardiographic laboratories. With normal aging, the LA cavity dimensions increase. The body of the LA is well visualized from multiple perspectives on TTE (Fig. 1). In contrast, the left atrial appendage (LAA) is a highly trabeculated and often multilobulated cul-de-sac arising from the midportion of the lateral wall of the LA near the entrance of the left upper pulmonary vein (Fig. 2). Although the LAA is often not visualized on TTE, the close proximity of the esophagus to the posterior LA (Fig. 3) and the absence of intervening bone or lung makes the TEE an ideal imaging tool for visualization of both the LA and the LAA. Several studies have documented the very high accuracy of TEE for the identification of LA and LAA thrombi when compared with intraoperative series (5a,b).

LEFT ATRIAL THROMBI LA thrombi are almost exclusively seen in association with atrial fibrillation and/or rheumatic mitral stenosis and are thought to account for nearly half of all cardiogenic thromboemboli. In the absence of mitral stenosis or atrial fibrillation, the incidental finding of an LA thrombus is very rare (6), even in the setting of embolic stroke or transient brain ischemia (7). A report of almost 3,000 consecutive patients who underwent TEE for various indications found an LA thrombus in only 0.3% of those in sinus rhythm (6). Another study of nearly 900 patients presenting with an embolic stroke or a transient ischemic episode and sinus rhythm identified an LA thrombus in only 1% of those without mitral valve disease (7). The community-based SPARC (Stroke Prevention: Assessment of Risk in a Community) study reported no atrial thrombi on initial TEE (8).

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MITRAL STENOSIS The strong association of rheumatic mitral stenosis and stroke has long been recognized, both in the sinus rhythm population and particularly among patients with atrial fibrillation. The normal adult mitral valve cross-sectional area is 4– 6 cm2. There is tremendous reserve, with clinical symptoms often lacking until the mitral valve area declines to ,2 cm2. The predominant cause of mitral stenosis is rheumatic fever leading to

Figure 1 Transthoracic echocardiogram in a normal subject. (A) Parasternal long-axis view in which the left atrium (LA) and the anterior septum and inferolateral walls of the left ventricle (LV) are seen. The anterior (small white arrow) and posterior mitral leaflets as well as the right coronary and noncoronary (thick white arrow) aortic leaflets are also visualized. (B) Parasternal short axis at the left of the aortic valve. The noncoronary (N) and left (L) coronary leaflets are identified. The LA, right atrium, and right ventricle (RV) are also depicted. (C) Apical four-chamber view depicting the right and left atria as well as the RV free wall and the septal and lateral walls of the LV. The anterior mitral leaflet (white arrow) is also seen. (D) Subcostal view demonstrating the RV and LV. The anterior mitral leaflet (white arrow) is again seen. Abbreviations: LV, left ventricle; LA, left atrium; RV, right ventricle; RA, right atrium; N, noncoronary; L, left coronary.

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Figure 1 Continued.

predominant mitral stenosis (especially common among women), mixed mitral stenosis and mitral regurgitation, or predominant mitral regurgitation (more common among men). With rheumatic valvular disease, the mitral leaflets fuse at their edges with thickening of the chordae. The stenotic mitral valve is typically funnel shaped (Fig. 4). Progressive mitral valve obstruction leads to increased intra-atrial pressure and progressive LA dilation. In addition, there may be endocardial fibrosis of the LA walls. Progressive LA dilation, blood stasis, and endocardial surface abnormalities are thought to promote thrombus formation, yet the incidence of thromboembolism does not appear to be related to the severity of mitral stenosis (9). Large thrombi within the body of the LA, especially “ball” thrombi (Fig. 5), are almost exclusively seen among patient with rheumatic mitral stenosis (and those with prosthetic mitral valve thrombosis). Though unusual, these ball thrombi are often readily appreciated by TTE. Prior to the availability of anticoagulation, both autopsy and surgical series showed an increased risk of clinical thromboembolism in the mitral stenosis population (10 – 12). Atrial fibrillation markedly increases the risk of thromboembolism in mitral stenosis (9,13), whereas mitral regurgitation appears to be somewhat protective (14). In addition

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Figure 2 (A) Transesophageal echocardiogram (TEE) demonstrating a thrombus (white arrow) within the left atrial appendage (LAA). (B) TEE demonstrating the far less common situation of mural thrombus (white arrow) along the wall of the body of the left atrium. Note that LAA is free of thrombus. Abbreviation: LA, left atrium.

to atrial fibrillation, clinical risk factors for stroke for patients with mitral stenosis include advancing age and progressive LV systolic dysfunction (9,15,16).

ATRIAL FIBRILLATION With atrial fibrillation, there is loss of organized atrial electrical and mechanical activity (Fig. 6), resulting in stagnation/stasis of blood within the body of the atria and especially within the LAA. LAA ejection velocity is markedly depressed (,20 cm/s) in patients with atrial fibrillation, with the risk of thrombus formation being inversely related to residual LAA ejection velocity (17). In addition to stasis, hematological studies suggest that atrial fibrillation is associated with a hypercoagulable state (18). More than 2.5 million people in the United States have atrial fibrillation, a population that greatly exceeds those with rheumatic mitral stenosis (19). As a result, the

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Figure 3 Lateral chest X-ray following a barium swallow, demonstrating close relationship of esophagus to left atrium.

clinical association of atrial thrombus and atrial fibrillation is far more common, with stroke rates as high as 20% per year among very-high-risk patients. In the setting of nonvalvular atrial fibrillation, atrial thrombi are most often seen completely within or primarily involving the LAA (20), a structure best imaged with TEE (Fig. 2). Coexistant spontaneous echo contrast (visualized as “smokelike” echoes), a marker of stasis, within the LAA and/or body of the LA may be seen in 60% of patients with atrial fibrillation and .85% of those with atrial fibrillation and LA thrombi (21,22). Prospective TEE studies show LA thrombi in 14% of patients with new-onset atrial fibrillation (20,23), increasing to 27% of those with chronic atrial fibrillation (24), and 45% in those presenting with atrial fibrillation and recent clinical thromboembolism (25). For the latter population, the frequency of LAA thrombus represents residual thrombus. TEE risk factors for subsequent thromboembolism include increased thrombus size and mobility. Although patients with atrial fibrillation and mitral stenosis remain at highest risk for clinical thromboembolism (estimated at 20% per year), several prospective clinical studies have now identified clinical risk factors for stroke among patients with nonvalvular atrial fibrillation, including systemic hypertension (systolic blood pressure .160 mmHg), age .75 years, congestive heart failure/LV systolic dysfunction, diabetes, and prior stroke/transient ischemic episode. These are best summarized by the CHADS2 criterion (Table 2) (26), which help guide the use of anticoagulant therapy (chap. 16). TTE- and

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Figure 4 Transthoracic echocardiogram in the parasternal long-axis view in a patient with rheumatic mitral stenosis. Note the mildly thickened leaflets with fixed posterior leaflet position and “hockey-stick” appearance (white arrow) of the anterior mitral leaflet. Abbreviation: LA, left atrium.

Figure 5 Transesophageal echocardiogram in a patient with rheumatic mitral stenosis. Note the free-floating intra-atrial thrombus ( ) within the body of the LA. Abbreviation: LA, left atrium.

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Figure 6 Transesophageal echocardiogram with pulsed sample volume in the mouth of the left atrial appendage in a patient with (A) sinus rhythm. Note the single ejection velocity (solid arrows) following each p-wave on the echocardiogram (dashed arrows). (B) Atrial flutter. Note the saw-tooth-like pattern with ejection velocities approaching 0.5 m/s. (C) Atrial fibrillation. Note the very irregular and low velocity (,0.2 m/s) ejection velocity pattern.

TEE-specific imaging risk factors for thromboembolism include increased LV systolic dysfunction, more pronounced spontaneous echo contrast, reduced LAA ejection velocity, and the presence of LAA thrombus and aortic atherosclerosis (22). Interestingly, moderate or greater mitral regurgitation does not appear to be “protective” for atrial thrombus

Table 2

CHADS2 Stroke Risk Strategy for Nonvalvular Atrial Fibrillation

C, congestive heart failure or left ventricular systolic dysfunction H, hypertension; SBP . 160 mmHg A, age . 75 yr D, diabetes S2, stroke or transient neurological event Minimum score ¼ 0 Maximum score ¼ 6 (a stroke or transient neurologic event gets two points) Abbreviation: SBP, spontaneous bacterial peritonitis.

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formation in new-onset atrial fibrillation (20), but moderate or greater mitral regurgitation is protective against clinical stroke in the chronic atrial fibrillation population (27). This difference may represent pathophysiologic differences between thrombus formation and thrombus migration. The LA size is absent from echocardiographic risk factors for stroke in atrial fibrillation. This is likely because of the confounding impact of LA dilation promoting stasis with LA dilation due to “protective” mitral regurgitation. Among patients with atrial thrombi, larger size and increased mobility are risk factors for clinical thromboembolism (28). Even among patients without a clinical history of stroke, studies show subclinical stroke in cranial CT among 15% of patients with atrial fibrillation (28). Systemic thromboembolism occurs in patients with dilated cardiomyopathy (LV thrombi) at an annual rate of 4%. LV thrombi had been presumed to be the source of emboli in these patients (29). However, TEE studies show that LAA thrombi are also a common culprit (30).

LEFT VENTRICULAR THROMBI LV thrombi are most often associated with acute myocardial infarction but can also be seen in patients with dilated (nonischemic) cardiomyopathy. Historically, LV thrombi are most often detected with TTE, which has a reported sensitivity and specificity exceeding 90% (Fig. 7) (31 –33a). The use of intravenous echo contrast may assist in the discrimination between apical trabeculations and thrombus (Fig. 8). Although the detection of apical LV thrombi has been reported (34), from a practical perspective, the frequent inability of TEE to visualize the true LV apex makes TEE a less appropriate imaging test for suspected LV apical thrombi. Moreover, a preliminary intraoperative validation report has suggested that delayed enhancement cardiac magnetic resonance is superior to both TTE and TEE for identifying LV thrombi (Fig. 9) (35). Until confirmation by others/larger series, TTE is considered the noninvasive “clinical gold standard” for those with suspected LV thrombi.

Figure 7 Transthoracic echocardiogram from the apical four-chamber orientation. Note the apical thrombus (white arrow) in this patient who had an anteroapical myocardial infarction. Abbreviation: LV, left ventricle.

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Figure 8 Apical left ventricular thrombus demonstrated by echo contrast. Transthoracic echocardiogram from the apical view after intravenous administration of an echo contrast agent. Note that the left ventricular cavity is now “bright” and the apical thrombus (T) appears dark.

MYOCARDIAL INFARCTION Among patients with acute infarction, the risk of clinical stroke is reported at up to 3.6% (36,37). The risk of stroke and thrombus formation is related to infarct location (anterior at higher risk) and infarct size. In the GISSI-3 trial (38), the incidence of LV thrombus among those with an anterior infarction increased to almost 18% for patients with an LV ejection fraction of ,40%, when compared with ,10% for those with a higher ejection fraction. The corresponding incidence for infarctions at nonanterior sites were 5.4% and 1.8%, respectively (34). Somewhat surprisingly, limited data do not suggest

Figure 9 Delayed enhancement cardiovascular magnetic resonance imaging in the (A) fourchamber and (B) two-chamber orientation. Note the extensive area of hyperenhancement (white arrowheads) with a nonenhancing subendocardial thrombus (white arrow). Source: Courtesy of Dr. Scott Flamm. Abbreviations: RV, right ventricle; LA, left atrium; LV, left ventricle.

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an independent benefit with the use of thrombolysis (39). This may be due to the development of most thrombi in the days following initial presentation. Using serial TTE, most thrombi are found to develop within the first two weeks after infarction (median 5 – 6 days) (40 – 42). Although some patients develop a new LV thrombus to a greater extent, it is most often in association with worsening LV systolic function (42 – 43). Thrombus mobility and protrusion are also associated with the increased risk of stroke (44).

DILATED CARDIOMYOPATHY Even in the absence of acute infarction, patients with depressed LV systolic function and heart failure are at increased risk for stroke (45 – 47). Like the setting of acute infarction, the risk of clinical stroke appears to be related to the severity of LV systolic dysfunction (46 –49). For patients with heart failure/low ejection fraction who sustain a stroke, the recurrence rate may reach 20% in the first year and 45% after five years (50,51). In addition to identification of LV thrombus and monitoring for thrombus resolution, TTE-visualized thrombus characteristics can help to identify those patients at high risk of clinical thromboembolism. The two most important risk factors include thrombus size and mobility (52 – 54).

PROSTHETIC VALVE THROMBI Thrombus formation and subsequent embolization may be seen in patients with valve prostheses, especially mechanical valve prostheses in the mitral or tricuspid position in the setting of suboptimal anticoagulation (55,56). Anticoagulation strategies are dependent on the type of prosthesis and valve position (Table 3), with patients requiring lifelong warfarin anticoagulation with a recommended international normalized ratio (INR) between 2.0 and 3.5 (57). Evaluation of prosthetic valves, especially prostheses in the mitral position, is best performed by TEE. It is often assumed clinically that patients with mechanical prostheses who present with systemic embolization have prosthetic valve thrombi, especially if there is no other obvious cause and/or the INR is suboptimal. Although TEE can confirm the diagnosis, it does not usually change the therapy (except for patients with valvular dysfunction due to a massive thrombus). In the setting of thromboembolism and a therapeutic INR, TEE is often helpful to distinguish valve dysfunction related to pannus ingrowth versus thrombus (56).

AORTIC ATHEROSCLEROSIS Among patients with ischemic stroke, TEE evidence of complex (mobile plaque or protrusion into the aortic lumen of .4 mm) aortic atherosclerosis is more common in patients without other known causes of thromboembolism, when compared with those with possible or likely other causes (58) (chap. 10). Ulcerated plaques in the aortic arch have been noted in more than 60% of patients without a known cause of cerebral infarction versus only 22% of those with another cause of brain infarction (59). Aortic atherosclerosis is most often clinically identified by TEE, though thoracic MRI is also able to identify and quantify thoracic aortic atherosclerosis (60). Atherosclerotic plaques on TEE are more likely in patients with a history of transient ischemic attack, stroke, or peripheral embolism (61), with a higher incidence of clinical

172 Table 3

Manning Anticoagulation Guidelines for Native and Prosthetic Valves

Condition Native valve Rheumatic MVD

Association condition

Atrial fibrillation Sinus rhythm, thromboembolism Sinus rhythm, LAD ?.5.5 cm Sinus rhythm, LAD ?,5.5 cm

Prosthetic valve Bileaflet—aortic Atrial fibrillation Bileaflet—mitral Atrial fibrillation Poor LV function Starr-Edwards—Aortic Starr-Edwards—Mitral Bioprosthetic—Mitral Atrial fibrillation Bioprosthetic—Aortic Atrial fibrillation

Target INR

2.0 – 3.0 2.0 – 3.0 2.0 – 3.0 aspirin 2.0 – 3.0 2.5 – 3.5 2.5 – 3.5 2.5 – 3.5 2.5 – 3.5 3.0 – 4.0 3.5 – 4.5 aspirin 2.0 – 3.0 aspirin 2.0 – 3.0

Abbreviations: MVD, mitral valve disease; LAD, left atrial dimension; LV, left ventricle; INR, international normalized ratio.

thromboembolism when the plaque is pedunculated and highly mobile (62 – 64), especially if located within the ascending aorta (65). Patients with complex aortic atherosclerosis and atrial fibrillation may be at particularly high risk for clinical thromboembolism (22). Atherosclerotic disease of the aortic arch is also a risk factor for recurrent ischemic stroke (66). Finally, aortic atherosclerotic “debris” (especially when mobile) on TEE also identifies patients in whom cardiac catheterization or insertion of an intra-aortic balloon pump carries a high risk for thromboembolism (67). This increased risk is most frequently associated with catheterization performed via a femoral approach.

INFECTIVE ENDOCARDITIS After congestive heart failure, arterial embolism is the most common life-threatening complication in patients with infective endocarditis. Embolization during the first week of antibiotic treatment is most common (68) and declines thereafter (69). Late thromboembolism (after completion of antibiotics) in the absence of recurrent infection is rare. Staphylococci and streptococcus species account for .80% of native valve endocarditis (70), with an increased risk of clinical thromboembolism among patients infected with staphylococci (68,69,71,72). Although one might expect increased clinical thromboembolism from aortic valve vegetations due to increased shear stress with LV ejection, data suggest that mitral valve vegetations lead to an increased propensity for thromboembolism (68,73,74). Although rarely the only clinical manifestations of endocarditis, the acuteness and magnitude of the event may be the primary cause for the patient to seek urgent care. TTE has relatively low sensitivity in endocarditis (75). A negative TTE does not preclude the diagnosis and should be followed by TEE (with superior spatial resolution) if the clinical suspicion is high or moderate (Fig. 10) (75,76). Consideration of direct TEE should also be considered for patients in whom a “negative” TTE would lead to a TEE.

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Figure 10 (A) Transesophageal echocardiogram demonstrating a large vegetation involving the posterior mitral leaflet (short arrow) and a much smaller vegetation at the tip of the anterior mitral leaflet (long arrow). (B) Transthoracic echocardiogram in the parasternal long-axis view. Note the vegetation (white arrow) on the left ventricular outflow tract side of the aortic valve. Abbreviations: LA, left atrium; LV, left ventricle.

TEE evidence for larger (.10 mm) vegetations and increased mobility identify patients at higher risk for clinical thromboembolism (77). VALVULAR CALCIFICATION Valvular calcification most often involves the aortic valve and mitral annulus. Case reports suggest that calcified material can spontaneously embolize from calcified bicuspid valves, rheumatic aortic stenosis, and senile degenerative aortic valves (78 –80). These events, however, are quite rare, and other causes for thromboembolism should be sought among patients with aortic stenosis presenting with thromboembolism. Although spontaneous embolism is quite rare, the frequency of clinical and subclinical thromboembolism may exceed 20% for patients with aortic stenosis undergoing cardiac catheterization during which the stenotic aortic valve is crossed (81). VALVE EXCRESCENCES Valve excrescences are thin, elongated, and mobile echoreflective structures with independent, undulating hypermobility seen near the leaflet’s line of closure. They occur on the

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atrial side of the mitral valve and the ventricular side of the aortic valve and are increasingly recognized in the elderly. Valve excrescences do not appear to be a primary source of cardioembolism (82). MITRAL ANNULAR CALCIFICATION The most common TTE finding among elderly patients referred for a cardiac source of embolism is a high reflective area in the posterior portion of the mitral annulus representing mitral annular calcification (MAC) (Fig. 11) (83,84). MAC is very common in the elderly. A study of more than 2,000 patients (mean age 81 years) found that 48% had MAC with an increased prevalence of atrial fibrillation (22% vs. 8% without MAC) (83). In addition to age, MAC is associated with hypertension and aortic atherosclerosis. During a 44-month follow-up, MAC was associated with an increased incidence of thromboembolism in patients both with and without atrial fibrillation. The incidence of stroke and the severity of calcification appear to be linearly related (84). Case report TEE observations suggest that the MAC may serve as a nidus for thrombus formation (85,86a,b). Alternatively, the association of MAC and aortic atheroma (84% vs. 33% without MAC) may partially explain the association of MAC with stroke (87). A recent study explored the role of MAC among 2723 American-Indians who did not have known cardiovascular disease (86a). The presence of MAC but not aortic valve sclerosis proved to be a strong risk factor for incident stroke, even after adjusting for multiple other risk factors (86a). INTRACARDIAC TUMORS Primary cardiac tumors are extremely rare, found in ,0.03% of autopsy studies, with myxomas constituting almost 60% of these lesions (88). Myxomas are histologically

Figure 11 Transthoracic echocardiogram in a patient with symmetric left ventricular hypertrophy and prominent echogenic areas along the posterior mitral annulus (black arrow) and extending to the anterior mitral annulus consistent with extensive mitral annular calcification. Abbreviation: LV, left ventricle.

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Figure 12 Transesophageal echocardiogram in a patient with a large left atrial myxoma (white arrow) attached to the interatrial septum in the area of the foramen. Abbreviation: RA, right atrium.

benign tumors that are most often found within the body of the LA and attached to the midportion of the interatrial septum in the area of the foramen (Fig. 12). Myxomas are more common among women. They are clinically important because more than half may present with thromboembolism, which may be due to embolization of either tumor or overlying thrombi. Multiple myxoma may be present in the uncommon (7%) familial myxoma syndrome. Another histologically benign tumor associated with emboli is a papillary fibroelastoma. These tumors are usually highly spherical, highly mobile pedunculated tumors most commonly located on the aortic (Fig. 12) or mitral valves. Less often, they may be present on endocardial surfaces. Echocardiographically, papillary fibroelastomas appear speckled with echolucencies near the edges (89). These tumors classically are not associated with valvular dysfunction, but they may be a source of systemic embolization due to migration of thrombus from the tumor surface (89) or tumor embolization (90). Both TTE and TEE are highly sensitive in detecting myxomas and papillary fibroelastomas, though TEE may provide more accurate anatomical details, such as the site of attachment and, in selected patients, may help to differentiate these tumors from thrombi.

LEFT ATRIAL SPONTANEOUS ECHO CONTRAST Spontaneous echo contrast or “smokelike” echoes within the LA and/or LAA (Fig. 13) is a common TEE finding among patients with atrial fibrillation (91,92) and mitral stenosis. Spontaneous echo contrast is believed to represent erythrocyte aggregation in low shear-rate conditions (93), a process mediated by plasma proteins, particularly fibrinogen, which promote red cell rouleaux formation (94). Spontaneous echo contrast has also been associated with elevated plasma fibrinogen concentration and a hypercoagulable state (95), thereby promoting thrombus formation. More than 60% of patients in atrial fibrillation and more than 80% of patients with LAA thrombi (vs. ,2% of patients with sinus

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Figure 13 Transesophageal echocardiogram in a patient with spontaneous echo contrast (swirling pattern) in the body of the left atrium suggesting slow/stagnant flow. Abbreviation: LA, left atrium.

rhythm) demonstrate spontaneous echo contrast (96). Among patients with atrial fibrillation, spontaneous echo contrast is associated with reduced peak LAA ejection velocity (95) and is an independent predictor of thromboembolic risk. In addition, more than two-thirds of patients with mitral stenosis have TEE evidence of spontaneous echo contrast, which is thought to indicate a relatively hypercoagulable state and atrial blood stasis (91). The finding of elevated LA levels of prothrombin fragments 1 and 2 (markers of coagulation activity) among patients with spontaneous echo contrast and mitral stenosis also supports an association with a hypercoagulable state (97). From a mechanistic perspective, the previously mentioned abnormalities provide the necessary pathophysiologic substrate for thromboembolism. In the normal circulatory system, the pulmonary arteriolar and capillary beds provide a “filtering system” that prevents venous thrombi from gaining access to the arterial system. For some patients, an abnormal connection between the right and left heart provides a conduit through which venous thrombi can bypass the pulmonary bed, thereby leading to “paradoxical” thromboembolism. The most common sites for “crossing” of these thrombi are at the atrial level.

ABNORMALITIES OF THE INTERATRIAL SEPTUM Abnormalities of the interatrial septum are associated with thromboembolism via two pathophysiologic mechanisms: right-to-left shunting and ASA. Patients with an atrial septal defect or PFO may have intermittent flow of blood from the right atrium to the LA. This can be induced on a daily basis by maneuvers that transiently increase right atrial pressure, such as coughing or Valsalva maneuvers during bowel movements (Fig. 14). A thrombus in the venous system may thereby cross to the left side of the heart, resulting in systemic thromboembolism (Fig. 15). A PFO is necessary during fetal development to facilitate shunting of blood from the right atrium to the LA, thereby bypassing the high-resistance pulmonary circuit. At birth or

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Figure 14 Transesophageal echocardiogram in a patient with a patent foramen ovale. After intravenous injection of agitated saline, microbubbles can be seen on the left atrial side of the septum (arrow). Abbreviations: LA, left atrium; RA, right atrium.

shortly thereafter, the septum primum and the septum secundum usually fuse, closing the interatrial septum to the flow of blood. Ostium secundum atrial septal defects occur when there is excess resorption of the septum primum or inadequate formation of the septum secundum. A PFO occurs when fusion of the septum primum with the septum secundum is inadequate.

Figure 15 Transesophageal echocardiogram in a patient who presented with acute onset of neurological symptoms. Note the thrombus (arrow) in transit through the intra-atrial septum. Abbreviation: RA, right atrium.

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The prevalence of a PFO varies depending on its definition. In an autopsy study of nearly 1,000 patients, a PFO was found in 27% of all hearts, declining from 34% among those ,30 years to 20% after 80 years (98). Thus, more than 50 – 70 million Americans have a PFO. A PFO may be identified noninvasively with the use of TTE and/or TEE with intravenous agitated saline contrast, with the appearance of microbubbles in the LA within three to five beats of full opacification of the right atrium. Imaging is usually performed at rest and with maneuvers designed to transiently increase the right atrial pressure, so as to promote right-to-left shunting—including Valsalva maneuver release and cough. The imaging with cough is felt to provide the highest sensitivity. The size of the shunt is graded semiqualitatively, with less than 10 bubbles considered “trivial,” 10 – 30 bubbles considered a “small shunt,” and more than 30 bubbles suggesting a “large shunt” (99). Although both TTE and TEE are considered sensitive, TEE is considered superior (100). Administration of saline contrast from the groin may be superior to introduction from the antecupital fossa (101). The relative quantity of contrast (or severity of right-to-left shunting) appearing in the LA after venous injection appears to be associated with increased risk (102 –104). Other novel methods to detect PFO include intravenous saline injection with transmitral Doppler (105) or transcranial Doppler sonography of the middle cerebral artery (106) and real-time MRI during injection of a gadolinium-based contrast agent (107). The latter two techniques are less well studied. An ASA is far less common than a PFO and is usually defined by echocardiography as a bulging/septal mobility in the region of the fossa ovalis (Fig. 16) due to redundant atrial septal tissue (108). The amount of septal excursion for an ASA is usually defined

Figure 16 (A) and (B) Transthoracic echocardiogram in a patient with an aneurysm of the interatrial septum. Note the wide magnitude of septal motion (arrows). (C) Transesophageal echocardiogram in another patient with an interatrial septal aneurysm. Abbreviations: LA, left atrium; RA, right atrium.

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as the sum of the greatest leftward and rightward deflections of at least 10 or 15 mm. Prevalence in the normal population is estimated to be 0.5% by TTE (109) and up to 5% by TEE (110,111). ASA is commonly associated with a PFO, with more than 50% of patients with an ASA having a coexistent PFO (112,113). The mechanism for stroke in ASA has been ascribed to coexistent PFO (paradoxical embolism), propensity for atrial arrhythmias (114), and direct thrombus formation in the neck of the aneurysm due to an irregular surface (115). The specific risk of ASA in the absence of PFO is uncertain. One prospective intraoperative study found that the incidence of embolic strokes associated with an atrial septal defect was quite low (111). Although a case report in 1930 described a patient who died from a stroke with a large thrombus across a PFO (116), the pathological role of PFO was largely unrecognized until Lechat et al. (117) reported a high prevalence of PFO among patients ,55 years with stroke. TTE evidence of a PFO was found in 40% of the study population, including 54% of patients with cryptogenic stroke, when compared with only 10% of a control group without stroke. Mas et al. (118) studied 598 patients aged 18– 35 with cryptogenic stroke. More than 36% had evidence of a PFO, 1.7% had an ASA, and 8.5% had both abnormalities. A meta-analysis of nine studies showed that the overall risk of stroke was associated with younger (,55 years) patients with a PFO [odds ratio (OR) 3.1], ASA (OR 6.1), or both (OR 15.6). As a result, the finding of a PFO has been considered presumptive evidence of a paradoxical embolus in younger (,55 years) patients with cryptogenic stroke. A similar relationship is less certain for patients .65 years (119,120). Although the primary mechanism of PFO-related stroke is believed to be paradoxical embolism of thrombus, documentation of such thrombi is quite limited. The incidence of deep venous thrombus may be quite low (121,122). A study of 197 patients with an embolic stroke reported that only 9.5% had a deep vein thrombosis on venography (122). In contrast, when peripheral lower-extremity venography was performed in 49 patients with systemic thromboembolism and PFO, peripheral venous thrombosis was seen in 57% (123), with more than half of the thrombi limited to the calf or popliteal veins. IMAGING PROCEDURES Transthoracic Vs. Transesophageal Echocardiography TTE performed with saline contrast is a minimally invasive procedure, whereas TEE is a moderately invasive procedure during which a modified gastroscope (containing an ultrasound crystal at its tip) is positioned within the esophagus. Imaging is performed within the esophagus and the gastric fundus. The close proximity of the esophagus to the posterior heart, the lack of intervening lung and bone, and the use of higher frequency imaging transducers result in enhanced spatial resolution. TEE should not be considered as a “better” echocardiogram but may be preferred for identification or exclusion of pathology that is particularly relevant to the patients presenting with history suggestive of thromboembolism, including identification of intra-atrial thrombi and tumors, PFO, valvular vegetations, atheromatous plaques within the aorta, and spontaneous echo contrast. TTE remains preferred for identification of LV regional systolic function and apical LV thrombi. SUMMARY AND RECOMMENDATIONS Although multiple potential cardiac sources for embolism can be identified by TTE, the use of this procedure among patients with unexplained stroke has recently come into

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question (124). In an unselected population, for example, the prevalence of a highly probable source of embolism was only 3– 15% (125,126), with the highest yield if the clinical history suggests a cardiac source (as with atrial fibrillation, rheumatic mitral stenosis, diffuse atherosclerosis, LV aneurysm, or clinical endocarditis). Aside from identification of apical LV thrombi and MAC, TEE is superior to TTE with a corresponding yield for cardiac source of 57 – 65% (126,127). Thus, for many patients, direct TEE (with omission of the TTE) may be the most expeditious route to identify a cardiac source of embolism.

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124. Chartier L, Bera J, Delomez M, et al. Free-floating thrombi in the right heart: Diagnosis, management, and prognostic indexes in 38 consecutive patients. Circulation 1999; 99:2779 – 2783. 125. Sansoy V, Abbott RD, Jayaweera AR, Kaul S. Low yield of transthoracic echocardiography for cardiac source of embolism. Am J Cardiol 1995; 75:166– 169. 126. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:66 – 72. 127. Rauh R, Fischereder M, Spengel FA. Transesophageal echocardiography in patients with focal cerebral ischemia of unknown cause. Stroke 1996; 27:691 – 694.

10 The Aorta as a Donor Source of Brain Embolism Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

EARLY PATHOLOGY-BASED REPORTS OF EMBOLISM FROM THE AORTA Although clinicians and pathologists have recognized for more than a century that atherosclerotic lesions appear early within the aorta and that aortic atherosclerosis is often severe, only recently has the relationship between aortic disease and stroke been studied during life. Studies of patients with stroke and transient ischemic attacks have now firmly established that the thoracic aorta is a very important source of brain embolism. The first report on this subject was published more than a half a century ago. Meyer in 1947 described two patients with syphilitic aortic aneurysms that developed cholesterol crystal embolism considered to have derived from material in the aneurysms (1). A decade later, Winter described two additional patients with syphilitic aneurysms of the proximal aorta (2). The ascending aorta of Winter’s first patient was “covered by innumerable atheromata most of which were eroded and partly calcified. Soft thrombi containing cholesterol crystals were adherent to many” (1). Many brain arteries were blocked by cholesterol crystal containing thrombi. In another patient who also had multiple brain cholesterol crystal emboli, the “entire intimal surface of the aorta, but in particular the aneurysm, was covered by atheromatous plaques, many of which were ulcerated and covered by soft thrombi” (2).

AORTIC ATHEROSCLEROSIS In 1965, Fisher et al. (3) examined the aorta and extracranial and intracranial arteries among 178 patients and found that only 37 aortas were free of ulceration and that the aorta was two to four times more likely to show severe atherosclerosis than the cervical carotid and vertebral arteries. The International Atherosclerosis Project was the first extensive attempt to characterize the distribution and relative severity of atherosclerosis in major systemic and cervico-cranial arteries (4,5). Sex, race, and geographical differences in severity and 187

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location of atherosclerosis were also studied (5). Pathologists is five countries examined 1,547 sets of aortas, as well as coronary and neck and cranial arteries. Fatty streaks, yellow lipid deposits that elevate the intima only slightly, were found in all groups of patients beginning in infancy but reaching a peak at puberty. Raised lesions, including fibrous plaques, calcified lesions, and lesions complicated by hemorrhage, ulceration, or thrombosis developed later (4,5). In all groups, fibrous plaques were more prevalent and more severe in the aorta than in the coronary and cervico-cranial arteries, and the abdominal aorta was more severely involved than the thoracic aorta. In the age group of 65 –69, in patients from Oslo, Norway, on average 40% of the surface area of the thoracic aorta contained raised atherosclerotic lesions (5). The International Atherosclerosis Project (4,5) and a more recent study showed that aortic atherosclerosis is more severe in whites compared with Asians and blacks and is usually more severe in men compared with premenopausal women (6). The aortic arch and ascending aorta contained significantly more 4 mm or larger plaques in whites compared with American blacks in Alabama (6). Complex plaques were also more common among whites (6). A study of the location of plaques found in the thoracic aorta using transesophageal echocardiography (TEE) showed the highest prevalence in the arch (27.6%) and descending aorta (38.2%) (7). The frequency of aortic atheromas increases dramatically with age, from 20% in the fifth decade at necropsy to 80% in patients .75 (8). Tobler et al. (9) studied at necropsy the presence and distribution of atherosclerotic plaques in the ascending aorta. Among 97 ascending aortas, 38% had atherosclerotic plaques .8 mm in diameter; the average diameter of plaques was 19 mm. Most of the 66 plaques were distributed anteriorly or posteriorly on the right side of the ascending aorta, and the upper and lower halves of the ascending aorta were equally involved (9). Plaques were also prevalent in the aortic arch, especially at the orifice of the innominate artery (21% of 48 arch specimens) (9). The presence and severity of atherosclerotic risk factors (hypertension, diabetes, hyperlipidemia) and inflammatory markers (C-reactive protein, fibrinogen levels, plasmin/antiplasmin complexes, and D-dimers) predict the severity of aortic atherosclerosis (10). Clinical, Pathological, and Echocardiographic Analyses of the Relation between Aortic Atherosclerosis and Stroke Further mention of aortic atherosclerotic disease as an important cause of stroke began to appear during the beginning of the last decade of the twentieth century (11). Until that time in vivo recognition of the presence and severity of aortic atherosclerosis was very limited. Tunick and his colleagues (12,13) at the New York University Medical Center published two reports that included four patients with unexplained brain ischemic events in whom TEE showed large protruding, often mobile atheromas. In one patient who had brain, leg, and arm emboli, TEE showed “a large mass with smaller mobile components, protruding into the lumen of the aortic arch” (13). Several aortic masses in this patient were removed surgically and showed severe atherosclerotic plaques with superimposed thrombi (13). Tunick et al. (14) later reported TEE results among 122 patients who had stroke, transient ischemic attacks (TIAs), or peripheral emboli, and 122 age and sexmatched controls. The presence of protruding atheromas were strongly related to the occurrence of embolic events (odds ratio 3.2, 95% confidence interval 1.6– 6.5, P , 0.001), and atheromas with mobile components were only found in patients with embolic events (14). Karalis et al. (15) also reported an observational TEE study of their experience with aortic atheromas. “Intraaortic atherosclerotic debris” was found in 7% of 556 patients

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studied by TEE; 11 patients with these atheromatous aortic lesions (31%) had embolic events (15). Embolic events were more often associated with pedunculated and mobile aortic lesions than those that were layered and immobile (15). These observational studies and case reports alerted the medical community to the possible importance of aortic atheromas as a cause of stroke and peripheral embolism. In 1992, Amarenco and his Paris colleagues (16,17) published two reports, which showed definitively that aortic atheromatous disease was an important cause of stroke and could be identified clinically during life. Amarenco et al. first published a necropsy study of 500 patients who had stroke or other neurologic diseases. Ulcerated aortic plaques were found in 26% of 239 patients with cerebrovascular disease, compared with only 5% of 261 patients with other neurological diseases ( P , 0.001) (16). The prevalence of aortic atheromas was 61% among patients with brain infarcts and no demonstrated cause and 22% among those with other defined causes ( P , 0.001) (16). The presence of ulcerated plaques in the aortic arch did not correlate with the presence of carotid artery stenosis, suggesting that aortic and carotid artery diseases were independent risk factors for stroke and were not necessarily proportionate (16). Amarenco et al. (17) also reported a study of 12 consecutive patients with cryptogenic stroke studied by TEE. Six (50%) patients had intraluminal echogenic masses in the aortic arch most often at the junction of the ascending aorta and the arch. In one patient, the mass was pedunculated, but in the other five the attachment was broadbased with a very irregular surface. The masses extended from 3 to 15 mm into the lumens of the aortas. Cholesterol emboli were found in quadriceps muscle biopsies in two patients with aortic masses (17). Amarenco and colleagues (18,19) also studied the risk of brain infarction according to the thickness of plaques in the ascending aorta or proximal aortic arch (Table 1). The occurrence of brain infarction correlated significantly with the thickness of aortic plaques. Other TEE studies in the United States (20,21), Japan (22), and Australia (23) confirmed the importance of aortic arch atheromas as a source of brain and peripheral embolism. Jones et al. (23) in an Australian study compared TEE findings in the aorta among 215 patients who had TIAs or brain infarcts with 202 healthy volunteers. They found simple plaques ,5 mm thick in the ascending aorta and arch in 33% of the brain ischemia patients and in 22% of controls. Plaques that were .5 mm thick and/or had irregular surfaces or mobile components (complex plaques) were found in 22% of patients and only 4% of controls, a 7.1-fold increase (23). Davila-Roman et al. (24) examined the frequency and nature of aortic plaques in patients who were to have coronary artery surgery, using epiaortic ultrasound probes. This technique allows exploration of the entire surface of

Table 1 Risk of Brain Infarction According to Aortic Atherosclerotic Plaque Thickness (Ascending Aorta or Proximal Arch) Plaque (mm)

Patients (%) n ¼ 250

Controls (%) n ¼ 250

,1 1 – 1.9 2 – 2.9 3 – 3.9 .4

99, 39.6% 28, 11.2% 56, 22.4% 31, 12.4% 36, 14.4%

189, 75.6% 16, 16.4% 26, 10.4% 14, 5.6% 5, 2%

Crude OR (95% CI)

Adjusted OR (95% CI)

P-value

1 3.3 (1.7– 6.5) 4.1 (2.4– 7) 4.2 (2.2– 8.3) 13.8 (5.2– 36.1)

1 4.4 (2.1– 8.9) 5.0 (2.7– 9) 3.4 (1.5– 7.4) 9.1 (3.3– 25.2)

— ,0.001 ,0.001 ,0.001 ,0.001

Abbreviations: CI, confidence interval; OR, odds ratio. Source: From Ref. 18.

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the ascending aorta from the aortic root to the proximal arch, a region difficult to image with TEE. Among 1,200 patients who had epiaortic ultrasound, 158 patients had a previous embolic event, and in 1042 no prior event was recognized. Among those with a prior embolic event, 26.6% had plaques .3 mm, compared to 18.1% of patients without events (24). Pathological studies provided further evidence of a relation between aortic disease and brain embolism. Masuda et al. (25) analyzed the clinical features and the distribution and pathology among 15 patients with brain atheromatous embolism studied clinically and at necropsy. Heart surgery, cardiac catheterization, and angiography triggered embolism in six (40%) patients in this series (25). Nine (60%) patients had extensive cortical, often hemorrhagic, infarcts in the regions of the arterial borderzones between the anterior cerebral arteries and middle cerebral arteries (MCA) and between the MCA and posterior cerebral arteries. Six (40%) patients had territorial infarcts of different sizes caused by occlusion of major or branch cerebral arteries (25). All patients had complicated atheromas in the ascending aorta and the aortic arch. Calcification, ulcerations, mural thrombi, and aneurysmal dilatations were prevalent. Cholesterol crystal emboli were often found in arteries within the borderzone regions (25). Two studies investigated the frequency of occurrence of vascular events in patients who had TEE-documented aortic arch atherosclerosis (26,27). The French Study Group followed 331 patients who presented with brain infarcts for two to four years (26). The frequency of subsequent brain infarction and other vascular events was closely correlated with the thickness of the aortic wall. The frequency of recurrent brain infarcts was 11.9/100 patient-years in those with aortic lesions that had thickness of .4 mm, compared to rates of 3.5/100 patient-years for those with 1– 3.9 mm thick aortic wall lesions, and 2.8/100 patient-years in those with aortic walls ,1 mm thick. After controlling for other confounding factors the relative risk of brain infarction was 3.8 (95% confidence interval 1.8 –7.8, P ¼ 0.0012) and of all vascular events 3.5 (95% confidence interval 2.1– 5.9, P , 0.001) in patients with aortic wall plaques .4 mm (26). In a prospective study conducted in two German University hospitals, physicians followed 136 patients with flat plaques ,5 mm in thickness, and 47 patients with either thick plaques .5 mm thick or complex plaques with mobile components for an average of 16 months (27). Embolic events developed in 15 patients; the incidence was 4.1/100 patient-years in patients with flat plaques versus 13.7/100 patient-years in those with complex, thick, or mobile plaques (27). Nonatherosclerotic Disease of the Aorta Atherosclerosis is not the only disease of the aorta that can serve as a donor source of embolic material. Syphilitic aortitis and aneurysms have long been known to ulcerate and cause thromboembolism (1,2). Physicians in Sri Lanka described ten patients who had an inflammatory aortitis different from Takayasu’s disease that caused brain embolism and strokes (28). The earliest histological changes in this condition were focal fragmentation of elastic lamella and an acute inflammatory aortitis in the media of the aortic arch. The aortic intima was edematous, and mural thrombi often formed on the endothelial surface of the aorta and embolized intracranially (28). Takayasu’s disease is especially common in India and Pakistan and in other neighboring countries. Takayasu’s disease, aortic trauma, and aortic dissection probably are also occasionally complicated by embolism arising from the aorta. In the case of aortic dissection, thrombus formation within the aorta and subsequent embolism should be separated from obliteration of the orifices of the

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branches of the arch by the dissection and from concurrent dissection of brachiocephalic arteries that often accompany aortic dissections (29 –31).

HEART SURGERY AND AORTIC ATHEROSCLEROSIS Strokes and Mortality after Heart Surgery Mounting evidence now also links the occurrence of postoperative strokes, encephalopathies, and cognitive dysfunction to ulcerative atherosclerotic lesions of the ascending aorta (25,32 –40). Yellow aortic plaques are often visible and can be palpated by the surgeon. They are more readily detected by epiaortic ultrasound probes placed on the aorta. When the aorta is clamped, an audible crunch is often heard. Cross-clamping of the aorta or aortotomy to anastomose the vein graft often liberates cholesterol crystals and calcific plaque debris. The most important risk factor for stroke after cardiopulmonary bypass surgery is aortic atheromatosis. The stroke rate after coronary artery bypass graft (CABG) increases sharply with age, from 1% in patients aged 51 – 60 to 9% in patients aged .80, paralleling the increase of aortic atheromas with age (8,34). The correlation between aortic atheromas and stroke after CABG was first shown at necropsy in a study that involved 221 patients (8). Atheroemboli were found in 37% of patients who had severe atherosclerosis of the ascending aorta but in only 2% of patients who did not have significant ascending aortic atheromas (8). In another study, cardiac surgeons retrospectively reviewed the records of 3279 consecutive patients having CABG at Johns Hopkins, seeking risk factors for postoperative stroke (40). Severe atherosclerosis of the ascending aorta was one of the most definitive risk factors found (40). Embolization can now be detected and quantified before, during, and after surgery using ultrasound. Transcranial Doppler (TCD) recording over the MCAs detects the arrival of microemboli in the cranial arteries. Figures 1 and 2 show TCD recordings

Figure 1 Transcranial Doppler recording from the middle cerebral artery during steady state cardiac bypass surgery at a time when the aorta was being manipulated. The white streaks represent microemboli. Kindly submitted by Dr. Denise Barbut. Source: From Ref. 32.

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Figure 2 Transcranial Doppler recording from the middle cerebral artery during cardiac bypass surgery. A few distinct emboli (white streaks in the left of the figure) are followed by a massive shower of emboli (whiteout) at the time of the release of aortic clamps. Kindly submitted by Dr. Denise Barbut. Source: From Ref. 32.

taken during cardiac surgery at various times during the procedure. Figure 2 shows recording just after clamping of the aorta. Intraoperative TEE can be used to detect the passage of emboli into and through the proximal aorta. Figure 3 is a TEE recorded during cardiac surgery that shows a shower of emboli entering the aortic lumen. More emboli are detected during intracardiac surgery than during CABG because these patients often have valve calcifications, valve vegetations, and intracardiac thrombi. By using TCD monitoring during closed cardiac operations, the number of microemboli vary from 0 to 1,200 within one MCA (average 130) (34). The numbers of emboli detected in the aorta by TEE is in thousands, reflecting the fact that only a fraction of the microembolic particles reach the brain (34,41). Embolization is not evenly distributed during the various stages of surgery. Maneuvers that involve manipulation of the aorta, such as clamping and unclamping, account for .60% of the total number of emboli (34,41). Flurries of emboli are detected during aortic cannulation and at the start and ending of cardiopulmonary bypass. During open cardiac procedures, the number of emboli detected by TCD is especially high during cardiac ejection after the release of the aortic cross clamps and immediately after bypass (34). Figure 2 is a TCD recording during cardiac surgery that shows a “whiteout” created by a massive shower of emboli that occurred immediately after release of aortic clamps. Many of the microemboli are gaseous particles. Aortic clamping and clamp release are followed by a snowstorm-like appearance of intensely echogenic, well-defined particles within the aorta and a corresponding flurry of particles within the brain arteries (34). The mean diameter of these particles is 0.85 mm. These microembolic particles are most likely atheromatous debris coming from the aorta. They are small enough to enter the brain circulation, although only a small fraction do so. The quantity of emboli is closely associated with the presence of atheromas in the ascending aorta and arch (42). Figure 4 shows a very atherosclerotic aorta found at autopsy.

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Figure 3 Transesophageal echocardiography recording during cardiac surgery from the aorta at the level of the origin of the left subclavian artery. A mobile plaque is seen protruding into the aortic lumen (small black arrow). This recording was taken after the release of aortic clamps and shows a “shower” of emboli within the aortic lumen beyond where the aorta was previously clamped. Kindly submitted by Dr. Denise Barbut. Source: From Ref. 32.

The presence and severity of atherosclerosis of the aorta has in the past been quantified by TEE before surgery, intraoperative TEE, or after the chest is opened, by palpation of the aorta by the surgeon, or by using epiaortic ultrasound probes placed on the surface of the aorta. The findings when performed before surgery can be used as one of the factors that gauge the risk of on-pump surgery and so help with the decision on surgery versus medical treatment. The location and severity of aortic atheromas can also guide the regions of the aorta to avoid during clamping or to choose between on or off-pump CABG—the latter not requiring clamping of the aorta. Marshall et al. (43) first reported the use of an intraoperative B-mode probe placed on the aorta in search of protruding plaques. Ultrasonic imaging showed plaques better than visual inspection and palpation. The amount, nature, and location of the plaques often altered the procedure

Figure 4 The aorta at necropsy in a patient with severe aortic atherosclerosis. Source: From Ref. 32.

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performed (43). Hangler et al. (44) used epiaortic ultrasonography applied before opening the pericardium among 352 patients undergoing CABG (44). When patients had moderate atherosclerosis, defined as aortic wall thickness of 3– 5 mm, single aortic cross clamping was performed. When the maximum wall thickness was .5 mm, a no-touch strategy was used. The operative technique was modified in 31% of patients with moderate disease and 91% of those with severe disease (44). In one study, among 5,737 patients, 913 were found by preoperative TEE to have severe aortic atheromatous disease. Among these patients, 235 (25.7%) patients had offpump CABG, and 678 (74.3%) had conventional on-pump CABG. In-hospital mortality was less in the off-pump patients—5.1 versus 8.7% (45). The authors compared mortality and stroke rate of 211 of the off-pump and 211 of the on-pump patients with severe aortic atheromatous disease matched for age, ejection fraction, stroke history, diabetes, renal disease, non-elective surgery, cerebrovascular disease, and prior heart surgery (46). Hospital mortality was 11.4% for on-pump, versus 3.8% for off-pump surgery. Ten on-pump patients had strokes (4.7%), compared with five (2.4% of off-pump strokes) (46).

ENCEPHALOPATHY, COGNITIVE, AND NEUROBEHAVIORAL ABNORMALITIES AFTER HEART SURGERY A broad spectrum of neuropsychiatric findings, including delirium, confusion, disorientation, drowsiness, and altered behavior, without focal neurological abnormalities are often bundled together under the broad term encephalopathy. In these patients, neuroimaging tests do not show new large focal brain infarcts. In a Cleveland Clinic series of CABG operations, 11.6% of patients were considered encephalopathic on the fourth postoperative day (47). In another very large series, 57 of 1669 (3.4%) patients who had CABG surgery had severe postoperative mental changes, including delirium and encephalopathy (48). Undoubtedly, the causes are multiple. Encephalopathy is especially common among older patients and those with a history of alcohol abuse and renal disease. Some patients have a hypoxic-ischemic encephalopathy because of a long surgical time, during which their brain was poorly perfused. An important number of cases are explained by medications. Sedatives, analgesics, especially narcotics, and most important haloperidol are common offenders. Haloperidol very often produces depressed alertness, stiffness, inertia, and drowsiness, and the drug stays in the body a long time. Haloperidol has been shown to retard recovery in animals with brain lesions (49,50). This drug should not be used in older surgical and medical patients, especially those with abnormal brains. When surgeons first became aware of postoperative changes in behavior after heart surgery, these abnormalities were attributed to psychological reactions to the milieu of intensive care units—constant light and stimulation, lack of sleep, and so on. The initial recognition that the encephalopathy and neurobehavioral changes were not psychiatric in origin was made by Sid Gilman in 1965 when he prospectively followed a series of open-heart surgery patients (51). Early researchers posited that the embolization of particulate matter that was related to the pump and its filters had led to the encephalopathy. The introduction of membrane rather than bubble oxygenators and in-line filtration led to a decrease in the risk of macroembolic particles (.25 mm) reaching the systemic circulation (52). A 1990 report of the necropsy findings in five patients and six dogs who all had cardiac surgery awakened new interest in this subject (53). Widely scattered in 10 of

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these 11 brains were focal small capillary and arteriolar dilations (SCADs). About half of the SCADs contained birefringent crystalline material within the dilated capillary regions (53). The vascular lesions affected medium-sized arterioles, terminal arterioles, and capillaries; they were often distributed in multiples in the same vessels or in clusters near each other. Two other patients had a small number of SCADs after arteriography. The authors thought that the findings were most consistent with iatrogenically induced release into the system of small particles of air or fat (53). Moody’s observations antedated TCD monitoring of brain arteries during cardiac surgery. Subsequent studies have shown that the number of microemboli that reach the brain correlates with the occurrence of encephalopathy and cognitive and behavioral abnormalities noted after surgery. Furthermore, the number of microemboli correlate with the severity of aortic atherosclerosis in patients who have on-pump cardiac surgery. Microemboli released from the aorta are likely to be the most important cause of encephalopathy and of persistent cognitive abnormalities after cardiopulmonary bypass surgery. Cognitive dysfunction without accompanying obvious focal motor, sensory, or visual dysfunction is the most common complication of CABG surgery. Some patients have obvious loss of intellect, whereas others have subtle problems detectable only by formal neuropsychological evaluation. Estimates of the frequency of cognitive dysfunction after CABG range from 30% (54) to 88% (55), depending on the timing and extent of neuropsychological testing. The most frequent cognitive abnormalities are defective memory, concentration, attention, and rapidity of response to stimuli (56). Although many patients improve considerably within a few months, studies show that a substantial number of patients have persistent loss of intellectual functions. Cognitive dysfunction was present in 35% of patients one year postoperatively (56) and in 20% (57) of patients at three years in two different studies. In a recent well-designed prospective study, 127 patients who had CABG surgery were tested in eight cognitive domains before surgery and at one month and one year after surgery. Only 12% of patients had no loss of function after surgery. Among the 88% of patients who showed cognitive loss in at least one domain, 10% had persistent decline in the domains of verbal memory, visual memory, attention, and visual-related construction after one year (55). Depression was also common after CABG. Advanced age and length of bypass are important risk factors for cognitive dysfunction after cardiopulmonary bypass (58). Recent prospective studies provide evidence that microembolism is the most important cause of cognitive deficits after cardiac surgery using cardiopulmonary bypass. Pugsley et al. (59) studied 100 patients who had cardiopulmonary bypass, 50 with an arterial line filter and 50 without a filter. TCD was used to monitor microemboli. All patients were given neuropsychological tests before and after surgery. Neuropsychological deficits at eight days and eight weeks postoperatively were more common in patients who had cardiopulmonary bypass without the arterial filter and neuropsychological abnormalities correlated with the number of microemboli (59). Pugsley et al. (59) found that 43% of patients with intraoperative embolic counts .1000 had cognitive abnormalities at eight weeks after cardiac surgery, compared with only 8% of patients with ,200 emboli. Barbut et al. (60) found that the average number of microemboli at the time of removal of aortic clamps was 166 in 6 patients with cognitive abnormalities compared with 73 microemboli in 11 patients who showed no loss of cognitive function. Goto et al. (61) in Japan studied 463 patients .60 years old who had CABG surgery. Aortic atherosclerosis was quantified using an epiaortic ultrasound probe. The 76 patients with severe aortic atherosclerosis had a rate of 26% of postoperative neuropsychological findings and a stroke rate of 10%; patients with moderate aortic atherosclerosis and

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Figure 5 Cholesterol crystals and other particulate debris are caught in a filter placed in the aorta at the time that aortic lamps are removed. Kindly submitted by Dr. Denise Barbut. Source: From Ref. 32.

those with mild or no atherosclerosis had rates of 7% and 8% for neuropsychological dysfunction and stroke rates of 1.8% and 1.2%, respectively (61). In this study, thickness of the aorta around the site of aortic manipulation and deformities due to clamp or cannulation were significantly associated with postoperative neurological dysfunction (61). Recently, cardiac surgeons have begun to introduce filter devices into the aorta when aortic clamps are removed during on-pump surgery to catch debris and cholesterol crystals. Figure 5 shows cholesterol crystals and other particulate debris caught in one of these filters.

IMAGING OF THE PROXIMAL AORTA TEE has become the standard way to image the aorta. There is good concordance between TEE images and pathology of the aorta (22,24,62). The limitations of TEE are that it is invasive and there is an area of the aorta that is obscured because of the bronchus and is not readily imaged. TEE has often been done before CABG or during the surgery. TEE can show large plaques and floating mobile thrombi within the lumen of the aorta. Figures 6 and 7 show various aortic plaques shown by TEE. Vaduganathan et al. (63) showed a 73% agreement between intraoperative TEE imaging of the thoracic aorta and histology. TEE did not always detect ulceration but was able to detect complex atheroma and mobile debris in every case. Epiaortic ultrasound applied at the beginning of surgery is also a useful method for detecting severe atheromas and intima-medial thickness of the aorta at various locations (44,61). The ascending aorta can also be insonated using a duplex ultrasound probe placed in the right supraclavicular fossa, and the arch and proximal descending thoracic aorta can be imaged using a left supraclavicular ultrasound probe (64). The results so far are preliminary but promising. The technique requires training to master and is not used in most centers. Most plaques are located in the curvature of the arch from the distal ascending

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Figure 6 Transesophageal echocardiographic image of the aorta showing small and large plaques.

aorta to the proximal descending aorta, regions well shown using B-mode ultrasound (64). The aorta has also been imaged by a suprasternal approach during transthoracic echocardiography using harmonic imaging; in one study large protruding plaques were found with a 91% positive predictive value, and negative findings had a 98% predictive value, but unfortunately adequate image quality for interpretation could only be obtained in 89% of patients studied (65).

Figure 7 Transesophageal echocardiographic image of the aorta showing a protruding large plaque that was highly mobile.

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Magnetic resonance angiography (MRA) and Magnetic resonance imaging (MRI) have also been used to image the proximal aorta. Kutz et al. (66) compared the sensitivity of detection of large plaques (.5 mm) using gadolinium enhanced MRA during breathholding versus TEE. The sensitivity was 54% with MRA versus 92% with TEE. Techniques that show the lumen of the aorta, such as MRA and standard angiography, usually do not show the wall of the aorta and so underestimate atherosclerotic plaques. Some researchers have experimented with techniques that enhance atherosclerotic plaques and the vascular endothelium. In a rabbit model, gadofluorine enhances plaques and allows for the detection of early atherosclerotic lesions (67). High-resolution MRI using plaque and endothelial enhancing agents has great promise for becoming the preferred imaging technique for detecting and quantifying aortic atherosclerosis in near future.

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18. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch in patients with stroke. N Engl J Med 1994; 331:1474– 1479. 19. Donnan GA, Davis SM, Jones EF, Amarenco P. Aortic source of brain embolism. Curr Treatment Options Cardiovasc Med 2003; 5:211– 219. 20. Horowitz DR, Tuhrim S, Budd J, Goldman ME. Aortic plaque in patients with brain ischemia. Neurology 1992; 42:1602– 1604. 21. Di Tullio MR, Sacco RL, Gersony D, et al. Aortic atheromas and acute ischemic stroke: a transesophageal echocardiographic study in an ethnically mixed population. Neurology 1996; 46:1560 – 1566. 22. Toyoda K, Yasaka M, Nagata S, Yamaguchi T. Aortogenic embolic stroke: a transesophageal echocardiographic approach. Stroke 1992; 23:1056– 1061. 23. Jones EF, Kalman JM, LaMonte M, et al. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke 1995; 26:218– 224. 24. Davila-Roman VG, Barzilai B, Wareing TH, et al. Atherosclerosis of the ascending aorta. Prevalence and role as independent predictor of cerebrovascular events in cardiac patients. Stroke 1994; 25:2010 – 2016. 25. Masuda J, Yutani C, Ogata J, Kuriyama Y, Yamaguchi T. Atheromatous embolism in the brain: a clinicopathologic analysis of 15 autopsy cases. Neurology 1994; 44:1231–1237. 26. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216– 1221. 27. Mitusch R, Doherty C, Wucherpfennig H, et al. Vascular events during follow-up in patients with aortic arch atherosclerosis. Stroke 1997; 28:36 – 39. 28. Wickremasinghe HR, Peiris J, Thenabadu PN, Sherifdeen AH. Transient emboligenic aortoarteritis. Noteworth new entity in young stroke patients. Arch Neurol 1978; 35:416 – 422. 29. Hirst AE, Johns VJ, Kime SW. Dissecting aneurysms of the aorta: a review of 505 cases. Medicine 1958; 37:217 –279. 30. Zurbrugg HR, Leupi F, Schupbach P, Althaus U. Duplex scanner study of carotid artery dissection following surgical treatment of aortic dissection type A. Stroke 1988; 19:970– 976. 31. Stecker M, Bavaria JE, Barclay DK, et al. Carotid dissection with acute aortic dissection. J Neurovasc Dis 1997; 2:166– 171. 32. Caplan LR. Stroke: A Clinical Approach. 3rd ed. Boston: Butterworth-Heinemann, 2000: 452– 460. 33. Chimowitz M. Neurological complications of cardiac surgery. In: Caplan LR, Hurst JW, Chimowitz M, eds. Clinical Neurocardiology. New York: Marcel Dekker, 1999:226 – 257. 34. Barbut D, Caplan LR. Brain complications of cardiac surgery. Curr Probl Cardiol 1997; 22: 447– 476. 35. Barbut D, Gold JP. Aortic atheromatosis and risks of cerebral embolization. J Cardiothoracic Vasc Anesthesia 1996; 10:24– 30. 36. Blauth CI, Cosgrove DM, Webb BW, et al. Atheroembolism from the ascending aorta. An emerging problem in cardiac surgery. J Thorac Cardiovasc Surg 1992; 103:1104–1112. 37. Katz ES, Tunick PA, Rusinek H, et al. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992; 20:70 – 77. 38. Mills NL, Everson CT. Atherosclerosis of the ascending aorta and coronary artery bypass. Pathology, clinical correlates and operative management. J Thorac Cardiovasc Surg 1991; 102:546 – 553. 39. Yao FSF, Barbut D, Hager DN, Trifiletti RR, Gold JP. Detection of aortic emboli by transesopageal echocardiography during coronary artery bypass surgery. J Cardiothoracic Vasc Anesthesia 1996; 10:314– 317. 40. Gardner TJ, Horneffer PJ, Manolio TA, et al. Stroke following coronary artery bypass grafting: a ten-year study. Ann Thorac Surg 1985; 40:574– 581. 41. Barbut D, Yao FS, Hager DN, et al. Comparison of transcranial Doppler ultrasonography and transesophageal echocardiography during coronary artery bypass surgery. Stroke 1996; 27:87 – 90.

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42. Mackensen GB, Ti LK, Phillips-Bute BG, Mathew JP, Newman MF, Grocott HP; Neurologic Outcome Research Group (NORG). Cerebral embolization during cardiac surgery: impact of aortic atheroma burden. Br J Anaesth 2003; 91:656– 661. 43. Marshall WG, Barzilai B, Kouchoukos NT, et al. Intraoperative ultrasonic imaging of the ascending aorta. Ann Thorac Surg 1989; 48:339– 344. 44. Hangler HB, Nagele G, Danzmayr M, Mueller I, Ruttman E, Laufer G, Bonatti J. Modification of surgical technique for ascending aortic atherosclerosis: impact on stroke reduction in coronary artery bypass grafting. Thorac Cardiovascular Surg 2003; 126:391– 400. 45. Grossi EA, Bizekis CS, Sharony R, et al. Routine intraoperative transesophageal echocardiography identifies patients with atheromatous aortas: impact on “off-pump” coronary artery bypass and perioperative stroke. J Am Soc Echocardiogr 2003; 16:751–755. 46. Sharony R, Bizekis CS, Kanchuger M, et al. Off-pump coronary artery bypass grafting reduces mortality and stroke in patients with atheromatous aortas: a cases control study. Circulation 2003; 108(suppl II):II-15 – 1120. 47. Breuer AC, Furlan AJ, Hanson MR, et al. Central nervous system complications of coronary artery bypass graft surgery: prospective analysis of 421 patients. Stroke 1983; 14:682 –687. 48. Coffey CE, Massey EW, Roberts KB, et al. Natural history of cerebral complication of coronary artery bypass graft surgery. Neurology 1983; 33:1416– 1421. 49. Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol and experience interact to affect the rate of recovery after motor cortex injury. Science 1982; 217:855–857. 50. Houda DA, Feeney DM. Haloperidol blocks amphetamine induced recovery of binocular depth perception of the bilateral visual cortex abilities in the cat. Proc West Pharmacol Soc 1985; 28:209 – 211. 51. Gilman S. Cerebral disorders after open heart operations. N Engl J Med 1965; 272:489 –498. 52. Sila C. Neuroimaging of cerebral infarction associated with coronary revascularization. AJNR 1991; 12:817 – 818. 53. Moody DM, Bell MA, Challa VR, et al. Brain microemboli during cardiac surgery or aortography. Ann Neurol 1990; 28:477– 486. 54. Sotaniemi K, Mononen H, Hokkanen T. Long-term cerebral outcome after open-heart surgery. Stroke 1986; 17:410 – 416. 55. McKann G, Goldsborough M, Borowicz L, et al. Cognitive outcome after coronary artery bypass: a one-year prospective study. Ann Thorac Surg 1997; 63:510 – 515. 56. Venn G, Klinger L, Smith P. Neuropsychological sequelae of bypass twelve months after coronary artery surgery. Br Heart J 1987; 57:565. 57. Martzke J, Murkin J, Baird D, et al. Perioperative predictors of neuropsychological outcome 3 years after coronary artery bypass surgery. Anest Analg 1996; 82:SCA 37. 58. Borowicz I, Goldsborough M, Selnes O, McKann G. Neuropsychologic change after cardiac surgery. A critical review. J Cardiothorac Vasc Anesth 1996; 10:105 – 111. 59. Pugsley W, Klinger L, Paschalis C, et al. The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 1994; 25:1393– 1399. 60. Barbut D, Hinton K, Szatrowski TP, et al. Cerebral emboli detected during bypass surgery are associated with clamp removal. Stroke 1994; 25:2398– 2402. 61. Goto T, Baba T, Matsuyama K, Honma K, Ura M, Koshiji T. Aortic atherosclerosis and postoperative neurological dysfunction in elderly coronary surgical patients. Ann Thor Surg 2003; 75:1912 – 1918. 62. Amarenco P, Cohen A. Update on imaging aortic atherosclerosis. In: Barnett HJM, Bogousslavsky J, Meldrum H, eds. Ischemic Stroke: Advances in Neurology. Vol. 92, Philadelphia: Lippincott, Williams and Wilkins, 2003:75 – 89. 63. Vaduganathan V, Ewton A, Nagueh SF, et al. Pathologic correlates of aortic plaques, thrombi and mobile “aortic debris” imaged in vivo with transesophageal echocardiograph. J Am Coll Cardiol 1997; 30:357– 363. 64. Weinberger J, Azhar S, Danisi F, Hayes R, Goldman M. A new noninvasive technique for imaging atherosclerotic plaque in the aortic arch of stroke patients by transcutaneous realtime B-mode ultrasonography. Stroke 1998; 29:673 – 676.

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11 Arterial Sources of Embolism Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

The extracranial and intracranial large arteries often act as donor sources for embolism to the brain. Arterial-source embolism is also referred to as artery-to-artery, intra-arterial, and “local” embolism.

DISEASES, PATHOLOGY, AND PATHOPHYSIOLOGY Although atherosclerosis is by far the commonest condition that serves as a donor source of intra-arterial embolism, other vascular diseases also can release embolic materials. Trauma and dissections of arteries lead to local thrombus formation and embolism. Occasionally, inflammatory diseases of the brachiocephalic branches of the aortic arch, such as temporal arteritis and Takayasu’s disease, can lead to intra-arterial embolism. Thrombi sometimes form within arterial aneurysms, both saccular (1,2) and fusiform dolicocephalic aneurysms (3), and can then break off and embolize to distal branch arteries. Fibromuscular dysplasia (FMD) is an important but relatively uncommon vascular disease that affects the pharyngeal and occasionally the intracranial portions of the carotid, and vertebral arteries that also can become a source of distal intra-arterial embolism. Thrombi can, on occasion, form within large arteries in the absence of important arterial disease in patients with cancer and other causes of hypercoagulability (4). Figure 1 is an angiogram showing a large thrombus within an internal carotid artery caused by hypercoagulability in a patient with cancer. These luminal thrombi then can embolize to intracranial arteries causing strokes.

ATHEROSCLEROSIS Atherosclerosis is the predominant cause of intra-arterial embolism. The initial arterial lesion is a fatty streak that develops during the first three decades of life on the surface of the intima and then enlarges, usually during a period of decades, into a raised atherosclerotic plaque. Plaques contain a mixture of lipid, smooth muscle, fibrous and collagen tissues, macrophages, and inflammatory cells (5 – 8). Plaques can enlarge quickly when 203

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Figure 1 Carotid angiogram lateral view. Dark filling defects (white arrowheads) represent thrombi within the internal carotid artery. The insert on the left shows the location of the thrombi.

hemorrhages occur within the plaques. When a critical plaque size and encroachment on the lumen are reached, the atherosclerotic process often accelerates. Reduced luminal area and the bulk of the protruding plaque alter the physical and mechanical properties of blood flow and create regions of local turbulence and stasis. Platelets often adhere to irregular surfaces of plaques. Secretion of chemical mediators within platelets and within the underlying vascular endothelium causes aggregation and further adherence of platelets to the endothelium. Platelets begin to stick together and adhere to the endothelial lining of the plaque. A “white clot” composed of platelets and fibrin develops. Plaques often interrupt the endothelial lining of arteries and ulcerate. Figure 2 shows an ulcerated, irregular plaque within a specimen of a carotid artery removed at surgery. Breaches in the endothelium allow cracks and fissures to form, allowing contact of the constituents of the plaque with the blood within the lumen. Tissue factor, an important stimulator of the bodies coagulation system, is released. The coagulation cascade is activated by this contact, and a “red thrombus” composed of erythrocytes and fibrin forms within the lumen. Platelet secretion can also activate the serine proteases that form the body’s coagulation system and also promote the formation of red clots. When white or red thrombi first form, they are poorly organized and only loosely adherent. They often propagate and embolize. Figure 3 shows an occluded carotid artery found at necropsy. The specimen contains a large, mobile, red thrombus, a part of which had embolized to the brain. Within a period of 1– 2 weeks, thrombi organize and become more adherent, and fragments are less likely to break off and embolize. A variety of different materials— cholesterol crystals, calcified plaque fragments, white clots, and red thrombi—can form the substance of intra-arterial emboli.

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A carotid endarterectomy specimen that shows an irregular ulcerated plaque.

ARTERIAL DISSECTIONS Arterial dissections are probably the second most common disease that leads to artery-toartery brain embolism. Stretching or tearing within the arterial media causes the formation of an intramural hematoma. Blood within the media dissects longitudinally along the arterial wall. Expansion of the arterial wall often impinges on the lumen, narrowing it. Figure 4 shows a vertebral artery dissection containing a large intramural hematoma. The expanding intramural hematoma can break through the intima and release fresh red congealed hematoma containing thrombus-like material into the arterial lumen. This red clot is, at first, not adherent to the endothelium and thus often embolizes. The intimal tear and the underlying intramural hematoma cause perturbation of the arterial endothelium that, in turn, causes the activation of platelets and the coagulation cascade, promoting the formation of a thrombus in situ within the lumen. Compromise of the lumen by expanding intramural lesion alters blood flow within the lumen, which also promotes thrombus formation. Thrombus can form in situ within the dissected artery or reach the lumen by the introduction of the intramural contents. In either case, the acute luminal thrombus is poorly organized and nonadherent and readily embolizes intracranially (9 – 12). Marfans, Ehlers-Danlos, Pseudoxanthoma elasticum, cystic medial necrosis, and FMD predispose to arterial dissection.

FIBROMUSCULAR DYSPLASIA First recognized in the renal arteries as a cause of hypertension in young women, FMD also affects other systemic arteries, including extracranial and intracranial arteries. FMD is a

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Figure 3 Autopsy specimen showing an occluded carotid artery. A large red thrombus is projecting into the lumen of the artery (white arrow).

nonatheromatous multifocal disease that can involve any or all layers of arterial walls. The major pathology is fibroblast-like transformation of smooth muscle cells (13,14). The major morphological abnormalities include: (i) severe elastic tissue destruction, (ii) thinning of the media, (iii) medial smooth muscle hyperplasia and fibrosis, and

Figure 4 Cut sections of a vertebral artery removed at surgery. The proximal portion of the artery is to the left of the figure. A large brown-appearing intramural hematoma is present, severely narrowing the arterial lumen.

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(iv) adventitial fibrosis (15). The most common type of FMD predominantly affects the arterial media. Constricting bands made up of fibrous dysplastic tissue and proliferating medial smooth muscle cells alternate with regions of luminal dilatation related to thinning of the media and disruption of the elastic membranes (16,17). These pathological changes explain the characteristic string-of-beads appearance found on cervicocranial cerebral angiography. Figure 5 is an angiogram that shows characteristic changes of FMD within the pharyngeal portion of an internal carotid artery. Focal regions of hypertrophy of fibrous tissues in the adventitia or intima cause segmental areas of stenosis. The severity of stenosis can vary on different vascular imaging studies because some of the luminal narrowing is due to reversible vasoconstriction. Patients with FMD have a much higher than normal frequency of intracranial aneurysms (13,15,18). Pathological examination of arteries with FMD often shows dissections, and evaluation of patients presenting with arterial dissections shows an increased frequency of FMD. The cause of FMD is unknown. The pathological abnormalities could result from a number of different disorders, all sharing the tendency for proliferation of fibrous tissue or smooth muscle. Hereditary and genetic factors are likely to be very important (13,18). About two-thirds of patients with FMD are women, and the mean age at presentation is 50 (18). Among 1,100 patients reported with FMD, 300 (27%) patients had involvement of aortocranial arteries (18). Among reports of patients with cerebrovascular FMD, 12 – 43% of patients have involvement of the pharyngeal portion of the internal carotid artery often accompanied by involvement of the cervical vertebral artery (19). The pharyngeal portion of the extracranial vertebral arteries is most often involved usually opposite the second cervical vertebrae; the lesions usually extend for about 1– 2 cm. Most reported patients with intracranial FMD have also had extracranial involvement of the vertebral or carotid arteries or both (19).

Figure 5 A carotid angiogram shows characteristic string-of-beads appearance (black arrows) characteristic of fibromuscular dysplasia within the pharyngeal portion of the artery.

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The mechanisms by which FMD causes brain ischemia are not very well understood. Luminal irregularity and endothelial abnormalities could promote the formation of white platelet fibrin or red fibrin-dependent thrombi with subsequent intra-arterial embolism. Undoubtedly, some brain infarcts are caused by dissections often unrecognized in the presence of FMD.

ARTERIAL ANEURYSMS AND DOLICHOECTATIC ARTERIES Saccular aneurysms are localized outpouchings along arterial walls. About 4 –6% of the population have aneurysms at necropsy (18,20,21), and as many as 10% of adults more than 20 years old may harbor aneurysms, and saccular aneurysms are more common in women. Among 7,010 patients with aneurysms in one large series, 56% were women (21,22). Saccular aneurysms are most often located at branch points and forks along the intracranial large arteries along the circle of Willis and in the basal cisterns. Conditions predisposing to aneurysm formation include FMD, polycystic kidney disease, and congenital disorders of connective tissue, such as the Ehlers-Danlos syndrome. Both congenital and acquired factors contribute to the formation and growth of saccular aneurysms. Figure 6 shows a large saccular basilar artery aneurysm shown at dye contrast cerebral angiography. Figure 7 is a CT angiogram that shows a large vertebral artery–posterior inferior cerebellar artery aneurysm. Each harbored thrombi. Large aneurysms have been shown to harbor thrombi that can embolize distally (1,2). Some patients are prone to elongated, ectatic, tortuous intracranial arteries. The intracranial arteries in these patients often contain regions of marked vascular dilatation variously referred to as dolichoectasia, dilatative arteriopathy, or fusiform aneurysm formation. The basilar artery is most often affected, but the intracranial vertebral arteries are also often involved (23). Some patients also often have similar dilatation of the petrosal, cavernous,

Figure 6 A cerebral dye contrast angiogram showing a very large basilar artery aneurysm (black arrow) that harbored a thrombus.

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Figure 7 A computed tomography angiogram showing an aneurysm at the vertebral-posterior inferior cerebellar artery junction (small white arrows). Thrombus material was present within the lumen.

and intradural segments of the internal carotid arteries and the middle cerebral arteries. Although usually found in older patients, especially those with hypertension and diabetes, dolichoectasia is also occasionally found in the very young and also occurs in children with AIDS (24–27). Hereditary factors probably play an important role especially in the young. Hypertension and diabetes may cause progressive vascular wall damage in patients with dilatative arteriopathy. Extensive atherosclerotic plaques—often with calcification, encroachment on the lumen, and thrombus formation—are often found at necropsy. Flow within dilated segments is sometimes abnormal. Recent studies using transcranial Doppler (TCD) ultrasound show reduced velocity, to-and-fro flow, and even zero flow near the arterial walls (28,29). As a result, thrombi often form within dilated segments (30–32). Figure 8 is a dye contrast angiogram that shows a large filling defect (thrombus) within a dolichoectatic basilar artery. Clots within the arteries can embolize distally, and plaques and thrombi can block the orifices of penetrating and circumferential artery branches thus causing ischemia in the territory of these branches (30–32).

DISTRIBUTION OF ARTERIAL LESIONS The distribution of arteriosclerotic occlusive lesions varies depending on race, sex, and risk factors (9,10,33 – 36). In white men, the predominant cervicocranial occlusive lesions are in the carotid and vertebral arteries in the neck at or near the origins of these arteries. Blacks, individuals of Asian origin, and women more often have occlusive lesions in the large intracranial arteries and their main branches and less often have severe occlusive vascular lesions in the neck. White men who have carotid artery disease also have a high frequency of co-existing coronary artery and occlusive lower limb artery disease, as well as hypertension, and hypercholesterolemia. Smoking also promotes the development and progression of atherosclerotic lesions within the proximal carotid and

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Figure 8 A dye-contrast cerebral angiogram that shows a large filling defect representing thrombus (small black arrows) within a dolichoectatic basilar artery. Note that the posterior cerebral artery does not fill. After intravenous recombinant tissue plasminogen activator, the thrombus lysed, and the posterior cerebral arteries and distal basilar artery recanalized fully.

vertebral arteries. After the menopause, the frequency of extracranial occlusive disease increases in women. Within the anterior circulation, the most frequent and most important occlusive lesion in white men is within the internal carotid artery in the neck. Atherosclerotic lesions usually begin along the posterior wall of the common carotid artery opposite the flow-divider between the internal and the external carotid arteries (6,7,37). Figure 9 illustrates this localization of plaque, and Figure 10 is a carotid angiogram showing a very severe stenosis at this location within the initial portion of the right internal carotid artery. Atherosclerotic plaques grow and begin to intrude on the lumen and spread cranially within the common carotid artery and the proximal portion of the internal and sometimes the external carotid arteries. The next most common atherosclerotic lesions in white men within the anterior (carotid) circulation are found within the intracranial internal carotid artery, in the proximal intracranial portion of the artery called the carotid siphon because of its S shape, and within the proximal portions of the middle cerebral arteries. These lesions all most often produce symptoms by embolism of fragments of clots that form upon the vascular endothelium of plaques or of particles of the plaques themselves. Women, blacks, and Asians often develop occlusive lesions within the middle cerebral arteries and their branches. ICA siphon and neck lesions are less often found. Blacks, Asians, and women who develop occlusive neck lesions often smoke and have important coexisting atherosclerotic risk factors, such as hypertension, diabetes, and hypercholesterolemia. Within the posterior (vertebro-basilar) circulation, the most common occlusive lesion among white men is at the vertebral artery origin in the neck and within the adjacent subclavian artery. Plaques usually begin within the subclavian arteries and extend into the

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Figure 9 A diagram generated from ultrasound reconstructions showing the location of an atherosclerotic plaque (single black arrow) opposite the flow divider (double arrows) and between the internal carotid artery to the left and the external carotid artery to the right.

vertebral arteries at their origins or begin at the origins or within the first few centimeters of the vertebral arteries. Figures 11 and 12 are dye contrast angiograms that show severe atherosclerotic stenosis at and near the vertebral artery origins. The next most common lesions are within the intracranial vertebral arteries and the basilar artery (38). White men with occlusive atherosclerotic lesions at the origins of the vertebral arteries also have a high frequency of coexisting carotid artery disease (37 – 40), as well as hypertension and hypercholesterolemia. Intracranial lesions are also very common both in white men and in women, blacks, and Asians. The predominant lesions are within the intracranial vertebral arteries. Atherosclerotic lesions within the ICVAs are often bilateral (38). Atherosclerotic lesions involving the posterior cerebral arteries are more common in women, blacks, and Asians (10). The predominant mechanism of brain ischemia within the posterior circulation, as within the anterior circulation, is embolism (10,38,41,42). Intra-arterial embolism is just as common and important a mechanism of stroke within the vertebrobasilar arterial system as it is within the carotid artery system. Arterial dissections most often involve the pharyngeal portions of the extracranial carotid and vertebral arteries (9,10). The pharyngeal portions of the neck arteries are relatively mobile, whereas the origins of the arteries and their penetrations into the cranial cavity are anchored and much less mobile. Tearing occurs in portions of arteries that are flexible and stretch with motion. Within the extracranial vertebral arteries, the most common site of dissection is the most distal portion of the artery that emerges from the intervertebral foramina and courses around the atlas to penetrate the dura mater and enter the foramen magnum (10,43,44). Dissections also occur in the mobile part of the

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Figure 10 A carotid angiogram showing a very severe stenosis within the initial portion of the right internal carotid artery (white arrowhead ).

Figure 11 A dye-contrast angiogram showing stenosis at the origin of the vertebral artery (white arrow) from the subclavian artery. The artery is dilated after the region of stenosis (poststenotic dilatation).

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Figure 12 A dye contrast angiogram showing stenosis a few centimeters beyond the origin of the vertebral artery (white arrow) from the subclavian artery.

proximal portion of the extracranial vertebral arteries above their origin from the subclavian arteries but before the arteries enter the vertebral column at the intervertebral foramen of the sixth or fifth cervical vertebrae (10). Figure 13 is an artist’s drawing of the locations within the vertebral artery that are predilection sites for atherosclerosis and dissections. Figure 14 contains arteriograms that show the findings in patients with dissections of the carotid and vertebral arteries in the neck. Intracranial dissections are much less common than extracranial dissections. In the anterior circulation, intracranial dissections most often affect the intracranial internal carotid arteries and extend into the middle and anterior cerebral arteries (45). Within the posterior circulation, the most common site is the intracranial vertebral arteries (10,43,46). Dissections within the ICVAs often spread into the basilar artery. Occasionally, the basilar artery is the primary site of dissection (46). Dissecting aneurysms as well as large saccular and dolicocephalic fusiform aneurysms can serve as a source of thrombus formation with subsequent distal embolization (46).

RELATION OF SYMPTOMS TO SEVERITY OF ATHEROSCLEROTIC ARTERIAL STENOSIS Unlike the situation within the coronary arteries, brain ischemia is closely related to the severity of arterial stenosis. Transient or persistent brain ischemia is far more likely to

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Figure 13 An artist’s drawing of the vertebral artery. The open arrowheads show the areas of predilection for atherosclerosis, and the black arrowheads show the areas predisposed to dissections.

develop, when arterial lumens are severely narrowed. The arterial lesions cause brain ischemia either by substantially reducing blood flow to a region of the brain supplied by the artery (hypoperfusion) or by providing the donor source for intra-arterial embolism. Most sizable brain infarcts in patients with arterial stenoses and occlusions are embolic. TCD studies show an increased rate of high intensity transient microembolic signals in patients with severe ICA stenosis, supporting the key role of embolization (47 – 50). Hypoperfusion and embolism may complement each other (51). Normal blood flow allows efficient clearance (washout) of microemboli. When blood flow is importantly diminished, emboli may not washout and so remain to obstruct intracranial arteries causing brain infarction (51). Severity of stenosis is widely accepted as the most important prognostic risk factor that indicates the likelihood of future development of stroke in patients with symptomatic and asymptomatic carotid artery disease in the neck (52 – 55). Norris et al. (56) found increasing cumulative rates of transient ischemia and stroke in relation to increasing grades of arterial stenosis. The incidence of ischemic events also correlated very closely with the progression of the luminal compromise. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the risk of stroke correlated highly with the degree of ICA stenosis in all patients with transient monocular blindness, transient hemispheral ischemic attacks, and minor strokes (52,54). The presence of “silent infarcts” on magnetic resonance imaging (MRI) (57), and even

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Figure 14 (A) A dye-contrast arteriogram showing a carotid artery dissection. There is a long area of narrowing—a so-called “string sign” (small black arrows). (B) A dye-contrast angiogram showing a dissecting aneurysm (black arrow) in the pharyngeal portion of a carotid artery. (C) A dye-contrast angiogram of a vertebral artery showing irregular regions of narrowing and dilatation in the rostral extracranial portion of the artery ( paired black arrows) and an aneurysmal outpouching in the intervertebral portion of the artery (lower single black arrow).

the size of brain infarcts (58), has been shown to depend on the severity of ICA stenosis in the neck. The severity of intracranial arterial stenosis also has been shown to correlate highly with the occurrence of symptoms of brain ischemia (59 – 61). When stenosis is severe, the altered physical characteristics of blood flow strongly promote thrombus formation within the lumen, and thromboembolism develops.

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Some patients with lesser degrees of arterial stenosis do develop intraarterial embolism. Most often these emboli are white clots that cause transient ischemia or minor strokes—a phenomenon that Miller Fisher calls acceptable minor embolism. The morphological characteristics of plaques from specimens removed at endarterectomy correlate with symptoms (11,62). Some features of plaques as they appear on B-mode images of the cervical arteries—their degree of surface irregularity, heterogenicity, and echogenicity—are helpful in predicting the likelihood of related stroke. Echolucent plaques are rich in lipids and are associated with elevated levels of triglyceride-rich lipoproteins (63,64). Soft, heterogeneous plaques with irregular surfaces are more often associated with symptoms compared to calcified, dense plaques with regular surfaces (64,65).

IMAGING AND LABORATORY EVALUATION OF POTENTIAL DONOR SOURCES OF EMBOLISM In patients suspected of having brain embolic events, a thorough evaluation of all potential sources—cardiac, aortic, and cerebrovascular—is usually indicated. Atherosclerotic plaques and occlusive lesions often coexist in the heart, aorta, and brachiocephalic arteries. Furthermore, patients with cerebrovascular occlusive lesions have a very high frequency of coronary atherosclerotic heart disease, and their coronary artery disease often is a more serious threat for mortality and disability than their cerebrovascular disease. Patients with myocardial infarcts and coronary atherosclerotic heart disease have a high frequency of occlusive lesions within their extracranial and intracranial vascular beds. Prophylactic treatment to prevent subsequent thromboembolism should optimally consider measures to prevent embolism from all potential donor sources, not only the one that caused the present embolism. The extracranial and intracranial arteries should be studied to define potential arterial donor sources of embolism. The four most common and effective means of studying the brachiocephalic arteries are by magnetic resonance angiography (MRA), computed tomographic angiography (CTA), extracranial duplex ultrasound, and cerebral catheterdye angiography. Brain imaging always should precede or accompany the vascular studies to show the location, severity, and distribution of related brain ischemia. Imaging of the brain and intracranial recipient arteries has been thoroughly discussed in Chapter 6. Optimal information is provided by thorough magnetic resonance imaging. MRI scans of the brain, including fluid-attenuated inversion recovery images and T1- and T2-weighted images show the extent of brain infarction and adequately show hemorrhages and hemorrhagic infarction. These studies can be accompanied by MRA of the extracranial and intracranial arteries. MRA provides a good image of the extracranial carotid arteries but can overestimate the severity of the stenosis (66 –68). When the arterial stenosis is very severe, there is often a gap in the arterial images indicating an impediment to flow, but gaps do not allow accurate quantification of the severity of the stenosis or the presence of thrombi. MRA of the intracranial anterior circulation arteries is a good screening test for occlusion or severe stenosis of the major arterial branches of the intracranial carotid arteries (69,70). Tortuous regions within the carotid artery in the siphon often are not imaged well, and MRA does not show distal branch artery occlusions. When the carotid artery is occluded in the neck, there may be too little flow to provide good images of the intracranial carotid artery and its major branches, although often these vessels are filled well by collaterals. MRA can also be used to screen for occlusive lesions within the vertebrobasilar circulation (10,71,72). Unfortunately, the origins of the vertebral arteries from the subclavian

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arteries are difficult to image unless a proximal view of the aortic arch arteries is included in the imaging. The extracranial and intracranial vertebral arteries are sometimes imaged using two different views—a neck and a head studies. Sometimes the neck view is cut off too high missing the origin of the artery, and the head view is cut off too high failing to include the proximal intracranial vertebral artery after its dural penetration. Care must be taken to ensure that the entire vertebral artery is seen. The basilar and posterior cerebral arteries are imaged well using MRA (10,71,72). The extracranial and intracranial arteries also can be accurately imaged by CTA (73,74). This technique employs rapid filming using a spiral (helical) CT scanner after the intravenous injection of a dye load. Reformatting of the CT images yields good reconstructions of the extracranial and intracranial arteries. The CT source films can be reviewed quickly to detect arterial occlusions, but time is sometimes needed to reproduce reformatted arterial images depending on the available software. CT scans of the brain are also acquired so that both brain and vascular images are created using the same technology and at one sitting. CTA is accurate in showing large artery occlusions, severe stenosis, and aneurysmal changes in both the anterior and posterior circulations (73,74). Ultrasound capabilities have dramatically improved and are now an integral part of the evaluation of patients with brain embolism. Ultrasound has the advantages of being portable, noninvasive, and relatively inexpensive when compared with MR and CT. Ultrasound can be repeated sequentially to study the effects of spontaneous or therapeutic reperfusion. In some centers, ultrasound equipment is available in the emergency room and at the bedside and can be used by examining physicians as an extension of the physical examination of the arteries. At present, Doppler ultrasound is available in almost all intensive care units to follow blood flow in various peripheral arteries. Duplex scanning (combined B-mode and multigated pulsed-Doppler) is used to image the extracranial carotid and vertebral arteries. Both duplex scans and C-W Doppler give accurate information about the ICA in the neck (67,75,76). Figure 15 shows a B-mode ultrasound of

Figure 15 (A) B-mode ultrasound showing echoes representing plaques. (B) (small white arrows) protruding into the lumen of the internal carotid artery from both the anterior and posterior walls of the artery. (C) Artists diagram of B-mode findings in a patient with a large plaque in the internal carotid artery. Abbreviations: ICA, internal carotid artery; ECA, external carotid artery; CCA, common carotid artery.

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Figure 16 Composite B-mode ultrasound showing clearly the innominate, right common, internal and external carotid arteries and the right subclavian and vertebral arteries. Abbreviations: IA, innominate artery; SA, subclavian artery; VA, vertebral artery; CCA, common carotid artery; ICA, internal carotid artery; ECA, external carotid artery.

plaques within the internal carotid artery and also an artists drawing of the findings from a B-mode ultrasound of a patient with an atherosclerotic plaque that extends from the common carotid artery along the posterior wall of the internal carotid artery. Color-flow Doppler imaging is probably even more effective in grading the severity of ICA stenosis and depicts flow abnormalities and regions of turbulence (77 –79). The innominate, subclavian, and vertebral arteries can also be studied using duplex and color-flow ultrasound (10,75,80,81). Ultrasound of the carotid and vertebral arteries is also useful in suggesting dissections (82 – 84). Figure 16 is a composite B-mode ultrasound picture that shows the extracranial arteries quite well. TCD ultrasound yields very important information about flow in the intracranial arteries (10,75,85,86). TCD has been thoroughly discussed in Chapter 7. Angiography of the extracranial and intracranial arteries is still important. Angiography is performed in patients: (1) in whom noninvasive vascular tests (CTA, MRA, extracranial and transcranial ultrasound) show lesions but not sufficiently to guide treatment, (2) when noninvasive testing shows a lesion that would be best treated by intra-arterial interventional radiology (intra-arterial thrombolysis and/or angioplasty), and (3) in whom noninvasive testing has not shown a donor source of embolism but an arterial source is suspected. Guidelines for the use of angiography in patients with brain ischemia have been published (87). CT, MRI, and MRA usually suffice to identify aneurysmally dilated, ectatic arteries and may suggest the presence of clot within the vessels. TCD is very helpful in diagnosis and may show reduced mean flow velocities, with relatively preserved peak flow velocities (29). Blood flow may be to and fro within the dilated artery causing reduced antegrade flow. The reduced antegrade flow may lead to poor opacification on MRA, falsely suggesting occlusion of the dolichoectatic artery. CTA and standard angiography are usually able to provide images of the dolichoectatic artery in that circumstance.

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29. Schwartz A, Rautenberg W, Hennerici M. Dolichoectatic intracranial arteries: review of selected aspects. Cerebrovasc Dis 1993; 3:273 – 279. 30. Pessin MS, Chimowitz MI, Levine SR et al. Stroke in patients with fusiform vertebrobasilar aneurysms. Neurology 1989; 39:16– 21. 31. DeGeorgia M, Belden J, Pao L, Pessin MS, Kwan E, Caplan LR. Thrombus in vertebrobasilar dolichoectatic artery treated with intravenous urokinase. Cerebrovasc Dis 1999; 9:28– 33. 32. Cohen MM, Hemalatha CP, D’Addario RT, Goldman HW. Embolism from a fusiform middle cerebral artery aneurysm. Stroke 1980; 11:158 –161. 33. Caplan JR, Gorelick PB, Hier DB. Race, sex, and occlusive cerebrovascular disease: a review. Stroke 1986; 17:648 – 655. 34. Gorelick PB, Caplan LR, Hier DB, et al. Racial differences in the distribution of anterior circulation occlusive disease. Neurology 1984; 34:54 – 59. 35. Gorelick PB, Caplan LR, Hier DB, et al. Racial differences in the distribution of posterior circulation occlusive disease. Stroke 1985; 16:785– 790. 36. Feldmann E, Daneault N, Kwan E, et al. Chinese-White differences in the distribution of occlusive cerebrovascular disease. Neurology 1990; 40:1541– 1545. 37. Fisher CM, Gore I, Okabe N, White PD. Atherosclerosis of the carotid and vertebral arteriesextracranial and intracranial. J Neuropathol Exp Neurol 1965; 24:455 – 476. 38. Caplan LR, Wityk R, Glass TA, et al. New England Medical Center Posterior Circulation Registry. Ann Neurol 2004; 56:389– 398. 39. Hutchinson EC, Yates PO. Carotico-vertebral stenosis. Lancet 1957; 1:2 – 8. 40. Hutchinson EC, Yates PO. The cervical portion of the vertebral artery. a clinicopathological study. Brain 1956; 79:319– 331. 41. Caplan LR. The E Graeme Robertson lecture: vertebrobasilar embolism. Clin Exp Neurol 1991; 28:1 –23. 42. Caplan LR, Tettenborn B. Vertebrobasilar occlusive disease: review of selected aspects. 2. Posterior circulation embolism. Cerebrovasc Dis 1992; 2:320– 326. 43. Caplan LR, Tettenborn B. Vertebrobasilar occlusive disease:review of selected aspects. 1. Spontaneous dissection of extracranial and intracranial posterior circulation arteries. Cerebrovasc Dis 1992; 2:256 – 265. 44. Caplan LR, Zarins C, Hemmatti M. Spontaneous dissection of the extracranial vertebral artery. Stroke 1985; 16:1030 – 1038. 45. Chaves C, Estol C, Esnaola MM, Gorson K, O’Donoghue M, DeWitt LD, Caplan LR. Spontaneous intracranial internal carotid artery dissection. Arch Neurol 2002; 59:977– 981. 46. Caplan LR, Baquis G, Pessin MS, et al. Dissection of the intracranial vertebral artery. Neurology 1988; 38:868 – 877. 47. Caplan LR. Brain embolism. In: Caplan LR, Hurst JW, Chimowitz M, eds. Clinical Neurocardiology. New York: Marcel Dekker, 1999:35– 185. 48. Siebler M, Kleinschmidt A, Sitzer M, et al. Cerebral microembolism in symptomatic and asymptomatic high-grade internal carotid artery stenosis. Neurology 1994; 44:615– 618. 49. Ries S, Schminke U, Daffertshofer M, et al. High-intensity transcranial signals in carotid artery disease. Cerebrovasc Dis 1995; 5:124 – 127. 50. Siebler M, Sitzer M, Rose G, et al. Silent cerebral embolism caused by neurologically symptomatic high-grade carotid stenosis: event rates before and after carotid endarterectomy. Brain 1993; 116:1005 – 1015. 51. Caplan LR, Hennerici M. (Hypothesis) Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55:1475 – 1482. 52. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445 – 453. 53. European Carotid Surgery Trialists Collaborator Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70 – 99%) and with mild (0– 29%) carotid stenosis. Lancet 1991; 337:1235– 1243.

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54. Streifler JY, Eliasziw M, Benavente OR et al. The risk of stroke in patients with first-ever retinal or hemispheral transient ischemic attacks and high-grade carotid stenosis. Arch Neurol 1995; 52:246 – 249. 55. Hennerici M, Hulsbower HB, Hefter K, et al. Natural history of asymptomatic extracranial disease: results of a long term prognostic study. Brain 1987; 110:777 – 791. 56. Norris JW, Zhu CZ, Bornstein N, Chambers BR. Vascular risks of asymptomatic carotid stenosis. Stroke 1991; 22:1485– 1490. 57. Fazekas F, Fazekas G, Schmidt R, et al. Magnetic Resonance Imaging correlates of transient cerebral ischemic attacks. Stroke 1996; 27:607– 611. 58. Lodder J, Hupperts R, Boreas A, Kessels F. The size of territorial brain infarction on CT relates to the degree of internal carotid artery obstruction. J Neurol 1996; 243:345 – 349. 59. Wechsler LR, Kistler JP, Davis KR, Kaminski MJ. The prognosis of carotid siphon stenosis. Stroke 1986; 17:714 – 718. 60. Craig DR, Meguro K, Watridge C, et al. Intracranial internal carotid artery stenosis. Stroke 1982; 13:825 – 828. 61. Chimowitz MI, Kokkinos J, Strong J, et al. The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488– 1493. 62. Imparato AM, Riles TS, Gorstein F. The carotid bifurcation plaque: pathological findings associated with cerebral ischemia. Stroke 1979; 10:238– 245. 63. Gronholdt M-L M, Nordestgaard BG, Nielsen TG, Sillesen H. Echolucent carotid artery plaques are associated with elevated levels of fasting and postprandial triglyceride-rich lipoproteins. Stroke 1996; 27:2166 – 2172. 64. European Carotid Plaque Study Group. Carotid artery plaque composition: relationship to clinical presentation and ultrasound B-mode imaging. Eur J Vasc Endovac Surg 1995; 10:23 – 30. 65. Geroulakos G, Ramaswami G, Nicolaides A, et al. Characterization of symptomatic and asymptomatic carotid plaques using high-resolution real-time ultrasonography. Br J Surg 1993; 80:1274 – 1277. 66. Kido DK, Panzer RJ, Szumowski J, et al. Clinical evaluation of stenosis of the carotid bifurcation with magnetic resonance angiographic techniques. Arch Neurol 1991; 48:484 – 489. 67. Riles TS, Eidelman EM, Litt AW, et al. Comparison of magnetic resonance angiography, conventional angiography, and Duplex scanning. Stroke 1992; 23:341 –346. 68. Anderson CM, Saloner D, Lee RE, et al. Assessment of carotid artery stenosis by MR angiography: comparison with x-ray angiography and color-coded Doppler ultrasound. AJNR 1992; 13:989 – 1003. 69. Gillard JH, Oliverio P, Barker PB, Oppenheimer SM, Bryan RN. MR angiography in acute cerebral ischemia of the anterior circulation: a preliminary report. AJNR 1997; 18:343– 350. 70. Johnson BA, Heiserman JE, Drayer BP, Keller P. Intracranial MR angiography: its role in the integrated approach to brain infarction. AJNR 1994; 15:901– 908. 71. Rother J, Wentz K-U, Rautenberg W, et al. Magnetic resonance angiography in vertebrobasilar ischemia. Stroke 1993; 24:1310 – 1315. 72. Bogousslavsky J, Regli F, Maeder P, et al. The etiology of posterior circulation infarcts: a prospective study using magnetic resonance imaging and magnetic resonance angiography. Neurology 1993; 43:1528 –1533. 73. Schwartz RB, Jones KM, Chernoff DM et al. Common carotid artery bifurcation: evaluation with spiral CT. Radiology 1992; 185:513 –519. 74. Alberico RA, Patel M, Casey S, et al. Evaluation of the circle of Willis with threedimensional CT angiography in patients with suspected intracranial aneurysms. AJNR 1995; 16:1571 – 1578. 75. von Reutern G-M, von Budingen HJ. Ultrasound diagnosis of cerebrovascular disease. Doppler Sonography of the Extra- and Intracranial Arteries, Duplex Scanning. New York: Thieme Med Publ, 1993. 76. Hennerici M, Freund H-J. Efficacy of C-W Doppler and Duplex system examinations for the evaluation of extracranial carotid disease. J Clin Ultrasound 1984; 12:155 – 161.

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12 Ultrasound of Cervical Arteries Michael Hennerici, Hansjoerg Baezner, and Michael Daffertshofer Department of Neurology, University of Heidelberg, Universita¨tsklinikum Mannheim, Mannheim, Germany

Ultrasound is a very important method of interrogating the neck arteries as potential donor sources of emboli. Modern ultrasound has greatly improved evaluation of arterial disease in the neck and head. The important advantage of ultrasound lies in the ability to image and study the arterial wall. Other imaging techniques—dye-contrast angiography and computed tomography and magnetic resonance angiography—provide images of the lumen of arteries but do not give information about the arterial wall or the nature of plaques that protrude from the arterial wall. Rapid progress in noninvasive ultrasound techniques has resulted in a wide variety of clinical applications, including evaluation of vascular aging as a degenerative process, depiction of early and small vascular lesions, and demonstration of plaque development, motion, and vulnerability. Echo-contrast agents have been used to compensate for difficulties in visualizing late, severe, or subtotal obstructive plaques. With increasing sophistication of ultrasound methods, it became essential to establish standards for data acquisition and interpretation. Consensus meetings have provided detailed recommendations on quantification of carotid atherosclerosis and characterization of carotid artery plaques (1,2), as well as detection of microembolism by transcranial Doppler (3). Although extensive research in atherosclerosis has been performed for more than a century, the mechanisms causing atherogenesis are still poorly understood. Atherosclerotic arterial disease has an irregular natural course with long asymptomatic stages until symptoms develop suddenly due to local thrombosis or distal embolism. Distinction from normal aging has long been difficult but is now facilitated by vascular ultrasound investigations, such as delineation of the intima – media thickness (IMT), plaque development, and vascular remodeling. Compensatory mechanisms can also be identified in patients with few symptoms but extensive vascular disease. These patients usually do not need surgical or interventional treatment because of the slowly developing collateral capacity of complex networks from large and small arteries. INTIMA – MEDIA THICKNESS: THE INITIAL STAGE OF ARTERIAL DISEASE Pignoli et al. (4) using B-mode ultrasound were the first to characterize a “double line” pattern of the normal carotid artery wall. These authors described the first echogenic 223

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line on the far wall as the lumen – intima interface and the second line as the mediaadventitia interface. They showed that measurements of the IMT in tissue specimens from common carotid arteries correlated highly with the distance between these two echogenic lines. This first report on the measurement of IMT with B-mode ultrasound was later validated in vitro (5) and was also shown to enable good intra- and interobserver reproducibility (6). However, Gamble et al. (7) questioned whether the double line was representative of the histologic situation. Others posited that the depiction of IMT with B-mode ultrasound could be a border-zone reflection artifact and compared it to the double-line pattern seen with Plexiglas, metal plates, and plastic foil (8). Notwithstanding these debates, the vast majority of later studies validated a close correlation between the IMT seen in histologic specimens and that measured with B-mode ultrasound. Studies later established associations between common carotid IMT, cardiovascular risk factors (9,10), and the prevalence of cardiovascular disease (11) using high-resolution ultrasonography. The increasing importance of the common carotid IMT is further reflected by its use as a surrogate end point for determining the success of interventions that lower levels of low-density lipoprotein cholesterol. Azen et al. (12) used serial measurements of IMT to assess the effect of supplementary vitamin E intake in reducing progression of age-related vascular degeneration in subjects not treated with lipidlowering drugs. A recent report confirmed these findings and identified increased carotid artery IMT as a risk factor for both myocardial infarction and stroke (13). In contrast to epidemiological and large clinical trials, other studies questioned the clinical usefulness of measuring carotid IMT in individual patients, because it was not specific or sensitive enough to identify those with or without significant coronary artery disease and is less rigorously related to atherosclerosis than to vascular degeneration. Increasing age, male sex, and diabetes were all associated with a coronary artery disease score significantly higher (P , 0.01) than average for any level of carotid IMT, suggesting different associations of these traditional risk factors on atherosclerosis in the coronary and common carotid arteries (14). Because of these controversial results, a consensus on the value of measuring IMT has not been reached. Ultrasound imaging is able to measure both IMT and plaque volume, nature, and development, making it possible to analyze in large epidemiological studies the importance of each regarding stroke and coronary artery disease (Fig. 1).

Intima – Media Thickness Sampling The selection of precise regions for the measurement of IMT is critical, because the focal location of reactive intimal thickening and initial plaque development in the carotid arteries are related to geometric transitions. Because any single ultrasound examination may fail to identify the site of maximal intimal thickening, IMT measurements over a range of incident angles and axial locations are recommended. A variety of IMT-sampling protocols have been proposed. Some use IMT measurements at the common carotid artery, where the double-line pattern is easiest to visualize, whereas others choose to measure IMT at the carotid bifurcation and within the internal carotid artery (ICA). Site-specific measurement of IMT focuses on arterial segments showing either wall thickening or plaques. In some studies, cut-off points of 0.75 or 1 mm are chosen to identify subjects with an abnormal IMT. In others, the IMT was considered abnormal if the value was one or two standard deviations above the mean for the population. In an attempt to assess the overall extent of the atherosclerotic burden, scoring systems have been developed for site-specific studies. These use aggregate summing of IMT

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Figure 1 B-mode common carotid artery images showing vessel wall interface with increasing atherosclerotic load: (A) normal arterial wall (far wall) with intima – media thickness (IMT) ,1.0 mm, (B) slightly increased IMT (1.1 mm; average from three measures), (C) slight IMT increase (1.6 mm; average of three measures) in an asymptomatic patient with several vascular risk factors, (D) definite atherosclerotic thickening of the intima– media complex with clear dissolution of the normal IMT pattern (IMT ¼ 1.9 mm), and (E) circumscribed atherosclerotic plaque at the carotid bifurcation.

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measurements from segments considered to be diseased, whereas normal-appearing arterial walls are assigned a score of zero (15). Other investigators calculate the mean thickness of both normal and abnormal walls (16,17). The method of IMT sampling, that is, combined measurements at different sites and measurements of mean or maximum wall thickness, depends on the research question and on the relative emphasis placed on confirmed atherosclerotic lesions (18). Assessment Over Time A major source of error in the longitudinal assessment of IMT is the difficulty in retrieving the same echographic view of the vessel. Although the mean IMT might be considered a reproducible target to evaluate differences between populations exposed to diverse risk factors, natural or therapy-induced changes in an individual may be better monitored on predefined carotid artery sectors. External landmarks have been used to increase reproducibility (19). Another approach uses discrete Fourier transforms to minimize the vessel contour after matching baseline ultrasonographic images with a corresponding view (20). Morphologic Correlates of IMT The common assumption that an increased IMT represents early atherosclerotic plaque formation is not true. Intimal hyperplasia and fibrocellular hypertrophy are nonatherosclerotic reactions associated with local modifications of flow and mural tension and likely represent adaptive or self-limiting compensatory changes continuously changing during life. Importantly, intimal fibrocellular hypertrophy, a layered widening of both smooth muscle cells and matrix fibers, can be extensive in a particular arterial segment and is not necessarily of uniform width. In contrast, early atherosclerotic lesions are characterized by a focal eccentric accumulation of lipid in the intima, both in the extracellular matrix interstices and in the smooth muscle cells. These early lesions do not project into the vessel lumen that remains anatomically intact. Intimal fibrocellular hypertrophy may modify the arterial surface contour, and intimal hyperplasia and atherosclerosis often coexist. IMT, as measured by B-mode ultrasound, is a heterogeneous entity, largely independent from atherogenesis and plaque development.

PLAQUE DEVELOPMENT: THE INTERMEDIATE STAGE OF ARTERIAL DISEASE High-Resolution B-Mode Imaging Owing to its noninvasive nature, real-time capabilities, and general availability, ultrasound is the most extensively utilized imaging technique to study the morphology of carotid artery plaques. Small atherosclerotic plaques with a luminal narrowing of ,40% are suspected using Doppler sonography if spectral broadening is present, indicating abnormal bloodflow components. However, as physiological flow separation and a variety of other hemodynamic variables may confound the interpretation of spectral broadening, high-resolution, B-mode imaging is needed to detect small atherosclerotic lesions and to assess plaque morphology. The increased use of real-time B-mode imaging results from an advancing transducer technology, the miniaturization of electronics through the development of digital circuitry, advances in computer software, and improved ultrasonic focusing. This results in continuously improving image quality and increased information content for real-time ultrasonographic evaluation of plaque morphology.

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Compounded Imaging Real-time compounded imaging is a new modality that has the potential to enhance ultrasonographic visualization and characterization of carotid artery plaques (21). This technique acquires ultrasound beams that are steered off-axis from the orthogonal beams used in conventional ultrasound. The number of frames and steering angles varies depending on the transducer characteristics. Frames acquired from sufficiently different angles contain independent random speckle patterns, which are averaged to reduce speckle and improve tissue differentiation. In comparison with high-resolution B-mode imaging, this new technology is able to suppress edge shadowing and improve contrast resolution. This new technology will enhance morphologic characterization of plaque-surface structure and aid in assessing the location and nature of plaque constituents.

Color Doppler Flow Imaging Color Doppler flow imaging (CDFI) is a scanning mode that combines gray-scale imaging with two-dimensional Doppler flow information in real time. A single representative Doppler shift (usually the mean) at each sampling site is color encoded by hue or intensity of color. By convention, red typically indicates motion in one direction, and blue indicates motion in the opposite direction. High-Doppler shifts are commonly displayed by decreased color saturation, whereas flow turbulence may also be color coded. Through their ability to contrast the intravascular lumen, color signals on CDFI can significantly improve evaluation of plaque surface and configuration (22 – 26). This is particularly helpful for showing weakly echogenic plaques, often hardly distinguishable from the intravascular lumen with B-mode scanning techniques alone (Fig. 2).

Power Doppler Imaging Power Doppler imaging is a more recent development that displays the amplitude of Doppler signals. Color and brightness of the signals are correlated with the number of blood cells producing the Doppler shift. The greater sensitivity of power Doppler imaging for the detection of blood flow when compared with that of color Doppler flow imaging is due to several factors. 1. 2. 3. 4. 5.

Noise can be assigned to a homogeneous background, thus allowing the gain to be increased over the level of CDFI. In power Doppler imaging, more of the dynamic range of the Doppler signal can be used to increase sensitivity. Power Doppler is less angle-dependent than CDFI, thus allowing better display of curving or tortuous vessels. By reliance upon Doppler amplitude, there is no aliasing, improving display of vessel wall pathology in areas of turbulent flow. Power Doppler is superior for displaying vessels with low-flow velocity.

The first report on the value of power Doppler imaging in cerebrovascular ultrasound showed a distinct advantage for the assessment of plaque-surface structure (Fig. 3) (27). Since then, this new technique has been further validated and is currently the gold standard in ultrasound for characterizing carotid artery plaque surfaces.

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Figure 2 Image of an atherosclerotic plaque: B-mode image (upper row; left side) that shows heterogeneous plaque texture and an irregular plaque surface difficult to evaluate. Color mode now displayed in grey and black (boxed area) additionally displays regular flow patterns without significant irregularities. Doppler registration (lower row) without flow increase indicates nonvulnerable plaque. Note the irregular cardiac cycles.

Figure 3 Complex plaque displayed with power mode shown in the boxed region of the figure. Power mode does not provide information about flow direction or about flow irregularities. The high sensitivity of the mode to identify slow flow velocities facilitates otherwise impossible delineation of this highly curved and complex plaque surface and also allows detection of ulcerative niches.

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Plaque Echogenicity Plaques with homogeneous echogenicity consist mainly of fibrotic tissue (28,29). Ulceration is rare in homogeneous plaques, perhaps accounting for the lack of significant correlation with the occurrence of focal brain ischemia. Heterogeneous plaques represent matrix deposition, cholesterol accumulation, necrosis, calcification, and intraplaque hemorrhage (28 – 30). High-resolution B-mode scanning can allow characterization of echomorphologic features of carotid plaques that correlate with histopathology (31). Fragments of thrombi, intraplaque hemorrhages, and accumulation of lipid materials can all yield echolucent regions within plaques (32). Plaque calcification produces acoustic shadowing in B-mode echotomograms. Depending on plaque location and the extent of calcification, this artifact can be a major obstacle for adequate visualization of the vessel and the plaque. Initial studies of plaque echogenicity with B-mode ultrasound reported an association between heterogeneous plaques and the occurrence of cerebrovascular events (33 –37). Examinations of endarterectomy specimens suggested a correlation between intraplaque hemorrhage and transient ischemic attacks and stroke (38 – 41). Later studies did not confirm this hypothesis (42 –44). Whether differences in plaque echogenicity can distinguish between symptomatic and asymptomatic patients continues to be debated. New ultrasonographic studies claim again that heterogeneous carotid plaques are more often associated with intraplaque hemorrhage and neurologic events and conclude that evaluation of plaque morphology may be helpful in selecting patients for carotid endarterectomy (45 – 47). Others argue that lipid-rich plaques are more prone to rupture and suggest that an association between an intraplaque hemorrhage and a highlipid content as revealed in B-mode ultrasound may support this theory (48). Others have found little correlation between plaque morphology and histologic specimens (49). Recently, a definitive study on the significance of heterogeneous plaque structure found no differences in volume of intraplaque hemorrhage, lipid core, necrotic core, or plaque calcification in patients with highly stenotic carotid artery lesions undergoing endarterectomy, regardless of preoperative symptom status (50).

Interobserver and Intraobserver Agreement of B-Mode Plaque Morphology In the Tromsø Study in Norway, interobserver and intraobserver agreement on plaque morphology classification was reported as high, with k-values ranging between 0.54 and 0.73 (51). However, most new studies on this subject report low interrater agreement, indicating that unaided visual evaluation of static B-mode pictures for assessing plaque morphology in patients with carotid stenosis is not very reliable (52). Reproducible grading of ultrasound images is not consistently achievable among experienced observers, and within-observer agreement may vary with time (53). In one study on subjective categorization of plaque types, the intraobserver agreement was moderate (k ¼ 0.44) and the interobserver agreement was low (k ¼ 0.38), emphasizing that subjective B-mode ultrasound categorization of atherosclerotic plaques cannot adequately determine the volume of fibrosis or lipids within plaques (54). The poor interobserver and intraobserver agreement concerning B-mode plaque morphology may explain the discrepant findings of previous attempts to characterize carotid artery plaques in relation to clinical events. The current subjective ultrasound characterization of carotid plaque morphology used in clinical trials may be associated with unacceptable levels of reproducibility in some centers.

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Computerized Evaluation of Plaque Echogenicity Owing to suboptimal interobserver and intraobserver agreement in estimating visually plaque morphology with ultrasound, various schemes for standardizing the assessment of carotid plaques have been introduced. Linear scaling of the adventitia and blood with gray-scale medians has been proposed for quantifying echo intensity. Using this technique, decreased echogenicity in terms of gray-scale median and percentage of echolucent pixels has been reported for symptomatic plaques (55). Other groups have also used computer processing to yield a measure of plaque echogenicity (56). Spectral analysis of echo signals acquired from human carotid endarterectomy specimens has been performed to improve classification of fibrous, lipid pool, and thrombus constituents (57). By using three parameters of the calibrated power spectrum (slope, intercept, and total power), the proportion of correctly classified tissue regions could be increased. These studies indicate that computer-aided analysis of ultrasonic B-mode features of carotid plaques may be valuable in multicenter clinical trials, where different operators and equipment are used.

Plaque-Surface Structure and Ulcerations Attempts to characterize plaque-surface structure with B-mode echotomography have been disappointing. Relatively good differentiation among smooth, irregular, and ulcerative plaque surfaces has been obtained for postmortem carotid artery specimens (29), but in vivo accuracy when compared with findings at carotid endarterectomy is considerably poorer (31,39,58,59). Surface defects showing a depth and a length of 2 mm with a welldefined base in the recess are often used to identify plaque ulceration (60). Using these criteria, B-mode imaging has failed to provide a satisfactory diagnostic yield for ulcerative plaques with a sensitivity of only 47%. Other groups have been unable to distinguish between the presence or the absence of intimal ulcerations with B-mode scans (61). Diagnostic sensitivity for detecting plaque ulceration with ultrasound is affected by the degree of carotid stenosis and increases to 77% in plaques associated with 50% stenosis (31). Power Doppler imaging could significantly improve the yield for reliable depiction of plaque ulcerations. Pathoanatomical comparisons with this technique, however, are lacking. Conventional dye-contrast angiography has likewise proven inadequate for the definition of ulcerative plaques, the sensitivity being 53% (31). Angiographic detection of ulceration when compared with surgical specimens was poor in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) study. A sensitivity of 45.9% and a specificity of 74.1% were found for 500 specimens, yielding a positive predictive value of only 71.8% (62). Angiographic assessment of plaque-surface morphology varies depending on the type of angiography and the quality of visualization of carotid artery stenosis (63). Whether plaque surface irregularities or ulcerations are useful for defining patients at risk for artery-to-artery embolism is debated. Advocates of a pathophysiological relationship maintain that ulcerations constitute a fertile ground for potential thrombosis and consequent embolic events. A recent report contends that the presence of an angiographically defined ulcer is associated with an increased risk of stroke in medically treated symptomatic patients (64). Some ulcers are smooth and thick and contain no thrombus (65). Endarterectomy specimens from asymptomatic patients with carotid artery plaques with .60% stenosis show an increased frequency of plaque hemorrhages, ulcerations, and mural thrombi, as well as of numerous healed ulcerations and organized thrombi (66). Both symptomatic and asymptomatic patients with stenotic carotid endarterectomy

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plaques show a high frequency of complex plaque structure and complications (42,67). There seems to be little difference in plaque constituents or plaque surface structure between specimens from symptomatic and asymptomatic patients. These findings confirm that a traditional description of plaque structure or identification of plaque ulceration as depicted in current clinical imaging techniques; that is, ultrasound, MRI, and angiography, is not useful for predicting which carotid plaques are most likely to become the donor source of artery-to-artery emboli.

Characterization of Plaque Motion Experimental work suggests that analysis of plaque motion—that is, translational plaque movements coincident with those of arterial walls, plaque rotations, and local, plaquespecific deformations—may provide new insights into plaque modeling and mechanisms of plaque rupture with subsequent embolism. For example, in vitro observations on the relative position of markers placed along plaque specimens during pressure loading have shown that prior to plaque fissuring, the markers display asymmetrical movement. Such plaque-surface movement may be attributable to deformations resulting from crack propagation of multiple local internal tears in the plaque. Identification of local variations in surface deformability could, therefore, provide information on the relative vulnerability to plaque fissuring or rupture. An approach for studying plaque-surface deformations has recently been reported (68). This technique uses four-dimensional (4D) ultrasonography to acquire temporal three-dimensional ultrasound data of carotid artery plaques. The ultrasound data are then analyzed with motion detection algorithms to determine apparent velocity fields, also known as optical flow, of the plaque surface. Using this method, differences in plaque motion patterns between patients with symptomatic and asymptomatic carotid artery disease have been characterized (68). Asymptomatic plaques typically show a homogeneous orientation and magnitude of computed-surface velocity vectors, coincident with arterial wall movement. Analysis of symptomatic plaques, however, has shown consistent evidence for plaque deformation, irrespective of arterial wall movements, although analysis of plaque motion in patients with carotid artery stenosis facilitates detection of patterns that suggest an increased risk for plaque complications. Plaque vulnerability likely depends on a number of nonlinearly active mechanisms rather than a simple abnormality.

Possible Mechanisms of Remodeling A very well-known phenomenon in vascular medicine is the ability of blood vessels continually to adapt their cross-sectional size to the needs of dynamic downstream blood supply. This dynamic process, termed “arterial remodeling,” came into the focus of vascular research when it became clear that remodeling and not plaque size was the primary determinant of lumen size in the presence of stable lesions. More recently, growing evidence seems to show an association of adequate outward remodeling with an increasing risk of plaque rupture as the underlying cause of acute coronary syndromes and sudden cardiac death. The term “remodeling” is used to describe various conditions as de novo atherosclerosis, restenosis, and transplant vasculopathy. Obviously, the predominant mechanisms involved in remodeling in each of these pathological conditions may be quite different.

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Remodeling and Hemodynamic Stimuli Under physiological conditions, vascular remodeling is a dynamic response to both flow changes to restore normal shear stress and alterations of circumferential stretch to adjust wall tension (69). Important factors that contribute to outward remodeling in response to increased flow are the shear-responsive endothelial production of nitric oxide (70) and the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 (71). Nitric oxide seems to be crucial in this process, as it has the potential to induce MMPs (72) and to inhibit proliferation and promote apoptosis of smooth muscle cells (73). In low-flow states, mitogenic and fibrogenic growth factors, such as platelet-derived growth factor and transforming growth factor, are preferably produced, which probably mediates inward remodeling by increasing smooth muscle cell proliferation and the deposition and cross-linking of collagen, whereas MMP induction helps to reorganize vessel structure (74,75). The effect of stretch on remodeling is less clear. Many of the earlier mentioned mediators are not only shear sensitive but also stretch responsive, so that a significant interaction between stretch and shear signals can be assumed (76). Most of the energy of pulsatile pressure is absorbed by elastin, whose production is highly stretch responsive. This makes it quite probable that an alteration in elastin production may be important in remodeling, as vessel elasticity is the chief determinant of resting vessel size (77). How these molecular and cellular events are spatially coordinated to result in morphological change remains unclear. Possibly certain transmembrane proteins, such as the highly shear- and stretch-sensitive connexins that have a rapid turnover, may play a role (78). Theoretically, endothelial dysfunction and increasing plaque depth may prevent remodeling in response to hemodynamic stimuli, because under such conditions effectors of remodeling must penetrate into atherosclerotic lesions. Furthermore, in focal lesions, the acceleration of flow both on the proximal and on the distal side of a protruding plaque is associated with a translesional deterioration in remodeling (79). At the same time, this leads to greater inflammatory infiltrate and less cellularity and collagen in the upstream side (80) and increased stenosis downstream (81), indicative of persistent shear sensitivity. Inflammation, Scarring, and Remodeling Several mechanisms contribute to the dynamic processes, finally leading to the atherosclerotic burden. First, inflammatory cells, by producing MMPs, play a major role in atherosclerotic remodeling. Cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM), have the ability to recruit monocytes and macrophages, which is a shear-sensitive process (82), partly explaining the predominance of this cell type on the upstream side of focal lesions (80). Secondly, the expression of MMPs by atherosclerotic lesions can be further promoted by an increasing infiltration of inflammatory cells due to hyperlipidemia. The reduction of MMP expression in plaques, mainly originating from macrophage-foam cells, is a possible mechanism of action of lipid lowering and reduction in lipid oxidation (83,84). This may explain the apparent stimulatory effect of hypercholesterolemia on outward remodeling response (85) that is reflected in ultrastructural changes in the internal elastic lamina (86) very similar to those induced by highblood flow (87). Both processes are MMP-dependent and can therefore lead to outward modeling. The same local MMP activity provoked by hypercholesterolemia may explain why some eccentric plaques appear to initiate remodeling in the vessel wall directly beneath the plaque (88) and why medial thinning underlying a plaque is directly proportional to plaque burden (89). Outward remodeling may be prevented by excessive collagen deposition

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within a lesion. Under certain clinical conditions, such as after angioplasty (90) and plaque rupture, sudden or focal fibrotic responses are induced, and scar contracture may result in inward remodeling. Clinical Observations Regarding the Mechanisms of Atherosclerotic Remodeling Although research on plaque formation has identified many factors that promote plaque growth, much less is known about possible determinants of remodeling. Some of the variation in remodeling response depends on the vascular bed involved, so that compensatory remodeling is often present in the carotid and coronary vessels, whereas ileofemoral arteries are prone to inadequate outward and/or inward remodeling. In contrast, this process is uncommon in the renal arteries (91). These regional differences possibly reflect differences in endothelial responses to altered hemodynamics (92) or variations in the underlying vessel composition, such as elastic versus muscular (93). Other factors seem to influence remodeling patterns, such as systemic conditions (e.g., insulin-dependent versus noninsulin-dependent diabetes) (94) and the presence of such risk factors as smoking, and make inadequate outward and inward remodeling more frequent, in contrast to hypercholesterolemia (90). Despite these factors, there is often marked variability in remodeling response along the same artery (95,96). Some lesion specificity in remodeling response can be attributed to altered local hemodynamics, such as in the inner curves of tortuous vessel segments, where low shear predisposes to atheroma (97) and may similarly impair outward remodeling (98). This may be particularly important in the carotid bifurcation, where outward remodeling is less frequent proximal to the bifurcation (99). Remodeling and Plaque Rupture Plaque rupture causes unstable angina, myocardial infarction, and sudden death from coronary artery disease (100). Most coronary lesions responsible for myocardial infarction were minimally occlusive prior to rupture, as was shown by several angiographic studies. This is consistent with the fact that many patients had no prior history of coronary ischemia (100). Postmortem studies showed that patients who died with plaque rupture without prior history of coronary disease had large lesions (101), suggesting that due to considerable outward remodeling, angiography would have failed to display stenosis despite significant histological stenosis. This is in keeping with several recent studies showing an association between outward remodeling and plaque rupture in the coronary circulation. Earlier findings suggest that the remodeling response correlates with mechanical characteristics and the clinical presentation of the patient with the plaque. Calcified plaques are associated with inadequate outward and/or inward remodeling in patients presenting for angioplasty (96), whereas soft plaques show better compensatory enlargement (102). Lesions responsible for unstable coronary syndromes are usually composed of larger, softer plaques with more outward remodeling, when compared with those patients who have stable angina and whose lesions are more fibrous and calcified (103,104,126). The interaction of remodeling and plaque rupture can be understood through involvement of MMPs and apoptosis in both processes. However, it remains uncertain whether this interaction is causal or due to common mechanisms. In the case of a causal relationship, longitudinal rates of remodeling might be able to predict acute events. In contrast, if MMP inhibitors are used to prevent plaque rupture, this may be at the expense of increasing luminal compromise and need for revascularization. If outward remodeling resulted in

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plaque rupture, it would be interesting to know whether subsequent fibrous healing culminates in inward remodeling. Because inflammatory responses are important in the association between outward remodeling and plaque rupture, anti-inflammatory and lipid-lowering agents might be useful because of their action to decrease outward remodeling responses. This may be a possible explanation for a relatively small regression in angiographic lumen stenosis, compared with the reduction in clinical events in lipidlowering trials (79). Remodeling and Stroke-Specific Aspects Although the sequence of progressive fixed stenosis and resulting ischemia is very common in coronary and peripheral arterial disease, this does not necessarily hold true in the cerebral circulation due to the availability of collateral circulation through the circle of Willis. Nevertheless, carotid and vertebral artery thrombosis, with artery-toartery embolism to intracranial arteries, is the major cause of brain infarction. Hence, the relationship between plaque rupture and remodeling is of great importance in the extra- and intracranial cerebral arteries. As plaque characteristics and local remodeling responses are extraordinarily accessible in the carotid circulation, there is great potential to quantitate the risk of plaque rupture both systemically (106) and locally (107) and to use statin therapy (108), anti-inflammatory drugs (60), and metalloproteinase inhibitors (109) more selectively to prevent plaque rupture. Remodeling in the cerebral circulation may be promoted or attenuated by several local factors. As previously shown in bifurcations within the coronary circulation (110), remodeling in the region of the carotid bifurcation is reduced, leading to more severe luminal narrowing in the internal carotid artery following each increment in plaque mass (111). In addition, the finding that blood flow in the patent carotid artery increases as a compensatory response to contralateral occlusion is of clinical relevance as this leads to greater local stimulation of the cascade of remodeling (79), inflammatory cell infiltration (89), and plaque rupture.

PLAQUE DEVELOPMENT: THE FINAL STAGE Although ultrasound technology has continued to improve, diagnosis and vessel wall characterization of severe degrees of carotid artery stenoses are limited. According to NASCET and European Carotid Surgery Trial (ECST), the distal and local degree of stenosis can be evaluated by dye-contrast angiography, but this technique often underestimates or overestimates the hemodynamic situation. Combined ultrasound imaging and hemodynamic Doppler studies are more able to show the actual degree of obstructions and should preferentially be used for therapeutic decisions (27) (Fig. 4). In patients with complex calcified plaques, a very high-grade stenosis may be mistaken for a complete occlusion. To overcome this limitation, ultrasound contrast agents have been developed to clarify arterial patency in cases not sufficiently characterized by conventional means (112). Such contrast agents were introduced during the early 1990s (112) and are widely used in studies of peripheral vessels (113 –115). They consist of microbubbles filled with air or gases that, depending on their size, are either filtered in the pulmonary capillary territories—making them ideal to prove right-to-left shunting, for example, through a patent foramen ovale—or survive the passage through the pulmonary capillary bed to enhance the signal-to-noise ratio during arterial ultrasound studies. Ultrasound reflectors (i.e., blood cells) in conventional Doppler/duplex scanning do not have ideal reflection

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Figure 4 High-grade (.80%) carotid stenosis in cross-section (left side; A and B) and longitudinal view (right side; C and D) in B-mode (upper row; A and C) and mode (lower row; B and D). Cross-sectional B-mode display (upper left) shows an eccentric plaque with a hyperechogenic fibrous cap and hypoechogenic core of the plaque. Longitudinal mode (lower right) shows areas aliasing as a proxy for highly increased flow velocities.

characteristics. This is the main reason for the limited capability of conventional ultrasound in differentiating (carotid artery) occlusion from high-grade stenosis, because under these circumstances, volume flow is maximally reduced, leading to a critical decrease in ultrasound reflectors. Addition of contrast agents improves ultrasound reflections and decreases the rare of false-negative results in showing high-grade stenosis. Contrast agents, after intravenous injection, usually increase the Doppler signal by up to 30 dB, and, depending on the concentration of the contrast agent and on the type of administration (perfusion vs. bolus), the enhancement usually occurs 30 –60 seconds after injection, with optimal contrast lasting 3 –6 minutes (116,117). Using ultrasound contrast agents in small groups of patients, controversial results have been reported as to the usefulness of these agents in the differentiation of carotid occlusion from subtotal stenosis (118,119). A multicenter comparative study using SH U 508 A (Levovistw) evaluated carotid artery stenosis by color and spectral Doppler sonography in patients who showed insufficient signal intensity by means of conventional ultrasonography, and the study showed that the contrast significantly improved diagnostic accuracy (120). Contrast was useful in a small but important number of patients (7/71). In these patients, grading of the severity of stenosis achieved by means of ultrasound without and after administration of echocontrast media was consistent with the angiographic classifications. Correlations between baseline ultrasound scans, contrast-enhanced ultrasound scans, and angiography showed no general improvement of ultrasound accuracy following contrast enhancement. Although visualization of pseudo-occlusion remained insufficient even after contrast enhancement in three out of 71 cases, this has no bearing on treatment, as these patients do not benefit from surgery.

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Originally, the underlying idea of the study to improve diagnostic accuracy was driven by the wish not to miss potential surgical candidates. The classical concept of an increasing stroke risk with increasing degree of stenosis (121,122) has been recently challenged. Stroke risk actually decreases considerably in patients whose severely stenosed ICA becomes totally occluded (123,124). In angiographic studies, the lumen of the poststenotic ICA is often collapsed or significantly reduced over a long distance (123,124). In the ECST, conservatively treated patients with an ICA/common carotid artery vessel diameter ratio of 0.4 had a significantly lower 5-year stroke risk for ipsilateral stroke (8 vs. 25%) compared with patients without poststenotic lumen narrowing (124). Similar results occurred in subgroups in the NASCET trial (123). Finally, endarterectomy of a very high-grade carotid artery stenosis that became symptomatic when the artery became completely occluded is a relatively high-risk procedure, which must be performed shortly after symptom onset. Results of such high-risk procedures are too heterogeneous to reliably predict benefit, risk, and outcome (125,126). For these reasons, the therapeutic relevance of contrast application to improve ultrasound quality in the evaluation of high-grade arterial stenosis is limited to rare and very well-defined cases, where the poststenotic lumen is not narrowed and conventional ultrasonographic measures are insufficient to definitely differentiate high-grade stenosis from occlusion. REFERENCES 1. de Bray JM, Glatt B. Quantification of atheromatous stenosis in the extracranial internal carotid artery. Cedrebrovasc Dis 1995; 5:414– 426. 2. de Bray JM, Baud JM, Dauzat M. Consensus concerning the morphology and the risk of carotid plaques. Cerebrovasc Dis 1997; 7:289– 296. 3. Consensus Committee of the Ninth international cerebral hemodynamic Symposium. Basic identification criteria of Doppler microembolic signals. TCD microemboli consensus. Stroke 1995; 26:1123. 4. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986; 74:1399– 1406. 5. Wong M, Edelstein J, Wollman J, Bond MG. Ultrasonic-pathological comparison of the human arterial wall. Verification of intima-media thickness. Arterioscler Thromb 1993; 13:482 –486. 6. Riley WA, Barnes RW, Applegate WB, Dempsey R, Hartwell T, Davis VG, Bond MG, Furberg CD. Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis. The Asymptomatic Carotid Artery Plaque Study. Stroke 1992; 23:1062– 1068. 7. Gamble G, Beaumont B, Smith H, Zorn J, Sanders G, Merrilees M, MacMahon S, Sharpe N. B-mode ultrasound images of the carotid artery wall: correlation of ultrasound with histological measurements. Atherosclerosis 1993; 102:163– 173. 8. Nolsoe CP, Engel U, Karstrup S, Torp-Pedersen S, Garre K, Holm HH. The aortic wall: an in vitro study of the double-line pattern in high-resolution US. Radiology 1990; 175:387– 390. 9. Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. A new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis 1988; 70:253– 261. 10. O’Leary DH, Polak JF, Kronmal RA, Savage PJ, Borhani NO, Kittner SJ, Tracy R, Gardin JM, Price TR, Furberg CD. Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke 1996; 27: 224– 231. 11. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: The Rotterdam Study. Circulation 1997; 96:1432 – 1437.

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96. Mintz GS, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses. An intravascular ultrasound study. Circulation 1997; 95:1791 – 1798. 97. Wensing PJ, Meiss L, Mali WP, Hillen B. Early atherosclerotic lesions spiraling through the femoral artery. Arterioscler Thromb Vasc Biol 1998; 18:1554 – 1558. 98. Krams R, Wentzel JJ, Oomen JA, Schuurbiers JC, Andhyiswara I, Kloet J, Post M, de Smet B, Borst C, Slager CJ, Serruys PW. Shear stress in atherosclerosis, and vascular remodelling. Semin Interv Cardiol 1998; 3:39– 44. 99. Bonithon-Kopp C, Touboul PJ, Berr C, Magne C, Ducimetiere P. Factors of carotid arterial enlargement in a population aged 59 to 71 years: The EVA study. Stroke 1996; 27:654 – 660. 100. Fuster V, Badimon J, Chesebro JH, Fallon JT. Plaque rupture, thrombosis, and therapeutic implications. Haemostasis 1996; 26(suppl 4):269– 284. 101. Qiao JH, Fishbein MC. The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis. J Am Coll Cardiol 1991; 17:1138 – 1142. 102. Kearney P, Erbel R, Rupprecht HJ, Ge J, Koch L, Voigtlander T, Stahr P, Gorge G, Meyer J. Differences in the morphology of unstable and stable coronary lesions and their impact on the mechanisms of angioplasty. An in vivo study with intravascular ultrasound. Eur Heart J 1996; 17:721 – 730. 103. Smits PC, Pasterkamp G, de Jaegere PP, de Feyter PJ, Borst C. Angioscopic complex lesions are predominantly compensatory enlarged: an angioscopy and intracoronary ultrasound study. Cardiovasc Res 1999; 41:458– 464. 104. Filardo SD, Schwarzacher SP, Lo ST, Herity NA, Lee DP, Huegel H, Mullen WL, Fitzgerald PJ, Ward MR, Yeung AC. Acute myocardial infarction and vascular remodeling. Am J Cardiol 2000; 85:760 – 762. 105. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979. 106. Casscells W, Hathorn B, David M, Krabach T, Vaughn WK, McAllister HA, Bearman G, Willerson JT. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996; 347:1447 – 1451. 107. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Maker GC, Braunwald E. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998; 98:839– 844. 108. de Smet BJ, de Kleijn D, Hanemaaijer R, Verheijen JH, Robertus L, van Der Helm YJ, Borst C, Post MJ. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig. Circulation 2000; 101: 2962– 2967. 109. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 2000; 101:598 –603. 110. Crouse JR, Goldbourt U, Evans G, Pinsky J, Sharrett AR, Sorlie P, Riley W, Heiss G. Arterial enlargement in the atherosclerosis risk in communities (ARIC) cohort. In vivo quantification of carotid arterial enlargement. The ARIC Investigators. Stroke 1994; 25:1354 – 1359. 111. Ringelstein EB. Echocontrast agents in neurovascular ultrasound. Eur Heart J Suppl 2002; 4(suppl C):C48 – C50. 112. Frush DP, Babcock DS, White KS, Barr LL. Quantification of intravenous contrast-enhanced Doppler power spectrum in the rabbit carotid artery. Ultrasound Med Biol 1995; 21:41– 47. 113. Gebel M, Caselitz M, Bowen-Davies PE, Weber S. A multicenter, prospective, open label, randomized, controlled phase IIIb study of SH U 508 a (Levovist) for Doppler signal enhancement in the portal vascular system. Ultraschall Med 1998; 19:148– 156. 114. Melany ML, Grant EG. Clinical experience with sonographic contrast agents. Semin Ultrasound CT MR 1997; 18:3 –12. 115. Schwarz KQ, Becher H, Schimpfky C, Vorwerk D, Bogdahn U, Schlief R. Doppler enhancement with SH U 508A in multiple vascular regions. Radiology 1994; 193:195– 201.

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PART IV:

PATHOPHYSIOLOGY

13 Vascular Hemostasis and Brain Embolism Gregory J. del Zoppo Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, U.S.A.

Little is known about the characteristics of the hemostatic system responses to injury in the central nervous system (CNS); however, hemostatic responses in the brain have been posited to differ significantly from other vascular beds. Differences relate, at least in part, to the uniqueness of the brain and spinal cord in terms of tissue architecture, cellular composition, and function (1). The microvascular beds of the CNS are unique. Brain capillaries are ternary vascular complexes consisting of an endothelial cell lining that is separated from the astrocyte end-feet, which are also components of capillaries, by the basal lamina or extracellular matrix (ECM). Astrocytes communicate with and support neurons that are subserved by the microvasculature. Arterioles have a myointimal layer that can regulate blood flow. Pericytes are located around or are embedded in the myointimal layer and are near the matrix (2,3). The two permeability barriers of the microvasculature are represented by the interendothelial tight junctions (blood – brain barrier) and the subtending ECM/basal lamina. Both barriers derive from the interaction of the endothelial cells and astrocytes during development and require these cells for their integrity (4 –8). The basal lamina consists of laminins, collagen type IV, fibronectin, heparan sulfate proteoglycans, nidogen, entactin, and other glycoproteins (GPs). These cellular and matrix relations are important for CNS vascular function, although their relation to hemostasis is not well understood. There is considerable functional differentiation of endothelial cells along the microvascular axis from arterioles to venules (9,10). The continuous interaction of the vascular endothelium with coagulation factors, components of the plasminogen activator (PA) system, platelets, and leukocytes together maintain the hemostatic system. In cerebral gray matter, the potent procoagulant tissue factor (TF) is found around microvessels .7.5 mm in diameter but not around capillaries (11). Disturbances of these antithrombotic features of the microvasculature occur during focal cerebral ischemia (ischemic stroke). In the CNS, alterations in hemostasis are manifest as thrombosis or hemorrhage and produce lasting injury to the extravascular tissue that the brain has limited capacity to repair. This chapter explores knowledge about the interaction of cerebrovascular hemostasis with the surrounding tissue and its responses following thromboembolism.

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THROMBOSIS AND THE PATHOPHYSIOLOGY OF BRAIN ISCHEMIA Thromboembolism from proximal arterial atherosclerotic lesions and cardiac sources are responsible for 56 –80% of ischemic strokes (12). The impact of thrombi depends on the size and the location of the arterial segment involved. Thrombus formation involves the interaction of platelets with activated endothelium and with fibrin generated from circulating fibrinogen via the extrinsic pathway. Platelet adhesion requires the interactions of subendothelial matrix proteins (e.g., collagen type IV); von Willebrand factor (vWF); the platelet GPs Ia, Ib, Ib/IIa, and Ib/V/IX; and platelet integrins a2b1 and allbb3. Exposure of ECM collagen in the basal lamina to flowing plasma initiates platelet adhesion via the platelet integrin a2b1. vWF sent to the surface of activated endothelial cell from storage granules arrests platelet transit at the site of vascular injury via interaction with the platelet GPIb/V/IX receptor. Following adhesion, release of dense granule adenosine diphosphate (ADP) from activated platelets and traces of thrombin initiate platelet aggregation. Exposure of the fibrinogen receptor, integrin allbb3 (GPIIb/IIIa), on activated platelets generates the platelet aggregates by selective binding to fibrinogen in a flowdependent manner. Subsequently, platelets release a group of pro-aggregatory substances from a granules, including b-thromboglobulin (b-TG), vWF, thrombospondin, fibrinogen, and PDGF, and from d granules [ADP, adenosine triphosphate (ATP), and serotonin] that stimulate further aggregation of platelets. Ex vivo flow studies corroborate that the mechanisms of platelet adhesion depend on the shear forces within the blood vessel. Thrombin is the central effector in thrombus formation, as it links platelet activation with fibrin formation from fibrinogen (Figs. 1 and 2). Thrombin is a serine protease that is enzymatically cleaved from prothrombin by the prothrombinase complex (factors Va and Xa, phospholipid, and Ca2) (13). Two different activation pathways lead to the formation of this complex (Fig. 1). In the extrinsic pathway, the initiating step is the exposure of subendothelial TF to plasma. TF is a 46 kDa membrane-bound lipoprotein that forms a complex with factor VIIa; the TF:VIIa complex then converts factor X to factor Xa. The intrinsic pathway is initiated by high-molecular-weight kininogen (HMWK) and prekallikrein, which promote factor XII activation. Factor IXa leads to the activation of factor VIII. Factor IXa, together with platelet phospholipid, Ca2þ, and factor VIIIa (the “tenase complex”), activates factor X to Xa. The platelet surface, which has specific receptors for factors V and VIII, provides the phospholipid workbench for the activation of coagulation. This series of serine protease activators ultimately lead to the cleavage of prothrombin (factor II) to stoichiometrically produce thrombin and its propeptide prothrombin fragment (PF) 1.2. Thrombin cleaves soluble fibrinogen, yielding a characteristic sequence of fibrin monomers. Factor XIIIa stabilizes the fibrin network by forming inter-fibrin linkages and insoluble, cross-linked fibrin polymers. The activation of factor XIII is itself thrombin dependent. In addition, thrombin promotes the generation of factors Va and VIIIa on the platelet surface, thereby enhancing its own production in a positive feedback loop. Moreover, thrombin is among the strongest physiological stimulators of platelet aggregation. Thrombin also interacts with specific receptors on cells in the CNS, including PARs 1 –4. In vitro studies suggest that thrombin can augment neuron toxicity (14,15). Hence, the perivascular distribution of protease nexin-1 (PN-1) in the CNS may limit the toxic effects of small amounts of thrombin generated in the plasma from microvessels, which might leak into the brain parenchyma (14 – 16). Intact endothelial cells prevent excess thrombin production related to three mechanisms: TF pathway inhibitor (TFPI), thrombomodulin, and antithrombin III (AT III). TFPI

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coagulation system activation intrinsic HMWK XI XII XIIa XIa

extrinsic HMWK prekal

TF + VII

kallikrein

vessel

TF:VIIa IX X VIIIa:IXa PL Ca+2

Xa:V:II PL Ca+2

platelet

thrombin (IIa) fibrinogen

fibrin

Figure 1 Activation of the intrinsic and extrinsic coagulation pathways. The intrinsic pathway relies upon the presence of high molecular weight kininogen (HMWK) and the activation of factors XI and XII. HMWK is associated with intact blood vessel wall integrity. The extrinsic pathway is initiated when perivascular tissue factor (TF) is exposed to the circulating coagulation factors. TF and factor VIIa interact to make the potent TF:VIIa complex. Both systems promote the activation of factors IX, VIII, V, and X on the surface of platelets, which have specific membrane receptors for factors V and VIII. The platelet provides a scaffold for formation of the “tenase complex” and the “prothrombinase complex,” which require the presence of phospholipid (PL) and Caþ2. Activation of the coagulation factors which participate in these complexes activate prothrombin (II) to thrombin. Thrombin cleaves fibrinogen to fibrin and specific fragments, and also causes feedback activation of several factors (dashed lines).

is expressed and released into the plasma by endothelial cells and circulates either bound to lipoproteins or as a quaternary complex with factor Xa and the TF:VIIa complex. Heparin enhances the release of TFPI. Thrombomodulin is an endothelial GP receptor that binds thrombin with high affinity; the thrombomodulin:thrombin complex promotes protein C activation. Together with protein S, activated protein C (APC) exerts an anti-thrombotic effect by neutralizing factors Va and VIIIa and PA inhibitor-1 (PAI-1). AT III and heparin cofactor II (HC II) are circulating proteins that act as antithrombotic substances. HC II is a specific inhibitor of thrombin, whereas AT III also interacts with factors IXa, Xa, XIa, and XIIa. The binding of heparin with AT III accelerates the inhibitory action of AT III and is partly responsible for the anti-coagulant effects of heparin. Growth of the platelet thrombus is limited at the site of the injured endothelium by release of the antiaggregatory substances PGI2, adenosine, and NO from intact endothelial cells. The presence of glycosaminoglycans on the cellular membrane also confers antithrombotic properties to the endothelium. These are potent modulators of platelet aggregation and thrombus growth.

CEREBROVASCULAR THROMBOSIS Along the vascular axis, alterations in hemostasis are manifest differently. Thrombosis in the CNS is clinically evident when large arteries or veins (.1 mm diameter) are involved

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prothrombin

thrombin platelets

PAR activation GP Ibα, GP V binding

fibrinogen

cleavage to fibrin (+ fibrinopeptides)

thrombolysis

cleavage of scu-PA cleavage of TAFI

endothelium

leukocyte adhesion receptors permeability protein C activation NO release angiogenesis ( VEGF-R1, R2)

smooth muscle cells

Ca2+ release, relaxation

cell homeostasis

toxicity

Figure 2 The general effects of the protease thrombin on vascular hemostasis. Platelet activation can be mediated by the interaction of thrombin with its receptors (PARs) and by binding to components of the glycoprotein (GP) Ib-V – IX complex. Thrombin cleaves circulating fibrinogen to fibrin and other degradation peptides (e.g., fibrinopeptides A and B). In addition, it can cleave single-chain urokinase (scu-PA) and also the thrombin activable fibrinolysis inhibitor (TAFI). Endothelial cells are also activated by thrombin. Leukocyte adhesion receptors are presented in response to thrombin exposure. Thrombin stimulates NO release, increases angiogenesis receptor expression, and, in conjunction with thrombomodulin, mediates protein C activation. Thrombin can stimulate vascular smooth muscle Caþ2 release and relaxation. However, thrombin has adverse effects on a number of cell types, including altering permeability (of endothelial cells) and direct toxic effects (e.g., neurons). Not to be forgotten is the important upregulatory role in thrombosis played by a-thrombin, in which it stimulates tissue factor Vlla formation. Thrombin also has many other important effects (via the various PARs), which makes it a protein mediator of many biological processes. Abbreviations: PAR, protease activable receptor; GP, glycoprotein; scu-PA, single chain urokinase plasminogen activator; TAFI, thrombin activable fibrinolysis inhibitor; VEGF, vascular endothelial growth factor.

(17). Among the artery-associated processes that alter the hemostatic balance toward thrombus formation, atherosclerosis is the most prevalent prothrombotic condition. The common carotid artery bifurcation and the proximal internal carotid artery (ICA) are common predilection sites affected in 50– 80% of ischemic stroke patients, followed in frequency by the origin of the vertebral artery, and the proximal subclavian arteries and individual intracranial arteries. Thrombosis of the cerebral veins and dural sinuses are less common causes of stroke. Coagulation activation contributes to cerebral venous thrombosis, reflecting the low-shear forces associated with venous flow and possible venular injury (e.g., inflammation or infection). Malignancy, inherited deficiencies of endogenous anticoagulants (i.e., AT III, protein C, and protein S), acquired anti-phospholipid antibody (APLA) syndrome, severe dehydration, and specific drug effects (e.g., oral contraceptives) suggest the importance of a procoagulant etiology (18 – 20). Hereditary or acquired disorders of hemostasis predispose to thrombosis more often in the cerebral venous circulation than in brain-supplying arteries. These prothrombotic disorders can

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account for about 1% of ischemic strokes and are relatively more frequent in young adult stroke patients (4 – 5%). Thromboemboli arise from cardiac structures in 17–28% of patients with ischemic stroke (21–25).These emboli originate from injury to the cardiac endothelial surface or from cardiac valves injured by rheumatic fever, mechanical or xenograft valve prostheses, areas of ventricular injury and dyskinesia (associated with myocardial infarction), or other causes. Left atrial thrombi can be associated with atrial fibrillation in the absence of valvular disease. Emboli migrating from the left ventricle and capable of occluding the middle cerebral artery (MCA:O) may be quite small, even submillimeter in cross-section. Occlusion of small arterioles (100 –500 mm in diameter) typifies certain cerebral microangiopathies that are thought to produce an imbalance in hemostasis. The APLA syndrome and anticardiolipin (ACL) antibodies are associated with small infarctions, which result from small arterial occlusion (26).These are similar to lesions observed in patients with systemic lupus erythematosis who develop neurological abnormalities (27). The direct causes of cerebral microvascular thrombosis associated with the APLA syndrome and ACL antibodies are not clear. However, it has been suggested that some antibodies from these families can bind to the endothelial cell membrane and alter the membrane’s antithrombotic properties. They may also promote systemic embolization from central sources, including the heart. Arterial thrombosis and downstream lodgment of thromboemboli cause brain ischemia. However, the evolving ischemic lesion can also provoke thrombosis within the microvascular bed downstream from the symptomatic arterial occlusion (28). Microvascular thrombosis of limited extent may remain clinically undetectable because of the large contribution of this bed to the cerebral vascular volume. Occlusion of the MCA, with reperfusion, can generate downstream arteriolar obstruction that is nonembolic. Microvessel occlusions in the ischemic territory contain activated platelets, fibrin, and polymorphonuclear (PMN) leukocytes (29 – 32). These can contribute to the “focal no-reflow phenomenon” first described by Ames et al. (28,33). Inhibitors of the platelet – fibrin interaction and of the PMN leukocyte adherence to the endothelium can significantly decrease microvessel obstruction in the ischemic bed (32). Those observations further emphasize the importance of the interrelationship of endothelial cell activation and hemostasis in the vascular response to ischemic injury.

HEMORRHAGIC TRANSFORMATION In the CNS, the maintenance of normal hemostasis is essential for preventing even limited injury to an organ with limited regenerative capacity. Both microvascular thrombosis and hemorrhage involve local disruptions of vascular integrity. It has been assumed that endogenous thrombolytic processes prevent or greatly limit cerebral vascular thrombosis. However, the presence of such processes beyond the components observed in the systemic circulation is not firmly established (34). Experiments with selective integrin allbb3 inhibitors have shown the absolute requirement for competent platelet function to limit or prevent hemorrhage during focal brain ischemia (35,36). Two scenarios explain the development of hemorrhage in the ischemic territory. Hemorrhagic infarction consists of scattered or confluent petechiae, implying extravasation of blood from the microvasculature (37 – 41). Focal ischemia causes an immediate loss of basal lamina integrity, with deterioration of laminins-1 and -5, collagen type IV, fibronectin, and perlecan which is accompanied by the generation of pro-matrix metalloproteinase-2 (MMP-2), select cathepsins, and urokinase PA (u-PA). These active proteases may

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contribute to ECM degradation (42 –46). Hemorrhagic transformation is significantly related to loss of the major microvessel matrix proteins (47). In nonhuman primates, ischemia-related hemorrhage is also associated with pro-MMP-9 expression in the ischemic tissue (43). However, it is possible that the appearance of MMP-9 is a tissue response to the hemorrhage, rather than a cause of ECM degradation (43). Parenchymal hemorrhage consists of confluent tissue hemorrhage (or a coagulum) originating mostly within the regions of ischemia, often producing mass effect. It is commonly associated with cardiogenic emboli under the conditions of anticoagulation (48 –50). These observations, experimental work, and postmortem studies imply that parenchymal hemorrhage results from arterial rupture (51). Local arterial wall necrosis and rupture following downstream translocation or lysis of a thromboembolism have been proposed as the root cause (37). Both petechial and parenchymal hemorrhage can occur in the absence of antithrombotic agents in the setting of focal ischemia, indicating that alterations in hemostasis are not required for hemorrhagic transformation. Nonetheless, all antithrombotic agents carry a risk of increasing the frequency of parenchymal hemorrhage. The risk increases from no intervention to antiplatelet agents, anticoagulants, and PAs monitonically. Two hypotheses are that severe hemorrhage observed with (i) anticoagulants may reflect inhibition of fibrin-thrombus formation superimposed on arterial rupture and (ii) PAs may reflect continuous plasmin-mediated fibrin (thrombus) degradation in the face of arterial rupture and TF-mediated fibrin generation. The combination of excessive anticoagulation and thrombolysis may produce excessive hemorrhagic risk in ischemic stroke (e.g., in the PROACT study) (52). The hemorrhagic risk associated with PAs depends on patient age, hypertension, and the presence of early signs of ischemic injury on baseline CT scan (53 –55). The incidence of hemorrhagic transformation depends on the time from ischemic onset to exposure to PA (53). This observation and those of Ueda et al. (56) suggest that the duration of ischemic injury and the depth of blood-flow reduction are necessary for detectable hemorrhage to develop. This concept of the development of hemorrhagic transformation is consistent with the causative factor being significant alterations in vascular integrity rather than changes in hemostasis alone.

STROKE AND CONSUMPTIVE COAGULOPATHY The content of TF in the brain, much greater in gray matter than in white matter, is the basis for the observation that closed-head injury can produce detectable consumptive coagulopathy (11). Mortality from impact injury is directly related to the degree and severity of the coagulopathy (57). A similar hypothesis has been proposed for atherothrombotic and embolic stroke (20). However, two sets of observations indicate that the situation following ischemic stroke may be more interesting. At the levels of resolution of current clinical assays, clear evidence of consumptive coagulopathy has not been confirmed. However, experiments in human-relevant systems demonstrate elements of consumptive coagulopathy in occluded microvessels that contain deposits of fibrin and activated platelets (29,32,58). This indicates that the local initiation of coagulation by the ischemic insult limits consumption to the CNS. An unanswered question is whether the microvascular coagulation extends tissue injury during the evolution of ischemia. The second observation is that alterations in peripheral markers of thrombosis do appear in the setting of ischemic stroke. Evidence for consistent measurable changes in platelet function, thrombin activation, and fibrin breakdown products is found in the early days following ischemic stroke (18,59 – 61).

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PLATELET ACTIVATION Release of the platelet a-granule-specific proteins b-TG and platelet factor 4 (PF4) occurs during the second phase of aggregation. Release of a-granule contents occurs with manipulation of the vasculature, angiography, inflammatory disease, and widespread atherosclerosis. In addition, elevated levels of PF4 and b-TG have been associated with brain ischemia. For instance, plasma b-TG levels increase by the second week after stroke and return to baseline thereafter. The underlying causes for these changes are unknown and are partly obscured by the sensitivity of these levels to collection technique, patient age, and vascular risk factors.

THROMBIN GENERATION Thrombin cleaves fibrinopeptides A and B (FPA and FPB) from the NH2-terminus of the a and b chains of fibrinogen and fibrin I, respectively, thereby converting fibrinogen to monomeric fibrins I and II. Interaction of thrombin with circulating AT III forms the TAT complex. Circulating detectable PF 1.2, FPA and FPB, and TAT complex levels mark evidence of thrombin action. An increase in plasma FPA levels followed by a gradual decline to normal levels during several weeks to months occurs after the ischemic event. No differences in FPA levels were identified between strokes of atherothrombotic and cardioembolic origin (18).

FIBRIN DEGRADATION Proteolysis of soluble-fibrin monomers by plasmin provides an indication of thrombolysis. Plasmin cleaves the fragments Bb1-42 and Bb15-42 from the NH2-terminal regions of fibrins I and II. Degradation of fibrinogen, soluble-fibrin monomers, and cross-linked fibrin by plasmin yields a variety of characteristic fibrin(ogen) degradation products (FDP). The degradation products derived from fibrinogen and fibrin differ. The presence of the D-dimer antigen specifies the presence of cross-linked fibrin in the circulation and implies also the generation of thrombin. Fragments Bb1-42 and Bb15-42 and D-dimer are markers for plasminogen activation and plasmin action. In addition, tissue PA (t-PA) antigen and activity, PAI-1 antigen and activity, a2-anti-plasmin, and plasmin – anti-plasmin complexes (PAP) can be measured directly. Normal or slightly elevated indicators of plasmin activity have been noted immediately after atherothrombotic stroke and increase substantially thereafter. A similar temporal profile of plasmin action has been reported in TIA patients. These hemostatic alterations do not conclusively support the generation of a systemic consumptive coagulopathy with secondary fibrinolysis. This interpretation is confounded by the observation of activation of inflammatory cells (e.g., PMN leukocytes) both in the brain and in the peripheral blood during focal brain ischemia. The known interrelationship of inflammation to ischemia and thrombosis is reflected in the evolution of brain infarction during ischemic stroke (62). These considerations underscore the general observation that ischemic stroke is a vascular disorder with neurological consequences in which thrombosis plays multiple roles.

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ENDOGENOUS PROTECTIVE MECHANISMS The relatively low frequency of detectable cerebrovascular events during youth and their increased frequency with age suggest that during development thrombotic causes of stroke are unusual and that time brings alterations in the vascular and hemostatic system that predispose to ischemic stroke. Some inherited disorders affecting hemostasis, including hyperhomocysteinemia, are certainly important causes of stroke. However, most of the causes of focal cerebral ischemia are acquired. The observation of frequent thromboemboli from the ICA into the cerebral circulation by duplex and transcranial ultrasonography in clinically asymptomatic patients suggests (i) the presence of a large reservoir represented by the brain microvasculature that can accommodate the impact of such emboli and/or (ii) the contribution of endogenous protective mechanisms that curtail the effects of embolism. On the basis of the limited experimental and clinical data, I consider next some of the known and presumed aspects of the protective features of the cerebrovasculature in the setting of thrombotic stroke.

CEREBROVASCULAR RESERVOIR During normal blood flow, not all capillaries are perfused (63). Hypercapnia and anesthesia elicit substantial increases in local blood flow that may involve the recruitment of closed capillaries or vasodilatation of extraparenchymal arterioles (63,64). A cerebrovascular reserve must exist that can be recruited on short notice. However, direct measurements indicate that capillaries of the pial and cortical circulation have plasma flow, and there is no capillary recruitment during forebrain ischemia (65,66). Observations in humans and in nonhuman primates suggest that the low-pressure –high-flow character of portions of the brain means that not all microvascular channels are perfused and that microvascular obstruction is “managed” by reversal of flow through adjacent channels (67). This may afford a type of protection. However, the presence of a nascent microvascular bed that can be recruited in the early moments of ischemia remains uncertain.

COLLATERAL CIRCUITS The circle of Willis, anastomoses between the anterior and the MCA territories, and connections between the posterior cerebral artery and the basilar system are obvious conduits that can reverse blood flow. Vasculopathies involving these conduits—from atherosclerosis, diabetes mellitus, or other injuries—can limit flow to a focal ischemic region. This may increase stroke severity (68,69).

MICROVESSEL-ASSOCIATED PROTECTION APL and ACL syndromes promote cerebral arterial disease (26,27,70 –72). Thrombosis within brain arterioles has been reported with APLAs, ACLs, and the lupus anticoagulant. Several prothrombotic mechanisms of APL antibodies have been described, including interference with the endothelial thrombomodulin-mediated protein C activation pathway. These are conditions that apparently overwhelm the endogenous anti-thrombotic characteristics of the microvascular endothelium.

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ENDOGENOUS THROMBUS LYSIS Thrombus dissolution and embolization is a continuous process. A conundrum is how emboli from proximal ICA sources can traverse the microvascular circuit without producing evidence of ischemia, whereas other thromboemboli produce clinically evident ischemic events. Three issues are probably relevant: (i) residual neuron injury, (ii) thrombus composition, and (iii) PA function. Although embolic events may be clinically “silent,” experimental studies show evidence of irreversible injury to neurons downstream even after short periods of arterial occlusion (73). Occlusion of microvessels, even transiently, could possibly lead to permanent clinically undetectable injuries. Embolus composition is probably relevant to the dissolution during its transit. Cholesterol-containing emboli can produce arterial occlusion and large injury volumes (74). Fibrin dissolution is mediated by thrombus-bound plasmin, generated by t-PA at the thrombus surface. t-PA is cosecreted with its inhibitor PAI-1 from activated endothelium (75,76). If endogenous fibrinolysis were a major contributor to embolus transit, based on volume considerations, small thrombi should be more susceptible than large. However, the evidence for enhanced endogenous thrombus lysis in the setting of ischemia is scant (44). Within the early hours of focal ischemia, u-PA and PAI-1 are generated in the ischemic tissue (44). However, t-PA activity does not change. In fact, there is a transient decrease in plasma t-PA level because of the formation of t-PA†PAI-1 complexes (44). Given the proinflammatory nature of early ischemic stroke, it would not be surprising if thromboembolism to the brain would not promote thrombus lysis there but rather results in attempts locally to limit injury extension. One problem with this notion is that in select small animal models, extension of the regions of injury occur because of inflammation.

VASCULAR MATRIX DEGRADATION Within capillaries and microvessels up to 100 mm diameter, the endothelium is separated from the end-feet of astrocytes by the basal lamina, a form of the ECM. ECM also encompasses the cells of the neuropil, but differs in composition from the vascular ECM. Experimental work has shown that during focal brain ischemia, the activities of hemostatic proteases and those of matrix metabolism intersect (Fig. 3). Indeed, hemostasis and matrix biology are connected. In primates, MCA:O produces an increase in u-PA and its principal inhibitor PAI-1 (44). u-PA appears to originate from microvascular cells and neurons (as shown by the appearance of its principal receptor) (45). PAI-1 is generated by the vascular endothelium, where it is released into the plasma and into the tissue. In contrast, t-PA activity does not change substantially (only decreasing transiently when it is bound to PAI-1). It is known that plasmin (derived from plasminogen activated by u-PA) can degrade vascular laminin, fibronectin, and collagen (77 –79). Active degradation of neurovascular laminin can occur early following MCA:O, which appears to be related in part at least to serine proteases, including u-PA (42). Importantly, these effects appear to be local and confined to the injured tissue. One consequence could be hemorrhagic transformation (47). However, other activities for these endogenous PAs may exist, including cell –cell signaling (80). Recently, it has been shown that certain MMPs, select cathepsins, and perhaps u-PA are responsible for the degradation of components of the vascular ECM within the early hours after MCA occlusion in the primate (46). Pro-MMP-2 is activated by membranetype (MT)-1 and MT-3 MMP, whereas pro-MMP-9 is activated by u-PA via plasmin. All components are generated within the ischemic core immediately after MCA occlusion

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matrix proteases pro-MMP-2

pro-MMP-9 plasminogen

MT1-MMP MT2-MMP MT3-MMP

u-PA t-PA

plasmin

MMP-9

MMP-2 laminins collagen IV fibronectin aggrecan elastin vitronectin

MMP-1 MMP-2 MMP-3 MMP-7 plasmin protease

laminins collagen IV fibronectin MBP

collagen IV fibronectin aggrecan elastin vitronectin

Figure 3 Relationships of plasminogen and select matrix metalloproteinases (MMPs). Activation of plasminogen to plasmin can facilitate activation of pro-MMP-2 and pro-MMP-9. Active MMP-2 and MMP-9 (underlined ) can be generated through a number of possible pathways. It should be noted that this scheme assumes that activation of the elements occurs at the cell surface. Some cell types in vivo may not support such activation. Activation of plasminogen is mediated by tissue plasminogen activator (t-PA) or urokinase (u-PA). During focal cerebral ischemia, u-PA is increased, but t-PA does not change in the ischemic core. t-PA is bound to its inhibitor in the circulation. The inactive precursor pro-MMP-2 is activated by cell surface– exposed membrane type (MT)-MMPs. MT1-MMP can indirectly activate pro-MMP-2 in conjunction with plasmin. Inactive pro-MMP-9 can be activated by specific active MMPs, plasmin, or specific serine proteases (e.g., chymotrypsin). Note that the matrix ligand specificity of the active matrix proteases differs. Plasmin can degrade laminins, type IV collagen, fibronectin, and myelin basic protein. MMP-9 does not degrade laminins, whereas MMP-2 does. The cell specificity of these iterations in the central nervous system is not resolved. Abbreviations: MBP, myelin basic protein; MMP, metalloproteinase; MT, membrane type.

(45). More intriguing is the appearance of protease activity that can degrade heparan sulfate proteoglycans within the vascular and extravascular matrix (46). These hygroscopic GPs connect the two matrix compartments, serve as a reservoir for growth factors, inactive MMPs, and other proteins, interact with heparins, and harbor water. With the breakdown of the capillary permeability barrier, the transudated water accumulates in the extracellular space, most probably in association with these hygroscopic proteoglycans.

MODULATION OF THROMBIN ACTIVITY With degradation of the two permeability barriers—the vascular matrix and the blood – brain barrier—activated hemostatic factors pour into the intercellular space of the neuropil. Among these, the impact of thrombin is so far the best characterized. Experimental studies have suggested that high concentrations of thrombin are neurotoxic in vitro

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(81,82). PN-1, a 43 kDa protease inhibitor, is localized around brain –blood vessels and is a tissue inhibitor of thrombin (u-PA and plasmin) (14 – 16). In the brain, PN-1 is secreted mainly by astrocytes. PN-1 is identical to the glia-derived neurite-promoting factor or gliaderived nexin. Its localization and specificity imply that PN-1 is a potent inhibitor that could protect the neuropil from extravasated thrombin. Given the large local concentrations of thrombin likely generated during TF exposure to the plasma in the impaired microvasculature during focal ischemia, the protective function of PN-1 may be overwhelmed. This speculation awaits formal proof. However, thrombin can also increase vascular permeability (e.g., pulmonary edema) (83), and its effects locally are likely to be nefarious.

MICROVESSEL INTEGRITY, HEMOSTASIS, AND SELECTIVE NEURON VULNERABILITY The relationship between arterial thrombosis and neuron injury is fundamental for conceptualizing the brain responses to ischemia and for understanding a number of treatment approaches. However, little is known about the impact of altered hemostasis within microvessels on proximate neurons. A causal relationship of neuron injury to microvessel obstruction has not been tested. Three considerations are relevant to the persistence of neuron injury following transient occlusion of the arterial supply. First, the distance from the neuron to the nearest neighboring microvessel may only be one contributor to neuron injury. Vogt and Vogt (84) and subsequently Pulsinelli (85) advanced the concept of selective neuronal vulnerability. Most often, neuron “vulnerability” has been assessed days, rather than hours, after the ischemic insult. Delayed-neuron vulnerability has been attributed to neuron subtype, differential glutamate sensitivity, ion-channel density, altered intrinsic excitability, and other attributes (85 –87). The events contributing to such vulnerability in the early moments after arterial occlusion are unknown. Siesjo et al. (88) showed that transient MCA occlusion lasting 30 minutes followed by extended reperfusion was associated with evidence of modest injury. This indicates that short periods of significantly reduced blood flow produce sustained and localized neuron injury. Local conditions that cause neuron injury are not yet explored. Very early following MCA occlusion, changes in the cell – matrix interactions of the astrocytes and endothelial cells are seen at the same time and only in the regions of neuron injury (89,90). Those observations suggest that in the regions of ischemic injury, microvessel events, and neuron injury are correlated. The roles of altered hemostasis in the relation of altered microvascular integrity to neuron viability are now being explored.

SUMMARY The CNS probably displays unique hemostatic characteristics when compared with other vascular beds. Local specialization of the endothelium with functional differences along brain’s arterial to venous axis is known to exist. Thromboembolism unleashes alterations in the hemostatic system both locally and systemically. These events are circular. The activation of coagulation and platelets (i.e., thrombin formation) that cause the signal thrombus, through ischemia of the downstream bed, initiates microvascular occlusions consisting of fibrin, activated platelets, and PMN leukocytes. Whether these local events cause unremediable neuron injury is uncertain, although the notion is attractive. Within the ischemic tissue (and microvasculature), u-PA, its receptor, and activated

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matrix proteases appear simultaneously with alterations in the appearance of vascular inflammatory cell receptors, vascular matrix degradation, and neuron injury. Matrix degradation and hemorrhage are linked, the latter augmented by antithrombotics. The effects of thromboembolism in the CNS underscore the close interrelationship of thrombosis (hemorrhage), ischemia, and inflammation.

ACKNOWLEDGMENTS This work was supported in part by grants NS 26945 and NS 38710 of the National Institutes of Neurological Disorders and Stroke. I thank Jason Kay for his expert assistance in preparing this chapter.

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61. Feinberg WM, Pearce LA, Hart RG, Cushman M, Cornell ES, Lip GY, et al. Markers of thrombin and platelet activity in patients with atrial fibrillation: Correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study. Stroke 1999; 30:2547 – 2553. 62. del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is it harmful? Arch Neurol 2001; 58:669 – 672. 63. Keyeux A, Ochrymowicz-Bemelmans D, Charlier AA. Induced response to hypercapnia in the two-compartment total cerebral blood volume: Influence on brain vascular reserve and flow efficiency. J Cereb Blood Flow Metab 1995; 15:1121 – 1131. 64. Weeks JB, Todd MM, Warner DS, Katz J. The influence of halothane, isoflurane, and pentobarbital on cerebral plasma volume in hypocapnic and normocapnic rats. Anesthesiology 1990; 73:461 – 466. 65. Seylaz J, Charbonne R, Nari K, VonEuw D, Borredon J, Kacem K, et al. Dynamic in vivo measurement of erythrocyte velocity and flow in capillaries and of microvessel diameter in therate brain by confocal laser microscopy. J Cereb Blood Flow Metab 1999; 19:863 –870. 66. Pinard E, Engrand N, Seylaz J. Dynamic cerebral microcirculatory changes in transient forebrain ischemia in rats: involvement of type I nitric oxide synthase. J Cereb Blood Flow Metab 2000; 20:1648 –1658. 67. Zulch K-J. The Cerebral Infarct: Pathology, Pathogenesis, and Computed Tomography. Heidelberg: Springer-Verlag, 1985. 68. Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke. Challenging the concept of a rigid and universal time window. Stroke 1995; 26:2219 – 2221. 69. del Zoppo GJ, von Kummer R, Hamann GF. Ischemic damage of brain microvessels: Inherent risks for thrombolytic treatment in stroke. J Neurol Neurosurg Psychiatry 1998; 65:1– 9. 70. Feldmann E, Levine SR. Cerebrovascular disease with antiphospholipid antibodies: immune mechanisms, significance, and therapeutic options. Ann Neurol 1995; 37:S114 – S130. 71. Weksler BB. Hematologic disorders and ischemic stroke. Curr Opin Neurol 1995; 8:38 – 44. 72. Panagariya A, Garg A, Sureka RK. Antiphospholipid antibody positive young stroke: an analysis of 12 cases. J Postgrad Med 2000; 46:258 – 261. 73. del Zoppo GJ. TIAs and the pathology of cerebral ischemia. Neurology 2004; 62:S15– S19. 74. Pascual M, Baumgartner JM, Bounameaux H. Stroke secondary to multiple spontaneous cholesterol emboli. Vasa 1991; 20:74– 77. 75. Levin EG. Latent tissue plasminogen activator produced by human endothelial cells in culture: Evidence for an enzyme-inhibitor complex. Proc Natl Acad Sci USA 1983; 80:6804 – 6808. 76. Levin EG, Santell L. Association of a plasminogen activator inhibitor (PAI-1) with the growth substratum and membrane of human endothelial cells. J Cell Biol 1987; 105:2543 –2549. 77. Sappino AP, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, et al. Extracellular proteolysis in adult murine brain. J Clin Invest 1993; 92:679– 685. 78. Keski-Oja J, Lohi J, Tuuttila A, Tryggvason K, Vartio T. Proteolytic processing of the 72,000Da type IV collagenase by urokinase plasminogen activator. Exp Cell Res 1992; 202:471 – 476. 79. Mazzieri R, Masiero L, Zanetta L, Monea S, Onisto M, Garbisa S, et al. Control of type IV collagenase activity by components of the urokinase-plasmin system: A regulatory mechanism with cell-bound reactants. EMBO J 1997; 16:2319– 2332. 80. Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11 – 25. 81. Festoff BW, D’Andrea MR, Citron BA, Salcedo RM, Smirnova IV, Andrade-Gordon P. Motor neuron cell death in wobbler mutant mice follows overexpression of the G-protein-coupled, protease-activated receptor for thrombin. Mol Med 2000; 6:410– 429. 82. Donovan FM, Pike CJ, Cotman CW, Cunningham DD. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neuroscience 1997; 17:5316– 5326. 83. Malik AB, Fenton JWII. Thrombin-mediated increase in vascular endothelial permeability. Semin Thromb Hemost 1992; 18:193 –199.

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84. Vogt C, Vogt O. Erkrankungen des grosshirnrinde im lichte der topistik, pathoklise und pathoarchitektonik. J Psychol Neurol 1922; 28:1– 89. 85. Pulsinelli WA. Selective neuronal vulnerability: Morphological and molecular characteristics. Prog Brain Res 1985; 63:29 – 37. 86. Calabresi P, Centonze D, Pisani A, Bernardi G. Metabotropic glutamate receptors and cell-typespecific vulnerability in the striatum: implication for ischemia and Huntington’s disease. Exp Neurol 1999; 158:97 – 108. 87. Centonze D, Marfia GA, Pisani A, Picconi B, Giacomini P, Bernardi G, et al. Ionic mechanisms underlying differential vulnerability to ischemia in striatal neurons. Prog Neurobiol 2001; 6:687 – 696. 88. Memezawa H, Smith M-L, Siesjo¨ BK. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 1992; 23:552 –559. 89. Tagaya M, Haring H-P, Stuiver I, Wagner S, Abumiya T, Lucero J, et al. Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J Cereb Blood Flow Metab 2001; 21:835 – 846. 90. Wagner S, Tagaya M, Koziol JA, Quaranta V, del Zoppo GJ. Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin a6b4 during focal cerebral ischemia/reperfusion. Stroke 1997; 28:858– 865.

PART V:

EMBOLIC MATERIALS

14 Embolic Particles Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Embolism, by definition, refers to distant travel of particulate materials generated at a distance from their ultimate destination. Potential embolic materials can be conveniently divided into three major groups: (i) substances ordinarily residing within the body’s heart and blood vessels, (ii) substances introduced from outside of the body, such as air, bacteria, fungi, and foreign bodies, and (iii) substances within the body but not normally within the vascular system, such as fat and tumor tissue. Table 1 shows this distribution. The nature of the embolic material is important because the effect of most prophylactic treatments is specific for one substance or other. For example, heparin may effectively prevent red thrombus formation and embolization but has no effect against white thrombi, calcium particles, or bacteria. This chapter will be devoted mostly to substances outside of the vascular system, as cardiac, aortic, and arterial sources have already been discussed thoroughly in chapters 8, 9, and 10.

CARDIAC-ORIGIN SUBSTANCES Red Thrombi The most common and most well-studied material that forms in the heart and embolizes is a red clot. Red thrombi are composed mostly of red blood cells and fibrin. They tend to form in areas of slowed blood flow. Their formation does not require an abnormal vessel wall or tissue thromboplastin. Figure 1 shows a typical red thrombus. Red clots are formed by activation of circulating coagulation factors. The final step in the coagulation cascade is the conversion of the soluble protein fibrinogen into insoluble polymers called fibrin. Fibrin strands form a network of fibers that entangle the formed blood elements (platelets, erythrocytes, and leukocytes) into a clot. Fibrin is quite adhesive and is capable of contracting. The fibrinogen ! fibrin reaction occurs when Factor II, prothrombin, is converted to thrombin. The amounts of circulating fibrinogen and prothrombin are important in these reactions. Prothrombin can be activated in two different ways. In the so-called extrinsic system of coagulation, a tissue or endothelial injury releases thromboplastic substances, tissue factors that, in turn, cause both platelet activation and activation of blood serine protease 259

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Cardiac Erythrocyte-fibrin (red) thrombi Platelet-fibrin (white) thrombi Bacteria, fungi (endocarditis) Fibrin strands, bland vegetations Calcium (valves and MAC) Myxoma, other cardiac tumors

Vascular

Body

Foreign

Erythrocyte-fibrin (red) thrombi Air Air Platelet-fibrin (white) thrombi Tumor tissue Foreign bodies Cholesterol crystals Fat Atheromatous debris (plaques) Calcium

Abbreviation: MAC, mitral annulus calcification.

coagulation factors, especially Factors V, VII, and X. Activation of Factor X catalyzes the reaction of prothrombin to thrombin. Activation of platelets causes them to agglutinate, to adhere to the injured vessel wall, and to release various intracellular substances that, in turn, also activate the coagulation system. The complementary intrinsic coagulation system refers to blood-coagulation factors that circulate in inactive forms (Factors V, VIII [antihemophilic globulin], IX, X, XI, XII) and are intrinsic to the blood. Activation of Factor XII from an inert precursor form to an activated form triggers a series of reactions, described as the coagulation cascade in which the various blood-clotting factors are sequentially converted to their active enzymatic forms. Ultimately, these reactions lead to activation of Factor X, which catalyzes the prothrombin ! thrombin reaction (1,2). Thrombin, in turn, in addition to converting fibrinogen to fibrin, has an important influence on blood platelets, causing them to swell, aggregate, and release substances that affect vascular tone and blood coagulability. Also important are various natural inhibitors of coagulation: antithrombin III, protein C, and protein S. Deficiencies in any of these serum proteins can cause increased

Figure 1 Phase microscope image of a red thrombus, composed of fibrin and erythrocytes, formed in a thrombogenic system, in a vessel with a low flow rate (courtesy of S.H. Hanson and Ch. Kessler, Emory University, Division of Hematology). Source: From Ref. 120.

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coagulability. Genetically transmitted disorders, such as the presence of the Leiden factor that causes functional resistance to the anticoagulant effects of activated protein C (3,4) and mutations in the prothrombin gene (5), can also lead to hypercoagulability. There are also naturally occurring factors that act to lyse clots once they are formed. Tissue plasminogen activator and other substances activate plasminogen to form plasmin, a potent fibrinolytic enzyme. Plasminogen is also activated by various coagulation factors, such as Factor XII, so that the process of coagulation itself activates the thrombolytic system. Various plasmin inhibitors (antiplasmins) are also present (6). Red thrombi are most apt to develop when flow is reduced. Dilated cardiac atria— especially those with inefficient contractility, as found with atrial fibrillation, regions of hypokinesia of the cardiac ventricles, and frank ventricular aneurysms—commonly harbor red clots. Red thrombi are also often formed in heart chambers when ejection fractions are low, that is, 25% or lower. Red thrombi tend to form on the surface of myocardial infarcts. Thrombi formed in the leg and pelvic veins that pass through defects in the cardiac atrial and ventricular septa or pass through arteriovenous fistulae in the lungs are nearly always red thrombi. Both red and white thrombi often form along damaged heart valves, especially those made of prosthetic materials. White Thrombi These so-called white clots are composed of platelets and fibrin and do not contain red blood cells (Fig. 2). White clots form almost exclusively in areas in which the endothelial surface is abnormal, characteristically in fast-moving bloodstreams. Irregular valvular and endothelial surfaces predispose to platelet-fibrin thrombi forming in areas of irregularities. In many cases, the thrombus begins as a white platelet fibrin clot, and then a red thrombus is laid down as a cap over the initial platelet mass (7,8).

Figure 2 Phase microscope image of a white fibrin-platelet thrombus formed in a high-flow system (courtesy of S.H. Hanson and Ch. Kessler, Emory University, Division of Hematology). Source: From Ref. 120.

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Platelets and platelet masses have been found on the surface of heart valves in a number of conditions that are inflammatory but not infective. The initial report of fibrous endocarditis by Libman and Sacks (9) contained descriptions of heart valve and endocardial abnormalities that consisted of fibrous valve thickening, often with grossly visible vegetations that contained mixtures of blood platelets and fibrin. The pathologist Libman found deposits of agglutinated blood platelets over large flat areas, beneath which the endocardial tissues were infiltrated with polymorphonuclear leukocytes and round cells. The blood platelet masses showed regions of fibroblastic invasion, resulting in vegetation formation and thickening of the atrial and ventricular surfaces of the valves (9). Later, Klemperer and Baehr, students of Libman described similar pathological findings and recognized that the disorder was a part of the syndrome of systemic lupus erythematosis (10,11). Similar vegetations occur in some patients with the antiphospholipid antibody syndrome (12,13) and in nonbacterial thrombotic endocarditis (13 – 16) (also called marantic endocarditis because of its association with cancer and debilitating illnesses). The cardiac valve and endothelial lesions in these three conditions—systemic lupus erythematosis, antiphospholipid antibody syndrome, and nonbacterial thrombotic endocarditis—are very similar and probably indistinguishable grossly and microscopically. Platelet deposition, incorporation of fibrin, and the formation of platelet thrombi on valve and endocardial surfaces are common to all three conditions. Calcified Particles Calcific emboli have been noted within the brain on computed tomography (CT) scans in patients who have calcific aortic valves (17 – 21). In each patient the calcific embolus was identified on noncontrast CT as a dense intravascular density. Bicuspid aortic valves are often the seat of the calcification, and, occasionally, calcium is present in other valves, especially those affected by rheumatic fever. Another potential source of calcific material is mitral annulus calcification (MAC). Calcification of the mitral annulus has a predilection for the posterior portion of the mitral annulus ring, but calcific masses may extend as far as 3.5 cm into the adjacent myocardium and, often, project superiorly toward the atrium and centrally into the cavity of the left ventricle (22). Calcified material may ulcerate and extrude through overlying cusps into the ventricular cavity in some patients (23). Thrombi may be attached to the ulcerated regions (23 – 27). The embolic material can be either calcium (as has also been shown in calcific aortic stenosis) or thrombus. Cranial CT scans in patients with MAC and brain embolism can show calcific flecks within intracranial branch arteries (26). Infectious Material: Bacteria and Fungi Because of poor vascularization of cardiac valves, when bacteria or fungi colonize upon valves they may form relatively large vegetations. Valvular vegetations in patients with infective endocarditis are composed of platelets, fibrin, erythrocytes, and inflammatory cells attached to the damaged endothelium of native and prosthetic valves. Organisms are enmeshed within the fibrinous material often deep within the vegetations, explaining why antibiotics have difficulty sterilizing them. Vegetations range in size from several millimeters to several centimeters, and their potential for embolization relates to their size and friability (13). Embolization of infected material can cause meningitis and arterial aneurysms. These so-called mycotic aneurysms are caused by embolization of infected material into the wall and adventitia of brain arteries. The aneurysms usually occur distally

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along arteries and tend to be multiple. Multiple brain abscesses can also develop in patients with staphylococcal endocarditis. Cessation of embolization is associated with sterilization of bacterial endocarditis.

Fibrin Strands Strands are mobile, thin, threadlike filaments attached to cardiac valves. They were first described during investigation of hearts at necropsy and are now often found during echocardiographic studies during life. The cause and significance of valvular strands remains uncertain even now. In 1856 Lambl first described filamentous outgrowths from the ventricular surfaces of aortic valves that he occasionally discovered at necropsy (28). Since his description, these fibrous strandlike lesions have often been referred to as Lambl excrescences. Magarey, nearly a century later, found similar filiform strands attached to the atrial surface of mitral valves examined at necropsy (29). The mitral valve strands, composed of a cellular connective tissue core covered by endothelium, were usually quite thin and long, measuring ,1 mm thick and ranging in length from 1 to 10 mm (29). Magarey noted that hearts with strands often had thickened mitral valves and posited that strands were derived from fibrinous deposits on the valve surfaces (29). Transesophageal echocardiography (TEE) has recently begun to show thin filamentous structures similar to those described by Lambl and Magarey at necropsy (30,31). Nighoghossian et al. (32) reported three patients who had brain ischemic events and mitral valve strands who had cardiac surgery. The valve lesions were described as a floating mass 6 mm thick on the ventricular surface of the mitral valve, a 6 mm lesion on the anterior mitral valve leaflet, and a sessile 5 mm lesion on the anterior mitral valve leaflet. Extensive evaluation, including angiography, showed no cause for stroke other than the abnormal strands attached to cardiac valves (32). Histopathological examinations showed that the cardiac lesions were composed of an acellular fibrous core with surrounding rings of granular material and endothelial cells. Thrombi were attached to the strands in two of the patients (32). Mitral valve strands are significantly more common in patients with brain infarcts than in controls and in patients with mitral valve thickening, defined as mitral valves .3 mm in thickness on two-dimensional (2D) TEEs (33,34). The TEE data and pathological studies suggest that strands are probably derived from fibrinous deposits on abnormal valve surfaces. The strands could potentially act as embolic particles, and emboli can arise from thrombi formed on the surfaces of the valves or formed on the strands. Many nonrheumatic, noninfective conditions cause the deposition of fibrous tissue, fibrin, and platelets within cardiac valves and on their surfaces.

Myxomatous and Other Tumor Tissue Myxomas are the most common heart tumors. The cells of origin are endocardial and arise from multipotential mesenchymal cells that persist as embryonal remnants during septation of the heart (35). Most myxomas originate from the interatrial septum at the edge of the fossa ovalis, but some originate from the posterior or anterior atrial walls or the auricular appendage, and they occasionally arise from the region of the heart valves (34,35). They are more common in the left atrium. Embolism is estimated to occur in 30– 50% of patients with cardiac myxomas (34 –40). Most emboli arise from the left atrium and go to the brain, eye, and systemic organs. Papillary fibroelastomas are another type of cardiac tumor that can give rise to brain embolism (41,42). The lesions consist of multiple papillary fronds that radiate from an

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avascular fibrocollagenous core attached by a short pedicle to the endothelium and most often arising from the aortic valves (44). ARTERIAL ORIGIN SOURCES Plaques within the aorta and systemic arteries contain a mixture of lipid, smooth muscle, fibrous and collagen tissues, and inflammatory cells (13,44 –46). Both white platelet – fibrin and red erythrocyte –fibrin thrombi form on the surfaces of irregular and ulcerated arterial endothelia. Atherosclerotic plaques also often calcify. Some substances that embolize from aortic and arterial lesions—white and red thrombi and calcific plaque— are similar to those that originate from the heart. The major substance unique to arterial versus cardiac lesions is cholesterol. Atheromatous emboli have been found in the brain at necropsy often in or near arterial border zones (47 –49). Cholesterol crystals and plaque debris containing cholesterol and other lipids can be released from plaques, especially after manipulation surgically or by angiography. They are especially commonly liberated during cardiac surgery when the aorta is clamped and manipulated (50 – 53). SUBSTANCES THAT ORIGINATE FROM OUTSIDE THE CARDIOVASCULAR SYSTEMS Some embolic materials that enter the systemic and brain circulations do not originate in the heart, aorta, or cervico-cranial arteries and are not composed of blood elements or thrombi. The types of particles are diverse as are the clinical syndromes and circumstances of brain embolization. These emboli types are all very uncommon when compared to emboli that arise from the heart, aorta, and great vessels discussed so far. Fat and gas bubbles cause microembolism to many small brain arteries, causing an encephalopathytype syndrome, whereas tumor and foreign body emboli usually block single discrete arteries, causing strokes. FAT EMBOLISM Fat embolism occurs most often after serious physical trauma that causes bone fractures. The first known report is usually credited to Zenker who, in 1861, in a monograph about lung anatomy and physiology included a description of fat droplets in the lungs of a railway worker who had sustained a severe crush injury (54). Since then, the frequency, clinical and laboratory features, and circumstances of the fat-embolism syndrome have been extensively described (55). The syndrome consists of a triad of respiratory distress, decreased alertness, and a petechial rash developing 24 to 48 hours after an injury. Table 2 lists the major features in patients with the fat-embolism syndrome. Fat embolism is most often found after blunt physical trauma with fractured bones but can occur after cardiac surgery and in patients who have bone infarctions. In patients with injuries, the long bones and pelvis are most often involved, especially the femurs. The fat-embolism syndrome is unusual in children and in patients with fractures limited to the upper extremities (55). Often, there are multiple fractures resulting from vehicular accidents (55 –61). Investigators retrospectively reviewed 10 years experience of the fat-embolism syndrome found at one trauma center and found 27 instances (0.9%) of long bone fractures among 3026 patients (56).

Embolic Particles Table 2

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Fat Embolism

Major clinical features Dyspnea and respiratory distress Decreased alertness and cognitive function Petechiae Other findings Fever Tachycardia Retinal infarcts Jaundice Laboratory and imaging Anemia Thrombocytopenia Hypoxia Abnormal chest X-ray Fat globules and lipid in the urine Microembolism during transcranial Doppler monitoring Fat emboli visible during transesophageal echocardiography MRI showing multiple infarcts and small hemorrhages Abbreviation: MRI, magnetic resonance imaging.

Occasionally, the fat-embolism syndrome develops after cardiac surgery, when the atria or ventricles are entered (62,63). The exact mechanism of fat embolism after open heart surgery is unclear, but fat from the sternotomy or epicardial fat may directly enter the systemic circulation (63). Cardiotomy suction tubes draining the pericardium during cardiopulmonary bypass contain variable quantities of fat globules (64). Fat embolism has also been reported in patients with sickle-cell anemia (homozygous S– S and those who have S –C disease) (65 – 68). In sickle-cell disease patients, the fat originates from bone and bone marrow infarcts. Bone and joint pain and crisis may precede fat embolism in some patients. Fat embolism has also been described after therapeutic procedures that use lipid substances to form stable drugs for injection. Lipiodol has been used to mix with anticancer drugs that are fat soluble to form stable covalent conjugates. This mixture is then injected into an artery feeding a tumor, for example, in the liver. Fat embolism has been described after such therapeutic procedures (68). The clinical findings included dyspnea and decreased alertness. Hypoxemia preceded or accompanied stupor. Magnetic resonance imaging (MRI) showed multiple focal abnormalities, mostly in border-zone regions. The neurological signs were severe but transient and cleared completely within weeks. None of the three reported patients had cardiac shunts demonstratable by echocardiography (68). Two main hypotheses of the pathogenesis of the fat-embolism syndrome are usually proffered. These are referred to as the mechanical and biochemical theories. According to the mechanical theory, the source of fat is the bone marrow and other loci where fat is stored (55,56,69,70). Bone or deposits of adipose tissue are injured, and fat globules enter damaged blood capillaries and veins at the site of injury. Increase in local tissue pressure related to the trauma promotes fat entry into the intravascular compartment. According to the biochemical theory, intravascular fat is derived from lipid mobilized from fat deposits in the body. Catecholamine release, loss of chylomicra emulsion stability, biochemical perturbations that result from trauma, and a variety of acute illnesses

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promote the formation and mobilization of fat globules. Fat that embolizes to the lungs is converted metabolically to free fatty acids by pulmonary lipases. Free fatty acids are toxic to the lungs and damage capillaries and small arterioles and veins, causing lung edema, hemorrhage, and atelectasis (55,61). Thromboplastin is also released after local tissue injury and induces platelet aggregation on injured surfaces and on fat globules enhancing thromboembolism. Fat within the lungs enters pulmonary veins and passes through the left side of the heart into the systemic circulation. In some cases, fat traverses a patent foramen ovale (PFO) to enter the systemic circulation (71 – 75). The two mechanisms, mechanical and biochemical, may coexist and interact. Fat first mechanically enters into the vascular system in relation to local traumatic injury. The primary injury and embolization of fat and marrow into the lungs can set in motion biochemical changes that enhance fat-globule formation, mobilization, and embolization. The fat-embolism syndrome usually develops after a delay of a few hours up to a few days after trauma. In one series of 14 patients, all of whom had traumatic injuries with long-bone fractures, the latency of onset of signs of fat embolism after trauma ranged from 12 to 72 hours (mean, 41 hours) (60). At times the clinical manifestations of fat embolism can be delayed for as long as five days (61). Most patients have symptom onset between 24 and 72 hours after injury. The major clinical manifestations of the fat embolism syndrome are dyspnea, tachypnea, fever, tachycardia, petechiae, and neurological dysfunction. Jaundice can also occur. Neurological symptoms and signs may precede or follow respiratory distress and are characterized as confusion with delirium, often followed by a decrease in the level of consciousness. Neurological symptoms and signs are present in .80% of patients. Most often, patients develop an encephalopathy characterized by restlessness, agitation, confusion, poor memory, and decreased alertness. This state often passes into stupor or coma. Seizures are common at onset or early during the course of illness. Seizures can be focal or generalized. Focal neurological signs are also common and include hemiparesis, conjugate eye deviation, aphasia, and visual-field abnormalities. Motor abnormalities, including increased tone in the lower extremities, Babinski signs, and decerebrate rigidity, are often found. Focal neurological signs were noted in 33% of patients in one series (61). Some patients have scotomas and other visual abnormalities related to retinal dysfunction caused by fat embolism. Pulmonary symptoms develop shortly after or concurrent with the neurological symptoms. Dyspnea and tachypnea are prominent, and patients may become cyanotic. Tachycardia, high fever, and circulatory collapse also occur; hypotension is often related to blood loss, hypoxemia, and hypovolemia. Renal failure can develop. An important clue to the presence of fat microemboli is the presence on physical examination of petechiae. Petechiae are found in 50– 75% of patients with the fat embolism syndrome. They are most often found in the lower palpebral conjunctivae and the skin of the neck, shoulder, and the axillary folds (55,58,59). Another important clinical clue is the appearance of fat emboli within the arteries of the eye. Microinfarcts are sometimes visible in the optic fundus, especially in the perimacular regions. Small hemorrhages, sometimes with white, pale centers, are also found. Fat globules can sometimes be seen within retinal arteries (58). Papilledema is occasionally found. In one series, 11 of 24 (46%) patients with fat embolism showed abnormalities during the ocular funduscopic examination (58). Laboratory tests are often helpful in diagnosis. Many patients develop abnormal chest X-rays. Fine stippling and fluffy lung infiltrates are common and are seen diffusely through the lung fields. Most patients have a drop in hemoglobin and hematocrit due to traumatic loss of blood and hemolysis. Thrombocytopenia, prolonged prothrombin time,

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and activated partial thromboplastin times are common and are attributed to a consumptive coagulopathy. Frank disseminated intravascular coagulation may also occur. Transcranial Doppler (TCD) monitoring of patients with long bone fractures can document fat emboli (76 –78). Forteza et al. (78) performed TCD monitoring of five patients with long-bone fractures and detected fat emboli in all of them. The microembolic signals disappeared by day 4. TEE during orthopedic procedures also can show fat embolism, occasionally in extensive amounts (79,80). In one patient, closure of a PFO dramatically decreased the quantity of fat emboli detected by TCD (76). Brain imaging may show small hemorrhages, brain edema, and focal infarcts, usually manifested by regions of gyral enhancement on CT or MRI scans. CT scans are most often normal but may show areas of hypodensity and small hemorrhages. MRI is much more sensitive and often shows abnormalities within the white matter and in borderzone regions (80). Fluid attenuating inversion recovery (FLAIR) and contrast-enhanced images are particularly helpful in showing microinfarcts (80). Figure 3 shows FLAIR MRI images in a patient who suddenly became unconscious 18 hours after a fracture of his right femur. Innumerable small embolic infarcts are seen throughout the cerebral hemispheres bilaterally. Magnetic resonance spectroscopy (MRS) can also be used to identify the presence of fat (81). In one reported patient who had fat embolism develop after a femoral fracture, MRS performed 35 hours after the onset of coma showed the presence of long-chain lipid resonance in high quantities in the periventricular white matter and occipital cerebral cortices of the patient with no associated lactate resonance. The lipid gradually disappeared on subsequent examinations (81). In questionable cases, MRS can be of help in diagnosis. Lipid globules are sometimes found in the urine when fat stains are used. In one series, 9 of 19 (47%) patients had free fat in the urine, 6 of whom had lipuria within the first 48 hours after trauma (58). Skin, renal, and muscle biopsies may show fat globules within small skin, muscle, and renal vessels and in renal glomeruli. Cryostat frozen sections of blood also can show the presence of neutral fat; in one series, neutral fat

Figure 3 (A) and (B) MRI FLAIR images. This patient suddenly became unconscious 18 hours after a fall that caused a fractured femur. Examination showed bilateral cerebral dysfunction with coma and preserved brainstem function. The scans show innumerable small infarcts dotted throughout the cerebral hemispheres caused by fat emboli. Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid attenuating inversion recovery.

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was most often found in patients with hypoxemia and PaCO2 of ,60 mm Hg (59). Hypoxemia is very common in patients with the fat-embolism syndrome. One of the most effective and specific tests for fat embolism is bronchopulmonary lavage (82,83). The technique involves microscopic examination of cells recovered by lavage and stained with a specific stain for neutral fat, for example, using oil red O dye. In one series, the five patients who had clinical evidence of the fat-embolism syndrome all had very positive results from bronchopulmonary lavage (82). Staining of bronchoalveolar cells in these five patients showed large intracellular fat droplets; the mean percentage of cells that contained fat droplets was 63% with a range of 31 – 82% (82). Trauma patients who did not have signs of the fat-embolism syndrome had ,2% of cells that contained fat (82). The mortality rate in patients with the fat-embolism syndrome is quite high (as much as 50%), although the mortality rate has declined over time (59,60). When coma, severe blood loss, hypotension, high fever, and disseminated intravascular coagulation are present, the mortality rate remains substantial. Necropsy of the brain of patients dying with the fat-embolism syndrome shows many small ball- or ring-shaped and perivascular hemorrhages, brain edema, and regions of microinfarction (84). Stains for fat reveal fat globules within hemorrhagic lesions and in small vessels throughout the brain (84). Small hemorrhages, edema, and hyaline membranes are often found in the lungs (60). Fat globules are also often visible in renal glomeruli, myocardium, liver, pancreas, spleen, and gastrointestinal mucosa. Treatment of patients with the fat-embolism syndrome has not been formally studied in therapeutic trials. Supportive care including oxygen administration, often with assisted respiration and fluid and blood replacement, is very important. Corticosteroids, heparin, and intravenous administration of 5% alcohol solutions have all been tried, but their effectiveness has not been well studied (58). Heparin has been used in patients with consumptive coagulopathies and also because of its posited lipolytic effect. Alcohol is also believed to have a lipolytic capability. Among these treatments, corticosteroids administration has been most frequently used.

AIR EMBOLISM Gas bubbles sometimes enter the systemic circulation and cause air embolism to the brain and other organs. The sources of air are quite diverse. In most instances, air is introduced iatrogenically during procedures and surgery. Air embolism can follow endoscopy, laparoscopy, and surgery on the gastrointestinal tract (85–88); spontaneous pneumothorax and procedures and surgery in the thorax involving the lungs (85,89); pneumo-orbitography, perineal and peritoneal air insufflation, pneumoarthrography, and surgery on the heart, neck, brain, and axilla (86). Air also can enter the cranium after fractures involving the cribiform plate and the paranasal sinuses (90) and after surgery on the sinuses. Venous and arterial catheterization and cardiopulmonary bypass are common causes of air embolism. Air can also be introduced during home infusion therapy (91). Less often, air embolism follows penetrating traumatic injuries to the thorax, lungs, or major blood vessels. Air introduction into the vascular system is quite common during cesarean deliveries (92). Precordial Doppler can demonstrate some air embolism in about half of all cesarean deliveries (92,93). More sensitive diagnostic techniques are estimated to show air embolism in .90% of cesarean deliveries, more so when the uterus is exteriorized (92,94). Another important and quite different circumstance that leads to air embolism is in relation to scuba diving and rapid ascents after descents into deep water (95,96).

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Introduction of a large quantity of air into the venous system can result in sudden blockage of the pulmonary artery and right ventricular outflow tract with resultant cardiac arrythmia and sudden death or circulatory collapse (92). Dyspnea, cyanosis, chest pain, restlessness, and a feeling of impending death can develop. When small amounts of air are released into the venous system, filtering by the pulmonary vessels protects the coronary and brain circulations (97,98). Lung edema can result from air in the lungs, especially when there is an increase in pulmonary artery pressure. Air can also stimulate the release of various thromboplastins, surfactants, and cytokines that cause lung injury and coagulopathy (98). Air bubbles in arteries supplying the brain cause an immediate but transient block in blood flow. Air quickly moves through the capillary bed into the venules and dissipates (85). The gas bubbles cause arterial vasoconstriction followed by dilatation and stasis of blood flow (85). During diving accidents, air becomes trapped in the alveoli of the lungs due to partial bronchial occlusion from mucous plugs and failure to exhale. Because the volume of a gas varies inversely with pressure (Boyle’s Law), pressurized air bubbles in the lungs increase dramatically in volume as the diver ascends and the ambient surrounding pressure falls (85). The rapid expansion of air in the lungs causes entry of air into the pulmonary arterial and venous outflow systems (96). Gas bubbles pass through the lung vasculature or through a PFO into the systemic circulation. Similar to the situation in fat embolism, many small particles enter the circulation and block the microvasculature. Cantais et al. (99) studied the frequency of PFOs using the TCD method in 101 divers who had clinical decompression syndromes and compared the findings to 101 control divers without decompression symptoms. Symptoms consisted of cerebral decompression illness and cochleovestibular symptoms. Cochleovestibular symptoms consisted of tinnitus, hearing loss, vertigo, nausea, and vomiting (99,100). Major right-to-left shunts were found in 49/59 patients in the decompression illness group versus 12/25 in the control group (odds ratio 8.7; 95% confidence interval 4.2– 18; P , 0.001) (99). Others have also confirmed that decompression illness is more common among divers who have a PFO (99,101,102). Symptoms and signs of brain gas embolism have been studied most thoroughly in individuals who have had diving-related incidents (85,96,99). These occur during scuba diving and have been well studied in naval personnel who escape too quickly from submerged submarines (96). Loss of consciousness often develops suddenly after the individual emerges onto the surface of the water. Dizziness, chest discomfort, paresthesias, weakness, blurred vision, nausea, and headache are the most common symptoms reported and may precede the loss of consciousness. Seizures and focal neurological signs, especially related to dysfunction of the brainstem and cerebellum are also quite common 87–89,96). Discrete focal collections of gas and multiple focal air collections are sometimes found in the brain on cranial CT examination (88 –89,98,103). Brain edema with compression of the ventricular system is another common and important finding on brain imaging examinations. TCD is quite sensitive for detection of air microemboli (99,104). Treatment has usually consisted of inhalation of 100% oxygen as well as the use of hyperbaric recompression chambers (92,98).

TUMOR EMBOLISM Occasionally, major arteries supplying the brain are occluded by tumor emboli. This happens when a neoplasm directly erodes into a cervical artery or a pulmonary vein or

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when a tumor erodes into a systemic vein, embolizes to the heart, and then passes through a cardiac septal abnormality to enter the systemic circulation. Most often, the tumors that have embolized are primary pulmonary neoplasms or tumors that have metastasized to the lungs (105). Brain embolism has sometimes occurred after lung surgery for cancer. Necropsy has usually shown tumor invasion of pulmonary veins or invasion of the left atrium (105). Surgical manipulation of the lungs in patients with lung tumors can promote systemic embolization of the tumor. Although most often the clinical syndrome is that of a stroke, embolism to other systemic organs also occurs. Tumor emboli can also pass through a PFO or another cardiac septal defect. Passage through a dilated PFO was documented in one patient with metastatic adenocarcinoma and bone metastases (74). After surgical intramedullary fixation of both femurs, the patient did not awaken from surgery and remained comatose and died. At necropsy, the patient had a PFO and an embolus consisting of tumor cells admixed with bone marrow in the left middle cerebral artery (MCA) and a large fatal infarct in the territory of the left MCA (74). Tumor emboli have also been reported in patients with thyroid and other neck cancers that eroded into neck arteries (106).

FOREIGN BODY EMBOLISM Occasionally, foreign bodies enter the systemic vascular system and embolize to the brain. Foreign bodies that embolize to the brain must either enter the lungs and pulmonary veins, enter directly into the left side of the heart itself, enter the right side of the heart and then traverse a defect in the cardiac septum, or penetrate the cervico-cranial arteries that supply the brain. Bullets and pellets may penetrate the skin and land in the heart. Kase et al. (107) described the case of a patient who came to the emergency room because of shotgun blast wounds to the thorax and abdomen. At thoracotomy, doctors repaired four small bullet wounds in the left ventricle. Initially, he was alert and a neurological screening examination was normal. After surgery, he developed severe hypotension followed by cardiac arrest. External cardiac massage was begun. After resuscitation, he was comatose and had severe hemiplegia. CT showed a 1– 2 mm piece of shotgun pellet and a large MCA territory infarct. Angiography showed two small shotgun pellets occluding the distal intracranial internal carotid artery and another fragment occluding the MCA (107). This case illustrates the small size of particles that can block a major intracranial artery leading to devastating neurological deficits. Others have also reported shotgun pellets that punctured a carotid artery in the neck causing brain infarction, and were later visible on cranial CT scans (108,109). Langenbach et al. (110) described the case of a 52-year-old man in whom a small metal particle penetrated his right neck while he was hammering. He soon developed severe left hemiplegia. Plain skull films showed a 2
7 mm metal-dense particle to the right of the pituitary fossa. CT showed a large right MCA territory infarct and angiography showed that the metal fragment was blocking the MCA (110). Foreign bodies, for a variety of reasons, can gain entry into the heart. Dato et al. (111) reported 14 patients who had posttraumatic and iatrogenic foreign bodies in the heart. Four were located in the left heart and 10 in the right heart. The foreign fragments were needles, bullets, a grenade fragment, and a piece of a circular saw (111). The others were introduced during medical and surgical procedures—venous catheters, a Swan-Ganz catheter, and a valvulotomy ring that had broken loose from its placement. No instance of brain embolism was noted in this report. Instances of passage of foreign bodies through PFOs have been occasionally reported (112,113).

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North et al. (114) reported the case of a 9-year-old boy who was noted to have severe right hemiplegia, right hemianopia, and right hemisensory loss detected immediately after awakening from surgical repair of a prosthetic heart valve. CT showed a foreign body within the head and infarction of the left midbrain, thalamus, and temporal and occipital lobes in the distribution of the left posterior cerebral artery (PCA). He died after hemorrhage into the region of infarction. Necropsy showed that the foreign body within the proximal left PCA was a fragment of the prosthetic valve with surrounding fibrosis (115). Retinal and brain arteries can become blocked by foreign particles in patients who mash drugs manufactured for oral use and inject the drugs intravenously (115 –118). The reported particles consist of talc and methylcellulose that are used to bind drugs to maintain them in pill form. The particles first block lung vessels. Pulmonary vascular obliteration causes pulmonary hypertension and arteriovenous shunting develops in the lungs, allowing the particles to enter the pulmonary veins and then the systemic circulation (115,116). Talc and cornstarch emboli can be seen in the retinal arteries of some of these drug abusers (117). Strokes have also been described in patients who have injected drugs directly into neck arteries (118,119).

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43. Fine G. Primary tumors of the pericardium and heart. Cardiovasc Clin 1973; 5:207–238. 44. Fisher CM, Ojemann RG. A clinico-pathologic study of carotid endarterectomy plaques. Rev Neurol 1986; 142:573 – 589. 45. Heistad DD. Unstable coronary-artery plaques. N Engl J Med 2003; 349:2285 – 2287. 46. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221 –225. 47. Masuda J, Yutani C, Ogata J, Kuriyama Y, Yamaguchi T. Atheromatous embolism in the brain: a clinicopathologic analysis of 15 autopsy cases. Neurology 1994; 44:1231 – 1237. 48. Price DL, Harris J. Cholesterol emboli in cerebral arteries as a complication of retrograde aortic perfusion during cardiac surgery. Neurology 1970; 20:1209 – 1214. 49. Beal MF, Williams RS, Richardson EP, Fisher CM. Cholesterol embolism as a cause of transient ischemic attacks and cerebral infarction. Neurology 1981; 31:860 –865. 50. Barbut D, Caplan LR. Brain complications of cardiac surgery. Current Problems in Cardiology 1997; 22:447 – 476. 51. Barbut D, Gold JP. Aortic atheromatosis and risks of cerebral embolization. J Cardio Thoracic Vasc Anesthesia 1996; 10:24 – 30. 52. Blauth CI, Cosgrove DM, Webb BW, et al. Atheroembolism from the ascending aorta. An emerging problem in cardiac surgery. J Thorac Cardiovasc Surg 1992; 103:1104 – 1112. 53. Barbut D, Hinton R, Szatrowski, et al. Cerebral emboli detected during bypass surgery are associated with clamp removal. Stroke 1994; 25:2398– 2402. 54. Zenker FA. Beitrage zur Anatomie und Physiologie de Lunge. Dresdaen, Germany: J Braunsdorf, 1861. 55. Parisi DM, Koval K, Egol K. Fat embolism syndrome. Am J Orthop 2002; 31:507 – 512. 56. Bulger E, Smith DG, Maier RV, Jurkovich G. Fat embolism syndrome. A 10-year review. Arch Surg 1997; 132:435– 439. 57. Sevitt S. Fat Embolism. London: Butterworth & Co, 1962. 58. Thomas JE, Ayyar DR, Systemic fat embolism. A diagnostic profile in 24 patients. Arch Neurol 1972; 26:517 – 523. 59. Dines DE, Linscheid RL, Didier EP. Fat embolism syndrome. Mayo Clin Proc 1972; 47: 237– 240. 60. Dines DE, Burgher LW, Okazaki H. The clinical and pathological correlation of fat embolism syndrome. Mayo Clin Proc 1975; 50:407 – 411. 61. Jacobson DM, Terrence CF, Reinmuth OM. The neurologic manifestations of fat embolism. Neurology 1986; 36:847– 851. 62. Hill JD, Aguilar MJ, Baranco AP, Gerbode F. Neuropathological manifestations of cardiac surgery. Ann Thorac Surg 1969; 7:409 – 517. 63. Ghatal NR, Sinnenberg RJ, DeBlois GG. Cerebral fat embolism following cardiac surgery. Stroke 1983; 14:619 – 621. 64. Charache S, Page DL. Infarction of bone marrow in sickle cell disorders. Ann Intern Med 1967; 67:1195 – 1200. 65. Hutchinson RM, Merrick MV, White JM. Fat embolism in sickle cell disease. J Clin Pathol 1973; 26:620 – 622. 66. Vichinsky E, Williams K, Das M, et al. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood 1994; 83:3107 – 3112. 67. Shelley WM, Curtis EM. Bone marrow and fat embolism in sickle cell anemia and sickle cell-hemoglobin C disease. Bull Johns Hopkins Hosp 1958; 103:8– 25. 68. Chmel H, Bertles J. Hemoglobin S/C disease in a pregnant woman with crisis and fat embolization syndrome. Am J Med 1975; 58:563 – 566. 69. Yoo KM, Yoo BG, Kim KS, Lee SU, Han BH. Cerebral lipiodol embolism during transcatheter arterial chemoembolism. Neurology 2004; 63:181– 183. 70. Qian Y, Ances BM, Pruitt A, Choi B, Moonis G. Intracranial fat embolization due to baclofen pump. Neurology 2005; 64:919. 71. Oh WH, Mital MA. Fat embolism: current concepts of pathogenesis, diagnosis, and treatment. Orthop Clin North Am 1978; 9:769– 779.

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72. Ing HR, Pellegrini VD. Fat embolism syndrome: a review of the pathophysiological basis of treatment. Clin Orthop 1982; 165:68– 82. 73. Pell AC, Hughes D, Keating J, et al. Brief report. Fulminating fat embolism syndrome caused by paradoxical embolism through a patent foramen ovale. N Engl J Med 1993; 329:926 – 929. 74. Oostenbrugge RJ, Freling G, Lodder J, Lalisang R, Twijnstra A. Fatal stroke due to paradoxical fat embolism. Cerebrovasc Dis 1996; 6:313– 314. 75. Dive AM, Dubois PE, Ide C, et al. Paradoxical cerebral fat embolism: an unusual cause of persistent unconsciousness after orthopedic surgery. Anesthesiology 2002; 96:1029 –1031. 76. Forteza AM, Rabinstein A, Koch S, et al. Endovascular closure of a patent foramen ovale in the fat embolism syndrome. Changes in the embolic pattern as detected by transcranial Doppler. Arch Neurol 2002; 59:455 – 459. 77. Riding G, Daly S, Hutchinson S, Rao S, Lovell M, McCollum C. Paradoxical cerebral embolism. J Bone Joint Surg 2004; 86:B95 – B98. 78. Forteza AM, Koch S, Romano JG, et al. Transcranial Doppler detection of fat emboli. Stroke 1999; 30:2687 – 2691. 79. Pitto RP, Hamer H, Fabiani R, Radespiel-Troeger M, Koessler M. Prophylaxis against fat and bone-marrow embolism during total hip arthroplasty reduces the incidence of postoperative deep-vein thrombosis. J Bone Joint Surg 2002; 84-A:39 – 48. 80. Simon A, Ulmer JL, Strottman JM. Contrast-enhanced MR imaging of cerebral fat embolism: case report and review of the literature. AJNR 2003; 24:97– 101. 81. Guillevin R, Vallee JN, Demeret S, et al. Cerebral fat embolism: usefulness of Magnetic Resonance Spectroscopy. Ann Neurol 2005; 57:434 – 439. 82. Chastre J, Fagon J-Y, Soler P, et al. Bronchoalveolar lavage for rapid diagnosis of the fat embolism syndrome in trauma patients. Ann Intern Med 1990; 113:583 – 588. 83. Godeau B, Schaeffer A, Bachir D, et al. Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism. Am J Resp Care Med 1996; 153:1691– 1696. 84. Kamenar E, Burger PC. Cerebral fat embolism: a neuropathological study of a microembolic state. Stroke 1980; 11:477– 484. 85. Menkin M, Schwartzman RJ. Cerebral air embolism. Report of five cases and review of the literature. Arch Neurol 1977; 34:169– 170. 86. Valentino R, Hilbert G, Vargas F, Gruson D. Computed tomographic scan of massive cerebral air embolism. Lancet 2003; 361:1848. 87. Demaerel P, Gevers A-M, De Brueker Y, Sunaert S, Wilms G. Stroke caused by cerebral air embolism during endoscopy. Gastrointest Endoscopy 2003; 1:134 – 135. 88. Weber M-A, Fiebach JB, Lichy MP, Schwark C, Grau A. Bilateral cerebral air embolism. J Neurol 2003; 250:1115– 1117. 89. Hodics T, Linfante I. Cerebral air embolism. Neurology 2003; 60:112. 90. Hertz JA, Schinco MA, Frykberg ER. Extensive pneumocranium. J Trauma, Injury, Infection, and Critical Care 2002; 52:188. 91. Laskey AL, Dyer C, Tobias JD. Venous air embolism during home infusion therapy. Pediatrics 2002; 109:e15. 92. Gei AF, Vadhera RB, Hankins GDV. Embolism during pregnancy: thrombus, air, and amniotic fluid. Anesthesiology Clin North America 2003; 21:165 – 182. 93. Malinow AM, Naulty JS, Hunt CO, et al. Precordial ultrasonic monitoring during cesarean delivery. Anesthesiology 1987; 66:816 – 319. 94. Lew TW, Tay DH, Thomas E. Venous air embolism during cesarean section: more common than previously thought. Anesth Analg 1993; 77:448 – 452. 95. Spencer MP, Campbell SD. Development of bubbles in venous and arterial blood during hyperbaric decompression. Bull Mason Clin 1968; 22:26– 32. 96. Gillen HW. Symptomatology of cerebral gas embolism. Neurology 1968; 18:507–512. 97. Butler BD, Hills BA. The lung as a filter for microbubbles. J Appl Physiol 1979; 47:537 – 543. 98. van Hulst RA, Klein J, Lachman B. Gas embolism: pathophysiology and treatment. Clin Physiol Funct Imaging 2003; 23:237 – 246.

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99. Cantais E, Louge P, Suppini A, Foster PP, Palmier B. Right-to-left shunt and risk of decompression illness with cochleovestibular and cerebral symptoms in divers: case control study in 101 consecutive dive accidents. Crit Care Med 2003; 31:84– 88. 100. Farmer JC, Thomas WG, Youngblood DG, et al. Inner ear decompression sickness. Laryngoscope 1976; 86:1315– 1327. 101. Laden GD. Patent foramen ovale and decompression illness in divers. Lancet 1997; 349:288. 102. Germonpre P, Dendale P, Unger P, et al. Patent foramen ovale and decompression sickness in sports divers. J Appl Physiol 1998; 84:1622 – 1626. 103. Hwang T-L, Fremax R, Sears ES, et al. Confirmation of cerebral air embolism with computerized tomography. Ann Neurol 1983; 13:214 – 215. 104. Yeh T, Austin EH, Sehic A, Edmonds HL. Rapid recognition and treatment of cerebral air embolism: the role of neuroimaging. J Thor Cardiovasc Surg 2003; 126:589 – 591. 105. Lefkovitz NW, Roessman U, Kori S. Major cerebral infarction from tumor embolus. Stroke 1986; 17:555 – 557. 106. Banerjee AK, Chopra JS. Cerebral embolism from a thyroid carcinoma. Arch Neurol 1972; 27:186 – 187. 107. Kase CS, White R, Vinson TL, Eichelberger RP. Shotgun pellet embolus to the middle cerebral artery. Neurology 1981; 31:458 – 461. 108. Yaari R, Abmadi J, Chang GY. Cerebral shotgun pellet embolism. Neurology 2000; 54:1487. 109. Duncan I, Fourie PA. Embolization of a bullet in the internal carotid artery. AJR 2002; 178:1572 – 1573. 110. Langenbach M, Leopold H-C, Hennerici M. Neck trauma with embolization of the middle cerebral artery by a metal splinter. Neurology 1990; 40:552. 111. Dato GMA, Arsianian A, Di marzio P, Filosso PL, Ruffini E. Posttraumatic and iatrogenic foreign bodies in the heart: report of fourteen cases and review of the literature. J Thor Cardiovascular Surg 2003; 126:408 – 414. 112. Crie JS, Hajar R, Folger G. Umbilical catheter masquerading at echocardiography as a left atrial mass. Clin Cardiol 1989; 12:728 – 730. 113. Mattox KL, Beall AC, Ennix CL, DeBakey ME. Intravascular migratory bullets. Am J Surg 1979; 137:192 – 195. 114. North K, Kan A, de Silva M, Ouvrier R. Hemiplegia due to posterior cerebral artery occlusion. Stroke 1993; 24:1757 – 1760. 115. Caplan LR, Thomas C, Banks G. Central nervous system complications of “Ts and blues” addiction. Neurology 1982; 32:623 – 628. 116. Aplan LR, Hier DB, Banks G. Stroke and drug abuse. Curr Concepts Cerebrovasc Dis (Stroke) 1982; 27:9 – 13. 117. Atlee W. Talc and cornstarch emboli in the eyes of drug abusers. JM 1972; 219:49 – 51. 118. Mizutami T, Lewis R, Gonatas N. Medial medullary syndrome in a drug abuser. Arch Neurol 1980; 37:425 – 428. 119. Chillar RK, Jackson AL, Alaan L. Hemiplegia after intracarotid injection of methylphenidate. Arch Neurol 1982; 39:598 – 599. 120. Caplan’s Stroke. A Clinical Approach. 3rd ed. Boston: Butterworth-Heinemann, 2000.

PART VI:

TREATMENT

15 Treatment of the Acute Embolic Event Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

The goals of this treatment are minimization of brain ischemic injury caused by the embolus and prevention of acute recurrent embolism. Strategies for accomplishing this fall into four broad categories: (i) reperfusion of the brain region rendered ischemic by the embolus, (ii) acute anticoagulation to prevent propagation and further embolization of thromboemboli, (iii) making the brain more resistant to ischemia, allowing survival of nerve cells despite ischemia, and (iv) managing complications of embolic infarction, such as brain edema and brain hemorrhage.

REPERFUSION The most important predictors of recovery from brain embolism is whether or not brain tissue rendered ischemic by an embolus blocking a recipient artery is reperfused with blood before irreversible damage occurs and how quickly reperfusion develops. Reperfusion occurs in two different complementary ways: recanalization of the occluded artery related to passage of the embolus, either spontaneously or after treatment, and augmentation of blood flow through collateral circulation sufficient to restore adequate nutrition to ischemic tissue. Opening of Blocked Recipient Arteries Rudolph Virchow, the great German pathologist, was the first to unequivocally show, through a series of experimental and necropsy observations performed during the first half of the nineteenth century, that thrombosis of arteries caused infarction of the tissues supplied by the thrombosed arteries and that thrombi formed in one area often embolized to distant regions rendering those areas ischemic (1,2). Charles Foix and his French colleagues (3,4) observed three-fourths of a century after Virchow’s observations that arteries that supplied infarcted brain regions very often did not contain occlusive thromboemboli. Among explanations that they offered to explain this observation was the possibility that an embolus had temporarily occluded the artery but then had passed. A quarter of a century after the report by Foix and colleagues and a century after Virchow’s report, Miller Fisher and Raymond Adams (5,6) observed that in necropsies 277

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in patients with brain infarcts, the arteries supplying the infarcts were often patent, especially if hemorrhagic infarction was present. In other patients, an occlusive thromboembolus was found too far distally within a recipient artery to explain the extent of infarction, much of which was located proximal to the blockage found at necropsy (5,6). Many of their patients, had cardiac sources of embolism. Fisher and Adams concluded that the embolus that arose from the heart had blocked the recipient artery supplying the infarcted zone and then passed distally. When angiography became feasible clinically, opacification of cervico-cranial arteries soon after symptom onset showed that the intracranial arteries in a very high percentage of patients showed occlusions when angiography was performed within six to eight hours of symptom onset (7,8). Clinical and angiographic studies proved that emboli often passed distally from their initial resting place within recipient arteries (9 –13). In some patients, passage of emboli was accompanied by dramatic clinical recovery (12,13). When angiograms were performed 48 hours or more after neurological symptom onset in patients in the Harvard Stroke Registry, emboli had mostly passed and were not visible angiographically (14,15). Alexandrov and Molina have discussed in chaper 7 documentation using transcranial Doppler (TCD) monitoring of sudden or gradual recanalization of intracranial arteries blocked by emboli. Clearly, emboli very often spontaneously pass. The frequency of spontaneous recanalization at various time intervals after symptom onset has not been well defined because the data are very scanty. In the Prolyse in Acute Cerebral Thromboembolism (PROACT II) study of the effectiveness of an intra-arterially administered agent, pro-urokinase, angiograms performed within six hours of symptom onset did not show intracranial occlusions in about one-fifth of patients studied (16). Many of these patients had emboli that had already spontaneously passed. Among angiograms repeated after infusion of placebo, 18% of patients had partial or complete recanalization (16). Acute studies using magnetic resonance imaging (MRI) protocols that include magnetic resonance angiography (MRA) and diffusion-weighted images have clearly shown that patients rarely develop progressive brain infarction when arteries have already recanalized (17 – 19). Angiographic and TCD studies of untreated patients and those treated with intravenous or intra-arterial thrombolytic agents also show clearly that patients whose arteries recanalize do much better than patients whose arteries remain occluded (20 –24). The extent of brain infarction and clinical recovery also correlate with the length of time that the recipient artery remained occluded (20 – 24). Arterial occlusion is the single most important determinant of outcome. Chemical or Mechanical Thrombolysis and Clot Removal Opening of occluded arteries can be accomplished chemically by administering drugs that lyse clots, or by mechanically using devices that extract thromboemboli. Thrombolytic drugs can be given either intravenously or intra-arterially. Each has advantages and disadvantages (20). Intravenous therapy can be given quickly and needs no special training. The amount of thrombolytic agent that reaches large obstructed arteries is however more limited than intra-arterial infusion of drug that delivers the drug locally within the obstructing clot. Intra-arterial therapy requires a trained interventionalist. Angiography is ordinarily required before, during, and after thrombolysis. This delays treatment. The major advantage of intra-arterial therapy is that the interventionalist can physically manipulate the clot, a process that facilitates thrombolysis and can perform angioplasty/stenting during the same procedure if necessary (25 –29). Usually, less drug is used during intraarterial therapy, and the rate of hemorrhagic complications is lower than with intravenous

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therapy (20). Mechanical removal of thromboemboli can be used as an adjunct to chemical thrombolysis or pursued when there are absolute or relative contraindications for thrombolysis and when thromboemboli are present (30 – 34). Selection of patients for thrombolysis or mechanical clot removal depends on assessing the benefit/risk ratio of treatment. The three key elements in the decision are: (i) whether an artery is occluded and where and how, (ii) the extent of brain already infarcted, and (iii) the brain still at risk for further infarction. Vascular studies [CT angiography (CTA), MRA, and TCD ultrasound] can assess the presence of blockage of major intracranial and extracranial arteries by emboli. Contrast can be administered during CT scanning to produce CT angiograms, and perfusion CT images can be obtained (35 –37). Alternatively, diffusion-weighted MRI (DWI) can be coupled with MRA to define the brain likely to be infarcted and the presence and location of any occlusive thromboemboli (38 – 41). Gadolinium infusion can define the areas underperfused with blood; a perfusion greater than diffusion imbalance indicates that there is still brain tissue at-risk for further ischemia if occluded arteries do not recanalize (38 –42). If the patient is seen and evaluated soon after stroke onset and embolic occlusions are identified by vascular studies, then an attempt at thrombolysis should be made unless there are contraindications or the patient already has a major brain infarct. The timing of thrombolysis is important if brain tissue is to be saved. The large cooperative intravenous thrombolysis trial sponsored by the National Institute of Neurological Diseases and Stroke (NINDS) limited thrombolytic treatment to those patients in whom recombinant tissue plasminogen activator (rt-PA) infusion could be started within three hours of symptom onset (43). Some patients in this study were treated with intravenous thrombolysis within 90 minutes (43a). In other large studies of the effectiveness of intravenous thrombolysis, the European Cooperative Acute Stroke Study (ECASS I and II), all patients were treated within six hours (44,45). The ability to salvage ischemic brain tissue varies considerably from patient to patient. After an embolic occlusion, three zones of brain tissue, supplied by the recipient recently-occluded artery, can be characterized. One zone, usually at the core center of blood supply, soon becomes irreversibly damaged, that is, infarcted. Brain regions at the periphery of supply often remain normal, as they usually receive adequate blood supply through adjacent collateral vascular channels. Between these two zones lies brain tissue that is in a state somewhere between infarcted and normal. This tissue has inadequate blood supply to function but is not irreversibly damaged. This state has been called “stunned brain” or penumbral tissue. Infarcted brain tissue contains cells that are dead and blood vessels that may have also been damaged by ischemia. Reperfusion does not reverse core tissue that is already infarcted. “Stunned brain tissue” may recover quickly when reperfused or may recover more slowly in hours or days (46). The major danger of thrombolysis and of spontaneous reperfusion is that reperfusion of these damaged vessels in the infarcted zone could cause major bleeding into ischemic brain tissue. The decision on whether or not to pursue thrombolysis should not rest solely on the time that has expired since symptom onset but instead on the presence or absence of persistent arterial occlusion, the presence of viable penumbral tissue that can be salvaged, and the extent of brain that is already infarcted. The extent of infarction determines the risk of treatment; the presence and size of penumbral stunned tissue determines the potential benefit of thrombolysis that accomplishes reperfusion. The newer MR techniques of diffusion-weighted and perfusion MR scans performed with echo-planer equipment, when coupled with MRA (38 – 42), or perfusion CT (35 –37) can give clinicians a quantitative

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estimate of these factors. Alternatively, clinicians estimate the extent of normal, infarcted and stunned brain supplied by the occluded artery by using brain imaging (CT and T2-weighted MRI scans), vascular studies (CTA, MRA, TCD, angiography), and the neurological examination. If the patient has a severe neurological deficit and a large infarct is present on brain scans, then much of the brain is infarcted, and there is little to gain by thrombolysis, which carries an important risk of hemorrhage in this circumstance. However, if the patient has a severe neurological deficit and brain scans are normal, there could be considerable stunned, salvagable brain that could be restored to function if thrombolysis were successful. Considerable data about outcome of thrombolytic treatment are now available from reports of patients treated with either intravenous or intra-arterial therapy after their occlusive lesions have been shown by angiography (20 – 22). Intracranial artery embolic occlusions respond better than thrombi formed locally in vessels that have severe atherostenosis. Freshly formed thromboemboli lyse more often than older clots. Thromboemboli that occlude the extracranial or intracranial internal carotid artery (ICA) do not respond well to intravenous thrombolysis. An especially important and common situation is an occlusive thrombus that formed in the ICA in the neck that has caused neurological deficit by a portion of the clot traveling intracranially to occlude the middle cerebral artery (MCA). Intravenous thrombolysis in this situation is usually ineffective because the drug does not reach the MCA clot because of proximal obstruction. An interventionalist may be able to pass a catheter through the clot in the neck, then manipulate the catheter to and within the MCA clot in order to deliver thrombolytic drug into the MCA clot. After lysing the intracranial clot, the catheter can be maneuvered back into the neck in order to lyse the neck clot and, if needed, perform an angioplasty with stenting of the atherostenotic ICA disease. MCA branch occlusions seem to lyse best with intravenous therapy. To date, very few patients with basilar artery thromboemboli have been studied after intravenous thrombolysis (47 – 50) but intra-arterial therapy of patients with basilar artery occlusion has often been effective, especially if the occlusion was embolic (47,50 –58). The most commonly used thrombolytic drugs for stroke patients are rt-PA and urokinase. Other thrombolytic agents that might have more fibrin specificty, so that they might localize more within fibrin thrombi and produce less systemic fibrinolysis, are now being developed and studied. Desmoteplase from bat wings is now undergoing trials. Streptokinase has had an unacceptable rate of bleeding complications when used for stroke. GpIIb/IIIa inhibitors have been given, either alone or in combination with rt-PA or urokinase, in order to lyse white platelet – fibrin thrombi (59 – 61). Occasionally, a white carpet of platelet thrombi will develop especially after procedures on arteries. Standard thrombolytic agents, such as rt-PA and urokinase, do not lyse white thrombi; in fact, they may induce activation of platelets. Ancrod, a substance derived from the purified protein fraction of venom from the Malayan pit viper, has defibrinolytic capabilities and has sometimes been given intravenously in acute stroke patients, but it is not clear if the defibrinization actually lyses thromboemboli (62,63). Recommendations for thrombolysis in acute stroke are noted in Table 1. Mechanical removal of thrombi has some theoretical advantages over chemical thrombolysis. Chemical thrombolysis, whether intravenous or intra-arterial, takes time. Recanalization can take one to two hours to accomplish after drug infusion (16,65). Thrombi can be extracted solely mechanically, or mechanical disruption could facilitate pharmacological thrombolysis by fragmenting the nonthrombotic components of the thrombus and increasing the surface area contact with the thrombolytic drugs. Mechanical thrombolysis should pose less of a threat for bleeding, as systemic or local fibrinolysis

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Recommendations for Stroke Thrombolysis

1. When patients are seen within 3 hrs and a cardiac-origin embolic cause is clear clinically (e.g., atrial fibrillation) and the CT does not show a large region of hypodensity, we recommend giving IV tPA using the published guidelines (63,64) without further study. 2. If the cause is not obvious and/or the patient does not meet published guidelines (stroke on awakening, ?.3 hrs of symptoms, minor or improving deficit, or a usual exclusion) then further brain and vascular imaging should be performed. Alternative protocols are: MRI with T2
, DWI, and MRA, or CT with CTA, or CT or MR with neck and TCD. A. After evaluation—situations in which thrombolysis is not recommended 1. Large infarct already present and little at-risk tissue 2. No occlusion and lacunar syndrome B. Situations in which IV thrombolysis is recommended 1. Occluded intracranial artery (MCA or branch or ICVA), especially if mechanism is embolic and no or small infarct is present and there remains considerable at risk tissue 2. Occluded ICA in the neck seen within 3 hrs (although treatment is often unsuccessful) C. Situations in which angiography is recommended with consideration of IA thrombolysis with or without angioplasty/stenting or mechanical clot removal 1. Basilar artery occlusions 2. Carotid T occlusions with considerable at risk tissue 3. ?.6 hrs after symptom onset 4. Some patients with ICA neck occlusions, especially if IV therapy has failed 5. Some patients whose clinical picture (demography and recurrent TIAs) suggest in-situ atherothrombotic intracranial occlusive disease, especially after IV treatment does not produce effective recanalization Abbreviations: CT, computed tomography; CTA, CT angiography; DWI, diffusion-weighted; ICA, internal carotid artery; ICVA, intracranial vertebral artery; IV, intravenous; MRA, magnetic resonance angiography; MCA, middle cerebral artery; TCD, transcranial Doppler; tPA, tissue plasminogen activator; TIA, transient ischemic attacks.

would not be used and so there would be no decreased coagulability. Mechanical clot removal could be pursued in patients who are presently excluded from chemical thrombolysis, for example, those who have had a recent procedure and those already treated with anticoagulants. A variety of mechanical devices have been used and are now being studied (30 –34). Stent placement with suctioning of the clot can be performed in some patients without chemical thrombolysis (29). Laser energy [endovascular photoacoustic recanalization (EPAR)] can be used to emulsify and suction thrombi (33). Some devices simply snare the thrombus and then drag it back through the arterial catheter (34). The major limitation of mechanical clot removal is the need for a trained and experienced interventionist who has familiarity and experience with the device used. Augmenting Brain Blood Flow Different medical strategies are available to try to improve circulation to brain regions rendered ischemic by a brain embolus. Optimal management of blood pressure, blood volume, and cardiac output can improve blood flow to the ischemic region. Cerebral blood flow increases with rising blood pressure until the pressure becomes very high, approaching the malignant range. During the acute period of brain ischemia, it is unwise to lower the systemic pressure unless it is extremely high—for example, above 200/120 torr. In some patients with low blood pressure, elevation of blood pressure with phenylephrine, ephedrine, or other catecholaminergic drugs might augment brain circulation.

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Blood volume also affects perfusion pressure and blood flow. Some patients who cannot eat normally will become dehydrated and relatively hemoconcentrated. Other factors—such as vomiting, restrictions on eating because of concern for aspiration, or simply the rush of diagnostic testing occupying patients at mealtimes—all contribute to reduced fluid intake during the early hours and days after the onset of brain embolism. It is best to keep blood volume, especially plasma volume, high. Fluids must often be given intravenously or by nasogastric or stomach tubes. Care, however, must be taken to avoid fluid overload and the complications of cardiac failure and brain edema. Careful monitoring of cardiac and cerebral function should accompany attempts to increase fluid volume. Many patients with brain embolism also have cardiac malfunction. A strong pump helps maximize cerebral blood flow. Attention to cardiac rhythm and pump function is important, especially during the acute, fragile period of brain ischemia after embolism. Cardiac output can sometimes be improved by the use of digitalis or vasodilators, use of pacemakers or medications to treat slow rhythms and heart block, adjustment of already prescribed drugs, such as digitalis and diuretics, correction of abnormal serum Kþ and Caþþ levels, and control of tachyarrhythmias. Cardiac-ejection fractions and output can be monitored by echocardiography.

ANTICOAGULATION Heparin and heparin-like compounds are often prescribed as a treatment for patients with acute thromboembolism. The posited purpose of heparinization is to prevent propagation of thrombi and break-off of the tail of existing thrombi and so prevent further embolization. As far as is known, heparin does not lyse existing thrombi, although cardiac clots often disappear during heparin treatment. The arguments used to recommend acute heparinization are twofold: preventing further activity in the embolus already present intracranially and preventing further clot formation in the original source region where the thrombus developed. Heparin is also often used after thrombolysis to maintain arterial patency. Most available information suggests that once an embolus has reached an intracranial artery recipient site, it most often fragments at some point in time and does not usually accrue further clot material. The first portion of this chapter reviews the data that suggests that spontaneous recanalization is prevalent, although it may take an extended period of time. The embolus that has already occurred then is not the main focus of heparin treatment. The decision on whether or not to prescribe heparin acutely to prevent the next thromboembolic stroke should depend on weighing the risk of acute re-embolization versus the risk of hemorrhage related to heparin therapy. The risk of further acute thrombus formation and embolization depends primarily on the nature of the cardiac and arterial source of the original thromboembolus. In patients with cardiac lesions that carry high rates of re-embolization—for example mitral stenosis with atrial fibrillation, atrial fibrillation with atrial thrombi or large left atria, and acute myocardial infarction with mural thrombi—acute heparinization is probably warranted. In patients with cardiac sources who have a low risk of acute re-embolization, such as chronic atrial fibrillation or mitral annulus calcification (MAC), heparin can be withheld during the acute period. Acute carotid and vertebral artery occlusions in the neck are important sources of intra-arterial embolism. When a thrombus first forms in a region of atherostenosis, the clot is not well organized and is not adherent to the arterial wall. The thrombus often

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extends, and a new thrombus forms, especially because flow is reduced above the thrombus. With time, probably three to four weeks, the thrombus becomes well organized and adherent, and further thrombus formation seems not to develop. Also during these weeks, collateral circulation develops and stabilizes. An argument can be made to use heparin and subsequently warfarin during the three to six week period, during which further thrombus development and embolization is a concern. The other aspect of the decision regarding heparinization concerns the risk of bleeding should heparin be used. The major risks factors are: hypertension, the presence of potential bleeding lesions, for example, peptic ulcer disease or hemorrhagic colitis, and the extent of brain infarction. If the patient has a large brain infarct, then the risk of brain hemorrhage after heparin is higher than when there is no brain infarct or a small brain infarct. The introduction of direct inhibitors of thrombin, such as ximelagatran and argatroban, into clinical care might change the method and risks of anticoagulation. Ximelagatran given orally produces rapid anticoagulant effects. This agent is given in a fixed dose and need not be monitored by either partial thromboplastin time (PTT) or International Normalized Ratio (INR) determinations making it easier to use and control. Direct thrombin inhibitors could replace both heparin and warfarin in treating stroke patients.

NEUROPROTECTIVE AGENTS Necropsy and experimental studies have characterized the cellular mechanisms and causes of brain cell death in relation to ischemic injuries (66). Clinicians have begun to give drugs in an effort to make the brain more resistant to ischemia. This type of therapy is usually called neuroprotective treatment. Neuroprotective therapy attempts to ameliorate the cellular metabolic consequences of ischemic injury (67 – 69). In an ischemic brain, calcium moves into cells via calcium-conducting channels and excitotoxic amino acids and free oxygen radicals. Leukocytes attracted to the ischemic zone promote cytotoxic injury to neurons (66). Alterations in growth factors and gene expression also contribute to programmed cell death. Knowledge of the mechanisms of cell injury have led to the development of many neuroprotective agents now in various stages of development and trials. These agents have very diverse posited modes of action and strategies for neuronal protection (66 – 69). Physicians hope that these agents can mitigate ischemic damage and delay neuronal death long enough to allow reperfusion. However, none of the agents used to date has been shown to be clearly effective in patients with brain ischemia. Hypothermia, statins, and citicholine have shown promise in preliminary studies. Hypothermia has been used for decades during cardiac and neurosurgical operations to reduce brain damage while brain perfusion is reduced. Mild and moderate hypothermia has been shown to reduce brain injury in patients with cardiac arrest (70,71) and traumatic brain injuries (72). There are strong theoretical reasons why hypothermia might be effective in patients with brain infarcts (73), and preliminary studies have shown that hypothermia can be used to reduce brain damage in patients with large cerebral hemisphere infarcts, either alone (74,75) or coupled with hemicraniectomy (76). A randomized trial is now studying the utility of hypothermia in patients with brain infarcts, mostly due to brain embolism (77). 3-Hydroxy-3-methylglutaryl coenzyme A (HMG coA) reductase inhibitors (statins), may have neuroprotective effects and their known salutary effect on blood lipids. Analysis of randomized trials of the prophylactic use of statins shows a clear and rather dramatic reduction in the incidence of stroke (78,79). Administration of statins after myocardial infarction and after the onset of brain ischemia has shown some

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effectiveness in preliminary clinical studiess (80,81). Citicholine is a precursor of phosphatidylcholine that can be given quite safely to patients with brain infarcts and hemorrhages. Trials have shown that this drug has some promise as a neuroprotective agent if given soon enough after brain infarction (82 – 84). MANAGING BRAIN EDEMA AND MASS EFFECT Brain edema also is an early occurrence in patients with embolic strokes. Ischemic edema can be intracellular (so-called cytotoxic edema or dry edema) or exist mostly in the extracellular spaces and connective tissue (vasogenic edema or wet edema) (85). Brain edema that lies in the interstices outside of cells might be posited to respond to osmotic diuretics, such as mannitol and glycerol, or to corticosteroids. However, studies have shown that these agents are not very effective in a series of stroke patients with large brain infarcts or hemorrhages. Most edema is probably within cells, and it signals that the cells are sick. Restitution of the normal metabolic functions of these cells is likely to be more therapeutic than so-called antiedema agents. There are some individuals, mostly young patients, who quickly develop extensive vasogenic, extracellular brain edema with the consequences of increased intracranial pressure and displacement and herniations of brain compartments. In these patients, a therapeutic trial of osmotic agents and/or corticosteroids is warranted because the situation is often desperate. In some patients with massive brain swelling and increased intracranial pressure, removal of the skull overlying the side of the infarct (hemicraniectomy) can be life-saving, but patients may be left with severe neurological residual deficits (75,86 – 88). Surprisingly, some patients make extraordinary recoveries after hemicraniectomies and survive with very little neurological deficit.

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53. Wijdicks EFM, Nichols DA, Thielen KR, et al. Intra-arterial thrombolysis in acute basilar artery thromboembolism: the initial Mayo Clinic experience. Mayo Clin Proc 1997; 72:1005 – 1013. 54. Cross lll, DT, Moran CJ, Akins PT, Angtuaco E, Diringer MN. Relationship between clot location and outcome after basilar artery thrombosis. AJNR 1997; 18:1221 – 1228. 55. Gonner F, Remonda L, Mattle H, et al. Local intra-arterial thrombolysis in acute ischemic stroke. Stroke 1998; 29:1894 – 1900. 56. 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. 57. Mitchell PJ, Gerraty RP, Donnan GA, et al. Thrombolysis in the vertebrobasilar circulation: the Australian Urokinase Stroke Trial. Cerebrovasc Dis 1997; 7:94 – 99. 58. Egan R, Clark W, Lutsep H, Nesbit G, Barnwell S, Kellogg J. Efficacy of intraarterial thrombolysis of basilar artery stroke. J Stroke Cerebrovasc Dis 1999; 8:22 – 27. 59. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein llb/llla receptors in cardiovascular medicine. N Engl J Med 1995; 332:1553– 15559. 60. Wallace RC, Furlan AJ, Moliterno DJ, et al. Basilar artery rethrombosis: successful treatment with platelet glycoprotein llb/llla receptor inhibitor. AJNR 1997; 18:1257– 1260. 61. Mousa SA, Mu D-X, Lucchesi BR. Prevention of carotid artery thrombosis by oral platelet GP llb/llla antagonists in dogs. Stroke 1997; 28:830– 836. 62. Hossman V, Dieter-Heiss W, Bewermeyer H, et al. Controlled trial of ancrod in ischemic stroke. Arch Neurol 1983; 40:803 – 808. 63. Olinger CP, Brott TG, Barsan TG, et al. Use of ancrod in acute or progressing ischemic cerebral infarction. Ann Emerg Med 1988; 17:1208– 1209. 64. Adams HP, Brott TG, Furlan AJ, et al. Use of thrombolytic drugs. A supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for Health Care Professionals from a special writing group of the Stroke Council American Heart Association. Stroke 1996; 27:1711 – 1718. 65. Alexandrov AV, Demchuk Am, Felberg RA, et al. High rate of recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-Mhz transcranial Doppler monitoring. Stroke 2000; 31:610– 614. 66. Garcia JH. Mechanisms of cell death in ischemia. In: Caplan LR ed. Brain Ischemia. Basic Concepts and Clinical Relevance. London: Springer-Verlag, 1995:7 – 18. 67. Caplan LR. Stroke: new therapies. Arch Neurol 1997; 54:1222 – 1224. 68. Fisher M, ed. Prophylactic neuroprotection in Stroke Therapy. Boston: Butterworth-Heinemann, 1995:233– 245. 69. Onal MZ, Fisher M. Thrombolytic and cytoprotective therapies for acute ischemic stroke: a clinical overview. Drugs of Today 1996; 32:573– 592. 70. The Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549–556. 71. Bernard SA. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557– 563. 72. Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997; 336:540– 546. 73. Milde LN. Clinical use of mild hypothermia for brain protection: a dream revisited. J Neurosurg Anesthesiol 1992; 4:211– 215. 74. Schwab S, Schwartz S, Spranger M, et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998; 29:2461 – 2466. 75. Schwab S, Georgiadis D, Berrouschot J, et al. Feasibility and safety of moderate hypothermia after massive hemisphere infarction. Stroke 2001; 32:2033– 2035. 76. Georgiadis D, Schwaqb S, Aschoff A, Schwab S. Hemicraniectomy and moderate hypothermia in patients with severe hemispheric stroke. Stroke 2002; 33:1884 –1888. 77. Krieger D, De Georgia MA, Abou-Chebl A, et al. Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 2001; 32:1847 – 1854.

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78. Hebert P, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278:313 – 321. 79. Blauw GJ, Lagaay AM, Smelt AHM, et al. Stroke, statins, and cholesterol. A meta-analysis of randomized placebo-controlled double-blind trials with HMG-CoA reductase inhibitors. Stroke 1997; 28:946 – 950. 80. Gotto AM Jr, Farmer JA. Reducing the risk of stroke in patients with myocardial infarction: A Myocardial Ischemia reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. Circulation 2002; 106:1595– 1598. 81. Montaner J, Chacon P, Krupinski, et al. Safety and efficacy of statins in the acute phase of ischemic stroke: The MISTICS Tria. Cerebrovasc Dis 2004; 17(suppl 5):129. 82. Warach S, Pettigrew LC, Dashe JF, et al. Effect of citicoline in ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators. Ann Neurol 2000; 48:713 – 722. 83. Adibhatla RM, Hatcher JF. Citicholine mechanisms and clinical efficacy in cerebral ischemia. J Neurosci Res 2002; 70:133 – 139. 84. Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicholine in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002; 33:2850 – 2857. 85. O’Brien MD. Ischemic cerebral edema in Brain ischemia. In: Caplan LR, ed. Basic Concepts and Clinical Relevance. London: Springer-Verlag, 1995:43 – 50. 86. Delashaw JB, Broaddus WC, Kassell NF, et al. Treatment of right hemisphere cerebral infarction by hemicraniectomy. Stroke 1990; 21:874 – 881. 87. Schwab S, Rieke K, Aschoff A, et al. Hemicraniotomy in space-occupying hemisopheric infarction: useful early intervention or desperate activism. Cerebrovasc Dis 1996; 6:325 – 329. 88. Schwab S, Steiner T, Aschoff A, et al. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke 1998; 29:1888– 1893.

16 Cardiac Source of Embolism: Treatment Warren J. Manning Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Just as our understanding of potential cardiac sources of embolism (chaps. 8 and 9) has greatly advanced over the past two decades, so has our knowledge regarding optimal treatment for these potential sources, particularly with regard to atrial fibrillation. Unfortunately, many questions regarding therapy for other potential sources remain, particularly with regards to treatment of patent foramen ovale (PFO), atrial septal aneurysm, and aortic atheroma. In this chapter, we summarize the current treatment recommendations for treating patients with many of the more common, suspected cardiac sources. ATRIAL FIBRILLATION Treatment of patients with atrial fibrillation in order to prevent primary or secondary thromboembolism is among the most common scenarios encountered by the clinician. The very prominent role of atrial fibrillation as a cause of clinical and subclinical stroke has been recognized for decades. For patients with atrial fibrillation, optimal therapy can be divided into prevention of thromboembolism among those needing cardioversion and issues related to chronic anticoagulation. We will first consider the use of anticoagulation for the patient who presents with new onset (first recognized episode) atrial fibrillation and for whom cardioversion is being contemplated and then consider treatment for the patient with recurrent and persistent (chronic/permanent) atrial fibrillation. NEW ONSET ATRIAL FIBRILLATION Thromboembolism from atrial thrombi can occur among patients with new onset, recurrent, and persistent atrial fibrillation. For patients with new onset atrial fibrillation, anticoagulation is an important component of the strategy used to restore sinus rhythm. Thromboembolism most often occurs during the first week after conversion (Fig. 1) (1). It has been described following spontaneous, chemical, as well as direct current cardioversion, and no method has been shown to proffer higher thromboembolic risk. Classically, thromboembolism after conversion to sinus rhythm has been attributed to dislodgment of 289

290

Manning

35 30 % of 25 Clinical Thrombo- 20 embolic Events 15 10 5 0 1D

2D

3D

4D

5D

6D

7D

>7D

Days following CV

Figure 1 Timing of clinical thromboembolic events following direct current cardioversion of atrial fibrillation or flutter. Abbreviation: CV, cardioversion. Source: From Ref. 1.

left atrial (appendage) thrombi that are present at the time of cardioversion (2). However, data suggest that the act of conversion (spontaneous, chemical, and electrical) is also associated with more depressed left atrial appendage (LAA) mechanical activity (Fig. 2) (3) with more intense spontaneous echo contrast (a marker of stasis) and new thrombus formation (4), thereby highlighting the importance of warfarin anticoagulation during the pericardioversion period. Anticoagulation for one month after conversion is

p = 0.05 0.5 p = 0.01 p = 0.001

LAA Velocity (m/sec)

0.4

0.3

0.2

0.1

0.0 Spontaneous Echo Contrast n = 12

No Echo Contrast n=8

Figure 2 Left atrial appendage ejection velocity following cardioversion of atrial fibrillation. Note that following successful direct current cardioversion, there is more depressed atrial ejection velocity. This occurs for both those with and those without spontaneous echo contrast. Abbreviation: LAA, left atrial appendage. Source: From Ref. 3.

Cardiac Source of Embolism: Treatment

291

*†

*†

2–3W

>3M

0.8 * Peak Transmitral A Wave (m/s)

0.6 * 0.4

0.2

0 Imm

3–6Hr

24Hr

4–7D

Figure 3 Recovery of left atrial mechanical function as assessed by transmitral Doppler following elective cardioversion of three months duration. Note that it takes several weeks for complete recovery of left atrial mechanical function.  P , 0.01 versus immediate. Source: From Ref. 5.

also often prescribed, as atrial mechanical function may remain depressed for up to a month (Fig. 3) (5) and is inversely related to the duration of anticoagulation (Fig. 4) (6). The first month after cardioversion also represents the period during which the patient is most vulnerable to a recurrence of atrial fibrillation. The use of warfarin therefore prevents thrombus formation if this occurs. There are no randomized prospective trials comparing the use of placebo with aspirin or warfarin for the prevention of thromboembolism in the patient who needs elective cardioversion. Our knowledge regarding thromboembolic risk is based on retrospective (7 –9) and nonrandomized data (10), inherently biased toward patient identification and recruitment. These data (Table 1) (7 – 10) suggest that for patients with atrial

0.8 Immediate 24 Hr 1 Wk

*

0.6

* p < 0.05 vs. Brief

Peak Transmitral A wave 0.4 Velocity

† p < 0.05 vs. Mod

* *

*

* *†

0.2

0.0

Brief ≤ 2 Wks

Moderate >2–6 Wks

Prolonged > 6 Wks

Duration of AF

Figure 4 Comparison of recovery of atrial mechanical function for those patients with atrial fibrillation of ,2 weeks: two to six weeks, and .6 weeks duration. Note the more rapid recovery of function associated with shorter duration atrial fibrillation. Abbreviation: AF, atrial fibrillation. Source: From Ref. 6.

292 Table 1

Manning Thromboembolism Without Warfarin Prior to Cardioversion of Atrial Fibrillation

Bjerkelunda (10) Weinberg (7) Arnold (8) Gentile (9)

Number of patients

Clinical thromboembolism rate (%)

209 28 179 115 50

5.6 7.1 6.3 (excluding postoperative atrial fibrillation) 1.7 (postoperative atrial fibrillation) 4.0

a

Prospective trial.

fibrillation of at least two days (or clinically unknown duration) the risk of clinical thromboembolism is 4 –7% if cardioversion is performed in the absence of warfarin. In contrast, retrospective and prospective data demonstrate that the use of warfarin [international normalized ratio (INR) 2.0 –3.0] is associated with a 90% reduction in thromboembolic risk, reducing risk to 0.6% (Table 2) (7–14). Though a therapeutic (INR 2–3) during the one-month period is generally considered sufficient, one study from Europe suggested that an INR of .2.5 at the time of cardioversion conveyed additional benefit (13). For patients in whom warfarin is initiated for cardioversion, the one-month “clock” begins with the first therapeutic INR ( 2.0). The mechanism of warfarin’s benefit is uncertain and has been presumed to be thrombus organization. However, data suggest that for patients with new onset atrial fibrillation, four to six weeks of warfarin is associated with a near 80% thrombus resolution (Fig. 5) (11,12,15 –17). This suggests that the mechanism of warfarin may facilitate thrombus resolution/silent migration. Should the INR fall to ,2.0 prior to cardioversion, the “one-month clock” is restarted, as transesophageal echocardiographic data have shown the likelihood of left atrial thrombus to be nearly 10% (18), a value quite similar to the 12% prevalence among patients with atrial fibrillation of unknown or prolonged (.2 day) duration who have not taken any chronic warfarin (4,11,16,19 – 21). For patients who have received a month of therapeutic warfarin, the routine use of transesophageal echocardiography (TEE) to document the absence of

Table 2 Thromboembolism with Warfarin (INR 2– 3) for Three to Four Weeks Prior to Elective Cardioversion of Atrial Fibrillation Number of patients Bjerkelunda (10) Weinberg (7) Arnold (8) Kleina (11) Seidla (12) Gentile (10) Gallagher (13)

209 51 153 101 64 357 788 1549

Stellbrinka (14)

248

a

Prospective control. Abbreviation: INR, international normalized ratio.

Clinical thromboembolism rate (%) 1.3 0.0 0.0 (excluding postoperative) 0.0 (postoperative) 1.6 0.8 0.8 0.5 0.0 if INR .2.5 at time of cardioversion 1.6

Cardiac Source of Embolism: Treatment

293

Figure 5 Serial transesophageal echocardiography examinations in a patient with atrial fibrillation and a thrombus (white arrows) in the body of the left atrium. Note the gradual resolution over several weeks with no intervening clinical event: (A) initial TEE, (B) one week, (C) three weeks, (D) 5.5 weeks. Abbreviations: LA, left atrium; Laa, left atrial appendage. Source: From Ref. 15.

thrombus after a month of warfarin does not reduce the incidence of embolic events (12), nor does it appear to be cost-effective (22). Such an approach, however, may be reasonable for the patient at very high risk, such as the patient with rheumatic valvular disease, dilated cardiomyopathy, or prior thromboembolism. For patients receiving one month of precardioversion warfarin, data regarding subclinical thromboembolism are currently unknown. TEE Guided Early Cardioversion With the advent of TEE and the ability to accurately identify thrombi within the atria (23 –27), there became available an imaging tool to screen for intracardiac thrombi and to cardiovert patients without the one-month delay. This was felt to be especially helpful as both the recovery of atrial mechanical function and the likelihood of maintaining sinus rhythm are inversely related to the duration of atrial fibrillation (6). There was initial interest that the use of TEE would obviate the need for any pericardioversion anticoagulation, but this was quickly tempered by anecdotal reports of thromboembolism after a “negative” TEE (28). The protocol that we have followed for over a decade is outlined in Figure 6. Patients with atrial fibrillation of unknown or more than two days’ duration are therapeutically anticoagulated with heparin or warfarin at the time of presentation. A TEE is then performed when the anticoagulation is therapeutic [INR  2.0 or partial thromboplastin time (PTT) .2x control]. If the TEE shows no thrombus, cardioversion is performed, and anticoagulation is continued for at least one month after cardioversion (19). Using this approach, TEE identifies thrombi in 12% of patients (Tables 3 and 4; 4,11,16,21,29), with nearly all within or involving the LAA. The prevalence increases to more than 30% for patients with mitral stenosis and atrial fibrillation (30). For those with nonvalvular atrial fibrillation, the best clinical predictors of a LAA thrombus are a history of thromboembolism and left ventricular systolic dysfunction (29). The greater

294

Manning

AF of Unknown or Prolonged (>2 days)

Heparin/Warfarin TEE when AC Therapeutic

No Thrombus

Thrombus

CARDIOVERSION During Index Admission Warfarin X 4 weeks

NO cardioversion Warfarin X 3–4 weeks Repeat TEE

Thrombus RESOLUTION: CARDIOVERSION Chronic warfarin

Thrombus PERSISTANCE: NO Cardioversion Chronic warfarin

Figure 6 Beth Israel Deaconess Medical Center – University of Connecticut Health Center TEE Guided Cardioversion Protocol for patients in whom an expedited cardioversion is desired. Patients presenting with atrial fibrillation of unknown or .2 days’ duration are given therapeutic heparin (PTT 2x control), and warfarin is begun. A TEE is then performed. If no thrombus is identified, cardioversion is performed. If a thrombus is identified (or cannot be excluded), cardioversion is deferred, and a repeat TEE is performed at four to six weeks of warfarin (INR 2 – 3). If thrombus has resolved, cardioversion may be performed. If there is persistant thrombus, cardioversion is again deferred. All warfarin eligible patients with TEE evidence of thrombus are given lifelong warfarin. Abbreviations: TEE, transesophageal echocardiography; AF, atrial fibrillation; AC, anticoagulation.

prevalence of thrombi (12%) as compared with the expected clinical thromboembolism (6%) is likely due to the imperfect specificity of TEE, the likelihood that not all left atrial thrombi will migrate, and that not all thrombi that migrate will cause a clinical event (31). In the absence of TEE evidence for atrial thrombus and using the strategy outlined in Figure 7, data from five prospective trials (4,6,11,16,19,21,29) show a clinical thromboembolism rate of 0.5%, similar to that expected with one month prior treatment with warfarin (Table 5). The randomized Assessment of Cardioversion Using

Table 3 TEE Evidence of Thrombi Among Patients with Atrial Fibrillation of Unknown or Prolonged Duration Study Stoddard (4) Klein (11) Corrado (16) Weigner (29) Klein (21)

Number of patients 206 56 123 501 619

Abbreviation: TEE, transesophageal echocardiography.

# (%) With atrial thrombi 37 7 11 70 76

(18%) (13%) (9%) (13%) (14%)

Cardiac Source of Embolism: Treatment

295

Table 4 Thromboembolism with Short-Term Warfarin (INR 2 – 3) or Heparin (PTT . 2x Control) and Screening TEE Negative for Atrial Thrombus Number of patients

Thromboembolism [(# (%)]

413 47 38 112 619

1 (0.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 5 (0.5%)

Weigner (29) Stoddard (4) Klein (11) Corrado (16) Klein (21)

Abbreviation: TEE, transesophageal echocardiography.

Transesophageal Echocardiography (ACUTE) trial data showing slightly higher (although nonsignificant) rate of clinical thromboembolism for the TEE arm (0.8%), as compared with conventional therapy suggested that this study may have been underpowered to show a benefit for conventional therapy. However, examination of the adverse events in that trial (21) shows that 60% of the adverse events in the TEE arm occurred while the patients were in atrial fibrillation and 80% of events occurred at a time the patients had a subtherapeutic INR, while all the adverse events in the conventional arm occurred during periods of therapeutic INR. Thus, we are left with the likely “equivalence” for the expedited cardioversion with TEE and more conventional one month of pre-cardioversion anticoagulation. At our institution, a TEE-expedited approach has become the “standard” for patients admitted to the hospital for treatment of atrial fibrillation, whereas conventional therapy is used for outpatients.

57 events (5.7%)

No

1,000 Patients with AF >2 days

warfarin

1 mo warfarin

12% thrombi on TEE (~50% embolism rate)

880 No LA clot

120 LA clot 80% thrombi resolve after 1 mo warfarin

96 clots resolve

24 clots persist ?30% embolism rate

For 1,000 pts ---> 7/1,000 =0.7% event rate If LA clot ---> 7/120 = 5.8% event rate

7 events

Figure 7 Rationale for follow-up TEE prior to cardioversion after TEE evidence for thrombus. In the absence of prolonged warfarin, data suggest that 5.7% of patients will have a clinical embolic event following cardioversion. TEE identifies 12% of patients with thrombi, or 120 thrombi in the population of 1,000 subjects. If we make the assumption, that 80% of the thrombi resolve and that thrombi are less likely to cause an embolic event (as more adherent/organized), 7 of the original 120 patients with thrombi would be expected to have an embolic event if screening TEE were not performed. This rate (7/120 ¼ 5.8%) is the same “unacceptable rate” as the original cohort of 1,000 subjects. Abbreviations: TEE, transesophageal echocardiography; LA, left atrium; AF, atrial fibrillation.

296

Manning

Table 5 Clinical Rate of Thromboembolism Following Cardioversion of Patients without TEE Evidence of Thrombi Study

Number of patients

Stoddard (4) Klein (11) Corrado (16) Weigner (29) Klein (21)

# (%) Post-CV thromboembolism

47 38 112 413 619

0 0 0 1 5

(0%) (0% vs. 1.6%) (0%) (0.2%) (0.8% vs. 0.5%)

Abbreviations: CV, cardioversion; TEE, transesophageal echocardiography.

Thrombus Resolution. For patients who have an atrial thrombus identified on their first TEE, conversion to sinus rhythm should be avoided and warfarin anticoagulation administered (INR 2– 3). Nearly 80% of thrombi will resolve after four to six weeks (12,15 –17,21) (see later). Decision-analysis assessment of cardiovascular risk suggests that these patients are at increased risk for thromboembolism and should undergo TEE to confirm thrombus resolution prior to attempted cardioversion (32). The rationale for this is presented in Figure 7 and is supported by data in the literature of 10% thromboembolism rates among patients with residual atrial thrombi who undergo elective cardioversion (33). In addition, though there are only indirect data to directly support this approach, I favor the use of chronic warfarin (target INR 2– 3) for all patients who have a documented atrial thrombus on TEE. This recommendation is independent of their rhythm or clinical risk factors (see the next section). Risks of Short-term Anticoagulation. The benefit of thromboembolism reduction must be weighed against the risk of hemorrhagic complication. Prospective data regarding hemorrhagic risk in the atrial fibrillation precardioversion population suggest a 1.5% risk of major hemorrhage and 4– 8% risk of minor hemorrhage (Table 6). Post-thoracotomy Atrial Fibrillation. The development of atrial fibrillation following cardiac surgery is a very common occurrence and is associated with an increase in in-hospital stroke (34), although it is uncertain as to the attributable risk to the arrhythmia itself as compared with comorbidities (35). In the absence of pre- and postoperative beta blockade, the incidence may approach 40% for those undergoing coronary artery bypass surgery and exceed 50% if this is combined with mitral valve surgery (34). In addition to valve surgery, risk factors for postoperative atrial fibrillation include advanced age and prior history of atrial fibrillation, especially among patients undergoing mitral valve surgery (34,36 –38a). Prophylactic therapy with beta blockers and amiodarone reduce the frequency of atrial fibrillation by 30 – 50% (39). Meta-analyses have also suggested a reduction in atrial fibrillation for patients who undergo off-pump bypass (40,41). The majority of first episodes of atrial fibrillation occur within the first two postoperative Table 6 Hemorrhagic Risk for Patients Prescribed Warfarin in Preparation for Elective Cardioversion

Weinberg (7) Klein (11) Klein (21)

Number of patients

Major hemorrhage (%)

Minor hemorrage (%)

76 64 603

1.3 1.6 1.5

7.8 4

Cardiac Source of Embolism: Treatment

297

days, and most recurrences occur within the first three days (37). Among those without a prior history of atrial fibrillation, the arrhythmia usually self-terminates within 24 hours (42). If cardioversion is desired, data suggest that with preserved left ventricular systolic function, the postoperative atrial fibrillation cohort represents a group at relatively low risk for thromboembolism even without anticoagulation (Table 1; 8), possibly related to the platelet dysfunction and coagulation consumption that occurs with cardiopulmonary bypass. The thromboembolic risk is primarily limited to those with atrial fibrillation of more than 48 hours and those who have high clinical risk factors (CHADS2 criterion) (43). Atrial Fibrillation of Less than Two Days. The recommendations regarding one month of warfarin or short-term warfarin anticoagulation and TEE apply to patients with atrial fibrillation of a duration of at least two days. With the exception of patients with valvular disease, prior stroke, or transient ischemic attack (TIA), the embolic risk associated with cardioversion appears to be quite low—even in the absence of warfarin or screening TEE—if cardioversion can be performed within 48 hours of atrial fibrillation onset. Two studies (13,44) have noted 0.6% clinical thromboembolism rates when these patients are converted early and without wafarin or screening TEE. This rate is nearly identical to that expected were this population to be treated with a month of warfarin or screening TEE (Tables 2, 5). RECURRENT OR PERSISTENT ATRIAL FIBRILLATION The prior section addressed the issue of anticoagulation treatment for patients with new onset atrial fibrillation for whom cardioversion is desired. Much more common is the scenario of the patient with recurrent or permanent atrial fibrillation, in whom issues of rhythm versus rate control and anticoagulation to prevent thromboembolism occur. Rhythm Versus Rate Control A comprehensive review of rhythm versus rate control is beyond the scope of this chapter. Until recently, physicians often were relatively aggressive in trying to maintain sinus rhythm under the belief that this would be beneficial with regard to prevention of thromboembolism and to improve the patient’s quality of life. However, data from two prospective trials have documented no thromboembolism or survival benefit to the rhythm control (repeated cardioversion and use of anti-arrhythmic medication to maintain sinus rhythm) versus ventricular rate control and warfarin for this population. The Atrial Fibrillation Follow-up Investigation in Rhythm Management (AFFIRM) study (45) included more than 4,000 subjects recruited from the United States and Canada who were over 65 years or under 65 years but who had at least one atrial fibrillation risk factor followed for 3.5 years. The primary and secondary end points were similar (Table 7). A major finding of this study was that the majority of strokes in both groups (67% of rate control and 95% of rhythm control) occurred when the patient was not taking wafarin or when the INR was subtherapeutic (,2.0). The smaller RAte Control versus Electrical (RACE) cardioversion for persistent atrial fibrillation (46) had similar results in a study of 522 patients from Holland followed for 2.3 years, with a primary endpoint reached in 17.2% of rate control subjects as compared with 22.6% of rhythm control patients. Thromboembolic complications occurred in 5.5% of rate control versus 7.9% of rhythm control subjects. The results of these two pivotal trials along with the later Pharmacological Intervention in Atrial Fibrillation (PIAF) (47) and Strategies of Treatment of Atrial Fibrillation (STAF) (48) trials emphasized that patients with atrial fibrillation remain at risk for clinical thromboembolism independent of rhythm (Table 8). The

298 Table 7

Manning Primary and Secondary End Points from AFFIRM

Event

Rate control (%)

Rhythm control (%)

P

25.9 32.7 5.5 1.1 0.8 0.1

26.7 32.0 7.1 1.3 0.8 0.5

0.08 0.33 0.79 0.73 0.68 0.16

Primary (death) Secondary (death, stroke, major bleed) Ischemic stroke Intracerebral hemorrhage Subdural/subarachnoid bleed Pulmonary embolism

Abbreviation: AFFIRM, atrial fibrillation follow-up investigation in rhythm management. Source: From Ref. 45.

reasons for this are unknown but include the strong likelihood that they have frequent episodes of asymptomatic atrial fibrillation (49) and other cardiac sources that are independent of heart rhythm, for example, aortic atherosclerosis (50) and left ventricular thrombi (51). Patients with atrial fibrillation, regardless of rhythm, should be chronically anticoagulated with warfarin based on their clinical risk profile (see the next section).

ATRIAL FIBRILLATION RISK PROFILE The overall risk of ischemic stroke among all patients with atrial fibrillation in both the clinical trial data and Framingham Heart Study is 4–5%/yr (52), but the absolute risk varies among patients. Extensive data from five prospective randomized stroke-prevention trials in patients with atrial fibrillation have been published—including the Copenhagen AFASAK Study (53), the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) (54), Stroke Prevention in Atrial Fibrillation (SPAF) (55), the Canadian Atrial Fibrillation Anticoagulation trial (CAFA) (56), and the Veterans Administration Stroke Prevention IN Atrial Fibrillation (SPINAF) (57). These studies showed a two-thirds reduction in clinical stroke risk with warfarin (Table 9) as compared with aspirin, but increased the risk of major bleeding rate by about 50% (58). Given the hemorrhagic risks associated with warfarin, individualizing care by quantifying the risk of stroke in the individual patient is crucial for determining which atrial fibrillation patients benefit most from warfarin. Risk stratification in patients with atrial fibrillation can be performed using both clinical and echocardiographic measures (58). The five primary prevention trials just Table 8

Rhythm versus Rate Control Event rate

Number of subjects

Rate control (%)

Rhythm control (%)

RR

P

AFFIRM (45) RACE (46) STAF (48) PIAF (47)

4060 522 266 252

5.7 2.4 1.0 0.8

7.3 5.3 3.0 3.9

1.28 2.25 3.0 4.92

0.12 0.13 0.52 0.22

Total

5100

4.7

6.3

1.36

0.04

Study

Abbreviation: AFFIRM, atrial fibrillation follow up investigatioin rhythm management; RACE, rate control versus electrical; STAF, strategies of treatment of atrial fibrillation; PIAF, pharmacologic intervention in atrial fibrillation; RR, relative risk.

Cardiac Source of Embolism: Treatment

299

Table 9 Nonvalvular Atrial Fibrillation Trials—Primary Prevention. Risk Reduction with Warfarin Event rate Trial AFASAK (53) SPAF I (55) BAATAF (54) CAFA (56) SPINAF (57)

End points

Target INR

Warfarin

Control

Stroke, TIA, Pemb Stroke, Pemb Stroke Stroke, Pemb, Hem Stroke

2.8– 4.2 2.0– 3.5 1.5– 2.7 2.0– 3.0 1.4– 2.8

2.0 2.3 0.4 3.5 0.9

5.5 7.4 3.0 5.2 4.3

Relative risk 59 67 86 37 79

( P , 0.05) ( P ¼ 0.01) ( P ¼ 0.002) ( P ¼ 0.2) ( P ¼ 0.001)

Abbreviations: INR, international normalized ratio; TIA, transient ischemic attack; Pemp, pulmonary embolism.

mentioned pooled their data in an attempt to develop a clinical risk stratification scheme (52) and identified age .65 years, history of stroke or TIA, diabetes mellitus, and a history of hypertension as the risk factors (Table 10). Patients without any risk factors (15% of the total) comprised a low-risk group in whom the annual stroke risk was ,1% with aspirin alone (52), whereas the risk for those with prior stroke exceeded 20%/year. Many other risk-factor strategies have been developed, including those by the American College of Chest Physicians (59) and an amalgamation of strategies called CHADS2. The CHADS2 (Table 11; 60) strategy assigns one point for each clinical criterion—congestive heart failure or left ventricular ejection fraction ,40%, hypertension, age . 75 years, and diabetes, with two points for prior stroke or TIA. Using the CHADS2 model, patients with a score of 0 had an adjusted rate of ischemic stroke or peripheral embolism of 1.8%/year, whereas those with a maximum score of six had an adjusted stroke rate of 18%/year. The CHADS2 strategy was compared in a patient dataset and found to be superior (61) and has been widely adopted due to its simplicity. The stroke rate for atrial fibrillation patients treated with aspirin increases from 0.5%/year (CHADS2 score of 0) to 1.5%/year (CHADS2 score of 1) to 2.5 (CHADS2 ¼ 2) to .5% (CHADS2 score 3) (61). In general, patients with a CHADS score of zero can be managed with aspirin alone, and those with a CHADS2 score of at least three should be given warfarin (INR 2.0 – 3.0). For those with an intermediate risk (CHADS2 scores of 1 or 2) with no prior embolic event, the choice between warfarin and aspirin is less certain (Table 12) (62). Echocardiographic parameters have also been studied as a means of identifying patients who are at increased risk for thromboembolism. More extensive transthoracic data exist, and pooled data from the three trials that collected transthoracic data identified left ventricular systolic dysfunction as a risk factor for stroke (63). In this analysis of more than a Table 10

Risk Factors for Stroke Annual stroke event rate (%)

Variable Prior stroke/TIA History of hypertension History of diabetes History of CHF

N

RR

No therapy (n ¼ 1236)

Warfarin (n ¼ 1222)

101 750 250 349

2.5 1.6 1.7 1.4

11.7 5.6 8.6 6.8

5.1 1.9 2.8 1.6

Abbreviations: CHF, congestive heart failure; TIA, transient ischemic attack; RR, relative risk. Source: From Ref. 50.

300 Table 11

Manning CHADS2 Stroke Risk Strategy

C, congestive heart failure or left ventricular systolic dysfunction H, hypertension, SBP . 160 mmHg A, age .75 years D, diabetes S2, stroke or transient neurological event Minimum score ¼ 0 Maximum score ¼ 6 (a stroke or transient neurologic event gets 2 points) Abbreviation: SBP, systolic blood pressure. Source: From Ref. 60.

thousand subjects, the relative risk (RR) of stroke was 2.5 for those with moderate or severe left ventricular systolic dysfunction. Increasing left-atrial dimension was not a predictor for stroke in the pooled analysis, possibly due to the confounding influence of mitral regurgitation, which was shown to be protective against thromboembolism (64), and increased stasis related to left-atrial dilation. Data regarding the prognostic value of TEE with regard to thromboembolism risk in the high-clinical risk atrial fibrillation population are largely derived from the TEE substudy of SPAF-III (Table 13; 50). This prospective substudy showed that 20% of high-clinical risk patients had TEE evidence for dense spontaneous echo contrast, 10% had atrial thrombi, and more than a third had complex aortic plaque. In the absence of TEE-identified risk factors of a left atrial abnormality (spontaneous echo contrast, atrial thrombus, atrial appendage ejection velocity , 0.2 m/s) and aortic plaque, event rates in subjects treated with a combination of aspirin and low-dose warfarin was only 1.3%/year but increased to 7.8%/year for patients with a left atrial abnormality, to 12%/year for those with complex aortic plaque, and to more than 20%/year if atrial and aortic risk factors were present (50). Although routine TEE has not been recommended for guiding anticoagulation, should TEE data be available, it is reasonable to consider these data with the CHADS2 clinical criteria in guiding the use of aspirin or warfarin.

COMBINATION THERAPY The role of combination therapy (aspirin 325 mg daily and low-dose warfarin, target INR 1.2 – 1.5) was shown to be ineffective for stroke prevention in the prematurely terminated Table 12

Estimated NNT to Prevent One Stroke Event rate/year

CHADS2 score 0 1 2 3 4 5–6

Warfarin

No warfarin

NNT

0.25 0.72 1.27 2.20 2.35 4.60

0.49 1.52 2.50 5.27 6.02 6.88

417 125 81 33 27 44

Abbreviation: NNT, number of patients needed to treat. Source: From Ref. 62.

Cardiac Source of Embolism: Treatment Table 13

301

Relative Risk of Thromboembolism with TEE Risk Measures Annual event rate (%)

Variable Dense SEC Atrial thrombus Peak LAA ejection ,0.2 m/s Complex aortic plaque

Combinationa

Warfarin

RR

P

18.2 12.9

4.5 17.9

2.6 2.7

0.09 ,0.05

13.1 15.8

6.7 4.0

2.6 12.3

,0.05 0.02

Abbreviations: TEE, transesophageal echocardiography; LAA, left atrial appondage; SEC, spontaneous echo contrast; RR, relative risk. Source: From Ref. 50.

high clinical risk SPAF-III study (Fig. 8) (65). For this trial, an INR of .1.9 was needed to convey benefit with no significant stroke benefit to adding low-dose warfarin to aspirin but a definite increase bleeding risk. Ximelagatran Although not approved for use in the United States, the oral thrombin inhibitor, ximelagatran, is available in several other countries. Taken twice a day, ximelagatran acts to inhibit the conversion of fibrinogen to fibrin by thrombin. Noninferiority of ximelagatran (36 mg BID) as compared with warfarin (INR 2 – 3) was shown in two large randomized trials of patients with atrial fibrillation and at least one additional risk factor for stroke: the 3,407patient, Europe –Asia –Australasia, open-labeled SPORTIF III trial (66) and the 3,922 subject, North American, blinded, SPORTIF V trial (67). The noninferiority primary end point (stroke and systemic embolization) was demonstrated in both trials. For SPORTIF III, primary events occurred in 2.3%/year of the warfarin (INR 2 –3) group versus 1.6% of the ximelagatran group, whereas in SPORTIF V, the rates were 1.2% 20

15 Annual Event Rate (%)

10

5

0 <1.2

->1.5

->1.9

->2.4

>2.4

INR

Figure 8 Data derived from the SPAF-III trial of low-dose warfarin and aspirin versus fulldose warfarin (INR ¼ 2 – 3). The benefit against thromboembolism was confined to an INR of at least 1.9. Abbreviation: INR, international normalized ratio. Source: From Ref. 65.

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for warfarin and 1.6% for ximelagatran (P ¼ NS). There was no difference in major bleeding between the two groups, but all bleeding (major and minor) was reduced in the ximelagatran group. However, ximelagatran has not received approval from the United States Food and Drug Administration, primarily because of concerns about the risk of severe liver injury. In SPORTIF V, liver enzyme elevation (serum ALT .3 times the upper limit of normal) occurred significantly more often with ximelagatran (6% vs. 0.8%), usually within the first six months. Although serum ALT tended to decline over time whether or not ximelagatran was continued, there was one documented and one suggestive case of fatal liver disease. Due to difficulties with monitoring and inconvenience, it is likely that safer alternatives to ximelagatran will be pursued in the coming years. Treatment of Left Atrial Thrombi: The Use of Warfarin More than 90% of thrombi in patients with nonvalvular atrial fibrillation lie within the left atrial appendage (68). Although there are no prospective or even retrospective data to support such action, many physicians recommend a higher target INR (e.g., 2.5–3.5) and the use of chronic warfarin (regardless of CHADS2 criteria) for patients with documented atrial thrombi on TEE. For patients with nonvalvular atrial fibrillation and left atrial thrombi, treatment with warfarin (INR 2–3) for one to two month is associated with thrombus resolution in almost 80% of subjects (Table 14). Despite thrombus resolution in the majority, data suggest that 10–18% of patients with LAA thrombi will have embolic events chronic warfarin (20,50). Preliminary data from a nonrandomized study of 113 patients with atrial fibrillation and TEE evidence of atrial appendage thrombi (69) suggested a potential benefit of surgery for those with larger thrombi. Emergent left atrial appendage appendectomy was performed in 25 surgical candidates who had thrombi .15 mm, whereas 88 patients who were not surgical candidates or had smaller thrombi were treated with warfarin alone. Preliminary results suggest freedom from stroke was superior among those who were candidates and treated with surgery (94% at 5 years vs. 57%). Nonpharmacological Alternatives As previously mentioned, the AFFIRM, RACE, STAF, and PIAF trials (45 –48) emphasized the importance of anticoagulation with warfarin independent of rhythm and that maintenance of sinus rhythm alone was not sufficient to prevent clinical thromboembolism in this population. As many thrombi that are thought to lead to stroke are likely to originate in the left atrial appendage (68). Left atrial appendage ligation, amputation, and occlusion have been studied as an alternative for patients who are not candidates for warfarin. Indeed, the standard MAZE procedure includes atrial appendage amputation, which is often performed in concert with mitral valve surgery (70). Unfortunately, surgical ligation or

Table 14

Thrombus Resolution in New Onset, Nonvalvular Atrial Fibrillation

Study Collins (15) Klein (22) Corrado (16) Jaber (17) Seidl (12)

Number of patients 14 6 11 161 55

Warfarin duration (month) 1 1.5 1–2 1.5 1

% Thrombus resolved 12 (86%) 3 (50%) 9 (82%) 129 (80%) 30 (55%)

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Figure 9 (A) Percutaneous closure device for patients with a patent foramen ovale or small atrial septal defect. Source: From Ref. 73. (B) Transesophageal echocardiography in a patient following septal-occluder device implantation. The left atrium side of the occluder device is readily seen (white arrow). Abbreviations: LA, left atrium; LAA, left atrial appendage.

stapling is often incomplete (71,72). Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) (73) is currently being studied as one of several percutaneous LAA closure device alternatives for clinically high-risk patients who are ineligible for chronic warfarin (Fig. 9). Early experience in the first 111 patients from one multicenter trial showed successful implantation among 97% of subjects with 3% risk of the hemopericardium requiring pericardiocentesis and 3% risk of stroke at 10 months. Other devices are also being studied (74). Larger series are needed before such an aggressive approach can be advocated. Although the setting of atrial fibrillation and stroke prevention has received considerable attention over the past three decades, other areas are less well defined. For many, such as the those with an intracardiac tumor or intraventricular thrombus, empiric treatment strategies have evolved without definitive randomized trials to demonstrate efficacy. For other areas, there continues to be even greater controversy.

304

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Treatment of Left Ventricular Thrombus Left ventricular (LV) thrombi (Fig. 10) are most commonly encountered in patients with large ST elevation anteroapical myocardial infarctions, often in concert with apical aneurysms. Based on transthoracic echocardiography (TTE), most thrombi develop within the first two weeks after infarction (75 –77). Though some patients may subsequently develop a new LV thrombus in association with worsening LV function. The use of high-dose, subcutaneous, unfractionated, heparin (12.5 K units q12 hours) as well as prophylactic, lowmolecular weight heparin reduces the development of LV thrombi with acute anterior Qwave myocardial infarction (78,79). For patients who have an LV thrombus, warfarin (INR 2 –3) substantially reduces the risk of clinical thromboembolism (80), although it may not impact thrombus resolution (81). Serial echocardiography is often used to monitor thrombi size (and hoped for resolution), though data suggest that cardiovascular magnetic resonance may be more sensitive for thrombus detection (51). Long-term management is more controversial. Though there are no data demonstrating efficacy, as in patients with atrial fibrillation, I generally prescribe chronic warfarin (INR 2 –3) for all patients with ventricular thrombi, recognizing that there is disagreement as to whether warfarin can be stopped after four to six month, a period of presumed endothelialization of the thrombus surface and organization/adherence to the underlying scarred subendocardium (82). Treatment of Aortic Atherosclerosis Aortic atherosclerotic plaques, which are most often seen on TEE (Fig. 11), are a manifestation of systemic atherosclerosis. They are associated with risk factors for atherosclerotic disease, including age, hypertension, and hypercholesterolemia, and are more common in patients with coronary artery disease and atrial fibrillation (50,83). Aortic atherosclerotic plaques are an important source of systemic emboli, leading to stroke, TIA, and arterial embolization (84 – 86). Embolic events in the setting of aortic atherosclerosis can occur spontaneously or they can be induced by interventions including cardiac catheterization,

Figure 10 Transthoracic echocardiogram from the apical four-chamber orientation. Note the apical thrombus (white arrow) in this patient who suffered an anteroapical myocardial infarction. Abbreviation: LV, left ventricle.

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305

Figure 11 Transesophageal echocardiography of the descending thoracic aorta in a patient with extensive complex (.4 mm) plaque (arrows).

intra-aortic balloon pumping, and cardiac surgery (87,88). Treatment of complex aortic plaques may prevent embolization, though the preferred treatment has not been identified. The rationale for warfarin and/or anticoagulation is that complex aortic plaques often contain thrombus as well as atheroma. The Argument for Anticoagulation. Three uncontrolled reports support the efficacy of warfarin therapy for patients with complex aortic plaque. The prospective TEE substudy of the SPAF-III trial compared adjusted-dose (INR 2 –3) warfarin to aspirin plus low-dose warfarin (INR 1.2 – 1.5) among a subset of 382 clinically high-risk patients (50). At a mean follow-up of 1.1 years, adjusted-dose warfarin reduced the incidence of clinical stroke in patients with complex aortic plaques from 15.8% to 4%. Two observational studies also suggested a benefit from warfarin. An observational study (89) of 31 patients with systemic thromboembolism and mobile aortic atheroma on TEE, followed for 10 months after hospital discharge, reported a significant reduction (5% vs. 45%) in vascular events (stroke and myocardial infarction) and stroke alone (0% vs. 27%) among the 20 treated with warfarin, as compared with the 11 patients who were not anticoagulated. Embolic events also occurred more frequently in those with mobile plaques. Another observational report on 129 patients with complex aortic atheroma who had undergone TEE for various indications (90) showed that at 2 years, there was a significant benefit of warfarin anticoagulation (vs. antiplatelet therapy) for patients with complex plaque (.4 mm and/or mobile). Thus, although no randomized data are available, the 2004 Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy recommended warfarin therapy in patients with complex (mobile and/or .4 mm) aortic atheroma (59). Though the target INR in this group has not been studied, it seem reasonable to use the same targets as that used for atrial fibrillation (e.g., INR 2– 3). (See chap. 17 for additional discussion of the treatment of aortic atherosclerotic disease.) The Argument for Lipid-lowering and Statin Therapy. In addition to warfarin anticoagulation, a strong argument can be made for statin therapy in this same group. A variety of potentially beneficial mechanisms have been described for statin therapy,

306

Manning

including regression of atherosclerosis and plaque stabilization (91). Like anticoagulation, the suggestion of a benefit of statin therapy for complex aortic plaque is largely based on nonrandomized, observational data. In the largest report that included 519 patients with complex aortic plaque (92), statin therapy was associated with a 17% risk reduction in embolic events. Interestingly, there was no benefit with aspirin, and there was only a trend toward benefit with warfarin. The intensity of statin therapy remains of uncertain clinical benefit, though plaque regression is associated with more intense therapy (91). Role of Surgical Therapy. Current data do not support operative procedures to prevent embolic events in patients with complex aortic atherosclerosis. Though no randomized prospective trials have been performed, in one report, excision of aortic arch atheroma was associated with an increased risk of stroke (35% vs. 12%), compared to those not having the procedure (93). Treatment of Endocarditis Issues related to the choice and duration of antibiotic treatment for endocarditis is beyond the scope of this chapter. Overall, early and prompt treatment with broad-spectrum antibiotics with subsequent tailored therapy after organism identification and antibiotic sensitivity are known to lead to the best outcome (94). What will be considered in this chapter are issues related to anticoagulation and indications for surgical intervention. Anticoagulation and Antiplatelet Therapy. The issue of anticoagulation in the setting of endocarditis is a surprisingly common situation as an increasing proportion of patients with endocarditis have infected prosthetic mechanical heart valves or are receiving chronic warfarin for other conditions (e.g., atrial fibrillation). The most common mechanism leading to central nervous system (CNS) complications is hemorrhagic transformation and septic arteritis, whereas mycotic aneurysm rupture is relatively uncommon (95,96). There are no published randomized trial data, and retrospective case series vary greatly in outcome, with some showing a benefit from continued anticoagulation (8% CNS events vs. 70%) (97,98) and other data suggesting an increased risk of complications if warfarin is continued (99). Overall, anticoagulation is thought to increase the risk of a hemorrhagic stroke (100). Despite this, it is generally recommended that anticoagulation be continued for those with an absolute indication for anticoagulation (e.g., mechanical heart valves) but that warfarin be held and shorter acting intravenous heparin or low molecular weight heparin be used. The use of heparin or low molecular weight heparin also minimizes the concern about the impact of antibiotics on the INR. For those patients not on warfarin, or those in whom there is no absolute indication (e.g., prophylaxis for thromboembolism in low- or moderate-risk atrial fibrillation), warfarin should be discontinued or not started. For patients who initially present with an embolic stroke, the clinician is faced with the issue of treating a patient with endocarditis and stroke who is also in need of therapeutic warfarin. In these subjects, withholding of warfarin is recommended due to the concern of a hemorrhagic conversion. The optimal time to restart anticoagulation is empiric for those with nonhemorrhagic strokes, with many suggesting that heparin can be started a few days after a small stroke and after one week for those with large infarctions (101). Even stronger are recommendations to withhold warfarin for patients with evidence of a hemorrhagic stroke. Indications for Surgery. For patients with endocarditis, indications for surgical intervention have expanded over the past decade. As discussed in Chapter 9, the risk of embolism is increased with larger and more mobile vegetations (102). Overall, the risk of surgical complications is slightly higher in patients with prosthetic-valve endocarditis. There is general consensus (Table 15; 70) that surgery is warranted for patients with any of

Cardiac Source of Embolism: Treatment Table 15

307

Recommendations for Surgery for Endocarditis

Native valve endocarditis Acute aortic or mitral regurgitation with heart failure Fungal endocarditis Annular or aortic abscess, sinus, or aortic true or false aneurysm Persistent infection (e.g., fever, leukocytosis, bacteremia) after seven to ten days despite appropriate antibiotic therapy and lack of noncardiac causes of infection Recurrent embolism despite appropriate antibiotics Prosthetic valve endocarditis Early (,1– 2 month after surgery) prosthetic valve endocarditis Heart failure with prosthetic valve dysfunction Fungal endocarditis Staphylococcal endocarditis not responding to antibiotic therapy Annular or aortic abscess, sinus or aortic aneurysm, fistula formation, or new conduction disturbance Persistent bacteremia after seven to ten days of appropriate antibiotics without a noncardiac cause for bacgteremia Recurrent embolism despite therapy Source: From Ref. 70.

the following conditions: (i) moderate to severe heart failure directly related to valve dysfunction (regurgitation), (ii) an unstable prosthesis or relapsing prosthetic valve endocarditis, (iii) resistant infection while receiving appropriate antibiotic therapy, including evidence of perivalvular abscess, and (iv) recurrent embolism, particularly in the presence of large vegetations (Fig. 12), though vegetation size alone is not an indication for surgery.

Treatment of Intracardiac Tumors The most common primary tumor of the heart is a myxoma, most often associated with the interatrial septum (Fig. 13). Once a presumptive diagnosis of myxoma has been made, prompt resection is essential in operative candidates because of the risk of embolization of overlying thrombus or the tumor itself (103,104). The outcome of surgical resection

Figure 12 Transesophageal echocardiography demonstrating a large vegetation involving the posterior mitral leaflet (short arrow) and a much smaller vegetation at the tip of the anterior mitral leaflet (long arrow).

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Manning

Figure 13 Transesophageal echocardiography in a patient with a large left atrial myxoma (white arrow) attached to the interatrial septum in the area of the foramen. Abbreviation: RA, right atrium.

is generally very good, with most series reporting an operative mortality of less than 5% (103 –105). Treatment of other cardiac tumors may be less decisive. Papillary fibroelastoma (Fig. 14) is the second most-common benign primary tumor of the heart. Like myxoma, a presumptive diagnosis can generally be made on imaging studies. There is general agreement that surgery is indicated for patients who have had embolic events or local complications related to tumor mobility (e.g., ostial coronary obstruction) those with highly mobile or large (1 cm) tumors (106), or for all patients (107). Others have suggested that careful observation is an acceptable option for asymptomatic patients who have small, nonmobile tumors (106).

Figure 14 Transesophageal echocardiogram in the parasternal short axis view in a patient with a small fibroelastoma (white arrow) attached to the aortic valve.

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309

ABNORMALITIES OF THE INTERATRIAL SEPTUM Abnormalities of the interatrial septum are associated with thromboembolism via two pathophysiological mechanisms: right-to-left shunting and interatrial septal aneurysms. As discussed in the prior chapters on diagnoses (Chapters 8 and 9), the role of PFO and stroke is undergoing intense scrutiny. Treatment options for those with stroke and a PFO include medical therapy with warfarin or antiplatelet agents, percutaneous closure using “clamshell” type devices and direct surgical closure. In the absence of neurological symptoms, data do not suggest specific treatment for either atrial septal aneurysm (108,109) or PFO are indicated. Even for patients with stroke or TIAs and recognized PFO or atrial septal aneurysm (or both), optimal treatment is uncertain, although physicians are often reluctant to provide no treatment. In a prospective study of 581 subjects 55 years, who had cryptogenic stroke treated with aspirin (300 mg daily) over four years (110), no difference was found in the incidence of recurrent neurological events between patients with either PFO or atrial septal aneurysm and patients with neither atrial septal abnormality. However, the combination of both abnormalities did constitute a subgroup at substantially increased risk for recurrent neurological events. Among patients with a PFO, a retrospective report suggested a benefit from warfarin (vs. aspirin or no therapy) in the prevention of recurrent stroke (111). Subsequent data from the largest randomized study suggested otherwise. Among 630 patients with cryptogenic stroke in the larger Warfarin Aspirin Randomization Study (WARS), there was no difference during two years of follow-up among patients prospectively randomized to aspirin (325 mg/day) or warfarin (target INR 1.4–2.8). Subsequently, the PFO in Cryptogenic Stroke Study (PICSS) reported on 98 of these subjects who had agreed to TEE (112). The prevalence of PFO was 39% in the cryptogenic stroke group versus only 30% of those with a known other cause of stroke. Large PFO were found in 20% of patients with cryptogenic stroke versus ,10% of those with a known cause of stroke. Even in this group, there was no difference in the incidence of stroke or death, and the size of the PFO and the presence of an atrial septal aneurysm did not influence the outcome. Although the incidence of major hemorrhage did not differ between warfarin and aspirin, warfarin did increase the rate of minor hemorrhage (23% vs. 8.7%), suggesting that aspirin 325 mg is preferred. Because a PFO represents a mechanically repairable condition, there has been interest in surgical closure using direct suture and/or patch methods. This is especially true for patients with moderate or large defects whose surgical mortality is ,1% (113). The outcome data with regard to stroke prevention varies greatly (Table 16). Homma reported Table 16

Outcome Following Surgical Closure of PFO

Study Harvey (114) Devuyst (115) Homma (112) Giroud (117) Dearani (118) Total Events/100 pt-years

Number of patients

Follow-up (month)

4 30 28 8 91

14 23 19 12 24

0 0 1 0 0

1 0 1

161

22

1 0.34

2 0.85

Stroke

Death

TIA 0 0 3 0 8 11 3.71

Abbreviations: TIA, transient ischemic attack; PFO, patent foramen ovale; pt, patient. Source: From Ref. 134.

Stroke, death, or TIA

4 0 9 13 5.55

310

Manning

on 28 patients with PFO and cryptogenic stroke who underwent surgical closure, as they either refused or were not warfarin candidates (116). Four (19%) of these patients had a neurological event at nineteen months, including one stroke and three transient events. All of the neurological events occurred among the 11 subjects over 45 years. In another prospective series of 30 patients ,60 years with stroke and large PFO [.50 microbubbles in the left atrium (LA) on contrast TEE], no events were reported after two years of follow-up (115). Finally, a retrospective study of 91 patients who had surgical closure found freedom from neurological events to be 92.5% at one year and 83% at two years (118). Percutaneous devices to close a PFO have been introduced over the past decade. Most are “clamshell” or “double umbrella –like” devices (Fig. 9), with several being available for compassionate use for patients who have had recurrent neurological events despite warfarin (119). As compared with direct surgical closure, complete elimination of rightto-left shunting (as defined by agitated saline TEE) is often not obtained initially but improves with time. Major complications (death, major hemorrhage, tamponade, fatal pulmonary embolism) of percutaneous PFO closure occur in 1 –2% of patients, and minor complications (atrial arrhythmias, device-arm fracture, device migration, device thrombosis) in another 7 –8% (120). Though uncommon, late complications include device thrombosis, atrial arrhythmias, bacterial infection, and device erosion/perforation. Pool analysis (120) of 12 studies suggested a neurological event rate of 0.5 – 4.9% (Table 17). Although underway, no blinded, randomized controlled data with medical or direct surgical therapy are currently available. Data from a prospective study of 308 patients with cryptogenic stroke and PFO (133) in which patients were treated with warfarin or aspirin versus percutaneous closure are available. After four years of follow-up, percutaneous closure had a nonsignificant trend toward reduced risk of combined death, stroke, or TIA (8.5% vs. 24.3%: P ¼ 0.05) and of recurrent stroke or TIA (7.8% vs. 22.2%). Although considered more “convenient” than surgical closure or warfarin, until the superiority of percutaneous

Table 17

Outcome Following Percutaneous Closure of PFO

Study Bridges (121) Ende (122) Hung (123) Sievert (124) Beitzke (125) Butera (126) Wahl (127) Martin (128) Du (129) Braun (130) Bruch (131) Onorato (132) Total Events/100 pt-years

Number of patients

Follow-up (month)

36 10 28 281 162 35 152 110 18 276 66 256

8 32 31 12 19 12 20 28 26 15 20 19

0 0 0 2 0 0 1 1 0 0 0 0

1430

18

4 0.19

Stroke

Death

TIA 4 0 3 7 3 0 6 1 0 8 0 0

2 0

2

4 0.66

32 1.52

Abbreviations: TIA, transient ischemic attack; PFO, patent foramen ovale; pt, patient. Source: From Ref. 134.

Stroke, death, or TIA 4 0 5 9 3 0 7 4 0 8 0 0 36 2.95

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PFO closure is established, the best candidates are those who have failed or are not candidates for medical (warfarin) therapy. Thus, for patients with stroke and PFO, optimal therapy has not been defined. For patients with a moderate or large PFO with documented venous thrombus, the implication of the PFO and more aggressive therapy (warfarin, consideration of mechanical closure) may seem reasonable. Given the high prevalence of PFO, for other less certain cases, the use of aspirin (325 mg daily) followed by warfarin and then mechanical closure (if recurrences develop) may be more reasonable. Blinded, multicenter trials comparing medical therapy with percutaneous closure are currently underway and are likely to define the utility of these devices for this common population.

REFERENCES 1. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998; 82:1545– 1547. 2. Kinch JW, Davidoff R. Prevention of embolic events after cardioversion of atrial fibrillation. Current and evolving strategies. Arch Intern Med 1995; 155:1353 – 1360. 3. Grimm RA, Stewart WJ, Maloney JD, et al. Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: characterization by simultaneous. J Am Coll Cardiol 1993; 22:1359– 1366. 4. Stoddard MF, Dawkins PR, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J 1995; 129:1204 – 1215. 5. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation J Am Coll Cardiol 1989; 13:617 – 623. 6. Manning WJ, Silverman DI, Katz SE, et al. Impaired left atrial mechanical function after cardioversion: Relationship to the duration of atrial fibrillation. J Am Coll Cardiol 1994; 23:1535 – 1540. 7. Weinberg DM, Mancini GBJ. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:745– 746. 8. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992; 19:851– 865. 9. Gentile F, Elhendy A, Khandheria BK, et al. Safety of electrical cardioversion in patients with atrial fibrillation. Mayo Clin Proc 2002; 77:897– 904. 10. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969; 23:208– 216. 11. Klein AL, Grimm RA, Black IW, et al. Cardioversion guided by transesophageal echocardiography: the ACUTE Pilot Study. A randomized, controlled trial. Assessment of Cardioversion Using Transesophageal Echocardiography. Ann Intern Med 1997; 126:200 –209. 12. Seidl K, Rameken M, Drogemuller A, et al. Embolic events in patients with atrial fibrillation and effective anticoagulation: Value of transesophageal echocardiography to guide directcurrent cardioversion. Final results of the Ludwigshafen Observational Cardioversion study. J Am Coll Cardiol 2002; 39:1436– 1442. 13. Gallagher M, Hennessy B, Edvardsson N, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002; 40:926– 933. 14. Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulation for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: The Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109:997– 1003.

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15. Collins LJ, Silverman DI, Douglas PS, Manning WJ. Cardioversion of nonrheumatic atrial fibrillation: Reduced thromboembolic complications with 4 weeks of pre-cardioversion anticoagulation are related to atrial thrombus resolution. Circulation 1995; 92:160– 163. 16. Corrado G, Tadeo G, Beretta S, et al. Atrial thrombi resolution after prolonged anticoagulation in patients with atrial fibrillation. Chest 1999; 115:140– 143. 17. Jaber WA, Prior DL, Thamilarasan M, et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: a transesophageal echocardiographic study. Am Heart J 2000; 140:150 – 156. 18. Corrado G, Beretta S, Sormani L, et al. Prevalence of atrial thrombi in patients with atrial fibrillation/flutter and subtherapeutic anticoagulation prior to cardioversion. Eur J Echocardiogr 2004; 5:257 – 261. 19. Manning WJ, Silverman DI, Gordon SP, Krumholz HM, Douglas PS. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328:750 – 755. 20. Manning WJ, Silverman DI, Keighley CS, et al. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: Final results of a prospective 4.5 year study. J Am Coll Cardiol 1995; 25:1354– 1361. 21. Klein AL, Grimm RA, Murray D, et al. for the Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344:1411 – 1420. 22. Seto TB, Taira DA, Tsevat J, Manning WJ. Cost-effectiveness of transesophageal echocardiographic-guided cardioversion: a decision analytic model for patients admitted to the hospital with atrial fibrillation. J Am Coll Cardiol 1997; 29:122 – 130. 23. Olson JD, Goldenberg IF, Pedersen W, et al. Exclusion of atrial thrombus by transesophageal echocardiography. J Am Soc Echocardiogr 1992; 5:52– 56. 24. Aschenberg W, Schluter M, Kremer P, Schroder E, Siglow V, Bleifeld W. Transesophageal two-dimensional echocardiography for the detection of left atrial appendage thrombus. J Am Coll Cardiol 1986; 7:163– 166. 25. Hwang JJ, Chen JJ, Lin SC, et al. Diagnostic accuracy of transesophageal echocardiography for detecting left atrial thrombi in patients with rheumatic heart disease having undergone mitral valve operations. Am J Cardiol 1993; 72:677 –681. 26. Manning WJ, Weintraub RM, Waksmonski CA, et al. Accuracy of transesophageal echocardiography for identifying left atrial thrombi. A prospective, intraoperative study. Ann Intern Med 1995; 123:817– 823. 27. Fatkin D, Scalia G, Jacobs N, et al. Accuracy of biplane transesophageal echocardiography in detecting left atrial thrombus. Am J Cardiol 1996; 77:321 – 323. 28. Black IW Fatkin D, Sagar KB, et al. Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial fibrillation. A multicenter study. Circulation 1991; 89:2509 – 2513. 29. Weigner MJ, Thomas LR, Patel U, et al. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2001; 110:694– 702. 30. Srimannarayana J, Varma RS, Satheesh S, Anilkumar R, Balachander J. Prevalence of left atrial thrombus in rheumatic mitral stenosis with atrial fibrillation and its response to anticoagulation: a transesophageal echocardiographic study. Indian Heart J 2003; 55:358 – 361. 31. Ezekowitz MD, James KE, Nazarian SM, et al. Silent cerebral infarction in patients with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Circulation 1996; 92:2178– 2182. 32. Seto TB, Taira DA, Manning WJ. Cardioversion in patients with atrial fibrillation and left atrial thrombi on initial transesophageal echocardiography: should transesophageal echocardiography be repeated before elective cardioversion? A cost-effectiveness analysis. J Am Soc Echocardiogr 1999; 12:508– 516. 33. Larsen JA, McPherson DD, Kadish AH, Goldberger JJ. Course of intraatrial thrombi resolution using transesophageal echocardiography. Echocardiography 2003; 20:121– 128.

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34. Creswell LL, Schuessler RB, Rosenbloom M, Cox, JL. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993; 56:539 – 549. 35. Hogue CW, Murphy SF, Schechtman KB, Davila-Roman, VG, Hogue CW Jr. Risk factors for early or delayed stroke after cardiac surgery. Circulation 1999; 100:642– 647. 36. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001; 135:1061 – 1073. 37. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation after cardiac surgery. J Am Med Assoc 2004; 291:1720 – 1729. 38. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 1996; 94: 390 – 397. 38a. Osranek M, Fatema K, Qaddoura F, et al. Left atrial volume predicts the risk of atrial fibrillation after cardiac surgery: a prospective study. J Am Coll Cardiol 2006 (in press). 39. Crystal E, Connolly SJ, Sleik K, Ginger TJ, Yusuf S. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002; 106:75 – 80. 40. Wijeysundera DN, Beattie WS, Djaiani G, et al. Off-pump coronary artery surgery for reducing mortality and morbidity. J Am Coll Cardiol 2005; 46:872– 882. 41. Athanasiou T, Aziz O, Mangoush O, et al. Do off-pump techniques reduce the incidence of postoperative atrial fibrillation in elderly patients undergoing coronary artery bypass grafting?. Ann Thorac Surg 2004; 77:1567 – 1574. 42. Lee JK, Klein GJ, Krahn AD, et al. Rate-control versus conversion strategy in postoperative atrial fibrillation: A prospective, randomized pilot study. Am Heart J 2000; 140:871– 877. 43. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation). Developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001; 38:1231–1266. 44. Weigner MJ, Caulfield TA, Danias PG, et al. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med 1997; 126:615 – 620. 45. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825 – 1833. 46. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834 – 1840. 47. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomized trial. Lancet 2000; 356: 1789– 1794. 48. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003; 41:1690– 1696. 49. Israel CW, Gronefeld G, Ehrlich JR, Li YG, Hohnloser SH. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device. Implications for optimal patient care. J Am Coll Cardiol 2004; 43:47– 52. 50. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998; 128:639– 647. 51. Mollet NR, Dymarkowski S, Volders W, et al. Visualization of ventricular thrombi with contrast-enhanced magnetic resonance imaging in patients with ischemic heart disease. Circulation 2002; 106:2873– 2876.

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52. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154:1449– 1457. 53. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989; 1:175– 179. 54. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of lowdose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323:1505– 1511. 55. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: Final results. Circulation 1991; 84:527 – 539. 56. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349– 355. 57. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992; 327:1406 – 1412. 58. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation. The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 429S – 456S. 59. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:483S– 512S. 60. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864 – 2870. 61. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation. Stroke risk stratification in patients taking aspirin. Circulation 2004; 110: 2287– 2292. 62. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685 – 2292. 63. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998; 158:1316– 1320. 64. Blackshear JL, Pearce LA, Asinger RW, et al. Mitral regurgitation associated with reduced thromboembolic events in high-risk patients with nonrheumatic atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators. Am J Cardiol 1993; 72:840 – 843. 65. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose wararin versus lowintensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation—Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Lancet 1996; 348:633–638. 66. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362:1691 – 1698. 67. Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. J Am Med Assoc 2005; 293:690 – 698. 68. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996; 61:755 –759. 69. Dote K, Katoh M, Sasaki S, Hasegawa D, Matsuda O, Nakano Y. Left atrial appendectomy for nonvalvular atrial fibrillation with appendage thrombus. [abstract] Circulation 2005; 112:II-416. 70. ACC/AHA guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association. Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998; 32:1486– 1588.

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71. Katz ES, Tsiamtsiouris T, Applebaum RM, Schwartzbard A, Tunick PA, Kronzon I. Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiographic study. J Am Coll Cardiol 2000; 36:468 – 471. 72. Healey JS, Crystal E, Lamy A, et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J 2005; 150:288 – 293. 73. Ostermayer SH, Reisman M, Kramer PH, et al. Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO System) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation. J Am Coll Cardiol 2005; 46:9 – 14. 74. Sick PB, Ulrich M, Schuler G, et al. Stroke prevention technology for patients with nonvalvular AF—early safety and feasibility of the WATCHMAN LAA system. [abstract] Circulation 2005; 112: II-416– 7. 75. Asinger RW, Mikell FL, Elsperger J, Hodges M. Incidence of left-ventricular thrombosis after acute transmural myocardial infarction. Serial evaluation by two-dimensional echocardiography. N Engl J Med 1981; 305:297 – 302. 76. Nihoyannopoulos P, Smith GC, Maseri A, Foale RA. The natural history of left ventricular thrombus in myocardial infarction: A rationale in support of masterly inactivity. J Am Coll Cardiol 1989; 14:903– 911. 77. Greaves SC, Zhi G, Lee RT, et al. Incidence and natural history of left ventricular thrombus following anterior wall acute myocardial infarction. Am J Cardiol 1997; 80:442 – 448. 78. Turpie AG, Robinson JG, Doyle DJ, et al. Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction. N Engl J Med 1989; 320:352 – 357. 79. Kontny F, Dale J, Abildgaard U, Pedersen TR. Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute myocardial infarction: The Fragmin in Acute Myocardial Infarction (FRAMI) study. J Am Coll Cardiol 1997; 30:962 – 969. 80. Weinreich DJ, Burke JF, Pauletto FJ. Left ventricular mural thrombi complicating acute myocardial infarction. Long-term follow-up with serial echocardiography. Ann Intern Med 1984; 100:789 – 794. 81. Vaitkus PT, Barnathan ES. Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: a meta-analysis. J Am Coll Cardiol 1993; 22:1004 – 1009. 82. Lapeyre AC 3rd, Steele PM, Kazmier FJ, et al. Systemic embolism in chronic left ventricular aneurysm: incidence and the role of anticoagulation. J Am Coll Cardiol 1985; 6:534 – 538. 83. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease. J Am Coll Cardiol 1993; 21:144– 150. 84. Tunick PA, Kronzon I. Atheromas of the thoracic aorta: Clinical and therapeutic update. J Am Coll Cardiol 2000; 35:545– 554. 85. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221 – 225. 86. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474 – 1479. 87. Karalis DG, Quinn V, Victor MF, et al. Risk of catheter-related emboli in patients with atherosclerotic debris in the thoracic aorta. Am Heart J 1996; 131:1149 – 1155. 88. Katz ES, Tunick PA, Rusinek H, Ribakove G, Spencer FC, Kronzon I. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: a review of our experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992; 20:70 – 77. 89. Dressler FA, Craig WR, Castello R, Labovitz AJ. Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke. J Am Coll Cardiol 1998; 31:134– 138.

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90. Ferrari E, Vidal R, Chevallier T, Baudouy M. Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants. J Am Coll Cardiol 1999; 33:1317 – 1322. 91. Conti R, Fuster V, Fayad ZA, et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, doubleblind trial with high-resolution magnetic resonance imaging, J Am Coll Cardiol 2005; 46:106 – 112. 92. Tunick PA, Nayar AC, Goodkin GM, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002; 90:1320–1325. 93. Stern A, Tunick PA, Culliford AT, et al. Protruding aortic arch atheromas: risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 1999; 138:746– 752. 94. Paschalis C, Pugsley W, John R, Harrison MJ. Rate of cerebral embolic events in relation to antibiotic and anticoagulant therapy in patients with bacterial endocarditis. Eur Neurol 1990; 30:87 – 89. 95. Hart RG, Kagan-Hallet K, Joerns SE. Mechanisms of intracranial hemorrhage in infective endocarditis. Stroke 1987; 18:1048 – 1056. 96. Masuda J, Yutani C, Waki R, Ogata J, Kuriyama Y, Yamaguchi T. Histopathological analysis of the mechanisms of intracranial hemorrhage complicating infective endocarditis. Stroke 1992; 23:843 – 850. 97. Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant therapy and central nervous system complications in patients with prosthetic valve endocarditis. Circulation 1978; 57:1004 – 1007. 98. Leport C, Vilde JL, Bricaire F, et al. Fifty cases of late prosthetic valve endocarditis: improvement in prognosis over a 15 year period. Br Heart J 1987; 58:66 – 71. 99. Lieberman A, Hass WK, Pinto R, et al. Intracranial hemorrhage and infarction in anticoagulated patients with prosthetic heart valves. Stroke 1978; 9:18– 24. 100. Delahaye JP, Poncet PH, Malquarti V, et al. Cerebrovascular accidents in infective endocarditis: role of anticoagulation. Eur Heart J 1990; 11:1074– 1078. 101. Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart disease— native and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:457S– 482S. 102. Mugge A, Daniel WG, Frank G, Lichtlen PR. Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by transthoracic and transesopahgeal approaches. J Am Coll Cardiol 1989; 14:631 – 638. 103. Keeling IM, Oberwalder P, Anelli-Monti M, et al. Cardiac myxomas: 24 years of experience in 49 patients. Eur J Cardiothorac Surg 2002; 22:971 – 977. 104. Selkane C, Amahzoune B, Chavanis N, et al. Changing management of cardiac myxoma based on a series of 40 cases with long-term follow-up. Ann thorac Surg 2003; 76:1935 –1938. 105. Bhan A, Mehrotra R, Choudhary K, et al. Surgical experience with intracardiac myxomas: Long-term follow-up. Ann Thorac Surg 1998; 66:810– 813. 106. Sun JP, Asher CR, Yang XS, et al. Clinical and echocardiographic characteristics of papillary fibroelastomas: a retrospective and prospective study in 162 patients. Circulation 2001; 103:2687 – 2693. 107. Grinda JM, Couetil JP, Chauvaud S, et al. Cardiac valve papillary fibroelastoma: Surgical excision for revealed or potential embolization. J Thorac Cardiovasc Surg 1999; 117:106– 110. 108. Burger AJ, Sherman HB, Charlamb MJ. Low incidence of embolic strokes with atrial septal aneurysms: a prospective, long-term study. Am Heart J 2000; 139:149– 152. 109. Burger AJ, Jadhav P, Kamalesh M, Stubbe I. Absence of cerebrovascular events in a prospective study of coronary artery bypass patients with atrial septal aneurysms taking aspirin. Am J Cardiol 1995; 75:305– 308. 110. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740 – 1746. 111. Cujec B, Mainra R, Johnson DH. Prevention of recurrent cerebral ischemic events in patients with patent foramen ovale and cryptogenic strokes or transient ischemic attacks. Can J Cardiol 1999; 15:57 – 64.

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112. Homma S, Sacco RL, DiTullio MR, Sciacca RR, Mohn JP. For the PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in cryptogenic stroke study. Circulation 2002; 105:2625 – 2631. 113. Nendaz MR, Sarasin FP, Junod AF, Bogousslavsky J. Preventing stroke recurrence in patients with patent foramen ovale: antithrombotic therapy, foramen closure, or therapeutic abstention? A decision analytic prerspective. Am Heart J 1998; 135:532 –541. 114. Harvey JR, Teague SM, Anderson JL, Voyles WF, Thadani U. Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 1986; 105:695– 697. 115. Devuyst G, Bogousslavsky J, Ruchat P, et al. Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial Doppler ultrasound. Neurology 1996; 47: 1162– 1166. 116. Homma S, Di Tullio MR, Sacco RL, Sciacca RR, Smith C, Mohr JP. Surgical closure of patent foramen ovale in cryptogenic stroke patients., Stroke 1997; 28:2376 – 2381. 117. Giroud M, Tatou E, Steinmetz E, et al. The interest of surgical closure of foramen ovale after stroke: a preliminary open study of 8 cases. Neurol Res 1998; 30:297– 301. 118. Dearani JA, Ugurlu BS, Danielson GK, et al. Surgical patent foramen ovale closure for prevention of paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999; 100 (suppl):II-171 – II-175. 119. Maisel WH, Laskey WK. Patent foramen ovale closure devices: moving beyond equipoise. JAMA 2005; 294:366 – 369. 120. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003; 139:753 – 760. 121. Bridges ND, Hellenbrand W, Latson L, Filiano J, Newburger JW, Lock JE. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992; 86:1902 – 1908. 122. Ende DJ, Chapra S, Rao S. Transcatheter closure of atrial septal defect or patent foramen ovale with the buttoned device for prevention of recurrence of paradoxic embolism. Am J Cardiol 1996; 78:233 – 236. 123. Hung J, Landzbert MJ, Jenkins KF, et al. Closure of patent foramen ovale for paradoxical emboli: intermediate-term risk of recurrent neurological events following transcatheter device placement. J Am Coll Cardiol 2000; 35:1311 – 1316. 124. Sievert H, Horvath K, Zadan E, et al. Patent foramen ovale closure in patients with transient ischemia attack/stroke. J Interv Cardiol 2001; 14:261– 266. 125. Beitzke A, Schuchlenz H, Gamillscheg, Stein JI, Wendelin G. Cagtheter closure of the persistent foramen ovale: mid-term results in 162 patients. J Interv Cardiol 2001; 14:223 – 229. 126. Butera G, Bini MR, Chessa M, et al. Transcatheter closure of patent foramen ovale in patients with cryptogenic stroke. Ital Heart J 2001; 2:115– 118. 127. Wahl A, Meier B, Hazel B, et al. Prognosis after percutaneous closure of patent foramen ovale for paradoxical embolism. Neurology 2001; 57:1330 – 1332. 128. Martin F, Sanches PL, Doherty E, et al. Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism. Circulation 2002; 106:1121– 1126. 129. Du ZD, Cao QL, Joseph A, et al. Transcatheter closure of patent foramen ovale in patients with paradoxical embolism: intermediate-term risk of recurrent neurological events. Cathet Cardiovasc Interv 2002; 55:189– 194. 130. Braun MU, Fassbender D, Schoen SP, et al. Transcatheter closure of patent foramen ovale in patients with cerebral ischemia. J Am Coll Cardiol 2002; 39:2019 – 2025. 131. Bruch L, Parsi A, Grad MO, et al. Transcatheter closure of interatrial communications for secondary prevention of paradoxical embolism: single-center experience. Circulation 2002; 105:2845 – 2848. 132. Onorato E, Melzi G, Casilli F, et al. Patent foramen ovale with paradoxical embolism: midterm results of transcatheter closure in 256 patients. J Interv Cardiol 2003; 16:43 – 50.

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17 Treatment of Aortic and Arterial Sources Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

TREATMENT OF AORTIC ATHEROMATOSIS Treatment of aortic atheromatous disease is controversial, and there have been no randomized therapeutic trials to study the effectiveness of various strategies. Anticoagulants have been posited to aggravate cholesterol crystal embolism (1), but in several patients, aortic thrombotic masses have disappeared after anticoagulant therapy (2,3). By preventing the formation of thrombi over ulcerated areas of aortic atheromas, heparin and/or coumadin could theoretically facilitate contact of the atheromatous material with the lumen and promote cholesterol embolism. Koren et al. (4) followed 78 patients who had protruding proximal aortic plaques .5 mm thick during an average of 29 weeks while they were being treated with antiplatelet drugs or anticoagulants. Four of the 38 patients taking heparin or warfarin developed a blue toe syndrome and/or renal insufficiency or an increased frequency of TIAs, although no patient taking antiplatelet drugs developed the blue toe syndrome (4). The blue toe syndrome was probably caused by cholesterol embolism. Anticoagulation may prevent red thrombus formation on top of atherosclerotic plaques, allowing the embolization of plaque components. Cholesterol embolism has also been described after thrombolytic treatment of patients with acute myocardial infarction (5). Similar to anticoagulants, thrombolytic agents could expose ulcerated areas to the circulation if thrombi were lysed. In the French Study of Aortic Plaques cohort and in another study that followed patients with protruding aortic plaques, no difference in cerebrovascular event rate was found between those taking antiplatelet drugs and those taking anticoagulants (6 – 8). Because large protruding aortic atheromas, especially those that are mobile, probably represent red thrombi, it seems prudent to manage these patients with anticoagulants during the acute period while following the patients by repeated imaging of the aortic plaques (8). In some patients, the combination of antiplatelet and anticoagulant drugs might prevent both white and red clot formation. A large international randomized trial of treatment with antiplatelets versus anticoagulants is now underway. This trial, the Aortic Arch Related Cerebral Hazard (ARCH) trial, will study the use of an antiplatelet regimen versus warfarin in patients with central or peripheral embolic events and proximal aortic arch atheromas .4 mm thick or mobile (9). 319

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Intravenous thrombolytic treatment (9–11) and surgical removal of protruding atheromas or replacement of the aortic arch (12,13) have also been reported to be successful in treating patients with aortic atheromas. One patient had multiple brain infarcts despite anticoagulant and antiplatelet therapy (12). Transcranial Doppler emboli monitoring showed 15 cerebral microembolic events during 30 minutes in the left cerebral hemisphere. A 9 mm thickening of a focal portion of the aortic arch just proximal to the left common carotid artery (CCA) was found on magnetic resonance imaging (MRI). At surgery, a friable mobile atheroma was found, and this region of the aorta was replaced with a Dacron graft (12). In another patient who had three brain embolic events despite warfarin anticoagulation, a carpet of protruding atheromas that involved the orifices of several brachiocephalic arteries was found, and the aortic arch was removed and replaced with a graft (13).

TREATMENT OF ARTERIAL SOURCE EMBOLI Medical Treatments Medical as well as surgical and interventional therapies are now widely used to treat lesions within arteries that have the potential to act as a source for artery-to-artery brain emboli. Medical therapy consists of reduction of risk factors for atherosclerosis, statins, antihypertensive agents, especially those that relate to angiotensin-converting enzyme (ACE) inhibition, and antiplatelet and anticoagulant agents. Hypertension, diabetes, smoking, the metabolic syndrome, obesity, and inactivity are recognized risk factors for large artery atherosclerosis (14 –16). Statins Recent interest has focussed on the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in stroke prevention, especially in patients with atherosclerotic plaques (17 – 22). Statins were originally marketed as agents that lower blood cholesterol levels and so were initially prescribed according to the levels of cholesterol and high- and low-density lipoproteins in the blood. Statins also have an important effect on the arterial endothelium and intima unrelated to their effect on blood lipids (23 –25). Some patients with atherosclerotic plaques have normal blood lipid levels. The endothelium acts to incorporate blood lipids and other substances into subintimal plaques. Statins treatment can reduce the thickness of intima –media arterial wall measurements (20 – 22), reduce the growth of plaques, and can sometimes result in a decrease in the size of arterial plaques and reduce the frequency of brain ischemic events. Physicians are now beginning to prescribe statins in patients with arterial plaques even when lipid levels are normal. Some studies are beginning to show that high doses of statins (equivalent to 80 mg of atorvastatin) are likely more effective in producing plaque regression and preventing coronary and stroke events than lower doses (22,26,27). A trial of the effectiveness of 80 mg of atorvastatin in stroke prevention (SPARCL) is underway, and the results will soon be available (28). In patients with important arterial atherosclerotic plaques, consideration should be given to adding a statin or increasing the dose of a statin if one is already being used. ACE Inhibitors and Receptor Blockers Control of hypertension has always been considered important in stroke prevention, especially in patients who already have evidence of atherosclerotic arterial disease.

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Recent studies suggest that ACE inhibitors and ACE-receptor blockers may have special benefits beyond their reduction in blood pressure (29 –37). In the HOPE study, Ramipril produced a 32% relative-risk reduction of stroke, compared with placebo despite only a 3.3 mmHg systolic and 1.4 mmHg diastolic reduction in daytime blood pressure (29). In the LIFE study, among 9,193 hypertensive patients randomized to receive either losartan (an ACE-receptor blocker) or atenolol, a beta-blocker, losartan conveyed a significant 25% relative-risk reduction of stroke when compared with atenolol (30). In this study, there was no significant difference in blood pressure recordings between the two treatments (30). In the PROGRESS trial, 6,105 patients with a history of cerebrovascular events were treated with perendopril (an ACE inhibitor) and placebo or a diuretic indapamide (31– 33). Perendopril was given to patients irrespective of their blood pressures, and some patients were normotensive at the time of treatment. The active treatment produced a 28% risk reduction in stroke despite only modest blood pressure reductions. Hypertensive patients had blood pressure reductions of 9.7 systolic/4 diastolic and 8.4 systolic/4.1 diastolic reduction in normotensive individuals (31– 33). The combination of perendopril and indapamide reduced the blood pressure on average 11.8/4.8 mmHg compared with 5.2/2.8 mmHg for those who were only taking perendopril (33). The anti-inflammatory and endothelial effects of ACE inhibition may lead to more stabilization of plaques than other antihypertensive drugs (34 – 37). Substances that Alter Platelet Functions Prescription of agents that alter platelet functions (so-called “antiplatelets”) has become routine in patients with arterial disease. The formation of a thrombus depends on many interrelated factors that include local vascular injury or roughening, the number of circulating platelets and their activation, and the presence of serum coagulant and anticoagulant substances (38 –41). So-called red clots, erythrocyte – fibrin thrombi tend to form in regions where there is low flow or stagnation, whereas smaller so-called white platelet clots adhere to roughened places in faster moving streams of blood. Standard anticoagulants, such as heparin (and low-molecular weight heparin, heparinoids) and warfarin, and direct thrombin inhibitors (hirudin, argabatran, and ximelagatran) theoretically are used to prevent formation of red clots. Antiplatelets should be better in preventing white platelet plugs (38 – 41). The optimal dose of aspirin is controversial. The early American (42) and Canadian (43) randomized therapeutic trials used 1300 mg aspirin daily. Smaller doses are posited to produce the desired inhibition of platelet functions and yet not have the unwanted effect of inhibiting production of prostacyclin by endothelial cells (44,45). In the British UK-TIA trial, one 300 mg aspirin a day was as effective as higher doses (46); in the Swedish Aspirin Low-Dose trial, 75 mg of aspirin a day resulted in a statistically significant 18% reduction in stroke and death (47); in the Dutch TIA trial, even 30 mg was as effective and was better tolerated than 300 mg of aspirin a day (48). Today most doctors prescribe between 50 and 325 mg aspirin a day for stroke prevention. Some observations suggest that aspirin sometimes does not have significant effects on platelet functions, as measured in vitro (49,50). Helgason et al. (49) studied the effectiveness of aspirin on platelet function measured in vitro (49). Among 107 patients given 325 mg aspirin per day, inhibition of platelet aggregation was complete in 85 (79%) and partial in 22 (20.5%) patients. Among nine patients who did not respond to 325 mg aspirin, increasing the dose to 650 mg a day resulted in complete platelet inhibition in five (56%) patients. Increasing to 975 mg caused complete inhibition in one of the four patients who did not respond to 650 mg. All three patients who did not respond to 975 mg had only

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partial inhibition at a 1300 mg aspirin dose (50). Genetic factors clearly play a role. Some patients require more aspirin than others. Platelets interact with the endothelium and arterial wall, and so platelet function is only one of the factors that relates to the deposition of platelet – fibrin and erythrocyte– fibrin thrombi. In therapeutic trials conducted in the 1980s, ticlopidine hydrochloride, a thienopyridine derivate, proved slightly more effective than aspirin (51,52). Ticlopidine had a relatively high rate of side effects, especially diarrhea and skin rash. Neutropenia, thrombotic thrombocytopenic purpura, and thrombocytopenia are important serious complications of ticlopidine use (53,54). Clopidogrel, a thienopyridine analogue of ticlopidine that differs from ticlopidine by the addition of a carboxymethyl side group, was introduced as another effective platelet antiaggregant. Clopidogrel and ticlopidine have similar antiplatelet effects, but clopidogrel has fewer serious hematological side effects when compared with ticlopidine. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a randomized double-blinded trial of clopidogrel (75 mg/day) versus aspirin (325 mg/day) in preventing ischemic events (ischemic stroke, myocardial infarction, and vascular death) (55). During three years, 19,185 patients were entered, including 6,421 ischemic stroke patients, 6,302 patients with myocardial infarcts, and 6,452 patients with atherosclerotic peripheral vascular occlusive disease. Clopidogrel had a relative-risk reduction over aspirin of 8.7%, considering all end points. The frequency of stroke was 405/17,636 (2.3%) for clopidogrel versus 430/17,519 (2.5%) for aspirin. The frequency of myocardial infarction was more effectively reduced by clopidogrel than the frequency of stroke (55). Clopidogrel had a very good safety record in this large trial; the frequency of neutropenia and thrombocytopenia in patients using clopidogrel were no different than for aspirin (55). Reasoning that decreasing platelet activities by two different mechanisms might prove superior to single agents alone, the MATCH trial tested aspirin (75 mg/day) þ clopidogrel (75 mg/day) against clopidogrel (75 mg/day) alone in patients with brain ischemia (56,57). The combination was not superior in decreasing the primary outcome measure (reduction in ischemic stroke, myocardial infarction, vascular death, and rehospitalization for acute ischemic events) and caused more life-threatening bleeding, often intracranial (56,57). Dipyridamole is a pyramidopyrimidine compound that, acting as a phosphodiesterase inhibitor, modestly reduces platelet function (58). Dipyridamole also has important endothelial activity and acts as a vasodilator. Dipyridamole inhibits the attachment of platelets to the endothelium. In early trials, the combination of aspirin and dipyridamole did not prove better than aspirin alone (59,60). Dipyridamole in the form given in these two trials had variable gastrointestinal absorption related to gastric acidity and required four times a day dosing because of its pharmacokinetics. The dose of dipyridamole was relatively low and likely did not produce adequate sustained blood levels. An extended release form of dypiridamole has longer activity and much improved absorption. Two European Stroke Prevention Studies (ESPS 1 and ESPS 2) reported an effect on stroke prevention of extended release dipyridamole when used with aspirin (61,62). In ESPS 1, dipyridamole 75 mg three times a day þ aspirin 330 mg three times a day for 2 years showed a 38% reduction in stroke when compared with placebo in patients with prior ischemic strokes or TIAs (61). In the ESPS 2 trial, 6,602 patients took either placebo, aspirin (25 mg twice a day), dipyridamole in a modified-release form (200 mg twice a day), or aspirin and dipyridamole (25 mg aspirin þ 200 mg modified-release dipyridamole twice a day) (62). The relative-risk reduction for the combined end points of stroke and death were 13.2% for aspirin, 15.4% for dipyridamole, and 24.4% for the

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combination of aspirin and dipyridamole. The combined therapy reduced the stroke risk by 23.1% over aspirin alone and 24.7% over dipyridamole alone (62). Cilostazole is another phosphodiesterase inhibitor that has both antiplatelet and vasodilator effects (63,64). In a Japanese trial that included more than 1,000 patients with brain infarcts acquired 1 –6 months before entry, cilostazole (100 mg twice daily) showed a 42.3% relative-risk reduction (10.3 – 62.9% CI, p ¼ 0.013) in reducing the frequency of recurrent brain infarction in an intention-to-treat analysis (65). In a study of Korean patients with intracranial arterial stenosis, 200 mg of cilostazole þ 100 mg of aspirin was more effective than 100 mg aspirin alone in reducing the frequency of progression and increasing the frequency of regression of stenotic lesions ( p ¼ 0.008) (66). The advent of drugs that are antagonists of the glycoprotein platelet llb/llla complex gives promise of even more effective inhibition of platelet functions. The platelet glycoprotein (Gp) llb/llla complex is the site of binding to adhesive proteins, including fibrinogen. Binding to fibrinogen activates platelet aggregation and adhesion to blood vessels. Abciximab, a humanized monoclonal antibody that binds to the GP llb/llla complex on platelets, has been mostly used acutely and intravenously in patients after invasive coronary and cerebral revascularization procedures (54,67 –70). Abciximab induces a profound impairment of platelet functions similar to a temporary thrombasthenia so that the rate of bleeding is potentially high (54). The use of abciximab during the first 24 hours after stroke proved safe in a preliminary study (71), and so this drug may gain increased use in the acute stroke setting. Other parenteral small molecule, nonantibody GP llb/llla antagonists, tirofiban, and eptifbatide have shorter duration of antiplatelet activity but have been shown to improve outcomes after coronary procedures and have less bleeding complications than abciximab (54,67,69). GP llb/llla inhibiting agents that can be used orally and chronically are now being tested but to date have been associated with excess bleeding and thus have not been introduced into clinical practice. There are three general strategies for reducing the formation of white platelet –fibrin clots: (1) agents whose function is entirely on platelets (aspirin, clopidogrel), (2) agents that affect platelets and the endothelium-preventing attachment of platelets to the endothelium (extended-release dipyridamole, cilostazole), or (3) agents that affect the attachment of platelets to fibrinogen (abciximab and other Gp llb/llla inhibitors). The future will see further exploration of novel antiplatelet agents and combinations. Effects on leukocytes and the endothelium may facilitate the capacity of agents or combinations in preventing brain infarction. There is growing interest in the potential effects of natural substances such as eicosopentanoic acid (EPA)—a substance found in high concentration in fish and in omega-3-oils, affect platelet functions and are contained in natural foods. EPA reduces fibrinogen levels and decreases whole blood viscosity as well as inhibiting platelet functions (72 – 74). Black tree fungus, a common component of Chinese foods, is also purported to have platelet-inhibiting functions. These and other natural food substances that have antiplatelet properties may become popular among patients who seek natural alternative remedies rather than prescription drugs.

SUBSTANCES THAT ALTER FIBRINOGEN CONCENTRATIONS Fibrinogen is a very important protein. Fibrinogen is converted to fibrin in a reaction catalyzed by thrombin. Fibrin is an important component of arterial plaques. Fibrin is also an integral part of both white and red clots. Fibrinogen is a relatively heavy protein. The fibrinogen level and the hematocrit are the two largest contributors to

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whole blood viscosity (75 –79). Reduction in whole blood viscosity has the potential to greatly improve cerebral blood flow, especially through narrowed intracranial arteries, arterioles, and capillaries (80). Fibrinogen levels predict the future occurrence of vascular events in population-based studies (81,82) and in patients with coronary and peripheral vascular disease (83,84). In patients who have had a previous TIA or stroke, the risks of recurrent ischemic stroke and acute coronary events increase linearly with fibrinogen levels (79). Despite these facts, few physicians routinely measure blood fibrinogen levels. Several agents are known to reduce fibrinogen levels, including EPA, benzafibrate, beta-blockers, pentoxifylline, and ticlopidine (74,77 – 79). Cessation of smoking and exercise also reduce fibrinogen levels (85). Measuring fibrinogen levels and attempting their reduction are important therapeutic strategies in patients with atherosclerotic and other occlusive vascular lesions and in those with hypercoagulability.

ANTICOAGULANTS Anticoagulants have been used in the past in patients with occlusive vascular disease, but there are very few modern randomized trials that have tested their utility and safety in patients with known vascular occlusive lesions. Heparin and heparin-like compounds have often been prescribed to treat patients with acute thromboembolism. The posited purpose of heparinization is to prevent propagation of thrombi and breaking loose of the tail of existing thrombi and so prevent further embolization. Heparin does not lyse existing thrombi. The arguments used to recommend acute heparinization are twofold: preventing further activity in the embolus already present intracranially and preventing further clot formation in the original source region where the thrombus developed. The decision on whether or not to prescribe heparin acutely to prevent the next thromboembolic stroke depends on weighing the risk of acute re-embolization versus the risk of hemorrhage related to heparin therapy. This issue is discussed in length in Chapter 15 on the treatment of the acute embolus. The risk of further acute thrombus formation and embolization depends primarily on the nature of the arterial source of the original thromboembolus. Acute carotid and vertebral artery occlusions in the neck are important sources of intra-arterial embolism. When a thrombus first forms in a region of atherostenosis, the clot is not well organized and is not adherent to the arterial wall. The thrombus often extends and new thrombus forms, especially because the flow is reduced above the thrombus. With time, probably 3 –4 weeks, the thrombus becomes well organized and adherent, and further thrombus formation does not develop. Also, during these weeks, collateral circulation develops and stabilizes. An argument can be made to use heparin and then warfarin during the 3 –6 week period, during which further thrombus development and embolization is a risk for further stroke damage. There is little data testing the use of heparins in relation to arterial diseases. The results of two trials suggest that heparin might be effective in patients with acute ischemic stroke due to large artery thromboembolism. In a trial performed in Hong Kong, among 312 patients with acute ischemic stroke, low-molecular weight heparin was more effective than placebo (86). There was a significant dose-dependent reduction in the risk of death or dependency among patients treated with low-molecular weight heparin (chi-square for trend ¼ 8.066, p ¼ 0.005). Although vascular studies were not mandated, most patients with ischemic stroke in Hong Kong have intracranial artery occlusive disease. Patients with cardiac lesions that required anticoagulation were not excluded from this study.

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In the TOAST trial, a heparinoid showed some effectiveness in a subgroup of patients with large artery occlusive disease (87,88). In this study, the low-molecular weight heparinoid, ORG 10172, was given within 24 hours of the onset of symptoms of an acute ischemic stroke (87). Heparinoid was given by continuous intravenous infusion for seven days, with the dose adjusted after 24 hours to maintain the antifactor Xa activity at 0.6– 0.8 units/mL. The antifactor Xa activity of danaparoid is attributed to its heparin sulfate component that has a high affinity for antithrombin III. Although danaparoid treatment was not effective in terms of the entire group of patients with ischemic stroke, there was effectiveness in the group of patients diagnosed as having large artery atherosclerosis, in whom heparinoid reduced the number of recurrences of stroke during the seven days of infusion. The rates of favorable and very favorable outcomes were significantly higher in patients given heparinoid when compared with placebo. Sixtyeight percent of patients with large artery atherosclerosis treated with danaparoid had favorable outcomes versus 54.7% treated with placebo ( p ¼ 0.04); 43% of patients with large artery atherosclerosis treated with danaparoid had very favorable outcomes versus 29.1% treated with placebo ( p ¼ 0.02). Recurrent strokes developed in 6% of danaparoid-treated patients who had large artery atherosclerosis versus 11% of those treated with placebo. Danaparoid was effective among the group of patients with large artery atherosclerosis, who had severe internal carotid artery (ICA) stenosis in the neck (.50% luminal narrowing or occlusion) (88). This was the only subgroup of patients in the TOAST study in whom all of the patients had vascular tests that defined the large artery lesions. Significantly, more patients with severe carotid artery disease had favorable and very favorable outcomes among patients treated with heparinoid. Heparin and then warfarin have customarily been given by most neurologists in patients with acute arterial dissections, although this strategy has not been studied in a randomized trial. Warfarin has often been used after heparinization, but its utility has also not been well tested. No published trial has studied warfarin in patients with carotid or vertebral artery occlusive lesions in the neck. The WARRS study compared the effectiveness of aspirin and warfarin in patients with brain ischemia (89). There was no superiority of either treatment, but there was a trend slightly in favor of aspirin. Vascular imaging was not mandated, and there was no data about patients with vascular occlusive disease documented by modern vascular imaging. In a retrospective analysis of outcomes in patients with intracranial occlusive disease treated with warfarin and platelet antiaggregants, patients with intracranial stenosis, most commonly of the middle cerebral artery (MCA), fared better on warfarin than on platelet antiaggregants (90). A prospective trial (WASID) compared the effectiveness of 1300 mg aspirin a day against warfarin in patients with intracranial artery occlusive disease (50 –99% stenosis) shown by angiography (91,92). Warfarin resulted in better efficacy but many more hemorrhages. Many patients were not maintained within the targeted therapeutic range for warfarin. When the data were analyzed for those within the therapeutic range, warfarin was more effective than aspirin (91,92). The data could not be analyzed for the severity of stenosis within the large 50 –99% range. Very severe stenosis would be a situation posited to be more likely to promote formation of red erythrocyte – fibrin thrombi that would be better treated with anticoagulants than with antiplatelets. The introduction of direct inhibitors of thrombin, such as hirudin, argatroban, and ximelagatran, into clinical care might change the method and risks of anticoagulation. Argatroban is only given intravenously and produces rapid anticoagulant effects similar to heparin. Ximelagatran given orally also produces rapid anticoagulant effects. This agent is given in a fixed dose and need not be monitored by either partial thromboplastin

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time (PTT) or international normalized ratio (INR) determinations, making it easier to use and control. Direct thrombin inhibitors could replace both heparin and warfarin in treating stroke patients. We recommend anticoagulation in selected patients with severe neck or intracranial occlusive disease. In patients with complete occlusions, we treat for 4 –6 weeks and then change to antiplatelets. In patients with continued severe stenosis, in whom the artery is not treated by surgery or interventional angioplasty/stenting, we continue anticoagulants until the artery either opens more widely or until 4– 6 weeks after it is known to occlude. We hope that in future, this strategy will be tested in trials.

SURGICAL AND INTERVENTIONAL TREATMENTS Surgery The traditional method of unblocking a severely stenotic neck artery is by direct surgery on that vessel—endarterectomy. Completely occluded vessels do not lend themselves to direct repair because, in the presence of low flow, clots form and propagate distally beyond the site of surgical access. Carotid endarterectomy has been shown to be clearly more effective than medical therapy in patients with neurologically symptomatic severe (.70% luminal narrowing) carotid artery stenosis (93 – 98). These patients have had TIAs or minor strokes in the distribution of the severely stenotic artery. Endarterectomy not only removes the obstructing lesion, thus dramatically augmenting flow, but also removes the source of intra-arterial emboli. The effectiveness of treatment was first shown in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) (93). In this prospective, multicenter clinical trial, patients having a recent history of transient monocular visual loss, transient cerebral ischemia, or nondisabling stroke were randomized to receive either carotid endarterectomy plus “optimal” medical management (predominantly antiplatelet therapy) or medical management alone for either 50 – 69% or 70 – 99% carotid stenosis documented on the appropriate side of the neck by arteriography. Carotid surgery was first shown to be effective in patients with severe stenosis (70 – 99% luminal narrowing) (93). A subsequent analysis of the NASCET and Aspirin and Carotid Endarterectomy (ACE) trials showed that the effectiveness of carotid surgery was similar in men and women (94). The MRC European Carotid Surgery trial confirmed these results, although they used a different method of measuring carotid artery stenosis (95). Endarterectomy was then shown to be somewhat effective in selected symptomatic brain ischemia patients with luminal stenosis in the 50– 69% range (96,97). However, patients must be carefully chosen because neurological and cardiac morbidity and mortality are significant risks. Vertebral artery surgery can also be performed successfully with low morbidity and mortality when performed by surgeons with extensive experience with the procedure (99 – 101). The most common method of vertebral artery reconstruction is to anastamose the vertebral artery to the carotid artery, but endarterectomy can also be performed. Surgical treatment of patients who have stenosis of arteries in the neck but no associated brain ischemic symptoms is more controversial (102,103). The designation asymptomatic can be problematic because some patients who deny symptoms have abnormal physical findings indicative of strokes and may have brain infarcts on computed tomography or MRI. The biological activity of the carotid artery lesion is different than in those with no such findings. The risk of stroke in patients without symptoms or signs of brain infarction is relatively low: 2– 2.5% a year even in those with severe stenosis. Among the 1,602 patients enrolled in the Asymptomatic Carotid Atherosclerosis

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Surgery (ACAS) trial, endarterectomy was more effective than medical treatment in preventing strokes in selected patients who had no symptoms of retinal or brain ischemia and who did not have severe cardiac disease or other serious comorbidities when operated upon by selected surgeons who had very low surgical complication rates (104). In the Asymptomatic Carotid Surgery Trial (ACST) performed in Europe, 3,120 patients with .60% carotid artery stenosis were randomized to immediate carotid endarterectomy or deferral until a definite indication occurred (105,106). The immediate surgical strategy proved more effective in preventing any stroke and fatal and disabling strokes. Immediate surgery was about equally effective in men and women, in those younger and older than 65, and for those with 70% as well as those with 80 – 90% stenosis (104). The decision on surgery depends on weighing the risks versus the benefits. Much depends on the complication rate of the surgeon who will perform the surgery. Sundt et al. (107) characterized the potential risks into those that were anatomic, those that related to the target organ, the brain, and those that related to medical comorbidities. The risks are tabulated in Table 1. The presence and severity of any neurological stroke deficit and the presence of neurological deficits (e.g., dementia) are clearly important considerations. Vascular risk factors include the length of the stenotic lesion, the presence of tandem intracranial disease in the ICA siphon and the MCA, the involvement of the CCA and the ECA, and the location of the carotid artery bifurcation (a very high bifurcation increases the technical difficulty of the vascular surgery). Coronary artery disease and myocardial infarction are the most important and severe non-neurological complications of CEN, so the presence of coronary artery disease is of great importance. Other diseases, such as pulmonary, hepatic, and renal diseases, and cancer clearly affect surgical risk and other treatment decisions. Hypertension and hyperperfusion are important complications of carotid surgery. Endarterectomy of a tightly stenotic vessel produces a sudden large increase in flow. During ischemia, capillaries and small arterioles, as well as neurons, are often damaged by ischemia. When flooded with blood under high pressure, these abnormal vessels then can bleed. The carotid sinus is also perturbed during endarterectomy, leading to Table 1

Risks of Carotid Endarterectomies

Neurological risks Progressive course Recent stroke Angiographic risks High bifurcation Very long lesion (.3 cm distally in ICA or 5 cm into CCA) Clot within the artery Contralateral ICA stenosis or occlusion Intracranial stenosis or occlusion Medical risks Hypertension Coronary artery disease Diabetes Obesity Smoking Chronic obstructive pulmonary disease (COPD) Congestive heart failure Abbreviations: CCA, common carotid artery; ICA, internal carotid artery. Source: From Ref. 107. Modified from Ref. 40.

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failure of the carotid sinus reflex and accelerated hypertension in the hours and days after carotid endarterectomy (108 – 110). The blood pressure elevation can become maximal days and even a week after surgery. High blood pressure and flooding of damaged vessels can lead to headache, seizures, brain edema in the hemisphere supplied by the operated artery, and intracerebral hemorrhage following carotid endarterectomy (110,111). Care must be taken in the timing of endarterectomy, and the blood pressure of patients undergoing carotid endarterectomy must be carefully monitored during the postoperative period and the subsequent days. Angioplasty and Stenting Beginning in the 1980s, case reports and experience with small series of patients showed that percutaneous transluminal angioplasty of the carotid artery was a reasonable alternative to surgical endarterectomy for patient with high internal carotid lesions near the skull base, recurrent stenosis after previous endarterectomy, or a history of neck irradiation (112). Stents were beginning to be used during the early 1990s to reduce the frequency of periprocedural embolic events and recurrent stenosis that were associated with angioplasty alone, and cerebral protection devices were later developed in an additional attempt to prevent strokes caused by atheromatous emboli dislodged during stent placement. Trials, reviews, and analyses of the risks and benefits of angioplasty/stenting with and without protective devices have now been reported (113 –122). In general, most studies have shown that the angioplasty/stenting and surgery have comparable risks and complication rates. The use of cerebral protection devices lowers the neurological complication rates of angioplasty/stenting (117,118,121). Myocardial infarction and severe hypertension are less common after percutaneous intervention than after surgery. Hypotension is probably more common after stenting. Much depends on the skill and experience of the surgeon and the interventionalist. Restenosis is a concern after interventional procedures as it is after carotid endarterectomy (123,124). Some arterial lesions are likely better treated by stenting and others by surgery. When the carotid bifurcation is high or the occlusive lesion extends well above the bifurcation, surgery is difficult and may require disarticulation of the jaw to enable the surgeon to reach the full lesion. In that circumstance, stenting is preferred. Very long smooth plaques and tandem lesions that are both extracranial and intracranial are likely better treated by stenting. Lesions that are very ulcerated and irregular might better be managed by surgery. The results of subsequent trials and reports might shed more light on the relative outcomes and advantages of each strategy. REFERENCES 1. Bruns JL, Segel DP, Adler S. Control of cholesterol embolization by discontinuation of anticoagulant therapy. Am J Med Sci 1978; 275:105 – 108. 2. Blackshear JL, Jahangir A, Oldenberg WA, Safford RE. Digital embolization from plaquerelated thrombus in the thoracic aorta: identification with transesophageal echocardiography and resolution with warfarin therapy. Mayo Clin Proc 1993; 68:268 – 272. 3. Freedberg RS, Tunick PA, Culliform AT, Tatelbaum RJ, Kronzon I. Disappearance of a large intraaortic mass in a patient with prior systemic embolization. Am Heart J 1993; 125: 1445– 1447. 4. Koren MJ, Bryant B, Hilton TC. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 332:1237. 5. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216 – 1221.

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6. Mitusch R, Doherty C, Wucherpfennig H, et al. Vascular events during follow-up in patients with aortic arch atherosclerosis. Stroke 1997; 28:36 –39. 7. Amarenco P, Cohen A. Update on imaging aortic atherosclerosis in advances in neurology. In: Barnett HJM, Bogousslavsky J, Meldrum H, eds. Ischemic Stroke. Vol. 82. Philadelphia: Lippincott Williams and Wilkins, 2003:75 –89. 8. Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: a review of 221 cases in the English literature. Angiology 1987; 38:769 – 784. 9. Donnan GA, Davis SM, Jones EF, Amarenco PA. Aortic source of brain embolism in current treatment options. Cardiovasc Med 2003; 5:211– 219. 10. Hausmann D, Gulba D, Bargheer K, et al. Successful thrombolysis of an aortic-arch thrombus in a patient after mesenteric embolism. N Engl J Med 1992; 327:500 – 501. 11. Ito H, Takahashi IK, Sasaki H, et al. Large thrombus in the ascending aorta successfully treated by thrombolysis—an unusual cause of massive myocardial infarction. Jpn Circ J 2001; 65:572–574. 12. Lancaster G, Lovoulos CJ, Moussouttas M, et al. Aortic arch replacement for recurrent cerebral embolization. Ann Thorac Surg 2002; 73:291 – 294. 13. Belden JR, Caplan LR, Bojar RM, et al. Treatment of multiple cerebral emboli from an ulcerated thrombogenic ascending aorta with aortectomy and graft replacement. Neurology 1997; 49:621 –622. 14. Gorelick PB, Alter M, eds. The Prevention of Stroke. London: Parthenon Publishing Group, 2002. 15. Norris JW, Hachinski VC, eds. Prevention of Stroke. New York: Springer-Verlag, 1991. 16. Kasner SE, Gorelick PB, eds. Prevention and Treatment of Ischemic Stroke. Boston: Butterworth-Heinemann, 2004. 17. Bucher HC, Griffith LE, Guyatt GH. Effect of HMGcoA reductase inhibitors on stroke. A meta-analysis of randomized controlled trials. Ann Intern Med 1998; 128:89 –95. 18. Furberg CD, Adams HP, Applegate WB, et al. for the Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovostatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994; 90:1679 –1687. 19. Heart protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363:757 –767. 20. Hodis HN, Mack WJ, LaBree L, et al. Reduction in carotid arterial wall thickness using lovostatin and dietary therapy. A randomized controlled clinical trial. Ann Intern Med 1996; 124:548 – 556. 21. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intimal medial thickness. Circulation 2002; 106:2055 – 2060. 22. Kent SM, Coyle LC, Flaherty PJ, Markwood TT, Taylor AJ. Marked low-density lipoprotein cholesterol reduction below current National Cholesterol Education program targets provides the greatest reduction in carotid atherosclerosis. Clin Cardiol 2004; 27:17– 21. 23. Frishman WH, Patel K. Lipid-Lowering Drugs in Cardiovascular Pharmacotherapeutics. In: Frishman WH, Sonnenblide EH, eds. New York: McGraw-Hill, 1996:399 – 479. 24. Anderson TJ, Meredith IT, Yeung AL, et al. Cholesterol-lowering therapy improves endothelial function in patients with coronary atherosclerosis. Circulation 1993; 88:I-368. 25. Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994; 89:2519. 26. Topol EJ. Intensive statin therapy— a sea change in cardiovascular prevention. N Engl J Med 2004; 350:1562 – 1564. 27. Almuti K, Rimawi R, Spevack D, Ostfeld RJ. Effects of statins beyond lipid lowering: potential for clinical benefits. Int J Cardiol 2006; 109:7 –15. 28. The SPARCL Investigators. Design and baseline characteristics of the Stroke Prevention by Aggressive reduction in Cholesterol Levels (SPARCL) Study. Cerebrovasc Dis 2003; 16:389 –395.

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53. Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine. A report of 60 cases. Ann Intern Med 1998; 128:541 – 544. 54. Weksler B. Antiplatelet agents in stroke prevention. Cerebrovasc Dis 2000; 10(suppl 5):41– 48. 55. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996; 348:1329 – 1339. 56. Diener H-C, Bogousslavsky J, Brass LM, et al. on behalf of the MATCH investigators. Aspirin and clopidogrel vs clopidogrel alone after recent ischemic stroke or transient ischemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial. Lancet 2004; 364:331 – 337. 57. Hankey GJ, Eikelboom JW. Adding aspirin to clopidogrel after TIA and ischemic stroke. Benefits do not match risks. Neurology 2005; 64:1117– 1121. 58. Fitzgerald GA. Dipyridamole. N Engl J Med 1987; 316:1247 – 1257. 59. Fields WS, Yatsu F, Conomy J, et al. Persantine – aspirin trial in cerebral ischemia: the American – Canadian Cooperative Study group. Stroke 1983; 14:97– 103. 60. Bousser MG, Eschwege E, Hagenah M, et al. “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Stroke 1983; 14:5– 14. 61. ESPS Group. European Stroke Prevention Study (ESPS): principal endpoints. Lancet 1987; 2:1351 –1354. 62. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1– 13. 63. Ikeda Y, Kikuchi M, Murakami H. Comparison of the inhibitory effects of cilostazole, acetylsalicylic acid, and ticlopidine on platelet function ex vivo: randomized, double-blind crossover study. Drug Res 1987; 37:563 – 566. 64. Tanaka K, Ishikawa T, Hagiwara M, et al. Effects of cilostazole, a selective camp phosphodiesterase inhibitor, on the contraction of vascular smooth muscle. Pharmacology 1988; 36: 313– 320. 65. Gotoh F, Tohgi H, Hirai S, et al. Cilostazole Stroke Prevention Study: a placebocontrolled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis 2000; 9:147– 157. 66. Kwon SU, Cho Y-J, Koo J-S, et al. Cilostazole prevents the progression of the symptomatic intracranial stenosis. The multicenter double-blind placebo-controlled trial of cilostazole in symptomatic intracranial arterial stenosis. Stroke 2005; 36:782 – 786. 67. Tcheng JE. Differences among the parenteral glycoprotein llb/llla inhibitors and implications for treatment. Am J Cardiol 1999; 83:7E– 15E. 68. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein llb/llla receptors in cardiovascular medicine. N Engl J Med 1995; 332:1553 – 1559. 69. Coller BS. Anti Gpllb/llla drugs: current status and future directions. Thromb Haemostast 2001; 86:427 – 443. 70. Wallace RC, Furlan AJ, Moliterno DJ, et al. Basilar artery rethrombosis: successful treatment with platelet glycoprotein llb/llla receptor inhibitor. AJNR 1997; 18:1257 – 1260. 71. Abciximab in Acute Ischemic Stroke Investigators: Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled dose-escalation study. Stroke 2000; 31:601 – 609. 72. Dyerberg J, Bang H, Stofferson E, et al. Eicosopentanoic acid and prevention of thrombosis and atherosclerosis. Lancet 1978; 2:117 – 119. 73. Radack K, Deck C, Huster G. Dietary supplementation with low-dose fish oils lowers fibrinogen levels: a randomized double-blind controlled study. Ann Int Med 1989; 111:757 – 758. 74. Kobayashi S, Hirai A, Terano T, et al. Reduction in blood viscosity by eicosopentaenoic acid. Lancet 1981; 2:197. 75. Grotta J, Ackerman R, Correia J, et al. Whole-blood viscosity parameters and cerebral blood flow. Stroke 1982; 13:296 – 298. 76. Thomas D. Whole blood viscosity and cerebral blood flow. Stroke 1982; 13:285– 287. 77. Drouet L. Fibrinogen, a treatable risk factor? Cerebrovasc Dis 1996; 6:2– 6.

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78. Kannel WB. Influence of fibrinogen on cardiovascular disease. Drugs 1997; 54(suppl 3):32–40. 79. Rothwell PM, Howard SC, Power DA, et al. Fibrinogen concentration and risk of ischemic stroke and acute coronary events in 5113 patients with transient ischemic attack and minor stroke. Stroke 2004; 35:2300 – 2305. 80. Kee DB Jr, Wood JH. Influence of blood rheology on cerebral circulation. In: Wood JH, ed. Cerebral Blood Flow: Physiological and Clinical Aspects. New York: McGraw-Hill, 1987:173 – 185. 81. Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. JAMA 1987; 258:1183– 1186. 82. Lowe G, Rumley A, Norrie J, et al. Blood rheology, cardiovascular risk factors, and cardiovascular disease: the West of Scotland Coronary Prevention Study. Thromb Haemost 2000; 84:553 –558. 83. Smith FB, Lee AJ, Fowkes GR, Price JF, Rumley A, Lowe GDO. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb 1997; 17:3321 – 3325. 84. Tanne D, Benderly M, Goldbourt U, et al. for the Bezafibrate Infarction Prevention Study Group. A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the Bezafibrate Infarction Prevention Study. Am J Med 2001; 111:457 – 463. 85. Wannamethee SG, Lowe GDO, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 2002; 105:1785 – 1790. 86. 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. 87. The 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. 88. Adams HP Jr, Bendixen BH, Leira EC, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal aortid artery. A report of the Trial of ORG 10172 in Acute Stroke treatment (TOAST). Neurology 1999; 53:122 – 125. 89. Mohr JP, Thompson JLP, Lazar RM, et al. for the Warfarin – Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345:1444 – 1451. 90. Chimowitz MI, Kokkinos J, Strong J, et al. The Warfarin – Aspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488 – 1493. 91. 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. 92. Koroshetz W. Warfarin, aspirin, and intracranial vascular disease. N Engl J Med 2005; 352:1368 – 1370. 93. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445 –453. 94. Alamowitch S, Eliasziw M, Barnett HJM, et al. The risk and benefit of endarterectomy in women with symptomatic internal carotid artery disease. Stroke 2005; 36:27– 31. 95. Barnett HJM, Taylor DW, Eliasziw M, et al. for the North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415. 96. MRC European Carotid Surgery Trial. Interim results for symptomatic patients with severe (70 –99%) or with mild (0– 29%) carotid stenosis. Lancet 1991; 337:1235 –1243. 97. European Carotid Surgery Trialists’Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998; 351:1379 – 1387. 98. Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1998; 29:554– 562.

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99. Berguer R, Flynn LM, Kline RA, Caplan LR. Surgical reconstruction of the extracranial vertebral artery management and outcome. J Vasc Surg 2000; 31:9 – 18. 100. Spetzler RF, Hadley MN, Martin NA, et al. Vertebrobasilar insufficiency: pt I. microsurgical treatment of extracranial vertebrobasilar disease. J Neurosurg 1987; 66:648 – 661. 101. Kieffer E, Koskas F, Bahnini A, Ruotolo C, Rancurel G. Long-term results after reconstruction of the cervical vertebral artery. In: Caplan LR, Shifrin EG, Nicolaides AN, Moore WS, eds. Cerebrovascular Ischaemia—Investigation & Management. London: Med-Orion, 1996: 617– 625. 102. Barnett HJM, Meldrum HE, Eliasziw M. The dilemna of surgical treatment for patients with asymptomatic carotid disease. Ann Intern Med 1995; 123:723– 725. 103. Caplan LR, Clinical crossroads. A 79 year old musician with asymptomatic carotid artery disease. JAMA 1995; 274:1383 – 1389. 104. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421 – 1428. 105. Halliday AW, Thomas DJ, Mansfield AO. The Asymptomatic Carotid Surgery trial (ACST): Rationale and design. Eur J Vasc Dis 1994; 8:703 –710. 106. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. Lancet 2004; 363:1491 – 1502. 107. Sundt TM, Sandok BA, Whisnant JP. Carotid endarterectomy complications and pre-operative assessment of risk. Mayo Clin Proc 1975; 50:301 – 306. 108. Lehv M, Salzman E, Silen W. Hypertension complicating carotid endarterectomy. Stroke 1970; 1:307 – 313. 109. Holton P, Wood J. The effects of bilateral removal of the carotid bodies and denervation of the carotid sinus in two human subjects. J Physiol 1965; 181:365– 378. 110. Breen JC, Caplan LR, DeWitt LD, et al. Brain edema after carotid surgery. Neurology 1996; 46:175 – 181. 111. Caplan LR, Skillman J, Ojemann R, et al. Intracerebral hemorrhage following carotid endarterectomy: a hypertensive complication. Stroke 1978; 9:457 – 460. 112. Dietrich EB, Ndiaye M, Reid DB. Stenting in the carotid artery: Initial experience in 110 patients. J Endovasc Surg 1996; 3:42– 62. 113. CAVATAS Investigators. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001; 357:1729 – 1737. 114. Wholey MH, Al-Mubarek N, Wholey MH. Updated review of the global carotid artery stent registry. Catheter Cardiovasc Interv 2003; 60:259– 266. 115. Kastrup A, Groschel K, Krapf H, et al. Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke 2003; 34:813 – 819. 116. CARESS Steering Committee. Carotid Revascularization using Endarterectomy or Stenting Systems (CARESS): Phase I clinical trial. J Endovasc Ther 2003; 10:1021 – 1030. 117. Yadav J, Wholey M, Kuntz KM, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004; 351:1493– 1501. 118. Meyers PM, Schumacher C, Higashida RT, Leary MC, Caplan LR. Use of stents in the treatment of cerebrovascular disease. Ann Revues Med 2006; 57:437 – 454. 119. Hobson RW II, Brott TG, Roubin GS, Silver FL, Barnett HJM. Carotid artery stenting. Meeting the recruitment challenge of a clinical trial. Stroke 2005; 36:1314– 1315. 120. Hobson RW II, Howard VJ, Roubin GS, Brott TG, Ferguson RD, Popma JJ, et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. J Vasc Surg 2004; 40:1106– 1111. 121. Kastrup A, Schulz JB, Raygrotzki S, Gro¨schel K, Ernemann U. Comparison of angioplasty and stenting with cerebral protection versus endarterectomy for treatment of internal carotid artery stenosis in elderly patients. J Vasc Surg 2004; 40:945 – 951.

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122. Coward LJ, Featherstone RL, Brown MM. Safety and efficacy of endovascular treatment of carotid artery stenosis compared with carotid endarterectomy. A cochrane systematic review of randomized evidence. Stroke 2005; 36:905 – 911. 123. McCabe DJH, Pereira AC, Clifton A, Bland JM, Brown MM on behalf of the CAVITAS Investigators. Restenosis after carotid angioplasty, stenting, or endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVITAS). Stroke 2005; 36:281 – 286. 124. Groschel K, Riecker A, Schulz J, Ernemann U, Kastrup A. Systematic review of early recurrent stenosis after carotid angioplasty and stenting. Stroke 2005; 36:367– 373.

PART VII:

THE FUTURE

18 A Look Towards the Future Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Warren J. Manning Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.

In order to know where things are headed in the future, it is important to know where they have been in the past and where they are now. We have tried in the preceding chapters to emphasize the historical aspects of brain embolism and to bring readers up-to-date on present knowledge. Looking to the future is another matter. Of course, we do not have an infallible crystal ball capable of unerringly looking ahead. The present chapter represents our best guesses, hopes, and predictions.

DIAGNOSTIC ADVANCES Technology for Studying the Brain and Its Blood Supply Ultrasound This book has repeatedly emphasized the importance of detecting the material that makes up a brain embolus in the individual patient. Treatment varies depending on embolus composition, not just the source or recipient artery. Future advances, especially in ultrasound, may help physicians recognize both the source of emboli and their composition. At present, probes placed on the skull during transcranial Doppler ultrasound (TCD) examinations usually monitor one site at a time. Attempts are now being made to create equipment that can monitor multiple sites simultaneously, and there are no important barriers to that accomplishment. Future TCD machines will have the capability of recording and displaying multiple channels. The array might look something like electroencephalography (EEG), in which multiple electrodes are placed on the scalp, fastened, and then multiple channels are used to record simultaneously from all of the electrode montages. One TCD probe could be placed over each internal carotid and vertebral artery in the neck. Other electrodes could be placed in positions to record microembolic signals from each middle cerebral artery (MCA) and posterior cerebral artery (PCA). Emboli that arise from the heart or aorta would arrive at a neck artery before traveling to the intracranial branch of that neck artery. Cardiac and aortic origin particles would pass under the 335

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right internal carotid artery (ICA) probe before being detected in the right MCA. Similarly emboli would arrive at either the right or left vertebral artery in the neck before reaching either PCA. Because four-fifths of the blood flow to the brain passes through the anterior circulation, emboli from a proximal cardio-aortic source would be expected to reach each ICA two-fifths of the time, and a vertebral artery one-fifth of the time. In contrast an embolus that arose from the right ICA would not be detected by the probe over that vessel but would be detected only repeatedly by the probe over the right MCA. No emboli would reach other probes. Similarly, an embolus arising from the left vertebral artery in the neck would not be detected in the neck but would reach either the right or left PCA only. In this way, physicians could separate cardio-aortic sources from a source in any of the neck arteries and recognize whether the left or right ICA or one of the vertebral arteries was the source of the microemboli. Fixation devices that can monitor more than one probe are now being tested. The various embolic substances have different compositions, shapes, densities, and sizes. Potential substances include: white platelet–fibrin clots, red erythrocyte–fibrin clots, calcific particles, cholesterol crystals, portions of plaques, bacteria, tumor tissue air, fat, and foreign bodies. Even a cursory glance at this list shows its heterogeneity. It may be possible through analysis of the fine aspects of microembolic signals to define the physical features of the particles passing under the probe, and so understand what they are and what they are not. Although TCD is widely used in some European and Asian countries, it is now very much underused in the United States. Hopefully its use will become much more widespread, especially if TCD technology improves, as discussed earlier. TCD machines are portable, and testing can be repeated often. TCD is safe and relatively inexpensive compared to other means of imaging arteries. Imaging of the aorta is presently a problem. Some researchers have been able to obtain images of the ascending aorta using a right supraclavicular probe and of the arch of the aorta and the proximal descending aorta using a left supraclavicular probe, although others have not had equal success with this technique. Perhaps in the future, use of an intravascular ultrasound probe or an angioscope would be able to provide information about aortic plaques, especially those that are large and mobile and are near the orifices of brachiocephalic arteries that branch from the proximal aorta. Ultrasound examinations of the neck using duplex recording devices and color-flow and power Doppler are already available. B-mode images can show the location and extent of plaques in neck arteries and can show their echodensity, morphology, and heterogeneity. These features can indicate the relative composition of plaques and estimate their stability and prognosis and response to treatments. The precision of these images can still be improved. More importantly, the present capabilities need to be distributed much more widely. Color-flow and B-mode images and recordings of the Doppler spectra can now give very useful information about the vertebral arteries in the neck, but many ultrasound laboratories now do not perform as detailed studies of the vertebral arteries as they do of the carotid arteries. In the past, this emphasis on the carotids was explained at least partially by the fact that vascular surgeons operated or controlled many diagnostic ultrasound laboratories and operations on the carotid artery far exceeded those on the vertebral arteries. With a shift in focus and frequency to angioplasty and stenting, this anterior circulation bias may diminish. In the future, with more stroke specialists and stroke neurologists, more ultrasound diagnostic laboratories might be controlled by neurologists and radiologists, and vascular surgery dominance is likely to wane. Computed Tomography Computed Tomography (CT) angiography is now able to provide very good images of the neck and cranial arteries, and CT venography shows adequate pictures of the dural sinuses

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and large veins. However, CT angiography and CT perfusion now have some limits in their capability of imaging patients with acute brain ischemia for example due to brain embolism. Now, only a few cross-sections can be studied during one passage of intravenous contrast. This limits the applicability of CT angiography (CTA) and CT perfusion to patients with anterior circulation ischemia. The posterior circulation and its arteries are now not well scanned. Improvement in this technology could allow CT perfusion and angiography to become applicable to all patients with acute brain ischemia. High-quality CT scanning is beginning to be used to define the characteristics of arterial plaques, in much the same way that ultrasound examinations are now used. This technology has made great advances with the use of newer 64-slice scanners, with 128- and 256-slice scanners on the near horizon. Radiation exposure and the need for iodinated contrast remain important issues for the foreseeable future. Magnetic Resonance Imaging (MRI) Major improvements in MR technology are occurring yearly. The use of higher fieldstrength magnets provide increased signal-to noise and may allow imaging of smaller caliber arteries than is now possible. Penetrating arteries may even be imaged in the future. MR is also now beginning to be used to provide images of arterial walls when arteries are viewed in cross-section. Arterial plaques and the aorta might be better imaged and characterized in the future. Gradient echo T2 weighted images (also called “susceptibility-weighted” images) can now show acute intracerebral and subarachnoid hemorrhages and also can suggest the presence of thrombi in intracranial arteries and veins and dural sinuses. Old hemorrhages and microbleeds are also well shown. Diffusion-weighted imaging can suggest areas of ischemia that in the great majority of instances become established infarcts. MRA can show occlusions in extracranial and intracranial arteries when the appropriate cuts are taken. These techniques can now show the data necessary to guide acute stroke treatment. There is no doubt among stroke neurologists who have had experience with both MRI and CT that MRI is superior. Also, MRA, unlike CTA and CT perfusion, requires no infusion of iodinated contrast. However, ready access to modern MRI testing 24 hours a day and seven days a week is available in only very few centers. This needs to be corrected, and the technology needs to become much more disseminated in the future. Technology for Studying the Heart Similar advances are being made with these same technologies for imaging the heart. Three-dimensional transthoracic echocardiography is just entering the clinical arena and will likely provide clinically useful information for patients with suspected cardiac sources—especially with regards to identification and characterization of ventricular thrombi and vegetations. Transesophageal echo-cardiography technology has been relatively stagnant for the past decade. Substantial probe miniaturization, three-dimensional (3D) imaging, and higher frequency transducers are widely anticipated advances that are likely to provide further improvements in spatial resolution. There has been an explosion in cardiovascular applications of both magnetic resonance and multidetector CT. Although initially studied as “replacement” or “me too” imaging modalities, more recently, unique properties of these high technology units are being exploited. Examples include delayed enhancement cardiac MR for the detection of myocardial infarction and chronic thrombi. We are witnessing the birth of molecular imaging—an area of “targeted imaging” in which a detectable agent is complexed to an antibody or other moiety so as to bind a specific tissue. This is especially promising for MRI applications to study atherosclerosis.

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THERAPEUTIC ADVANCES During the last few decades, there has been an awakening of interest and research activity in stroke treatment and stroke prevention. In the coming years, this activity will increase and new methods of treatment and improvements in present strategies will surely occur. THROMBOLYSIS The major early randomized trials of stroke thrombolysis in the United States and Europe used intravenously administered tissue plasminogen activator (t-PA) given within three hours. A CT scan was the only imaging test required. Advances in brain and vascular imaging have occurred since these early trials, and now it is possible and feasible to image the brain and vascular system safely and quickly. Newer MRI, CT, and ultrasound technology now make it possible to determine the areas of brain already infarcted and the presence and location of any occlusive arterial lesion. Clinicians and researchers have learned that the ability of the brain to withstand vascular occlusions is quite variable and cannot be predicted solely by the time that symptoms begin. In some patients, a brain embolus causes severe irreversible brain damage within one hour. In other patients, the brain can remain ischemic for many hours without permanent brain infarction. Furthermore, brain emboli can pass or be lysed spontaneously by the bodies own thrombolytic system. Instead of treating patients by the clock, clinicians who have the available technology can base treatment on: (i) the presence and location of any occlusive emboli, (ii) the presence, location, and size of brain tissue already infarcted, and (iii) the amount of brain tissue still at risk of further brain infarction. Using this information, doctors of the future can decide whether or not to administer a thrombolytic drug (or a mechanical device capable of inducing reperfusion), and whether an intravenous or intra-arterial route of administration seems most likely to be effective. Some physicians will choose to first try an intravenous route, and if this does not result in reperfusion, then pursue intra-arterial treatment. The thrombolytic drugs used and their doses will also be the target of future research. Researchers are seeking drugs that have a high affinity for attaching to thrombi and cause less systemic fibrinolytic effects. Such a substance would more effectively lyse clots and cause less bleeding. A derivative of bat wings, desmoteplase, is now being tested. Various other thrombolytic agents are also the targets of active research and will likely become available in the foreseeable future. Doctors are also exploring ways to enhance the activity of the presently available thrombolytic drugs. The energy provided by ultrasound, when thrombolysis is monitored by constant monitoring using a TCD probe over the occluded artery, may facilitate thrombolysis. Preliminary studies also suggest that intravenous agents now used to enhance ultrasound signals in Europe may also facilitate thrombolysis. Facilitation of clot lysis using various energy sources and intravenous agents will continue to be a target for research and clinical care in the future. MECHANICAL DEVICES The very last years of the twentieth century and the first years of the twenty-first century will likely be recognized as a time when vascular interventions and interventionists came into prominence and even dominance in the treatment of a variety of vascular conditions. Various devices are now available that can mechanically retrieve thromboemboli and open

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blocked arteries. Interventionists are now using various balloons and angioplasty technology and are employing a variety of different vascular stents to open arteries and to keep arteries open. Research on stents is occurring at a rapid pace. Drug-eluting stents are now being made that promise to diminish the frequency of restenosis of vessels and of thrombosis. In some situations in which thrombolytics are now contraindicated because of the risk of bleeding, mechanical clot removal will become the preferred treatment. Interventionists of the future will have a menu of different agents—thrombolytics, antiplatelets, vasodilators—and different devices that they can use once they have navigated catheters to the location of the vascular lesion.

ANTIPLATELET AGENTS Thromboemboli are composed of either red erythrocyte –fibrin clots or white platelet – fibrin thrombi. Thrombolytic drugs now in use lyse red clots by breaking up fibrin bridges that entrap red blood cells. These agents do not lyse white clots but actually activate platelets and enhance the formation of white platelet thrombi. In some situations, for example, recent carotid surgery, a carpet of white platelet thrombi can form and embolize intracranially. In other situations, such as irregular arterial plaques and cardiac valves, white clots form and stimulate the formation of superimposed red thrombi. The attachment of platelets to fibrinogen is mediated through a Gpllb/llla receptor. Gpllb/llla inhibitors offer great promise in preventing white clots from forming and lysing white clots that are already present. The Gpllb/llla inhibitor abxiximab (reopro) can lyse white clots when given intravenously. Unfortunately, present attempts to introduce oral Gpllb/llla inhibitors have been thwarted by excess bleeding. In the future, it will probably be possible to introduce into clinical care an oral Gpllb/llla inhibitor that effectively prevents white clot formation while carrying only a minimal bleeding risk. Another target for preventive treatment of white clot formation is the attachment of platelets to the endothelium. Now there are two agents, extended-release dipyridamole and cilostazole, whose mechanism of action relates to the endothelial attachment of platelets. Future research may lead to improvement in these drugs and introduction of others with a similar mechanism of action.

ANTICOAGULANTS The presently used anticoagulants, heparins and warfarin, can effectively prevent red clot formation, propagation, and embolization when they are properly administered and monitored. However, they have significant limitations in patient care. Heparins must be given intravenously or subcutaneously and can cause significant bleeding if not well controlled. Dose differs and monitoring of low-molecular-weight heparins is difficult at present. Heparin-induced thrombocytopenia is a risk of treatment with unfractionated heparin. Warfarin acts as a prothrombin antagonist. Warfarin anticoagulation is difficult to control because of individual variance in dose and the effect of a variety of foods and other pharmaceutical agents on vitamin k, prothrombin, and liver functions. Direct inhibitors of thrombin offer many potential advantages. Two direct thrombin inhibitors are available and have been used in trials. Argatroban is an intravenous agent that is used often in Asia instead of heparin. Ximelagatran is an oral agent that has been used in trials and approved in Europe but has not yet been approved in the United States. It acts quickly, so heparin or any other acute anticoagulant would not be needed.

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The dose is constant and does not require monitoring. There is no important effect of foods or other drugs. Unfortunately, ximelagatran needs to be given twice a day and can cause an elevation of liver enzymes and can potentially cause liver damage in a small minority of patients. In the future, ximelagatran or another direct thrombin inhibitor will likely replace heparins and warfarins for rapid, safe, and effective anticoagulation.

NEUROPROTECTANTS Substances that are given to render the brain more resistant to ischemia are called neuroprotectants. To date, no putative neuroprotectant that has been tested in trials has found to be effective. However, the methodology of the trials in our opinion has been faulty. Trials have enrolled all ischemic stroke patients, excluding only those with minor strokes because there was little opportunity for them to significantly improve. However a large group of stroke patients are unlikely to be effectively treated with neuroprotectant agents: (i) those patients that already have large infarcts and there is little brain still at risk for infarction; (ii) those patients in whom large brain-supply arteries are still occluded—the intravenously administered agent would likely not reach ischemic brain tissue in sufficient quantity to be effective, and (iii) those patients with predominantly white matter infarcts, as the agents are mostly cytoprotective and would likely only protect grey matter from ischemic damage. Trials that have a good chance of showing whether or not a neuroprotectant is effective and safe ideally should include patients with predominantly sizable regions of grey matter ischemia in whom the arteries supplying the ischemic regions are open or will be soon opened with thrombolytic drugs or by mechanical means. Modern brain and vascular imaging can select this group of patients before treatment. If an agent proves effective in this selected group of patients and proves safe, then it will be widely used. We predict that agents will be found that, when given in selected circumstances, can make the brain more resistant to ischemia.

PERSONNEL AND SYSTEMS OF CARE There are presently five major problems hindering delivery of good stroke care to the general population: (i) insufficient public knowledge about stroke and its symptoms; (ii) not enough stroke centers that are able to deliver rapid and excellent care to acute stroke patients; (iii) not enough dissemination of modern brain and vascular imaging to these potential stroke centers; (iv) not enough well-trained experienced stroke specialists; and (v) insufficient systems and protocols that ensure that patients are rapidly delivered to stroke centers and that ensure rapid throughput at those stroke centers. Stroke care begins with the patient who first develops symptoms. Patients and their significant others are often not well educated about stroke symptoms and what to do if they occur. When they call 911 or other emergency access, the person responding must be trained to set in motion rapid delivery to the highest-level stroke center in the vicinity of the patient. The ambulance system is now not geared to deliver stroke patients quickly to the best available specialist center, although they have been trained and experienced for years to do this with trauma patients. In the future, more stroke specialists will undoubtedly be trained. Certification of the qualifications of primary and advanced stroke centers will ensure that these centers have the personnel, technology, experience, and systems to efficiently and expertly care for stroke patients.

Index

ACA. See anterior cerebral artery. ACE inhibitors, arterial source emboli and, 320– 321 AChA. See anterior choroidal artery. AF. See amaurosis fugax. AION. See anterior ischemic optic neuropathy. Air embolism, embolic particles and, 268–269 Alexia without agraphia, posterior cerebral artery (PCA) territory infarcts and, 71 Altered memory, posterior cerebral artery (PCA) territory infarcts and, 72 Amaurosis fugax (AF), 83 Angiographic sites, embolic brain infarcts and, 49 – 51 Angioplasty, 328 Anomic sensory aphasia, posterior cerebral artery (PCA) territory infarcts and, 71 Anterior cerebral artery (ACA), 26 ischemia, 69 Anterior choroidal artery (AChA), 26 ischemia, 69 – 70 Anterior circulation embolism, anterior cerebral artery ischemia, 69 Anterior choroidal artery territory ischemia, 69 – 70 Anterior circulation embolism brain ischemia and, 67 – 70 MCA ischemia inferior division, 68– 69 striatocapsular ischemia, 68 superior division MCA ischemia, 68 Anterior ischemic optic neuropathy (AION), 87 Anticoagulants aortic sources and, 324– 326 atrial fibrillation and, treatments, 289– 297 embolic event treatment of, 282– 283 embolism, future care and prevention, 339– 340

prosthetic valve thrombi and, guidelines, 172 Antiphospholopid antibody syndrome (APIA), 141 Antiplatelet agents, embolism, future care and prevention, 339 Aorta, brain embolism and, proximal aorta imaging, 196– 198 Aorta, brain embolism and, relationship between, 187–198 Aortic atheromatosis platelet function alterations, 321– 323 treatment of, 319– 320 Aortic atherosclerosis brain embolism and, 187– 188 clinical analyses between, 188– 190 echocardiographic analyses between, 188– 190 pathological analyses between, 188– 190 combination therapy and, 304 –306 emboli source and, 171– 172 heart surgery, 191– 194 postoperative risk factors, 191– 194 nonatherosclerotic disease, 190– 191 plaque thickness, 189 post-heart surgery cognitive abnormalities, 194– 196 encephalopathy abnormalities, 194– 196 neurobehavioral abnormalities, 194– 196 Aortic sources anticoagulants, 324– 326 interventional treatments, 326– 328 surgical treatments, 326–328 Aortic valve disease, 132– 134 APIA. See antiphospholopid antibody syndrome. Arrhythmias, 130– 144 aortic valve disease, 132– 134 atrial fibrillation, 130– 131 341

342 Arrhythmias (Continued) atrial flutter, 131 cardiac valve disease, 131– 132 infective endocarditis, 137– 139 mitral annulus calcification, 135– 136 mitral valve prolapse, 134– 135 noninfective fibrinous endocardial lesions, 139– 144 noninfective fibrous endocardial lesions, 139– 144 prosthetic cardiac valves, 136– 137 rheumatic mitral valve disease, 132 Arterial aneurysms, 208– 209 dissections, 205 occlusions, transcranial Doppler and, 114– 117 origin sources, embolic particles and, 264 remodeling, 231–234 hemodynamic stimuli, 232 inflammation, 232– 233 mechanisms of, 233 plaque rupture, 233– 234 scarring, 232– 233 stroke-specific aspects, 234 Arterial-source emboli ACE inhibitors, 320– 321 medical treatment of, 320–323 statins, 320 receptor blockers, 320–321 embolism, 203– 218 arterial aneurysms, 208– 209 arterial dissections, 205 atherosclerosis, 203– 204 dolichoectatic arteries, 208– 209 fibromuscular dysplasia, 205– 208 imaging evaluation, 216– 218 laboratory evaluation, 216–218 lesion distribution, 209– 213 relationship of symptoms to severity, 213– 216 endarterectomy, surgical treatment, 326– 328 interventional treatments, 326– 328 surgical treatments, 326– 328 Artery-to-artery embolism, detection of, transcranial Doppler and, 121– 122 Associative visual agnosia, posterior cerebral artery (PCA) territory infarcts and, 72 Atherosclerosis, arterial-source embolism and, 203– 204

Index Atrial fibrillation, 130– 131 anticoagulation treatments, 289– 297 emboli source and, 165– 169 embolism and, 289– 311 new onset atrial fibrillation, 289– 297 treatment, recurrent cases of, 297– 298 risk profile, 298 Atrial flutter, 131 Bacteria, cardiac-origin substances and, 262– 263 Basilar ischemia, 72 – 75 Blocked recipient arteries, reperfusion and, 277– 278 B-mode, imaging, 226 Brain blood flow augmentation, reperfusion and, 281– 282 Brain edema management, embolic event and, 284 Brain embolism aorta proximal aorta imaging, 196– 198 relationship between, 187– 198 aortic atherosclerosis, 187– 188 clinical analyses between, 188– 190 echocardiographic analyses between, 188– 190 pathological analyses between, 188– 190 cardiac sources of, 129– 151 arrhythmias, 130– 144 cardiac chamber lesions, 144– 147 cardiac myxomas, 147– 151 myocardial chamber lesions, 144– 147 major components, 25 – 29 embolic material, 27– 28 recipient arteries, 25 –27 observational history of, 1 – 19 secondary prevention of, 28 – 29 vascular hemostasis, 243– 253 Brain imaging computed tomography perfusion, 104– 106 intracranial vascular imaging, 97 – 101 magnetic resonance perfusion imaging, 101– 104 perfusion, other diagnostic techniques, 106– 108 recipient arteries and, 93 – 108 Brain ischemia anterior circulation embolism, 67 – 70 Basilar ischemia, 72 –75 cerebellar infarcts, 75 pathophysiology, thrombosis and, 244–245 PICA cerebellar infarcts, 76 – 77

Index posterior cerebral artery (PCA) territory infarcts, 70 – 72 posterior circulation embolism, 70 recipient artery and, 61 – 77 superior cerebellar artery territory infarction, 75– 76 systemic embolism, 64 – 66 transient ischemic attacks, 63 –64 Brain neuroimaging computed tomography (CT), effectiveness of, 93 –97 evaluation of, 93 – 97 key physician questions, 94 magnetic resonance imaging, effectiveness of, 93 –97 Brain shifts, embolic brain infarcts and, 55 – 57 Calcified particles, 262 Cardiac chamber lesions, 144– 147 nonischemic cardiomyopathies, 146– 147 Cardiac myxomas, 147– 151 cardiac septal lesions, 148– 151 paradoxical embolism, 148– 151 Cardiac septal lesions, cardiac myxomas and, 148– 151 Cardiac sources arrhythmias, 130– 144 brain embolism and, 129– 151 cardiac chamber lesions, 144–147 cardiac myxomas, 147–151 embolism and, 161– 180 imaging procedures, 179– 180 interatrial septum abnormalities, 309– 311 treatment of, 289– 311 combination therapy, 300– 308 myocardial chamber lesions, 144– 147 Cardiac valve disease, 131–132 Cardiac-origin substances calcified particles, 262 embolic particles and, 259– 264 fibrin strands, 263 infectious material, 262– 263 myxomas, 263–264 papillary fibroelastomas, 263– 264 red thrombi, 259– 261 white thrombi, 261– 262 Cardiogenic emboli, vs. intra-arterial emboli, 52 – 54 Carotid artery circulation embolism. See anterior circulation embolism. CDFI. See color Doppler flow imaging. Central retinal artery branch occlusions (CRABO), 86 – 87

343 Central retinal artery occlusion (CRAO), 85 – 86 Cerebellar artery territory infarction, brain ischemia and, 75 – 76 Cerebellar infarcts, brain ischemia and, 75 Cerebral angiography, Harvard Stroke registry, 53 Cerebrovascular reservoir, vascular hemostasis and, 249 Cerebrovascular thrombosis, 246 Cervical arteries intima-media thickness (IMT), 223– 224 plaque development, intermediate stage, 226– 234 ultrasound, 223– 236 Chemical thrombolysis, reperfusion and, 278– 281 Clinical analyses, brain embolism and aortic atherosclerosis, 188– 190 Clot removal, reperfusion and, 278–281 Cognitive difficulties, postoperative heart surgery abnormalities and, 194– 196 Collateral circuits, vascular hemostasis and, 249– 250 Color Doppler flow imaging (CDFI), 227 Combination therapy aortic atherosclerosis, 304–306 embolism treatment and, 300 –308 endocarditis, 306– 307 intracardiac tumors, 307– 308 left ventricular thrombus treatment, 304 nonpharmacological alternatives, 302– 303 warfarin, 302 ximelagatran, 301– 302 Compounded imaging, 227 Computed tomography angiography (CTA), 99 – 101 Computed tomography perfusion, protocols of, 104– 106 Computed tomography brain neuroimaging, effectiveness of, 93 – 97 embolism future care and prevention, 336– 337 Consciousness, decreased level of, systemic embolism and, 66 Consumptive coagulapathy, vascular hemostasis and, 248 CRABO. See central retinal artery branch occlusions. CRAO. See central retinal artery occlusion. CTA. See computed tomography angiography.

344 Dilated cardiomyopathy, emboli source and, 171 Dolichoectatic arteries, 208– 209 Dye contrast catheter angiography, 97 – 99 embolism indications, 98 Echocardiographic analyses, brain embolism and aortic atherosclerosis, 188– 190 ECVA. See extracranial vertebral artery. Edema, embolic brain infarcts and, 55 – 57 Emboli passing, 26 transcranial Doppler and, 122– 123 Embolic brain infarcts angiographic sites, 49 – 51 brain shifts, 55 – 57 edema, 55– 57 intra-arterial vs. cardiogenic, 52 – 54 location of, 36 multiple emboli, 51 – 52 posterior circulation sites, 44 –49 size of, 36 – 43, 54 – 55 types, 36 – 43 treatment of, 277– 284 anticoagulation, 282– 283 brain edema management, 284 neuroprotective agents, 283– 284 reperfusion, 277– 284 Embolic material, brain embolism and, 27 – 28 Embolic particles, 259– 263 air embolism, 268– 269 arterial origin sources, 264 cardiac-origin substances, 259– 264 fat embolism, 264– 268 foreign body embolism, 270– 271 substances from outside the body, 264–271 tumor embolism, 269– 270 Embolism arterial sources of, 203– 218 artery-to-artery, 121– 122 cardiac source of, 161– 180 interatrial septum abnormalities, 309– 311 imaging procedures, 179– 180 treatment of, 289– 311 combination therapy, 300– 308 TTE vs. TEE, 179– 180 eye, investigating techniques of, 87 – 88 future care and prevention, 335– 340 anticoagulants, 339– 340 antiplatelet agents, 339 computed tomography, 336– 337 heart imaging technology, 337

Index Embolism (Continued) magnetic resonance imaging, 337 neuroprotectants, 340 thrombolysis, 338 ultrasound, 335– 336 major source of, 161– 179 retinal differential diagnosis, 88 – 89 usual causes, 89 – 90 sources of aortic atherosclerosis, 171– 172 atrial fibrillation, 165– 169 dilated cardiomyopathy, 171 infective endocarditis, 172– 173 intacardiac tumors, 174– 175 interatrial septum abnormalities, 176–179 left atrial thrombi, 162 left atrial, spontaneous echo contrast, 175– 176 left ventricular thrombi, 169 mitral annular calcification, 174 mitral stenosis, 163– 165 myocardial infarction, 170– 171 prosthetic valve thrombi, 171 valve excrescences, 173– 174 valvular calcification, 173 treatment of, atrial fibrillation, 289–311 Embolism, vs. thrombosis, recipient artery and, 31 – 32 Encephalopathy, postoperative heart surgery abnormalities and, 194– 196 Endarterectomy, 326– 328 Endocarditic lesions, 139– 144 antiphospholopid antibody syndrome (APIA), 141 nonbacterial thrombotic endocarditis (NBTE), 141 systemic lupus erythematosis (SLE), 141 Endocarditis, combination therapy and, 306– 307 Endogenous protective mechanisms, vascular hemostasis and, 250 Endogenous thrombus lysis, vascular hemostasis and, 251 Extrancranial vertebral artery (ECVA), 26 Eye embolism investigating techniques, 87 – 88 retinal embolism, 88 – 89 Eye ischemia, 83 – 87 amaurosis fugax (AF), 83 anterior ischemic optic neuropathy (AION), 87 central retinal artery branch occlusions (CRABO), 86 – 87

Index Eye ischemia (Continued) central retinal artery occlusion (CRAO), 85 – 86 embolism, investigating techniques, 87 – 88 major syndromes, 83 – 87 retinal embolism, 88 – 89 transient monocular blindness (TMB), 83 transient monocular visual loss (TMVL), 83 – 84 treatment of, 90 Eye artery anatomy, 81 – 82 as recipient artery, 81– 90 Fat embolism, embolic particles and, 264–268 Fibrin degradation, vascular hemostatis and, 248– 249 Fibrin strands, cardiac-origin substances and, 263 Fibrinogen concentrations, altering properties, 323– 324 Fibrinous endocardial lesions, 139– 144 Fibromuscular dysplasia, 205–208 Fibrous endocardial lesions, 139– 144 Foreign body embolism, embolic particles and, 270– 271 Fungi, cardiac-origin substances and, 262–263 Gerstmann’s syndrome, posterior cerebral artery (PCA) territory infarcts and, 71 – 72 Harvard Stroke registry, 53 Headache, systemic embolism and, 65 Heart imaging technology, embolism future care and prevention, 337– 338 surgery aortic atherosclerosis and, 191– 194 postoperative risk factors, 191– 194 postoperative abnormalities cognitive difficulties, 194– 196 encephalopathy, 194– 196 neurobehavioral, 194– 196 Hemodynamic stimuli, 232 Hemorrhagic infarction, recipient artery and, 33 – 36 Hemorrhagic transformation, vascular hemostasis and, 247– 248 High-intensity transient signals (HITS), 26 HITS. See high-intensity transient signals. ICA. See internal carotid artery. ICVA. See intracranial vertebral artery.

345 ICVA. See intracranial vertebral artery. Imaging arterial-source embolism and, 216– 218 emboli cardiac sources and, 179– 180 IMT. See intima-media thickness. Infectious material bacteria, 262–263 cardiac-origin substances and, 262– 263 fungi, 262– 263 Infective endocarditis, 137–139 emboli source and, 172– 173 Inflammation, arterial remodeling and, 232– 233 Interatrial septum abnormalities embolism and, 309– 311 source of, 176– 179 Internal carotid artery (ICA), 26 Interventional treatments, aortic sources, arterial sources, 326– 328 Intima-media thickness (IMT) assessment of, 226 cervical arteries and, 223– 224 morphologic correlates, 226 sampling of, 224– 226 Intra-arterial emboli, vs. cardiogenic, 52 – 54 Intracardiac tumors combination therapy and, 307– 308 emboli sources and, 174– 175 Intracranial artery stenosis, transcranial Doppler and, 121– 122 Intracranial vascular imaging, 97 – 101 computed tomography angiography (CTA), 99 – 101 dye contrast catheter angiography, 97– 99 magnetic resonance angiography (MRA), 99 Intracranial vertebral artery (ICVA), 25 – 26 Left atrial thrombi, emboli sources and, 162 Left atrial, spontaneous echo contrast, emboli sources and, 175– 176 Left ventricular thrombi, emboli source and, 169 Left ventricular thrombus treatment, combination therapy, 304 Lesion distribution, arterial-source embolism and, 209– 213 Magnetic resonance angiography (MRA), 99 Magnetic resonance imaging brain neuroimaging and, effectiveness of, 93 – 97 embolism future care and prevention, 337 perfusion imaging, 101– 104 protocols of, 101–104

346 MCA ischemia inferior division, 68 – 69 MCA. See middle cerebral artery. Mechanical thrombolysis, reperfusion and, 278– 281 Microvessel integrity, vascular hemostasis and, 253 Microvessel-associated protection, vascular hemostasis and, 250 Middle cerebral artery (MCA), 25 – 26 Mitral annular calcification, 135– 136 emboli sources and, 174 Mitral stenosis, emboli source and, 163– 165 Mitral valve prolapse, 134– 135 MRA. See magnetic resonance angiography. Multiple emboli, embolic brain infarcts and, 51 – 52 Myocardial chamber lesions, 144– 147 myocardial infarction, 144– 146 Myocardial infarction emboli source and, 170– 171 myocardial chamber lesions and, 144– 146 Myxomas, cardiac, 147– 151 cardiac-origin substances and, 263– 264 NBTE. See nonbacterial thrombotic endocarditis. Neurobehavioral, postoperative heart surgery abnormalities and, 194– 196 Neurologic symptoms, recipient artery and, 66 – 67 Neuroprotectants, embolism future care and prevention, 340 Neuroprotective agents, embolic event treatment and, 283– 284 New onset atrial fibrillation, treatment of, 289– 297 Nonatherosclerotic disease, 190– 191 Nonbacterial thrombotic endocarditis (NBTE), 141 Noninfective fibrinous endocardial lesions, 139– 144 Noninfective fibrous lesions, 139– 144 Nonischemic cardiomyopathies, 146– 147 Nonpharmacological alternatives, combination therapy and, 302– 303 Papillary fibroelastomas, cardiac-origin substances and, 263– 264 Paradoxical embolism, cardiac myxomas and, 148– 151 Passing emboli, 26 high-intensity transient signals (HITS), 26 transient ischemic attack (TIA), 26

Index Pathological analysis, brain embolism and aortic atherosclerosis, 188– 190 PCA. See posterior cerebral artery. Perfusion, diagnostic techniques other diagnostic techniques, 106– 108 positron-emission tomography (PET), 107 single photon emission computed tomography (SPECT), 107 xenon inhalation, 106 PET. See positron-emission tomography. PICA cerebellar infarcts, 76 – 77 PICA. See posterior inferior cerebellar artery. Plaque development final stage, ultrasound and, 234– 236 intermediate stage, 226– 234 arterial remodeling, 231–234 B-mode imaging, 226 plaque morphology, 229 color Doppler flow imaging (CDFI), 227 compounded imaging, 227 plaque echogenicity, 229 plaque motion, 231 plaque-surface structure, 230– 231 ulcerations, 230–231 Plaque echogenicity, computerized evaluation, 230 Plaque morphology, B-mode and, 229 Plaque motion, 231 Plaque rupture, arterial remodeling and, 233– 234 Plaque-surface structure, 230– 231 Plaque-surface ulcerations, 230– 231 Platelet activation, vascular hemostasis and, 249 Platelet function altering agents, aortic atheromatosis and, 321– 323 Positron-emission tomography (PET), 107 Posterior cerebral artery (PCA), 25 territory infarcts, 70 – 72 alexia without agraphia, 71 altered memory, 72 anomic sensory aphasia, 71 associative visual agnosia, 72 Gerstmann’s syndrome, 71 – 72 transcortical sensory aphasia, 71 Posterior circulation embolism, 70 Posterior circulation sites, embolic brain infarcts and, 44 – 49 Posterior inferior cerebellar artery (PICA), 70 Prosthetic cardiac valves, 136– 137 Prosthetic valve thrombi anticoagulation guidelines, 172 emboli source and, 171– 172 Proximal aorta imaging, 196– 198

Index Receptor blockers arterial source emboli and, 320– 321 anterior cerebral artery (ACA), 26 anterior choroidal artery (AChA), 26 blocked, reperfusion and, 277– 278 brain embolism and, 25 – 27 cerebral angiography, Harvard Stroke registry, 53 extracranial vertebral artery (ECVA), 26 imaging evaluation of, 93 – 108 brain neuroimaging, 93 – 97 internal carotid artery (ICA), 26 intracranial vertebral artery (ICVA), 25 – 26 middle cerebral artery (MCA), 25 –26 passing emboli, 26 posterior cerebral artery (PCA), 25 superior cerebellar arteries (SCAs), 26 Recipient artery anatomy of, 31 –57 brain ischemia, 61 – 77 anterior circulation embolism, 67 – 70 clinical symptoms, 61 – 63 systemic embolism, 64 – 66 transient ischemic attacks, 63 – 64 clinical symptoms, 61 – 77 embolic brain infarcts location, 36 size, 36 – 43 types, 36 – 43 embolism vs. thrombosis, 31 – 32 eye ischemia, 83 –87 eye, 81 – 90 hemorrhagic infarction, 33 – 36 neurologic symptoms, clinical patterns of, 66 – 67 pathology of, 31 – 57 Recurrent atrial fibrillation, treatment of, 297– 298 Red thrombi, 259 –261 Reperfusion blocked recipient arteries opened, 277– 278 brain blood flow augmentation, 281 –282 chemical thrombolysis, 278– 281 clot removal, 278– 281 embolic event treatment and, 277–284 mechanical thrombolysis and, 278– 281 Retinal embolism differential diagnosis, 88 – 89 usual causes, 89 – 90 Rheumatic mitral value disease, 132 Right-to-left shunt, detection of, transcranial Doppler and, 123– 124

347 Scarring, arterial remodeling and, 232– 233 SCAs. See superior cerebellar arteries. Seizures, systemic embolism and, 65 – 66 Selective neuron vulnerability, vascular hemostasis and, 253 Single photon emission computed tomography (SPECT), 107 SLE. See systemic lupus erythematosis. SPECT. See single photon emission computed tomography. Spontaneous echo contrast, emboli source and, 175– 176 Statins, arterial source emboli and, 320 Stenting, 328 Striatocapsular ischemia, 68 Stroke thrombolysis, recommendations for, 281 Stroke, observational history of, 1 – 19 Stroke, specific aspects, arterial remodeling and, 234 Superior cerebellar arteries (SCAs), 26 Superior division MCA ischemia, 68 Surgical treatments angioplasty, 328 aortic sources, 326– 328 arterial sources, 326– 328 endarterectomy, 326– 328 stenting, 328 Systemic embolism, 64 – 66 consciousness decreased, 66 headache, 65 seizures, 65 – 66 Systemic lupus erythematosis (SLE), 141 TCD. See transcranial Doppler ultrasound. TEE, vs. TTE, imaging, emboli cardiac sources, 179– 180 Thrombin activity, vascular hemostasis and, 252– 253 Thrombin generation, vascular hemostasis and, 249 Thrombolysis, chemical, 278– 281 Thrombolysis embolism future care and prevention, 338 mechanical, 278– 281 stroke, recommendations for, 281 transcranial Doppler and, 117– 121 Thrombosis brain ischemia pathophysiology, 244– 245 embolism vs., recipient artery and, 31 – 32 TIA. See transient ischemic attack.

348 TMB. See transient monocular blindness. TMVL. See transient monocular visual loss. Transcortical sensory aphasia, posterior cerebral artery (PCA) territory infarcts and, 71 Transcranial Doppler ultrasound (TCD), 113– 124 arterial occlusions diagnosis, 114– 117 artery-to-artery embolism, detection of, 121– 122 emboli monitoring, 122– 123 intracranial artery stenosis, detection of, 121– 122 right-to-left shunt, detection of, 123– 124 thrombolysis, 117– 121 Transient ischemic attacks (TIA), 26, 63 – 64 Transient monocular blindness (TMB), 83 Transient monocular visual loss (TMVL), 83 – 84 TTE, vs. TEE, imaging, emboli cardiac sources, 179– 180 Tumor embolism, embolic particles and, 269– 270 Ultrasound cervical arteries, 223– 226 embolism future care and prevention, 335– 336 plaque development final stage, 234– 236 intermediate stage, 226– 234 transcranial Doppler (TCD), 113– 124

Index Valve excrescences, emboli source and, 173– 174 Valvular calcification, emboli source and, 173 Vascular hemostasis brain embolism and, 243– 253 cerebrovascular reservoir, 250 cerebrovascular thrombosis, 245– 247 collateral circuits, 250 consumptive coagulapathy, 248 endogenous protective mechanisms, 250 endogenous thrombus lysis, 251 fibrin degradation, 249 hemorrhagic transformation, 247– 248 microvessel integrity, 253 microvessel-associated protection, 250 platelet activation, 249 selective neuron vulnerability, 253 thrombin activity, 252– 253 thrombin generation, 249 thrombosis, brain ischemia pathophysiology, 244– 245 vascular matrix degradation, 251– 252 Vascular matrix degradation, vascular hemostasis and, 251– 252 Vertebro-Basilar arteries embolism. See posterior circulation embolism. Warfarin, 302 White thrombi, 261– 262 Xenon inhalation, 106 Ximelagatran, 301– 302

About the Editors

LOUIS R. CAPLAN is Professor of Neurology at Harvard Medical School, Boston, Massachusetts, and Chief of Cerebrovascular Diseases at Beth Israel Deaconess Medical Center, Boston, Massachusetts. Previously, he was Professor and Chair of the Neurology Departments at the University of Chicago, Illinois, and Tufts University, Medford, Massachusetts. Dr. Caplan is a member of numerous professional societies, has been a member of many journal editorial boards, and has served as an officer of several committees for the American Heart Association. He has been an invited lecturer at many national and international universities and has authored or coauthored over 175 articles and reports and 31 books. Dr. Caplan received his M.D. degree from the University of Maryland School of Medicine, Baltimore, Maryland. WARREN J. MANNING is Section Chief of Noninvasive Cardiac Imaging and Codirector of the Cardiac MR Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, and Professor of Medicine and Radiology, Harvard Medical School, Boston, Massachusetts. His fields of interest include the application of echocardiography to the management of atrial fibrillation and the application of magnetic resonance to the cardiovascular system. Dr. Manning is an editorial consultant and member of various editorial boards including Circulation and the Journal of the American College of Cardiology. He has coauthored over 160 peer-reviewed articles, and nearly 100 reviews/book chapters. Dr. Manning received his B.S. degree from the Massachusetts Institute of Technology, Cambridge, Massachusetts, and his M.D. degree from Harvard Medical School, Boston, Massachusetts. This was followed by internship/residency in internal medicine and fellowship in cardiovascular diseases at the former Beth Israel Hospital, Boston, Massachusetts.