Handbook of Cerebrovascular Diseases, Second Edition, Revised and Expanded (Neurological Disease and Therapy)

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Handbook of Cerebrovascular Diseases Second Edition, Revised and Expanded

NEUROLOGICAL DISEASE AND THERAPY Advisory Board Louis R. Caplan, M.D. Professor of Neurology Harvard University School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

William C. Koller, M.D. Mount Sinai School of Medicine New York, New York

John C. Morris, M.D. Friedman Professor of Neurology Co-Director, Alzheimer’s Disease Research Center Washington University School of Medicine St. Louis, Missouri

Bruce Ransom, M.D., Ph.D. Warren Magnuson Professor Chair, Department of Neurology University of Washington School of Medicine Seattle, Washington

Kapil Sethi, M.D. Professor of Neurology Director, Movement Disorders Program Medical College of Georgia Augusta, Georgia

Mark Tuszynski, M.D., Ph.D. Associate Professor of Neurosciences Director, Center for Neural Repair University of California–San Diego La Jolla, California

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 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 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.

Additional Volumes in Preparation

Handbook of Cerebrovascular Diseases Second Edition, Revised and Expanded

edited by

Harold P. Adams, Jr.

Marcel Dekker

New York

This edition published in the Taylor & Francis e-Library, 2005.

“To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.”

The ﬁrst edition was published as Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr. (Marcel Dekker, Inc., 1994). Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide speciﬁc advice or recommendations for any speciﬁc situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identiﬁcation and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN 0-203-99694-1 Master e-book ISBN

ISBN: 0-8247-5390-9 (Print Edition) Headquarters Marcel Dekker 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 World Wide Web http://www.dekker.com The publisher oﬀers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright n 2005 by Marcel Dekker. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microﬁlming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.

This book is dedicated to my family for their unfailing love and support. This book also is dedicated to the memory of Drs. A. L. Sahs, M. W. Van Allen, and R. W. Fincham. These mentors and colleagues provided invaluable guidance and help to me as I started my career in academic neurology.

Preface, Acknowledgements and Thanks

The ﬁrst edition of the Handbook of Cerebrovascular Diseases was published in 1993. Since the publication of that book, management of vascular diseases of the nervous system has changed dramatically. The evaluation of patients has evolved with the improvement of diagnostic studies. New medical therapies and interventions to prevent stroke have been developed including medications to help stabilize the arterial wall. Thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke. New methods to prevent or control complications of stroke are being instituted. Finally, measures to maximize recovery through rehabilitation are being employed. These advances support the importance of a new edition of the Handbook of Cerebrovascular Diseases. I thank the publisher for taking the leadership in sponsoring this publication. I also thank the authors of the chapters in this book, many of them contributed to the ﬁrst edition. These colleagues are very busy and I appreciate their taking time to collaborate in this endeavor. The quality of their contributions is excellent. I also thank them for asking junior colleagues to participate in these submissions. Such a strategy is an important way to allow young physicians to contribute to the medical literature. I thank my colleagues at the University of Iowa who have supported by activities in education, patient care, and research. I thank the nurse coordinators, in particular Karla Grimsman, who have expedited my clinical research projects. I also thank my secretaries, who have provided great assistance in the production of this book. In particular, I acknowledge the help of Beth Bell, Jill Trumm, and Jessica Fritz.

v

Contents

Preface Contributors PART I.

v xi

CLINICAL FEATURES AND DIAGNOSIS

1. Epidemiology and Risk Factors for Stroke James C. Torner 2. Diagnosis and Prognosis of Transient Ischemic Attacks S. Claiborne Johnston and Naomi L. Ruﬀ 3. Ischemic Stroke Syndromes: Clinical Features, Anatomy, Vascular Territories, and Prognosis Gabriel R. de Freitas and Julien Bogousslavsky

1

21

43

4. Intracerebral Hemorrhage Ku-Chou Chang

73

5. Brain Imaging in Stroke Chelsea S. Kidwell, Jeﬀrey Saver, Bruce Ovbiagele, and Steven Warach

81

6. Evaluation of Patients with Stroke Including Vascular and Cardiac Imaging Timea Hodics and Louis R. Caplan 7. Interactions Between Cardiovascular and Cerebrovascular Disease Giuseppe Di Pasquale, Stefano Urbinati, and Giuseppe Pinelli

101

133 vii

viii

Contents

PART II. 8.

9.

10.

MANAGEMENT OF CEREBROVASCULAR DISEASE

Organization of Stroke Services in the Hospital and the Community J. Kennedy, A. M. Buchan, and D. L. Sandler Complications of Acute Ischemic Stroke and Their Management J. Hofmeijer, H. B. van der Worp, and L. J. Kappelle Management of Modiﬁable Risk Factors for Stroke or Accelerated Atherosclerosis Pierre Fayad

163

183

205

11.

Rehabilitation After Stroke Udo Kischka and Derick T. Wade

231

12.

Cognitive Impairments After Stroke: Diagnosis and Treatment R. D. Jones and Daniel Tranel

243

13.

Neuropsychiatric Disorders Following Stroke Robert G. Robinson and Ricardo Jorge

261

PART III.

MANAGEMENT OF ISCHEMIC CEREBROVASCULAR DISEASE

14.

Evaluation and Treatment of Asymptomatic Carotid Artery Disease Patricia H. Davis

283

15.

Antithrombotic Therapies for Prevention of Ischemic Stroke Harold P. Adams, Jr.

305

16.

Surgical Management Options to Prevent Ischemic Stroke Brian E. Snell, Robert J. Wienecke, and Christopher M. Loftus

351

17.

Thrombolysis for Acute Stroke John Marler

363

18.

Anticoagulant and Antiplatelet Treatment of Acute Ischemic Stroke Eivind Berge and Peter Sandercock

383

19.

Neuroprotective Agents and Other Therapies for Acute Stroke Nils Gunnar Wahlgren and Niaz Ahmed

409

20.

Balloon- and Stent-Assisted Percutaneous Transluminal Angioplasty of Cerebrovascular Occlusive Disease for the Prevention of Stroke John C. Chaloupka, Niranjan Ganeshan, Ali Elahi, John B. Weigele, and Walter S. Lesley

433

Contents

PART IV.

ix

MANAGEMENT OF HEMORRHAGIC CEREBROVASCULAR DISEASE

21.

Medical and Surgical Management of Intracerebral Hemorrhage Daniel J. Guillaume and Patrick W. Hitchon

489

22.

Management of Subarachnoid Hemorrhage J. van Gijn and G. J. E. Rinkel

513

23.

Surgical Management of Ruptured Aneurysms Carlo Bortolotti, Giuseppe Lanzino, and Neal F. Kassell

551

24.

Management of Patients with Unruptured Intracranial Aneurysms David O. Wiebers

565

25.

Arteriovenous Malformations and Other Vascular Anomalies J. P. Mohr, Alexander V. Khaw, and John Pile-Spellman

583

PART V.

SPECIAL ISSUES IN CEREBROVASCULAR DISEASE

26.

The Diagnosis and Management of Cerebral Venous Thrombosis David Lee Gordon

605

27.

Diagnosis and Management of Vascular Disease of the Spinal Cord Enrique C. Leira, Osamah J. Al-baker, and Saleem I. Abdulrauf

637

28.

Cerebral Vasculitis Jose´ Biller and Rafael G. Grau

653

29.

Neurological Complications of Cardiac Procedures Osvaldo Camilo and Larry B. Goldstein

681

30.

Hematological Abnormalities in Stroke Bruce M. Coull and Scott Olson

713

31.

Genetic Causes of Stroke James F. Meschia

743

32.

The Relationship Between Stroke and Migraine Mark Gorman, Steven R. Levine, Paul Hart, and Nabih M. Ramadan

763

33.

Overview of Stroke in Children and Young Adults Michael Reardon and Katherine D. Mathews

779

34.

Diagnosis and Management of Cerebrovascular Disorders in Pregnancy Kathleen B. Digre, Michael W. Varner, Elaine Skalabrin, and Michael A. Belfort

805

Index

851

Contributors

Saleem I. Abdulrauf

Saint Louis University, St. Louis, Missouri, U.S.A.

Osamah J. Al-baker

Saint Louis University, St. Louis, Missouri, U.S.A.

Harold P. Adams, Jr. U.S.A. Niaz Ahmed

University of Iowa Carver College of Medicine, Iowa City, Iowa,

Karolinska University Hospital, Stockholm, Sweden

Michael A. Belfort

The University of Utah, Logan, Utah, U.S.A.

Eivind Berge Ulleva˚l University Hospital, Oslo, Norway Jose´ Biller Indiana University School of Medicine, Indianapolis, Indiana, U.S.A. Julien Bogousslavsky Carlo Bortolotti Illinois, U.S.A. A. M. Buchan

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Bellaria Hospital, Bologna, Italy and University of Illinois, Peoria,

University of Calgary, Calgary, Alberta, Canada

Osvaldo Camilo

Duke University, Durham, North Carolina, U.S.A.

Louis R. Caplan

Beth Israel Deaconess Medical Center, Boston, Massachusetts

John C. Chaloupka University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A. Ku-Chou Chang Chang Gung Memorial Hospital, Kaohsiung, Taiwan

xi

xii

Contributors

Bruce M. Coull The University of Arizona College of Medicine, Tucson, Arizona, U.S.A. University of Iowa, Iowa City, Iowa, U.S.A.

Patricia H. Davis

Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Gabriel R. de Freitas Giuseppe Di Pasquale

Maggioze Hospital, Bologna, Italy

Kathleen B. Digre The University of Utah, Logan, Utah, U.S.A. Ali Elahi University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A. University of Nebraska College of Medicine, Omaha, Nebraska, U.S.A.

Pierre Fayad

Niranjan Ganeshan

University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

University Medical Center, Utrecht, The Netherlands

J. van Gijn

Larry B. Goldstein

VA Medical Center, Durham, North Carolina, U.S.A.

David Lee Gordon University of Miami School of Medicine, Miami, Florida, U.S.A. Mark Gorman

Yale University School of Medicine, New Haven, Connecticut, U.S.A.

Rafael G. Grau

Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

Daniel J. Guillaume Paul Hart

University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

The Mount Sinai School of Medicine, New York, New York, U.S.A.

Patrick W. Hitchon

University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

Beth Israel Deaconess Medical Center, Boston, Massachusetts

Timea Hodics

University Medical Center Utrecht, Utrecht, The Netherlands

J. Hofmeijer

S. Claiborne Johnston University of California, San Francisco, San Francisco, California, U.S.A. University of Iowa, Iowa City, Iowa, U.S.A.

R. D. Jones

Ricardo Jorge

The University of Iowa, Iowa City, Iowa, U.S.A.

L. J. Kappelle

University Medical Center Utrecht, Utrecht, The Netherlands

Neal F. Kassell University of Virginia Health Sciences Center, Charlottesville, Virginia, U.S.A. J. Kennedy

University of Calgary, Calgary, Alberta, Canada

Contributors

xiii

Alexander V. Khaw

Columbia University, New York, New York, U.S.A.

Chelsea S. Kidwell

UCLA Medical Center, Los Angeles, California, U.S.A.

Udo Kischka Rivermead Rehabilitation Research Centre, Oxford Centre for Enablement, Oxford, England University of Illinois, Peoria, Illinois, U.S.A.

Giuseppe Lanzino Enrique C. Leira

Saint Louis University, St. Louis, Missouri, U.S.A.

Walter S. Lesley

St. Louis University School of Medicine, St. Louis, Missouri, U.S.A. The Mount Sinai School of Medicine, New York, New York,

Steven R. Levine U.S.A.

The University of Oklahoma College of Medicine, Oklahoma City,

Christopher M. Loftus Oklahoma, U.S.A.

John Marler National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A. Katherine D. Mathews

University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

James F. Meschia Mayo Clinic, Jacksonville, Florida, U.S.A. and Mayo Medical School, Rochester, Minnesota, U.S.A. J. P. Mohr Columbia University, New York, New York, U.S.A. Scott Olson

The University of California, San Diego, California, U.S.A. UCLA Medical Center, Los Angeles, California, U.S.A.

Bruce Ovbiagele

Columbia University, New York, New York, U.S.A.

John Pile-Spellman

Bellaria Hospital, Bologna, Italy

Giuseppe Pinelli

Nabih M. Ramadan Rosalino Franklin University of Medicine and Science, Chicago, Illinois, U.S.A. Driscoll Children’s Hospital, Corpus Christi, Texas, U.S.A.

Michael Reardon G. J. E. Rinkel

University Medical Center, Utrecht, The Netherlands

Robert G. Robinson Naomi L. Ruﬀ

The University of Iowa, Iowa City, Iowa, U.S.A.

Oakland, California, U.S.A.

Peter Sandercock

Western General Hospital, Edinburgh, Scotland, UK

xiv

Contributors

D. L. Sandler

Birmingham Heartlands Hospital, Birmingham, England

Jeﬀrey Saver

UCLA Medical Center, Los Angeles, California, U.S.A. The University of Utah, Logan, Utah, U.S.A.

Elaine Skalabrin Brian E. Snell U.S.A.

University of Oklahoma College of Medicine, Oklahoma City, Oklahoma,

Daniel Tranel

University of Iowa, Iowa City, Iowa, U.S.A. University of Iowa, Iowa City, Iowa, U.S.A.

James C. Torner

Stefano Urbinati Bellaria Hospital, Bologna, Italy The University of Utah, Logan, Utah, U.S.A.

Michael W. Varner

Derick T. Wade Rivermead Rehabilitation Research Centre, Oxford Centre for Enablement, Oxford, England Nils Gunnar Wahlgren Karolinska University Hospital, Stockholm, Sweden Steven Warach

National Institutes of Health, Bethesda, Maryland, U.S.A.

John B. Weigele U.S.A.

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania,

David O. Wiebers

Mayo Clinic and Mayo Medical School, Rochester, Minnesota, U.S.A.

Robert J. Wienecke Oklahoma, U.S.A.

University of Oklahoma College of Medicine, Oklahoma City,

H. B. van der Worp University Medical Center Utrecht, Utrecht, The Netherlands

1 Epidemiology and Risk Factors for Stroke James C. Torner University of Iowa, Iowa City, Iowa, U.S.A.

I. INTRODUCTION Stroke is part of the complex of vascular diseases that have been the leading cause of mortality and morbidity in the countries where infectious disease has been controlled. Vascular diseases have their origin early in life and subsequently manifest themselves with death and disability with increasing age. Coronary heart disease, peripheral vascular disease, and cerebrovascular disease have etiologically diﬀerential risk factors but can be simultaneously present as the atherosclerotic process advances. Stroke and the speciﬁc type of stroke are related to the selectivity of risk factors for cerebrovascular disease, including age. Stroke can also be the consequence of coronary and peripheral embolic disease. Approximately one-third of ischemic strokes are of cardioembolic origin. Stroke is the third leading cause of death and a major a cause of long-term disability in the United States. It is estimated from population studies that 500,000 new cases and 200,000 recurrent cases of stroke occur each year [1]. Every minute a person suﬀers a stroke in United States, and nearly 20 persons will die from stroke every hour. In the year 2000, the total prevalence of stroke is estimated to be 4.7 million people in the United States. Stroke costs approximately $51.2 billion every year for acute care and long-term consequences. Stroke has declined over the past 30 years but this decline has slowed in the most recent decade. The control of high blood pressure was probably responsible for most of the decline. Hence, stroke mortality reduction still remains a major health care issue for the U.S. population. The Healthy People Program has set decade-speciﬁc goals as part of the National Health Promotion and Disease Prevention Objectives [2]. The Healthy People 2000 goal was a one-third reduction in stroke mortality with a reduction in blacks of nearly 50%. As of 1999, neither goal had been achieved. However, the reduction of overall stroke mortality occurred with a total decrease of one-sixth and for blacks of approximately oneﬁfth. The Healthy People 2010 Program goal is to (1) reduce stroke death rates in the United States to 48/100,000 (age-adjusted to the 2000 standard population) and (2) to increase the proportion of adults who are aware of the early warning symptoms and signs of a stroke. The target was set based upon a goal of a 20% improvement in stroke mortality from a level of 60/100,000. 1

2

Torner

II. DEFINITION In order to examine the epidemiology of stroke, a deﬁnition and the taxonomy needs clear speciﬁcation. Stroke has the following hallmark warning signs and symptoms: (1) acute sudden numbness or weakness of the face, arm, or leg, especially on one side of the body, (2) confusion, trouble speaking or understanding, (3) trouble seeing in one or both eyes, (4) diﬃculty walking, dizziness, loss of balance or coordination, and/or (5) severe headache with no known cause. Stroke has been classiﬁed in several ways. The World Health Organization (WHO) deﬁnes stroke as rapidly developing clinical signs of focal or global disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause except of vascular origin [3,4]. A transient ischemic attack (TIA) is a focal neurological deﬁcit with a duration of less than 24 hours. However, the advent of advanced imaging has led to the term silent infarction, which represents a transient neurological event with resulting pathology evident by radiology. The International Classiﬁcation of Diseases (ICD) used etiology and pathology in dividing stroke into nine major groupings. Hemorrhagic stroke includes subarachnoid and intracerebral hemorrhage as well as other or unspeciﬁed intracranial hemorrhage. Ischemic stroke classiﬁcation is based upon the location and duration of the occlusion. In addition, nonspeciﬁc categories of acute but ill-deﬁned and late eﬀects of cerebrovascular disease are also used. ICD9 has transformed into new codes in ICD10 but the classiﬁcation is similar [5] (Table 1). Initial investigation of the comparability of ICD-9 and ICD-10 for cerebrovascular disease shows an increase by 6% for ICD-10 due to the inclusion of deaths from pneumonia secondary to stroke. [5] In 1990 the NINDS group recognized the diﬀerential utilization of a broad classiﬁcation for epidemiological, pathological and clinical purposes [6]. The classiﬁcation scheme derived categorized stroke by etiology, location and temporal occurrence (Table 2). The etiological classiﬁcation is most relevant to the epidemiology of stroke.

Table 1 Classiﬁcation of Cerebrovascular Diseases 430.0 431.0 432.0

Subarachnoid hemorrhage Intracerebral hemorrhage Other and unspeciﬁed intracranial hemorrhage

433.0

Occlusion and stenosis of precerebral arteries

434.0

Occlusion of cerebral arteries

435.0 436.0

Transient cerebral ischemia Acute ill-deﬁned cerebrovascular disease Other and ill-deﬁned cerebrovascular disease Eﬀects of cerebrovascular disease

437.0 438.0

Source: http://www.cdc.gov/nchs/icd9.htm

I60 I61 I62 I63 I65

I66

I64

Subarachnoid hemorrhage Intracerebral hemorrhage Other nontraumatic intracranial hemorrhage Cerebral infarction Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction

I67

Stroke, not speciﬁed as hemorrhage or infarction Other cerebrovascular disease

I69

Sequelae of cerebrovascular disease

Epidemiology and Risk Factors for Stroke

3

Table 2 Classiﬁcation of Stroke Etiology Transient cerebral ischemia Cerebral infarction Thrombosis Embolism Intracerebral hemorrhage Ruptured cerebral aneurysm Ruptured vascular malformation Inﬂammatory disease Cerebral venous thrombosis

Location

Temporal proﬁle

Extracranial Intracranial Intracerebral Vertebral Basilar Carotid

Transient Progressive Completed

The most common variety of complete stroke is atherothrombotic brain infarction, which accounts for the majority of all strokes (excluding TIA). Hemorrhagic stroke of intracerebral origin accounts for between 6% and 17% and subarachnoid hemorrhage, where a structural lesion such as cerebral aneurysm or arteriovenous malformation is linked to most occurrences, is associated with 3–13% of strokes. The proportions vary by geographic region and completeness of diagnostic methods (Figure 1) [7].

III. CHANGES IN DIAGNOSIS Stroke diagnosis changed dramatically in the mid-1970s with the development and utilization of the computed tomography (CT) scan. Epidemiological studies prior to 1980 did not have the advantage of cerebral imaging other than radiography and arteriography [8]. Hence the use of cerebral imaging changed classiﬁcation. The changes were from symptoms and course to those of visual diagnosis based upon radiologically conﬁrmed pathological changes. Hence, the pre-CT incidence and prevalence estimates of

Figure 1 Percentage distribution of stroke subtypes. (From Ref. 7.)

4

Torner

Table 3 NIH Stroke Scale 1.a. 1.b. 1.c. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Level of Consciousness Level of Consciousness—Questions Level of Consciousness—Commands Gaze Visual ﬁeld Facial movement (facial paresis) Motor function—arms (left and right arm) Motor function—legs (left and right leg) Limb ataxia Sensory Best language Dysarthria Neglect (extinction and inattention)

ischemic or hemorrhagic etiology were not as accurate as post-CT estimates [9]. Careful examination of community-based studies indicates underestimates of stroke and stroke types because of the underuse of imaging. Other technologies such as magnetic resonance imaging (MRI), transcranial Doppler and cerebral ﬂow assessment, and positron emission tomography (PET) have added to the determination of the magnitude and severity of a stroke episode. In addition, transesophageal echocardiography, carotid Doppler evaluation, and three-dimensional imaging including magnetic resonance angiography (MRA) and helical CT and advances in laboratory assays related to hematology have improved etiological assessments. While these may not aﬀect the incidence and prevalence estimates, they have contributed to better etiological and prognostic evaluation and likely contribute to lower mortality rates poststroke. A more recent advance has been key in the classiﬁcation of ischemic stroke based upon location labeled as stroke subtypes [10]. The classiﬁcation is based upon stroke etiology, i.e., occlusive disease and embolic origin. Large vessel occlusive disease and small vessel disease have diﬀerential causation and prognosis. Nearly one-third of strokes are of embolic origin, small vessel thrombotic events comprise 20%, and large vessel thrombotic events 31%. Hemorrhagic stroke accounts for the remainder, at 17% [11]. However, such classiﬁcation requires completion of diagnostic tests and imaging. Another advance that has been used in stroke clinical assessment, prognostic evaluation, and outcome has been the development of stroke scales. The NIH Stroke Scale is a universally used representative of these measures, which assesses the domains of neurological deﬁcits as well as their severity (Table 3) [12]. The reliability of measurement of the diﬀerent components and among diﬀerent health-care providers given training has been shown to be excellent [13].

IV. MAGNITUDE OF STROKE A. Mortality Stroke killed 158,448 people and accounted for about 1 of every 14.8 deaths in 2000 in the United States [14]. Stroke ranks as the third leading cause of death behind heart disease and cancer. Nearly half of the deaths occur after acute hospitalization. Twenty-two percent of

Epidemiology and Risk Factors for Stroke

5

Figure 2 Mortality rate in the United States in the year 2000 by age and gender. (From Ref. 15.)

men and 25% of women who have an initial stroke die within a year. Age is the strongest predictor of mortality. Half of men and women under the age of 65 who have a stroke will die within 8 years. The mortality rate is 7.6% for ischemic stroke and 37.5% for hemorrhagic stroke at 30 days postonset. Stroke mortality diﬀerentially aﬀects individuals by race and gender. Figures 2 and 3 show the year 2000 mortality by age, gender, and racial groupings [15]. The highest risk group is black males. In 2000, the rate for black males was 87.1, for black females 78.1, for

Figure 3 Mortality rate in the United States in the year 2000 by gender and race. (From Ref. 15.)

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white males 58.6, and for white females 57.6. Hispanics and Asian/Paciﬁc Islanders and American Indian/Alaskan Native groups have lower rates of stroke mortality. From 1990 to 2000, the stroke mortality rate fell 12.3%. However the actual number of strokes rose 9.9%. With the increasing number of persons 65 years and older, the number of stroke deaths will continue to increase. While childhood stroke is rare, the mortality rate has decreased by 19%, with hemorrhagic stroke greater than ischemic stroke in decline [16]. There is geographic variation in stroke. Mortality rates for stroke are higher in the southeast part of the United States [17]. This is known as the stroke belt. The lowest rates are found in the Mountain States. Diﬀerences may be due to risk factors such as hypertension and diabetes and suggested diﬀerences in access and type of care for stroke. International Trends in Stroke Mortality show that from 1985 to 1992, the greatest annual decline (6–7%) in coronary heart disease (CHD) was seen in Israel among men and in France among women; the United States was in the intermediate range (4%), while there were increases in Poland and Romania. Stroke death rates declined the most in Australia, Italy, and France (8–9%), and in the United States about 3% [18]. A cautionary note regarding current estimates and the future is the impact of using a population standard for calculating incidence rates. Until recently many researchers used the 1940 standard population to age-adjust data. The new Year 2000 Age Standard has resulted in increased stroke rates because of the change in age and decrease in black/white racial diﬀerence [19]. B. Hospital Discharges for Stroke The number of hospital discharges has increased over time. In 2000 the National Hospital Discharge Survey estimated the number of ﬁrst-listed diagnosis of 981,000 and of all-listed discharges at nearly 2 million in short-term hospital stays. An estimated 457,000 men and 553,000 women were discharged from hospitals in 1998 after having a stroke [20,21]. The majority of stroke discharges are in those older than 65 years (711,000) [14]. The length of stay for stroke has dramatically decreased by nearly one half in the past decade, but this was accompanied by only a 22% decrease in total person-days due to the increase in numbers of patients with stroke. From 1979 to 1998 these discharges increased 35.4%. The increase was found in person 65 years or older. The rate of discharge is 35.3/10,000, with the highest discharge rate in the northeastern (41.3) and southeastern United States (38.9). The lowest rate is in the west (23.9). The hospitalization costs are the major costs of stroke. The overall estimated 2001 direct costs of stroke were $28 billion. Most of the cost is related to acute care and hospitalization [22]. In Rochester, Minnesota, nearly 50% of the costs accrued from the stroke and initial hospital care [23]. Factors related to stroke cost were severity and type of stroke as well as the residence of the stroke victim when it occurred. Stroke, because of its propensity for disability, also has costs attributed to rehabilitation, loss of productivity, residence in care facilities, and burden on caregivers [24]. C. Prevalence of Stroke The prevalence, like the incidence, of stroke has been increasing. Using data from the NHANES III survey from 1988–1994, the American Heart Association estimated the prevalence of all stroke to be 4.7 million persons [14]. Because most stroke cases are 65 years or older, this is an indication of the huge burden that stroke has on the elderly and will have in the future.

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D. Incidence Rate by Stroke Type Few population-based studies of stroke exist, particularly in the United States. In Rochester, Minnesota, the ischemic stroke incidence in 1985–1989 was 145/100,000 population, which was virtually unchanged from 1980 to 1984 and 13% higher than the rate determined in 1975–1979 [1,25]. The impact of radiological imaging, increased number of patients with heart disease, and the inclusion of milder cases of stroke may all be factors. Ischemic stroke subtypes were determined to be as follows: large vessel cervical or intracranial atherosclerosis with >50% stenosis, 27/100,000; cardioembolic, 40/100,000; lacuna, 25/100,000; uncertain cause, 52/100,000; other or uncommon cause, 4/100,000 [26]. Men are more likely to have atherosclerosis with stenosis (47/100,000) when compared to women (12/100,000). In northern Manhattan, using hospital discharge data for persons over 40 years of age, the incidence rate was 327/100,000 [27,28]. Stroke incidence increased with age and was greater in men than in women. The average annual age-adjusted stroke incidence rate was 223/ 100,000 for blacks, 196/100,000 for Hispanics, and 93/100,000 for whites. Cerebral infarction was the largest stroke subtype at 77%, followed by intracerebral hemorrhage at 17%, and subarachnoid hemorrhage at 6%. The Greater Cincinnati/Northern Kentucky Stroke Study identiﬁed all hospitalized and autopsied cases of stroke and TIA among 1.3 million persons from July 1, 1993, to June 30, 1994 [29]. The overall incidence rate for all ﬁrst-ever hospitalized or autopsied strokes (excluding TIAs) among blacks was 288/100, 000 and the incidence rate for ﬁrst-ever and recurrent strokes (excluding TIAs) was 411/100,000. Annual incidence rates for ischemic stroke subtypes among blacks were: uncertain cause, 103/100,000; cardioembolic stroke, 56/100,000; small vessel infarction, 52/100,000; large vessel infarction, 17/100,000; and other causes, 17/100,000. Stroke incidence varies across populations, but methods of case ascertainment and operational deﬁnitions diﬀer. Hence, data do not exist comparing diﬀerent regions of the world, including Africa, Asia, and South America [30]. The importance of complete, community-based case ascertainment, including strokes managed outside the hospital, is

Figure 4 Incidence of stroke and stroke subtypes in population-based registries. (From Ref. 32.)

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emphasized. The WHO MONICA Project has established registries in 10 countries to monitor stroke [31]. Standard diagnostic criteria were used. Highest rates of persons ages 35–64 years were seen in Novosibirsk (388/100,000) and Lithuania (308/100,000) in men and in Novosibirsk (312/100,0000) in women. Over the observation period (approximately 5 years) most sites saw decreases in stroke, but stroke incidence in Warsaw increased for men and women. Population-based estimates of stroke from 11 studies in Europe, Russia, Australasia, and the United States were surveyed [32]. The age- and sex-standardized annual incidence rates for subjects aged 45–84 years were similar (300–500/100,000) in most studies. Rates were lower in Dijon, France (238/100,000), and higher in Novosibirsk, Russia (627/100,000). Rates were equivalent among the elderly. Cerebral infarction was highest in Denmark (339/100,000) and Sweden (349/100,000), intracerebral hemorrhage was highest in Sweden (49/100,000) and Italy (60/100,000), and subarachnoid hemorrhage was high in Australia (19/100,000), England, Italy, and the United States (17/100,000) (Figure 4) [32].

V. STROKE RISK FACTORS Stroke risk factors can be classiﬁed in terms of nonmodiﬁable risk factors and modiﬁable risk factors [33]. Those not modiﬁable include age, gender, race, and family history. Nonmodiﬁable risk factors alert us to populations in which we can target modiﬁable risk factors. Those modiﬁable factors include hypertension, smoking, diabetes, cardiac disease, hyperlipidemia, physical activity, obesity, nutrition, drug abuse, hormone therapy, inﬂammatory disease, and biomarkers of risk. Stroke increases exponentially with age. Population-based data from Rochester, Minnesota, and Framhingham, Massachusetts, indicate a doubling of risk for stroke for each decade. Most cases are 65 years or older. Stroke mortality is dramatically increased by age [34]. In general the stroke incidence is about 30% greater for men. However, the number of strokes is higher in women because of the increased number of women at risk in advanced age. Stroke subtypes indicate a stronger risk of ischemic stroke and intracerebral hemorrhage for men, while subarachnoid hemorrhage occurs more frequently in women. Blacks have a higher rate of stroke at younger ages than whites. Racial risk is highest for blacks compared to Hispanics and whites. Family history also increases stroke risk. Family history of stroke is often underconsidered. A paternal history of stroke increases the risk of ischemic stroke by 2.4 times and a maternal history increases the risk by 1.4 times. Studies of twins have demonstrated a fourfold risk for monozygotic pairs compared to dizygotic pairs [35]. High blood pressure remains the major risk factor for heart disease and stroke. The Multiple Risk Factor Intervention Trial (MRFIT) examined 350,000 men from 1973 to 1975 and followed them for major fatal outcomes. During 11.6 years of follow-up there were 733 stroke deaths. There was an eightfold gradient of risk across systolic blood pressure (SBP) deciles and a fourfold risk for diastolic blood pressure (DBP) [36,37]. Men over the age of 65 years with isolated hypertension have over twice the risk for ischemic stroke and women just under 2 [38]. A comprehensive analysis of risk according to blood pressure by MacMahon et al. showed that the associations of diastolic DBP with stroke demonstrated a ‘‘positive, continuous, and apparently independent association’’ that was consistent across all studies [39]. Within the range of DBP (70–110 mmHg), there was no evidence of any ‘‘threshold.’’

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Approximately 50 million adults in the United States have high blood pressure. There has been an increase in the awareness of high blood pressure. The National High Blood Pressure Education Program began in 1972, and it has increased awareness of the importance of detection and control of blood pressure, which has resulted not only in more hypertension control but also in the reduction of heart disease and stroke [14,37]. Stroke risk increases with cigarette smoking independent of hypertension or age [40]. The general increase is nearly 40% for men and 60% for women. The risk for smokers of 2 packs per day is approximately twice that of smokers who smoke less than 1⁄2 pack per day [41]. Evidence suggests that smokers decrease their risk when they quit and are back at the risk of nonsmokers 5 years after quitting. The risk for stroke is greater with the presence of diabetes. Studies have demonstrated a 1.5- to 3.0-fold increase in risk. Diabetes has been shown to be a consistent factor for atherothrombotic stroke. For hemorrhagic stroke the risk is reversed. Diabetics have higher age-adjusted stroke mortality and morbidity rates than nondiabetics [42]. The increased stroke rates in diabetics remain after adjusting for systolic blood pressure. The relative risk (RR) for stroke mortality and morbidity associated with diabetes was 1.8 in men and 2.2 women. As evidence of the progression of atherosclerosis and increased risk for stroke, severity of carotid stenosis is an important indicator. The risk of carotid disease was clearly demonstrated in the prospective follow-up of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [43]. The follow-up of patients with 70–99% stenosis demonstrated that the risk of any ipsilateral stroke at 3 years was 28.3% for the medically randomized arm, and the combined disabling or fatal ipsilateral stroke risk was 14.0%. Over 80% of the ﬁrst strokes were of large artery origin. It is still a matter of debate what the cutoﬀ for risk is and whether patients should be screened. Cardiac abnormalities including coronary artery disease, congestive heart failure, left ventricular hypertrophy, valvular heart disease, atrial ﬁbrillation, and cardiac thrombosis increase the risk of stroke. In Rochester, Minnesota, the relative risk estimate for stroke was 2.2 and in Framingham the magnitude was similar—1.9 for men and 2.2 for women [44]. Studies of young patients with ischemic stroke have shown a high prevalence of mitral valve prolapse (up to 40%). However, this has not always been demonstrated. In a casecontrol study of 213 consecutive patients 45 years old or younger with documented ischemic stroke or transient ischemic attack, the prevalence of mitral valve prolapse was present in young patients with stroke (1.9%) as compared with controls (2.7%) [45]. Paradoxical cerebral embolism (PCE) through a patent foramen ovale (PFO) has been associated as a cause of ischemic stroke, particularly in young patients. However, studies have shown a rather low stroke recurrence rate in patients with PFO [46,47]. Atrial ﬁbrillation aﬀects close to 2 million individuals in the United States [14,44]. Atrial ﬁbrillation increases with age and is more prevalent in males. Nearly 70% of atrial ﬁbrillation patients are between the ages of 65 and 85. Fifteen percent of strokes occur in patients with atrial ﬁbrillation. With a greater percentage of the population living longer and with more persons surviving a heart attack, the number of atrial ﬁbrillation cases will be increasing. Data from Rochester, Minnesota, indicated that atrial ﬁbrillation has been increasing as a cause of ischemic stroke for both men and women and is independent of age. Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings, suggesting genetic factors. Studies of HLA typing have shown that speciﬁc HLA alleles may inﬂuence the risk of stroke in children with SCA [48]. A recent study has shown that speciﬁc HLA alleles inﬂuence stroke risk and appear to contribute diﬀerently to small and large vessel stroke subtypes [49]. HLA testing

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may serve as a useful biomarker for the identiﬁcation of SCA patients at high risk for stroke. Infarction from sickle cell disease may also be preventable. A randomized clinical trial (Stroke Prevention in Sickle Cell Anemia) evaluated the prevention of a ﬁrst stroke in children with sickle cell disease [50]. Regular red cell transfusions suﬃcient to reduce the Hb S gene product from over 90% to less than 30% of total hemoglobin was associated with a marked reduction in stroke. The untreated risk of 10% per year was reduced over 90% with treatment. High plasma levels of lipids are an important modiﬁable risk factor for coronary heart disease [51]. Pathophysiological evidence links lipids to major systemic artery disease. However, the role of circulating lipids and lipoproteins in the pathogenesis of ischemic stroke remains uncertain. The Atherosclerosis Risk in Communities (ARIC) study of 305 subjects with clinical ischemic stroke demonstrated weak and inconsistent associations with each of the ﬁve lipid factors [52]. Only among women was high-density lipoprotein (HDL) cholesterol associated with decreased risk of stroke. Obesity is a major epidemic, and obese adults are at an increased risk of developing numerous chronic diseases. In the women of the Nurses’ Health Study and the men in the Health Professionals Follow-Up Study the risk of developing stroke increased with severity of overweight among both women and men [53]. During 10 years of follow-up, the occurrence of diabetes, gallstones, hypertension, heart disease, colon cancer, and stroke (in men only) increased with degree of overweight. The incidence of ischemic stroke, hemorrhagic stroke (subarachnoid or intraparenchymal hemorrhage), and total stroke was examined in the Nurses Health Study [54]. During 16 years of follow-up, 866 total strokes (including 403 ischemic strokes and 269 hemorrhagic strokes) occurred. Women with increased body mass index (BMI) (z27 kg/ m2) had signiﬁcantly increased risk of ischemic stroke, with relative risks of 1.75, for BMI of 27–28.9 kg/m2; 1.90 for BMI of 29–31.9 kg/m2; and 2.37 for BMI of z32 kg/m2. For hemorrhagic stroke there was a nonsigniﬁcant inverse relation between obesity and hemorrhagic stroke. Weight gain from age 18 years until 1976 was associated with an RR for ischemic stroke of 1.69 for a gain of 11–19.9 kg and 2.52 for a gain of z20 kg. Weight change was not related to risk of hemorrhagic stroke. Physical inactivity has been demonstrated to increase the risk of stroke two- to threefold. In a cohort study in Finland of 2011 men, the risk of low cardiorespiratory ﬁtness was evaluated with the maximum oxygen consumption. The relative risk was 3.2 for all stroke and 3.5 for ischemic stroke [55]. Chlamydia pneumoniae has been identiﬁed in atherosclerotic plaque of patients with cerebrovascular and cardiovascular disease. Plaque-positive rates for C. pneumoniae were present in 15% of patients [56]. High serum antichlamydial IgA levels (z1:128) were associated with occurrence of symptomatic disease. However, the association of C. pneumoniae antibodies has not been consistent. A positive association was found in the Northern Manhattan Study and not in the West Birmingham Stroke Study [57–61]. Another controversial risk factor has been the use of exogenous estrogens. Use of oral contraceptives has increased, and there is uncertainty about the stroke risk associated with their use. In case-control studies of women with ischemic stroke from four Melbourne hospitals, the current dosage of oral contraceptives (V50 Ag estrogen) was not associated with an increased risk of ischemic stroke [62]. In female members of the California Kaiser Permanente Medical Care Program, the odds ratio for ischemic stroke among current users of oral contraceptives, as compared with former users and women who had never used such drugs, was 1.18 [63]. The adjusted odds ratio for hemorrhagic stroke was 1.14. However, with respect to the risk of

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hemorrhagic stroke, there was a positive interaction between the current use of oral contraceptives and smoking. For postmenopausal estrogens the observational studies warranted prospective trials. The Women’s Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse eﬀects, including an increased risk of stroke in the estrogen plus progestin group [64]. For combined ischemic and hemorrhagic strokes, the intention-totreat hazard ratio (HR) for estrogen plus progestin vs. placebo was 1.31. The HR for ischemic stroke was 1.44 and for hemorrhagic stroke, 0.82. Excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, and use of hormones, statins, or aspirin. Another randomized, double-blind, placebo-controlled trial of estrogen therapy was done in postmenopausal women who had recently had an ischemic stroke or transient ischemic attack [65]. With a mean follow-up period of 2.8 years, the women in the estrogen group compared to the placebo group showed no beneﬁt (RR in the estradiol group = 1.1) The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (RR = 2.9). This therapy was then shown not to be eﬀective for the primary or secondary prevention of cerebrovascular disease.

VI. BIOMARKERS OF RISK Early recognition of the apparent paradox between lipid levels and stroke incidence has played a major role in examining the eﬀects of statin therapy and the search for inﬂammatory biomarkers that might be strong determinants of stroke [66]. Epidemiological evidence, animal studies, angiographic and ultrasound studies in humans, and a limited number of clinical trials suggest that vitamins C and E may be protective and that folate, B6, and B12, by lowering homocysteine levels, may reduce stroke. Few population-based studies have examined the relationship between dietary intake of folate and risk of stroke. In the National Health and Nutrition Examination Survey I Epidemiologic Follow-Up Study (NHEFS), dietary intake of folate was assessed at baseline using a 24-hour dietary recall [67]. Incidence data for stroke over an average of 19 years of follow-up showed a relative risk of 0.79. In one study, lipoprotein and hemostatic proﬁles including coagulation inhibitors were measured to examine the role of these factors in stroke subtypes. Based on clinical examination, cerebral CT, Doppler ultrasonography of precerebral arteries, and transthoracic echocardiography, the strokes were classiﬁed as cardioembolic, noncardioembolic, and mixed cardioembolic/hypertensive. Patients with cardioembolic stroke were older than patients with noncardioembolic stroke. Lipoprotein(a) was higher in the cardioembolic than in the noncardioembolic group. Lipoprotein(a) was not signiﬁcantly correlated to the other lipid levels and may represent an independent lipid risk factor. The noncardioembolic group had higher levels of total cholesterol, triglycerides, total cholesterol/HDL cholesterol ratio, low-density lipoprotein (LDL) cholesterol, apolipoprotein A1, and apolipoprotein B. The cardioembolic group had higher concentrations of ﬁbrinogen and D-dimer and lower levels of antithrombin, protein C, protein S, and heparin cofactor 2 than the noncardioembolic group. Lipoprotein(a) seems to be more associated with coagulation markers of thrombosis than with atherosclerosis, whereas the other lipids mainly seem to be risk factors for atherosclerosis. Although hypercoagulable states are most often associated with venous thrombosis, arterial thromboses are reported in protein S, protein C, and antithrombin III deﬁciencies,

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factor V Leiden and prothrombin gene mutations, hyperhomocysteinemia, dysﬁbrinogenemia, plasminogen deﬁciency, sickle cell disease, and antiphospholipid antibody syndrome [68]. Antiphospholipid antibodies have been associated with increased stroke risk. In a case-control study comparing acute ischemic stroke patients and community controls, titers of IgG > 16 IgG phospholipid units or IgM > 22 IgM phospholipid units were associated with stroke, and the odds ratio was 5.6 IgG antiphospholipid antibodies and 2.9 for IgM antiphospholipid antibodies [70]. In the Stroke Prevention in Young Women Study, a positive anticardiolipin antibody and/or lupus anticoagulant was found in a greater number of cases [71]. The ﬁndings support the importance of more research to determine the role of antiphospholipid antibodies as an independent risk factor for stroke. The role of statins as an anti-inﬂammatory agent has prompted research into the role of C-reactive protein (CRP). CRP been shown in several studies to predict incident stroke independent of LDL cholesterol. Statins have also been shown to reduce CRP independent of lipid changes. In the Physicians’ Health Study of healthy middle-aged men and in the Women’s Health Study of healthy postmenopausal women, total cholesterol and CRP both predict incident myocardial infarction and only CRP predicts incident stroke [72–74]. Similar ﬁndings have been found in the National Health and Nutrition Examination Survey (NHANES), the Leiden 85-Plus Study, and the Framingham Heart Study [75]. In the Framingham Heart Study, CRP was to be a strong predictor of stroke even after adjustment for other risk factors [76]. The plaque stabilization concept through antiinﬂammatory mechanisms provides a working hypothesis as to why statins might reduce cerebrovascular risk [77,78]. Engstro¨m et al. in a large-scale study of Swedish men measured ﬁve inﬂammation-sensitive proteins: a1-antitrypsin, haptoglobin, ceruloplasmin, orosomucoid, and the hemostatic marker ﬁbrinogen [79]. After risk factor adjustment, the men with hyperlipidemia and high inﬂammation-sensitive protein levels had signiﬁcantly increased risks of ischemic stroke (RR = 2.1). Without high inﬂammation-sensitive protein levels, hyperlipidemia was no longer associated with ischemic stroke. In the Cardiovascular Health Study the relative risk was 1.6 for the highest quartile of CRP. There was an interaction of CRP with carotid intimal thickness [80].

VII. PREVENTION STRATEGIES FOR STROKE Primary prevention includes modifying risk factors of lifestyle and behavior such as not smoking; diet involving increased consumption of ﬁsh, fruits, and vegetables; adequate physical exercise; limiting alcohol; and adhering to physician recommendations for screening, monitoring, and treating blood pressure, cholesterol, and diabetes (blood glucose). Secondary prevention requires intervention by the health-care provider, which includes hypertension treatment, cholesterol treatment (e.g., statins), TIA treatment, antiplatelets, anticoagulation for atrial ﬁbrillation and other cardiac sources. A. Blood Pressure Recently the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) completed a double-blind, active-controlled trial [81,82]. The study enrolled 42,448 patients, >55 years old, with hypertension (systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg) and at least one other CHD risk factor. Treatment comparisons were with the diuretic chlorthalidone and three other agents. In January 2000 the doxazosin treatment arm of the blood pressure–lowering component of the trial was

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stopped due to a statistically signiﬁcant higher incidence of major cardiovascular disease (CVD) events with doxazosin compared to chlorthalidone [81]. The doxazosin arm, compared with the chlorthalidone arm, had a higher risk of stroke (RR = 1.19). Lisinopril had higher 6-year rates of combined stroke than chlorthalidone (6.3% vs. 5.6%; RR = 1.15) [83]. Thiazide-type diuretics were found to be superior. In a meta-analysis the odd ratios were calculated for diﬀerences in systolic pressure among subgroups of 62,605 hypertensive patients [84]. Compared with old drugs (diuretics and h-blockers), calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors oﬀered similar overall cardiovascular protection, but calcium channel blockers provided more reduction in the risk of stroke (13.5%). All of the antihypertensive drugs had similar long-term eﬃcacy and safety, but calcium channel blockers were more eﬀective in stroke prevention. B. Statins and Stroke The Scandinavian Simvastatin Survival Study demonstrated with 5.4 years of follow-up a signiﬁcant change in stroke risk by lowering cholesterol of 3.4% vs. 4.6%( p = 0.03) [85]. They showed that a 28% risk reduction in stroke and TIA could be achieved. It was noted in the study that 55% of the subjects also were on aspirin. Another study, the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID), demonstrated a similar result of 3.4% compared 4.4% p = 0.02 [86]. The risk reduction of 24% was found in nonhemorrhagic strokes. Eighty-four percent of the patients were also on aspirin. Three metaanalyses of randomized placebo-controlled trials and cohort studies on stroke reported that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/L reduction and 17% for a 1.8 mmol/L reduction. Statins can lower LDL cholesterol and hence can reduce the risk of ischemic heart disease–related events by about 60% and stroke by 17% [87]. Aspirin has been studied in a number of trials with diﬀering dosages. A meta-analysis of 16 trials with a dosage ranging from 75 to 1500 mg/day was done [88]. The hemorrhagic stroke risk was 0.26%, or an increased risk of 12% was found. However, the ischemic stroke rate of 1.7% was associated with a 39% risk reduction. Hence there was greater beneﬁt than risk with aspirin use. Anticoagulants have been evaluated in stroke prevention [89]. For patients with atrial ﬁbrillation, warfarin reduces stroke by 64%. The annual stroke rate reduced from 4.5 to 1.4% per year. However, there is a tendency for cardioembolic stroke to undergo hemorrhagic transformation. Also, patients under 60 years old with lone atrial ﬁbrillation without other stroke risk factors were observed to not need warfarin. C. Carotid Endarterectomy Surgical prevention of stroke was shown to be eﬃcacious through the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [43]. Patients less than 80 years old with a recent hemispheric TIA or nondisabling stroke and atherosclerotic lesion were included in the trial. Patients with a stroke from a cardioembolic source or uncontrollable hypertension or diabetes were not included. The average age was 66 years (range 35–80 years) and one third of the subjects were women. Thirty-two percent had a prior stroke. Most risk for surgery was early, with a 5.8% incidence of stroke or death. However, at 2 years the risk of ipsilateral stroke was reduced by 65% in patients with a >70% carotid stenosis. The European Carotid Surgery Trial (ECST) and the VA Cooperative Study (VACS) also demonstrated that carotid endarterectomy (CEA) decreases stroke in symp-

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tomatic patients with high-grade extracranial carotid artery stenosis [90]. The combined risk ratio estimate was 0.67 and found a similar beneﬁt for men and women. Carotid endarterectomy (CEA) to reduce the incidence of cerebral infarction in patients with asymptomatic carotid artery stenosis was studied in a prospective, randomized, multicenter trial [91]. Patients with asymptomatic carotid artery stenosis of 60% or greater reduction in diameter were randomized, and after a median follow-up of 2.7 years the aggregate risk over 5 years for ipsilateral stroke and any perioperative stroke or death was estimated to be 5.1% for surgical patients and 11.0% for patients treated medically. One question is whether carotid endarterectomy is universally beneﬁcial. Among Medicare patients undergoing CEA in all nonfederal institutional settings, a retrospective national cohort study was done [92]. Medicare patients undergoing CEA during 1992 and 1993 in ‘‘trial hospitals’’ (those participating in NASCET and ACAS, n = 86) and ‘‘nontrial hospitals’’ (all other nonfederal institutions performing CEAs, n = 2613) were evaluated. Nontrial hospitals were stratiﬁed into tertiles based on volume of CEAs performed. The perioperative mortality rate was 1.4% at trial hospitals, and the mortality in nontrial hospitals was higher: 1.7% in high volume; 1.9% in average volume; and 2.5% in low volume. In Medicare patients perioperative mortality following CEA is substantially higher than that reported in the trials. The controversy surrounding endarterectomy versus angioplasty for secondary prevention is ongoing and is being pursued in a new trial. The Carotid Revascularization Endarterectomy versus Stent Trial (CREST) contrasts the relative eﬃcacy of CEA and carotid angioplasty-stent (CAS) in preventing primary outcomes of stroke, myocardial infarction, or death during a 30-day peri-procedural period, or ipsilateral stroke [93]. The primary eligibility criterion is carotid stenosis of 50% or greater of the carotid artery in patients with transient ischemic attack or ipsilateral nondisabling stroke. Two thousand ﬁve hundred patients will be randomized to the treatments. Tertiary prevention to prevent stroke disability and death also should be considered when comparing stroke outcomes. Advances in antiplatelet therapy, use of anticoagulants, and acute thrombolytic therapy have improved the quality of care [94]. The mortality and morbidity of stroke has been shown to be decreased by early intervention with thrombolytic treatment. However, access remains a major problem. Eﬀorts to provide access has only worked in a few communities. The major eﬀort toward providing optimal care through a uniﬁed, cohesive stroke system is only starting to take hold [95]. Stroke prevention requires a combination or continuum of risk factor assessment, modiﬁcation, and interventions. Factors such as blood pressure, cholesterol, blood sugar, body mass index, homocysteine, and smoking habits can be routinely determined. A diet low in saturated fat and cholesterol, low in sodium, high in potassium and calcium, and containing a lot of fruits and vegetables reduces blood pressure. Such a diet can be recommended as a source of not only natural proportions of vitamins and antioxidants but also blood pressure control. Prescription and adherence of blood pressure medications, statins, and antiplatelets agents have been shown to be eﬀective as secondary prevention methods. Surgical prevention by carotid endarterectomy has also proven to be eﬀective but should be reserved for those with high-grade stenosis. The role of angioplasty in secondary or tertiary prevention of ischemic stroke still requires evidential proof.

VIII. CONCLUSION The underuse of preventive therapies and acute interventions is a major problem is improving the burden of stroke. The underrecognition of risk factors by the public has

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limited the application of proven methods such as lowering blood pressure and cholesterol, decreasing smoking and obesity, and heeding early warning signs. This has led to a situation in which over half of ideal patients are not receiving treatment. Discontinuation of interventions results in many patients not reaching treatment goals. The results of recent trials indicate that statin treatment reduces not only the risk of coronary heart disease, but also the risk of stroke, in patients with existing heart disease. The need for treatment of such patients is now generally recognized. Mechanisms for risk reduction include the retardation of plaque progression, plaque stabilization, and reducing the risk of coronary events. Questions remain regarding the discrepancy between epidemiological data and statin trials data, the precise mechanism of action of statins, and their role in the prevention of recurrent stroke in individuals who have experienced a previous stroke or transient ischemic attack but are free of coronary disease.

IX. CHALLENGES Key areas requiring further attention are: (1) the aging population and the resulting increase in stroke, which will have a huge impact on health-care providers and cost, (2) the lack of population-based surveillance of stroke incidence, risk factors, prognostic factors, and outcomes, and (3) the need for studies of systematic organization on prevention and treatment of stroke, i.e., stroke systems. Improvement in stroke epidemiology requires population-based registries and cohort studies, rigorous evaluation of interventions of existing and new strategies for prevention, and increased understanding of the etiology of early lesions related to stroke subtypes [96]. Subtype diﬀerences in risk factors, prevention, and treatment are likely to be the most successful in the future. The U.S. Congress allocated $4.1 million in 2001 to establish the Paul Coverdell Stroke Registries [97]. Patient-level and hospital-level variables have been recommended. The goals are to reﬂect the type and quality of care rendered. The goal may then be establishment of a National Stroke Registry. If this comes about, epidemiological and intervention evaluation of stroke prevention and treatment can be done to improve the recognition and treatment of stroke subtypes.

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74. Gussekloo J, Schaap MC, Frolich M, et al. C-reactive protein is a strong but nonspeciﬁc risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol 2000; 20:1047–1051. 75. Ford ES, Giles WH. Serum C-reactive protein and self-reported stroke: ﬁndings from the Third National Health and Nutrition Examination Survey. Arterioscler Thromb Vasc Biol 2000; 20:1052–1056. 76. Rost NS, Wolf PA, Kase C, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke 2001; 32:2575–2579. 77. Ridker PM, Rifai N, Pfeﬀer M, et al. Long-term eﬀects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999; 100:230–235. 78. Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001; 103:1191–1193. 79. Engstro¨m G, Lind P, Hedblad B, et al. Eﬀects of cholesterol and inﬂammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 2002; 105:2632– 2637. 80. Cao JJ, Thack C, Manolio TA, et al. C-reactive protein, carotid intima-media thickness and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation 2003; 108(2):166–170. 81. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000; 283(15):1967–1975. 82. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis C, Proschan M, Pressel S, Black HR, Hawkins CM. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens 1996; 9(4 pt 1):342–360. 83. The ALLHAT Oﬃcers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288(23):2981–2997. 84. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001; 358(9290):1305–1315. 85. Anonymous. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344(8934):1383–1389. 86. Anonymous. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339(19):1349–1357. 87. Law MR, Wald NJ, Rudnicka AR. Quantifying eﬀect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326(7404):1423. 88. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998; 280(22):1930–1935. 89. Morley J, Marinchak R, Rials SJ, Kowey P. Atrial ﬁbrillation, anticoagulation, and stroke. Am J Cardiol 1996; 77(3):38A–44A. 90. Goldstein LB, Hasselblad V, Matchar DB, McCrory DC. Comparison and meta-analysis of randomized trials of endarterectomy for symptomatic carotid artery stenosis. Neurology 1995; 45(11):1965–1970. 91. Anonymous. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273(18):1421–1428. 92. Wennberg DE, Lucas FL, Birkmeyer JD, Bredenberg CE, Fisher ES. Variation in carotid endarterectomy mortality in the Medicare population: trial hospitals, volume, and patient characteristics. JAMA 1998; 279(16):1278–1281.

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2 Diagnosis and Prognosis of Transient Ischemic Attacks S. Claiborne Johnston University of California, San Francisco, San Francisco, California, U.S.A.

Naomi L. Ruff Oakland, California, U.S.A.

I. INTRODUCTION Stroke is a major public health problem. In addition to causing high rates of morbidity and mortality, resulting in high health care costs, it is also personally devastating. Prevention of stroke should therefore be a high priority in health care management. Transient ischemic attack (TIA), generally deﬁned as a neurological deﬁcit of abrupt onset attributed to focal cerebral ischemia and lasting less than 24 hours, is often a precursor of a more severe ischemic attack [1]: about 11% of individuals with TIA will have a stroke within 90 days, and 10–15% of strokes are foreshadowed by a TIA [2,3]. However, public awareness of the implications of TIA is low, and many patients do not even seek medical care [4,5]. Even when a patient receives medical attention rapidly after the onset of a TIA, the appropriate management may be unclear. One reason is that TIAs are notoriously diﬃcult to diagnose. There are several other common causes of transient neurological symptoms, such as migraine, syncope, and seizure, whose symptoms may be indistinguishable from those of focal ischemia, and due to the transient nature of the symptoms the patient is often not seen during the episode. In spite of this diagnostic uncertainty, spells that are diagnosed as TIA represent a tremendous opportunity to prevent stroke in a high-risk group. However, the need for urgent evaluation and treatment is not always obvious for patients with TIA, whose function has often returned to baseline by the time they are evaluated, and the opportunity for intervention and prevention of stroke following TIA is often missed [6]. Furthermore, little research has been devoted speciﬁcally to TIA, so it is not always clear which therapies are most appropriate and cost-eﬀective. In this chapter, we will review the burden of TIA in the population, the diﬃculties with the accurate diagnosis of TIA, the prognosis following TIA, and methods of treatment and management. We will also discuss the current deﬁnitions of TIA and other forms of recovered ischemia and various proposals to update them. 21

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II. BURDEN OF ILLNESS Knowing the incidence, prevalence, and natural history of TIA would aid in estimating the public health impact and designing prevention programs and clinical trials [5,7]. Each year 750,000 people in the United States alone suﬀer a stroke [8]; research suggests that 15–19% of them have had a previous TIA [3,5]. Stroke and TIA take an enormous toll both in personal terms and in economic costs [9]. Although the costs for each patient who is hospitalized are considerably less for TIA than for stroke [10,11], they are still substantial, averaging $3350 over 3.4 days of hospitalization for TIA, as compared to $5837 over 5.9 days of hospitalization for completed stroke [12]. Overall, stroke costs the United States $30 billion annually, and the average cost per patient is $15,000 in the ﬁrst 90 days after a stroke [8]. If strokes could be prevented in those with TIA, the impact on public health and expenditures would be tremendous. Furthermore, the number of people older than 65 grows by more than a half-million each year in the United States [13], and the incidence of TIA and the burden of stroke are likely to rise as life expectancy increases. Any estimate of incidence or prevalence is likely to be highly dependent on the methodology used to identify cases. The transient nature of the symptoms makes TIA diﬃcult to diagnose deﬁnitively and reproducibly, and underreporting is a signiﬁcant problem. Many cases, perhaps sometimes even a majority, are not brought to the attention of the medical system [2,5,14,15], due in part to the failure of many to understand the serious nature of TIA and stroke [5,16]. As with other critical illnesses [17], the resolution of symptoms in TIA is often perceived as a sign that urgent evaluation is not needed. As a result, studies based on medical registries tend to report lower incidence, in the tens per 100,000 population [2,18,19], whereas those relying on survey methodologies report higher incidence rates into the hundreds per 100,000 population [20,21]. The true value likely lies in between [14]. Estimates of the prevalence of TIA have ranged from 1.1% to 6.3% in the United States [13,15,22–26] and were reported to be as low as 0.2% for those aged 40 or over in a town in western Japan [27]. A recent telephone survey of more than 10,000 participants in the United States found that 2.3% of adults had a physician diagnosis of TIA [5]. In the United States, the community of Rochester, Minnesota has been particularly well represented in reports of incidence because of the interconnected medical reporting system of the Mayo Clinic and other hospitals in the community [7,13,28]. In the period from 1955 to 1969, the average annual incidence rate for TIA was 31 per 100,000 population, and increased from 1 per 100,000 in those under 45 years of age to 68 per 100,000 in those 75 years old or older. This increase in incidence with age is seen consistently in other studies as well [5,21,29]. A later report covering the late 1980s [7] put the overall incidence of TIA in Rochester at 68 per 100,000 population, including 13 cases of amaurosis fugax, 38 of anterior cerebral TIA, and 15 of vertebrobasilar TIA per 100,000 population. Although some studies have found a similar predominance of TIAs of carotid distribution [2] others have not [21,22,27]. The higher overall rate of TIA in this study compared to the earlier one [28] was attributed to more accurate detection of cases in the database. Others [30] have maintained that the numbers reported for Rochester may not be representative of the United States as a whole because the residents of Rochester are predominantly white and aﬄuent, and rates of TIA or stroke have been found to vary with racial and socioeconomic group [5,23]. Given the similarities in the prevalence of stroke and TIA [5,15] and the failure of patients to seek medical attention for symptoms consistent with TIA, the true incidence of TIA is probably similar to or greater than that of stroke.

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III. DIAGNOSIS The symptoms of TIA are diﬀerentiated from those of focal ischemic stroke only by duration—lasting less than 24 hours—and vary according to the location of the ischemia. Ischemia within the distribution of the carotid artery often causes weakness, incoordination, or sensory alteration of one or both of the contralateral limbs or face; speech or language disturbance; or loss or blurring of vision in all or part of the ipsilateral eye. Vertebrobasilar TIA results in weakness or incoordination that sometimes changes from side to side; sensory alteration; blindness in both eyes or homonymous hemianopia; ataxia, imbalance, or unsteadiness that is not associated with vertigo; and diplopia, dysphagia, dysarthria, and vertigo, most often in combinations of two or more symptoms. Certain symptoms are more suggestive of etiologies other than TIA, including altered consciousness, syncope, dizziness, amnesia, or confusion alone; ‘‘positive’’ symptoms (such as with seizures and migraine); or incontinence. A march of symptoms, in which diﬀerent parts of the body are aﬀected in succession, are more likely to be caused by migraine or seizure than TIA [31]. Symptoms consistent with TIA can be caused by a number of pathophysiologies other than ischemia, and it is often extremely diﬃcult to diﬀerentiate TIA from other causes of transient neurological symptoms. In most cases, the initial diagnosis is made by an emergency department or primary care physician, and reports of the reliability of diagnoses by nonneurologists have varied considerably [1,14,32–34]. However, even when neurologists review the same cases, disagreement on whether a TIA occurred is frequent [35–37]. The problem of accurate diagnosis is complicated by the frequent reliance on retrospective reports from the patient or the patient’s companions, who were often too frightened, distracted, or neurologically impaired to remember details with any accuracy. As might be expected, examination while the TIA is ongoing increases the likelihood of obtaining a ﬁrm diagnosis [38]. However, other studies have found that patient reports are generally reliable, and that physician interpretation of the patient’s descriptions may be the more variable factor [35]. Interphysician agreement can be improved by using a checklist of symptoms listed in plain language [39] or by the use of a computer algorithm [15]. The 1990 Classiﬁcation of Cerebrovascular Disorders III [40] suggests adopting a diagnosis of ‘‘possible TIA’’ in cases where there is insuﬃcient evidence for a more deﬁnitive diagnosis, but the breakpoints between deﬁnite, possible, and unlikely TIA will never be clearly deﬁned if we rely on current diagnostic tools. No diagnostic study is sensitive for TIA, and, with the exception of the detection of new infarction present on brain imaging, no diagnostic test results are speciﬁc for the diagnosis. TIA-like symptoms can also be caused by global cerebral ischemia due to hypotension (syncope) or to one of several nonischemic syndromes, such as migraine [41], seizure [42], systemic infections [43], or hyperventilation due to anxiety [44,45]. Space-occupying lesions, such as subdural hematomas or tumors, can also lead to transient neurological symptoms [43], including aphasia [46]. Diﬀerentiating migraine from TIA can be particularly diﬃcult, especially in older individuals. Several authors have reported on diﬀerentiating migraine ‘‘accompaniments’’ from TIA. These nonheadache symptoms, most prominently visual disturbances such as scintillating scotoma, are usually associated with headache in younger patients, but may appear without headache in patients in midlife (>40–50 years old) [47], even in those with no prior history of migraine. The visual symptoms can help in the diﬀerential diagnosis: those of migraine accompaniments usually last 5–30 minutes, and in 75% of cases develop over time or expand to occupy an increasingly large portion of visual space, a feature that is not

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associated with ischemic episodes [41]. Vasospasm can also cause amaurosis fugax, with or without headache [48], and may be a cause of other forms of TIA [49]. Although the diagnosis of TIA is primarily based on history and physical examination, a thorough work-up can conﬁrm both the diagnosis of TIA and its likely etiology [50], as well as rule out alternative diagnoses [51]. The evaluation should be guided by the patient’s speciﬁc history and symptoms, taking into account the likelihood of the test being positive, the implications for management of a positive or negative result, the cost, and the risk to the patient [31]. Because many patients with TIA have more than one risk factor that could have contributed to the episode [6], it may be impossible to positively identify the cause of the TIA. For example, the presence of severe carotid stenosis does not rule out another proximal cause for an ischemic event [52]. Diagnostic work-ups can bring to light conditions and disease risk factors that may have been associated with the TIA and that will need to be addressed as part of the patient’s care, but it may not be cost-eﬀective or useful to rule out rare causes if common risk factors are present. More extensive testing for rare causes may be warranted in patients without known risk factors. However, the diagnostic procedures should always be chosen with a particular question in mind, or else the information obtained may be a source of confusion rather than a help [50]. The cause of a TIA may be particularly diﬃcult to diagnose in young patients without risk factors for atherosclerosis [31] but is more likely to be related to factors such as hemodynamic disorders and pregnancy than it is in older patients [53]. Laboratory tests, including the evaluation of sodium, glucose, hematocrit, white blood cell count, platelet count, and other tests as indicated by the clinical history, are helpful in ruling out metabolic or hematological etiologies, such as hypoglycemia, hyponatremia, and thrombocytosis or other prothrombotic conditions. An elevated erythrocyte sedimentation rate may suggest bacterial endocarditis or temporal arteritis. Consensus guidelines recommend standard 12-lead electrocardiography (ECG) for the initial evaluation of TIA [31,54,55], which can identify atrial ﬁbrillation, recent myocardial infarction, or left ventricular aneurysm as a potential cause [56]. ECG abnormalities are independently associated with an increased risk of cardiac events over the long term [57] and, more importantly for initial management, in the ﬁrst few months following a TIA [56]. Ambulatory heart rhythm monitoring may also be indicated when paroxysmal atrial ﬁbrillation is a possible cause for a TIA. Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain can rule out space-occupying lesions or hemorrhage and may identify a region of infarct. CT identiﬁes a nonvascular cause for the neurological symptoms in about 1% of patients [58– 60], although the yield is very low in patients with vertebrobasilar or ocular TIAs [58]. MRI is more sensitive than CT [61], and the use of diﬀusion-weighted MRI may improve the detection of acute lesions caused by TIA [62,63]. However, MRI is also more expensive and time-consuming and is not available in some facilities. MRI is excluded for patients who are claustrophobic or who have metal implants, such as heart pacemakers. Because the presence of ‘‘covert’’ infarcts does not in general change the clinical management of patients with TIA, MRI may not be warranted. On the other hand, the detection of new infarction may identify those with a ‘‘true’’ TIA. Since stroke is much less likely in those with another etiology for their transient neurological symptoms, a new infarction may be associated with greater risk of subsequent stroke [64]. Thus, MRI may prove useful for identifying a highrisk group in whom acute intervention may be more cost-eﬀective. Carotid ultrasound or another noninvasive screening technique (such as magnetic resonance angiography) should be performed in all patients suspected of having a TIA with

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25

anterior (carotid) distribution [50] to determine the extent of internal carotid artery stenosis. Identifying a carotid stenosis rapidly, ideally within 24 hours, is important since the risk of stroke is high and endarterectomy is eﬀective at reducing it (see below) [65,66].

IV. NATURAL HISTORY AND PROGNOSIS The impression that TIA is associated with an increased risk of stroke is not a recent one [67,68]. A number of studies have evaluated the risk of stroke following a TIA [69–79]; however, most have been small, and few have examined the very short-term risk of stroke or correlated that risk with prognostic factors. Three population-based studies of acute outcomes following TIA have been reported [1,28,80]. The ﬁrst study included 198 patients diagnosed with TIA in Rochester, Minnesota, from 1955 through 1969 [28]. The study found a 10% risk of stroke in the 3 months following a TIA, with a 7.5% risk in the ﬁrst month; at the end of the ﬁrst year, 19% had returned with a stroke. The risk of mortality (primarily from cardiac disease, followed in frequency by stroke) was greatly increased within the ﬁrst month after TIA, and leveled oﬀ to about 1.5 times the expected population rate after 2 years [81]. The second study found a stroke risk of 4% in the ﬁrst month among 184 patients diagnosed with TIA in Oxfordshire, England, between 1981 and 1986, and 11.6% risk over the ﬁrst year [80]. These risks may be lower in part because the patients were enrolled at a median of 3 days after the index TIA, so that strokes occurring very early after TIA would have been missed. My colleagues and I performed the third and largest of the studies [1], which included 1707 members of a health maintenance organization in northern California who were diagnosed in the emergency department with TIA in 1997 and 1998. More than 99% arrived in the emergency department within 1 day of symptom onset, and symptoms were present on arrival in half of the patients. Strokes occurred in 180 of the patients (10.5%) within 90 days (Fig. 1)—over 50 times that expected in a cohort of a similar age [30,82]—and were fatal in 21% and disabling in 64%. Ninety-one of these strokes occurred in the ﬁrst 2 days after the TIA. This is consistent with what has been seen in other studies [81,83]. Other adverse events, including deaths, hospitalization for cardiovascular events, and recurrent TIAs, were also common. We were able to identify ﬁve independent risk factors for stroke within 90 days (Table 1): age > 60 years, diabetes mellitus, duration of episode >10 minutes, weakness with episode, and speech impairment; the risk of stroke was correlated with the number of risk factors present. These risk factors, which require validation in an independent cohort, may identify a group that was more likely to have presented with a ‘‘true’’ TIA. However, the diagnosis of TIA was conﬁrmed by neurologist review in 94% of the patients, and the risk of stroke was not signiﬁcantly diﬀerent for the entire cohort versus those whose diagnosis of TIA was conﬁrmed by neurologist review. This supports the view that the diagnosis of the treating physician, usually an emergency department or primary care physician, is suﬃcient for the management of patients with TIA because it is accurate in identifying a group at high risk of subsequent adverse events. Interestingly, patients whose TIA included only sensory symptoms of short duration (V10 minutes) were more likely to experience recurrent TIA than completed ischemic stroke following the index TIA [49]. Thus, simple characteristics of the symptoms may identify distinct subgroups of patients with diﬀerent natural histories and, probably, diﬀerent pathophysiologies for the event. It is of interest to know whether the risk of stroke varies with the location of the ischemia. The risk of stroke after retinal TIA has been shown to be about half that of nonretinal TIA [84,85], although patients with amaurosis fugax are more likely to have

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Figure 1 Stroke occurred in 10.5% of patients within 90 days of TIA in a study of 1707 patients diagnosed in emergency departments in Northern California. Adverse events, including stroke, recurrent TIA, death, and hospitalization for cardiovascular events (myocardial infarction, unstable angina, ventricular arrhythmia, and heart failure), occurred in 25.1%. Source: Ref. [1].

atherosclerotic lesions of the carotid arteries, especially on the ipsilateral side, than patients with cerebral TIA [86]. However, no diﬀerence was found for TIAs of carotid or vertebrobasilar distribution over the course of years [87]; in both cases, cardiovascular disease was the most frequent cause of death. In many studies, the long-term risk of stroke after stroke is greater than after TIA [88]. However, TIA may confer a higher short-term risk of subsequent stroke than does completed stroke, particularly when events are counted beginning in the ﬁrst few hours. Based on a review of recent studies, the risk of stroke within 90 days of a completed stroke is about 5%, as compared to a 12% risk of stroke in the 90 days following a TIA (Table 2)

Table 1 Independent Risk Factors for Stroke Within 90 daysa Risk factor Age > 60 years Diabetes mellitus Duration of episode > 10 minutes Weakness with episode Speech impairment with episode a

Based on logistic regression analysis. Source: Ref. 1.

Odds ratio (95% conﬁdence interval) 1.8 2.0 2.3 1.9 1.5

(1.1–2.7) (1.4–2.9) (1.3–4.2) (1.4–2.6) (1.1–2.1)

Diagnosis and Prognosis of Transient Ischemic Attacks

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Table 2 Short-Term Stroke Risk after TIA and After Stroke Study setting Transient ischemic attack Northern California [1] Rochester, Minnesota [28] Oxfordshire, UK [80] Iowa City, Iowa [148] Iowa City, Iowa [149] London, UK [103] NASCET [83] Average Ischemic stroke Rochester, Minnesota [89] Oxfordshire, UK [90] New York, New York [91] Perth, Australia [92] New York, New York [93] Lehigh Valley, Pennsylvania [94] NINDS Stroke Data Bank [95,96] London, UK [103] IST [97] CAST [98] TOAST [99] FISS [100] TAIST [101] NASCET [83]

Cohort study Population-based cohort study Population-based cohort study Pilot trial (placebo group) Cohort study Cohort study Randomized trial (medical therapy)

Delay (days)

Stroke risk

Projected 90-day stroke riska

1,526 198

0 0

10.6%/3 m 10%/3 m

11% 10%

184

3

4%/1 m

11%

55

2

29.1%/6 d

16%

74 83 603

1 0 0

6.8%/6 d 29%/6 m 20.1%/3 m

13% 20% 12%

1,111

0

9%/6 m

f7%

545

0

f8%/6 m

f4%

323

0

6% /1m

f7%

250

0

f7% /6 m

297

0

7.4%/3 m

Cohort study

621

0

Cohort study

1,273

0

3.3%/1 m

Cohort study Randomized trial (aspirin/placebo) Randomized trial (placebo) Randomized trial (placebo) Randomized trial (placebo) Randomized trial (aspirin) Randomized trial (medical therapy)

83 9,717

0 1

7%/6 m 3.3%/2 w

10,320

1

2.5%/1 m

628

1

5.7%/3 m

6%

105

1

3.8%/3 m

4%

491

1

3.1%/5 d

526

0

2.3%/3 m

Population-based cohort study Population-based cohort study Population-based cohort study Population-based cohort study Cohort study

Average Stroke with ischemic recovery Northern California [1] Cohort study NINDS tPA Randomized trial Trial [147] (placebo) Houston, Texas [146] Cohort study (included some TIAs) Average a

N

9%/12 m

f5% 7% f4% f4%

2% 5%

181 312

0 0

10.4%/3 m >12%/ 10 d

50

0

16%/1 d

10%

10%

For TIA, projections were calculated by interpolating outside the period of study with the risk from Ref. 1. When 90day risks were not provided directly, they were estimated from survival curves (indicated by f). Averages are weighted by study size; studies in which an estimate of 90-day risk were not available were not included.

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[83,89–101]. As with TIAs, the risk of stroke recurrence appears to be highest in the ﬁrst few days after the event. Comparison of rates of stroke from these studies is limited, however, by variable inclusion criteria and ascertainment of events in follow-up. Three studies have directly compared the short-term risk of subsequent ischemic stroke among the acute ischemic cerebrovascular syndromes. In patients with hemispheric (rather than retinal) ischemia enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the 90-day risk of stroke was 20.1% in those with an index TIA and 2.3% in those with an index ischemic stroke [83]. A population-based study from Rochester, Minnesota compared the risk of ischemic stroke after TIA, completed stroke, and transient ischemia that took more than 24 hours but less than 3 weeks to resolve (reversible ischemic neurologic deﬁcit, RIND); the short-term risks were greatest for TIA and RIND resolving within 7 days, with lower risks for longer-duration RIND and ischemic stroke [102]. Similarly, an observational study of consecutive patients with acute ischemic cerebrovascular syndromes found a greater 6-month risk of recurrence after TIA (29%) and RIND (26%) than after completed stroke (7%) [103]. Reversal of ischemia may be associated with greater instability than completed stroke (see below). In addition to stroke, there is also a substantial risk of cardiac events following TIA [28,87,104]. TIA with ‘‘atypical’’ symptoms, including various visual disturbances, sensory symptoms alone, and coordination diﬃculties, among others, has been associated with a greater probability of cardiac outcomes than typical stroke [105], while TIA of longer duration (>1 hour) has been linked to underlying cardiac pathology [106]. In our northern California study [1], 44 patients (2.6%) were hospitalized for cardiovascular events within 90 days of the TIA.

V. MANAGEMENT The high risk of stroke or cardiovascular events following TIA justiﬁes urgent treatment, but only if the intervention can alter the outcome. The American Heart Association [31,50,54,55] and the National Stroke Association [107] have published guidelines for the management of TIA (Table 3). However, these are generally vague, and treatment practices vary considerably [108]. Cost may also play a role in the management strategy that treating physicians choose [108]. As TIA by deﬁnition does not produce lasting symptoms, management of TIA focuses on reducing the risk of subsequent events. This approach may include lifestyle changes, medical treatments, or surgery. The selection of the appropriate mix of these methods must depend on the patient’s history and the etiology of the TIA, and will therefore vary considerably from patient to patient. Risk reduction involves managing the major risk factors for TIA and stroke: hypertension, diabetes, hyperlipidemia, smoking, lack of physical activity, excessive alcohol consumption (>2 drinks/day), and obesity. Many of these require the patient to make lifestyle and behavioral changes, and counseling or formal programs should be provided to aid in smoking cessation, reduction in alcohol use, increase in exercise, and weight reduction. Antihypertensives, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, and cholesterol-lowering drugs, such as statins, should be considered for the management of hypertension and hyperlipidemia, and diabetes should be properly managed. Whether or not to admit patients presenting with TIA to the hospital has been a matter of debate, and practice diﬀers from hospital to hospital and between the United States and

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the United Kingdom [109]. Although a retrospective study found that many hospitalizations for TIA and stroke were not medically justiﬁed, half of the hospitalizations for TIA that were justiﬁed in retrospect would not have been deemed so in the emergency department [109]. It may therefore be better to err on the side of caution and to recommend hospitalization, which may expedite evaluation and treatment in the high-risk few days following TIA [31,55]. Although hospitalization may increase short-term costs, even a small reduction in future stroke might lower overall costs. The Task Force on Hospital Utilization for Stroke of the American Academy of Neurology has recommended hospital admission for all patients with onset of TIA within the previous 48 hours, prolonged or frequent TIA, suspected high-grade carotid stenosis, or evidence of posterior circulation ischemia that might require anticoagulation, radiological procedures, or surgery [110]. Rapid evaluation and treatment in the emergency department is possible in some facilities, so the decision to admit is likely to vary from hospital to hospital and from patient to patient. Certain treatments are well established for subtypes of TIA. For example, carotid endarterectomy has been shown to reduce subsequent stroke when the internal carotid artery is >70% stenosed [111,112]. The beneﬁts of endarterectomy are less clear for less extensive stenosis. Endarterectomy results in only a small reduction in subsequent stroke for patients with 50–69% stenosis, but the risks of the surgery may outweigh the beneﬁts in some cases [66]. Endarterectomy provides no beneﬁt over medical therapy for those with less than 50% stenosis [66]. The optimal timing of endarterectomy is also debated [113,114]. No large-scale trial has evaluated the timing of endarterectomy, so it is unknown whether the beneﬁt of urgent surgery—a reduction in the short-term risk of stroke—outweighs the potential risks due to unstable plaque or acute thrombus. There is little evidence to support delaying endarterectomy for more than 6 weeks to reduce the risk of brain hemorrhage [113,114], and the surgery should probably be performed as soon as possible unless an acute infarct is present on imaging. Stenoses of the internal carotid artery, vertebral artery, and basilar artery have been successfully dilated with angioplasty and the placement of stents, but these techniques require a high level of procedural expertise that is not yet widely available [107] and have not been compared to endarterectomy in an adequately powered randomized trial. Anticoagulants, such as heparin or warfarin, have been tested extensively for secondary prevention following acute stroke [97,99], but have not been speciﬁcally tested for stroke prevention following TIA. In patients with stroke, any beneﬁt of anticoagulants from reduced risk of ischemic stroke is oﬀset by increase in brain hemorrhage [97,101,115, 116]. Therefore, although some experts continue to recommend their use [117], anticoagulants have not been routinely recommended following TIA. The exception is for patients with a cardiac source of embolism, such as atrial ﬁbrillation [31], and without an intracranial hemorrhage or other source of bleeding. Anticoagulation with warfarin is eﬀective at reducing the risk of stroke recurrence in patients with atrial ﬁbrillation [118]. However, early anticoagulation with heparin after stroke was no more eﬀective than aspirin in a small trial (n = 449) of patients with stroke and atrial ﬁbrillation [119]. A larger trial showed a >50% reduction in ischemic stroke risk over 14 days with unfractionated heparin, but this beneﬁt was eliminated by an increase in brain hemorrhage [120]. Because there is a lower risk of hemorrhage with less severe ischemic events [99], the net beneﬁt may be greater after TIA than after completed stroke. Therefore, it may be justiﬁed to initiate anticoagulation with heparin or low-molecular weight heparin soon after a TIA attributed to atrial ﬁbrillation. Aspirin has been shown to reduce the long-term risk of stroke and cardiovascular events after stroke or TIA [97,98] and is therefore recommended for patients with TIA who

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Table 3 Consensus Guidelines for the Care of Patients with TIA Intervention Evaluation

American heart association Prompt evaluation

Hospitalization

No recommendation

Laboratory testing

Determined by history to identify etiologies of TIA requiring speciﬁc therapies, to assess modiﬁable risk factors, and to determine prognosis Recommended CT in all patients; routine use of MRI not recommended due to higher cost and lower tolerability Prompt ultrasound, MR angiography, or CT angiography

Electrocardiogram Head imaging

Carotid imaging

Antithrombotic medications Cardioembolic etiology

Noncardioembolic etiology

Carotid endarterectomy

No speciﬁc recommendation on short-term use of heparin; long-term oral anticoagulation for patients with atrial ﬁbrillation Antiplatelet therapy with aspirin (50–325 mg/day), clopidogrel, ticlopidine, or aspirin–dipyridamole Anticoagulation not generally recommended

Recommended for good surgical candidates with 70–99% stenosis with TIA during prior 2 years; considered for patients with 50–69% stenosis based on clinical features that inﬂuence stroke risk and surgical morbidity; timing not discussed

National stroke association Evaluation within hours of symptom onset Recommended if appropriate imaging studies are not immediately available No speciﬁc recommendation

Recommended No speciﬁc recommendation

Urgent evaluation not further speciﬁed

Acute anticoagulation can be considered (modest supportive evidence)

Antiplatelet therapy with aspirin (50–325 mg/day); consider clopidogrel, ticlopidine, or aspirin– dipyridamole in those who are intolerant of aspirin or had the TIA while taking aspirin; anticoagulation not generally recommended Recommended without delay for those with symptomatic stenosis 50–99%

Diagnosis and Prognosis of Transient Ischemic Attacks

31

Table 3 Continued Intervention Risk factor management Hypertension

Diabetes Hyperlipidemia

Cigarette smoking

Physical activity Alcohol consumption

Obesity

American heart association

National stroke association

Maintain systolic blood pressure below 140 mmHg and diastolic blood pressure below 90 mmHg; for persons with diabetes, maintain systolic blood pressure below 130 mmHg and diastolic blood pressure below 85 mmHg. Maintain fasting blood glucose levels below 126 mg/dL Diet and/or lipid-lowering agent with goal to maintain LDL cholesterol less than 100 mg/dL Counseling, nicotine replacement therapies, and bupropion to support cessation. Exercise 30–60 minutes, three or more times per week Formal alcohol cessation programs to eliminate excessive use; mild to moderate use (1–2 drinks/day) may be beneﬁcial Diet and exercise to reduce weight to less than 120% of ideal weight for height.

Source: 31, 49, 50, 54, 55, 107.

are not receiving anticoagulants [55,121–123]. Aspirin, like anticoagulants, elevates the risk of brain hemorrhage, which reduces its beneﬁt following acute stroke, but this risk may be lower after TIA. Doses of 75–325 mg provide a level of protection similar to that provided by higher doses, but cause gastrointestinal symptoms and bleeding less frequently. For patients who experienced a TIA while on aspirin therapy or who are sensitive to aspirin, clopidogrel [124] or aspirin/dipyridamole [125] can be prescribed. Unfortunately, antiplatelet and anticoagulant therapies are underused in the prevention of stroke following TIA, even when their beneﬁt is understood [6,14]. Thrombolytic therapy is not appropriate for a rapidly improving neurological deﬁcit, such as is seen with TIA [107].

VI. SHOULD THE DEFINITION OF TIA BE REVISED? The currently accepted deﬁnition of TIA—a neurological deﬁcit of abrupt onset that is attributable to focal ischemia and resolves completely within 24 hours—is based on the

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1975 report of the Ad Hoc Committee of the Advisory Council for the National Institute of Neurological and Communicative Disorders and Stroke [126], which states that TIAs are: . . . episodes of temporary and focal [bold in original] cerebral dysfunction of vascular origin, which are variable in duration, commonly lasting from 2 to 15 minutes, but occasionally lasting as long as a day (24 hours). They leave no persistent neurological deﬁcit. These attacks are usually called transient ischemic attacks because their pathogenesis is believed to be ischemic. However, in rare instances, it is possible that such attacks may be associated with other types of vascular pathophysiology.

This rather ﬂexible deﬁnition replaced a previous one put forth by the same group in 1958 [68], which limited TIAs to those episodes resolving within 1 hour, but also included migraine as a type of transient cerebral ischemia. Both of these deﬁnitions were predicated on the assumption that ischemia that resolved quickly enough to cause only transient symptoms was unlikely to have caused permanent brain injury or infarct, a quite reasonable assumption in the days before CT or MRI, and when even arteriography was rarely performed. However, advances in imaging technology have revealed that many TIAs are in fact associated with new infarct in up to 48% of cases [63,127–130]. Although the likelihood of infarct increases with the length of the attack [106,127,129,131], infarct is sometimes seen even in attacks lasting less than a minute [127]. A more recent classiﬁcation [40] acknowledges much of this uncertainty, deﬁning TIAs as: . . . brief episodes of focal loss of brain function, thought to be due to ischemia, that can usually be localized to that portion of the brain supplied by one vascular system . . . and for which no other cause can be found. Arbitrarily, by convention, episodes lasing<24 hours are classiﬁed as TIAs. . . .

The newer classiﬁcation also recognizes that TIAs are often associated with cerebral infarct, and acknowledges that there are ‘‘unusual instances that fall outside this deﬁnition.’’ A spectrum of acute ischemic cerebrovascular syndromes has now been described, with TIA at one end and completed ischemic stroke at the other. In between are reversible ischemic neurological deﬁcit (RIND) [102], deﬁned as symptoms that last more than 24 hours but no more than 21 days (although some deﬁne the end of the RIND period as 1 week [130]), RIND with incomplete resolution [59], and completed stroke with minimum residuum [130]. When TIAs were found to be frequently associated with cerebral infarct, a separate category, cerebral infarct with transient signs (CITS), was described [132,133]. However, TIAs are primarily clinical entities, independent of ﬁndings on imaging or laboratory tests [134], and the presence or absence of an infarct may [60] or may not [128,135] be clinically important. The usefulness of the various terms, and whether they should be considered distinct entities or steps along a continuum, has been debated for some time [59,127,133,136,137]. TIA and stroke are indistiguishable while symptoms are still present, and the cutoﬀ points of 24 hours and 3 weeks for TIA and RIND are arbitrary; in fact, the RIND designation is now rarely used. Although most TIAs resolve within 1 hour [138], some ischemic episodes have improved but not reached full resolution before the 24-hour cutoﬀ. Symptom duration is unlikely to reﬂect reliably a distinct pathophysiology and is only imperfectly correlated with the severity of neurological impairment and disability [106] and the risk of subsequent stroke [1,103]. Certainly, it is useful to describe the permanent impact of an ischemic event on a patient, but this may be more directly deﬁned by the severity of impairment at any particular

Diagnosis and Prognosis of Transient Ischemic Attacks

33

point in time [139]. This may aid in determining the level of care that the patient requires as well as in balancing the cost and risk of any acute or prophylactic therapies. Thus, distinguishing TIA from stroke is unnecessary for deﬁning impact on the patient as long as an adjective describing the severity of the deﬁcit is provided. Distinguishing TIA from stroke may also be important if it has implications for pathophysiology and treatment. The etiologies of TIA and stroke are very similar, and include hypertension, diabetes, and dyslipidemia as predisposing factors [140], with atherothrombosis, atrial ﬁbrillation, and large and small artery disease in the brain as more proximate causes [31]. Measures that target these risk factors have proven eﬀective in preventing secondary stroke [141,142], and recommendations for secondary prophylaxis are nearly identical regardless of whether the ischemic event was classiﬁed as a stroke or TIA [31,50,54,55,143]. However, although most of the data on risk of stroke after TIA and after stroke have been generated from studies with variable methodology, the literature suggests that the short-term risk of stroke is lower after completed stroke (Table 2). One possible explanation is that if an unstable atherosclerotic plaque is responsible for the ischemic episode, it could still produce new symptoms following a transient attack, but is less likely to do so when the area supplied by the vessel is already infarcted. Similarly, a patient with a completed stroke is less likely to gain from interventional treatments [136]. Therefore, transient ischemia of any duration may represent a more unstable situation, regardless of whether recovery is complete, and may provide a greater opportunity for intervention and prevention of further ischemia. Various proposals have been put forward to amend the deﬁnition of TIA. One is to revert to complete recovery within 1 hour as a criterion for deﬁning TIA [144,145]. A new proposal deﬁnes TIA as ‘‘. . . a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction’’ [145]. These deﬁnitions discourage physicians from waiting further for symptoms to resolve before initiating treatment. However, it is not clear that a TIA resolving within 1 hour is truly a diﬀerent entity from one lasting 2 or 3 hours, or that the presence of infarct is important in a person who recovers completely within 1 hour; treatment and prognosis are unlikely to diﬀer. A functional deﬁnition that included the cause of the ischemia, the anatomy, and the severity of the functional deﬁcits would shift the focus away from terminology and toward patient management [136]. It may also be important to consider whether signiﬁcant early recovery has occurred, even if some residual symptoms remain, rather than whether symptoms have fully resolved at any particular time point. Patients with rapid recovery have a high incidence of deterioration within the day or several days following treatment, regardless of whether the initial recovery is complete [1,146,147]. Routinely describing the presence and degree of early recovery, consistent with reversal of ischemia, may provide more useful information about natural history, pathophysiology, and, eventually, about treatment than trying to distinguish TIA from stroke, regardless of the deﬁnition applied.

VII. CONCLUSIONS Transient ischemic attacks are common and are likely to become more so as the population ages. TIA is often a precursor of more severe ischemic events—both cerebrovascular and cardiovascular—many of which occur within a few days of the TIA. TIA is thus a serious condition that needs to be evaluated urgently and treated with endarterectomy, antiplatelet

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agents, anticoagulants, and lifestyle changes as appropriate for the patient’s history and the etiology of the event. The public also needs to be made more aware of the seriousness of TIA and the need to seek medical care even for short-lived episodes. Although therapies speciﬁc for TIA have not been tested, TIA should ultimately be viewed as an opportunity to prevent much more debilitating and costly ischemic events.

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Friedman L, Kerlikowske K, Perry M, Prineas R, Schron E. Eﬀect of antihypertensive treatment in patients having already suﬀered from stroke. Gathering the evidence. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) Project Collaborators. Stroke 1997; 28(12):2557–2562. Hebert PR, 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(4):313– 321. Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA, et al. Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council. American Heart Association. Circulation 1994; 90(3):1588–1601. Brust JC. Transient ischemic attacks: natural history and anticoagulation. Neurology 1977; 27(8):701–707. Albers GW, Caplan LR, Easton JD, Fayad PB, Mohr JP, Saver JL, Sherman DG. Transient ischemic attack—proposal for a new deﬁnition. N Engl J Med 2002; 347(21):1713–1716. Alexandrov AV, Felberg RA, Demchuk AM, Christou I, Burgin WS, Malkoﬀ M, Wojner AW, Grotta JC. Deterioration following spontaneous improvement: sonographic ﬁndings in patients with acutely resolving symptoms of cerebral ischemia. Stroke 2000; 31(4):915–919. Grotta JC, Welch KM, Fagan SC, Lu M, Frankel MR, Brott T, Levine SR, Lyden PD. Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke 2001; 32(3):661–668. Biller J, Bruno A, Adams HP Jr, Godersky JC, Loftus CM, Mitchell VL, Banwart KJ, Jones MP. A randomized trial of aspirin or heparin in hospitalized patients with recent transient ischemic attacks. A pilot study. Stroke 1989; 20(4):441–447. Putman SF, Adams HP Jr. Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol 1985; 42(10):960–962.

3 Ischemic Stroke Syndromes: Clinical Features, Anatomy, Vascular Territories, and Prognosis Gabriel R. de Freitas Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Julien Bogousslavsky Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

I. INTRODUCTION Cerebral ischemia can be divided into global and focal; in the latter, the neurological deﬁcit reﬂects the location of the infarct. The supply of speciﬁc cerebral areas by speciﬁc arteries is so reliable that the neurologist can sometimes precisely predict which arterial branch is aﬀected. However, a cerebrovascular lesion does not always express itself as a clearly delineated syndrome. Ischemic stroke syndromes depend not only on the artery involved, but also on factors such as the collateral circulation, whether the occlusion lies proximal or distal to the circle of Willis, variations in the circle of Willis, and variations in the region supplied by a particular artery. Thus, the same syndrome may result from an arterial lesion in diﬀerent areas, and, occasionally, an arterial lesion in the same area may cause diﬀerent syndromes in two individuals. With the development of modern neuroimaging techniques in the last decades, especially magnetic resonance imaging (MRI), it has been possible to conﬁrm the clinical manifestations of brain lesions in a larger series of patients and even to describe features of previously unknown vascular territories. The result of these developments is that there is now no doubt that certain regions are related to certain functions, and, with the improvement in neuroimaging techniques, the anatomy of high-order physiological and psychological functions, such as attention, memory and thought, is being delineated. In this chapter we focus on ischemic lesions, since hemorrhagic stroke may involve the territory of more than one artery and is often accompanied by mass eﬀect, causing dysfunction in adjoining structures, making clinical correlations diﬃcult. We divided ischemic stroke syndromes into those caused by occlusion of the internal carotid artery (ICA) and its branches (anterior circulation) and those caused by occlusion of the vertebral and basilar arteries or their branches (posterior circulation). Since watershed infarctions may involve both circulations, these are discussed separately at the end of the chapter. 43

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II. ANTERIOR CIRCULATION A. Anterior Cerebral Artery 1. Anatomy and Vascular Territory The anterior cerebral artery (ACA) arises from the anterior clinoid portion of the ICA and runs rostrally, reaching the interhemispheric ﬁssure, where it connects with the opposite ACA through the anterior communicating artery (ACoA). The distal ACA begins in the ACoA and runs dorsally around the genu of corpus callosum, then in a sulcus between the corpus callosum and the cingulate gyrus up to the parietooccipital ﬁssure. The deep branches of the ACA arise from the proximal portion, near the circle of Willis, whereas the cortical branches, usually 11 in number, arise from the distal ACA (Fig. 1) [1]. The largest of these deep branches is the recurrent artery of Heubner. The ACA cortical branches supply blood to the anterior three quarters of the medial surfaces of the hemisphere, including the medial-orbital surface of the frontal lobe, the frontal pole, a strip of the lateral surface of the hemisphere along the superior border, and the anterior four ﬁfths of the corpus callosum. The deep branches supply the head of the caudate nucleus, the anterior limb of the internal capsule, the anterior part of the globus pallidus and putamen, and the anterior hypothalamus (Fig. 2). 2. Etiology and Frequency ACA infarcts (Fig. 3) are rare, accounting for 0.6–3% of acute ischemic strokes [2,3] (Table 1). Out of 1490 patients with ﬁrst-ever stroke (ischemic or hemorrhagic) admitted to our center and entered into the Lausanne Stroke Registry (LSR) during its ﬁrst 7 years of existence, only 27 had an infarct limited to the ACA territory, as shown by computed tomography (CT) [4]. Since the ACA on one side can supply the opposite ACA through the ACoA, occlusion of one ACA stem may be asymptomatic, and this may partly explain the infrequency of infarcts in the ACA territory. Embolism from either the carotid artery or the heart is the most common cause of ACA infarcts in Caucasians [3,4], while in Asian populations they are mainly attributable to intracranial atherosclerosis [2]. They can also be secondary to rupture or surgery of a saccular aneurysm of the ACoA.

Figure 1 brain: 1, posterior posterior

Diagram of the main branches of the anterior cerebral artery on the medial surface of the orbitofrontal; 2, frontopolar; 3, anterior internal frontal; 4, middle internal frontal; 5, internal frontal; 6, paracentral; 7, precuneal; 8, parietoccipital; 9, callosomarginal; 10, pericallosal. PC pericallosal. (From Ref. 1.)

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Figure 2 Templates of the territories of the deep perforators in the carotid system. (From Ref. 9.)

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Figure 3 MRI scan of a hypertensive 57-year-old man presenting with left leg weakness, showing a small infarct in the territory of the right anterior cerebral artery on FLAIR (A sagital; C coronal) and diﬀusion-weighted sequences.

3. Clinical Features Motor weakness, the most common neurological disturbance, is seen in almost all patients. The paresis classically involves mainly or only the lower limb, although faciobrachial paresis may occasionally be seen [4]. Isolated facial weakness has been described after deep (caudate) infarcts [5]. Complete hemiparesis may be due to extension of the lesion into deep structures [6]. Sensory impairments are present in about half of the patients, always with hemiparesis, which shows almost the same distribution [4]. A contralateral grasp reﬂex may be present after lesions involving the orbitofrontal cortex or underlying white matter. Urinary and fecal incontinence may be observed in patients with bilateral infarcts. The language disorders of initial mutism and transcortical motor aphasia (i.e., decreased spontaneous speech, intact repetition, and good comprehension) are occasionally Table 1 Arterial Territories Involved in 3803 Patients with First-Ever Ischemic Stroke Enrolled in the Lausanne Stroke Registry, 1979–1997 Arterial territory Subcorticala Anterior MCA Brainstem Complete MCAb Posterior MCA Posterior cerebral artery Thalamus Cerebellum Multiple cortical Multiple subcortical Multiple VB Watershed Anterior cerebral artery Total

N

%

927 549 486 387 377 231 186 147 146 110 104 93 60 3803

24.4 14.4 12.8 10.2 9.9 6.1 4.9 3.9 3.8 2.9 2.7 2.4 1.6 100.0

MCA = middle cerebral artery; VB = vertebrobasilar. a Deep infarcts in the anterior circulation (perforators of the MCA, anterior cerebral artery, and anterior choroidal artery). b Includes concomitant MCA and anterior cerebral artery infarcts or concomitant MCA and posterior cerebral artery infarcts.

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seen. Mutism may be observed after either right or left lesions. Transcortical motor aphasia is present after left lesions, and its prognosis is usually good [7]. Neuropsychological disturbances are common and include motor or spatial neglect, callosal disconnection syndrome, and mood disorders. Callosal disconnection syndrome, originally described after postsurgery occlusion of the left ACA [8] is characterized by left ideomotor apraxia (inability to execute skilled movements with the left hand) and left-hand agraphia and/or tactile anomia (inability to name objects placed in the left hand) and is relatively rare. It is speculated that, due to callosal lesion, inputs from the right hemisphere cannot reach the areas responsible for ideomotor praxis and language in the left hemisphere, and the right hemisphere cannot function properly in isolation [8]. A variety of mood disorders are observed, such as acute confusion, disinhibition syndrome with euphoria and inappropriate laughing (Witzelsucht), and a continuum from abulia (lack of spontaneity of action and speech) with unilateral lesions to akinetic mutism with bilateral lesions. Akinetic mutism refers to a state of absence of speech, voluntary movements, emotional expression, and limited responsiveness to stimuli, with integrity of primary motor and sensory functions. Similar ﬁndings can be present after deep infarcts in the ACA territory involving the caudate nuclei and neighboring structures and are attributed to interruption of corticalsubcortical circuits [5]. The clinical ﬁndings after ACA infarcts are summarized in Table 2 [9].

Table 2 Anterior Cerebral Artery Territory Infarcts: Neurological Features Hemiparesis: Crural predominance Brachiofacial (with deep extension of the infarct) Hemihypesthesia: Same distribution as hemiparesis Contralateral grasp reﬂex Urinary (fecal) incontinence Left-side lesions: Initial mutism Transcortical motor aphasia or minor variants (Right motor neglect) Unilateral left apraxia Abulia, apathy (euphoria, disinhibition) ‘‘Frontal’’ syndrome (impaired ability to perform conﬂicting tasks) Right-sided lesions: (Initial mutism) Left motor, spatial neglect Abulia, apathy (euphoria, disinhibition) Acute confusional state ‘‘Frontal’’ syndrome Ipsilateral grasp reaction Bilateral lesions: Bilateral hemiparesis including pseudoparaplegia Akinetic mutism, severe mood disturbances Long-lasting incontinence Parentheses indicate uncommon manifestations. Source: Ref. 9.

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B. Anterior Choroidal Artery 1. Anatomy and Vascular Territory The anterior choroidal artery (AChA) is a long, narrow artery that usually arises from the stem of the ICA, just above the origin of the posterior communicating artery. It runs posteriorly and divides into the superﬁcial and perforating branches. The perforating branches supply the posterior two thirds of the posterior limb of the internal capsule, the internal segment of the globus pallidus, and part of the ventro-lateral thalamus (Fig. 2). The superﬁcial branches supply the optic tract and radiation, part of the lateral geniculate body, and part of the temporal lobe, where it penetrates to supply the choroid plexus and anastomose with the posterior choroidal artery. It is disputable whether the posterior paraventricular corona radiata is supplied by its perforating branches [10]. 2. Etiology and Frequency For a long time, AChA infarcts (Fig. 4) were considered rare. However, in one study on 100 consecutive patients with an infarct in the territory of the deep perforators from the carotid system, 23% had infarcts in the territory of the AChA [11]. Whether AChA infarcts are caused by small-artery disease or embolism is a matter of dispute. Most AChA small infarcts are probably secondary to small-artery disease [10], while, in large infarcts, large-artery disease and cardioembolism play an important role [12]. Surgical ligation of the AChA has been performed to abolish the tremor of Parkinson’s disease. 3. Clinical Features First described by Foix et al. in 1925 [13], the triad of hemiplegia, hemianesthesia, and hemianopia was considered for some time as the classical triad of AChA infarcts. However, CT studies have extended the clinical spectrum of these infarcts [11,12,14–16]. Motor weakness is almost always present, usually involving the face, arm, and leg. The severity of the weakness is impressive [14], especially after large infarcts. Paradoxically, serious hemiparesis is rarely reported after AChA surgical ligation [15]. Sensory impairment is usually incomplete and transient [15]. Lacunar syndromes, such as pure motor syndrome, sensorimotor syndrome, and ataxic hemiparesis, are common in patients with small AChA infarcts and were present in 67 out of 77 patients in one study [10]. Another lacunar syndrome, hypesthesic ataxic hemiparesis, was ﬁrst described after an AChA infarct [16]. Visual ﬁeld defects are probably the most inconsistent feature of the clinical triad and, when present, are often temporary. They may be caused by ischemia in three diﬀerent parts of the

Figure 4 Left anterior choroidal artery infarct shown by T2-weighted MRI (arrow) (A), diﬀusionweighted MRI (B), or a coronal slice of a FLAIR sequence (arrows) (C).

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visual pathway: the optic tract, lateral geniculate body, and optic radiation (geniculocalcarine tract). The optic radiation is the structure most frequently aﬀected and leads to a congruent homonymous hemianopia with macular sparing. Involvement of the lateral geniculate body causes hemianopia with sparing of a horizontal sector or superior quadrantanopia with macular sparing. Optic tract infarction should produce incongruent hemianopia without pupillary reaction to light stimuli, but in a review of described AChA infarcts [15] this was not found to be the case. Cortical signs are often seen after large infarcts. They include visual neglect, anosognosia, apraxia, motor impersistence, and eye and head deviation [12,14,15]. These ﬁndings may be explained by lesions in the posterior limb of the internal capsule, interrupting the connections between the thalamus and cortex [14]. In one study AChA infarcts had a lower 30-day case fatality and 1-year mortality than other small deep infarcts, but because of the low number of patients, multivariate analysis could not be pursued [10]. C. Middle Cerebral Artery 1. Anatomy and Vascular Territories The anatomy is shown in Figure 5 and the blood supply in Figure 6 [17]. The middle cerebral artery (MCA) arises from the bifurcation of the ICA at the medial end of the Sylvian ﬁssure, just lateral to the optic chiasm. The horizontal (M1) segment generally gives rise to 5–17 small arteries (lenticulostriate branches of Duret, deep penetrators). These are classiﬁed into medial and lateral branches and penetrate into the posterior and lateral portions of the anterior perforated substance. The MCA stem then often divides into two trunks (anterior or superior, and posterior or inferior) or, more rarely, into three trunks or multiple smaller divisions with no major trunk [17]. It turns 90j and runs over the insula forming the M2 (or insular) segment, which terminates in the circular

Figure 5 Segments of the middle cerebral artery: M1, sphenoidal segment; M2, insular segment; M3, opercular segment; M4, cortical segment; LS, lenticulostriated arteries; ME, medullary arteries.

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Figure 6 Cortical territories of the 12 branches of the middle cerebral artery. Orb. Fr., orbitofrontal; Pre. Fr., prefrontal; Pre. Cent., precentral; Cent., central; Ant. Par., anterior parietal, Post. Par., posterior parietal; Ang., angular artery; Temp. Occ., temporooccipital; Post. Temp., posterior temporal; Mid. Temp., middle temporal; Ant. Temp., anterior temporal; Temp. Pol., temporopolar. (From Ref. 17.)

sulcus of the insula. The M3 (opercular) segment courses over the surface of the opercula and reaches the superﬁcial part of the Sylvian ﬁssure, where it makes two 180j turns. The branches forming the M4 (cortical) segment begin at the surface of the Sylvian ﬁssure and extend over the cortical surface. The medullary branches arise from the superﬁcial branches, perforate the white matter of the hemispheres, and run toward the upper part of the lateral ventricles. The MCA cortical territory encompasses most of the lateral surface of the hemisphere, all the insular and opercular surfaces, the lateral part of the orbital surface of the frontal lobe, the temporal lobe, and the lateral part of the inferior surface of the temporal lobe. The lenticulostriate branches of the MCA supply part of the head and body of the caudate nucleus, the upper part of the anterior limb, the genu and anterior part of the posterior limb of the internal capsule, the putamen, and the lateral pallidum (Fig. 2). The medullary branches of the superﬁcial MCA system supply the centrum semiovale, which comprises the central white matter of the cerebral hemispheres, the superﬁcial part of the corona radiata, and the long association bundles. We will describe separately the causes and clinical ﬁndings of occlusion of the MCA stem (complete MCA), its superﬁcial branches, deep perforators, and medullary branches. 2. Superﬁcial (Pial) and Complete (Deep Plus Superﬁcial) Middle Cerebral Artery Infarcts a. Etiology and Frequency. Infarcts within the complete territory of the MCA and within the territory of the superﬁcial branches of the MCA are often due to cardioembolism or large artery disease [18–20]. Although in situ atherosclerosis of the MCA stem is considered rare, it may be much more frequent in black or oriental patients [20]. In the LSR, cardiac sources of embolism were more common in patients with infarcts in the

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Figure 7 T2 (A) and diﬀusion-weighted (B) MRI sequences showing an infarct involving almost all the territory of the middle cerebral artery; part of the inferior (posterior) division is spared.

territory of the posterior division of the MCA than in those with infarcts in the territory of the anterior division [21]. These infarcts constitute one third (34.5%) of all ischemic infarcts in the LSR: 14.4% in the territory of the anterior division of the MCA, 9.9% in the territory of the posterior division, and 10.2% in the territory of the deep and superﬁcial divisions (complete MCA infarct) (Table 1). b. Clinical Features Complete Middle Cerebral Artery Territory Infarct. These infarcts (Fig. 7) are very severe and are characterized by contralateral massive hemiplegia aﬀecting the face, arm, and leg, hemianesthesia, and homonymous hemianopia, and head and conjugate ocular deviation toward the infarct. Global aphasia is present in left-sided lesions, whereas hemineglect and visuospatial impairment are seen with right-sided lesions. ‘‘Peripheral’’ vegetative changes are likely to develop in this type of large cerebral infarction, but are commonly overlooked (Table 3). Patients may initially be alert, but from the ﬁrst to the fourth day after stroke, impairment of consciousness develops due to cerebral edema. Impairment of consciousness may be present from the beginning and, in the experience of one of us (JB), is the best predictor of death [22]. The prognosis is very poor, with only 10% of patients being independent at one year [23]. Mortality is also high, but the death rate varies from 22 to 78%, probably due to diﬀerent selection criteria [22,24].

Table 3 ‘‘Peripheral’’ Vegetative Changes After Large Hemispheric Infarcts Acute: Ipsilateral Thermoregulatory hemihypohydrosis Central Horner syndrome (telodiencephalic ischemic syndrome) Contralateral Hyperhydrosis Decrease in skin temperature (cold stroke syndrome) Chronic: Contralateral Painful trophic changes Muscle denervation Source: Ref. 9.

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Superﬁcial (Pial) Middle Cerebral Artery Territory Infarct. Involvement of all the anterior and posterior superﬁcial branches, with sparing of the deep territories, is rare. The clinical ﬁndings are similar to those for complete MCA infarcts, contralateral homonymous hemianopia and head and conjugate eye deviation toward the lesion often being present, but the motor and sensory impairment usually spare the leg, the prognosis is not as bad as for complete MCA infarcts, and the better level of consciousness allows the observation of various neuropsychological ﬁndings. Left-side lesions are characterized by global or Broca’s aphasia (poor and reduced speech, agrammatism, and moderate comprehension deﬁcits) and ideomotor apraxia. Several behavior abnormalities may be seen after right-sided infarcts; these include anosognosia (denial of illness), left spatial neglect, motor impersistence, dressing and constructional apraxia, extinction on double-simultaneous stimulation, acute confusion, and prosopagnosia (inability to recognize familiar faces) [25]. Motor impersistence is closely correlated with anosognosia and more severe hemiplegia and is often seen after large lesions. Aprosodia, which refers to monotonous speech without melodic and emotional inﬂections, is rare. Anterior Pial Middle Cerebral Artery Territory Infarct. The neurological picture includes faciobrachial paresis and sensory loss and conjugate eye deviation toward the lesion [26,27]. Hemianopia is very rare. After left-sided infarcts, Broca’s aphasia may be observed from the beginning or a few days after initial mutism (aphemia). Depression is often reported after left frontal infarcts. Aprosodia and anosognosia may be seen with rightsided infarcts. Infarcts in the Territory of Branches of the Anterior Pial MCA. The territory supplied by each artery and the clinical picture observed after isolated lesions are summarized in Table 4. Posterior Pial Middle Cerebral Artery Territory Infarct. When infarcts in this territory (Fig. 8) cause weakness, it is slight and mainly present in the face and arm. Similarly, when present, sensory impairment is mild and often accompanied by contralateral extinction on double-simultaneous stimulation. Contralateral homonymous hemianopia or upper quadrantanopia is found in almost all patients. After left-sided infarcts, Wernicke’s aphasia is usually seen. It is identiﬁed by ﬂuent speech, impaired repetition and comprehension, and phonemic and verbal paraphasias, sometimes with jargon paraphasia and acute agitation. Conduction aphasia may be observed initially, or, more often, as an evolution of Wernicke’s aphasia. It is characterized by ﬂuent speech with word search and good comprehension, contrasting with impaired repetition. Right-side infarcts promote a series of neuropsychological disturbances, the most common being left spatial neglect, constructional apraxia, extinction on double-simultaneous stimulation, and severe agitated delirium [29]. Infarcts in the Territory of the Branches of the Posterior Pial Middle Cerebral Artery. The clinical ﬁndings are summarized in Table 5. 3. Deep MCA Infarcts These infarcts are due to involvement of the lenticulostriate arteries of the MCA. They can be divided into two groups, small deep or large deep infarcts, with diﬀerent causes, prevalence, clinical ﬁndings, and prognosis. a. Small Deep Infarcts, or Lacunar Infarcts. These are secondary to involvement of the territory of only one MCA lenticulostriate artery and are caused by lipohyalinosis, a process linked to hypertension. Atheromatosis and embolic occlusion of small vessels may also play a role [30]. Large-artery disease and cardioembolism are other potential causes of

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Table 4 Clinical Findings in Isolated Infarcts in Branches of the Anterior Middle Cerebral Artery Artery

Territory

Orbitofrontal

Orbital portion of the middle and inferior frontal gyri and the inferior part of the frontal lobe

Precentral

Anterior and middle parts of the precentral gyrus, posterior middle frontal gyrus, and superior orbital part of the frontal lobe.

Central sulcus

Posterior precentral sulcus and anterior half of the postcentral gyrus.

Anterior parietal

Posterior postcentral gyrus, parasagital part of the central sulcus, anterior part of the inferior parietal gyrus, supramarginal gyrus, parts of the upper and middle temporal gyrus

Clinical ﬁndings ‘‘Prefrontal syndrome of Luria’’: loss of programming abilities, utilization and imitation behaviors, grasp reﬂex, perseverations, apathy, abulia Proximal brachial paresis, ‘‘premotor syndrome of Luria’’: inability to perform successive motor sequences smoothly, motor impersistence. Left-sided lesions: transcortical motor aphasia. Faciobrachial paresis and sensory loss, or isolated arm and hand motor weakness with mild sensory loss. Rarely, isolated cheiro-oral sensory loss (posterior operculum syndrome of Bruyn). Left-sided lesions: Mild Broca’s aphasia Bilateral: Pseudobulbar palsy (Foix-Chavany-Marie syndrome). Pseudothalamic syndrome of FoixRoussy: faciobrachiocrural sensory loss mainly in the upper limb, associated with neuropsychological dysfunction. Rarely, opercular cheiro-oral syndrome. Left-sided lesions: conduction aphasia, ideomotor apraxia. Right-sided lesions: hemisensory and spatial neglect.

Source: Ref. 28.

these infarcts. On CT or MRI they appear as lesions smaller than 1.5 cm, known, together with deep small infarcts of other artery territories, as ‘‘lacunes.’’ Taken together, deep infarcts in the territory of the MCA, ACA, and AChoA account for a quarter of all ischemic strokes (Table 1). The clinical ﬁndings may be stereotyped and are therefore called ‘‘lacunar syndromes.’’ Although more than 70 syndromes related to lacunar infarcts have been reported, most are minor variants of another [31]. Classical lacunar syndromes include pure motor hemiplegia (involving the face, arm, and leg), pure sensory stroke, sensorimotor stroke, ataxic-hemiparesis, and dysarthria–clumsy hand syndrome. The lacunar syndrome most commonly observed in the MCA territory is pure motor hemiplegia. Infarcts restricted to the genu of the internal capsule may involve corticopontine ﬁbers and produce a special clinical pattern of severe contralateral facial and lingual hemiparesis with dysarthria

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Figure 8 MRI scan (A, B) of a 42-year-old patient with no known risk factors for stroke presenting with Wernicke aphasia and mild right hemiparesis and hemihypoesthesia, involving predominantly the face and arm. Note the involvement of the lateral part of the temporal lobe on the coronal sequence (B).

Table 5 Clinical Findings in Isolated Infarcts in Branches of the Posterior Middle Cerebral Artery Artery

Territory

Clinical ﬁndings

Posterior parietal

Posterior parts of the superior and inferior parietal lobules, including the supramarginal gyrus

Angular

Posterior portions of the superior and inferior parietal lobules, inferior portion of the lateral occipital gyrus, and variable portions of the supramarginal and angular gyri

Temporal (ﬁve temporal arteries: temporooccipital, posterior temporal, middle temporal, anterior temporal, temporopolar)

Inferior part of the lateral occipital gyrus, superior, middle and inferior temporal gyri

Cortical sensory syndrome: astereognosia, agraphestesia, loss of proprioception. Left-sided lesions: Wernicke’s aphasia; Gerstmann’s syndrome (right-left disorientation, ﬁnger agnosia, acalculia, agraphia); anomic aphasia. Right-sided lesions: extinction, spatial neglect. Contralateral hemianopia or lower quadrantanopia, transient motor weakness. Left-sided lesions: isolated Gerstmann’s syndrome, or accompanied by Wernicke’s aphasia, transcortical sensory aphasia or anomic aphasia. Right-sided lesions: extinction, spatial neglect, asomatognosia, constructional apraxia. Bilateral: Balint’s syndrome (psychic gaze paralysis, optic ataxia, visual inattention) Contralateral hemianopia or superior quadrantanopia, transient motor weakness and sensory loss. Left-sided lesions: isolated Wernicke’s aphasia, or accompanied by right hemianopia. Right-sided lesions: extinction, spatial neglect, constructional apraxia, agitated confusional state. Bilateral: Pure word deafness, cortical deafness.

Source: Ref. 28.

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(‘‘upper capsular genu syndrome’’) [32]. Involvement of thalamofrontal connections has been proposed to explain an acute confusional state with ﬂuctuating alertness also seen after small lesions of the genu of the internal capsule (‘‘lower capsular genu syndrome’’) [33]. Movement disorders may occasionally be seen after lacunes in the MCA territory [30]. Patients with lacunar infarction often have a good prognosis. The fatality rate of lacunar infarction is low (about 1% at one month), and death is generally not due to direct neurological sequelae of the infarct [34]. Patients presenting with certain classical lacunar syndromes, such as pure motor hemiparesis and pure sensory syndrome, have a better prognosis than those presenting with sensorimotor stroke [34]. Large Deep Infarcts or Striatocapsular Infarcts. These are often caused by cardioembolism or large-artery disease. Occlusion of the MCA trunk leads to an infarct in the territory of all lenticulostriated arteries, while adequate collateral ﬂow to the overlying cortex via transcortical and transdural anastomoses explains the cortical sparing. These infarcts typically appear on the CT or MRI as a comma-shaped lesion greater than 3 cm (Fig. 9). They are rather uncommon, accounting for 1–6% of all strokes [35,36]. The most common clinical presentation is that of hemiparesis and hemisensory loss with accompanying cortical features. The weakness aﬀects mainly the upper limb. Cortical ﬁndings, such as aphasia, apraxia, and neglect, are present in more than two thirds of patients [35]. The prognosis of patients with striatocapsular infarcts appears to be intermediate between the good prognosis of lacunar infarction and the poor prognosis of cortical/ subcortical infarction [35]. In one series, two thirds of the patients had at least a functional recovery, and half of these were able to return to work [35]. Predictors of good outcome were younger age, absence of cortical signs at presentation, and no hemodynamically signiﬁcant disease on cerebral angiography. 4. Centrum Ovale Infarcts These are caused by involvement of the medullary branches. In the LSR, an infarct restricted to the white matter territory of the centrum ovale was found in 1.6% of patients admitted for ﬁrst-ever stroke [37]. As with deep subcortical infarcts, these infarcts can be divided into two groups, small and large. Small Centrum Ovale Infarcts. These are the most common type of stroke limited to the centrum ovale (72%). They are round or ovoid, and their maximal diameter is less than 1.5 cm (Fig. 10). Among patients with small infarcts, chronic hypertension and diabetes are

Figure 9 T2 (A, B) and diﬀusion-weighted (C) MRI sequences showing a ‘‘comma-shaped’’ infarct involving the territory of the lenticulostriated arteries (arrows).

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Figure 10 Bilateral small centrum ovale infarcts on an MRI scan.

frequent, but carotid disease is rare [37]. These ﬁndings suggest that small centrum ovale infarcts are related to small-vessel disease involving the medullary branches in the same way as lacunar infarction is caused by disease involving the deep perforators of the MCA. The neurological deﬁcit, consisting of facio-bracio-crural or partial hemiparesis, sensorimotor stroke, and ataxic hemiparesis, is compatible with lacunar syndromes. Small infarcts in the centrum ovale are frequently clinically silent and are detected accidentally [38]. Large Centrum Ovale Infarcts. This type of infarct involves the territory of more than one medullary branch. They have a maximal diameter greater than 1.5 cm, an irregular shape, and the geographical margins follow the inner border of the cortex. The mechanisms of large infarcts are not clear. Ipsilateral carotid occlusion or greater than 50% stenosis is common (80%), which may suggest distal hemodynamic failure [37]. However, artery-toartery embolism or cardiac embolism cannot be formally excluded in many instances. The neurological signs are similar to those found in large superﬁcial or extended MCA infarcts. The deﬁcits are characterized by marked hemiparesis aﬀecting the upper limb and face more than the lower extremities, with an accompanying sensory deﬁcit, which follows a similar pattern of facio-brachial predominance. Additional elements include aphasia (dominant hemisphere infarct) or visuospatial disturbances (nondominant hemisphere involvement).

III. POSTERIOR CIRCULATION A. Posterior Cerebral Artery 1. Anatomy and Vascular Territories The anatomy is shown in Figure 11 [39]. The posterior cerebral arteries (PCAs) arise from the basilar bifurcation in the pontomesencephalic junction. They course around the midbrain, anastomose with the posterior communicating arteries (PCommAs), and divide into cortical branches as they reach the dorsal surface of the midbrain. In about a quarter of patients, one of the PCAs arises from the ICA; this is known as a fetal-type PCA. A useful way to designate the PCA segments is to divide the artery into the precommunal segment, which extends from the bifurcation to the origin of the PCommA, and the postcommunal

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Figure 11 Anatomy of the posterior cerebral artery: 1, internal carotid artery; 2, posterior communicating artery; 3, basilar artery; 4, anterior thalamoperforate arteries; 5, posterior thalamoperforate arteries; 6, posterior cerebral artery; 7, medial posterior choroidal artery; 8, lateral posterior choroidal arteries; 9, posterior pericallosal artery; 10, parietooccipital artery; 11, calcarine artery; 12, occipitotemporal artery; 13, anterior temporal ramus. (From Ref. 39.)

segment, from the origin of the PCommA to the division into cortical branches. The precommunal segment gives rise to the interpeduncular arteries, paramedian mesencephalic arteries (also called thalamoperforate), and the medial posterior choroidal arteries, which supply the most median part of the midbrain and thalamus (Fig. 12). From the postcommunal segment arise the inferolateral artery (or thalamogeniculate artery) and the posterior choroidal arteries, which supply the lateral geniculate body and the posterior parts of the thalamus. The polar region of the thalamus is supplied by the tuberothalamic (polar) artery, which usually originates from the anterior circulation and arises from the PCommA. The cortical branches include the posterior temporal artery, parieto-occipital artery, and calcarine arteries, which supply the inferomedial part of the temporal lobe and the medial occipital lobe, including the cuneus, precuneus, and visual areas 17, 18, and 19. For practical purposes, we diﬀerentiate those clinical ﬁndings due to distal occlusions involving the hemispheral PCA territory and those due to proximal occlusions causing thalamic and midbrain infarcts. Infarcts involving both the proximal and distal territories are also seen, but they are rare. Midbrain infarcts due to proximal occlusions are discussed in another section of this chapter. 2. Cortical PCA Infarcts a. Etiology and Frequency. The frequency of all PCA infarcts is about 10% (Table 1), and most of these involve the cortical PCA territory [40] (Fig. 13). Most cortical PCA infarcts (about 70%) are caused by an embolic mechanism, mainly cardioembolism and intra-arterial embolism [41]. As with MCA infarcts, PCA stenosis is not common, causing about 10% of the infarcts [42,43]. Although migranous stroke most often involves the PCA, the signiﬁcance of migraine in PCA infarcts is controversial [40]. b. Clinical Features. Almost all patients (90–97%) have initial visual symptoms and are usually aware of visual loss, complaining of loss on one side of the visual space. Hallucinations in the lost visual ﬁeld occur and may be a relatively common complaint when routinely sought [44]. In addition, visual signs are found in more than 80% of the patients. Homonymous hemianopia is the most common, but macular sparing, homonymous scotoma, and upper quadrantanopia can also be seen. Sometimes, hemichromatopsia (an

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Figure 12 Arterial supply to the thalamus: arterial branches (a) and template of territories (b). Arterial branches: 1, internal carotid artery; 2, basilar artery; 3, posterior cerebral artery P1 (or mesencephalic artery); 4, posterior cerebral artery; 5, posterior communicating artery; 6, tuberothalamic (or polar) artery group; 7, thalamoperforate (or paramedian) artery group; 8, thalamogeniculate (or inferolateral) artery group; 9, posterior choridal arteries. LGB lateral geniculate body; DM dorsomedial nucleus; VA ventral anterior nucleus; VL ventral lateral nucleus; VP ventral posterior nucleus; P pulvinar; IL intralaminar nuclei. (From Ref. 48.)

Figure 13 MRI scan (A, B) showing a cortical left-sided posterior cerebral artery territory infarct. Note the involvement of the medial part of the temporal lobe on the coronal sequence (B), in contrast to Figure 8.

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inability to identify colors within the ﬁeld) is the only visual defect. Visual perseverations (palinopsia) are not common, but are speciﬁc for occipital infarcts. Headache, present in about half of the patients, suggests PCA infarcts. About 40% of the patients have sensory ﬁndings, most often in the face and hand; these are attributed to involvement of the thalamus or adjacent white matter pathways. Hemiparesis, mostly transient and slight, is present in about a quarter of the patients. (Table 6). A variety of neuropsychological abnormalities may be seen. After left-sided infarcts, an inability to read without other language basic abnormalities (so-called alexia without agraphia) is rarely observed. It is considered a disconnection syndrome, with involvement of the corpus callosum impeding the stimulus from the right occipital lobe from arriving at the left angular gyrus. Alexia with agraphia also occurs after left-sided PCA infarcts, but can also be seen after posterior MCA lesions. Transcortical sensory aphasia, characterized by ﬂuent speech, with jargon words and paraphasic errors, and impaired comprehension, but relatively preserved repetition, is associated with large PCA infarcts. Anomia, conduction aphasia, and color anomia are occasionally seen. Visual agnosia (inability to name objects shown visually) may be seen after large left-sided lesions. Verbal memory and learning disturbances are often observed after temporomesial involvement [45]. Confusional states may follow left-sided lesions [46], but have also been observed after right-sided lesions [44]. Following right-sided lesions, fewer abnormalities are noted, but visual neglect, visual amnesia, constructional apraxia, and disorientation to place may be found. Table 6 Cortical Posterior Cerebral Artery Territory Infarcts: Neurological Features Structure involved Medial temporal lobe Occipital lobe

Neurological dysfunction Memory disturbances Lateral hemianopia or other homonymous lateral visual ﬁeld cut Visual hallucinations, metamorphosias, monocular diplopia Impairment of movement perception, astereotopsis left tactile-visual anomia/left hand diagonostic apraxia (posterior callosal involvement) Left-sided lesion: dysmnesia (for verbal material), transient global amnesia Pure alexia, optic aphasia (visual anomia) Transcortical sensory aphasia Hemiachromatopsia, color anomia Visual hemineglect Acute confusional state, acute delirium Right-sided lesion: dysmnesia (for nonverbal material), transient global amnesia Visual hemineglect Palinopia Prosopoagnosia (disputable) Impaired mental imagery (Charcot-Wilbrandt syndrome) Bilateral: bilateral hemianopia, sometimes with tubular vision Cortical blindness, Anton’s syndrome Balint’s syndrome Altitudinal hemianopia Prosopoagnosia, visual object agnosia Klu¨ver-Bucy syndrome Amnesia

Source: Ref. 9.

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Patients with bilateral lesions may have cortical blindness with anosognosia (Anton’s syndrome). Agitated delirium and severe amnesia may accompany the syndrome. Balint’s syndrome, consisting of simultagnosia (inability to see a full scene at one time), optic ataxia (abnormal hand-eye coordination), and ocular apraxia (inability to accurately ﬁx on a object), results from bilateral occipital infarcts with lesions above the calcarine ﬁssure. Prosopagnosia (inability to recognize faces) is observed after bilateral lesions under the calcarine ﬁssure. While patients with superﬁcial PCA territory infarct generally have a good outcome, there is a risk of death for those with additional involvement of midbrain. These patients have a poorer functional outcome as their motor deﬁcits are severe and persistent [40]. In one study, 7% of the patients died in the acute stroke phase; all of them had infarcts in the deep PCA territory [44]. Visual and neuropsychological disturbances consist of the most frequent and important long-term disabilities. 3. Thalamic Infarcts a. Etiology and Frequency. Infarcts restricted to the thalamus account for 11% of vertebrobasilar infarcts [47]. In a study carried out in our center, the main cause of thalamic infarcts was found to be small artery disease (14/40), followed by large artery atheroma (7/ 40), cardioembolism (5/40), and migraine stroke (4/40) [48]. Except in the case of bilateral paramedian infarcts, which were highly suggestive of cardioembolism, involvement of one of the main arterial territories of the thalamus was not associated with a particular cause of stroke. Clinical-radiological-anatomical studies suggest that it is appropriate to divide thalamic infarcts into four groups based on the four main arterial territories. Inferolateral infarcts are the most common (45%), followed by paramedian (35%), polar (12.5%), and posterior choroidal (7.5%) infarcts [48]. Only one of 40 patients in one study of thalamic infarcts died in the acute phase, and the annual death or stroke risk was 7.4% [48]. Late disability in survivors was related to neuropsychological sequelae, and, more rarely, to persisting pain. b. Clinical Features Inferolateral Infarcts. Pure sensory stroke is the most common manifestation. The hemisensory deﬁcit may involve the entire hemibody, but may also be partial, with cheiro-oral, cheiro-podo-oral, or pseudo-radicular patterns. In their initial report, Deje´rine and Roussy [49] mentioned that delayed (weeks to months) pain may develop (anesthe´sie douloureuse). In a few instances the infarct can involve the adjacent portion of the internal capsule, with corresponding hemiparesis associated with sensory loss. Hemiataxia also occurs with inferolateral infarcts. Even when impairment of position sense is present, the ataxia shows characteristics that also suggest a cerebellar type of dysfunction. Delayed (weeks) dystonia and jerks may develop in the hand contralateral to the infarct, usually in patients with marked sensory loss and ataxia (thalamic hand and unstable ataxic hand). Paramedian Infarcts. The classical syndrome of unilateral infarction associates acute loss of, or decreased, consciousness (usually transient), frequently followed by neuropsychological disturbances, with upward gaze limitation, but very few motor or sensory abnormalities [50,51]. Bilateral infarcts account for at least a third of paramedian thalamic infarcts [48]. The explanation for this is the frequent ﬁnding of a unilateral paramedian pedicle supplying the paramedian region on both sides. Neurological and neuropsychological disturbances are usually more severe and long-lasting than in the case of unilateral involvement (Fig. 14).

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Figure 14 A right-sided paramedian infarct shown by diﬀusion weighted MRI during the acute phase (A) and, 2 days later, by T2-weighted MRI (B).

Peculiar behavioral/neuropsychological disturbances include akinetic mutism, ‘‘thalamic dementia,’’ and loss of psychic self-activation or robot syndrome [50]. Polar Infarcts. Clinical dysfunction is mainly neuropsychological. Left-sided infarcts are associated with the same aphasic disturbances seen in ‘‘subcortical’’ aphasia in general, while right-sided infarcts are associated with hemineglect and impaired visuospatial processing [48,52]. In a few instances, unilateral left or, more often, bilateral infarcts can result in acute amnesia as the main dysfunction. Sensorimotor disturbances, when present, are mild and transient. Posterior Choroidal Infarcts. The following three neurological features are the most important symptoms of these infarcts: (1) visual dysfunction, including upper or lower quadrantanopia or, more typically, horizontal sectoranopia; (2) sensorimotor hemisyndrome; (3) neuropsychological disturbances. Involuntary movements, such as acute-onset choreoathethosis, may also develop. B. Basilar and Vertebral Arteries 1. Brain Stem Infarcts: Blood Supply and Vascular Territories These are shown in Figure 15. The main arterial trunks supplying the brainstem include the vertebral artery (VA), anterior spinal artery, posterior inferior cerebellar artery (PICA), basilar artery (BA), anterior inferior cerebellar artery (AICA), superior cerebellar artery (SCA), PCA, posterior communicating artery, and AChoA. The collaterals of these arteries are divided into four arterial groups (anteriomedial, anterolateral, lateral, and posterior), which supply the brainstem [53]. At each level of the brainstem, the origin of the arterial supply varies: Medulla: (1) the anteromedial and anterolateral groups arise from the VA and anterior spinal arteries; (2) the lateral group arises from the PICA, VA, BA, and AICA; (3) the posterior group arises from the PICA for the upper part of medulla and from the posterior spinal artery for the lower part. Pons: (1) the anteromedial and anterolateral groups arise from the BA; (2) the lateral group arises from the AICA and BA (lateral pontine arteries); (3) the posterior group arises from the SCA. Midbrain: the BA supplies the paramedian region, mainly its ventral part, the SCA supplies the lateral-dorsal region of the caudal two thirds via its circumferential branches, and the contribution of the PCA increases caudorostrally, so that the

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Figure 15 Arterial supply to the medulla oblongata (A), upper middle pons (B), and midbrain. PICA, posterior and inferior cerebellar artery; CST, corticospinal tract; V, trigeminal nerve; PCF, pontocerebellar ﬁbers; ML, medial lemniscus; CTT, central tegment tract; MLF, medial longitudinal fasciculus; III, oculomotor nerve; SCA, superior cerebellar artery; PCA, posterior cerebral artery.

upper half of the midbrain is supplied through direct branches from the distal BA and proximal PCA. The PCA provides supply to the anteriomedial group (middle rami of the interpeduncular fossa). The collicular and posteromedial choroidal arteries are the main source of the anterolateral and lateral group; the posterior group is supplied by the SCA, collicular and posteromedial choroidal artery. The anterior choroidal and PCA may also supply the anterolateral group. 2. Medullary Infarcts These can be divided into medial and lateral medullary syndromes and a combination of both (hemimedullary infarct).

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a. Lateral Medullary Infarct Etiology and Frequency. Lateral medullary infarct, so-called Wallenberg’s syndrome, is one of the most common brainstem infarcts and accounts for about 2% of all admissions for acute stroke [54]. It is caused mainly by occlusion of the VA and/or the PICA. Often the occlusion is a result of atherosclerosis, but dissection of the VA may be an important cause in young patients [55]. Clinical Features. An ipsilateral Horner’s syndrome (ptosis, miosis, enoftalmia, and loss of facial sweating) due to involvement of sympathetic ﬁbers may be seen in up to 95% of the patients, mainly in its incomplete form [54]. Ipsilateral limb ataxia is also common and is caused by a lesion of the spinocerebellar tracts or restiform body or by an accompanying cerebellar infarct. Ipsilateral sensory loss in the face always involves pain and temperature sensation, and light touch is also often aﬀected [56]. It is probably due to involvement of the nucleus of the descending tract of the V nerve. The corneal reﬂex is often absent. Facial pain, usually described as burning, is common and is usually localized around the eye or in the entire face. Mild ipsilateral facial weakness may seen in some patients, but its explanation is not clear. Dysarthria, dysphagia, and dysphonia may be seen as a result of ipsilateral vocal cord and palatal weakness due to involvement of the nucleus ambiguus. Contralateral sensory loss in the trunk and extremities may be present secondary to crossed spinothalamic tract involvement. Vertigo is common and is caused by lesion in the vestibular nuclei or their connections. Many ocular abnormalities, such as nystagmus, skew deviation with ipsilateral hypotropia and diplopia, and ocular lateropulsion toward the side of the infarct, may be observed. Hiccups are sometimes present and are attributed to respiratory center involvement. It is not possible to predict whether there is an associated cerebellar infarction on the basis of the clinical examination alone. In one series 11% of the patients died during the acute phase from respiratory and cardiovascular complications [54]. b. Medial Medullary Infarct Etiology and Frequency. Deje´rine syndrome is relative rare, being seen in 1 out of 28 medullary infarcts in one series [55]. The cause of the infarction is often atherothrombosis of the VA or the anterior spinal artery [57]. Clinical Features. Contralateral hemiparesis (rarely ipsilateral) and a hemisensory deﬁcit sparing the face are the most common symptoms [57]. Ipsilateral lingual paresis or clumsy tongue movements may be occasionally observed. c. Hemimedullary Infarct. Also called Babinski-Nageotte syndrome, this is very rare [55,58] (Fig. 16); the clinical picture is a combination of the symptoms of lateral and medial medullary infarcts. 3. Pontine Infarcts a. Etiology and Frequency. In a study performed by one of us (JB), pontine infarcts accounted for 15% of the infarcts in the posterior circulation [59]. BA branch disease was the most common cause of stroke (44%) and was associated with large ventral infarcts with severe clinical symptomatology (Fig. 17A). Small-artery disease (25%) was usually associated with small ventral or tegmental infarcts and rapidly improving lacunar syndromes (Fig. 17B) [59]. b. Clinical Features. Pontine infarcts can be classiﬁed into four main groups: 1. Ventromedial pontine infarcts, associated with moderate to severe hemiparesis, either alone (pure motor hemiparesis) or accompanied by homolateral ataxia (ataxic hemiparesis). Some patients may also have contralateral crural ataxia.

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Figure 16 T2-weighted MRI, showing an infarct involving the right hemimedulla. (From Ref. 58.)

2. Ventrolateral infarcts, often present as a mild hemiparesis, sometimes associated with homolateral ataxia (ataxic hemiparesis or pure motor hemiparesis). A variant of ataxic hemiparesis, called dysarthria clumsy-hand syndrome, is occasionally found [60]. Some patients may have mild signs of tegmental involvement, such as ocular abnormalities, vertigo, and sensory loss (sensorimotor stroke). 3. Tegmental pontine infarcts, possibly presenting as vertigo, diplopia, eye movement disturbances, cranial nerve palsies, truncal and extremities sensory loss, and mild motor deﬁcit. 4. Bilateral ventrotegmental infarcts, associated with acute pseudobulbar palsy and uni- or bilateral sensorimotor dysfunction. Bilateral large ventral infarcts may cause the locked-in syndrome, characterized by tetraplegia, facial diplegia, pharyngeal palsy, horizontal gaze palsy with normal consciousness, communication only being possible using blinking or vertical movement of the eyes. Short-term prognosis was good in two thirds of the patients in one study including patients with isolated pontine infarcts [59]. However, the subgroup of patients with large

Figure 17 (A) A 57-year-old hypertensive diabetic man presented with right hemiplegia and hemianesthesia involving the face, arm, and leg, severe dysarthria, and conjugated left-sided eye palsy. The MRI showed a large pontine infarct caused by basilar atherosclerotic stenosis (‘‘branch disease’’). (B) A 62-year-old hypertensive man presented with a sudden painful feeling in his left eye and nose (‘‘salt and pepper in the face’’ pain) and mild right hemiparesis. The MRI showed a small tegmental pontine infarct, probably caused by small artery disease.

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ventral infarcts had a less favorable outcome, with good recovery in only one third of the cases. 4. Midbrain Infarcts a. Etiology and Frequency. These account for 8% of all infarcts in the posterior circulation [61]. BA disease (27%), cardioembolism (23%), and small-artery disease (23%) were found to be equally common causes in a study performed in the LSR [61]. b. Clinical Features. Most infarcts are localized in the middle part of the midbrain and are characterized by nuclear (bilateral ptosis, bilateral superior rectus weakness, or bilateral mydriasis) or peripheral (unilateral adduction/upward/downward palsy with ptosis and mydriasis) third nerve involvement, with or without hemiparesis. Infarcts in the upper or lower midbrain usually have no localizing ﬁndings and often include a combination of ataxia and hemiparesis (ataxic hemiparesis or pure motor hemiparesis). C. Cerebellar Infarcts 1. Blood Supply and Vascular Territories These are shown in Figure 18. The PICA arises from the terminal portion of the VA and gives rise to two branches, medial and lateral. It vascularizes the inferior vermis and the

Figure 18 Arterial supply to the brainstem and cerebellum. SCAm, medial territory of the superior cerebral artery; SCA1, lateral territory of the superior cerebral artery; AICA, territory of the anterior and inferior cerebellar artery; PICAm, medial territory of the posterior and inferior cerebellar artery; PICA1, lateral territory of the posterior and inferior cerebellar artery. (From Ref 66.)

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inferior and posterior surfaces of the cerebellar hemispheres. The medial branch also supplies the dorsolateral region of the medulla oblongata. The AICA arises from the caudal third of the BA and supplies the anterior surface of the simple and superior and inferior semilunar lobules, the ﬂocculus, and the middle cerebral peduncle. It also supplies the lateral portion of the pons. The SCA arises from the rostral BA and divides into medial and lateral branches. It vascularizes the superior half of the cerebellar hemisphere and the vermis, including the dentate nucleus. The medial SCA also supplies a small portion of the brainstem, namely the laterotegmental region of the rostral pons and lower midbrain [53,62]. 2. Etiology and Frequency Cerebellar infarcts account for about 2% of all infarcts. PICA and SCA territory infarcts are equally frequent, accounting, respectively, for 47% and 38% of cerebellar infarcts [62]. AICA territory infarcts are rarer. Some patients have cerebellar infarcts involving more than one territory, whereas others have infarcts in junctional areas. The etiology varies according to the territory aﬀected. Most AICA infarcts are caused by BA atherosclerosis [63], whereas SCA infarcts are often caused by cardioembolism. PICA infarcts are caused by cardioembolism or VA atherosclerosis, depending on the branch aﬀected [62]. 3. Clinical Features a. PICA Territory Infarcts. When the medulla is involved, a typical Wallenberg’s syndrome (see above) may be present. Infarcts of the whole PICA territory and the medial PICA territory (Fig. 19) manifest as rotatory vertigo, nausea, and vomiting. Patients have signs of cerebellar dysfunction, with truncal ataxia and mild ipsilateral limb dysmetria. Patients with an isolated infarct in the territory of the lateral PICA present with cerebellar ataxia involving mainly the limbs, without trunk ataxia [62]. b. AICA Territory Infarcts. Most patients have cranial nerve involvement (V, VII, or VIII), Horner’s syndrome, or contralateral temperature and pain sensory loss, indicating a concomitant lateral pontine lesion [64]. In AICA infarcts sparing the pons, there may be vertigo and dysarthria. c. SCA Territory Infarcts. Many patients have concomitant involvement of other territories (Fig. 20) and may present with a ‘‘top of the basilar syndrome,’’ with a thalamic syndrome, behavioral changes, visual ﬁeld defects, disorders of ocular movement, and hemi-

Figure 19 MRI scan (A, B), showing an infarct in the territory of the posterior and inferior cerebellar artery involving the cerebellum and the dorsolateral portion of the medulla.

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Figure 20 Bilateral infarcts involving both superior cerebellar artery territories shown by MRI axial (A) and coronal (B) slices.

or tetraparesia [65]. In isolated cerebellar infarcts, the presentation includes cerebellar dysarthria, unsteadiness or vertigo, nystagmus, and limb or trunk ataxia. When the dorsal mesencephalic territory of the SCA is involved, the rare classical picture of limb ataxia, Horner’s syndrome, IV nerve palsy, and contralateral sensory impairment is present [62,65]. Whole PICA and SCA territory infarcts and multiple territory infarcts may have a severe evolution with brainstem compression, and the patient’s condition may worsen toward deep coma.

IV. BORDER ZONE TERRITORIES (WATERSHED OR BORDER ZONE INFARCTS) A. Etiology and Frequency Infarction may develop at the collateral border zone between two main pial arterial territories. These extraterritorial infarcts, commonly called watershed infarcts, account for about 3% of the infarcts in the LSR (Table 1). Most watershed infarcts are in the anterior circulation, although they may also be present in the cerebellum, brainstem, and thalamus. The regions most often involved are the border zones between the middle and anterior cerebral arteries (anterior watershed infarcts) and between the middle and posterior cerebral arteries (posterior watershed infarcts). Infarcts between the superﬁcial and deep territories of the MCA are sometimes called subcortical watershed infarcts, but, according to some authors, the term ‘‘subcortical junctional infarct’’ is more appropriate, since they occur between deep perforators, which do not have collaterals, and the term ‘‘watershed’’ implies a border zone between two pial territories, at the level of their collateral network. The clinical evidence suggests that watershed infarcts are hemodynamic in nature, since events are commonly precipitated by an iatrogenic drop in blood pressure or standing up, loss of consciousness is observed at stroke onset, half of the patients have an elevated hematocrit, heart disease associated with hypotension is common (especially bradyarrhythmia), and most patients have occlusions or severe obstructions of the ipsilateral [67] and contralateral ICA [68]. However, embolism may be responsible in some cases, and in many instances both embolism and hypoperfusion may play a role [69]. B. Clinical Features These are summarized in Table 7.

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Table 7 Watershed Infarcts: Main Neurological Features Anterior watershed infarcts Hemiparesis with crural predominance (when infarct extends subcortically) with proximal brachial predominance (when infarct mainly cortical) Hemihypesthesia with the same distribution Left-side infarct: transcortical motor aphasia (often after initial mutism) Right-side infarct: Motor hemineglect Apathy, euphoria Anosognosia (disputable) Bilateral: bilateral diplegia or man-in-the-barrel syndrome Posterior watershed infarcts Cortical hemihypoesthesia with faciobrachial predominance Lateral hemianopia or upper quadrantanopia Left side infarct: Transcortical sensory aphasia or isolated anomia Right side infarct: Spatial hemineglect Anosognosia Source: Ref. 9.

V. CONCLUSION Knowledge of clinical syndromes resulting from the involvement of arterial territories is essential for all neurologists, but especially for those dealing with neurological emergencies, cerebrovascular diseases, or behavior abnormalities. The early identiﬁcation of the artery involved and its mechanisms may have implications for therapeutic management and determine the investigations to be carried out. Clinico-radiological correlations using new techniques, such as diﬀusion and perfusion MRI, may help to provide a better delineation of the anatomy of brain functions.

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4 Intracerebral Hemorrhage Ku-Chou Chang Chang Gung Memorial Hospital, Kaohsiung, Taiwan

I. INTRODUCTION Intracranial hemorrhage is deﬁned as the pathological accumulation of blood (hematoma) within the cranial vault, resulting in clinical dysfunction of the nervous system. The accumulation can occur within the parenchyma (intracerebral hemorrhage), the surrounding meningeal spaces (subarachnoid hemorrhage), or into the ventricles (intraventricular hemorrhage). Bleeding inside the skull that results in epidural and subdural hematoma is usually traumatic in origin (head injury). Intracerebral hemorrhage (ICH) is more than twice as common as subarachnoid hemorrhage [1]. Nontraumatic intracerebral hemorrhage has several causes (Table 1), but it is most commonly caused by hypertension [primary or spontaneous intracerebral hemorrhage (PICH)]. Hypertensive ICH is often life-threatening, accounting for approximately 5–10% of strokes. Hemorrhages attributed to hypertension usually originate in the putamen, globus pallidum, thalamus, internal capsule, deep perventricular white matter, pons, or cerebellum. This chapter focuses on this type of hemorrhagic stroke because most clinical research has focused on this entity. ICH accounts for about 10–15% of all strokes in North America and Europe and for about 20–30% in East Asia [2], but it is the most devastating form and has the worst prognosis. With the emergence of the computed tomography (CT) scan in 1976 [3], studies showed a decline in ICH mortality rate due to better and earlier detection of ICH for all race and sex groups. The decline in mortality was also credited to improved control of hypertension [4], since it is the strongest and most consistent risk factor. However, even with this decline, mortality remains at 30–50%, a rate that rises with increasing age [5], young African Americans [6,7], low socioeconomic status [8], and Asian population [2,9,10]. Therefore, studies are continually being conducted to identify the risk factors and new approaches that could signiﬁcantly aﬀect the outcome from ICH. Retrospective and prospective studies identify several factors as being associated with high early and late mortality rates in ICH. Level of consciousness (usually measured by Glasgow Coma Scores) on admission is the strongest predictor of fatal outcome at 30 days and during the ﬁrst year of bleeding based on the data of population registry. Populationbased stroke registers provide more accurate data on stroke incidence than routine statistics and also more valid measures of stroke trend when maintained according to the standardized procedures for case ascertainment and validation [11]. 73

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Table 1 Causes of Nontraumatic Intracranial Hemorrhage Main causes: 1. Less than 40 years old: rupture of aneurysm or arteriovenous malformation and illicit drug use 2. 40–69 years old: hypertension predominates 3. Elderly: cause is often unknown, possible arteriopathy like amyloid angiopathy Other causes: 1. Altered hemostasis: use of anticoagulants, thrombolytics, and probably aspirin 2. Hemorrhagic necrosis: tumor, infection 3. Autoregulatory dysfunction with excessive cerebral blood ﬂow: reperfusion injury, hemorrhagic transformation, cold exposure 4. Venous outﬂow obstruction: cerebral venous thrombosis

II. EARLY MORTALITY PREDICTORS ICH is associated with high risk of early death. From population registry data, four factors had been suggested to predict death at one month (in decreasing order): the level of consciousness at the initial examination, an intraventricular hemorrhage, a hematoma volume over 11 cm3, and men aged over 70 years. In a prospective study [12] conducted in PICH, a 38.8% 30-day mortality was observed wherein the level of consciousness on admission was the independent predictor. Presence of intraventricular hemorrhage in patients with PICH was noted to have larger intraparenchymal hemorrhages and lower initial Glasgow Coma Score (level of consciousness) [13]. The 30-day mortality rate of patients with intraventricular spread was 43% compared with only 9% among those without ventricular extension. This study has conﬁrmed the results of Mase et al. [14], who found these three independent predictors of 30-day mortality (intraventricular spread of blood, volume of hemorrhage, and Glasgow Coma Scores) an eﬀective way to predict survival with a high degree of sensitivity and speciﬁcity. A retrospective study in in-hospital mortality and morbidity secondary to ICH have shown a 49.6% 30-day mortality rate, which had a signiﬁcant correlation with Glasgow Coma Score of V6 on admission, age > 60, and the presence of intraventricular hemorrhage in a multivariate analysis [15]. Hydrocephalus and Glasgow Coma Score of V8 were also shown to be independent predictors of the 30-day mortality in putaminal hemorrhage, the most common form of ICH in hypertensives. A multivariate analysis done by Phan et al. incorporated these two independent prognostic indicators in a model showed a sensitivity of 57% and speciﬁcity of 91% for predicting 30-day mortality for putaminal hemorrhage [16]. When these two factors were present in putaminal hemorrhage 11% of patients survived, and when these two factors were absent 100% of patients survived. This trial had a 30-day mortality of 29%, and hydrocephalus was present in 76% of those who died. Another important predictor of one-month survival was the ﬁrst-day mean arterial blood pressure (MAP), which showed only 33% survival rate in patients with ﬁrst-day MAP > 145 mmHg [17,18]. A rapid decline in MAP within 24 hours was reported with increased mortality in patients with ICH [19]. It was shown in another study that increased blood pressure and volume of hematoma on admission in putaminal and thalamic hemorrhage were related to increased mortality, while in patients with subcortical, cerebellar, and

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Table 2 Independent Predictors in ICH Score Independent predictors Glasgow coma score 3–4 5–12 13–15 Age z80 years <80 years Infratentorial origin Yes No ICH volume z30 cm3 <30 cm3 Intraventricular hemorrhage Yes No

ICH score 2 1 0 1 0 1 0 1 0 1 0

pontine hemorrhages the mean blood pressure was not related to the clinical outcome [20]. Likewise, high stress reactions like diabetes and leukocytosis were other potential predictors of 30-day mortality, having rates of 54.3% and 35%, respectively [21,22]. Hemphill et al. developed a risk-stratiﬁed scale (ICH score) based on the strength of association of the independent predictors [23]. The factors that were independently associated with 30-day mortality were Glasgow Coma Scale, age z 80 years, infratentorial origin of ICH, ICH volume, and presence of intraventricular hemorrhage. The ICH score was the sum of the individual points assigned to each factor, as shown in Table 2. This scoring system was performed by reviewing the records of patients with acute ICH and showed that patients with an ICH score of 0 survived and patients with an ICH score of 5 died. Modiﬁcation of the scale was performed by Cheung et al. [24] to improve the predictions of 30-day mortality and morbidity in ICH patients. This modiﬁed scoring system replaced the Glasgow Coma Scale with the National Institutes of Health Stroke Scale (NIHSS). Other independent predictors for mortality were intraventricular hemorrhage, subarachnoid extension, and narrow pulse pressure. On the other hand, independent factors for good outcome were low NIHSS score and low admission temperature. Another modiﬁcation was done by Hallevy after identifying six signiﬁcant and independent prognostic variables (decreased level of consciousness, severe hemiparesis, age older than 60, large hematoma size, midline shift, and intraventricular extension on CT) [25]. The original and modiﬁed ICH scores are reliable predictors of mortality and good outcome, which are useful in clinical research trials and standardization of clinical protocol to predict short-term functional outcome upon admission of PICH patients.

III. LATE MORTALITY AND RECOVERY Population registry data shows that in long-term survival, level of consciousness at the initial clinical examination remains the principal predictive factor of case fatality followed by age

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over 70 years. It has been shown that the overall mortality rate in primary ICH was 47% at one year [26]. Large hematomas (z25 cm3) on admission are associated with a high risk of hematoma growth, which is the major cause of clinical deterioration. Analysis had demonstrated that patients with history of brain infarction, liver disease, interaction of poorly controlled diabetics with high systolic blood pressure on admission were at high risk of hematoma enlargement [27]. It was recommended before that patients with larger hematomas should be treated surgically. However, previous studies in patients with spontaneous ICH who were randomly assigned to surgery or conservative treatment within 12 hours after the bleed show that surgery did not oﬀer any deﬁnite long-term advantage over conservative treatment [28,29]. Recent reports suggest a favorable eﬀect of stereotactic blood clot removal after liquefaction by means of intraoperative instillation of plasminogen activator (urokinase) [30]. Results show that mortality rate at 6 months was similar in surgical (56%) and nonsurgical (59%) treatment. Still, the superiority of surgical interventions over conservative treatment is yet to be proven [31]. A new surgical technique to help dissect hypertensive intracranial hematomas called endoscopic-assisted keyhole operation (EAKO) has been studied. The outcome of this procedure was compared to craniotomy and showed better clinical outcome in EAKO (good recovery rate as deﬁned by Glasgow Outcome Scale) [32]. This promising technique needs further trials to prove its positive eﬀect in the mortality rates of ICH. In a prospective stroke registry over a 10-year period, site of bleeding was compared with the remaining ICH cases by means of logistic regression analysis. The overall in-house mortality rate was 31%, but this varied from 65% for multiple topographic involvement, 44% for intraventricular ICH, 40% for the ICH in the brainstem, to 16% in the internal capsule-basal ganglia. These data show the heterogeneous clinical proﬁles of ICH, but they also suggest a diﬀerence in the clinical spectrum and in-hospital mortality according to the site of bleeding [33]. Hydrocephalus was also identiﬁed as a predictor of late mortality [34]. Hospital mortality rate was higher in patients with hydrocephalus (51% vs. 2%). Patients with hydrocephalus were observed to be younger, had lower GCS scores, were more likely to have ganglionic or thalamic hemorrhages, and were intubated more frequently. Ventriculostomy did not make any diﬀerence in the outcome, although postoperative 48-hour GCS score was better than the preoperative score [35].

IV. RECOVERY Recovery of patients from stroke was measured by diﬀerent outcome measures in diﬀerent studies. The Glasgow Outcome Scale was used in a Schwartz et al. trial to classify outcome of spontaneous ICH patients on discharge [36]. Outcomes included no symptoms in 9% of patients, moderate disability in 26% of patients, severe disability in 41% of patients, vegetative state in 2%, and death in 22%. Independent prognostic factors during the ﬁrst 72 hours were duration of fever, secondary hemorrhage, GCS score of V7, ventricular hemorrhage, hematoma volume of >60 cm3, duration of increased blood pressure, and duration of increased blood pressure and blood glucose of more than 48 hours. For those patients who survived the ﬁrst 72 hours, the duration of fever (high incidence in patients with ventricular hemorrhage) is associated with poor outcome. However, in the study of Lampl et al., intraventricular blood expansion was found to be associated with a better prognosis in thalamic bleeding and poorer prognosis in lobar hemorrhage [37]. The functional outcome

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after 6 months was directly correlated with size of bleeding area in lobar and putaminal hemorrhages, but no correlation was found in thalamic bleeding. A better prognosis for good recovery was found in patients with lobar hematoma in the temporal lobe. In another study, the Rankin scale was used to evaluate functional condition of ICH patients and showed that younger patients with lower levels of blood glucose on admission and smaller hematomas on CT achieved better functional status on hospital discharge [38]. Thirty-six percent of patients who survived were independent, 50.6% were partially dependent, and 13.4% were totally dependent. Older patients (>85 years) had poorer outcome, i.e., higher in-hospital mortality and moderate or severe neurological deﬁcit [39]. In other studies [40,41]. Functional Independence Measure (FIM) was used to assess the functional status of stroke patients and showed that, on admission, patients with ICH had greater functional impairment compared to patients with infarctions but had a signiﬁcantly greater recovery. Initial severity of disability, age, and duration of therapy were the best predictors of functional outcome after rehabilitation. As of now, there is no clear indication for surgical evacuation of ICH in majority of the patients. Surgical evacuation appears to have a positive eﬀect on clinical outcome in only a small number of the patients. Removal of clot in current practice might include patients with superﬁcial hemorrhage, clot volume 20–80 mL, worsening of neurological status, relatively young patients [42], hemorrhage causing midline shift/raised ICP, and cerebellar hematomas > 3 cm or causing hydrocephalus. Maira et al. showed that cases with poor natural outcome (stuporous and comatose patients) beneﬁted from surgical evacuation of clot [43]. Patients who had signs of a high probability of severe intracranial hypertension with an ICH ranging from 24 to 75 mL were submitted to surgery. A decompressive craniectomy with dural enlargement was performed afterward in patients expected to progress in brain swelling. Results showed that at one year postsurgery, there was a 40% complete recovery and 38% improvement. This has proven the usefulness of surgical evacuation in a group of severely compromised patients by minimizing the life-threatening progression of intracranial hypertension. A validated quality-of-life instrument (54-item HSQuale) was developed and tested at one year in hemorrhagic stroke survivors. Comparisons were made between HSQuale and other commonly used outcome measures (Barthel Index and Short Form-36) and shows that HSQuale assesses a broader range of deﬁcits and is better able to discriminate among subgroups of hemorrhagic stroke survivors (intracerebral vs. subarachnoid hemorrhage) [44].

V. RECURRENCE Recurrence PICH is not uncommon. Survivors of PICH are at risk for both recurrent hemorrhage and ischemic cerebrovascular disease [45]. Studies show that survivors had a high risk for second hemorrhage within 2 years of the ﬁrst hemorrhage (34% within 1 year and 32.1% within 1–2 years). The site of the second hemorrhage was diﬀerent from the initial site in all patients. The common topographic pattern of bleeding was ganglionic (putamen/ caudate nucleus) to ganglionic (21.4%), which is likely the result of hypertension and was associated with poor prognosis. Patients with initial lobar hemorrhage have a 3.8-fold increased risk of recurrent ICH. Risk factors included hypertension, diabetes, and tobacco and alcohol use. It has been shown that long-term regular control of hypertension lowers the risk of recurrent hemorrhage [46,47]. Usually there is a poor outcome after the recurrent hemorrhage with severe cognitive impairment and an overall mortality of 32% [47,48].

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Most studies on stroke have used the logistic regression model in identifying early clinical and radiographic predictors of mortality after ICH. However, a new method called artiﬁcial neural network (ANN) was reported to improve the prediction of mortality [49]. ANN was compared to the logistic regression model by analyzing data collected prospectively, showing that the ANN model correctly classiﬁed all (100%) patients as alive or dead as compared with 85% correct classiﬁcation using a logistic regression model. With the superiority of this new well-validated method over the logistic regression model, clinical management of ICH might improve.

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17. Fogelholm R, Avikainen S, Murros K. Prognostic value and determinants of ﬁrst-day mean arterial pressure in spontaneous supratentorial intracerebral hemorrhage. Stroke 1997; 28:1396– 1400. 18. Dandapani BK, Suzuki S, Kelley RE, Reyes-Iglesias Y, Duncan RC. Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995; 26:21–24. 19. Qureshi AI, Bliwise DL, Bliwise NG, Akbar MS, Uzen G, Frankel MR. Rate of 24-hour blood pressure decline and mortality after spontaneous intracerebral hemorrhage: a retrospective analysis with a random eﬀects regression model. Crit Care Med 1999; 27:480–485. 20. Terayama Y, Tanahashi N, Fukuuchi Y, Gotoh F. Prognostic value of admission blood pressure in patients with intracerebral hemorrhage. Keio Cooperative Stroke Study. Stroke 1997; 28:1185–1188. 21. Arboix A, Massons J, Garcia-Eroles L, Oliveres M, Targa C. Diabetes is an independent risk factor for in-hospital mortality from acute spontaneous intracerebral hemorrhage. Diabetes Care 2000; 23:1527–1532. 22. Bestue-Cardiel M, Martin-Martinez J, Iturriaga-Heras C, Ara-Callizo JR, Oliveros-Juste A. Leucocytes and primary intracerebral hemorrhage. Rev Neurol 1999; 29:968–971. 23. Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001; 32:891–897. 24. Cheung RT, Zou LY. Use of the original, modiﬁed, or new intracerebral hemorrhage score to predict mortality and morbidity after intracerebral hemorrhage. Stroke 2003; 34(7):1717–1722. 25. Hallevy C, Ifergane G, Kordysh E, Herishanu Y. Spontaneous supratentorial intracerebral hemorrhage. Criteria for short-term functional outcome prediction. J Neurol 2002; 249:1704– 1709. 26. Nilsson OG, Lindgren A, Brandt L, Saveland H. Prediction of death with primary intracerebral hemorrhage: a prospective study of a deﬁned population. J Neurosurg 2002; 97:531–536. 27. Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke 1997; 28(12):2370–2375. 28. Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology 1998; 51(5):1359–1363. 29. Schwartz S, Jauss M, Krieger D, Dorﬂer A, Albert F, Hacke W. Haematoma evacuation does not improve outcome in spontaneous supratentorial intracerebral hemorrhage: a case-control study. Acta Neurochir (Wien) 1997; 139:897–904. 30. Teernstra OP, Evers SM, Lodder J, Leﬀers P, Franke CL, Blaauw G. Stereotactic treatment of intracerebral hematoma by means of a plasminogen activator: a multicenter randomized controlled trial (SICHPA). Stroke 2003; 34:968–974. 31. Prasad K, Shrivastava A. Surgery for primary supratentorial intracerebral hemorrhage. Cochrane Database Syst Rev 2000 (CD000200). 32. Qui Y, Lin Y, Tian X, Luo Q. Hypertensive intracranial hematomas: endoscopic-assisted keyhole evacuation and application of patent viewing dissector. Chin Med J (Engl) 2003; 116:195–199. 33. Arboix A, Comes E, Garcia-Eroles L, et al. Site of bleeding and early outcome in primary intracerebral hemorrhage. Acta Neurol Scand 2002; 105:282–288. 34. Diringer MN, Edwards DF, Zazulia AR. Hydrocephalus: a previously unrecognized predictor of poor outcome from supratentorial intracerebral hemorrhage. Stroke 1998; 29:1352–1357. 35. Liliang PC, Liang CL, Lu CH, Chang HW, Cheng CH, Lee TC, Chen HJ. Hypertensive caudate hemorrhage prognostic, outcome, and role of external ventricular drainage. Stroke 2001; 32:1195–2001. 36. Schwartz A, Hafner K, Aschoﬀ A, Schwab S. Incidence and prognostic signiﬁcance of fever following intracerebral hemorrhage. Neurology 2000; 54:354–361. 37. Lampl Y, Gilad R, Eshel Y, Sarova-Pinhas I. Neurologicl and functioning outcome in patients with supratentorial hemorrhages. A prospective study. Stroke 1995; 26(12):2249–2253. 38. Lopez-Gonzales FJ, Aldrey JM, Pardellas H, Castillo J. Morbidity due to intracerebral hemorrhage. Rev Neurol 1998; 27(159):755–758.

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39. Gebel JM, Brott TG, Sila CA, et al. Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage. Stroke 2000; 31(3):596–600. 40. Inouye M, Kishi K, Ikeda Y, et al. Prediction of functional outcome after stroke rehabilitation. Am J Phys Med Rehab 2000; 79:513–518. 41. Kelly PJ, Furie KL, Shafqat S, Rallis N, Chang Y, Stein J. Functional recovery following rehabilitation after hemorrhagic and ischemic stroke. Arch Phys Med Rehab 2003; 84(7):968– 972. 42. Hardemark HG, Wesslen N, Persson L. Inﬂuence of clinical factors, CT ﬁndings and early management on outcome in supratentorial intracerebral hemorrhage. Cerebrovasc Dis 1999; 9:10–21. 43. Maira G, Anile C, Colosimo C, Rossi GF. Surgical treatment of primary supratentorial intracerebral hemorrhage in stuporous and comatose patients. Neurol Res 2002; 24:54–60. 44. Hamedani AG, Wells CK, Brass LM, et al. A quality of life instrument for young hemorrhagic stroke patients. Stroke 2001; 32:687–695. 45. Hill MD, Silver FL, Austin PC, Tu JV. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke 2000; 31(1):123–127. 46. Bae H, Jeong D, Doh J, Lee K, Yun I, Byun B. Recurrence of bleeding in patients with hypertensive intracerebral hemorrhage. Cerebrovasc Dis 1999; 9(2):102–108. 47. Gonzalez-Duarte A, Canti C, Ruiz-Sandoval JL, Barinagarrementeria F. Recurrent primary cerebral hemorrhage: frequency, mechanisms, and prognosis. Stroke 1998; 29:1802–1805. 48. Neau JP, Ingrand P, Couderg C, Rosier MP, Bailbe M, Dumas P, Vandermarcq P, Gil R. Recurrent intracerebral hemorrhage. Neurology 1998; 51(3):924–925. 49. Edwards DF, Hollingsworth H, Zazulla AR, Diringer MN. Artiﬁcial neural networks improve the prediction of mortality in intracerebral hemorrhage. Neurology 1999; 53:351–357.

5 Brain Imaging in Stroke Chelsea S. Kidwell, Jeffrey Saver, and Bruce Ovbiagele UCLA Medical Center, Los Angeles, California, U.S.A.

Steven Warach National Institutes of Health, Bethesda, Maryland, U.S.A.

I. INTRODUCTION Technological advances in recent years have revolutionized the ﬁeld of neuroimaging of cerebrovascular disease. As therapeutic options for treatment of acute stroke and for secondary stroke prevention evolve, neuroimaging strategies are assuming an increasingly important role in patient evaluation and management. Both acute and long-term treatment decisions for stroke patients should optimally incorporate information provided by neuroimaging studies regarding tissue injury (size, location, vascular distribution, and degree of reversibility of ischemic injury as well as presence of hemorrhage), vessel status (site and severity of stenoses and occlusions), and cerebral perfusion (size, location, and severity of hypoperfusion) (Fig. 1; Table 1). The ultimate clinical utility of an imaging technique is inﬂuenced by a variety of factors including availability, duration and ease of data acquisition, expense, and risks to the patient (radiation exposure, invasiveness). The ideal neuroimaging modality for stroke should be widely available, inexpensive, and provide rapid, noninvasive multimodal information. In the realm of acute stroke, the ability to map the evolving ischemic penumbra should allow treatment decisions to be based on individual patient pathophysiology and hemodynamics. While no single method currently fulﬁlls all these goals, the combination of advanced imaging techniques, particularly in the realm of computed tomography (CT) and magnetic resonance imaging (MRI), shows enormous promise in providing clinicians with critical information to guide treatment decisions.

II. TISSUE STATUS A. Ischemia 1. Computed Tomography Noncontrast head CT is employed as the initial brain imaging study in more patients with suspected acute ischemic stroke. CT is used as a screening tool to exclude hemorrhage and other nonischemic causes of acute neurological deﬁcits (tumor, infection) and has the 81

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Figure 1 Approach to neuroimaging of cerebrovascular disease. A comprehensive evaluation should provide information regarding (1) tissue status (size, location and severity of ischemic or hemorrhagic injury), (2) hemodynamic status (size, location and severity of hypoperfusion), and (3) vessel status (site and severity of vessel stenoses or presence of occlusions).

advantages of being rapid and relatively inexpensive with widespread availability. While CT is the gold standard to which other brain imaging studies are compared, it is relatively insensitive in detecting acute and small cortical or subcortical infarctions, especially in the posterior fossa. In most cases the use of a contrast infusion does not provide additional information and is not necessary unless it is required for CT angiography (and more recently CT perfusion) or there is a concern about a brain tumor or infectious process. With the advent of rt-PA treatment, interest has grown in using CT to identify subtle, early signs of ischemic brain injury (early infarct signs) or arterial occlusion that might aﬀect decisions about treatment. These ﬁndings include the hyperdense middle cerebral artery sign that is indicative of a thrombus or embolus in the ﬁrst portion of the middle cerebral artery, loss of the gray-white diﬀerentiation in the cortical ribbon (particularly at the lateral margins of the insula) or the lentiform nucleus, and sulcal eﬀacement (Figs. 2, 3) [1]. These signs may be detected within 6 hours of onset of symptoms in up to 82% of patients with ischemia in the territory of the middle cerebral artery [2]. The presence of widespread signs of early infarction has been correlated with a higher risk of hemorrhagic transformation following treatment with thrombolytic agents. In the National Institutes of Neurologic Disorders and Stroke (NINDS) trials of intravenous rtPA administered within 3 hours of symptom onset, CT evidence of early edema or mass eﬀect was accompanied by an eightfold increase in the risk of symptomatic hemorrhage [3]. A second report from this same trial analyzed outcome in patients with evidence of both mild and major early infarction including loss of gray–white matter distinction, hypodensity or hypoattenuation, and sulcal eﬀacement or compression of cerebrospinal ﬂuid (CSF) spaces (focal and/or diﬀuse brain swelling) [4]. In this second analysis, early infarct signs involving more than one third of the territory of the middle cerebral artery were not independently associated with increased risk of adverse outcome after rt-PA treatment, and as a group these patients still beneﬁted from therapy. In a European trial in which thrombolytic therapy was administered within 6 hours of symptom onset, patients estimated to have involvement of more than one third of the territory of the middle cerebral artery had

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Table 1 Advantages and Disadvantages of Various Techniques for Acute Stroke Evaluation

Tissue state MR with DWI and GRE

Advantages

Disadvantages

Highly sensitive to early ischemia

Patient contraindications (claustrophobia, metal implants) Availability Sensitivity to hemorrhage (GRE) not fully validated Sensitive to artifacts Optimally requires EPI capability

Brief acquisition time High conspicuity of lesion

Rapid Widely available Highly sensitive to hemorrhage

Limited sensitivity to size, location of early ischemia

Noninvasive Rapid acquisition of data from both intra- and extracranial circulations

Overestimates stenoses Sensitive to motion and other technical artifacts

CTA

Noninvasive

Relatively long data acquisition time Potential toxicity of or allergy to contrast agent Limited scan slab with single detector systems Requires helical capability

DSA

Standard for imaging vasculature Collateral ﬂow information and ﬂow data

Invasive (0.5–2% risk) Relatively contraindicated with systemic tPA Time consuming

Ultrasounda

Flow data Noninvasive Portable Repeatable, serial studies Low cost

Highly user dependent Time consuming Technical constraints (e.g., absent bone windows for TCD)

Rapid Good spatial resolution

Relative, not quantitative data Patient contraindications to MR Possible allergic contrast reaction

Rapid

Potential toxicity of or allergy to contrast agent Radiation exposure Relative, not quantitative data Only 2–4 slice data currently Requires helical capability

CT

Cerebral vasculature MRA

Tissue perfusion Perfusion MR

Perfusion CT

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Table 1 Continued Advantages

Disadvantages

Xenon CT

Quantitative CBF data

Behavioral side eﬀects from xenon Time consuming Sensitive to motion artifacts Radiation exposure Limited spatial resolution

PET

Gold standard for CBF measures

Logistically demanding/impractical in acute setting Arterial sampling relatively contraindicated with systemic thrombolysis High cost Limited availability

Provides measures of oxygen extraction fraction and metabolism

SPECT

May inject tracer in Emergency Department

Relative, not quantitative data Limited availability

a

Carotid Doppler and TCD.

an increased risk of intracerebral hemorrhage, whereas those with less involvement beneﬁted the most from thrombolytic treatment [5]. However, physicians’ ability to reliably and reproducibly recognize early CT changes is uncertain. The accuracy in detecting ischemic areas involving more than one third of the territory of the middle cerebral artery is approximately 70–80% [6]. Use of scoring systems for early CT changes may improve identiﬁcation of cerebral ischemia and might provide valuable prognostic information, but are not validated for outcome [7].

Figure 2 Early infarct signs demonstrated on CT: image on the left shows a hyperdense right middle cerebral (MCA) artery sign; image on the right shows a corresponding region of frank hypodensity in the MCA territory.

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Figure 3 Early infarct signs demonstrated on CT in a patient presenting at 11⁄2 hours after onset of right hemiparesis and aphasia: image on the left shows loss of gray–white diﬀerentiation (insular ribbon sign) (arrowheads), while image on the right shows early edema with sulcal eﬀacement (long arrows).

Based on a synthesis of data available to date, current AHA guidelines for the treatment of acute stroke recommend the following [8]: A physician skilled in assessing CT studies should be available to interpret the scan (Grade B). The study should be formally evaluated for evidence of early signs of infarction. The presence of early infarct signs on CT (even if they involve greater than 1/3 of the middle cerebral artery territory) in patients with a well established stroke onset time < 3 hours does not preclude treatment with IV rt-PA or suggest an unfavorable response to therapy (Grade 1). There are insuﬃcient data to make a strong recommendation regarding the use of IV rt-PA treatment in the rare patient whose CT reveals extensive (greater than 1/3 of the middle cerebral artery territory) and clearly identiﬁable hypodensity in patients with a well-established stroke onset time < 3 hours. While diﬀerences of opinion exist, some experts would recommend that thrombolytic therapy not be administered in these patients because they suspect that the risk/beneﬁt ratio is unlikely to be favorable. For patients beyond 3 hours of symptom onset, intravenous tissue plasminogen activator is not of proven beneﬁt and is best contemplated only in the setting of a clinical trial, regardless of CT ﬁndings. For patients who are candidates for treatment with rt-PA, the goal is to complete the CT examination within 25 minutes of arrival to the emergency department with the study interpreted within an additional 20 minutes (door to interpretation time of 45 minutes). A subsequent CT often is obtained if the patient worsens neurologically and may be especially helpful in identifying hemorrhagic transformation following administration of rt-PA.

In the subacute phase, ischemic infarcts evolve into frank hypodense regions. At 2–3 weeks the hypodensity may disappear, a phenomenon sometimes termed the fogging eﬀect, and the infarct may be indistinguishable from normal brain. This phenomenon is thought to be due to capillary proliferation and macrophage invasion within the infarct. In the chronic phase, the infarct becomes necrotic and cystic, again appearing as a hypodense region. 2. Magnetic Resonance Imaging a. Conventional MRI. Within the ﬁrst few hours of ischemia onset, standard MRI sequences [9] and ﬂuid-attenuated inversion recovery (FLAIR) are relatively insensitive to

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ischemia, showing abnormalities in under 50% of cases [10]. The earliest changes, seen as increased signal on T2-weighted and FLAIR sequences, are due to a net increase in overall tissue water content primarily due to vasogenic edema—a process that takes several hours to develop to levels detectable by MRI. Although the majority of ischemic lesions are evident on both CT and conventional MRI by 24 hours, standard MRI is superior to CT in identifying posterior fossa, subcortical, and small cortical lesions. b. Diﬀusion-Weighted Imaging. Diﬀusion-weighted imaging (DWI) allows visualization of regions of ischemia within minutes of ischemia onset [9]. When strong diﬀusion-weighted sensitizing gradients are applied during a standard spin-echo sequence, the random movement of water protons within a tissue can be detected. During ischemia, there is decreased free water diﬀusion in brain tissue related to the ﬂux of water from the extracellular to intracellular space leading to early cytotoxic edema. This impaired water motion causes an increased (bright) signal on DWI sequences (Fig. 4). The decrease in diﬀusion can be quantitatively measured on the apparent diﬀusion coeﬃcient (ADC) maps, with darker areas representing decreased diﬀusion (Fig. 4). The increase in signal on DWI may persist for several weeks or longer partially due to a T2 eﬀect. The ADC, however, returns to normal or supranormal levels within 7–10 days from ischemia onset [11]. Diﬀusion imaging has a high degree of sensitivity (88–100%) and speciﬁcity (95– 100%) for acute ischemia, even at very early time points. Studies performed in the acute stroke setting have consistently demonstrated marked superiority in accuracy of diagnosis of ischemic change for DWI (95–100%) compared to CT (42–75%) or standard MRI sequences such as FLAIR (46%). A study comparing DWI lesions to pathologically conﬁrmed infarction at autopsy also demonstrated on overall accuracy of 95%. Occasionally, DWI hyperintensities may be seen in a number of other cerebral disorders including status epilepticus, tumors, and Jakob-Creutzfeld disease. Information on the natural history of diﬀusion imaging lesion growth comes from several clinical trials and case series. Ischemic lesions follow a relatively consistent pattern of growth during the ﬁrst 3 days, followed by subsequent decrease in size to days 5–7. Numerous studies have shown that initial diﬀusion lesion volume correlates well with both ﬁnal infarct volume as well as neurological and functional outcomes in stroke patients, suggesting that

Figure 4 Example of hyperacute stroke visualized on diﬀusion MR obtained at 21⁄2 hours after symptom onset. The region of ischemia appears as increased signal in the left frontal lobe on diﬀusionweighted imaging (left) and decreased signal in the same region on the ADC map (middle) with normal T2-weighted image (right).

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diﬀusion MR can provide important early prognostic information. While these correlations have been repeatedly demonstrated in anterior circulation ischemia, several small case series have suggested that acute DWI lesion volumes correlate poorly with clinical measures in the posterior circulation since small strategic brainstem infarcts can lead to devastating clinical syndromes while large cerebellar infarcts may cause minimal symptomatology. An increasing number of studies have provided data demonstrating the clinical utility of diﬀusion MR in current practice (Figs. 5, 6). Diﬀusion imaging allows early identiﬁcation of lesion size, neuroanatomical site, and vascular territory involved. A distinctive advantage of DWI is its ability to distinguish acute from chronic ischemia, allowing new lesions to be identiﬁed in patients even when these are near or within areas of prior ischemic injury. Another important insight into stroke pathophysiology oﬀered by diﬀusion MR is the frequent visualization of multiple acute lesions in diﬀerent vascular territories in patients who have only one clinically symptomatic acute insult, providing evidence of an embolic stroke mechanism. Diﬀusion imaging has also provided important insights into the pathophysiology of transient ischemic attacks. Aggregate data from a number of observational studies reported in abstract or manuscript format have clearly demonstrated that almost one half of patients with clinical TIA syndromes have a DWI abnormality (Fig. 7) [12–14]. Although the majority of these studies suggest that the likelihood of DWI positivity increases with increasing symptom duration, this relationship is not absolute. While these lesions may resolve in some cases, the majority of patients have imaging evidence of permanent ischemic injury. B. Hemorrhage 1. Computed Tomography Routine noncontrast head CT has been considered the gold standard for evaluation of early intracranial hemorrhage. Acute blood appears as a hyperdense region and may be visualized in the brain parenchyma, ventricles, subarachnoid space, subdural space, and epidural space, with characteristic patterns for each. Each type of hemorrhage has a characteristic appearance (Fig. 8). It is important to note that the initial CT scan may be normal in

Figure 5 Three examples illustrating the clinical utility of diﬀusion imaging compared to noncontrast CT in characterizing ischemic lesions and underlying stroke mechanism. Images on the far left show dense right MCA ischemic lesion on DWI, while CT shows only subtle early infarct signs. Middle image clearly demonstrates left thalamic lacunar stroke on DWI, which is not well visualized on CT. Images on far right demonstrate multiple scattered ischemic lesions on DWI suggestive of proximal embolic source, while CT is normal.

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Figure 6 Watershed infarct in the MCA-ACA territory demonstrated on DWI with right internal carotid artery occlusion demonstrated on intracranial MRA.

approximately 10% of patients with subarachnoid hemorrhage. A normal CT is most likely defeated among patients with mild hemorrhages—in these cases, a lumbar puncture is required to make the diagnosis. Intraparenchymal hemorrhages occurring in subcortical regions, particularly the putamen, are most commonly due to hypertension, while lobar hemorrhages in the elderly are frequently related to amyloid angiopathy. A rim of hypodensity indicative of perihematomal edema is often visualized surrounding the hematoma. Approximately one third of hematomas will expand over time from the baseline to follow-up imaging studies—this growth has been associated with neurological deterioration [15]. Attenuation of the density changes seen on CT generally occurs gradually over 2–4 weeks. In the chronic stage, intraparenchymal hemorrhages appear as a slit-like cavity. Hemorrhagic transformation of an ischemic infarction is a common occurrence, visualized in up to 42% or more of patients in pathological series. Numerous studies have demonstrated that hemorrhagic transformation is much more frequent in cardioembolic strokes with estimates ranging from 30% to 74% in CT studies. Generally, a distinction is made between parenchymatous hematomas, which are frequently symptomatic, and petechial HT, which is generally asymptomatic.

Figure 7 Example of a DWI-positive scan (left image) in a patient with a clinical TIA syndrome. No abnormality was visualized on the corresponding FLAIR image (right).

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Figure 8 Examples of various types of intracranial hemorrhages visualized with CT: top left— primary intracerebral hemorrhage in the right putamen secondary to hypertension; top middle—right frontal lobar hemorrhage in a patient diagnosed with amyloid angiopathy; top right—subarachnoid hemorrhage due to ruptured aneurysm; bottom left—left subdural hematoma; bottom right—left epidural hematoma.

2. Magnetic Resonance Imaging While conventional T1- and T2-weighted MRI sequences are highly sensitive for the detection of subacute and chronic blood, they are less sensitive to parenchymal hemorrhage under 6 hours. Recent studies have demonstrated that hyperacute parenchymal blood can be accurately detected using gradient echo (GRE/T2*) sequences or EPI susceptibilityweighted imaging (SWI). These sequences detect the paramagnetic eﬀects of deoxyhemoglobin and methemoglobin, leading to a loss of signal in regions of both acute and chronic blood. Hyperacute hemorrhage has a characteristic appearance on gradient echo sequences. Typically, the tissue rim outside the hematoma appears hyperintense, the hematoma periphery hypointense, and the hematoma core either isointense or having regions of mixed signal (Table 2; Fig. 9).

Table 2 Appearance of Hemorrhage at Various Times as Visualized on Diﬀerent MRI Sequences Time 0–6 h

Blood breakdown product

GRE and SWI

T1-W

T2-W

Rim: deoxyhemoglobin

Rim: hypointense,

Hypo- or isointense

Iso- or hyperintense

Core: oxyhemoglobin

Hypo- or isointense

Hyperintense

Hypo- or isointense Hyperintense

Hypointense Hyper- or hypointense Hypointense

6–24 h

Rim: deoxyhemoglobin Core: oxyhemoglobin

24–72 h 3–7 days

Deoxyhemoglobin Methemoglobin

Core: iso- or mixed signal intensity Rim hypointense, Core isointense or mixed signal Hypointense Hypointense

>7 days

Hemosiderin and ferritin

Hypointense

Hypo- or isointense

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Figure 9 Hyperacute hemorrhage demonstrated on CT (left) gradient echo MRI (middle) and echoplanar susceptibility-weighted MRI (right). MRI was obtained at 11⁄2 hours after symptom onset.

Preliminary reports from two prospective studies have recently been reported demonstrating that MRI is as accurate as CT in detecting hyperacute intraparenchymal hemorrhage in patients presenting with stroke symptoms within 6 hours of onset [16,17]. These ﬁndings may allow MRI to be employed as the sole imaging modality to evaluate acute stroke patients, including candidates for thrombolytic treatment. However, in patients presenting with symptoms suggestive of subarachnoid hemorrhage, a CT should always be performed. The MR appearance of hemorrhagic transformation of an ischemic infarct is similar to that seen with primary intracerebral hemorrhage. Frequently, gradient echo sequences may demonstrate regions of petechial hemorrhage not visualized with CT or standard MR sequences. In addition, gradient echo sequences have the ability to detect clinically silent prior microbleeds not visualized on CT (Fig. 10). MRI evidence of microbleeds is seen in 38–66% of patients with primary intracerebral hemorrhages, in 21–26% of patients with ischemic stroke, and in 5–6% of asymptomatic or healthy elderly individuals [18]. A histopathological analysis of small regions of signal loss visualized on GRE MRI sequences conﬁrmed

Figure 10 Example of multiple microbleeds visualized on gradient echo imaging.

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that these regions indicate previous extravasation of blood and are related to bleeding prone microangiopathy, usually due to hypertension, prior ischemic injury, or amyloid angiopathy [19]. Recent data suggest that microbleeds visualized on gradient echo MR sequences represent markers of bleeding-prone angiopathy and increased risk of hemorrhagic transformation following antithrombotic and thrombolytic therapy. However, the role of microbleeds in thrombolytic decision making remains uncertain.

III. PERFUSION STATUS Cerebral ischemia occurs when disruption in cerebral blood ﬂow deprives tissue of the nutrients required for normal cell function and homeostasis. Within minutes of an ischemic insult, a core region of tissue experiences profound blood ﬂow reduction and becomes irreversibly injured even if blood ﬂow is rapidly restored. However, surrounding this core is a zone of moderate blood ﬂow reduction and ischemic tissue that may still be rescued for several hours or more from symptom onset. Changes in cerebral blood ﬂow result in a continuum of metabolic and ionic disturbances that occur in a predictable order. Regional cerebral blood ﬂow (rCBF) below 12 mL/100 g/min results in tissue necrosis, while only transient deﬁcits occur when rCBF remains above 22 mL/100 g/min [20]. Tissue with rCBF between 12 and 22 mL/100 g/min represents the ischemic penumbra, an area of stunned parenchyma surrounding the ischemic core, which has the potential for recovery, but only if reperfusion is rapidly established. A number of imaging modalities are available to assess the hemodynamic status of the brain. Most of these techniques yield a variety of perfusion measures including cerebral blood ﬂow, cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) measures. While positron emission tomography remains the gold standard for measuring cerebral blood ﬂow, it is impractical in the acute stroke setting. Meanwhile, recent advances in technology are leading to a growing interest in employing perfusion MR and perfusion CT to assist in clinical decision making. In the acute stroke setting, blood ﬂow studies can be performed to determine the site and severity of hemodynamic impairment. These techniques may be used alone or in combination with other sequences to identify ischemic penumbral tissue (this aspect of perfusion imaging will be addressed in more detail in the section on multimodal imaging below). In the subacute or chronic setting, blood ﬂow studies can be used to identify regions of chronic hypoperfusion due to vessel stenoses or occlusions. The studies often are performed with and without an acetazolamide challenge to determine cerebrovascular reserve. In general, blood ﬂow measures should increase in response to acetazolamide, which behaves as a vasodilator. If no increase in blood ﬂow occurs (or if blood ﬂow decreases) following the injection, this suggests that vessels are already maximally dilated and there is no vascular reserve (ability to increase ﬂow in response to a stress). A. Xenon-Enhanced CT Xenon-enhanced CT (XeCT) provides an absolute quantitative measurement of cerebral blood ﬂow. As the patient inhales a 33% mixture of inert xenon gas, a steady state of xenon is achieved in the brain parenchyma. The density changes within the brain parenchyma following xenon gas inhalation can be equated to cerebral blood ﬂow. Several studies suggest that thresholds of reversible and irreversible ischemia in acute stroke patients may be identiﬁed using xenon CT [21,22]. One study reported that a CBF of

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V6 cm3/100 g1/min1 correlated with regions of irreversible infarction in patients with acute middle cerebral artery stroke [22]. This same group also found that patients with neurological deﬁcits but CBF in the mildly reduced or normal range were likely to have subsequent resolution of their symptoms, suggesting that xenon CT could be used to triage acutely symptomatic patients between conservative and thrombolytic therapeutic regimens [23]. Xenon CT is currently limited by a low total number of scan levels, poor signal-to-noise ratio, sensitivity to patient motion, the requirement for rigorous protocol adherence, and xenon gas availability and regulatory approval for stroke assessment. B. Perfusion CT Perfusion CT is an emerging method to assess cerebral perfusion. The technique uses helical CT scanning to track the ﬁrst pass of a bolus of contrast material delivered intravenously. Two types of perfusion techniques are currently available. Whole brain perfusion CT provides a map of brain perfusion analogous to cerebral blood ﬂow. While this technique has the advantage of providing whole brain coverage, it is limited by its inability to provide measures of cerebral blood ﬂow or mean transit time. Alternatively, the second technique, dynamic perfusion CT, has the potential to provide absolute measures of CBF, MTT, and CBV but is currently limited to two to four brain slices, providing incomplete visualization of all pertinent vascular territories. Although the ability of perfusion CT to provide absolute blood ﬂow measures is promising, limitations regarding the validity of perfusion values remain. Recent reports demonstrate a high degree of sensitivity and speciﬁcity for detecting cerebral ischemia with these techniques. As with perfusion MR and xenon CT, several studies demonstrate that perfusion CT may be able to diﬀerentiate thresholds of reversible and irreversible ischemia (see section on multimodal imaging below) [24,25]. C. Perfusion-Weighted Magnetic Resonance Imaging Perfusion-weighted imaging (PWI) is most commonly performed by the rapid injection of an intravenous paramagnetic contrast agent. The temporal passage of the contrast agent through contiguous slices of brain tissue is tracked with a sequence of rapid MR scans. This signal intensity information is then used to derive a tissue concentration time curve. Image post-processing employing deconvolution of an arterial input function may provide a means to calculate absolute, rather than relative perfusion measures, but validation studies are also needed. Controversy persists regarding the best perfusion measure and the ability to obtain reliable quantitative perfusion measures in the acute stroke setting. Arterial spin tag labeling techniques also oﬀer promise as a means to quantify cerebral perfusion without the need for injection of a contrast agent. However, these techniques are limited by prolonged acquisition times, sensitivity to degradation by head movement, and insensitivity to slow ﬂow or collateral ﬂow. In the future, technical advances may overcome these diﬃculties [26,27]. Numerous studies demonstrate that baseline MR perfusion lesion volumes correlate well with ﬁnal infarct volume as well as neurological and functional outcome, and in fact correlate somewhat better than the baseline diﬀusion lesion volumes [28]. The stronger association might be explained by the fact that the perfusion lesion volume identiﬁes all tissue at risk of infarction if vessel recanalization does not occur. The ability of MR to delineate the ischemic penumbra is discussed further in the section on multimodal imaging below.

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D. Positron Emission Tomography Oxygen-15 positron emission tomography (PET) is the gold standard for quantifying cerebral perfusion and oxygen consumption. PET studies provided the ﬁrst documentation of an ischemic penumbra in humans by identifying regions of decreased cerebral blood ﬂow and increased oxygen extraction fraction (OEF) with relatively preserved oxygen metabolism (misery perfusion) [29,30]. Various studies have demonstrated that this state can be detected up to 16–48 hours after symptom onset in some humans [31]. Serial 15O-H2O PET studies have been performed without arterial sampling to measure rCBF in patients undergoing intravenous thrombolysis [32]. The volume of severe hypoperfusion predicted the development of subsequent infarction and long-term clinical outcome. A signiﬁcant correlation was also found between clinical course and extent of reperfusion. Other minimally invasive methods to identify the ischemic penumbra with PET have been described that employ radioligands to molecules, such as ﬂumazenil and ﬂuoromisonidazole, that are preferentially trapped in penumbral ﬁelds [33,34]. While PET remains impractical as an imaging modality in the acute stroke setting, it may play an important role in identifying patients with carotid occlusion who may beneﬁt from bypass therapy. Previous studies have demonstrated that increased cerebral OEF detected by PET scanning predicted stroke in patients with symptomatic carotid occlusion [35]. The role of PET in selecting patients for surgery in this setting is currently being evaluated in a phase III clinical trial. E. Single Photon Emission Computed Tomography Single photon emission CT (SPECT) provides a noninvasive evaluation of relative CBF by measuring the concentration of a radioactive tracer trapped within the brain parenchyma. Several studies show that SPECT may be able to identify thresholds for reversible ischemia and may be useful in predicting clinical outcome and monitoring response to therapy. One group reported that tissue with rCBF > 55% of cerebellar ﬂow may still be salvageable up to 12 hours from symptom onset, while tissue with rCBF< 35% of cerebellar ﬂow may be at risk for hemorrhagic transformation [36]. Another group reported that 99mtechnetiumethyl-cysteinae-dimer SPECT performed within 6 hours of symptom onset is highly accurate at predicting fatal ischemic brain edema and at diﬀerentiating transient ischemic symptoms from stroke [37,38]. Although SPECT is less invasive than 15O-PET, its practicality in the acute stroke setting is restricted. Additional limitations include availability, expense, tracer preparation, and the fact that SPECT provides relative, not absolute, measures of blood ﬂow.

IV. VESSEL STATUS A wide variety of imaging techniques are now available to assess the status of large and medium-caliber cervicocephalic vessels. Choice of imaging modality in a particular clinical setting depends on availability, individual patient characteristics, and type of information sought. It is widely recognized that performance of at least one of these techniques is mandatory in the standard evaluation of anterior circulation ischemia to assess for cervical carotid artery stenosis, since the presence of moderate to severe symptomatic carotid stenosis warrants evaluation for carotid endarterectomy [39,40].

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A. CT Angiography Helical CT angiography is performed by rapid administration of an intravenous contrast agent followed by data acquisition over the time of passage of the bolus within large vessels of the target vascular system. The method relies on continuous scanning as the patient is moved through the x-ray beam, allowing for volumetric rather than conventional tomographic data acquisition. In addition to acquisition of axial cuts, image postprocessing permits the data to be visualized using multiplanar reformatting, surface or 3D volume rendering, and maximum intensity projection (MIP) techniques. CTA provides a means to rapidly and noninvasively evaluate the neurovasculature in the acute, subacute, and chronic stroke setting, providing potentially important information about the presence of vessel occlusions or stenoses. CTA is used increasingly in the evaluation of the extracranial carotid and vertebral arteries with accuracy rates comparable to ultrasound for carotid bifurcation disease. The feasibility of this technique has also been demonstrated in the acute setting with preliminary data, suggesting high diagnostic accuracy for evaluation of large vessel intracranial occlusions compared with ultrasound and digital subtraction angiography [41,42]. Disadvantages of CTA include the requirement for intravenous contrast dosing and use of ionizing radiation. B. Magnetic Resonance Angiography In recent years magnetic resonance angiography (MRA) has become an increasingly useful tool for noninvasive screening of the cervical and intracranial circulation. When compared to digital subtraction angiography for detection of cervical and intracranial stenoses, sensitivity and speciﬁcity have ranged from 70% to 100% in various studies [43–46]. A recent systematic review comparing MRA to digital subtraction angiography (DSA) for evaluation of carotid stenosis concluded that for the diagnosis of 70–99% stenosis, MRA had a pooled sensitivity of 95% and a pooled speciﬁcity of 90% [47]. In the intracranial vasculature, time-of-ﬂight MRA is useful in identifying acute proximal large vessel occlusions, but is not reliably able to identify distal or branch occlusions. MRA is susceptible to a number of ﬂow artifacts including in-plane ﬂow saturation, susceptibility to turbulent or complex ﬂow, and ﬂow-like eﬀects from adjacent short T1 substances, such as thrombus and fat. A main disadvantage of MRA is therefore the tendency to overestimate the degree of stenosis, making the technique inadequate in the identiﬁcation of near occlusions. Power-injector, contrast-enhanced techniques and higher strength magnets may mitigate some of the limitations of standard MRA. Contrastenhanced MRA of the extracranial vessels is now a common practice at many institutions. However, contrast-enhanced MRA of the intracranial vessels presents technical challenges, limiting its current adoption in standard clinical practice. C. Ultrasound Carotid and transcranial Doppler techniques are noninvasive approaches to assessing the vasculature. Ultrasound is particularly appealing due to its bedside availability, noninvasive nature, low cost, good diagnostic performance compared to catheter angiography, and options for serial monitoring. Ultrasound is limited by operator dependency, reliance on inferred rather than direct measurements of stenosis, diﬃculty distinguishing occlusions from near occlusions, and poor or absent transtemporal windows (TCD) in some patients. The use of contrast-enhanced techniques may overcome some of these limitations in the future [48].

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1. Carotid Doppler Ultrasound Ultrasound study of carotid bifurcation is a well-established noninvasive test for the evaluation of proximal carotid artery disease. A full carotid ultrasonography battery includes continuous wave Doppler measurement of blood velocity, B-mode imaging of vessel anatomy, and color-ﬂow imaging of ﬂow direction and lumen caliber. The Doppler spectral wave forms allow hemodynamic quantiﬁcation of pathological ﬁndings. Compared to catheter angiography, color-coded Doppler ultrasound techniques have demonstrated sensitivity of 91–95% and speciﬁcity of 86–97% for the detection and quantiﬁcation of proximal carotid artery abnormalities. Carotid ultrasound is limited in its ability to detect abnormalities near the aortic arch and distal portions of the carotid artery and does not reliably diﬀerentiate a high-grade stenosis from an occlusion. Many centers rely on carotid duplex scanning alone in decision making for endarterectomy. Carotid duplex is generally the imaging modality of choice for serial monitoring following endarterectomy and angioplasty to identify vessel restenosis. 2. Transcranial Doppler Transcranial Doppler (TCD) ultrasound employs a low-frequency probe to penetrate the skull and interrogate the major basal intracranial arteries [49]. TCD has been compared to a sophisticated stethoscope that allows the clinician to ‘‘listen’’ to hemodynamic derangements of the cerebral circulation. Contrast-enhanced and color-coded TCD techniques are increasingly being employed to overcome limitations of conventional TCD including poor sound penetration through the temporal bone, unfavorable insonation angles, or low-ﬂow velocity or volume. Table 3 lists the current clinical applications for TCD in the evaluation of cerebrovascular disease. In the routine evaluation of stroke and TIA, TCD oﬀers a means to identify intracranial stenoses and occlusions, proximal right-to-left shunts (cardiac or pulmonary), and provides a means to assess vascular reserve with CO2-monitoring techniques. TCD has the unique ability to detect asymptomatic microembolic signals (MES). Information obtained from TCD microemboli testing can be used to (1) assist in diagnosing stroke mechanism or etiology, (2) adjust antithrombotic regimen, (3) optimize surgical or interventional procedures, and (4) assist in surgical decision making about carotid endarterectomy. D. Digital Subtraction Angiography DSA remains the gold standard imaging modality to assess vessel anatomy and pathology while providing important collateral ﬂow information. In DSA the ﬂow of contrast agent is ﬁlmed with a frequency of one to six images per second and results in images of the vascular

Table 3 Applications of Transcranial Doppler in Cerebrovascular Disease Identiﬁcation and serial monitoring of intracranial large vessel occlusions and stenoses Serial monitoring of patients with subarachnoid hemorrhage for detection of vasospasm Embolus detection (from proximal large vessel disease, cardioembolic sources, during surgical or interventional procedures) Identiﬁcation of proximal right-to-left shunts Serial monitoring of patients with sickle cell anemia Evaluation of cerebral vasomotor reactivity and hemodynamic reserve

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tree alone when the skull and soft tissues are subtracted. Angiography continues to play a valuable role in the diagnosis of vascular conditions including moyamoya disease, vasculitis, veno-occlusive disease, subclavian steal syndrome, and suspected aneuryms or arteriovenous malformations. Advantages include better visualization of medium and small vessels than with noninvasive techniques and the ability to proceed directly to an endovascular intervention after diagnostic imaging. Disadvantages include periprocedural risks of stroke, exposure to iodinated contrast with nephrotoxicity and potential for allergic response, and lack of round-the-clock availability outside of large medical centers. While the 1% permanent neurological complication risk makes other noninvasive vessel imaging techniques such as CTA and MRA very attractive, particularly as advances in technology lead to improved resolution, it is likely that catheter angiography will continue to play an important role in evaluation of select cases, particularly in light of the rapid advances in the ﬁeld of endovascular interventions for stroke including mechanical embolectomy, intra-arterial thrombolysis, and angioplasty/stenting.

V. MULTIMODAL IMAGING AND ACUTE STROKE THERAPIES AND GENERAL APPROACH TO IMAGING THE STROKE PATIENT There is growing interest in employing multimodal CT and MR techniques for acute stroke evaluation. Each of these approaches includes a sequence to assess (1) tissue status, (2) perfusion or hemodynamic status, and (3) vessel status. The data combined from these approaches may assist in selecting the best candidates for acute therapies by identifying (1) the size and location of salvageable penumbral tissue, (2) the size and location of irreversibly injured tissue, and (3) the site of vessel occlusion. Preliminary studies employing MR imply that multimodal data could be used to identify patients at increased risk of developing hemorrhagic transformation with acute revascularization therapies. These multimodal approaches may allow therapies to be tailored to each patient’s underlying pathophysiology. The multimodal CT approach includes a noncontrast CT, perfusion CT, and CT angiography (Fig. 11). It has been suggested that the ischemic penumbra can be delineated employing the CT perfusion approach. It has also been suggested that tissue with a CBV

Figure 11 Multimodal CT approach to stroke evaluation including noncontrast CT (left), perfusion CT (middle), and CTA (right).

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Figure 12 Example of diﬀusion–perfusion mismatch in acute stroke (top row) with salvage of the mismatch region as well as reversal of the diﬀusion abnormality following thrombolytic therapy.

value of<2.5 mL per 100 g represents the ischemic core and is equivalent to the DWI lesion and that tissue with an rCBF of<34% of the corresponding contralateral region encompasses the total ischemic region (core plus penumbra) [25]. The penumbra thus equals the entire ischemic region minus the core. The multimodal MR approach includes DWI and gradient echo imaging, perfusion weighted MRI, and MR angiography (Fig. 1). It has been suggested that early MR can characterize the ischemic penumbra as regions of perfusion but not diﬀusion abnormality (diﬀusion-perfusion mismatch) (Fig. 12). These are regions in which blood ﬂow is reduced, but in which tissue bioenergetic failure as evidenced by cytotoxic edema has not yet developed. While mismatch may provide a simple and practical means of identifying the penumbra in acute stroke, it is important to note that prior animal studies and recent case series in humans undergoing thrombolytic therapy have shown that diﬀusion abnormalities can be partially reversed with early reperfusion [50]. These data suggest that early after ischemia onset, the penumbra likely includes not only regions of diﬀusion/perfusion mismatch, but also portions of the region of diﬀusion abnormality. Eﬀorts are underway to identify more speciﬁc multivariate MRI models to predict tissue outcome in the hyperacute window. The diagnostic yield and clinical utility of newer neuroimaging procedures must be weighed against the time cost of acquiring the data, as well as the availability and ﬁnancial costs of these tests. At present, the clinical utility of these techniques in the emergent evaluation of patients with ischemic stroke is not fully demonstrated and additional research is required. There is a general agreement that the performance of these tests should not delay treatment with intravenous rt-PA. The choice of imaging depends upon availability, individual patient characteristics, and the type of information being sought.

VI. CONCLUSIONS Due to remarkable technological advances, acute neuroimaging studies can now provide critical information in the stroke setting that allows clinicians to make informed decisions regarding early therapeutic interventions and long-term treatment decisions. With the CT strategy, early tissue infarct signs can be recognized with appropriate training, while

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subsequent CTA with perfusion CT or xenon CT may provide important complementary vessel and hemodynamic data. The combination of diﬀusion and perfusion MR imaging plus MRA allows early detection and better characterization of the location, extent, and severity of tissue injury as well as information about the status of cervical and large intracranial vessels. The combined data from these techniques provide a powerful tool for making etiological diagnoses and allow thrombolytic and other interventional management decisions to be informed by precise characterization of individual pathophysiological processes.

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6 Evaluation of Patients with Stroke Including Vascular and Cardiac Imaging Timea Hodics and Louis R. Caplan Beth Israel Deaconess Medical Center, Boston, Massachusetts

I. INTRODUCTION Developments in brain and vascular imaging techniques and functional tests provide physicians with a plethora of tests to evaluate stroke patients. Unless ordering of procedures is based on thorough clinical evaluation, appropriate knowledge of the available imaging techniques, expected pathology, and normal variants, the results can be confusing. As an example, an early cerebral angiography study of ‘‘normal prisoners’’ by Faris et al. showed a high incidence of arterial occlusions and stenoses [1]. A more recent study using computed tomography (CT) angiography in young asymptomatic subjects found marked variation in the size of the vertebral artery relative to the transverse foramen, with the vertebral artery occupying 8–85% of the foramen. Such variability in normal vessel size may make it challenging to interpret vertebral artery pathology on CT angiograms [2]. Almost a quarter (22.7%) of the 629 patients without history of prior stroke enrolled in the Trial of Organon 10172 in Acute Stroke (TOAST) study had clinically silent lesions on baseline CT scans [3]. These observations belie the old adage dear to many neurosurgeons that an ounce of dye is worth all the neurologists in the room [4]. Physicians have four basic goals when evaluating cerebrovascular patients: (1) to determine the cause and mechanism of the stroke, (2) to localize the lesion or lesions in the brain and its vascular supply, (3) to assess the severity of the brain damage in order to guide management decisions and provide a prognosis, and (4) to identify immediate and future risk factors for further strokes and other complications. Clinicians need to apply diagnostic tests wisely; invasive studies should be reserved for those patients for whom the expected beneﬁt outweighs the risks of such testing. Clinicians must order even noninvasive or minimally invasive tests frugally: no society can aﬀord unlimited expensive tests. With these goals and restraints in mind, the following rules should guide the evaluation: (1) the clinical data should be acquired ﬁrst, before laboratory and imaging evaluation, and (2) at each stage of evaluation, clinicians should generate and test hypotheses as to the cause of the stroke and the location of the brain and vascular lesions [4]. 101

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II. CLINICAL EVALUATION Certain key questions should guide our decisions during the clinical encounter. How ill is the patient? Is the patient a candidate for a speciﬁc treatment? In some situations only supportive therapy may be proper. Neither a severely demented, bedridden 90-year-old nursing home resident, nor a 52-year-old breast cancer patient with metastatic lesions in the brain and bones in constant pain are candidates for aggressive evaluation and therapy. On the other hand, certain debilitating acute deﬁcits that seem severe initially may be reversible. Occasionally patients with major neurological syndromes such as aphasia, cognitive deﬁcits with hemiparesis, or tetraplegia recover rapidly and leave the hospital with minimal or no neurological deﬁcits. Mohr used the term ‘‘spectacular shrinking deﬁcit’’ (SSD) to describe such a turn of events. In a Japanese study of 118 patients with an initial major hemispheric syndrome, 14 patients (12%) had SSD. All but one SSD patient met criteria for cardiogenic brain embolism [5]. Out of 231 patients diagnosed with cardioembolic ischemia, 11 had a spectacular shrinking deﬁcit in a prospective stroke registry in Barcelona [6]. In addition, some lesions might be treatable, while others might not be. Acute hydrocephalus, subdural hematoma, and drainable hemorrhages are a few examples of potentially reversible conditions. Time is important. If we conclude that the patient will beneﬁt from intervention, it should be undertaken without delay. Table 1 illustrates the major stroke mechanisms a clinician should keep in mind when dealing with cerebrovascular patients. Once a clinician suspects stroke, their ﬁrst step should be to distinguish too much blood from too little blood in the head, i.e., hemorrhage from ischemia. Hemorrhages can be either subarachnoid (SAH) or intracerebral (ICH). Ischemic lesion types consist of thrombotic, embolic, and pump failure with systemic hypoperfusion. Thrombotic refers to a vascular occlusion that derives from an in situ lesion as opposed to embolism, where the occlusive particle arrives from a proximal vascular site via the bloodstream. In instances of systemic hypoperfusion, decreased ﬂow often results because the heart fails to pump enough blood to the brain due to decreased blood volume or as a result of heart failure, rather than due to local vascular occlusion. The patient’s description of the neurological symptoms and the neurological signs on examination will determine where the malfunctioning area or areas lie within the brain. Clinicians usually use pattern-matching strategy to place the lesion in one of six general sites: (1) left anterior cerebral hemisphere in the territory of the internal carotid artery (ICA) and its anterior cerebral artery (ACA) and middle cerebral artery (MCA) branches, (2) right cerebral hemisphere in the anterior circulation, (3) left posterior cerebral hemisphere in the distribution of the posterior cerebral artery (PCA), (4) right PCA territory, (5) brainstem and cerebellum in the territory of the vertebrobasilar system, and (6) deep hemisphere, where the lesion would likely be small. Table 1 Major Stroke Mechanisms Hemorrhage Ischemia

!SAH !ICH !Thrombosis !Embolism !Systemic hypoperfusion

!Large extracranial artery !Large intracranial artery !Small penetrating artery !Cardiac origin !Intra-arterial origin

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Determining the cause and location of the stroke should be pursued concurrently. Upon completing the history, the clinician should list the probabilities of each diagnostic option. During and after the physical exam, this initial assessment should be further reﬁned. The imaging and laboratory investigations should be planned accordingly.

III. BRAIN IMAGING Following the clinical evaluation, patients usually will have a brain imaging test to determine: (1) if the lesion is due to ischemia or hemorrhage, (2) where the lesion is located, and (3) how large and old the lesion is, depending on the availability of the testing apparatus, lesion localization, timing, and expected pathology. In some instances additional tests may be necessary to determine whether the problem is caused by hemorrhage or ischemia, such as in some cases of suspected SAH. The accuracy of head CT in demonstrating SAH diminishes with time. Approximately 5 out of every 100 patients with SAH have negative scans in the ﬁrst 24 hours, 10 out of 100 one day after the bleeding, and 26 out of 100 on the third day following the hemorrhage [7]. The sensitivity of head CT to detect SAH has not changed signiﬁcantly with recent developments in CT technology [8]. When the clinical encounter suggests subarachnoid hemorrhage and a CT scan lacks conﬁrmation, a spinal tap should be performed to ascertain the presence or absence of blood. The usual ﬁnding is blood-tinged or xantochromic cerebrospinal ﬂuid (CSF) under increased pressure with increased protein content and an elevated number of polymorphonuclear leukocytes. Although not widely used because of the routinely available CT or MRI, CSF ﬁndings can also be used to diﬀerentiate ICH from ischemia. In the case of a small ICH that does not reach the ventricular surface, the CSF can still appear clear on inspection. However, spectrophotometric CSF analysis discloses blood products in nearly all cases of ICH [9,10]. The location and distribution of the cerebral infarcts or hemorrhages suggest the likely site and nature of vascular pathology. The clinical information and the imaging abnormalities should be considered together, keeping in mind that some of the compromised brain areas may appear normal depending on the imaging technique, location, and timing of the imaging. Likewise, some abnormalities seen on imaging, e.g., ‘‘silent infarcts,’’ can be unrelated to the current event.

IV. VASCULAR IMAGING TECHNIQUES Vascular imaging attempts to answer questions about the mechanism of the stroke and the risk for future cerebrovascular events. It identiﬁes and localizes the occlusion in extracranial and intracranial vessels and quantiﬁes the degree of stenosis. It also allows us to determine the underlying pathology, such as atherosclerosis, dissection, vascular malformation, aneurysm, arterial compression, and venous thrombosis. The information gathered can be used for choosing therapeutic modalities to prevent further strokes. At present there is no routine recommendation for performing conventional angiography in patients with acute stroke. However, this recommendation may change once experimental intraarterial therapeutic interventions prove useful in reversing acute stroke [11–14]. Intraarterial r-proUK treatment within 6 hours of the onset of acute MCA ischemic stroke seems a promising approach [15,16]. The only currently available thrombolytic agent, tPA appears to be safe when administered intra-arterially in postoperative patients [17]. Vascular imaging makes it possible to locate and grade vascular occlusions and monitor

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the process of recanalization. A new vascular classiﬁcation scheme based on angiographic features, such as collateral supply, location, and TIMI grading of the pretreatment occlusion and response to intra-arterial thrombolytic agent, may help predict outcomes of ischemic strokes [18]. If the lesion is schemic, careful scrutiny of CT and magnetic resonance imaging (MRI) scans both with and without contrast can provide information about the vessels involved in the ischemic process. For example, acute occlusive emboli may appear as cylindrical hyperdensities on unenhanced CT scans. The most commonly aﬀected artery is the MCA; therefore, the term hyperdense MCA sign was coined [19,20]. A similar sign of acute thromboembolism on MRI was described as hypointense MCA sign [21,22]. Fusiform or large berry aneurysms that can serve as the source of emboli are often visible on enhanced CT and MRI scans. The presence of heterogeneous shadows in the aneurysmal bed can suggest the presence of a clot. The absence of the normal ﬂow void in the vessels on MRI can also suggest vascular occlusion. MRI is helpful in arterial dissection by demonstrating intramural hemorrhage and eccentrically narrowed and possibly thrombosed artery [4]. The available vascular imaging techniques can be categorized as noninvasive when contrast agent is not used, relatively noninvasive when intravenous contrast material is used, and invasive when intraarterial contrast agent is used. Ultrasonography (US) and magnetic resonance angiography (MRA) without contrast are considered noninvasive tests. CT angiography, contrast-enhanced MRA, and single-photon emission computed tomography (SPECT) are relatively noninvasive, and conventional radiographic angiography is invasive. Catheter angiography (CA) is still considered the gold standard investigation for both intracranial and extracranial vascular stenoses and occlusion. A problem with this assumption is that any CA errors are considered errors in the noninvasive technique. Angiography uses an approximation of the distance between the vessel walls in one plane, whereas less invasive methods use functional and anatomical data to image vessels. For example, sonography displays a hemodynamic parameter (velocity) in addition to directly imaging wall and plaque texture. Velocity would likely correlate more closely with the surface area size of a stenotic lumen. There is a predictable relationship between diameter and area stenosis if the stenosis is circular. The diﬃculty lies in determining which diameter is most representative for the area stenosis for an elongated shape narrowing. The reproducibility of carotid angiogram reading on the degree of stenosis is also variable, somewhere around 94% [23–25]. Some experts argue, therefore, that the gold standard should be the pathological specimen rather than angiography [26]. Nevertheless, conventional selective angiography or digital subtraction arteriography can reliably identify and quantify degree of stenosis, localize occlusion, determine pathology, delineate the morphology of an atheromatous plaque, and disclose other vascular lesions. CA’s limitations in imaging ischemic disease include its inability to demonstrate mural changes such as intraplaque hemorrhage and thrombus attached to the wall. Mural changes may be identiﬁed with transcranial Doppler (TCD) or CT angiography [11]. Conventional angiography is expensive and invasive; its risks include vascular damage, ionizing radiation, stroke, and systemic reactions, and its use is contraindicated or risky in certain conditions such as renal failure, coagulopathies, and absent femoral pulses.

V. NECK ULTRASOUND Ultrasound is an attractive technique for studying local and embolic disease in the cervicocranial arteries [27]. It is noninvasive and can provide valuable information

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regarding ﬂow characteristics, wall composition, vessel size, and embolic signals in intraand extracranial large vessels. As the name ultrasound implies, the emitted sound frequency from ultrasound transducers is above the range detectable to human ears. The Doppler eﬀect is a change or shift in frequency (or wavelength) as a result of the relative movement between the emitter source and the receiver. We all remember listening to the siren of an ambulance that seems higher pitched (higher frequency sound) when the ambulance approaches the listener than when it passes. The Doppler frequency shift depends on the speed of blood ﬂow, angle of insonation (the angle between the sound beam and the direction of blood ﬂow), the frequency of the ultrasound, and the speed of sound in the soft tissue. The frequency shift is maximal when the angle of insonation is parallel with the direction of ﬂow. In contrast, the frequency shift approaches zero when it is perpendicular to the blood ﬂow. A positive Doppler shift (toward the probe) or negative Doppler shift (ﬂow away from the probe) determines the direction of blood ﬂow. For practical purposes, we prefer to display blood ﬂow velocity instead of Doppler frequency shift to avoid potential confusion when comparing results obtained by diﬀerent machines using diﬀerent transducer frequencies and angle of insonation [28]. Various ultrasound methodologies can be used for imaging ﬂow or structural conditions. These methodologies include Doppler recordings from selected sample volumes (one-dimensional), B-mode imaging (two-dimensional), and three-dimensional imaging. Understanding the basic principles of each imaging method is essential in order to request the appropriate test for a particular problem. Doppler transducers can be divided into two basic categories depending on whether they emit and receive waves continuously (continuous-wave, or c-w, Doppler) or intermittently in a series of pulses (pulsed-wave, or p-w, Doppler). Continuous-wave Doppler has the advantage of being able to accurately evaluate even very high velocities in the observation window. However, continuous-wave Doppler lacks the ability to measure the depth of the tissue that generated the signal. In addition, continuous-wave Doppler often includes noise from other undesired vascular structures in the vicinity of the target tissue. Pulsed Doppler, on the other hand, is able to select sample depths by varying the wait time for reﬂected sound in between the emitted pulses. One drawback of this method is that it may not accurately assess high-frequency shifts generated by very high blood ﬂow velocities because of the ﬁxed rate of repetition of sound impulses. This phenomenon, often referred to as aliasing, is similar to the spokes of the wagon wheels in old western movies that appear to go in reverse. Increasing the pulse repetition frequency often eliminates aliasing [28]. In normal vessels laminar blood ﬂow acts like small reﬂectors moving at diﬀerent speeds and directions to create a spectrum of ﬂow velocities, rather than a single moving vector. This velocity spectrum is displayed as a compact, narrow, smooth velocity envelope in normal vessels. In contrast, in vessels with disturbed ﬂow, turbulence appears as irregular acoustic envelopes with broadened waveform and reverse ﬂow depicted below the baseline. Ultrasound is commonly used to evaluate the degree of stenosis in an intra- or extracranial vessels, most often in the internal carotid artery. Most published criteria used to estimate the severity of a stenosis are based on the peak systolic and diastolic velocities. Many suggested criteria use adjunctive parameters as well, such as velocity ratios between proximal and distal vessels, side-to-side velocity diﬀerences, spectral appearance of the high-velocity signal, and the appearance of the plaque on B-mode imaging [28]. B-mode ultrasound (brightness mode) provides a two-dimensional gray scale image of the underlying soft tissue and vascular structures. The sound beam is reﬂected, scattered, transmitted, bent, or absorbed as heat depending on the acoustic properties of the soft tissue, the interfaces between tissue layers, and the angle at which it is

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insonated. The ability of the technique to identify two points as separate along the axis of the sound beam is called axial resolution, while the ability to separate two points in the plain perpendicular to the axis is called lateral resolution. Using higher-frequency transducers improves axial resolution at a price of decreased tissue penetration. For example, carotid artery B-mode imaging uses 7.5–10 MHz transducer frequencies to achieve high spatial resolution. Lateral resolution is improved by using narrower ultrasound beam. Sweeping a series of B-mode scan lines through the tissue in a single plane creates the twodimensional image. B-mode imaging is well suited for detailed imaging of the vessel wall, intima-media thickness, and plaque features. Color-ﬂow imaging (CFI) displays color-coded information about ﬂow speed and direction over the real-time B-mode image. Although CFI cannot provide the same quality hemodynamic data as Doppler spectral analysis, it does have several advantages over grayscale duplex sonography. CFI allows faster identiﬁcation of the presence and direction of blood ﬂow, can guide the placement of the Doppler probe to the highest velocity area of the stenosis, and allows better characterization of the plaque surface features. CFI may also identify a thread of residual ﬂow in nearly occluded vessels, which is diﬃcult to see with conventional gray-scale imaging. In addition, CFI provides a way of rapidly understanding the kinks and coils or other anomalous anatomical patterns in blood vessels. Duplex scans combine B-mode and pulsed Doppler spectra. B-mode ultrasound produces real-time images of the vasculature, while pulsed-wave Doppler displays ﬂowvelocity proﬁles of the arteries insonated. Duplex sonography is the standard technique in the evaluation of the carotid and vertebral arteries. Most laboratories use color-ﬂow technique, rather than gray-scale Duplex alone. Power Doppler imaging (PDI) is a new Doppler technique based on the integrated power (amplitude intensity resulting from the amount of erythrocytes within the sample volume) of the Doppler signal, rather than the phase shift in frequency. Its advantages include relative angle independence and lack of aliasing. In addition, this technique increases the signal-to-noise ratio, allowing higher sensitivity to detect blood ﬂow and intravascular surface edge deﬁnition [29,30]. PDI can be useful in situations when the insonation angle is close to perpendicular relative to the blood ﬂow direction and when the blood ﬂow velocity is very low. Plaque calciﬁcation does not cause artifacts with PDI. Also, PDI provides a somewhat more accurate picture of the stenotic carotid artery lumen than CFI [30,31]. When PDI was used with intravenous contrast-enhancing agent, its sensitivity for distinguishing internal carotid artery pseudo-occlusion from complete occlusion was 94%, with 100% speciﬁcity [32]. The NASCET study [33], VA Cooperative study [34], and the European Carotid Surgery Trial [35] have conﬁrmed that patients with severe symptomatic carotid stenosis in the neck beneﬁt from carotid endarterectomy. Carotid surgery in patients without symptoms is more controversial, but selected patients may have better outcomes with carotid endarterectomy if an experienced surgeon performs it [36–38]. These studies provided a strong incentive for using noninvasive screening methods for carotid disease. Duplex ultrasonography can approach 90% sensitivity and speciﬁcity for estimating the degree of clinically signiﬁcant carotid stenosis [28]. Color-ﬂow Doppler may also display some residual ﬂow in vessels with very tight stenosis that appear occluded on duplex scan [39,40] or MRA. Color-ﬂow Doppler is less accurate, however, when there is a calciﬁed plaque [41]. Power Doppler imaging promises to further enhance the accuracy of carotid US testing [30], especially when used with echo contrast agents [32]. Factors other than degree of stenosis and history of neurological events may also be important in estimating the risk of stroke caused by a carotid plaque. For example, hypertension, echolucent plaques, and progressive lesions seem to be associated with an

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increased risk of neurological events [42,43]. Echolucent plaques are usually rich in cholesterol or contain intraplaque hemorrhage and often grow or regress in size on follow-up imaging [44]. In contrast, ﬁbrotic echodense or calciﬁed plaques tend to remain stable over time. Heterogeneous and ulcerated plaques carry a higher risk of cerebral or retinal ischemia [45–47]. B-mode ultrasound provides information about risk factors related to plaque features. In particular, the following can be assessed through B-mode ultrasound: distribution of the plaque (concentric or eccentric, length), surface features (smooth, irregular, or crater), echodensity or calciﬁcation, texture (homogeneous, heterogeneous, or in plaque hemorrhage), and pulsation pattern (normal radial or longitudinal pattern). Recently, transcranial doppler-detected microembolic signals have emerged as predictors of increased risk of stroke, transient ischemic attack (TIA), and retinal ischemia [48–51]. The most important and common lesion in the pharyngeal internal carotid artery above the bifurcation is dissection. In 76% of patients of one study, an intense systolic low-frequency Doppler signal of alternating ﬂow direction was found in the neck by Doppler spectra [52]. Duplex scans may show intimal ﬂaps, double lumen, tapering of the internal carotid artery lumen distal to the bulb in addition to the ﬁndings seen with Doppler spectra [53]. Staccato ﬂow strongly suggests dissection in both the carotid and the vertebral artery according to a recent study [54]. Ultrasound is also useful in evaluating the vertebral arteries. In our vascular laboratory, we divide the extracranial VA into three regions: (1) the VAO region, (2) segment 1, between the VAO and where the vertebral artery enters the transverse foramina, and (3) segment 2, the intervertebral region. These segments are displayed best with separate ultrasound techniques. Continuous-wave Doppler uses a high-frequency signal and can be readily moved to various regions of the neck. During evaluation of the vertebrobasilar circulation, this procedure is most helpful in determining the presence and direction of ﬂow in the second, interosseous portion of the extracranial vertebral arteries and in the third portion of the arteries just before they penetrate the dura. Color-ﬂow Doppler provides real-time information about blood ﬂow during B-mode imaging, including ﬂow direction, turbulence, and velocity in anatomical image format. Color-ﬂow Doppler images are readily obtained at the VA origin, within the intraosseus region, and at the atlas loop. Using Duplex ultrasound, one study demonstrated that the vertebral artery origin could be imaged in 81% of the cases on the right and in 65% of the cases on the left side [55]. Color-ﬂow Doppler imaging allows better visualization of the proximal and distal segments of the vertebral arteries, compared to conventional duplex ultrasonography. The distal V1 and V2 regions imaged well with both techniques [56]. Extracranial VA dissection usually occurs at the distal segment of the VA before piercing the dura as it winds around the upper cervical vertebrae. Ultrasound is often helpful in the diagnosis and follow-up of vertebral artery dissections. One study of vertebral dissections found decreased pulsatility in usually dilated vessels and abnormal intravascular echos. Above the dilated segments, the study noted that ﬂow signals were frequently reduced in amplitude [57]. Staccato ﬂow was seen in three out of four diagnosed vertebral artery dissections [54].

VI. TRANSCRANIAL ULTRASOUND (TCD) Noninvasive study of the intracranial circulation only became widely available after the report of Aaslid and colleagues about the use of Doppler sonography of the basal cerebral arteries in 1982 [58]. Transcranial Doppler uses a Pulsed-wave Doppler system that

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operates at low frequencies of 1.5–2.0 MHz and high ultrasound power. The pulses are range gated and can deeply penetrate tissue. There are three routinely used acoustic windows for TCD: (1) the temporal acoustic window in front of the ear, just above the zygomatic arch, that is used for insonation of the middle, anterior, and posterior cerebral arteries, (2) the suboccipital acoustic window via the foramen magnum from the midline or just lateral to the cervical paraspinal muscles to study the vertebral and basilar arteries, and (3) the orbital acoustic window through the optic foramen by placing the probe over the lateral upper part of the eyeball to insonate the ophthalmic artery and the ICA siphon. The conventional ‘‘blind’’ TCD method uses the direction of ﬂow, depth of the sample, the direction of the transducer ﬂow velocity and signal characteristics of the blood ﬂow in order to identify the vessels insonated [59,60]. The use of echo contrast agents with ultrasound can further enhance the accuracy of the testing by increasing the signal-to-noise ratio in both intra- and extracranial vessels. One of the most frequently used contrast-enhancing agents consists of galactose microparticles with an average diameter of 3 Am stabilized by palmitic acid (Levovist) [61,62]. The surfaces of these granules serve as foci for the adhesion of air microbubbles, which increase the Doppler signal after intravenous application. Intavenous injection of echo contrast agent can be particularly useful in transcranial color-coded Doppler examinations [62,63]. Insonation through the suboccipital window allows good detection of blood ﬂow velocities in the intracranial VAs and the proximal basilar artery. The distal third of the basilar artery is more diﬃcult to study because of the loss of signal at this distance from the foramen magnum [4]. Transcranial Doppler ultrasonography allows the detection of intracranial embolisation. Posterior circulation microembolic high-intensity transient signals (HITS) on transcranial Doppler ultrasound were associated with cardiac sources of embolism in a study by Koennecke and collegues [64]. Transcranial Doppler is useful in evaluation and follow-up of MCA stenosis [65]. Its noninvasive nature enables us to perform serial TCD examinations that show dynamic changes in cerebral circulation [66,67]. Transcranial Doppler can exclude M1 segment occlusion, but it is not useful for detecting distal branch occlusion. Enhanced blood ﬂow velocity in the anterior cerebral artery due to leptomeningeal collateral ﬂow may be used as a corroborating criterion for MCA occlusion [68]. MCA occlusions frequently recanalize spontaneously and in many cases are followed by transient hyperemia [68–71]. In a Chinese TCD follow-up study of MCA stenosis or occlusion, 42 patients (29%) normalized, 88 patients (62%) remained stable, and 13 patients (9%) progressed. Progression of the MCA lesions may predict further vascular events [71]. Conventional TCD has relatively low sensitivity for detection of intracranial MCA stenosis. However, PDI [29,72] and contrast-enhanced color-coded Doppler provide higher sensitivity of testing not only of the anterior circulation, but also of the posterior circulation large vessels. Contrast-enhanced color-coded Doppler was superior to power Doppler in depiction of the M2, A1 and A2, P1 segments, and the basilar artery using the transtemporal approach, but it did not provide additional advantage over power Doppler in the vertebrobasilar circulation from the transforaminal approach [73]. The use of contrast-enhancing agents for patients with nondiagnostic routine TCD exams can achieve 83% sensitivity and 82% speciﬁcity in establishing the diagnosis of intracranial artery stenosis according to one study. In this study, echo contrast material application improved diagnostic evaluation of the vessels in 75% of the cases during transtemporal and 81% of the cases during transforaminal insonation for those patients where standard TCD and Transcranial Color-coded Doppler could not provide reliable results [74].

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TCD can be used for monitoring intracranial clot lysis with tPA administration [75,76]. One group suggested the Thrombolysis in Brain Ischemia (TIBI) scale as the TCD counterpart of the angiographic TIMI classiﬁcation to assess arterial recanalisation during tPA administration [75]. TCD can accurately predict complete recanalization (PPV 91%) and complete occlusion (PPV 100%) in the MCA when compared with DSA ﬁndings of the same vessel. Partial occlusion deﬁned as blunted or dampened ﬂow signals should be interpreted as evidence of persisting occlusion [77]. In addition, Doppler waves during TCD examination seem to accelerate thrombolysis providing a possible avenue to increase the speed and eﬃcacy of clot lysis [76,78–83].

VII. EMBOLI MONITORING One of the most important advances in TCD technology was the introduction of emboli monitoring. During this procedure the probes are positioned over the cerebral arteries on both sides, most often over the MCA and PCA. Particles passing under the probe create a chirping noise and high-intensity transient signals (HITS) visible on the oscilloscope. These signals are often referred to as microembolic signals (MES), because they are believed to represent small emboli passing through the observation window. Recently, multigated TCD embolus detection was developed to diﬀerentiate artifact from emboli. In this technique, the probe listens over distal and proximal sample volumes along the same vessel. MES should appear sequentially, while artifact should appear at the same time [84]. During online monitoring, multifrequency TCD can achieve a relatively high sensitivity and speciﬁcity in distinguishing between microembolic signal and artifact [85]. The characteristic features of the microembolic signal depend on the nature of the particles passing under the probe. Multifrequency online TCD monitoring permits distinguishing between gaseous and solid microembolic signals [86,87], but diﬀerentiation between sizes and types of solid particles is more diﬃcult [88]. Placing the probes simultaneously on the neck and over the cerebral arteries allows the distinction of cardiac or aortic origin emboli from those originating from the neck. Emboli arising from the heart or aorta are seen ﬁrst in the neck, then in the cerebral arteries proportionately in the anterior and posterior circulation. In contrast, embolic signals originating from the neck do not appear at the probe placed over the neck. These embolic signals are only detectable over the intracerebral vessel distal from the source artery. For example, embolic signal from a dissected right carotid artery will appear only in the right MCA. Transcranial emboli monitoring has shown that cerebral embolization is relatively common and results in cerebral infarction much less often than previously thought [48,50,51,64,89–100]. Some of these embolic signals represent gaseous rather than solid particles. These gaseous embolic signals are not necessarily indicative of the patients’ stroke risk, such as in patients with prosthetic aortic valves [101–103]. Several studies noted, however, that MES were more frequently observed in symptomatic than in asymptomatic arteries [94,97,104,105] and seemed to predict future ischemic events [50,51,102]. Moreover, carotid endarterectomy seems to reduce the number of MES detected [97,100,106]. Several studies found correlation between plaque features such as plaque ulceration or luminal thrombosis and MES in high-grade carotid stenosis [51,96,105,107]. Recent studies demonstrated microembolic signals more frequently in patients with carotid disease than in patients with a potential cardiac source of embolism [92,108]. HITS occur predominantly in patients with large-vessel territory stroke patterns and are rare in patients with small-vessel disease [92,95].

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Several studies detected a myriad of microembolic signals in the MCA with TCD monitoring during cardiopulmonary bypass surgery. HITS were particularly numerous during clamping and unclamping of the aorta [109–111]. Cardiac and aortic-origin embolism likely contribute to the organic brain damage often seen after cardiac surgery [112,113]. Although TCD is generally used for evaluation of the large vessels, Kidwell and collegues found that elevation in pulsatility indices on TCD that had been postulated to reﬂect downstream increased vascular resistance shows correlation with MRI evidence of small-vessel disease [114].

VIII. MAGNETIC RESONANCE ANGIOGRAPHY MRA is not a single technique, but rather a generic term for diﬀerent imaging methods. The two current noncontrast techniques are based on inﬂow enhancement (time-of-ﬂight methods) or use velocity-induced phase shifts (phase-contrast methods). The contrast of the movement of the magnetically polarized blood against the magnetically saturated background creates the representation of the vascular bed. The resulting image contains, therefore, both anatomical and physiological information. MRA is noninvasive and quite safe. It has the additional advantage that it can be performed in the same setting when the brain MRI images are acquired. Time-of-ﬂight (TOF) acquisitions are useful for viewing vessel morphology, whereas phase-contrast methods provide additional information about velocity and direction of blood ﬂow and volume ﬂow rates. Two-dimensional (slice-by-slice) or three-dimensional (volumetric) acquisitions are available. Two-dimensional (2D) TOF provides a strong vascular signal, even if the blood ﬂow velocity is low. Two-dimensional (2D) TOF provides advantages for large area coverage (e.g., the extracranial carotid artery) and slowﬂow situations (e.g., venous sinuses) if spatial resolution is not critical. Three-dimensional (3D) TOF provides superior, submillimeter resolution, but at the expense of sensitivity to ﬂow. The weak vascular signal of 3D TOF in slow-ﬂow situations may be improved by the use of multiple overlapping thin slab acquisition (MOTSA) [115]. 3D TOF imaging is well suited for studies that require high spatial resolution to evaluate ﬁne vessel details, such as intracranial arteriograms. The original slices from 3D TOF acquisition may allow one to see some features of the plaque directly, but carotid atheromatous ulceration is not reliably visualized with MRA. Overlapping thin slabs or 3D phase-contrast acquisitions can achieve the best quality images on normal or slightly stenotic vessels. MRA represents advanced arterial stenosis as luminal narrowing and by an overall drop-oﬀ in signal intensity. The degree of stenosis tends to be overestimated due to turbulence, loss of laminar ﬂow that produces better quality signal, and decreased signal due to small blood volume. When MRA is compared with conventional angiography, the concurrence rate varies widely between studies (39% to 98%) [116]. Most disagreements derive from overestimation of the degree of stenosis [116–118]. Use of intravenous contrast agent might suﬃciently increase the signal of the diminished blood ﬂow through a vascular stenosis [119]. Contrast-enhanced methods are available in order to create a quick and robust vascular map that is not impaired by slow-ﬂow situations. Contrast-enhanced MRA serves as a good choice for patients who cannot maintain a position for prolonged periods, in particular for the study of the aortic arch [25,120,121]. Unfortunately, it requires MRI systems with enhanced gradient hardware. Contrast-enhanced MRA is a promising technique, but its diagnostic value awaits further validation [11].

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The proven beneﬁt of carotid endarterectomy for high-grade carotid stenosis triggered a search for a reliable noninvasive imaging method for this condition. Most of the studies compare 2D TOF MRA and US to conventional angiography as a gold standard for the evaluation of the carotid bifurcation [122–124]. The American Heart Association (AHA) scientiﬁc statement on extracranial MRA analyzed the prospective comparative studies of MRA and CA and found that the median sensitivity for a highgrade lesion was 93%, whereas the median speciﬁcity was 88% [25]. Overestimation of the degree of stenosis results in lower speciﬁcity and lower positive predictive values for detecting narrowing of >70%. The majority of patients with a ﬂow void on 3D TOF MRA imaging had high-grade stenosis in the carotid artery (PPV 84.3%) [125]. The combination of MRA with duplex ultrasound improves the sensitivity and speciﬁcity of the noninvasive carotid testing. Nevertheless, combination imaging misclassiﬁes approximately 3% of the patients showing negative noninvasive testing, while conventional angiography shows more then 70% stenosis. Noninvasive imaging shows occlusion in the carotid artery in 9% of patients when angiography conﬁrms some degree of luminal patency [126]. Some clinicians reserve angiography for patients with disparate results on the combination of MRA and ultrasound testing, which might be a more cost-eﬀective approach [127]. The carotid siphons and intracranial arteries are best imaged with MOTSA. The agreement between MRA and conventional angiography in evaluating intracerebral vascular lesions was found to be less than that for the carotid artery, approximately 62% [116]. Shorter acquisition time and greater resolution makes 3D TOF technique the method of choice for imaging the intracranial circulation in search of occlusive disease. In posterior circulation ischemia MRA may identify the vascular pathology in the subclavian artery, extracranial and intracranial vertebral arteries, basilar artery, and its branches. Overlapping arteries may make it diﬃcult to adequately image the origins of the vertebral arteries. MRA shows the second portion of the vertebral artery within the intervertebral foramina well. The third portion that curves around the rostral cervical vertebrae is more diﬃcult to image well because of the curvature of the VA. It is important to remember when interpreting these MRA images that some normal vessel segments may not be well visualized because of planar exclusion, depending on tortuosity and ﬁeld placement. The intracranial vertebral arteries and the basilar artery with its bifurcation and the origins of its branches are usually clearly visible. However, clinically important lesions can be missed by MRA in the ICVA. MRA tends to more accurately characterize occlusive lesions in Basilar Artery (BAs) than in Extracranial Vertebral Artery (ECVAs) or Intracranial Vertebral Artery (ICVAs) [128]. The Anterior Inferior Cerebellar Artery (AICA) appears less consistently then the other branches. In ﬁbromuscular dysplasia MRA cannot distinguish between long segmental narrowing and dissection [4,11]. The disadvantages of MRA are high cost, relative unavailability, claustrophobic reactions, and limitations of use for patients with ferromagnetic fragments and certain implants. MRA sensitivity and speciﬁcity are insuﬃcient to establish an indication for carotid endarterectomy. Compared with conventional angiography, MRA is less costly, safer, but less accurate.

IX. CT ANGIOGRAPHY CTA The recent development of rapid spiral (helical) CT scanners has enabled the introduction of CT angiography (CTA) into clinical practice. This technique creates an anatomical map of the vasculature utilizing intravenous dye bolus. CTA combines two

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recent technological developments: slip-ring CT scanning and computerized three-dimensional reconstruction. In cases of greatly reduced blood ﬂow it has theoretical advantage over MRA. The ICAS in the neck are usually easily seen. Compared with carotid angiography, there are few false-positive or false-negative studies; the results are comparable with MR angiography [129–133]. CTA is multiplanar and allows diﬀerentiation of calciﬁed plaque from contrast material. It provides information about plaque calciﬁcation, ulceration, and size that cannot be obtained with conventional angiography [130]. CTA can show intracranial arterial stenoses, aneurysm, dolichoectasia [134,135], and it can be useful in children [136]. While intraobserver reliability for both MRA and CTA is good, diﬀerent observers tend to interpret CTA more variably then they do MRA [135]. Most recently, multislice detectors in spiral CT can achieve high resolution in a short imaging time [137]. This development is an important step considering the time constraints involved when dealing with acute stroke patients.

X. SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) SPECT is currently not routinely used in the clinical management of stroke, but it can be useful in a question-driven evaluation of patients with vascular disease [138]. SPECT uses radionuclides such as technetium 99m, thallium 201, and iodine 123 that emit a single photon when they undergo nuclear decay. This radioactivity is used to create a map of regional brain function in the more often used static images. The radionuclides cross the blood-brain barrier, distribute, and become trapped in the cells in proportion to the regional blood ﬂow, which in most cases parallels brain tissue metabolism. Because of this unique feature, SPECT is often considered ‘‘ the poor man’s Positron Emission Tomography (PET).’’ SPECT provides information about cerebral perfusion on the tissue level that the previously mentioned techniques cannot achieve. A perfusion (ﬁxation) defect is usually visible immediately after the onset of a cortical ischemic stroke. Moreover, the image of the cerebral perfusion pattern at the time of the administration of the intravenous agent is ﬁxed, like a photograph, since the radioactive agent gets trapped in the tissue. This allows one to scan the patient at a later time, avoiding delays in therapy. SPECT’s potential uses include diﬀerentiation of cortical stroke from lacunes in patients with clinical evidence of stroke and negative MRI and CT [139]. It also may be used to identify patients with higher risk of postthrombolysis hemorrhage [140]. SPECT can be used to evaluate cerebrovascular reserve [141–150]. Decreased hemodynamic reserve by 123I N-Isopropyl-p (I123) Iodoamphetamine (IMP) SPECT after acetazolamide administration corresponds to increased oxygen extraction fraction on PET [146]. Decreased cerebrovascular reserve confers a higher risk of stroke after carotid or middle cerebral artery occlusion [143,144,147,148,151], although some found no correlation between the two [149]. The ensuing strokes may be caused by hypoperfusion or by impaired washout of embolic particles as a result of reduced perfusion. The fact that the favored sites for embolic infarcts are in the watershed areas of the brain supports this idea [152]. SPECT can diﬀerentiate epileptic events from transient ischemic attacks [11]. Smallvessel arteritis in SLE may cause vanishing areas of ischemia on SPECT [153]. SPECT demonstrated improvement in brain perfusion with ASA therapy in a case of antiphospolipid syndrome as the patient improved clinically [154]. Ischemic lesions in Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) might be better demonstrated with SPECT that with MRI or CT [155]. SPECT may have a promising future for providing additional information on the prognosis of strokes [156], evaluating the risk of hemorrhagic transformation, and identifying tissue reperfusion [157].

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XI. CARDIAC TESTING Cardiac imaging and rhythm monitoring are also essential parts of the evaluation of stroke patients. Approximately 30% of ischemic strokes are cardiac in origin, although the proportion varies in the literature depending on the diagnostic criteria used. Ischemic and hemorrhagic strokes are also known to cause changes in cardiac function. The cardiac evaluation usually begins with an electrocardiogram (ECG), followed by a transthoracic echocardiogram (TTE). Rapid intravenous injection of agitated saline ﬂoods the right heart with microbubbles. The examiner can detect right-to-left shunting across a patent foramen ovale by listening over the cardiac septum with an ultrasound probe. Simultaneous TCD monitoring of the intracranial vessels can also reveal the passage of microemboli if right-to-left shunting is present. Examinations can be performed from the transesophageal approach as well. Comparative studies between the two approaches have suggested a higher yield for potential cardiac source of embolus when transesophageal echocardiogram (TEE) is used compared with TTE [158,159]. Mitral stenosis, cardiomyopathy, and LV mural thrombus are equally well identiﬁed with either technique. The additive cost, inconvenience, and risk of TEE cannot be justiﬁed once TTE has detected these abnormalities. Conversely, since the esophagus lies just behind the left atrium, TEE is uniquely suited for detection of left atrial spontaneous contrast, left atrial thrombi, atrial septal aneurysm, right-to-left shunting through a patent foramen ovale, and atheroma of the aortic arch. These entities are thought to have embolic potential [160]. A recent study recommended using TEE for older stroke patients if the TTE was abnormal but not suﬃciently informative [161]. Aortic atheromas are particularly important sources of brain embolism after conventional angiography and cardiac surgery. In a recent study TEE also visualized the aortic branches, including the vertebral arteries in most cases [162]. Typically a physician should reserve cardiac diagnostic testing for situations when the information gathered is expected to change therapy. The presence of patent foramen ovale (PFO) in stroke patients does not appear to increase the chance of adverse events regardless of PFO size or the presence of atrial septal aneurysm in patients on either ASA or warfarin. There was also no diﬀerence between event rate for patients with PFO on ASA or warfarin in a recent study [163]. Atrial ﬁbrillation and sick sinus sydrome are other important sources of cardiogenic embolism. In some patients, such as patients with known irregular heartbeat and palpitation, known heart disease, or in whom the initial evaluation did not reveal the source of the suspected cardiogenic embolism, rhythm monitoring can be helpful. Highrisk atrial ﬁbrillation patients beneﬁt from anticoagulation with warfarin [164]. Dipyridamole-thallium scan and ultrafast CT can characterize cardiac function in selected patients with known cardiac disease.

XII. EVALUATION OF PATIENTS WITH INTRACEREBRAL HEMORRHAGE If the lesion is an intracerebral hemorrhage, CT and MRI can provide important information, such as the mechanism, vascular territory, size, drainage patterns, presence and amount of surrounding edema, mass eﬀect, blockage of CSF pathways causing hydrocephalus, shape, homogeneity, and morphological characteristics of the lesion, and the presence of additional brain lesions, especially old hematoma cavities. By far the most common cause of intracranial hemorrhage is hypertensive angiopathy. Hypertensive angiopathy does not produce visible lesions on the available vascular

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imaging techniques: conventional angiography, MRA, CTA, or routine TCD. The presence of high blood pressure at presentation and typical location of the bleed in the putamen, caudate, thalamus, pons, or cerebellum suggests hypertensive hemorrhage. Vascular studies are not useful for evaluating hematomas caused by amyloid angiopathy, trauma, or bleeding diathesis except for ruling out other causes of bleeding. They are referred to as microangiopathies because the pathological vascular lesion in these disorders is visible only under a microscope. Angiography’s main value is in evaluating nonhypertensive forms of ICH, multiple ICHs, or those located in unusual sites to disclose a possible underlying vascular malformation, aneurysm, or tumor.

XIII. ANTERIOVENOUS MALFORMATIONS (AVMs) Among vascular malformations, cavernous and venous angiomas typically image well on MRI but are not detected by vascular imaging. AVMs, on the other hand, are usually well shown by angiogram, at times with MRA and TCD. MRA usually shows the large feeding vessels, but it is insuﬃcient for planning surgery without conventional angiography. Important details such as the presence of an aneurysm on intranidal or feeding arteries, comprehensive data on venous drainage pattern, or subtle AVM nidus characterization are not adequately assessed on MRA. Superselective conventional angiography can provide further data for planned intervention. Based on available data, the Stroke Council recommends performing an MRI and a four-vessel angiogram to delineate the anatomy of an AVM [165]. Careful consideration of the likelihood and severity of future AVM bleeding in comparison with the risk of surgery, radiosurgery, or embolization is essential in planning therapeutic interventions. Spetzler and Martin designed a grading system to estimate the surgical risk of a patient with AVM that uses size, pattern of venous drainage, and neurological eloquence of adjacent brain to create six risk levels [166]. The long-term prognosis for AVMs is poor, largely due to recurrent hemorrhages and seizures. According to several studies, approximately half of the patients with recurrent bleeding died or had some disability after 20–40 years of follow-up [167,168]. A recent study found a lower rate of morbidity associated with hemorrhage from AVMs than previously assumed [169]. Some studies on the natural history of the disease suggest an average 3–4% yearly risk of AVM hemorrhage [170,171]. Others found 6% rebleed during the ﬁrst year after presentation and 1–2% yearly thereafter [168]. Several authors have associated certain radiological features with higher rate of hemorrhage in AVMs. Among these are small AVM size [172–174], high feeding artery pressures [175], periventricular or intraventricular location [176], basal ganglia location [177], and venous pattern—presence of a deep venous drainage [174–178], associated intranidal or feeder artery aneurysm [176,177,179], vertebrobasilar supply and supply via perforators [177,180]. Presentation with seizures and epilepsy was associated with cortical location of the AVM or cortical feeding artery, feeding by the MCA, presence of varices in the venous drainage, absence of aneurysms [181], AVM size of >3 cm, and temporal lobe AVM location [182]. Posterior fossa AVMs are rare (5–7% of all AVMs) but most often are found in the vermis of the cerebellum and present typically with hemorrhages or progressive neurological deﬁcit [183], while seizures are rare [182]. TCD may identify and follow the progression of large and medium-size AVMs. However, TCD can be considered only an adjunct to angiography to diagnose AVMs [27,184,185]. Arteries that supply high-ﬂow malformations usually show high velocity and

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low resistance, carrying increased ﬂow volume. The low resistance derives from direct arteriovenous connections distally in the vascular bed and results in decreased pulsatility. Collateralization pattern and steal eﬀects can be shown by mean and peak velocity values below average levels. Echo-enhanced power Doppler promises to be a sensitive method to identify AVMs and measure ﬂow velocities [186]. Feeding artery pressures may help determine higher risk of hemorrhage in AVMs [175]. Unfortunately, TCD detected proximal mean velocity values correlated poorly with the feeding mean arterial pressure in AVMs in a recent study [187].

XIV. SUBARACHNOID HEMORRHAGE (SAH) Similar vascular lesions can cause ICH and SAH. Most frequently, aneurysms or AVMs are responsible for nontraumatic SAH. The distribution of blood and presence and thickness of thick clots on CT or, less frequently, on MRI imaging may suggest the location of the vascular lesion. A negative head CT (or MRI) does not rule out SAH. A spinal tap should always follow a negative imaging study for patients with a clinical suspicion of SAH. When blood is present in the CSF, the quantity of blood in the ﬁrst and third or fourth tube and the opening pressure can be measured and followed by repeated spinal taps. When erythrocytes lyse, they release oxyhemoglobin into the spinal ﬂuid, creating a reddish-orange color. It reaches its peak concentration in approximately 36 hours and gradually clears in 7–10 days. CSF gradually turns yellow as bilirubin appears. Bilirubin is ﬁrst detectable in approximately 10 hours, reaches its peak concentration in 48 hours, and is present for about 2–4 weeks after large hemorrhages. Although blood tends to clear over successive collection tubes with traumatic spinal tap, this is not a reliable sign to exclude SAH. On the other hand, the presence of xanthochromia in the spun supernatant of fresh CSF specimen is diagnostic of SAH, regardless of the cell count [188–190]. Other CSF features characteristic of SAH include faint pink color of supernatant ﬂuid if examined within 4–5 hours of the bleed, elevated protein and opening pressure, predominantly mononuclear pleocytosis, and normal glucose [190]. Lumbar puncture can help identify other conditions that may mimic SAH, for example, tumor or infection. Dolichoectatic and dissecting aneurysms can also rupture, but the majority of aneurysmal bleeds result from saccular aneurysms. All four vessels should be studied, because approximately a quarter of patients have more than one aneurysm. Digital subtraction angiography (DSA) and selective catheter cerebral angiography is the gold standard in the preoperative evaluation of aneurysms. DSA allows rapid, excellent arterial opaciﬁcation with less dye. If no aneurysm is found, the prognosis is usually better, but the etiologies are diverse. The explanations include subependymal AVMs, trauma, blood dyscrasias, thrombosis of a ruptured aneurysm, leakage from a small nonaneurysmal artery on the brain surface, dural AVMs, intracranial arterial dissections, cocaine abuse, pituitary apoplexy, and spinal AVM. Perimesencephalic (pretruncal) hemorrhages, when blood is centered around the prepontine cistern and angiography is negative, have a much more benign prognosis then patients with aneurysm shown on angiography. They seldom rebleed acutely, develop delayed cerebral infarction or hydrocephalus, or die [190,191]. MRA can reliably show aneurysms larger than 3–4 mm [192–194], but the relationship of the neck of the aneurysm to adjoining branches usually requires high-resolution angiography. This recommendation may change with the development of high-resolution and contrast-enhanced 3D MRA technology [195]. A Japanese group was able to substitute DSA with 3D MRA in nearly half of the cases for preoperative evaluation of

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ruptured cerebral aneurysms [196]. MRA also provides advantages over DSA in the evaluation of intracerebral aneurysms in complex anatomical areas and in case of a mural thrombus [194]. CTA can usually identify intracranial aneurysms [134]. It displays aneurysms from multiple diﬀerent projections that make this technique particularly attractive. However, conventional angiography cannot be bypassed during preoperative evaluation of aneurysms. The fact that CTA does not reliably show small intracranial vessels such as the posterior communicating, anterior choroidal, and orbitofrontal arteries limits its use [197]. Multislice 3D CTA may overcome this limitation [198]. Both CTA and MRA can be useful in screening patients with a strong family history of SAH and patients with polycystic kidneys, ﬁbromuscular dysplasia, Marfan syndrome, coarctation of aortae, and pseudoxanthoma elasticum. Power Doppler technology can also be used transcranially, and it appears to be superior to conventional color-coded Doppler technology in detecting aneurysms [72]. Of 36 intracranial aneurysms, 32 were correctly identiﬁed using contrast-enhanced power Doppler technology. This sensitivity was superior to color-ﬂow Doppler with or without contrast agent or power Doppler without the use of intravenous contrast agent [199]. While there is no reliable method to predict which aneurysm is prone to rebleed, the amount of blood seen on the initial brain scan helps predict the likelihood of subsequent vasoconstriction [200,201]. Clinical evaluation, TCD, SPECT, and perfusion MRI are also used for monitoring cerebral vasoconstriction in patients with aneurysmal subarachnoid hemorrhage. Most ultrasound studies concentrated on the MCA and the anterior circulation, where TCDs role is best established. Meta-analysis of trials comparing TCD to cerebral angiography concluded that in the middle cerebral artery TCD is not likely to indicate spasm when angiography does not show vasoconstriction (99% speciﬁcity), and TCD may be used to identify patients with vasoconstriction (97% PPV) This meta-analysis concluded that the sensitivity of TCD in detecting vasoconstriction is low (67% in the MCA, and even lower for ACA, ICA, and PCA) [202–204]. In the posterior circulation following SAH, Sloan et al. found that transcranial Doppler is highly speciﬁc (100%) for vertebral and basilar artery vasoconstriction when ﬂow velocities are z80 and z95 cm/s, respectively. However, the sensitivity was low for vertebral artery vasoconstriction [205]. Intracranial/extracranial Flow Velocity (FV) ratio can be used to diﬀerentiate BA vasoconstriction from hyperemia [206,207]. SPECT is a sensitive and fairly speciﬁc alternative method for monitoring vasoconstriction after SAH [208,209]. Davis et al. found SPECT more speciﬁc than TCD in identifying vasoconstriction after SAH [209]. Quantitative measurements of the mean cerebral blood ﬂow (mCBF) are also possible with SPECT. The mCBF measurements using 99mTc-ethyl cysteinate dimer SPECT have a 78% sensitivity, 88% speciﬁcity, 70% Positive Predictive Value (PPV) 92% Negative Predictive Value (NPV) for vasoconstriction following SAH according to one study [210]. Visual inspection of the SPECT images had much lower sensitivity and speciﬁcity [210]. One possible pitfall is an apparent hypoperfusion around the clipping site, possibly due to edema, on visual inspection of the SPECT images that should not be read as a sign of vasospasm [210,211]. Dynamic DSA (serial images of cerebral DSA) can be used to display cerebral perfusion during angiography. This computerized technique can be useful in monitoring the eﬀectiveness of endovascular therapy in patients with vasoconstriction after SAH [212,213]. Cerebral microcirculatory changes as detected by cerebral circulation time on DSA correlated well with rCBF measurements by SPECT in a Japanese study. The authors suggested that impaired autoregulatory vasodilatation or constriction in the distal intraparenchymal vessels may take part in brain ischemia during vasoconstriction [214].

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SPECT, TCD, and DSA use diﬀerent methods to detect vasoconstriction and may be used as complementary sources of information to evaluate vasoconstriction [209,215]. Diﬀusion and perfusion MRI imaging correlated well with the clinical exam in patients with SAH and can be useful in the evaluation of delayed vasospasm according to several studies [216–219]. The admission evaluation for a patient with SAH or ICH should also include baseline electrocardiogram, electrolytes, complete blood count, and clotting parameters. ECG changes such as peaked P waves, elevated T waves, prolonged QT intervals, and depressed ST segments are frequently reported to be associated with SAH and can be the result of elevated catecholamine levels. Subarachnoid bleed in the right Sylvian ﬁssure may be associated with abnormal ECG changes [220]. Ischemic ECG changes or MI were associated with more severe neurological injury, but did not appear to cause increased mortality in a recent study [221]. The pathological changes in the cardiac muscle cells during SAH are often referred to as myocytolysis, or contraction band necrosis. The cardiac muscle cells die in a hypercontracted state, and calcium enters early, causing calciﬁcations. (Martin Samuels uses the expression: ‘‘The heart turns to stone.’’) The rapid-onset pulmonary edema with high protein content in the edema ﬂuid is neurogenic in origin, and Weir suggested that it is caused by a rapid rise in ICP that triggers a massive autonomic discharge [222]. Careful monitoring of the vital signs, congestive heart failure, arrhythmias, ECG, and cardiac enzymes is important. Fluid and electrolyte disturbances are most frequent with aneurysms of the AcomA, but slight hyponatremia and hyperkalemia occur often after SAH [190]. Hyponatremia may be related to the increased cardiac release of atrial and brain natriuretic peptide [190,223]. Severe ﬂuid and electrolyte imbalance is associated with hypothalamic damage.

XV. VENOUS OCCLUSIONS Hemorrhagic infarcts and brain edema may result from thrombosis of dural sinuses and cerebral and cerebellar veins, although it is much less often diagnosed then arterial strokes. Recently the Canadian Pediatric Ischemic Stroke Registry found a low incidence of sinovenous thrombosis (0.67 cases per 100,000 children per year), most of whom were neonates [224]. The most common etiologies are infections, hormonal factors, and blood and coagulation abnormalities. Typically, patients are at least 30 years younger than in the case of arterial diseases, usually female, and lack the usual cerebrovascular risk factors. Elevated homocysteine levels and anemia are likely important in causing puerperal dural sinus thrombosis in India and Mexico. The variable extent and location of thrombus, venous collateral vessels, and rate of progression causes this condition’s remarkable diversity in the clinical presentation that still makes it a diagnostic and therapeutic challenge despite the recent advances in diagnostic technology. The most frequent signs of cerebral venous thrombosis (CVT) include headache, focal deﬁcits, seizures, disorders of consciousness, and papilledema, which can present in isolation or in association [225]. The prognosis of cerebral venous sinus thrombosis is variable, and outcome may range from complete recovery to death [224,226,227]. While in the past the diagnosis of CVT could only be made by cerebral angiography, now contrast-enhanced CT scan, MRI, MRA, and MR venogram can aid in establishing the diagnosis. A CT scan is usually the ﬁrst investigation performed on an emergency basis. Although it can sometimes detect spontaneously hyperdense thrombosed sinuses, it usually shows nonspeciﬁc changes such as hypodensities, hyperdensities, and contrast

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enhancement, and in up to 30% of cases it is normal. The present gold standard for the diagnosis of CVT is no longer angiography but MRI. MRI shows the thrombosed sinus as an increased signal on both T1- and T2-weighted imaging. Indications for MR angiography, venography, or helical CT venography are very early (before day 5) or late (after 6 weeks) stages of venous thrombosis, when false-negatives may occur, or whenever MRI shows equivocal signs [225]. Three-dimensional phase contrast MRA can also diﬀerentiate thrombus from blood ﬂow [11]. Although optimal treatment is still controversial, the role of anticoagulation seems to be established, even in the presence of an intracerebral hemorrhage [225,228–230], although others did not conﬁrm improved outcome with anticoagulant treatment [231]. Evaluation of the pattern of occlusion on imaging in addition to the clinical ﬁndings might provide clues to the prognosis of the disease. Involvement of the deep venous system [232– 234], extension into cerebral veins [235], coma [229,236], seizures at the onset [224], rate of evolution of deﬁcits [229,236], hemorrhagic infarcts, and presence of focal ﬁndings [229] may promote poor outcome. Several studies applied intravascular thrombolytic therapy with success in patients with multiple sinuses occluded and with poor expected outcome [232–235,237,238].

XVI. BLOOD TESTS Hematological disorders play an important role in the pathogenesis of both ischemic and hemorrhagic strokes. Screening for blood abnormalities should be part of the evaluation for all stroke patients. In patients with cerebral ischemia, the most important questions are: (1) Could blood hypercoagulability have played a role in precipitating a vascular occlusion? and (2) Are there hemorrheologic factors present that might impede brain perfusion? Both cellular and serological elements can be responsible for an abnormal tendency to form clots or the inability to seal the injured vessel wall. Elevated red blood cell (RBC) and platelet count can precipitate thrombus formation, especially in already narrowed vessels. Low platelet count can suggest antiphospholipid syndrome, consumptive coagulopathy, thrombotic thrombocytopenic purpura, or lupus erythematosus. Some qualitative disorders of erythrocytes and platelets can also cause thrombosis. Careful scrutiny of blood smears will show abnormal morphology of the RBCs that can suggest a hemoglobinopathy. Sickle cell anemia, spherocytosis, and erythrocytosis are a few examples of RBC disorders that can cause vascular occlusions. Although qualitative platelet abnormality (‘‘sticky platelets’’) does exist, there is no widely accepted method of studying platelet function at the bedside. In this disorder, ischemic events often follow emotional stress and can be eﬀectively treated by low-dose aspirin [239]. In the majority of patients with hypercoagulable states, the prothrombin time and the activated partial thromboplastin time are abnormally accelerated. AHA guidelines recommend performing complete blood count, platelet count, prothrombin time, partial thromboplastin time, as well as serum electrolytes, blood glucose, arterial blood gas levels (if hypoxia is suspected), and renal and hepatic chemical analyses on an emergency basis for the evaluation of acute ischemic stroke patients [240]. In patients with a personal or family history of coagulation disorders and in patients with unrevealing history and routine cardiac, vascular, and laboratory testing, we order antithrombin III, protein C, Factor V Leiden, protein S, serine coagulation levels and activity factors (V, VII, VIII, IX, X, XII), von Willebrand factor, and tissue plasminogen activator and inhibitor. Antiphospholipid antibodies should be measured in patients with lupus erythematosus,

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those with a history of miscarriage, venous thromboembolism, myocardial infarction and stroke, those with thrombocytopenia, and unexplained cardiac valvular lesions. Antiphospholipid antibodies (aPLs) are a group of antibodies directed against phospholipids or phospholipid-protein complexes. Lupus anticoagulant (LA), an aPL, appears to be less sensitive but more speciﬁc for the diagnosis of antiphospholipid syndrome than the anticardiolipin antibody (aCL). Anti-beta 2-GPI, a subgroup of antibodies to PLbinding proteins, are closely associated with thrombosis and may be more sensitive markers of APS than aPLs detected by standard tests [241]. Although the association of aPL with stroke is documented, the importance of antiphospholipid antibodies as independent stroke risk factors is controversial [242–248]. The WARSS study [249] subgroup analysis did not suggest beneﬁt from anticoagulant (INR 1.4–2.8) over aspirin. Although patients are usually on a high dose of anticoagulant (INR target 3.5), the rate of recurrent thrombosis is still high in patients who had clinical signs of the disease [250]. Blood ﬂow, particularly in the brain microcirculation, is heavily dependent on blood viscosity. Hematocrit and ﬁbrinogen level are the two major components that most often determine blood viscosity [251,252]. Polycythemia and hyperﬁbrinogenemia therefore can increase whole blood viscosity and decrease cerebral blood ﬂow. Cerebral blood ﬂow at a hematocrit of 45 is about half the ﬂow at a hematocrit of 33. High ﬁbrinogen levels are known to increase the risk of stroke and large-vessel disease [253]. Ancrod (Malaysian pit viper venom) can lower ﬁbrinogen levels and potentially lyse thrombi. Other conditions, such as ones that cause high globulin levels (i.e., Waldenstro¨m’s macroglobulinemia, multiple myeloma) also can increase blood viscosity, but these are much less common. Very high leukocyte numbers seen in certain leukemias, such as acute myelomonocytic and myeloid leukemias, also increase blood viscosity [254]. Occasionally, high levels of serum lipids can also cause hyperviscosity syndrome [255]. The role of elevated homocysteine level as a vascular risk factor has long been suggested [256–259]. Although homocysteine can be lowered easily with small doses of folic acid, vitamin B12 and vitamin B6, it is not known whether lowering homocysteine will prevent stroke and other cardiovascular events [260–263]. Every patient with an ischemic stroke or TIA should have a measurement of the lipid proﬁle (total, high- and low-density lipoproteins, cholesterol). These levels are useful to analyze in patients with familial hyperlipidemia, premature atherosclerosis, and hyperviscosity syndromes, since elevated blood lipids can increase blood viscosity. Elevated erythrocyte sedimentation rate can be an indicator of an infectious or inﬂammatory condition. It should be ordered for an elderly patient suspected of temporal arteritis or for any patient with unexplained strokes or possible vasculitis. Occasionally embolic particles arise from foreign bodies, e.g., fat embolism or air embolism with trauma, bacterial emboli from cardiac valve vegetation, or tumor cells, which can dislodge and form emboli. However, vascular occlusions result from thrombi or atherosclerotic debris in the majority of the cases. Experts recognize three diﬀerent kinds of thrombi. Arterial occlusions usually result from the so-called white thrombus, while venous occlusions result from a red thrombus. The main building blocks of the white clot are platelets and a ﬁbrin net that form almost exclusively at areas where the vessel wall is abnormal. In contrast, the red clot consists mostly of red blood cells and ﬁbrin. The third type of clot consists of disseminated ﬁbrin deposition that can form in small vessels. These types of thrombi are distinct, and therefore they respond to diﬀerent therapeutic agents [264,265]. In patients with intracranial hemorrhage, bleeding diatheses are important causes for both SAH and ICH. The most common bleeding disorders are iatrogenic prescription of anticoagulants and ﬁbrinolytic and perhaps antiplatelet agents. PT and PTT measure-

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ments are usually suﬃcient to screen for these abnormalities. Platelet counts and bleeding time can detect quantitative or qualitative defects of platelets. Familial bleeding disorders like hemophilia are usually known from the history of the patient. Urine and stool can be tested for blood, and purpura should be looked for during the physical examination.

XVII. LUMBAR PUNCTURE Other than in the previously mentioned SAH, lumbar puncture is also helpful in the diagnosis of infectious or inﬂammatory conditions that can lead to ischemic or hemorrhagic stroke. In such patients CSF pleocytosis, elevated protein and immunoglobulin content, and elevated opening pressure are frequently found. The infectious agent usually can be identiﬁed from the CSF sample. In vasculitis the changes are less speciﬁc. In Behcß et’s syndrome, moderate pleocytosis, which is predominantly lymphocytic, and increased protein content, usually <100 mg/dL, can be found [266]. The most consistent abnormality in the CSF in isolated granulomatous angiitis is an increase in protein content, frequently >100 mg/dL, although the CSF is occasionally entirely normal. Red cells and increased immunglobulins are reported. The opening pressure may be increased, and many patients have moderate lymphocytic pleocytosis, usually<150 cells/AL, mimicking ‘‘chronic meningitis’’ at presentation. CSF examination is usually normal in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts and Leukoencaphalopathy (CADASIL), although oligoclonal bands with pleocytosis have been reported. CSF examination is negative in only 1 out of every 10 patient with cerebral venous sinus thrombosis. The most typical abnormalities are increased protein and red blood cell content. CSF examination is vital to rule out meningitis, which can present clinically with striking similarities to benign intracranial hypertension as a manifestation of cerebral venous thrombosis. The practical value of additional CSF studies is currently limited. Determination of stroke anatomy, pathological and pathophysiological ﬁndings using clinical skills, and results of advanced imaging techniques oﬀer great advantages compared with simple CT scans to guide the selection of patients for a speciﬁc type and route of treatment. In the near future clinical trials with documented vascular lesions should shed more light on optimal therapy.

REFERENCES 1. Faris CP, Wilmore D, et al. Radiologic visualization of neck vessels in healthy men. Neurology 1963; 13:386–396. 2. Sanelli PC, TS, Gonzalez RG, Eskey CJ. Normal variation of vertebral artery on CT angiography and its implications for diagnosis of acquired pathology. J Comput Assist Tomogr 2002; 26(3):462–470. 3. Davis PH, et al. Silent cerebral infarction in patients enrolled in the TOAST Study. Neurology 1996; 46(4):942–948. 4. Caplan L, DeWitt L, Breen J. Neuroimaging in patients with cerebrovascular disease. In: Greenberg JO, ed. Neuroimaging. New York: McGraw-Hill, 1999:493–520. 5. Minematsu K, Yamaguchi T, Omae T. ‘Spectacular shrinking deﬁcit’: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology 1992; 42(1):157–162.

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171. Horton JC, et al. Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1990; 27(6):867–872. 172. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg 1983; 58(3):331–337. 173. Morello G, Borghi GP. Cerebral angiomas. A report of 154 personal cases and a comparison between the results of surgical excision and conservative management. Acta Neurochir (Wien) 1973; 28(3):135–155. 174. Kader A, et al. The inﬂuence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1994; 34(5):801–808. 175. Duong DH, et al. Feeding artery pressure and venous drainage pattern are primary determinants of hemorrhage from cerebral arteriovenous malformations. Stroke 1998; 29(6):1167–1176. 176. Marks MP, et al. Hemorrhage in intracerebral arteriovenous malformations: angiographic determinants. Radiology 1990; 176(3):807–813. 177. Turjman F, et al. Correlation of the angioarchitectural features of cerebral arteriovenous malformations with clinical presentation of hemorrhage. Neurosurgery 1995; 37(5):856–862. 178. Miyasaka Y, et al. An analysis of the venous drainage system as a factor in hemorrhage from arteriovenous malformations. J Neurosurg 1992; 76(2):239–243. 179. Batjer H, Suss RA, Samson D. Intracranial arteriovenous malformations associated with aneurysms. Neurosurgery 1986; 18(1):29–35. 180. Shin M, et al. Retrospective analysis of a 10-year experience of stereotactic radio surgery for arteriovenous malformations in children and adolescents. J Neurosurg 2002; 97(4):779–784. 181. Turjman F, et al. Epilepsy associated with cerebral arteriovenous malformations: a multivariate analysis of angioarchitectural characteristics. AJNR Am J Neuroradiol 1995; 16(2):345–350. 182. Hoh BL, et al. Results of multimodality treatment for 141 patients with brain arteriovenous malformations and seizures: factors associated with seizure incidence and seizure outcomes. Neurosurgery 2002; 51(2):303–311. 183. Batjer H, Samson D. Arteriovenous malformations of the posterior fossa: clinical presentation, diagnostic evaluation and surgical treatment. Neurosurg Rev 1986; 9(4):287–296. 184. Schwartz A, Hennerici M. Noninvasive transcranial Doppler ultrasound in intracranial angiomas. Neurology 1986; 36(5):626–635. 185. Mast H, et al. Transcranial Doppler ultrasonography in cerebral arteriovenous malformations. Diagnostic sensitivity and association of ﬂow velocity with spontaneous hemorrhage and focal neurological deﬁcit. Stroke 1995; 26(6):1024–1027. 186. Uggowitzer MM, et al. Cerebral arteriovenous malformations: diagnostic value of echoenhanced transcranial Doppler sonography compared with angiography. AJNR Am J Neuroradiol 1999; 20(1):101–106. 187. Fleischer LH, et al. Relationship of transcranial Doppler ﬂow velocities and arteriovenous malformation feeding artery pressures. Stroke 1993; 24(12):1897–1902. 188. Zabramski JM, Spetzler RF. Intracranial aneurysms. In: Barnett HJ, et al., ed. Stroke: Pathophysiology, Diagnosis, and Management. Edinburgh: Churchill Livingstone, 1998:1263–1298. 189. Norman D, et al. Quantitative aspects of computed tomography of the blood and cerebrospinal ﬂuid. Radiology 1977; 123(2):335–338. 190. Caplan LR. Caplan’s Stroke: A clinical approach. 3rd ed. Boston: Butterworth-Heinemann, 2000:343–381. 191. Rinkel GJ, et al. The clinical course of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Ann Neurol 1991; 29(5):463–468. 192. Ross JS, et al. Intracranial aneurysms: evaluation by MR angiography. AJNR Am J Neuroradiol 1990; 11(3):449–455. 193. Okahara M, et al. Diagnostic accuracy of magnetic resonance angiography for cerebral aneurysms in correlation with 3D-digital subtraction angiographic images: a study of 133 aneurysms. Stroke 2002; 33(7):1803–1808.

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194. Adams WM, Laitt RD, Jackson A. The role of MR angiography in the pretreatment assessment of intracranial aneurysms: a comparative study. AJNR Am J Neuroradiol 2000; 21(9):1618–1628. 195. Bernstein MA, et al. High-resolution intracranial and cervical MRA at 3.0T: technical considerations and initial experience. Magn Reson Med 2001; 46(5):955–962. 196. Watanabe Z, et al. The usefulness of 3D MR angiography in surgery for ruptured cerebral aneurysms. Surg Neurol 2001; 55(6):359–364. 197. Ng SH, et al. CT angiography of intracranial aneurysms: advantages and pitfalls. Eur J Radiol 1997; 25(1):14–19. 198. Kato Y, et al. Multi-slice 3D-CTA - an improvement over single slice helical CTA for cerebral aneurysms. Acta Neurochir (Wien) 2002; 144(7):715–722. 199. Griewing B, et al. Transcranial power mode Doppler duplex sonography of intracranial aneurysms. J Neuroimaging 1998; 8(3):155–158. 200. Hijdra A, et al. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 1988; 19(10):1250–1256. 201. Brouwers PJ, et al. Amount of blood on computed tomography as an independent predictor after aneurysm rupture. Stroke 1993; 24(6):809–814. 202. Wozniak MA, et al. Detection of vasospasm by transcranial Doppler sonography. The challenges of the anterior and posterior cerebral arteries. J Neuroimaging 1996; 6(2):87–93. 203. Burch CM, et al. Detection of intracranial internal carotid artery and middle cerebral artery vasospasm following subarachnoid hemorrhage. J Neuroimaging 1996; 6(1):8–15. 204. Lysakowski C, et al. Transcranial Doppler versus angiography in patients with vasospasm due to a ruptured cerebral aneurysm: a systematic review. Stroke 2001; 32(10):2292–2298. 205. Sloan MA, et al. Transcranial Doppler detection of vertebrobasilar vasospasm following subarachnoid hemorrhage. Stroke 1994; 25(11):2187–2197. 206. Soustiel JF, et al. Basilar vasospasm diagnosis: investigation of a modiﬁed ‘‘Lindegaard Index’’ based on imaging studies and blood velocity measurements of the basilar artery. Stroke 2002; 33(1):72–77. 207. Sloan MA. Diagnosis of basilar artery vasospasm. Stroke 2002; 33(7):1746–1747. 208. Powsner RA, et al. SPECT imaging in cerebral vasospasm following subarachnoid hemorrhage. J Nucl Med 1998; 39(5):765–769. 209. Davis SM, et al. Correlations between cerebral arterial velocities, blood ﬂow, and delayed ischemia after subarachnoid hemorrhage. Stroke 1992; 23(4):492–497. 210. Hosono M, et al. Non-invasive quantitative monitoring of cerebral blood ﬂow in aneurysmal subarachnoid haemorrhage with 99mTc-ECD. Nucl Med Commun 2002; 23(1):5–11. 211. Rosen JM, et al. Postoperative changes on brain SPECT imaging after aneurysmal subarachnoid hemorrhage. A potential pitfall in the evaluation of vasospasm. Clin Nucl Med 1994; 19(7):595–597. 212. Iseda T, et al. Angiographic cerebral circulation time before and after endovascular therapy for symptomatic vasospasm. Clin Radiol 2000; 55(9):679–683. 213. Hirata M, et al. Computational imaging of cerebral perfusion by real time processing of DSA images. Clinical applications. Neurol Res 1998; 20(4):327–332. 214. Ohkuma H, et al. Impact of cerebral microcirculatory changes on cerebral blood ﬂow during cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2000; 31(7):1621– 1627. 215. Rajendran JG, et al. Brain SPECT used to evaluate vasospasm after subarachnoid hemorrhage: correlation with angiography and transcranial Doppler. Clin Nucl Med 2001; 26(2):125–130. 216. Rordorf G, et al. Diﬀusion- and perfusion-weighted imaging in vasospasm after subarachnoid hemorrhage. Stroke 1999; 30(3):599–605. 217. Leclerc X, et al. Symptomatic vasospasm after subarachnoid haemorrhage: assessment of brain damage by diﬀusion and perfusion-weighted MRI and single-photon emission computed tomography. Neuroradiology 2002; 44(7):610–616.

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218. Bracard S, et al. Relevance of diﬀusion and perfusion weighted MRI for endovascular treatment of vasospasm in subarachnoid hemorrhage. J Neuroradiol 2001; 28(1):27–32. 219. Condette-Auliac S, et al. Vasospasm after subarachnoid hemorrhage: interest in diﬀusionweighted MR imaging. Stroke 2001; 32(8):1818–1824. 220. Hirashima Y, et al. Right Sylvian ﬁssure subarachnoid hemorrhage has electrocardiographic consequences. Stroke 2001; 32(10):2278–2281. 221. Zaroﬀ JG, et al. Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery 1999; 44(1):34–40. 222. Weir BK. Pulmonary edema following fatal aneurysm rupture. J Neurosurg 1978; 49(4):502–507. 223. Espiner EA, et al. The neuro-cardio-endocrine response to acute subarachnoid haemorrhage. Clin Endocrinol (Oxf) 2002; 56(5):629–635. 224. deVeber G, Andrew M. Cerebral sinovenous thrombosis in children. N Engl J Med 2001; 345(6):417–423. 225. Bousser MG. Cerebral venous thrombosis: nothing, heparin or local thrombolysis? Stroke 1999; 30(3):481–483. 226. de Bruijn SF, de Haan RJ, Stam J. Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. For The Cerebral Venous Sinus Thrombosis Study Group. J Neurol Neurosurg Psychiatry 2001; 70(1):105–108. 227. de Bruijn SF, et al. Long-term outcome of cognition and functional health after cerebral venous sinus thrombosis. Neurology 2000; 54(8):1687–1689. 228. Einhaupl KM, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338(8767):597–600. 229. Ameri A, Bousser MG. Cerebral venous thrombosis. Neurol Clin 1992; 10(1):87–111. 230. Brucker AB, et al. Heparin treatment in acute cerebral sinus venous thrombosis: a retrospective clinical and MR analysis of 42 cases. Cerebrovasc Dis 1998; 8(6):331–337. 231. deBruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30(3):484–488. 232. Haley EC Jr, et al. Deep cerebral venous thrombosis. Clinical, neuroradiological, and neuropsychological correlates. Arch Neurol 1989; 46(3):337–340. 233. Smith AG, Cornblath WT, Deveikis JP. Local thrombolytic therapy in deep cerebral venous thrombosis. Neurology 1997; 48(6):1613–1619. 234. Gerszten PC, et al. Isolated deep cerebral venous thrombosis treated by direct endovascular thrombolysis. Surg Neurol 1997; 48(3):261–266. 235. Chow K, et al. Endovascular treatment of dural sinus thrombosis with rheolytic thrombectomy and intra-arterial thrombolysis. Stroke 2000; 31(6):1420–1425. 236. Scott DJ, et al. Venous thrombolysis. Eur J Vasc Surg 1988; 2(4):274. 237. Dowd CF, et al. Application of a rheolytic thrombectomy device in the treatment of dural sinus thrombosis: a new technique. AJNR Am J Neuroradiol 1999; 20(4):568–570. 238. Wasay M, et al. Nonrandomized comparison of local urokinase thrombolysis versus systemic heparin anticoagulation for superior sagittal sinus thrombosis. Stroke 2001; 32(10):2310–2317. 239. Mammen EF. Sticky platelet syndrome. Semin Thromb Hemost 1999; 25(4):361–365. 240. Adams HP Jr, et al. Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the Stroke Council. American Heart Association. Stroke 1994; 25(9):1901–1914. 241. Carreras LO, Forastiero RR, Martinuzzo ME. Which are the best biological markers of the antiphospholipid syndrome? J Autoimmun 2000; 15(2):163–172. 242. Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. The Antiphospholipid Antibodies and Stroke Study Group (APASS). Neurology 1997; 48(1):91–94. 243. Tuhrim S, et al. Antiphosphatidyl serine antibodies are independently associated with ischemic stroke. Neurology 1999; 53(7):1523–1527. 244. Ahmed E, et al. Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Vasterbotten cohort project. Stroke 2000; 31(6):1289–1293.

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245. Tuhrim S, et al. Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999; 30(8):1561–1565. 246. Muir KW, et al. Anticardiolipin antibodies in an unselected stroke population. Lancet 1994; 344(8920):452–456. 247. Brey RL, et al. Antiphospholipid antibodies and stroke in young women. Stroke 2002; 33(10):2396–2400. 248. Mohr JP. [Prevention of recurrent ischemic stroke: recent clinical trial results]. Neurologia 2002; 17(7):378–382. 249. Mohr JP, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345(20):1444–1451. 250. Ruiz-Irastorza G, et al. Bleeding and recurrent thrombosis in deﬁnite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med 2002; 162(10):1164–1169. 251. Grotta J, et al. Whole blood viscosity parameters and cerebral blood ﬂow. Stroke 1982; 13(3):296–301. 252. Coull BM, et al. Chronic blood hyperviscosity in subjects with acute stroke, transient ischemic attack, and risk factors for stroke. Stroke 1991; 22(2):162–168. 253. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118(12):956–963. 254. Roath S, Davenport P. Leucocyte numbers and quality: their eﬀect on viscosity. Clin Lab Haematol 1991; 13(3):255–262. 255. Rosenson RS, et al. Hyperviscosity syndrome in a hypercholesterolemic patient with primary biliary cirrhosis. Gastroenterology 1990; 98(5 pt 1):1351–1357. 256. Kittner SJ, et al. Homocysteine and risk of cerebral infarction in a biracial population: the stroke prevention in young women study. Stroke 1999; 30(8):1554–1560. 257. Verhoef P, et al. A prospective study of plasma homocysteine and risk of ischemic stroke. Stroke 1994; 25(10):1924–1930. 258. Eikelboom JW, et al. Homocysteine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131(5):363–375. 259. Harjai KJ. Potential new cardiovascular risk factors: left ventricular hypertrophy, homocysteine, lipoprotein(a), triglycerides, oxidative stress, and ﬁbrinogen. Ann Intern Med 1999; 131(5):376–386. 260. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis 2002; 13(2):120–126. 261. Toole JF. Vitamin intervention for stroke prevention. J Neurol Sci 2002; 203–204:121–124. 262. Sato Y, et al. Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic stroke: eﬀect of combined therapy with folic acid and mecobalamine. J Neurol Sci 2002; 202(1–2):65–68. 263. Spence JD, et al. Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design. Neuroepidemiology 2001; 20(1):16–25. 264. Deykin D. Thrombogenesis. N Engl J Med 1967; 276(11):622–628. 265. Caplan LR. Caplan’s Stroke: A Clinical Approach. 3rd ed. Boston: Butterworth-Heinemann, 2000:17–50. 266. O’Duﬀy JD, Goldstein NP. Neurologic involvement in seven patients with Behcßet’s disease. Am J Med 1976; 61(2):170–178.

7 Interactions Between Cardiovascular and Cerebrovascular Disease Giuseppe Di Pasquale Maggioze Hospital, Bologna, Italy

Stefano Urbinati and Giuseppe Pinelli Bellaria Hospital, Bologna, Italy

Possible connections between heart and brain have long been suggested. Recent interest in heart-brain interactions has implications for both research and clinical practice [1–4]. Awareness of the need for a multidisciplinary approach to atherosclerotic disease, the widespread use of transesophageal echocardiography (TEE) for identifying cardioembolic lesions in patients with cerebral ischemia, and the common experience in developing coronary care units and intensive stroke units have reinforced the cooperation between cardiologists and neurologists. The major topics of interest in this ﬁeld include the association of cerebrovascular and coronary artery disease (CAD) and cardioembolic stroke. Coexisting CAD and cardiac sources of embolism should be sought in every patient with cerebral ischemia [5] (Fig. 1).

I. ASSOCIATION OF CEREBROVASCULAR AND CORONARY ARTERY DISEASE A. Epidemiology of Atherosclerotic Disease Atherosclerosis, the leading cause of mortality in the western world, is a progressive, multifocal disease that becomes symptomatic in middle to late adulthood. During the development of atherosclerotic disease, coronary and carotid atherosclerotic lesions may often coexist. Clinical research performed in the last 20 years on atherosclerotic disease has improved our knowledge of the natural history of atherosclerotic disease, which can be summarized as follows: Atherosclerosis has ‘‘elective’’ arterial localizations such as carotid bifurcation, interventricular coronary artery, ascending and abdominal aorta. Coronary lesions usually develop earlier than peripheral or carotid lesions. 133

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Figure 1 Algorithm of cardiac evaluation in patients with cerebrovascular disease.

Atherosclerosis produces clinical events with diﬀerent pathophysiological mechanisms: embolism is more frequent in cerebral transient ischemic attack (TIA) and stroke; thrombosis is more frequent in acute myocardial infarction (MI). There is a hierarchy among atherosclerotic lesions, and the prognosis is mainly inﬂuenced by the presence of coronary lesions. B. Pathophysiology of Atherosclerotic Disease Atherosclerotic disease results from complex interactions between environmental risk factors and genetic traits. Recently, a third factor, the individual reaction to systemic (infective?) triggers [6–10], expressed by ‘‘inﬂammatory’’ markers such as C-reactive protein [11,12], has been identiﬁed. The evaluation of patients with atherosclerosis independently by the site of clinical presentation of the disease should address the following questions: Which risk factors for atherosclerosis are present? Is atherosclerotic disease detectable in siblings? Are inﬂammatory markers, such as C-reactive protein, abnormal? Are there atherosclerotic lesions in other arteries? What is the short- and long-term risk of future cardiovascular events? C. Early Identification of Patients with Carotid and Coronary Artery Disease Prevention of cardiovascular events is usually classiﬁed as primary prevention in subjects without a history of events, and secondary prevention in patients with previous cardiovascular events. Recently, this classiﬁcation has been challenged by the identiﬁcation of a third group of subjects: those at high risk of cardiovascular events, even if without history of previous events. These subjects, who usually have multiple risk factors (mostly diabetes mellitus) and high prevalence of atherosclerosis in siblings, should be carefully evaluated and more aggressively treated. In recent years in both the United States and Europe, risk charts have been developed to predict the probability of cardiovascular events within 5 years by age, sex, smoking habits, arterial blood pression, cholesterolemia, and presence of diabetes mellitus [13–15].

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In patients with high risk of cardiovascular events, a further risk stratiﬁcation should include inﬂammatory markers, such as C-reactive protein [11,12], expression of active atherosclerotic lesions, and markers of early atherosclerotic lesions, such as abnormal carotid intima-media thickness [16–20], coronary calciﬁcations identiﬁed by multislice computed tomography (CT) [21–23], or abnormal ankle-brachial index [24], an expression of early peripheral artery disease.

D. Algorithm for Identifying CAD in Patients with Carotid Artery Disease Patients with symptomatic or asymptomatic carotid artery disease have a high risk of coexistent CAD that may strongly inﬂuence the prognosis [25,26]. MI and sudden death are the leading long-term causes of death in patients with cerebrovascular disease [27]. One third of patients with TIA or stroke have a history of previous MI or angina pectoris [28]. A similar prevalence of symptomatic CAD may be found in patients with asymptomatic carotid disease. Patients with carotid lesions have signiﬁcant risk of coronary events during follow-up. After a TIA, cerebrovascular mortality was nearly 2% per year, while the coronary mortality is nearly 5% per year [29]. Even in patients with asymptomatic carotid bruits, which are detectable in 5% of the population aged z45 years, the prevalence rate of coronary death is three times the cerebrovascular mortality [30]. In patients undergoing carotid endarterectomy, MI is the leading cause of early and late morbidity and mortality. The annual mortality for coronary events is 5%, while the occurrence of fatal stroke is nearly 3% [31]. Several institutions in 1980s adopted a cardiological algorithm for identifying a coexistent CAD. In 1985 Hertzer et al. [32] investigated 506 carotid endarterectomy candidates by coronary angiography and found a 65% angiographic prevalence of critical coronary artery stenosis. Among patients without a history of CAD, the prevalence of critical stenosis was 40%. In the following years, several authors suggested cardiologic algorithms for researching a coexistent CAD in cerebrovascular patients [33]. Exercise electrocardiogram (ECG) testing is a well-established, safe, inexpensive method for detecting CAD and should be considered the ﬁrst-choice test in patients able to exercise. According to the Bayes theorem, in patients with a high prevalence of CAD, such as those with cerebrovascular ischemic disease, the predictive value of abnormal tests is very high. In patients with abnormal exercise testing the screening can stop. Nevertheless, in patients with abnormal, but asymptomatic or indeterminant exercise ECG testing, a second marker of myocardial ischemia, such as myocardial perfusion scintigraphy, should be recommended. Di Pasquale et al. [34], showed coexistent silent CAD in 28% of 190 consecutive patients with cerebral ischemia undergoing carotid endarterectomy. Later, Urbinati et al. [35] conﬁrmed the good prognostic signiﬁcance of this cardiological algorithm, even in patients without a history of CAD. After a mean follow-up period of 5.4 years, among the 25% of patients with silent CAD the occurrence of coronary events was 29%, whereas among those with normal ECG testing it was only 1.2%. The prognosis of patients with silent CAD was similar to that of cerebrovascular patients with previous MI [36]. In patients unable to exercise, CAD may be identiﬁed by alternative tests [37]. Dipyridamole myocardial perfusion scintigraphy and dipyridamole echocardiography are the most used tests. Both tests showed adequate sensitivity and speciﬁcity for the detection of a coexistent CAD [38–44].

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Other noninvasive studies have conﬁrmed the role of carotid artery disease [45,46] as a predictor of severe CAD. Adams et al. nearly 20 years ago expressed the need for a new approach for patients with carotid TIA including careful cardiological monitoring [47]. E. Algorithm for Identifying Carotid Artery Disease in Patients with CAD In patients with CAD, the identiﬁcation of coexistent carotid disease has not been recommended by most important U.S. and European guidelines, probably because in the multivariate analysis on the prognostic predictors after acute MI, the role of noncoronary artery disease has not been fully investigated. Only in recent years have analyses from large databases of patients with known CAD shown a prognostic role of carotid and peripheral artery disease for predicting cardiovascular events [48–52]. Nevertheless, shifting from a quantitative to a qualitative analysis of carotid lesions, the prognostic signiﬁcance of this investigation assumes a more intriguing role. Urbinati et al. [53] studied the morphology of carotid lesions in patients with unstable or stable CAD, ﬁnding a higher prevalence of active plaques in those with unstable CAD. After a 1.2-year follow-up, most patients with active plaques developed quiescent plaques. Systemic activation (by infective agents or immunity mechanisms) of atherosclerotic lesions may trigger acute coronary syndrome. Another intriguing question raised by these studies concerns the relationship between the evidence of active carotid plaques and the risk of embolism. Several studies suggest that left ventricular thrombosis cannot explain most strokes occurring in patients with acute MI [54]. Bodenheimer et al. [55] observed that the occurrence of ischemic stroke is similar in patients with anterior and inferior MI, while left ventricular thrombosis occurs more frequently in those with anterior MI. Modrego-Pardo et al. [56] investigated a series of patients with or without angina pectoris by cerebral MRI showing that patients with acute coronary syndromes have a higher prevalence of silent brain infarcts. Tanne et al. [57] observed that the risk of stroke is higher in patients with unstable than stable angina, suggesting that patients with unstable angina may have active carotid or aortic lesions. Finally, in a recent study on elderly patients with MI, alternative sources of embolism, such as ascending aortic plaques, are suggested to explain the high prevalence of cerebrovascular complications [58]. In conclusion, patients with known CAD should be routinely evaluated for identiﬁcation of coexistent carotid arteries. Qualitative analysis of these lesions and the detection of abnormal levels of inﬂammatory markers could improve the prediction of future cardiovascular events. F. Treatment of Patients with Coronary and Carotid Artery Disease Patients with CAD and carotid artery disease should be aggressively monitored and treated because of their very high risk of future cardiovascular events. Non-pharmacological treatment should include diet modiﬁcation, smoking cessation, regular exercise, and weight control. Such programs should be performed in specialized settings with a multidisciplinary approach for secondary prevention, including educational programs [59,60]. Evidence-based pharmacological intervention for preventing cardiovascular events includes 1. Antithrombotic treatment: Aspirin is the ﬁrst choice, followed by ticlopidine or clopidogrel [61,62]. Ongoing studies are investigating if the association of aspirin and clopidogrel may be superior to aspirin alone.

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2. Statins: Statins are very eﬀective for preventing cardiovascular events in patients with hypercholesterolemia, as both primary and secondary prevention. Recent studies suggest that statins may prevent coronary and cerebrovascular events in patients with normal cholesterolemia, probably by alternative mechanisms, such as plaque stabilization [63,64]. 3. ACE inhibitors: In recent studies, ACE inhibitors reduced cardiovascular events in high-risk patients, probably because of endothelial protective eﬀects [65]. In patients with severe CAD and carotid artery disease in whom surgical revascularization is indicated, the choice between staged or combined operations is determined by assessment of the relative severity of carotid and coronary risk factors and by the experience of the center [66–69]. The development of percutaneous coronary interventions and, more recently, of percutaneous carotid interventions has challenged the previous guidelines. In most cases a hybrid treatment including both surgical and percutaneous interventions may be feasible; nevertheless, no randomized studies on these new approaches are available.

II. CARDIOEMBOLIC STROKE Nearly one quarter of all ischemic strokes are cardioembolic (Table 1). Nonvalvular atrial ﬁbrillation (NVAF) accounts for about 50% of cardioembolic strokes [70–75]. In recent years, the widespread use of TEE has allowed more frequent identiﬁcation of potential cardiac sources of embolism in patients with cryptogenetic stroke, particularly in those aged <45 years. TEE is able to show lesions undetectable by transthoracic echocardiography (TTE), such as left atrial appendage thrombosis and spontaneous echocontrast, occurring mainly in patients with mitral valve stenosis or atrial ﬁbrillation (AF), patent foramen ovale (PFO), and atrial septal aneurysm (ASA) (mainly in young patients with cryptogenetic stroke), and ascending aorta atherosclerotic lesions (mainly in aged population) [76–82].

A. Clinical Diagnosis of Cardioembolic Stroke The diagnosis of cardioembolic stroke is often diﬃcult and frequently uncertain. So far, diagnosis of cardioembolic stroke is done by exclusion in the absence of signiﬁcant carotid disease. Neurological symptoms of stroke and neuroimaging ﬁndings may be suggestive but are not entirely speciﬁc for the diagnosis of cardioembolic stroke. Also, lacunar strokes,

Table 1 Possible Mechanisms for Stroke in Cardiac Patients Mechanism Cardioembolism

Atheroembolism Lacunar

Major causes AF, recent MI, rheumatic mitral stenosis, prosthetic heart valves dilated cardiomyopathies, cardiac tumors, infective endocarditis, complicated aortic plaques Coexisting carotid artery disease in patients with CAD Hypertensive heart disease

AF = atrial ﬁbrillation; MI = myocardial infarction; CAD = coronary artery disease.

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usually attributed to small vessel disease, have recently been associated with cardioembolic disease. The cardiac lesions more frequently detected in patients with TIA or stroke include: 1. Lesions at high embolic risk: ventricular thrombi (detectable in acute MI and dilatative cardiomyopathies), left atrial appendage thrombi (detectable in patients with AF, sick sinus syndrome, and atrial ﬂutter), often associated to spontaneous echo contrast and left atrial appendage dysfunction, endocarditic vegetations (both infective and degenerative or marantic), rheumatic mitral valve disease, thrombosis of prosthetic heart valves, cardiac tumors, and aortic atherosclerotic plaques. 2. Lesions at low or uncertain embolic risk: ASA, PFO, mitral annular calciﬁcation, aortic valve calciﬁcation or calciﬁed aortic valve stenosis, and mitral valve prolapse (MVP) (Table 2). Besides physical examination, echocardiography is the technique of choice for the conﬁrmation of cardiac sources of embolism suspected at clinical examination and for the detection of occult cardiac lesions in patients with normal clinical examination. B. Transthoracic and Transesophageal Echocardiography TTE, which was ﬁrst introduced in clinical practice in the 1970s, is used regularly in the cardiological investigation of patients with ischemic stroke [83]. Studies show that TEE is eﬀective in detecting potential cardiac sources of embolism in many patients with history and clinical evidence of heart disease [84,85]. Conversely, a negative echocardiographic Table 2 Risk Stratiﬁcation of Cardiac Sources of Embolism High embolic risk Atrial ﬁbrillation Rheumatic mitral stenosis Prosthetic cardiac valves Recent myocardial infarction Dilated cardiomyopathy Cardiac tumors Infective endocarditis Low or uncertain embolic risk Atrial ﬂutter Mitral valve prolapse Mitral annular calciﬁcation Valvular strands Patent foramen ovale Atrial septal aneurysm Chiari’s network Aortic valve calciﬁcation Calciﬁed aortic stenosis Hypertrophic cardiomyopathy Remote myocardial infarction Left ventricular aneurysm Aortic plaques

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result was found in nearly 95% of patients with normal ﬁndings. In these patients the yield of TTE was only 1.5% (range 0–6%). An exception is represented by patients younger than 45 years. For these patients, who have a low prevalence of cerebrovascular disease, a hidden cardioembolic lesion is detectable in about 35% of cases by TTE [80,82,86–88]. In other words, TTE is an adequate tool for searching potentially cardioembolic lesions in patients with known cardiac disease, whereas it has a very low sensitivity in patients without overt cardiac disease. An important advancement of our knowledge about the possible sources of cardioembolic stroke has been achieved with the routine use of TEE. TEE provides detailed visualization of the morphology and function of cardiac structures, which cannot be obtained by the transthoracic approach. The superiority of the transesophageal approach is related to the proximity of the probe to the heart chambers with an absence of intervening structures. TEE gives an unimpaired view of the right and left atrial chambers, of the interatrial septum, and of the atrioventricular valves and allows the exploration of the left atrial appendage. This structure is inaccessible with the transthoracic approach and is frequently occupied by thrombi. The search for potential cardiac sources of embolic stroke actually represents one of the major indications for transesophageal echocardiography in most institutions [89]. C. Other Cardiac Techniques Cardiac ultrafast CT, magnetic resonance imaging (MRI), and Indium 111–labeled platelet scintigraphy are supplemental imaging techniques that can be used when echocardiographic studies are nondiagnostic. Indium 111–labeled platelet scintigraphy is an imaging technique for detecting ongoing platelet deposition on the surfaces of thrombi. It allows evaluation of thrombus activity, particularly in unstable conditions such as prosthetic cardiac valve thrombosis and acute myocardial infarction. The high cost and long duration of the study are the main limits of this technique. ECG Holter monitoring in patients with TIA or stroke may disclose potentially embologenic arrhythmias in less than 4% of cases. These data suggest that Holter monitoring should be reserved for patients with suspected paroxysmal AF or sick sinus syndrome. Although the mechanism of stroke in patients with sick sinus syndrome is yet to be elucidated, episodes of transient AF or severe bradycardia, in the presence of critical atherosclerotic carotid lesions may be involved. D. Patients with Overt Cardiac Disease In patients with overt cardiac disease the sensitivity of TTE was 76% and that of TEE 85% [72–75]. TEE provides additional information on the cardiac disease and can disclose left atrial or appendage thrombi, spontaneous echocontrast, and left atrial appendage dysfunction, which are signiﬁcant predictors of high thromboembolic risk. 1. Atrial Fibrillation Among the possible cardiac sources of embolism, NVAF is the most frequent, accounting for 45% of cardioembolic strokes [71]. NVAF carries a high risk of systemic embolism, in particular stroke. The risk of stroke ranges widely between 0.4% and 12% per year, with an average of 4.5% per year [90–92]. Overall, the mortality associated with stroke in NVAF is twice that of stroke from other causes.

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The eﬃcacy of oral anticoagulant treatment (OAT) for the prevention of stroke has been deﬁnitely assessed by large randomized clinical trials [93–97]. Warfarin decreased the frequency of all strokes by 68%, and the risk of bleeding was quite low (1.3% in warfarintreated patients) [98]. However, the bleeding risk is likely higher in patients treated in general clinical practice, because patients included in these trials were carefully selected, representing only 7–39% of the screened patients. Moreover, the safety of long-term OAT has not been completely deﬁned among patients older than 75 years. A risk stratiﬁcation is therefore warranted for identifying patients at high and low risk of stroke in order to plan optimal antithrombotic treatment. Clinical echocardiographic risk factors have been identiﬁed and prospectively validated [99]. According to recent guidelines on antithrombotic treatment in NVAF, OAT is mandatory in patients with recent congestive heart failure or left ventricular dysfunction, previous thromboembolism, systolic blood pressure z160 mmHg and age z75 years [100]. In the presence of any of these risk factors, patients with NVAF should be treated with adjusted-dose warfarin with target International Normalized Ratio (INR) ranging from 2 to 3. In patients aged 65–75 years with diabetes mellitus or CAD without left ventricular dysfunction, OAT should be preferred if at least two risk factors are present. Finally, patients without any of these risk factors and aged V65 years have low risk of thromboembolism (lone AF), and can be treated with aspirin 325 mg. According to these criteria, approximately 60% of patients with NVAF should be treated with OAT, perhaps more if a history of hypertension is taken into account. TEE allows the detection of further markers of thromboembolism in patients with NVAF. These markers include left atrial and left atrial appendage thrombi, spontaneous echo contrast, and left atrial appendage dysfunction [101–103]. The prevalence of these ﬁndings is signiﬁcantly higher in AF patients who have suﬀered stroke or systemic embolism. Recently, several authors suggested that in patients with NVAF with contraindications for OAT, percutaneous occlusion of left atrial appendage may be safe and feasible. Sievert at al. [104] reported the results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) device. The device consists of a nitinol cage covered with a polymeric membrane and has a series of hooks to help anchor it in the mouth of the left atrial appendage. In their ﬁrst 15 patients at 6-month follow-up, Sievert et al. reported no complications and no strokes. Later, the study extended the series to 87 patients: implantation was successful in 86 of the 87 patients, and after a mean follow-up of 10 months only one minor stroke and two TIA had occurred [105]. The hypothesis that the persistence of sinus rhythm in patients with AF could be an eﬀective prophylaxis for embolic events was a secondary results of a number of recent randomized trials comparing the two strategies of rate control and rhythm control. In the AFFIRM trial [106], the rhythm control arm discontinued OAT after sinus rhythm had been achieved and maintained for one month. After an average 3.5-year follow-up period, 85– 90% of the patients in the rate control group remained in OAT versus 70% of rhythm control group. INR < 2.0 was detected in 33% of rate control and in 58% of those in the rhythm control arm. At follow-up, 60% of patients in the rhythm control arm were in normal sinus rhythm. Ischemic stroke occurred in 5.7% of rate control and in 7.3% of rhythm control patients. Likewise, in the RACE trial [107], in which OAT was discontinued in patients in whom sinus rhythm had been achieved and maintained for one month, patients in the rhythm control group experienced more thromboembolic complications (7.5%) compared to those in the rate control arm (5.5%). A meta-analysis of four studies comparing rate control with rhythm control strategies (AFFIRM, RACE, STAF, and PIAF) including

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5034 patients with AF demonstrated an odds ratio of 1.36 (95% CI 1.03–1.78; p = 0.04) for ischemic stroke with the rhythm control strategy in comparison with rate control. The cumulative results of these studies clearly indicate that a strategy of vigorous rhythm control by means of cardioversion and antiarrhythmic prophylaxis is not suﬃcient protection against thromboembolism. Continuous OAT, even after restoration of sinus rhythm, seems warranted in most patients with AF and risk factors for stroke. Finally, when electrical cardioversion of AF is planned, OAT should be performed at least 4 weeks before the attempt to achieve sinus rhythm restoration. Several studies suggest that in patients with recent NVAF, if LAA thrombosis or echocontrast are absent at TEE, electrical cardioversion may be feasible and safe after a 24- to 48-hour period of heparin treatment [108–110]. 2. Atrial Flutter Only in recent years has it been established that the risk of stroke is not neglegible in patients with atrial ﬂutter. Similarly to AF, atrial ﬂutter exhibits evidence of left atrial and left atrial appendage dysfunction either in persistent atrial ﬂutter or after electrical cardioversion or radio-frequency ablation [111–114]. Moreover, prevalence of left atrial thrombi and spontaneous echo contrast of 10% and 30%, respectively, have been documented in patients with atrial ﬂutter by TEE [115–118]. The prevalence of systemic thromboembolism and stroke is about 7%, with an estimated risk of 1.8% per year, which is only slightly less than that observed in patients with AF [119–122]. Eﬀective OAT achieves a signiﬁcant reduction of the embolic risk. In the absence of controlled clinical trials, the indications for OAT should be the same as established in the guidelines for AF. 3. Acute Myocardial Infarction Since the 1980s several studies have focused on the risk of stroke and systemic thromboembolism in patients with recent MI. Embolic risk is high in patients with anterior MI and in those with left ventricular thrombosis [123–126]. The risk of ischemic stroke is presumed to be 1–3% for all MI patients and 2–6% for the anterior location [127]. Echocardiographic studies have reported a high incidence of left ventricular thrombi following MI. In a meta-analysis of several echocardiographic studies including 2018 patients with recent MI, the prevalence of left ventricular thrombosis was 27% [128]. This ﬁnding is almost exclusive to patients with anterior MI (39%), whereas for the inferior location the prevalence of thrombus is very low (0–5%). About 90% of mural thrombi occur when the ventricular apex is involved. In most cases thrombus occurs within 48 hours from the acute MI, although it may be found even after 1–2 weeks [129]. The risk of stroke is undoubtedly high when left ventricular thrombus is detected. Indeed, the rate of embolic events was 18% in a pooling of 921 patients with thrombus, in comparison with 2% in patients without. Furthermore, a meta-analysis from 11 echocardiographic studies performed in patients with acute MI showed a ﬁvefold increase in the embolic risk in the presence of left ventricular thrombosis [130]. The morphological characteristics of thrombi have a clinical importance because thrombi with mobility and protrusion into the left ventricular cavity have higher embolic potential. The prevalence of embolic events is 55% for mobile thrombus versus 10% for stratiﬁed thrombus, and 47% for protruding thrombus versus 7% for stratiﬁed thrombi [127,128]. Most embolic events, including stroke, occur within 3 weeks from acute MI. OAT has been shown to reduce the prevalence of intracardiac thrombus (odds ratio 0.32), as well

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as to decrease the risk for systemic embolism. In the previously mentioned pooled review of echocardiographic studies, patients with left ventricular thrombosis who were on OAT exhibited a relative risk of 0.3% to suﬀer an embolic event [128]. This means that OAT decreases the embolic risk by 70% in patients with MI and echocardiographic documentation of thrombus. Guidelines recommend the use of OAT following MI in patients at high risk for embolic events. Patients with large anterior MI or with apex involvement should receive heparin treatment independent from the use of thrombolytics. In those with mural thrombus or at high risk for embolism (heart failure, previous embolic event, AF), oral warfarin is given to reach an INR between 2.0 and 3.0. OAT must be continued for at least 3 months because embolic risk declines thereafter; anticoagulation should be continued in patients with chronic AF or other documented risk factors, such as left ventricular dysfunction [131]. Long-term trials with antiplatelet agents or OAT following MI show a signiﬁcant reduction in the occurrence of stroke. Because of the low embolic risk after 3 weeks from MI, it is conceivable that antithrombotic therapy prevents atherothrombotic stroke due to carotid artery disease, rather than from cardioembolic sources. Particularly, aspirin is able to reduce non fatal stroke by 25% at 27 months [132]. Clinical investigations with OAT versus placebo show a higher reduction of stroke (from 40% in Sixty Plus [133] and 42% in ASPECT [134] to 55% in WARIS [135]), in spite of a reasonably low hemorrhagic risk. However, intensity of anticoagulation in these studies was higher (INR 2.7–4.8) than that recommended in clinical practice. A subsequent analysis from ASPECT investigators has shown that optimal intensity of OAT is between INR of 3 and 4, because the mildly increased risk of bleeding complications is oﬀset by a marked reduction in ischemic events during a 3-year period [136]. Comparison between aspirin and OAT following MI has been tested in two trials, but no conclusive results are available [137,138]. The combination of aspirin and OAT has been recently investigated in randomized clinical trials. The ﬁrst studies tested the eﬃcacy of low ﬁxed doses of warfarin. CARS compared aspirin alone with aspirin plus warfarin in two ﬁxed regimens in patients following MI [139]. The mean INR was 1.3. Mortality, recurrences of MI, and stroke were similar among the three groups. CHAMP, although using a higher mean INR level (1.8), failed to show signiﬁcative improvement in prognosis [140]. Overall, the strategy to use ﬁxed-dose warfarin and INR < 2 did not prevent stroke better than aspirin alone. Conversely, a meta-analysis showed that moderate- to high-intensity OAT plus aspirin was better than aspirin alone for reducting mortality, recurrences of MI, and stroke [141]. In 2002 three studies compared aspirin versus high-dose OAT plus aspirin. ASPECT 2 [142] showed that the combination of aspirin and warfarin (INR target 3.0–4.0) is better than asprin alone. APRICOT 2 [143], performed in patients undergoing thrombolysis, showed that event-free survival was 83% in patients treated with aspirin and OAT and 70% in patients with aspirin alone. Finally, WARIS 2 [144] showed that OAT plus aspirin signiﬁcantly reduced the occurrence of reinfarction and thromboembolic stroke. Nevertheless, in WARIS 2 nearly 30% of patients receiving OAT was below the target range, nearly 30% discontinued OAT during the 80-month study period, 5–7% were withdrawn due to hemorrhagic complications, and 2–3% were deemed noncompliant. Long-term OAT is not recommended in patients with left ventricular postinfarction aneurysm. Indeed, prevalence of intracardiac thrombus is quite high (48–66% in surgical series, 49% at autopsy), but risk of systemic embolism is low (0.35 per 100 patients per year), presumably because the thrombus is contained within the noncontractile aneurysmal cavity [145]. OAT is recommended only in patients with thrombus presenting any previously described high-risk morphological ﬁndings.

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4. Prosthetic Cardiac Valves Patients with prosthetic cardiac valves are at high risk of systemic embolism, and stroke is the most common clinical presentation [146]. In patients with mechanical valves the incidence of major embolic events is about 4% per year in the absence of antithrombotic treatment, whereas it is 2% during antiplatelet therapy and 1% with anticoagulants [147]. The embolic risk is diﬀerent depending on the prosthetic model and the position. Embolism is twofold higher for a mechanical mitral prosthesis when compared to the aortic position. Also, embolic risk is higher for the caged-ball type (e.g., Starr-Edwards) than for the single tilting disk (Bjork Shiley) or the bileaﬂet model (e.g., St. Jude Medical). Patients at highest embolic risk are those with multiple prosthetic valves, AF, advanced age (>70 years), and poor left ventricular function. In patients with bioprosthetic valves the embolic risk is moderatey high during the ﬁrst 3-month period following operation. Thereafter, endothelialization of the bioprosthetic ring has a protective role, and the risk of thromboembolism approximates that of patients with mechanical prosthetic valves who are receiving OAT [148,149]. Patients with mechanical prosthetic valves require long-term OAT, which must be initiated as soon as possible (within 6–12 hours) following surgery [150]. Prevalence of major bleeding during OAT is 1.4% per year [151]. In selected patients with aortic valve replacement without additional embolic risk factors, low-intensity OAT (INR 2.0–3.0) is adequate for the prevention of thromboembolic events, while reducing the incidence of thromboembolic complications. The overall incidence of adverse events, either tromboembolic or hemorrhagic, is minimal when the INR is between 2.5 and 4.9 according to a European study [151] and between 2.5 and 3.6 according to a meta-analysis from 12 North American studies [150]. The combination of antiplatelet therapy with OAT has been proposed in order to further reduce the risk of thromboembolism. Dipyridamole has been used with conﬂicting results [152,153]. The combination of high-dose aspirin (500–1000 mg/day) with lowintensity OAT (INR 1.8–2.3) has decreased embolic events, but increased the incidence of gastroenteric bleeding [154,155]. Otherwise the combination of low-dose aspirin (100 mg/ day) with warfarin (INR 3.0–4.5) has been beneﬁcial in patients with prosthetic valves at high embolic risk (coexisting AF or previous embolism) [156]. Indeed, such a regimen signiﬁcantly decreased systemic embolism and death, but increased minor (but not major) hemorrhagic complications. Finally, the combination of low-dose aspirin (100 mg/day) plus lower-intensity OAT (INR 2.5–3.5) showed similar antithrombotic protection and fewer bleeds in comparison with high-intensity OAT (INR 3.5–4.5) alone [157]. In conclusion, the association of aspirin with OAT is advisable in patients who have suﬀered an embolic event during adequate OAT, patients who have additional embolic risk factors (AF, previous thromboembolism, left atrial thrombosis, poor left ventricular function), or in patients with strong indication for aspirin treatment (i.e., coexisting CAD, previous TIA or stroke). In patients with bioprosthetic valves low-intensity anticoagulation (INR 2.0–3.0) is indicated during the ﬁrst 3 months following surgery; thereafter aspirin is a suﬃcient prophylaxis [158,159]. Long-term OAT treatment is warranted only in patients at high risk for embolism. 5. Valvular Heart Disease Rheumatic mitral valve stenosis has the highest embolic risk in comparison with any other cardiac disorder. The embolic risk is even higher when AF is present, in the elderly, and in those with low cardiac output. The embolic risk is not related to the severity of stenosis,

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valvular calciﬁcation, or New York Heart Association (NYHA) class [160]. During longterm follow-up, the risk of cerebrovascular events was similar in patients with mitral or aortic valve stenosis [161]. Despite the lack of randomized trials, OAT is undoubtedly useful to reduce systemic embolism and stroke. Deﬁnite indications for OAT (INR 2.0–3.0) are previous thromboembolic event and AF, either paroxysmal or chronic. OAT is recommended in patients with sinus rhythm and moderate left atrial enlargement (>5 cm) who are at high risk for AF. OAT is also recommended in elderly patients and in those with severe mitral valve stenosis [162]. In patients suﬀering from embolism despite OAT, two options exist: either increase the intensity of anticoagulation (INR up to 3.5) or combine OAT with low-dose aspirin or dipyridamole. Aortic valve calciﬁcation and calciﬁed aortic stenosis are reported in about 1% of patients with TIA or stroke undergoing echocardiography. Case reports provide evidence of brain infarction, retinal ischemia, or peripheral vascular occlusion due to calciﬁc emboli from aortic valves [163,164]. Embolism can complicate cardiac catheterization and valvuloplasty [165]. Primary oxalosis with calcium inﬁltration in the aortic valve and left ventricle has been reported as a cause of cardioembolic stroke [166]. However, in a prospective controlled study of 815 patients with aortic valve calciﬁcation or calciﬁed aortic valve stenosis, stroke was not signiﬁcantly associated with the severity of the aortic valve disease, while hypertension and carotid artery stenosis were frequently associated [167]. 6. Cardiomyopathies In patients with dilated cardiomyopathy the prevalence of ventricular thrombi is substantial, ranging from 11 to 60% among nonanticoagulated patients [168–171]. Stroke and systemic thromboembolism are reported in 8.4–18% of patients. The embolic risk is signiﬁcantly higher in the presence of AF and advanced congestive heart failure [172,173]. There are no prospective studies of the risk/beneﬁt ratio of OAT in patients with dilatative cardiomyopathy. However, nonrandomized observational studies show of OAT to be eﬀective for the prevention of embolism in these patients. The annual incidence of thromboembolism in four nonrandomized studies was 0 in patients undergoing OAT and 1.6– 4.5% in nontreated patients [174–176]. In the absence of deﬁnite guidelines based on prospective randomized trials, OAT is indicated in patients with dilated cardiomyopathy at higher embolic risk, such as those with AF, advanced congestive heart failure, and left ventricular thrombosis [177]. In patients with hypertrophic cardiomyopathy systemic embolism and stroke are possible complications during the natural history of the heart disease [178–180]. Hypertrophic cardiomyopathy per se is not an embologenic heart disease. The embolic risk is related to the occurrence of one of three events: AF, infective endocarditis, or evolution toward a dilatative form with systolic dysfunction and congestive heart failure. The embolic risk is particularly high in the presence of paroxysmal or chronic AF with a deﬁnite indication for OAT (INR 2.0–3.0). 7. Heart Failure In 1994 Baker and Wright [181] reviewed the incidence of arterial thromboembolism in patients with heart failure. The incidence of embolic events, ranging from 0.9 to 5.5 events per 100 patients per year (mean 1.9% per year), was signiﬁcantly higher than the incidence in the general population aged 50–75 years, i.e., 0.5 events per 100 subjects per year. Nevertheless, the authors concluded that no subset of patients with heart failure has a deﬁnitively

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higher embolic risk except those with AF. Moreover, in the SPAF I, among patients with NVAF, left ventricular dysfunction and history of heart failure were independent predictors of thromboembolism [99]. According to most important international guidelines, in patients with heart failure and AF, left ventricular thrombosis, or history of embolic events, OAT is strongly recommended [100]. Sharma et al. [182] showed that among patients with heart failure and left ventricular thrombosis, the history of recent MI and severe left ventricular dilatation were predictors of embolic risk. Stratton et al. [183], after a 2-year follow-up, showed that left ventricular thrombosis disappeared in 29% of patients without OAT and in 59% of those with OAT. Even the occurrence of severe left ventricular dysfunction or left ventricular dilatation is considered a possible indication for OAT. In the SAVE study [131] of patients with recent MI and left ventricular dysfunction, univariate analysis showed that patients with an ejection fraction V28% had a twofold increase in relative risk of stroke. In SOLVD studies [184], which enrolled patients with ejection fraction V35%, with ischemic etiology in most cases, OAT showed a reduction of total mortality, but failed to show a reduction of embolic events, probably because of the low incidence of embolic events. Recent trials comparing OAT and aspirin in patients with recent MI are not helpful in this controversy because of the low prevalence of heart failure (5–12%) in those series [142–144]. Recently, a comparison between the recommendations and the use of OAT in patients with heart failure showed inadequate adherence to the guidelines. The two predictors of nonuse of OAT in patients with evidence-based indications for OAT are history of hypertension and older age [185]. The controversy about OAT in patients with heart failure continues, and large randomized clinical trials are ongoing [186]. 8. Infective Endocarditis Ischemic stroke may occur in patients with infective endocarditis in about 20% of patients [187–190]. Most strokes occur within 48 hours of diagnosis during uncontrolled infection, while a late stroke occurs only in about 5% of patients [187–189]. The stroke rate is higher with endocarditis due to Staphylococcus aureus. The risk of stroke is reduced by the control of the infection with speciﬁc antimicrobial therapy. A recent large study on 217 patients with endocarditis showed a rate of embolic events in 12.9% of cases. The risk of embolism turned out to be correlated to etiology (highest prevalence if Staphylococcus is the infective agent), mitral position (for native valves), and prosthetic valve involvement [191]. No evidence of beneﬁt is available for OAT in patients with infective endocarditis of the native valve [192]. Moreover, several authors have reported a high incidence of cerebral bleeding during OAT. Thus, OAT is not indicated for the prevention of stroke and systemic embolism in patients with infective endocarditis. The only exception is the case of patients with endocarditis of mechanical prosthetic valves already undergoing OAT. Antiplatelet therapy has not been studied in patients with endocarditis.

E. Patients Without Overt Cardiac Disease In patients with cryptogenic stroke and normal clinical examination, echocardiography may allow the detection of silent embologenic cardiac lesions. A series of studies showed a correlation between cerebral ischemia and hidden cardiac lesions such as MVP, ASA, and left atrial myxoma before the introduction of TEE. However, after the introduction of TEE

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the detection of silent potential cardiac sources of embolism was dramatically improved. Several studies showed that TEE may detect potentially cardioembolic lesions in 30–60% of patients with cryptogenic stroke and a negative TTE result [193]. 1. Atrial Septal Aneurysm ASA, a localized bulging of the interatrial septum, is detected by TEE in about 1% (range 0.2–4%) of patients undergoing TEE and in about 10% (range 1–21%) of patients with TIA or stroke [194–199]. The prevalence in patients with cryptogenic stroke is even higher (range 16–28%). Nearly one half of the ASAs detected by TEE are not visualized by routine TTE [199]. Cerebral ischemia in patients with ASA could be secondary to embolism from thrombi of the aneurysmal sac or to paradoxical embolism through a PFO coexisting in 60–75% of cases. Other potential mechanisms of embolism in patients with ASA include coexistent myxomatous mitral valvulopathy and Chiari’s network. Chiari’s network has been discovered in up to 4% of autopsy studies and in 2% of patients undergoing TEE, but it is more common in patients with cryptogenic strokes [200]. A recent prospective long-term study showed a low incidence of embolic stroke in patients with ASA [201]. TEE studies suggested a strong association between interatrial septum thickness >5 mm and cerebrovascular events [202]. A thickened interatrial septum was found in 75% of patients with history of ischemic stroke and in 24% of those without history of cerebral ischemia. ASA has been particularly associated with small lacunar infarcts [203]. Overall, the risk of stroke in patients with ASA has not been deﬁnitively assessed, and if ASA is detected in a patient with stroke, the risk of cerebrovascular recurrences is unclear. Aspirin can prevent thromboembolism in these patients, but no long-term comparison between warfarin and aspirin for preventing stroke is available. Previous studies showed that the probability of recurrences of cerebrovascular events is 33 times higher in patients with associated ASA and PFO [204]. Mas et al. [205] conﬁrmed these data: if PFO and ASA coexist, the probability of stroke or TIA after 48 months exceeds 30%. 2. Patent Foramen Ovale PFO has been found in autoptic studies in 10–18% of cases in the general population and in 30%–35% of patients with a history of cerebral ischemia. Two studies with contrast TTE detected PFO in 40–50% of young adults with cryptogenic cerebral ischemia and in about 10% of controls [206,207]. These observations have been conﬁrmed by a large number of case-control studies, which consistently showed an increased prevalence of PFO among young adults with TIA or ischemic stroke (about 40%, range 32–48%) and particularly cryptogenic stroke (about 50%, range 49–61%) [207–213]. De Castro et al. [214] showed that patients with acute stroke and PFO more frequently have a right-to-left shunt at rest and membrane mobility. Conversely, Steiner et al. [215] found no relationship between large shunts and the occurrence of cerebral infarcts detected by brain-imaging techniques. Finally, recent studies identiﬁed a common genetic trait in patients with PFO [216,217]. The mechanism for stroke in patients with PFO is paradoxical embolism deﬁned as embolic material originating in the venous circulation or right cardiac chambers, migrating into the systemic circulation through vascular shunts that bypass the pulmonary capillary bed. In patients with PFO there is no sustained right-to-left interatrial shunting, but para-

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doxical embolism could be permitted by transient shunting occurring during the elevation of right atrial pressure provoked by cough or Valsalva’s maneuver [210,212]. Because of the high prevalence of PFO in the general population, caution is required in the diagnosis of paradoxical embolism. In many patients with stroke, the PFO is likely to not be etiologically related to the cerebral ischemia. In patients with cryptogenic stroke the PFO is only incidentally associated in more than one third of cases. The pathogenetic role of PFO is more likely when the following conditions are present: (1) no evidence of other sources of embolism; (2) coexistence of deep venous thrombosis or pulmonary embolism; (3) large PFO or larger amounts of interatrial shunting or both; (4) association of PFO with ASA (25%) or with MVP, both potential cardioembolic sources. Current therapeutic options for secondary prevention include chronic OAT and invasive procedures such as surgical closure or transcatheter closure of the defect [218]. The risk of stroke recurrence is relatively low (1%/year, range 0–4%) in patients treated with aspirin or short-term OAT followed by aspirin if concurrent venous thrombosis is absent [219–221]. The risk of recurrent stroke is unknown for patients with complicated PFO (PFO associated with ASA or MVP) or with coexisting venous thrombosis versus patients with isolated PFO, as all PFOs are combined in the few existing clinical studies. In the recent Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), 630 stroke patients were randomized to warfarin (INR 1.4–2.8) and aspirin 325 mg. PFO was present in 203 patients (33.8%). In patients with PFO there was no signiﬁcant diﬀerence in the time of primary endpoints (recurrent ischemic stroke or death) between those treated with warfarin and those treated with aspirin ( p = 0.49; hazard ratio 1.29; CI 0.63–2.64; 2-year event rates 16.5% vs. 13.2%). Preliminary studies suggest that the recurrences of cerebral ischemia in patients with PFO may be signiﬁcantly lowered by mechanical closure (surgical or transcatheter technique) [223–228]. Nevertheless, several authors showed that PFO closure does not completely prevent recurrences. Bridges et al. [224] reported the results of percutaneous PFO closure with the clamshell device: a complete closure of PFO was conﬁrmed by echocardiography in 28 of 36 patients, and during follow-up 4 patients suﬀered recurrences of cerebral TIA. Homma et al. [225] followed up 28 patients with cryptogenic stroke and PFO after surgical closure of PFO by open thoracotomy. One recurrent ischemic stroke and three TIA were observed. Sievert et al. [226] followed up 46 patients after percutaneous closure of PFO by atrial septal defect occlusion system (ASDOS); only one patient suﬀered a recurrent TIA 7 months after the procedure. Windecker et al. [229], during a 5-year follow-up of 80 patients with percutaneous PFO closure, observed TIA in 2.5% and peripheral embolism in 0.9% of patients. The incidence of periprocedural complications was high (10%). The postprocedural shunt was a predictor of recurrent paradoxical embolism, emphasizing the importance of achieving a complete PFO procedure. Finally, the optimal antithrombotic treatment after the procedure is questionable, and 100 mg of aspirin is probably inadequate. In the absence of deﬁnite indications, the following recommendations are proposed for the secondary prevention of stroke: 1. Aspirin in patients with isolated PFO 2. Long-term OAT in patients with PFO associated with ASA, deep venous thrombosis, or coagulation abnormalities 3. Transcatheter closure of PFO in selected patients (e.g., stroke recurrence during OAT or contraindications to OAT)

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3. Mitral Valve Prolapse Since the early 1970s, MVP was postulated to be a possible source of cerebral emboli. Many reports, mainly concerning stroke in young adults, have suggested a high prevalence of MVP in stroke [230]. Nevertheless, if restrictive echocardiographic criteria are adopted, MVP is less frequently identiﬁed, its prevalence rate approximating that in a healthy population (4– 6%) [82]. Indeed, the prevalence of cerebral ischemia in patients with MVP is low, approximately 0.5%/year [231]. Thickening of the mitral leaﬂets with myxomatous ﬁndings and mitral insuﬃciency may increase the risk of systemic emboli [231,232], although these data were recently not conﬁrmed [233,234]. The risk is further increased in patients with AF or endocarditis. Scarce data are available concerning the occurrence of thrombi on the leaﬂets. Detection of MVP should not preclude a search for other causes of emboli. MVP can be associated with an ASA, PFO, or, rarely, with idiopathic lesions of cerebral arteries caused by systemic connective tissue disorders [82]. The combination of MVP with abnormal platelet activity and clotting disorders has been documented [235–237]. Primary prevention of embolism with antiplatelet agents should not be recommended. Aspirin can be given to patients with MVP after TIA. OAT has been advocated if antiplatelet therapy fails and in patients with AF. 4. Mitral Annular Calciﬁcation Mitral annular calciﬁcation, which is detectable by TTE, has been reported in association with ischemic stroke [238–241] and in one epidemiological study [241] presented as an independent risk factor. The presumed mechanism for stroke is the detachment of small calciﬁc emboli from the degenerated mitral annulus. However, a causal relationship between mitral annular calciﬁcation and stroke is diﬃcult to demonstrate because mitral annular calciﬁcation is often associated with advanced age, congestive heart failure, and particularly with AF [94,242]. 5. Valvular Strands Mobile ﬁlamentous strands of the cardiac valves have been associated with stroke and systemic embolization [243–245]. The association with cerebral ischemia has been reported for strands on both the mitral and aortic valves. In a recent case-control study the association was greatest in younger patients [246]. However, their clinical signiﬁcance is not yet certain. 6. Cardiac Tumors Atrial myxomas represent more than 50% of primary cardiac tumors; 75% of the myxomas occur in the left atrium [247]. Systemic embolism and stroke occur in 40% of cases. Emboli are of two types: platelet-ﬁbrin and tumor fragments [248]. Most atrial myxomas can be detected by TTE, but only TEE and MRI allow a precise deﬁnition of the mass and its connections with the cardiac structures. Atrial myxomas are found in about 1 in 200 young adults with stroke/TIA and in perhaps 1 of 750 older patients with cerebral ischemia. 7. Aortic Plaques Since 1990, an association between protruding atherosclerotic plaques of ascending aorta and embolic events was found in TEE studies [248–250], autoptic studies [251], and

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intraoperative epiaortic evaluations during surgery [252]. Later prospective studies conﬁrmed the association between aortic plaques and cerebral embolism [253]. Patients with aortic plaques frequently have associated carotid artery disease [254], CAD [255], and multiple risk factors for atherosclerosis [253]. Moreover, a further intriguing association was seen between aortic plaques and AF. The SPAF Investigators detected complicated aortic plaques in 35% of patients, with a risk of stroke of 12–20%, suggesting that in patients with NVAF, cerebral embolism may be due to aortoembolism in 10–20% of cases [256]. A routine TEE has shown the presence of aortic atherosclerotic plaques in nearly one half of patients with ischemic stroke. Aortic plaques can be occasionally detected by TTE, but only the TEE approach can systematically detect aortic plaques, providing a detailed deﬁnition of the intimal surface of the thoracic aorta. Aortic plaques are detected mainly in older patients. Stratiﬁcation of the embolic risk of aortic plaques has been attempted in several studies. Amarenco et al. [257] investigated the prevalence and characteristics of high-risk aortic plaques. The authors observed that embolic risk was signiﬁcantly higher if the atheroma protruded or had a thickness of more than 4 mm. The same authors demonstrated an increased recurrence of embolic events (nearly fourfold) in patients with ischemic stroke and aortic plaques. Morphological ﬁndings are highly predictive of embolic risk. The prevalence of mobile lesions and of ulceration >2 mm was found to correlate with cryptogenic stroke [258]. Cohen et al. [259] followed up 338 patients aged z60 years for 2–4 years. Hypoechoic plaques, calciﬁcations, and ulcerations were common in plaques z4 mm; the highest embolic risk was found in noncalciﬁed plaques, which may be considered ‘‘vulnerable’’ plaques. In most cases thrombi are present in mobile and ulcerated lesions. Nevertheless, in studies based on TEE monitoring, thrombi were resolved at second examination in most cases [260], and in autoptic studies thrombi may be undetectable, probably because they often spontaneously disappeared within 24–48 hours of the event. An emerging issue concerns the risk of embolism from aortic plaques during left heart catheterization [261] and cardiac surgery [262,263]. The high prevalence of aged patients undergoing coronary angiography signiﬁcantly enhanced the risk of complications. In nearly 50% of cases, the guiding catheter may scrape the aortic debris with a high risk of embolization. Frequently, visible atheromatous material is retrieved from a guiding catheter that had been passed up the aorta from the femoral artery [261]. The risk of aortoembolic event during cardiac surgery is even higher, occurring in 2– 7% of patients. During cardiac surgery in patients with aortic plaques, cross clamping, incannulation, and manipulation of the ascending aorta may present a very high risk of embolic complications. In aged patients and in those with aortic valve disease, a preoperative TEE or intraoperative TEE may be performed in order to identify the site of a safe incannulation and cross clamping or to perform an alternative, minimally invasive direct coronary artery bypass graft [68,69,253,262,263]. A recent controversy concerns the ‘‘atherothrombotic syndrome’’ from aortic plaques consisting of renal failure, skin lesions, blue toes, and other signs of peripheral embolism. Several authors suggest that the atherothrombotic syndrome may be secondary to cholesterinic embolism from aortic plaques [264–266]. Possible treatments in patients with aortic plaques for preventing stroke include aspirin, statins, OAT, and surgical removal [253]. Previous reports claimed that OAT is harmful and can precipitate systemic embolism [267,268], although in a recent report the risk of atherothrombotic syndrome during OAT in patients with aortic plaques was

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considered low [256]. Three studies have investigated the role of OAT in patients with aortic plaques. Dressler et al. [269] observed a high incidence of vascular events in patients not treated with OAT (45%) versus patients treated with OAT (5%). The SPAF Investigators reevaluated the results of the study by the results of TEE [256]. Among patients with aortic plaques and NVAF, OAT proved protective against the risk of stroke. Finally, Ferrari et al. [270], in a prognostic nonrandomized study, showed a better outcome, with fewer embolic events among patients treated with OAT versus antiplatelets. OAT is mainly eﬀective in patients with aortic plaques >4 mm with ulcerations and with soft morphology. In another recent retrospective nonrandomized study, the eﬀect of treatment on the incidence of stroke and other embolic events was studied in 519 patients with severe thoracic aortic plaque [271]. An embolic event occurred in 11 patients (21%). Multivariate analysis showed that statin use was independently protective against recurrent events ( p = 0.0001). No protective eﬀect was found for warfarin or antiplatelet drugs. F. Protocol for the Detection of Cardiac Sources of Embolism Cardiac evaluation integrated with echocardiography allows the detection of cardiac sources of embolism in many patients with cerebral ischemia. The following algorithm for the search for cardiac sources of embolism in patients with stroke is proposed: 1. Cardiac evaluation should be reserved for patients potentially eligible for OAT or cardiac surgery. 2. In patients younger than 45 years with unexplained stroke, TEE is always warranted. 3. In patients older than 45 years without a history of cardiac disease and with unexplained stroke, TEE is warranted, whereas in those with a history of cardiac disease, TTE is often suﬃcient, possibly followed by TEE in selected patients. 4. In patients with AF, echocardiography may be redundant because the indication for OAT after stroke is deﬁnite. TTE is occasionally needed to clarify underlying structural cardiac disease. TEE is appropriate in selected cases, mainly when a causal relationship between AF and stroke is possible.

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8 Organization of Stroke Services in the Hospital and the Community J. Kennedy and A. M. Buchan University of Calgary, Calgary, Alberta, Canada

D. L. Sandler Birmingham Heartlands Hospital, Birmingham, England

I. INTRODUCTION Stroke medicine is an evolving specialty driven in part by the identiﬁcation of eﬀective emergent therapies as well as the realization that organized stroke care results in reduced patient mortality and morbidity. The publication of the National Institute of Neurological Disorders and Stroke (NINDS) trial demonstrated the beneﬁt of tissue plasminogen activator (tPA), which has changed the outlook for eligible stroke patients and provided the opportunity for change in general acute stroke care [1]. Acute stroke services employing these therapies are now required to be time sensitive [2], which in turn means there is a need to develop seamless patient care from the point of onset to discharge. The purpose of this chapter is to consider the stroke patient’s journey of care, identifying best current practice and guidelines, concentrating on the organization of emergency stroke care as well as postacute care organization in the hospital and the community.

II. ACUTE STROKE CARE The demonstration of thrombolysis, both intravenously and intra-arterially, as an eﬀective intervention in acute ischemic stroke to reduce disability has by necessity changed the organization of acute stroke care [1,3]. Intravenous thrombolysis confers an absolute risk reduction of death or dependency of 16% [4]. However, it is not a treatment without risk, which increases in patients treated by inexperienced physicians or outside established treatment guidelines [5–7]. At present, a relatively low percentage of patients that suﬀer acute ischemic stroke (AIS) are eligible to receive therapy [8]. Therefore, the organization of acute care becomes crucial in order to maximize the number of patients that may beneﬁt from thrombolysis. 163

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Focusing solely on thrombolysis misses the broader beneﬁts to general neurological care that reorganizing acute stroke services may bring [9]. Along with prompt treatment of AIS, early treatment of stroke ‘‘mimics’’ may be of beneﬁt to patients (Table 1). Given the evidence from both animal and human data that the duration and the degree of ischemia determine the extent of irreversible cell damage [10–12], reorganizing stroke care where time to clinical assessment is crucial may also aﬀord the opportunity to study other potentially useful therapeutic interventions in stroke, be they pharmacological or mechanical. The ‘‘chain of recovery,’’ which relies on the patient and the general public, is vital in initiating the ﬁrst steps of organized care [13]. Figure 1 outlines a potential pathway of management of the patient with acute stroke [14] from presentation to treatment. A. Recognition Given the narrow time window for potential therapeutic beneﬁt for thrombolysis, public awareness of the symptoms and signs of stroke is crucial to early presentation and treatment. Education has been aimed at increasing public awareness to recognize the symptoms and signs of stroke. Public knowledge of stroke symptoms/signs is poor, even when identiﬁed in the emergency room as strokelike symptoms [15,16]. A telephone survey of the general population in the metropolitan area of Greater Cincinnati found that 43% of those interviewed were unable to identify a single stroke warning sign and 32% could not name a single risk factor for stroke (see Table 2) [15]. Only 8% were able to name three out of ﬁve stroke warning signs as deﬁned by the NINDS. This disappointing level of knowledge may be an overestimate given the potential bias of responders over nonresponders in the telephone survey and an unfair reﬂection of the broader community’s knowledge of stroke due to the fact that the local stroke team had been extremely active in education programs prior to the study [17,18]. Those interviewed in the emergency department (ED) who had presented with a presumed diagnosis of stroke were no better [16]. Only 49% of those asked were able to identify that stroke is caused by injury to the brain, and 39% of those surveyed could not name a single stroke sign or symptom, with 43% being unable to name a single risk factor. Again, the older participants (>65 years of age) were less likely to identify a single stroke sign/symptom or risk factor for stroke than their younger counterparts. Race, sex, education, income, and ﬁnal discharge diagnosis all had no bearing on knowledge base. The general population identiﬁed methods of mass media (television, magazines, and newspapers) as the most common source of information regarding stroke (combined total

Table 1 Ischemic Stroke Mimics Hypoglycemia Seizure Brain tumor Intracranial hemorrhage (extradural, subdural, subarachnoid, intracerebral) Trauma Metabolic derangement Migraine Infection (meningitis, abscess, encephalitis)

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Figure 1 Potential management pathway for patients with acute ischemic stroke.

64%), with physicians cited as the fourth most likely source (18%). In the population who had presented to the ED, it was family and friends of the patient who were the most commonly identiﬁed source (35%), with only 2% of those interviewed citing their physician as their source of knowledge. The hope has been that widespread education will increase early arrival at the ED following symptom onset. In itself, knowledge of stroke has not been shown to lead to early presentation [19]. However, education strategies have met with varied success. The Duke Stroke Program was able to increase the number of acute ischemic strokes presenting within 24 hours of symptom onset from 40% to 85%. The educational program consisted of mass media strategies (newspaper articles, TV/radio features on treatment,

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Table 2 Factors Associated with Increased Knowledge of Stroke Warning Signs and Risk Factors Stroke warning signs Younger age Female sex Higher level of education History of hypertension Previous smoker History of previous stroke/TIA

Stroke risk factors Younger age Female sex Higher level of education History of hypertension White race

interviews with survivors and physicians), professional meetings advertising the program to coincide with the opening of the acute care unit, and improving referral patterns among physicians in primary care, local hospitals, and the ED [20]. No randomized controlled evidence exists in the stroke literature as to the true eﬀect of mass media intervention on the public’s knowledge and impact on early presentation to medical attention. Coronary reperfusion strategies are limited by the same problems as those in stroke, in that patients delay seeking medical attention, thereby reducing the numbers that may beneﬁt from treatment and the eﬀectiveness of treatment [21,22]. A large randomized controlled trial in this setting addressing the role of mass media failed to show evidence of decreased delay in patient presentation [23]. One of 10 matched pairs of cities in the United States was randomized to either receive an 18-month intervention or not. The main outcome measures were symptom onset to ED arrival and emergency medical services (EMS) usage. This carefully designed trial involved a multifaceted intervention based upon aspects of behavioral theory [24]. Communities, professional and public organizations, as well as individuals were targeted. Examples of intervention used are listed in Table 3. Despite this comprehensive strategy, there was no diﬀerence in the delay to arrival in the ED following symptom onset between the communities who had received the intervention and the reference communities. Therefore, it appears that while public education about stroke and the need to seek medical treatment quickly is logically the right thing to do, its impact on changing patient behavior is hard to quantify and not necessarily eﬀective.

Table 3 Examples of Intervention in the Rapid Early Action for Coronary Treatment (REACT) Trial Mass media

Small media

Community and patient groups

TV/Radio public service announcements Newspaper inserts TV/radio news stories Direct mail Billboards Movie screen public service announcements Point-of-purchase displays Presentations to high-risk patients Community presentations Health fairs

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B. Reaction Reaction covers the time from development of symptoms/signs to arriving in the ED. Factors associated with early or delayed arrival in the ED are listed in Tables 4 and 5 [25–37]. EMS use is the most consistently reported factor in reducing the delay to arrival at the ED. Factors associated with increased EMS utilization are listed in Table 6. Given its crucial role in determining the early arrival of patients, attempts have focused on increasing the identiﬁcation of patients with possible stroke by the EMS starting with the dispatchers to the crews that attend to the patient. In a retrospective review of stroke and TIA patients, EMS dispatcher classiﬁcation and triage of the 911 calls were studied and the tape recordings of the 911 calls reviewed [38]. Some 53% of 182 consecutive patients used EMS, 31% of which were coded as stroke. The callers identiﬁed the reason for assistance as stroke in 51% of cases, but the call was coded as stroke in fewer than half of these calls. Only 41% of EMS cases were sent as high priority. When EMS response times were compared in patients with stroke and myocardial infarct, there was no diﬀerence in dispatch to scene, time at scene, and transport time to the ED [39]. Emergency medical technologists (EMT) are the ﬁrst members of the health care profession that a stroke patient encounters in the majority of cases. Groups have focused on improving EMT recognition of stroke, which may result in reducing delay of arrival to ED and prioritizing patients to specialist stroke centers that may be warned in advance to expect a code stroke patient. These tools have been based around a focused neurological exam. Two of the tools are similar, being focused around a very abbreviated neurological exam alone. The Cincinnati Prehospital Stroke Scale (CPSS) is a simpliﬁcation of the National Institute of Health Stroke Scale (NIHSS) [40,41]. It focuses on the presence or absence of facial palsy, asymmetrical arm drift, and speech abnormalities in potential stroke patients. In the case of speech, the patient is asked to repeat the sentence ‘‘The sky is blue in Cincinnati.’’ It is abnormal if words are slurred, wrong words are used or the patient fails to respond. The Face Arm Speech Test (FAST) was developed in the United Kingdom to complement existing paramedic assessments [42]. Face and arm weakness are assessed as in the CPSS, but speech is assessed through normal conversation with the patient. Both tests require a short period of training prior to use and have been shown to aid identiﬁcation of stroke patients. The CPSS identiﬁed anterior circulation strokes with a sensitivity of 88%. The utility of the FAST was assessed by comparing the positive

Table 4 Factors Associated with Delay in Arrival at ED from Symptom Onset Method of transport to ED other than EMS Onset at night Patient alone at symptom onset >70 years old Mild stroke severity Attending primary care physician ﬁrst At home at onset Fluctuating symptoms Living in large urban population Onset at weekend

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Table 5 Factors Associated with Early Arrival Following Symptom Onset Increased age Sudden onset of stable deﬁcit Initial recognition having stroke Hemorrhage EMS use Severe stroke <70 years old Bystander present >55 years old Daytime Receiving hospital’s experience Onset at work Previous stroke Speech disturbance at onset Sudden onset White History of atrial ﬁbrillation History of congestive heart failure

predictive value (PPV) of ﬁnal diagnosis of stroke in patients with suspected stroke referred via three routes: the trained EMT using the FAST, primary care physicians, and ED physicians. There was a trend to higher diagnostic accuracy in the EMT referrals (PPV 78%) over the primary care and ED physicians (both PPV 71%). This may have been accounted for by the higher number of severe strokes, particularly anterior circulation, referred by the EMT. The Los Angeles Prehospital Stroke Score (LAPSS) incorporates the same three examination items as the CPSS and FAST [43]. In addition, it features four history items— age > 45, history of epilepsy/seizures, symptom duration less than 24 hours, patient at baseline not wheelchair bound or bed bound—and requires that a blood glucose be measured as normal. EMT underwent an hour-long training session in how to perform the LAPSS. Its utility was then tested prospectively in 1298 unselected patients transported to the UCLA Medical Center. The LAPSS was completed in 206 patients. The sensitivity of

Table 6 Factors Associated with Increased EMS Use >55 years old >75 years old Black Unemployed Medicare patient Hemorrhage History of >2 cardiovascular disease diagnoses History of atrial ﬁbrillation History of congestive heart failure

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the LAPSS when performed by EMTs was 91% (95% CI 76–98%), speciﬁcity 97% (95% CI 93–99%), positive predictive value 86% (95% CI 70–95%), and negative predictive value 97% (95% CI 84–99%). When corrected for four documentation errors, the positive predictive value rose to 97% (95% CI 84–99%). The ability to identify patients with suspected stroke early is important in maximizing the access of patients to specialized care. A modeling study used Canadian demographic data and access to hospitals with CT scanner, neurologist, emergency physician on staﬀ to determine the percentage of the population with access available to a facility with the capabilities to treat with tPA [44]. The transport distances for 60, 90, and 120 minutes were calculated at 32, 64, and 105 km, respectively. Some 67.3%, 78.2%, and 85.3% of the Canadian population lie within those distances from adequately staﬀed medical facilities for the provision of tPA. This highlights the need for a coordinated strategy to maximize coverage and minimize delay in presentation to the ED because a 60-minute delay in arrival eliminated 5.1 million people from potential treatment. Other methods have been looked at in an attempt to remove the barriers of access to appropriate care. Two centers have reported a favorable experience with the transport of stroke patients by helicopter to a tertiary referral center either following tPA administration at a peripheral hospital or for assessment [45]. Telemedicine, or ‘‘Telestroke,’’ potentially removes the need to move the patient from peripheral centers. By utilizing improved video technology, physicians at a peripheral center may be guided through an assessment of a patient by the stroke team at a specialist center. In conjunction with transmission of the necessary radiology, this may extend the reach of the specialist and improve the rate of thrombolysis beyond the specialist centers [46]. Above all, cooperation and understanding is required among all providers to facilitate the appropriate delivery of care to this group of patients. The experience of the Acute Stroke Team in South-Eastern Ontario, Canada, points to what may be achieved with good organization [47]. The aim of drawing together dispatch personnel, paramedics, physicians, community service providers, and emergency and inpatient staﬀ was to provide equitable access to tertiary acute stroke care in a 20,000 km2 area. By implementing a regional acute stroke protocol, access was improved, geographical barriers were removed, and the tPA was given to 5% of all stroke patients and 10% of all acute ischemic stroke, compared with the U.S. national average of 2–3% [48]. C. Response One of the intended eﬀects of actively involving the EMT in the pathway of care for stroke patients is to facilitate the arrival and immediate assessment of the patients by either the ED staﬀ or members of the acute stroke team. NINDS guidelines (see Table 7) have set the

Table 7 NINDS-Recommended Speciﬁc In-Hospital Time-Related Goals Door Door Door Door Door Door

to to to to to to

emergency physician evaluation: 10 min stroke physician evaluation: 15 min CT scan: 25 min CT scan interpretation: 45 min tPA administration: 60 min transfer to in-patient setting: 180 min

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target of assessment of the patient within 10 minutes of arrival in the ED [49]. In a comprehensive review of the available literature [37], only 2 of 13 groups from nine studies reported a mean delay time within this stated goal [50,51]. D. Reveal Computed tomography scanning of the head is an integral part of the assessment of the acute stroke patient for tPA, given the poor predictive value of any clinical score for intracranial hemorrhage. The NINDS set a goal of 25 minutes door to CT scan. Most studies report a mean or median delay of one hour between arrival in the ED and CT scanning [37], with one group reporting that only 17% of patients had a CT scan within the time set in the NINDS guidelines [30]. E. Rx (Treatment) tPA protocols have been developed in line with the NINDS trial, an example of which is seen in Table 8. These outline the parameters under which tPA should be given. Review of the provision of acute stroke care in North Carolina found that tPA protocols were in place in 54 of 125 medical facilities in 46 of the 100 counties, covering a total of 74% of the state’s population [52]. Those facilities with a tPA protocol were more likely to have a stroke team (31% vs. 8%), stroke care maps (56% vs. 17%), a stroke unit (33% vs. 7%), and neurology available to consult on the patient (78% vs. 38%) when compared to those without. These centers also were more likely to have community stroke awareness programs to ensure the public were aware of stroke symptoms and what to do once they are recognized (41% vs. 17%). Acute care receiving hospitals in Illinois, when surveyed with a 91% response rate, showed that about 70% had a tPA protocol in place [53]. In Illinois, 93.2% of the population lived in a county with one or more acute facility with a tPA protocol. However, outside of the greater Chicago metropolitan area, neurologists or neurosurgeons were by and large unavailable. Specialist stroke diagnostics, stroke community awareness programs, and stroke teams were also generally absent from acute facilities. In the period leading up to the start of the NINDS trial, the participating centers took part in a total quality improvement approach to attempt to minimize the delays seen in the emergency department through to the initiation of tPA [54]. This approach used established techniques to identify process issues that may cause delay and implement improvement prior to the commencement of the trial [55,56]. Key processes were identiﬁed using ﬂow-charting at each site that led to ineﬃciency and variability in the delivery of care. This allowed all team members to address methods by which these processes may be improved. Delays identiﬁed ranged from the stroke team being unable to assess the patient without the permission of the ED physicians, delay in return of the necessary blood test results, to the ready access to CT scanning. Through negotiations with the necessary parties, solutions were found so that achieving the protocol aims of enrolling patients within 180 minutes were achievable for the main trial. F. Experience in the Standard Delivery of Care A summary of various centers’ experience of giving tPA is shown in Table 9 [7,57–63]. The Houston experience reports that their close collaboration with the city of Houston Fire Department EMS is the single main reason why they have been able to increase the rate

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Table 8 University of Calgary Stroke Team at the Foothills Medical Centre, Calgary, Guidelines Procedures Prior to tPA Infusion History and physical examination consistent with an acute ischemic stroke Pretreatment test: CBC, electrolytes, glucose, PT/PTT, ﬁbrinogen, type and cross-match, ECG Pretreatment noncontrast head CT scan Attendance of stroke physician Compatibility with inclusion criteria and treatment contraindications Procedures: tPA Infusion and Subsequent Management Infuse tPA in 0.9 mg/kg (maximum 90 mg) continuous iv infusion over 60 minutes with initial bolus of 10% of total dose Monitor in acute setting for neurological change or bleeding: BP q15 min 2 h then q30 min 6 h then q1 h 16 h Neurovital signs q1 h 12 then q2 h 12 h Neurological examination (NIHSS or CNS) q1 h 6 h then q3 h 72 h Check for orolingual angioedema—if present during infusion consider stopping tPA; consider giving antihistamines and/or corticosteroids Daily neurological evaluation after ﬁrst 24 h NPO 3 h postinfusion, then reassess Bedrest 24 h postinfusion, then reassess Maintain BP < 185/105 mmHg If clinical deterioration, consider: Discontinue tPA infusion Immediate CT scan Giving cryoprecipitate and platelets Repeat CT scan at 24 h in all cases No iv heparin or ASA for 24 h or until 24-h CT scan has ruled out hemorrhage Inclusion Criteria Acute ischemic stroke tPA infusion to be commenced within 3 hours of symptom onset Absolute Contraindications TIA or stroke with rapidly improving deﬁcit History and examination compatible with subarachnoid hemorrhage BP > 185/110 after 2 attempts to reduce BP below that level Pretreatment CT scan showing: hemorrhage, mass eﬀect or edema, tumor, or AVM Major surgery or trauma in the last 14 days Active internal bleeding Arterial puncture at a noncompressible site in the last 7 days History of hematological abnormality or coagulopathy or anticoagulation for any reason (PT > 15 s, INR > 1.4, PTT > 40 s, platelets < 100 109/L) Relative Contraindications Decreased level of consciousness CT showing large area of early infarct change Intracranial surgery or intraspinal surgery < 2 months Stroke or head injury in the preceding 3 months History of GI or GU hemorrhage in the preceding 21 days Glucose < 2.7 mmol/L or >22.2 mmol/L Seizure at stroke onset Pregnancy Endocarditis, acute pericarditis Serious underlying medical illness, including liver failure Source: Courtesy of University of Calgary Stroke Team.

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Table 9 Results of tPA Use for Acute Ischemic Stroke Reported in the Literature

Time period (months)

No. of patients

Baseline NIHSS

Houston Calgary

54 60

269 189

14 15

Vancouver Berlin Cologne Cleveland STARS OSF

33 24 18 12 23 30

46 75 100 70 389 57

14 13 12 12 13 14

a b

Onset to needle time (min)

Door to needle time (min)

137 154a 126.1b 165 144 124 157 164 148

70 98.3a 64.5b 84 79 48 96

Symptomatic intracranial hemorrhage rate (%)

Ref.

5.6 7.1a 3.4b 2.2 2.7 5.0 15.7 3.3 5.0

57 58 58 59 60 61 7 62 63

General neurology team assessing patient for tPA eligibility. Stroke team assessing patient for tPA eligibility.

with which tPA is given to acute stroke patients. By gaining a reputation for promoting stroke research, a collaborative approach and availability, potential tPA candidates may be actively triaged to the centers with special expertise, in Houston’s case 1 of 4 centers [57]. This still means that expertise is spread out among centers. In other health care systems with a single payer, patients with suspected acute stroke may be always triaged to a single identiﬁed center within a city [58]. By focusing resources at a single center, a dedicated stroke team has been shown to reduce signiﬁcantly onset-to-needle times and reduce door-to-needle times to almost those set in the NINDS guidelines and increase the number of patients treated, when compared to a general neurology team provided the ﬁrst point of contact for acute stroke patients. This focused model of care has been advocated by the Brain Attack Coalition (BAC) as a means to improving the outcome for patients with stroke [47]. Stroke shares characteristics with major trauma in that both are unpredictable medical emergencies, whose management can be enhanced by the presence of clear management pathways. Trauma centers were developed out of the realization that many patients’ survival was at risk due to the ineﬃciencies of health care delivery, and they have been clearly shown to improve outcomes from major trauma [64,65]. The BAC recommends that a two-tier system of stroke centers be developed. Primary stroke centers (characteristics listed in Table 10) would provide a wide-ranging level of basic services, referring the more complex cases and those requiring specialist intervention to comprehensive stroke centers. The primary stroke centers are envisaged as the crystallizing point for the evidence presented previously. These centers would provide the leadership to increase the eﬃcient delivery of appropriate care to those with stroke with the expectation that morbidity and mortality can be avoided through the increased use of acute stroke therapies. This in turn would lead to reduced costs to the health care system and most importantly to improved long-term outcomes. These attempts to improve the quality of in-hospital care are yet to be subject to close scrutiny in the literature. A review of stroke performance measures identiﬁed only 3 of 44 recommendations that were backed by the highest level of evidence, namely stroke units, antithrombotic therapy initiated by time of discharge, and warfarin for patients with

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Table 10 Characteristics of a Primary Stroke Center Acute stroke team Written care protocols Emergency medical services Emergency department Stroke unit Neurosurgical services Commitment and support of medical organization Neuroimaging services Laboratory services Outcome and quality improvement activities Continuing medical education

atrial ﬁbrillation [66]. Most performance measures identiﬁed (34 out of 44) across the domains of in-hospital care had low levels of evidence, highlighting the absence of clear evidence for much of what constitutes standard of care for patients with stroke. Steps are now being taken to implement national registries of standardized data collection or audits to help with monitoring the implementation of evidence-based care and assist in quality improvement [67–69]. However, the BAC does not make recommendations regarding rehabilitation, the part of the journey of care that perhaps the majority of patients share. This is addressed in the next section.

III. BEYOND THROMBOLYSIS While a large amount of eﬀort goes into assessing the suitability of patients for thrombolysis, the majority of patients with stroke are not eligible for treatment. Care for most stroke patients beneﬁts from an organized approach. Stroke may result in death and dependency, with a proportion of patients deteriorating within the ﬁrst few days post– initial event. The majority of patients will be cared for within a hospital inpatient setting, but some may be managed within their home by their family physician with appropriate support from other health professionals. In planning the organization of postacute stroke care, awareness of the best current medical/nursing evidence is essential in addition to knowledge of the availability of local resources. A signiﬁcant factor in determining postacute stroke care may be the wishes of the patient and their carers. Inpatient stroke care comes in a variety of guises. It can be undertaken solely in general medical hospital wards with nonspecialized rehabilitation. Some stroke care may be within general rehabilitation wards along with patients who require rehabilitation through other medical conditions. A proportion of strokes may be looked after within a geographically deﬁned stroke unit [70], which may provide acute stroke care, postacute rehabilitation, or a mixture of both. In practice, stroke patients may spend some time in diﬀerent types of unit, depending on local practices, policies, and resources. Mobile stroke teams may organize care and rehabilitation in nonspecialist stroke environments. Practice is not uniform throughout the world, and stroke patients may not be admitted to the hospital in some countries, but are managed at home [71] by their physicians supported by other health professionals. A number of studies have looked at

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ways of supporting early discharge of stroke patients to the community [72,73]. The past decade has seen a gradual change in practice in patients who suﬀer from acute stroke, with more evidence accruing regarding the eﬃcacy of stroke units as well as the increasing availability of thrombolytic services. A. Stroke Units Stroke unit care has been investigated quite extensively over the last decade. The most recent Stroke Unit Trialists’ Collaboration [74] reported on 23 clinical trials with some 4911 patients involved. Organized inpatient stroke services have been compared to alternatives including general medical wards and diﬀerent forms of organized stroke care. The results suggest a lower case fatality in people who had been looked after in a stroke unit, with the likelihood of dependency poststroke signiﬁcantly reduced in patients admitted for organized stroke care. The median follow-up for most of the stroke units studied ranged from 6 weeks to 12 months, although there are two longer-term studies, which suggest a prolonged eﬀect of stroke unit care even 5–10 years postadmission [75,76]. The same studies suggest a signiﬁcantly improved quality of life in patients discharged from stroke units, and analysis of length of stay does not show a signiﬁcant increase in patient stay due to the use of stroke units. Indeed, length of stay may be marginally reduced by the implementation of organized stroke care [77]. The beneﬁts of stroke unit care appear to be conferred on all age groups and any severity of stroke, with no diﬀerence between the sexes in terms of actual beneﬁt. There is evidence to suggest that patients in stroke units recover faster even with less therapy input [77] and are more likely to have medical interventions [78] to decrease the likelihood of further events. Patients who have been admitted to stroke units may show less emotional distress and more social integration as a result [79]. Most of the comparisons made between stroke unit care and less organized care has been where the latter has been in general medical wards. Few studies have directly compared diﬀerent forms of organized stroke care. Wood et al. [80] found a signiﬁcant eﬀect in terms of stroke recovery, although Kalra et al. found that by comparison mobile stroke teams were less eﬀective than stroke unit care [72]. There are again few studies directly comparing stroke units and general rehabilitation wards [81,82], but the trend would suggest that in direct comparison there are signiﬁcantly fewer deaths in stroke units and a trend towards less dependency. Overall analysis from the Stroke Unit Trialists Data [74] would suggest that for every 100 patients managed in a stroke unit, 3 additional patients will survive, 3 patients will avoid longer-term care, and 6 will return home with a chance of functional independence. B. What Constitutes a Stroke Unit? A number of features are common to an organized multidisciplinary stroke unit. It should have responsibility to a deﬁnite geographical area, and it should house the multi-disciplinary team. The staﬀ should have specialist knowledge of stroke [83], and an education program should be in place to ensure best possible practice. Guidelines for common problems should exist, and staﬀ members should meet regularly to coordinate patient management [83]. The precise nature and function of the unit will determine its location; patients admitted acutely may require proximity to neuroimaging, intensive therapy unit, and other specialty support. Stable rehabilitation patients are less likely to need such input. The size of the unit will depend on local needs. It should be large enough to be viable and should have full access to medical and nursing staﬀ, physiotherapy, occupational therapy,

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speech therapy, dietetics, psychology, and social services. Other health professionals may be involved as the individual situation dictates Most stroke patients are suitable for stroke unit admission, although there is little evidence of beneﬁt in those who are minimally aﬀected or those in coma, and thus in a situation where stroke unit beds are underprovided, some form of prioritization may be required to ensure that those who may beneﬁt most have access to the resource. Again, there is no evidence to suggest an absolute length of time that patients must stay in stroke units to derive beneﬁt. Artiﬁcial time limits are a means of managing the stroke unit while achieving throughput, but they require ﬂexibility in the face of clinical change in the patient. C. Operational Factors of a Stroke Unit Organization of stroke care appears to be critical in achieving good outcomes. We have already discussed acute care, the need for early diagnosis, and the possibility of interventional management of AIS. As stroke patients evolve, their medical and nursing needs change, as do their rehabilitation needs. A crucial part of care within the stroke unit is interdisciplinary assessment and management, and we suggest that it include a comprehensive assessment of conscious level, safety of swallow, nutritional risk, need for pressurerelieving devices, cognition and functional assessment, as well as a review of moving and handling issues [83]. Positioning should be looked at with advice from physiotherapists and measures taken to reduce the risk of pulmonary thromboembolism [84]. Plans should be in place to monitor and manage incontinence, and staﬀ should be aware of the possibility of depression and treat appropriately. Rehabilitation strategies should be discussed among the multidisciplinary team and goals agreed upon with the patient and carergivers. Attempts at secondary prevention should be started within the stroke unit. The addition of antithrombotic therapy in the absence of cerebral hemorrhage [85] and the use of anticoagulants in the presence of atrial ﬁbrillation, valvular heart disease, or prosthetic heart valves [86] should all be considered. Blood pressure should be measured and treated as per local guidelines, and lipids should likewise be estimated [87]. If the stroke is ischemic in nature and of a carotid distribution, imaging of the carotids should be undertaken, and if signiﬁcant internal carotid stenosis is present surgery should be oﬀered [88]. One way to ensure delivery of care and monitoring deviation is through critical care pathways speciﬁcally developed for stroke. A recent review by Kwan and Sandercock [89] found no diﬀerence between groups managed in units with critical care pathway as compared to standard care in terms of death, dependency, and discharge destination. There was some evidence that urinary tract infection is less common and there is better access to CT scanning and carotid scanning in people who are managed via pathways, but at present there appears to be insuﬃcient evidence supporting their routine use in acute stroke management or rehabilitation. D. Organization of Community Rehabilitation Stroke accounts for substantial bed use in both the acute hospital sector and long-term care facilities [90]. Consideration has been given to the possibility of managing stroke patients at home acutely as a feasible alternative to hospital admission. A few studies have looked at this issue, and a Cochrane Systematic Review exists [91]. Studies involving stroke patients [72,92,93] have considered the possibility of avoiding admission to the hospital by the provision of physical support in the community. The trials have displayed

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considerable heterogeneity, and though there was no statistically signiﬁcant diﬀerence between patients managed at home or in the hospital, a trend towards poorer outcomes in the groups managed at home existed with no apparent reduction in bed use. At present, there is no evidence to support the widespread management of acute stroke in the community through these plans. A further approach to reducing length of hospital stay for stroke patients has been through plans to support early discharge to the community. These services may be termed early supported discharge, accelerated discharge programs, or postdischarge support. Again, a Cochrane review exists [94] and a number of randomized controlled studies [95– 97] have looked at this question in a variety of diﬀerent countries, mostly in urban settings. Organization and provision of care was the responsibility of the early supported discharge team in some of the studies, while in others the team merely coordinated stroke care. Control patients were patients discharged from stroke units as well as general medical wards. There was no diﬀerence in mortality or morbidity in patients with early supported discharge from the hospital after a stroke, though a deﬁnite reduction in length of stay with no increase in readmission rate or costs was apparent. The data, however, are limited, and the methods and provision of community support were diﬀerent among the various studies, with no formal assessment of service quality, making the need for further work on this aspect of stroke care necessary. A number of community-based rehabilitative services are in existence. These include continued inpatient rehabilitation in community hospitals or centers, outpatient therapy via clinic, or using a day hospital for organized interdisciplinary care. Rehabilitation may be based at home with visiting therapists and nurses or a mixture of all forms of input. A number of studies have compared diﬀerent forms of community rehabilitation [98]. Day hospital, where rehabilitation tends to be coordinated and involve the multidisciplinary team, has been compared to outpatient therapy, neurology team care, specialist domiciliary care, as well as single therapist care in some small studies. Stroke patients requiring the services of the interdisciplinary team may beneﬁt from the organized care that the day hospital provides, though domiciliary services may well have an advantage in those patients who cannot travel.

IV. CONCLUSION The delivery of good stroke care in both the acute and postacute phases requires service organization to maximize the beneﬁt to the stroke patient. As newer therapies and more complex methods of delivery evolve, so will the need to reorganize, augment, and adapt services to keep pace with change. At present, organized stroke care allows the possibility of thrombolytic treatment for some patients but results in high-quality care for the majority who are not eligible for speciﬁc therapy. In the postacute phases of stroke care, it potentially improves outcomes, namely death and dependency, in addition to reduced inpatient hospital stay.

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9 Complications of Acute Ischemic Stroke and Their Management J. Hofmeijer, H. B. van der Worp, and L. J. Kappelle University Medical Center Utrecht, Utrecht, The Netherlands

Neurological and medical complications endanger the life of the stroke patient. They can prolong hospitalization and hamper or delay successful rehabilitation. This chapter will focus on the incidence, consequences, and management of complications in the acute phase after cerebral infarction.

I. CASE FATALITY In recent studies, 30-day case fatality rates for ischemic stroke in western communities have varied between 10% and 17% [1–5]. Old age [1,5] and impaired consciousness on admission are important predictors of early mortality [4,6]. Other risk factors include severity of the neurological deﬁcit, persistent middle cerebral artery occlusion, heart failure, persistent atrial ﬁbrillation, recurrent stroke, and ischemic heart disease [5]. In the ﬁrst 10 days, patients with vertebrobasilar territory infarction have a poorer prognosis than those with carotid territory infarction, but after 30 days the case fatality rate is similar [4]. Basilar artery occlusion may cause sudden coma or a locked-in syndrome and will cause death by impairment of vital functions in the majority of patients. Transtentorial herniation as a result of edema is the most important cause of death in patients with a large hemispheric infarct during the ﬁrst week [2,7]. Thereafter, pneumonia, pulmonary embolism, sepsis, and other medical complications account for the majority of deaths, mostly in patients with a poor neurological status [2]. Cardiac deaths occur throughout the ﬁrst month in patients with small functional deﬁcits [2]. In young patients, cardiac and other systemic complications are less common, and neurological factors account for the majority of deaths in the ﬁrst 30 days [8]. 183

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II. NEUROLOGICAL COMPLICATIONS A. Progressive Neurological Deficit In up to 43% of patients, deterioration of the neurological status, including a decrease in consciousness or progression of focal deﬁcits, occurs during the ﬁrst week of admission [9– 12]. In most patients, deterioration ends within 48 hours after stroke onset [9,11–13]. Early deterioration is associated with a poorer outcome [9,10,12,14]. Extension or hemorrhagic transformation of the infarct, recurrent infarction, and edema formation are the most common causes of neurological deterioration. Risk factors of early progression are hypertension [11,12], diabetes mellitus [11], an elevated blood glucose on admission [9,12], and an early focal hypodensity on computed tomography (CT) with both cortical and subcortical distribution [9]. Management of neurological worsening depends on its cause, which is usually established by CT or magnetic resonance imaging (MRI) examination. B. Brain Edema and Herniation Large cerebral infarcts may be associated with surrounding edema [15]. In severe cases this may lead to transtentorial or uncal herniation. Fatal space-occupying brain edema occurs in 1–5% of all patients with a supratentorial infarct [2,16]. The case fatality rate of spaceoccupying cerebral infarcts may be as high as 80%, despite maximal conservative therapy on an intensive care unit [15,17]. Serious edema formation usually manifests itself between the second and ﬁfth day after stroke onset. The ﬁrst symptom is drowsiness, often accompanied by pupillary asymmetry [18,19]. Periodic breathing is the next most common early sign, followed by Babinski’s sign contralateral to the hemiparesis [18]. Patients drowsy at admission may become fully alert during subsequent days before consciousness deteriorates again [18]. Several treatment modalities have been suggested to reduce intracranial pressure in patients who deteriorate as a result of edema formation, but none has been proven to improve clinical outcome [20]. According to the guidelines of the American Heart Association, these patients should be treated with osmotic agents and hyperventilation [21]. However, several reports suggest that these measures are ineﬀective [15,17,22] or even detrimental [23]. Osmotic agents, such as mannitol or hypertonic saline, are presumed to draw water from interstitial and intracellular spaces into the intravascular compartment by creating an osmotic pressure gradient over the semi-permeable blood–brain barrier [24]. Hyperventilation lowers intracranial pressure by inducing serum alkalosis and vasoconstriction, thereby reducing cerebral blood ﬂow and cerebral blood volume [25,26]. These treatment modalities are based mainly on the perception that a raised intracranial pressure is the dominant cause of neurological deterioration. However, displacement of brain tissue rather than increased intracranial pressure probably is the most likely cause of the initial decrease in consciousness and further neurological deterioration [19]. Intracranial pressure monitoring has not been shown as helpful in guiding long-term treatment [27]. Treatment with osmotic agents or hyperventilation might even be harmful, because the reduction in volume of the contralateral hemisphere, where the blood–brain barrier and cerebral autoregulation are still intact, might be more pronounced than that of the infarcted hemisphere, resulting in increased brain tissue shifts [19]. Moreover, osmotic agents may accumulate in the aﬀected tissue, thereby reversing the osmotic gradient between tissue and plasma, leading to an exacerbation of edema [26]. Some experts advise hypothermia or decompressive surgery in these patients. Nonrandomized studies in patients with severe space-occupying edema after MCA infarction

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suggested that moderate hypothermia (32–34jC) can help to control critically elevated intracranial pressure values and to improve clinical outcome [28–30]. Decompressive surgery by means of hemicraniectomy and duraplasty has been shown to revert brain tissue shifts and to normalize intracranial pressure, and is therefore presumed to increase cerebral blood ﬂow and to prevent secondary brain damage. In two nonrandomized prospective series, mortality was substantially lower in the groups who underwent hemicraniectomy than in the groups who received optimal medical care, without an increase in the number of severely disabled survivors [31,32]. Multicenter randomized trials of decompressive surgery for space-occupying hemispheric infarction are on their way [33,34]. Next to the uncertainty concerning the diﬀerent treatment options, it remains unclear which patients should be candidates for intensive antiedema treatment. Several parameters have been suggested to be predictors of the development of fatal brain edema. An increased risk was found to be associated with clinical conditions such as a high score on the NIH Stroke Scale on admission, early nausea and vomiting, hypertension, and cardiac failure, but the predictive value of the diﬀerent conditions was weak [35,36]. Radiological predictors of fatal brain edema include hypodensity of 50% or more of the MCA territory on the early CT scan [35,36] and lesion volume on diﬀusion-weighted MRI exceeding 145 cm3 [37]. Nevertheless, in our view, an unambiguous decision to start antiedema treatment based on one or on a combination of these parameters cannot be made yet. In patients with space-occupying infarction, factors increasing intracranial pressure such as hypoxia, hypercapnia, and hyperthermia should be treated and the head should be elevated by 20–30 degrees. Excessive water administration and, when the patient is mechanically ventilated, increased intrathoracic pressure should be avoided [38,21]. Hyperventilation will decrease intracranial pressure almost immediately but, if started at all, should not be continued for more than 24 hours. Mannitol can be given intravenously in an initial dose of 0.5–1 g/kg, followed by 0.25–0.5 g/kg every 3–5 hours depending on intracranial pressure, serum osmolarity, and clinical ﬁndings. A single intravenous bolus of 40 mg furosemide may be given in the acute stage. Surgical decompression by means of hemicraniectomy and dural augmentation can be a life-saving procedure and in some cases result in a favorable outcome, but it should be carefully considered on case-by-case basis. Like the above measures there is currently not enough evidence to support the routine use of physical or chemical cooling therapy [39]. Progression of symptoms due to edema after cerebellar infarction requires a speciﬁc approach. This condition may lead to brain stem compression and obstructive hydrocephalus [40,41], which, in turn, may cause additional neurological damage. Although many patients with a cerebellar infarct and a decreased level of consciousness or acute hydrocephalus on the initial CT scan have a good outcome when managed conservatively, clinical and CT features cannot reliably predict in which patients a conservative approach will be successful [42]. In general, conservative management under close clinical observation is advised in conscious patients. When decrease of consciousness is accompanied by hydrocephalus, the patient can be treated by external ventricular drainage. Major complications of this procedure, such as upward herniation, are rare, and outcome is often good [42]. If the neurological situation does not rapidly improve, urgent craniectomy and evacuation of the infarct is warranted [42]. In comatose patients without hydrocephalus, surgical decompression may also be life-saving (Figs. 1 and 2). C. Hemorrhagic Transformation The term ‘‘hemorrhagic transformation’’ covers a wide variety of bleeding events, ranging in severity from small petechiae to frank hematomas. From the point of view of pathological

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Figure 1 (a) CT scan of a 32-year-old patient with a large infarct in the territory of the right anterior and middle cerebral arteries, accompanied by space-occupying edema and midline shift, one day after the onset of symptoms. (b) CT scan of the same patient after decompressive surgery.

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Figure 2 CT scan showing an infarct in the territory of the right middle cerebral artery 5 days after onset of symptoms, with marked hemorrhagic transformation.

anatomy, the distinction between pale and hemorrhagic infarcts is arbitrary. Most recent infarcts show a few scattered petechiae along their margins [43]. Hemorrhagic transformation usually occurs within 2 weeks of stroke onset [44]. In cardioembolic infarcts, hemorrhages usually occur within the ﬁrst 2 days [43]. In prospective studies, bleeding in the infarcted area resulted in clinical deterioration in 0–11% of the cases [44,45], but usually had no eﬀect on long-term outcome [46,47]. The precise frequency of hemorrhagic transformation is unknown. In autopsy studies, the frequency varied from 18% to 42% [43]. In the stringently selected patient populations enrolled in recent studies of thrombolysis, about 40% of the infarcts in the placebotreated groups became hemorrhagic [48–50]. However, symptomatic cerebral hemorrhages occurred in only 0.6–2.6% of the control patients [50,51]. After thrombolysis, hemorrhage caused clinical deterioration in up to 21% of patients [48–53]. For more information on the incidence and treatment of hemorrhagic complications after thrombolysis, the reader is referred to Chapter 17. Hemorrhagic transformation is more frequent in cardioembolic than in atherosclerotic infarcts [43,44]. The risk of hemorrhagic transformation is related with the size of the infarct [43–46], with an early hypodensity on CT [47,48], and with contrast enhancement on CT or MRI [46]. It is recommended that patients with ischemic stroke be treated with aspirin as soon as possible, whereas treatment with heparin should be withheld because of the increased

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risk of symptomatic hemorrhagic transformation [54]. In patients with cardioembolic stroke who have hemorrhagic transformation, the risk of anticoagulation must be balanced against the likelihood of recurrent embolism or other thrombotic complications if no treatment is given. Antithrombotic drugs should not be used in the ﬁrst 24 hours after thrombolytic treatment [55]. D. Stroke Recurrence The cumulative risk of recurrence for all infarctions is about 2% in the ﬁrst 14 days [56]. Within one month, the risk of recurrence is about 8% after atherothrombotic infarction, 4– 22% after cardioembolism, and 2% after lacunar infarction [56,57]. A history of hypertension, hyperglycemia on admission, diabetes mellitus, and high age were found to be associated with early recurrence [5,56]. Early recurrence increases the duration of initial hospital stay and results in a higher case fatality rate [56]. Two large randomized trials [the Chinese Acute Stroke Trial (CAST) and the International Stroke Trial (IST)] have shown that starting daily aspirin promptly in patients with acute ischemic stroke reduces the risk of long-term stroke recurrence, but also further stroke or death within the ﬁrst 2 weeks [54,58]. Also, patients allocated to heparin had fewer recurrent ischemic strokes, but this was oﬀset by a similar sized increase in symptomatic hemorrhagic strokes, so there was no overall diﬀerence in death or recurrent stroke, even in patients with atrial ﬁbrillation [54]. The HAEST (Heparin in Acute Embolic Stroke Trial) also did not show superiority of heparin to aspirin in patients with acute ischemic stroke and atrial ﬁbrillation [59]. Therefore, it is recommended only to start aspirin as soon as possible. Oral anticoagulant therapy is recommended in patients with presumed cardioembolism within a few days, after exclusion of major intracerebral hemorrhage. E. Epileptic Seizures Up to 6.5% of patients suﬀer from epileptic seizures in the ﬁrst 2 weeks after cerebral infarction [60–63]. These early seizures usually occur at stroke onset or within 24 hours after infarction [62–64]. Early seizures are more often partial than generalized, and status epilepticus is uncommon [62,64,65]. Most seizures occur in patients with cortical involvement, but seizures secondary to subcortical or lacunar infarctions have also been reported [61]. When matched for stroke subtype, no relation between lesion size and occurrence of seizures has been found [62]. It is controversial whether early seizures are more frequent after cardioembolic than after atherosclerotic stroke [61–63]. Seizures probably occur earlier in cardioembolic stroke [66]. Poststroke seizures are not associated with a higher mortality or worse functional outcome [62]. The natural history of early seizures after stroke is unknown, as most patients are promptly treated with anticonvulsants. In a recent study, only 21% of the patients with early seizures developed epilepsy [63]. In the acute stage, administration of anticonvulsant drugs to prevent recurrent seizures is recommended [21]. When treated, seizures are usually readily controlled with a single drug [64]. Chronic antiepileptic drug treatment is usually not warranted, but should be considered when an early seizure is followed by a late seizure [63]. F. Hiccups Persistent hiccups are uncommon in patients with recent stroke. In a retrospective series of 270 stroke patients, intractable hiccups were reported in three cases. All suﬀered from

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ponto-medullary involvement. Despite relatively high disability scores, hiccups were related to prolonged hospitalization. The associated dysphagia and loss of airway control led to respiratory complications in all three patients [67]. Chlorpromazine is the most widely suggested initial treatment for isolated persistent hiccup [68]. However, in patients with acute stroke, chlorpromazine is reported to be poorly tolerated because of its sedative properties [67]. Many alternative treatments, including carbamazepine [69], haloperidol [70], and baclofen [71,72], have been proposed. The optimal regimen remains uncertain, and medical treatment should be optimized on a case-bycase basis.

III. PSYCHIATRIC COMPLICATIONS A. Mood Disorders Up to 50% of patients develop a depression in the ﬁrst 2 weeks after stroke, of whom more than half are diagnosed as having a major depression [73,74]. Mania is rare after stroke [74]. Depression in the acute phase is inversely associated with intellectual, functional, and social outcome of stroke [74,75]. The relationship between lesion location and poststroke depression remains unclear. In some studies, lesions involving the left frontal cortex or left basal ganglia were associated with higher frequencies of major depression than other lesions [73,74], whereas in other studies, relationships with lesions in the right cerebral hemisphere [76] or with frontal and temporal lobe locations without respect to laterality [77] were found. Preexisting subcortical atrophy may be an important risk factor for the development of poststroke depression [74]. In the acute phase, motor deﬁcit is not and functional impairment is only weakly associated with the severity of depression [73]. Aphasia was found to have no eﬀect on the frequency of mood disorders, but the presence of depression is diﬃcult to detect in patients with aphasia [74]. Sleep apnea may contribute to the development of a depressed mood [78]. The prevalence of major depressive symptoms increases steadily during the ﬁrst half year after stroke [79]. Major depression may remit spontaneously 1–2 years after the stroke, whereas the majority of patients with minor depression after acute stroke remain depressed during the following 2 years [73]. Infarcts in the territory of the middle cerebral artery produce longer-lasting depressive disorders than posterior circulation infarcts [74]. Poststroke depressions may be treated eﬀectively with tricyclic antidepressants, but contraindications and side eﬀects may limit their use. The selective serotonin reuptake inhibitor (SSRI) citalopram was found to be safe and eﬀective in depressed patients 2–52 weeks after stroke [80]. Most other second-generation antidepressants have not been tested appropriately in poststroke depression but may be eﬀective as well. Unfortunately, mood disorders are often not recognized in stroke patients and are, therefore, left untreated [74,81].

B. Confusion In the ﬁrst week after ischemic stroke, up to 50% of patients are found to be confused [82]. Severe paresis, previous acute confusional states, left-sided brain lesions, old age, and treatment with anticholinergic drugs are predictors of the development of confusion [67]. In addition, medical complications [67] and sleep apnea [78] may contribute to the development of acute confusional states. Confusion may be caused by ischemia-induced changes of cerebral neurotransmitter levels or occur as a nonspeciﬁc reaction to stress and activation

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of the hypothalamic-pituitary-adrenal axis [67,82]. Treatment should be aimed primarily at the avoidance of potential stressors, which may be as simple as the prevention or treatment of urinary retention. Carefully prescribed sedative or neuroleptic drugs can be of additional help.

IV. CARDIAC COMPLICATIONS Signiﬁcant coronary artery disease has been found in up to 58% of patients with transient ischemic attack (TIA) or ischemic stroke [83], and its presence strongly inﬂuences long-term prognosis [84]. About one third of patients with acute ischemic stroke or TIA monitored by continuous electrocardiography has episodes of ST segment depression and ventricular arrhythmias within the ﬁrst 5 days after the event [85]. Previously undiagnosed arrhythmias, including atrial ﬁbrillation, can be found in about half of patients within 2 days after stroke onset [86]. Rhythmic disorders other than atrial ﬁbrilation are usually benign and resolve over a period of days to months [87]. The causes of the ECG changes often include a combination of factors, such as concomitant coronary artery disease and cardiopathological changes, with instability of the ventricular myocardium. Total serum CPK levels are often raised in the ﬁrst few days after stroke onset, but only 11% of patients have increased CPK-MB isoenzyme concentrations, indicative of myocardial damage [88]. Contrary to acute myocardial infarction, CPK-MB levels after stroke rise slowly over the ﬁrst days [88], and evidence of coronary occlusion is usually not found in the patients with ECG abnormalities [87]. Animal studies indicate that cardiac abnormalities may be related to the location of the cerebral infarct, with lesions of the insular cortex predisposing to ECG changes, cardiac arrhythmias and sudden death [89,90]. Several other observations suggest that cardiac eﬀects are most commonly found with stroke in the right hemisphere. Right hemisphere infarction in the rat was associated with increased plasma norepinehrine levels and a signiﬁcantly increased QT interval [91]. In humans, supraventricular tachycardias were observed more often after right than after left MCA infarction [92], whereas left-sided lesions were found to be a predictor of ST segment depression [85]. After stroke, mortality is substantially higher in patients with new ECG abnormalities [87]. In addition to the 12-lead electrocardiogram and clinical cardiac examination as components of the emergent evaluation of patients with ischemic stroke, continuous electrocardiography for 24–48 hours is recommended in all patients with acute cerebral infarction. At any rate, close cardiac monitoring and cardiological consultation are indicated in patients with overt ECG abnormalities and (suspected) symptomatic coronary artery disease. Abnormal electrolyte levels could induce further exacerbation of ECG abnormalities and should be prevented [93].

V. SYSTEMIC COMPLICATIONS A. Hyper- and Hypotension Both high and low blood pressure are related to poor outcome after ischemic stroke. Systolic blood pressure between 150 and 170 mmHg may be associated with the best prognosis [94]. At the time of admission for acute stroke, arterial blood pressure is elevated in the majority of patients [95]. Previously diagnosed hypertensive patients have higher initial blood pressure values than normotensive patients [96]. Systolic and diastolic blood

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pressures fall markedly during the ﬁrst 7 days and change little thereafter [96,97]. In patients with mild to moderate infarction or TIA, elevated blood pressure drops earlier as compared to patients with severe cerebral infarction [98]. Hypertension may be attributed to transient increases in plasma catecholamines, stress reactions [99], urinary retention, pain, or increased intracranial pressure. An increase in blood pressure can be a pathophysiological response to maintain or enhance perfusion of ischemic brain tissue, where normal cerebral autoregulation of blood ﬂow is impaired [100,101]. Therefore, lowering blood pressure in the acute phase of stroke could jeopardize perfusion to compromised tissues and increase ischemic damage [100,102]. By means of single photon emission computed tomography (SPECT), an inverse relationship was recorded between the maximum fall in blood pressure and improvement in cerebral blood ﬂow [97]. In another study, systolic blood pressure on admission was inversely related to early progression of stroke [11]. Most importantly, a correlation between diastolic blood pressure reduction in nimodipine-treated patients and unfavorable neurological outcome was found in the Intravenous Nimodipine West European Stroke Trial [103]. The optimal management of hypertension during the ﬁrst week after stroke onset is not established. Emergent treatment of elevated blood pressure is mandatory in patients with the clinical syndrome of malignant hypertension, which is characterized by retinopathy, nephropathy, encephalopathy, microangiopathic hemolytic anemia, and cardiac failure [104]. Myocardial ischemia and dissection of the thoracic aorta may also require blood pressure lowering [21]. In the absence of such conditions, lowering blood pressure has no proven beneﬁt [104–106]. However, most experts recommend antihypertensive treatment when the mean arterial blood pressure is greater than 130 mmHg or the systolic blood pressure is greater than 220 mmHg [21]. Oral antihypertensive agents, such as captopril, perindopril [107], and nicardipine, are preferred. If intravenous therapy is necessary, the best drugs are those that can be easily titrated and have a minimal eﬀect on cerebral blood vessels, such as labetolol or enalapril [21]. Too rapid reduction of blood pressure should be avoided and the neurological status should be monitored carefully in order to be able to return the blood pressure to higher levels in case of neurological deterioration. During the ﬁrst 24 hours after thrombolytic therapy, very careful management of blood pressure is necessary. If systolic blood pressure rises above 185 mmHg or if diastolic blood pressure rises above 110 mmHg, hypertension should be treated by means of intravenous labetolol or, in refractory cases, by means of intravenous sodium nitroprusside [55]. Low blood pressure is rare in patients with acute ischemic stroke and is mostly caused by hypovolemia. Fluid status and cardiac output should be optimized by means of intravenous ﬂuids, if necessary supplemented by vasopressor agents. Selected patients, particularly those with a severe symptomatic stenosis or occlusion of intracerebral or cerebropetal arteries, may beneﬁt from blood pressure elevation by, for example, phenylephrine [108]. B. Hyperglycemia In the ﬁrst 24 hours after stroke onset, plasma glucose concentrations are elevated in 40– 50% of patients, more than half of whom are not known to have diabetes mellitus [109,110]. Plasma glucose decreases to preexisting levels over the ﬁrst 7 days [111,112]. The cause of this hyperglycemia, apart from previous (latent) diabetes mellitus, has not been ﬁrmly established. Suggestions that hyperglycemia is due to a stress response after stroke are supported by the relationship between plasma glucose levels and the volume of the cerebral lesion or serum cortisol [111,112]. Several studies have found no correlation between hyperglycemia and the size of the infarcted area [109], stroke severity at onset [110], or plasma

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catecholamine levels [110]. Therefore, it is uncertain whether hyperglycemia is caused by stress alone [110]. Although data are conﬂicting [113], most studies suggest that an initially high blood glucose concentration in patients with acute stroke is a predictor of poor outcome, even in the absence of diabetes [109–111,114–117]. However, it is unclear whether hyperglycemia reﬂects only the severity of the brain lesion, or directly contributes to the poorer outcome itself. No human data exist on the beneﬁts of treating hyperglycemia to improve the prognosis of stroke, but experimental studies suggest that insulin treatment of hyperglycemic animals has a beneﬁcial eﬀect in focal and global brain ischemia [118]. Until more data are available, management in the acute stage of stroke should be aimed at maintaining glucose levels within the normal range [21]. C. Venous Thrombosis and Pulmonary Embolism Deep venous thrombosis is one of the most frequent complications of ischemic stroke, occurring in about 50% of the patients without prophylactic therapy [119]. Deep venous thrombosis is conﬁned mainly to the paretic leg. Severe leg weakness, a shortened activated partial thromboplastin time [120], and atrial ﬁbrillation [121] are associated with an increased risk of deep venous thrombosis. The complication is feared mainly because of the risk of pulmonary embolism, which occurs in 5–6% of patients [119] and may account for up to 15% of deaths [2,120]. Overall, prophylactic administration of heparin, low molecular weight heparins, or heparinoid is associated with an 81% reduction in deep venous thrombosis as detected by I125 ﬁbrinogen scanning or venogram [119]. These antithrombotic drugs also prevent pulmonary embolism [119]. The International Stroke Trial recorded a non-signiﬁcant reduction of pulmonary embolism in aspirin-treated patients [54]. In patients with a contraindication to antithrombotic treatment, pneumatic stockings are advised [21]. Although getting out of bed is not an absolute guarantee against venous thromboembolism [7], patients should be mobilized as early as possible. When deep venous thrombosis occurs despite prophylaxis, treatment with subcutaneous low molecular weight heparin is as least as eﬀective as classic intravenous heparin [122,123]. The risk–beneﬁt ratio of antithrombotic therapy for this indication in the acute phase after stroke is uncertain, because the possible beneﬁt may be oﬀset by an increase in hemorrhagic complications [54]. D. Infections Chest infections were found to occur in 12–31% of patients hospitalized after acute stroke [124]. Pneumonia accounts for about one quarter of deaths in the ﬁrst month [2,125] and occurs more often in patients with a decreased consciousness or dysphagia. Urinary tract infections are also common [124] and occur more frequently in patients with an indwelling catheter. Infections should be treated appropriately, and to reduce the risk of infection, patients should be mobilized as soon as possible, aspiration of food should be prevented, and, if possible, indwelling catheters should be avoided. E. Fever Between 22% and 43% of patients develop fever or subfebrile temperatures during the ﬁrst days after stroke [126,127]. In most cases, pulmonary or urinary tract infection is the cause of hyperthermia, but fever may also exist without signs of an overt infection [126,128].

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Fever is more common in patients with larger infarcts [126,129]. Subfebrile temperatures and fever in the ﬁrst days after stroke are associated with an increased case fatality and poor functional outcome [127,128,130,131], but a threshold above which hyperthermia is detrimental has not been established. The relationship between brain damage and high temperature is stronger if the increase of temperature occurs earlier after stroke onset [132]. The harmful eﬀects of fever have been attributed to increased cerebral metabolic demands [128], changes in the blood–brain barrier permeability, acidosis, and an increased release of excitatory amino acids [133,134]. Nonrandomized studies suggest that moderate hypothermia could help to improve clinical outcome in patients with massive space-occupying cerebral infarction [28–30]. However, there is currently no evidence from randomized trials to support the routine use of physical or chemical cooling therapy in acute stroke [39]. Until more data become available, the source of fever should be determined and treated and hyperthermia should be reduced with antipyretics. F. Respiratory Insufficiency A decrease in consciousness after ischemic stroke leading to a loss of protective pharyngeal reﬂexes and an inability to clear secretions or leading to recurrent apnea may necessitate endotracheal intubation and mechanical ventilation. This condition may be caused by herniation syndromes in case of excessive edema formation or by brainstem lesions in case of thrombosis of the basilar artery. Pneumonia, pulmonary embolism, or aspiration may also cause respiratory insuﬃciency. In addition, intubation may be required because of status epilepticus or hemodynamic failure. No information is available on the incidence of respiratory insuﬃciency in the acute phase after ischemic stroke, but the outcome of patients requiring endotracheal intubation and mechanical ventilation for various reasons is very poor [135–137]. Mortality depended mainly on neurological impairment, and in most patients intensive-care management did not substantially aﬀect the natural history of stroke. Therefore, mechanical ventilation is indicated in patients with limited neurological impairment who require intubation because of status epilepticus or nonneurological complications, but should be doubted in patients with a decrease in consciousness due to massive stroke. G. Urinary Incontinence The incidence of urinary incontinence one week after stroke onset is reported to be 60% and declines to 42% and 29% among survivors at 4 and 12 weeks, respectively [138]. Incontinence is often associated with moderate to severe motor deﬁcit, aphasia and cognitive impairment, but not with gender or side of the stroke [138,139]. Increasing severity of incontinence in the acute phase is associated with a progressively worse outcome [140] and higher institutionalization rates [140–142]. Three major factors are responsible for urinary incontinence after stroke [139]. First, cerebral infarction may cause disruption of the neuromicturition pathways, resulting in a loss of voluntary control of the reﬂex arc between the bladder and the sacral spinal cord, leading to detrusor hyperreﬂexia and urge incontinence. The speciﬁc location of lesions that cause detrusor hyperreﬂexia in humans remains speculative [139]. A second cause of incontinence is formed by stroke-related cognitive and language deﬁcits with normal bladder function. Patients may not be able to communicate the need to void, to handle a urinal, or to maneuver safely to a commode. Third, concurrent diabetic neuropathy or use of anti-

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cholinergic medication can result in bladder hyporeﬂexia and overﬂow incontinence. Bladder hyporeﬂexia may also occur within the ﬁrst 48 hours as a direct consequence of stroke, with subsequent normalization of bladder function [139]. Nursing strategies, such as scheduled voiding, intermittent catherization, or the use of condom catheters in men are useful ﬁrst-line treatments [139]. Whenever possible, indwelling catheters should be avoided because of the hazards of urinary tract infections. When incontinence persists, urodynamic studies are helpful in establishing the cause. After urological consultation, refractory bladder hyperreﬂexia can be treated with anticholinergic or antispasmodic medications and overﬂow incontinence with cholinergics [139].

H. Constipation and Fecal Incontinence In the acute phase after stroke, constipation is common and may, paradoxically, lead to diarrhea and fecal incontinence. Immobility and a reduced intake of ﬂuid and food are the usual causes. In most cases, physical examination of the abdomen and rectum will suﬃce to exclude serious pathology. Increasing the intake of ﬁber and ﬂuid is the preferred therapy, but often laxatives, suppositories, or enemas are required.

I. Pressure Sores Decubital ulcers are found in about 15% of patients hospitalized for acute ischemic stroke and are seen more frequently with increasing age [143]. Immobilization is the most important cause. Prevention should include regular turning of the patient, relief of bony prominences, early mobilization, and adequate nutrition. Close attention to impending pressure sores and early treatment with hydrocolloid dressings or copolymer membranes [144] may prevent development of large ulcerations.

J. Dysphagia The incidence of swallowing diﬃculties in the ﬁrst days after acute stroke is estimated to be as high as 50% even when unconscious patients are excluded [145]. Although dysphagia is more common in patients with lower brain stem lesions and level of alertness is an important factor in the ability to eat and swallow [146], it is found on admission in one third of conscious patients with unilateral hemispheric stroke, especially when aphasia and facial weakness are present [147]. Anterior and subcortical periventricular white matter lesions are associated with a higher risk of swallowing problems [148]. The magnitude of dysphagia in unilateral stroke is probably related to pharyngeal motor representation in the unaﬀected hemisphere [149]. In most of these patients the deﬁcit resolves itself by the end of the ﬁrst week, and by one month only a minority of survivors still have swallowing problems [147,150]. Patients with impaired swallowing have a high risk of aspiration and chest infection, a poor nutritional state [145], and may easily become dehydrated. Dysphagia is associated with an increased risk of death [145] and is inversely related to functional outcome [147]. Swallowing function should be assessed in all stroke patients. Interviews, observations, and a water swallow test at the bedside should be performed in each patient admitted at the stroke unit [145,151–153]. Swallowing can also be assessed by video-ﬂuoroscopic

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modiﬁed barium swallow evaluation, which may be the basis for developing an individualized dysphagia treatment plan [154]. Swallowing cannot be tested in patients with a decreased consciousness, but is usually impaired. When dysphagia is mild (as indicated by the absence of drooling, which means that patients can swallow their own saliva), feeding can be started cautiously in an upright position with food of appropriate consistency. In more severe cases, a nasogastric or nasoduodenal tube may be necessary for feeding and administration of medications. Gastrostomy tube feeding is probably superior to nasogastric tube feeding, where improvement in nutritional state, survival, and early discharge are concerned [155,156], and is usually well tolerated [157]. Some experts suggest that percutaneous endoscopic gastrostomy should be considered if thickened ﬂuids are insuﬃciently tolerated 14 days after the onset of stroke [158]. In most cases, however, timing will be performed on an individual basis. In the subacute stage (about 4–6 weeks after stroke), patient and family instruction concerning diet modiﬁcations and compensatory swallowing techniques are eﬀective in the prevention of dysphagia-related complications, and in most cases dysphagia-therapist control of the diet and daily instruction of compensatory swallowing techniques will not be necessary [159]. Medical treatment with calcium antagonists has not shown signiﬁcant beneﬁt [160]. Computerized biofeedback therapy, however, might become useful in the treatment of these patients [161]. Late recovery of swallowing occurs and patients should have follow-up swallow assessment [157].

K. Malnutrition Malnutrition occurs in up to one third of hospitalized patients within 2 weeks after stroke onset [162]. The most important associated factors are stroke severity and swallowing diﬃculties. Malnutrition is associated with a poor functional prognosis [162]. Surprisingly, early appropriate enteral feeding does not always prevent malnourishment, and stroke patients must therefore probably be considered moderately hypercatabolic [162]. Although the beneﬁcial eﬀects of enteral feeding in critically ill patients have been established, the role and timing of nutritional intervention after stroke therefore remain unclear. Nevertheless, in view of the lack of data from controlled trials and the relatively few potential disadvantages except the risk of aspiration pneumonia, early enteral feeding is recommended in all stroke patients, even those with swallowing diﬃculties. Manipulation of ﬂuid thickness using objective measurements may improve the dietary management in patients without tube feeding [163].

L. Gastrointestinal Hemorrhage The incidence of gastrointestinal hemorrhage in the ﬁrst month after stroke onset is 0.1–3% [164,165]. In a minority it directly contributes to death [165]. Patients with gastrointestinal bleeding are usually older and have suﬀered more severe strokes [165]. Gastritis or esophageal, gastric, or duodenal ulcers are the source of bleeding in most patients. Risk factors include the use of nonsteroidal anti-inﬂammatory drugs, aspirin, or corticosteroids, prolonged anticoagulation, and previous peptic ulcer disease [164,165]. Patients with gastrointestinal hemorrhage after stroke may need endoscopy and treatment with H2 antagonists or omeprazole. Blood transfusion or intravenous ﬂuids may be required in severe cases.

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VI. CONCLUSION Management of neurological and medical complications constitutes an important part of the care for patients with acute ischemic stroke. Adequate prevention, diagnosis, and treatment of these complications may decrease morbidity and mortality and may contribute to an improved functional outcome. Therefore, patients with acute ischemic stroke should be monitored closely for early detection and treatment of complications. Care is best when the patient is admitted to a specialized stroke unit. A multidisciplinary approach provided by stroke units, including specialized medical, nursing, and remedial therapy, has been proven to reduce the duration of hospitalization and to decrease mortality [166]. However, for many complications optimal treatment and its eﬀect on outcome after stroke have not been established. Therefore, in addition to the ongoing acute intervention trials, well-designed randomized trials are urgently needed to address the prevention and treatment of complications and their eﬀect on stroke outcome.

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10 Management of Modifiable Risk Factors for Stroke or Accelerated Atherosclerosis Pierre Fayad University of Nebraska College of Medicine, Omaha, Nebraska, U.S.A.

I. INTRODUCTION Preventing stroke is key to reducing its societal burden from a human and ﬁnancial perspective. Ischemic stroke represents 70–80% of all strokes, whereas atherosclerosis of the brain and heart vasculature play the predominant pathological role. It is well established that a majority of strokes are largely preventable. Major risk reductions in stroke are achieved in focused groups of patients where speciﬁc interventions can be prescribed, for example up to 80% are achieved with oral anticoagulation in patients with atrial ﬁbrillation; and carotid endarterectomy reduces the risk of stroke by more than 60% in patients with symptomatic carotid stenosis. Yet in the general population at risk for stroke, there remain wide opportunities to reduce the risk of stroke beyond the use of oral antiplatelet medications which achieve at best a relative risk reduction of 25%. Therefore, modifying atherosclerotic risk factors that place patients at risk for stroke is key to reducing its burden. Stroke prevention can begin before any neurological symptoms are evident (primary prevention) and becomes even more important following transient ischemic attack (TIA) or stroke (secondary prevention), conditions that ﬂag patients at highest risk for future stroke over the coming months or years. The vast amount of information gained from epidemiological and observational studies and randomized trials allows the identiﬁcation of risk factors and proﬁles for persons at highest stroke risk and provides guidelines for management [1]. Furthermore, advances in the past decade provide us with the possibility to identify patients at risk of developing the major atherosclerotic risk factors, like hypertension and diabetes, with the proven ability to prevent them from occurring through behavioral, dietary, and pharmacological interventions. In the following discussion, the focus will be on the major established modiﬁable atherosclerotic risk factors and provide information on ways to assess, treat, and prevent them, relying heavily on the recommendations from major consensus and recommendations. 205

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II. HYPERTENSION Hypertension is the most powerful and modiﬁable risk factor for stroke. It represents a major health epidemic aﬀecting around 50 million individuals in the United States and one billion persons worldwide. With an increasingly aging population, hypertension will become an even larger societal health burden. The Framingham Heart Study suggests that normotensive individuals at age 55 have a 90% lifetime risk of developing hypertension later in life [2] . There is a continuous and consistent relationship between blood pressure (BP) and the risk of major vascular complications, which include stroke, myocardial infarction, heart failure, and kidney disease. The risk of these complications doubles with even small magnitudes of change in blood pressure of 20 mmHg systolic or 10 mmHg diastolic [3]. Up to 50% of strokes may be attributable to hypertension due to its high prevalence. Patients with hypertension have a threefold higher risk of stroke than nonhypertensives, while borderline hypertensives still have one and a half times the risk of those with normal blood pressure. The recently published Seventh Report from the Joint National Commission on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) provides a thorough review of the classiﬁcation, risks, and recommendations for the management of hypertension [4]. The most recent classiﬁcation of arterial hypertension and its treatment from JNC-7 is outlined in Table 1. A new stage in the classiﬁcation of hypertension termed ‘‘prehypertension’’ was introduced to emphasize the need to detect persons at high risk for developing hypertension and to signal its preventability. This is particularly important since up to 30% of hypertensive individuals remain unaware of having hypertension. Various antihypertensive therapies are now well proven to reduce major vascular events. Eﬀective blood pressure control can be achieved in most hypertensive patients, but the majority will require two or more antihypertensive drugs [5,6]. Treatment of hypertension in clinical trials is associated with 35–40% reduction in stroke, 20–25% reduction in myocardial infarction, and more than 50% reduction in heart failure [7]. Achieving a sustained 12 mmHg reduction in SBP over 10 years in patients with stage 1 hypertension and additional cardiovascular risk factors provides a substantial reduction in mortality estimated at one less death for every 11 patients treated [8]. Systolic hypertension is a more important risk factor for stroke and cardiovascular disease than diastolic hypertension in the majority of patients except in those younger than age 50 [9]. Systolic hypertension is typically more common in older individuals and considerably more diﬃcult to control than diastolic hypertension. In persons with systolic hypertension, the risk of stroke does not increase with increasing diastolic blood pressures (DBP). Comparatively, in patients with diastolic hypertension, the incidence of stroke rises steadily with increasing systolic blood pressures (SBP). Dementia and cognitive impairment occur more commonly in hypertensive individuals, while signiﬁcant reductions in cognitive impairment occur with eﬀective antihypertensive therapy [10,11]. The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality through blood pressure control. Reducing systolic and diastolic blood pressure to less than140/90 mmHg signiﬁcantly decreases cardiovascular complications. A blood pressure goal of less than130/80 mmHg is targeted in patients with diabetes or renal disease, who are generally at higher risk. Most persons with hypertension, especially those over age 50, will reach the diastolic blood pressure (DBP) goal once the systolic blood pressure (SBP) goal is achieved; the primary focus should be on achieving the SBP goal. Thiazide-type diuretics should be used as initial therapy for most patients with hypertension, either alone or in combination with one of the other classes (angiotensin-converting enzyme

or z100

z160

Stage II hypertension

Yes

Encouraged Yes Yes

Lifestyle modiﬁcation No antihypertensive drug indicated No antihypertensive drug indicated Thiazide-type diuretics for most May consider ACEI, ARB, BB, CCB, or combination Two-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB)

Initial drug therapy without compelling indications

Drug(s) for compelling indicationsc Drug(s) for compelling indicationsc Drug(s) for the compelling indicationsc Other antihypertensive drugs (diuretics, ARB, BB, CCB) as needed Drug(s) for the compelling indicationsc Other antihypertensive drugs (diuretics, ARB, BB, CCB) as needed

Initial drug therapy with compelling indications

DBP, diastolic blood pressure; SBP, systolic blood pressure. Drug abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; CCB, calcium channel blocker. a Treatment determined by highest BP category. b Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. c Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. Source: Adapted from Ref. 4.

and <80 or 80–89 or 90–99

<120 120–139 140–159

DBPa (mmHg)

Normal Prehypertension Stage I hypertension

BP classiﬁcation

SBPa (mmHg)

Table 1 Classiﬁcation and Management of Hypertension for Adults

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Table 2 Lifestyle Modiﬁcations to Manage Hypertension Modiﬁcation Weight reduction Adopt DASH eating plan

Dietary sodium reduction Physical activity

Moderation of alcohol consumption

Recommendation

Range SBP reduction

Maintain normal body weight [body mass index (BMI) 18.5–24.9 kg/m2] Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat Reduce dietary sodium intake to no more than 100 mmol per day (2.4 g sodium or 6 g sodium chloride) Engage in regular aerobic physical activity such as brisk walking (at least 30 min per day, most days of the week) Limit consumption to no more than 2 drinks per day in most men and to no more than 1 drink per day in women and lighter-weight persons

5–20 mmHg per 10 kg weight loss 8–14 mmHg

2–8 mmHg

4–9 mmHg

2–4 mmHg

DASH = Dietary Approaches to Stop Hypertension. For overall cardiovascular risk reduction, stop smoking. The eﬀects of implementing these modiﬁcations are dose- and time-dependent and could be greater for some individuals. Source: Adapted from Ref. 4.

inhibitors, angiotensin receptor blockers, h-adrenergic blockers, calcium-channel blockers) demonstrated to be beneﬁcial in randomized controlled outcome trials [4]. Some intriguing results from recent trials suggest that classes of antihypertensive medications may have diﬀerential eﬀects on stroke prevention, with some classes being more eﬀective than others [12], and that antihypertensive agents may be eﬀective at preventing stroke even in normotensive individuals with atherosclerosis [13,14]. These questions will undoubtedly be the topic of research and debate over the coming years. Key advances have been made in the area of hypertension preventability, which prompted the JNC-7 classiﬁcation to include the prehypertension stage, to focus on patients at high risk of developing hypertension, and preventing its occurrence [4]. Patients with prehypertension have twice the risk of developing hypertension than those in the normal category. Adopting healthy lifestyles is critical for the prevention of hypertension and is indispensable for its management, as discussed in Table 2. Major lifestyle modiﬁcations shown to lower BP include weight reduction in those individuals who are overweight or obese [15,16], adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan, a diet rich in potassium and calcium, dietary sodium reduction [17– 19], physical activity [20,21], and moderation in alcohol consumption [22]. Lifestyle modiﬁcations are eﬀective at reducing blood pressure, enhancing antihypertensive drug eﬃcacy, and decreasing cardiovascular risk. When two or more lifestyle modiﬁcations are adopted, the results are even more successful.

III. DIABETES Diabetes is a well-established risk factor for cardiovascular disease in general and stroke in particular and is a growing epidemic. Criteria and recommendations for diagnosing and

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Table 3 Criteria for the Diagnosis of Diabetes 1. Symptoms of diabetes and a casual plasma glucose = 200 mg/dL (11.1 mmol/L) Casual is deﬁned as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. OR 2. Fasting plasma glucose (FPG) = 126 mg/dL (7.0 mmol/L) Fasting is deﬁned as no caloric intake for at least 8 h. OR 3. 2-h plasma glucose =200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT) The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. Note: The oral glucose tolerance test (OGTT) or fasting plasma glucose (FPG) test may be used to diagnose diabetes; however, in clinical settings the FPG test is greatly preferred because of ease of administration, convenience, acceptability to patients, and lower cost. In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be conﬁrmed by repeat testing on a diﬀerent day. The OGTT is not recommended for routine clinical use but may be required in the evaluation of patients with impaired fasting glucose (IFG) or when diabetes is still suspected despite a normal FPG. Source: Adapted from Ref. 23.

testing for diabetes mellitus come from the 2003 American Diabetes Association Recommendations [23], summarized in Tables 3 and 4. In the third National Health and Nutrition Examination Survey (NHANES), the unadjusted prevalence in 1999–2000 of total diabetes (diagnosed and undiagnosed) is 8.3%, aﬀecting an estimated 16.7 million persons aged 20 and over. The lifetime risk of developing diabetes for individuals born in 2000 in the United States is 32.8% for males and 38.5% for females according to the National Health Interview Survey [24]. The highest estimated lifetime risk for diabetes is among Hispanics, amounting to 52.2% for Hispanic females. The relative risk of stroke in

Table 4 Criteria for Testing for Diabetes in Asymptomatic, Undiagnosed Individuals 1. Testing for diabetes should be considered in individuals at age 45 years and above, particularly in those with a body mass index (BMI) of 25 kg/m2a; if normal, it should be repeated at 3-year intervals. 2. Testing should be considered at a younger age or be carried out more frequently in individuals who are overweight (BMI = 25 kg/m2a) and have additional risk factors: Have a ﬁrst-degree relative with diabetes Are habitually physically inactive Are members of a high-risk ethnic population (e.g., African American, Hispanic American, Native American, Asian American, Paciﬁc Islander) Have delivered a baby weighing > 9 lb or have been diagnosed with gestational diabetes mellitus Are hypertensive (140/90) Have an HDL cholesterol level 35 mg/dL (0.90 mmol/L) and/or a triglyceride level 250 mg/dL (2.82 mmol/L) Have a clinical condition associated with insulin resistance (i.e., acanthosis nigricans or other) On previous testing, had IGT or IFG Have a history of vascular disease a

May not be correct for all ethnic groups. Source: Adapted from Ref. 23.

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diabetics varies between 1.5 and 3.0. In a recent epidemiological study of northern Manhattan, the odds ratio for stroke in diabetics was 1.7 [25]. Factors found to be predictive of a ﬁrst stroke in the United Kingdom Prospective Diabetes Study (UKPDS) include duration of diagnosis, female sex, smoking, atrial ﬁbrillation systolic hypertension, and dyslipidemia [26]. In the Freemantle Diabetes Study, the presence of a carotid bruit was highly predictive of a ﬁrst stroke [27]. Diabetes can cause both macrovascular disease (coronary, cerebral, and peripheral arteries) and microvascular disease (retinopathy, nephropathy, and neuropathy). Stroke in diabetes has been associated with small vessel disease or lacunar stroke subtype in hospital-based studies [28,29]. Epidemiological studies, however, could not conﬁrm such an association between lacunar stroke and diabetes [30,31]. Diabetes, on the other hand, is highly prevalent among patients with extracranial carotid occlusive disease, being present in 23% and 19%, respectively, in the asymptomatic carotid artery stenosis trial [32] and in the North American Symptomatic carotid surgery trial [33]. In both instances diabetics beneﬁted from carotid endarterectomy like the other subgroups and had similar rates of perioperative stroke or death. The strong correlation between diabetes and stroke suggests that a strict control of hypoglycemia would result in a signiﬁcant reduction in the risk of stroke. Unfortunately, the randomized trials that evaluated the eﬀect of intensive diabetes control showed statistically signiﬁcant reductions only in the diabetic microvascular complications, such as retinopathy, nephropathy, or even neuropathy [34,35]. The macrovascular complications, such as stroke, myocardial infarction, or sudden death, were not found to be signiﬁcantly decreased in several studies assessing intensive diabetes control in insulindependent [35] or non–insulin-dependent diabetics, with insulin or with oral hypoglycemics [34]. Intensive treatment of diabetes, however, was found to correlate signiﬁcantly with a decrease in the progression of carotid intima-media thickness, a common measure of atherosclerosis, as compared to those on conventional treatment 6 years after the study [36]. These results are not surprising, since diabetes is rarely isolated without other pathologies like hypertension, microalbuminuria, and dyslipidemia along with other risk factors like obesity, tobacco smoking, and physical inactivity [37]. The treatment of hypertension, with a prevalence of 40–60% among diabetics, reduces the risk of stroke and

Table 5 Summary of Recommendations for Adults with Diabetes Mellitus Glycemic control A1C Preprandial plasma glucose Peak postprandial plasma glucose Blood pressure Lipids LDL Triglyceridesb HDLc a

<7.0%a 90–130 mg/dL (5.0–7.2 mmol/L) <180 mg/dL (<10.0 mmol/L) <130/80 mmHg <100 mg/dL (<2.6 mmol/L) <150 mg/dL (<1.7 mmol/L) >40 mg/dL (>1.1 mmol/L)

Referenced to a nondiabetic range of 4.0–6.0% using a DCCT-based assay. Current NCEP/ATP III guidelines suggest that in patients with triglycerides 200 mg/dL, the non-HDL cholesterol (total cholesterol minus HDL) be utilized. The goal is 130 mg/dL. c For women, it has been suggested that the HDL goal be increased by 10 mg/dL. Source: Adapted from Ref. 23. b

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cardiovascular disease in diabetics more eﬀectively than in patients without diabetes [38,39]. Even lower targets of systolic and diastolic blood pressures are recommended in diabetics because of the important additional beneﬁcial eﬀects [4]. Intensive management of all other vascular risk factors in diabetics result in signiﬁcant reductions in macrovascular and microvascular outcomes [40]. There is cumulative evidence showing that diabetes mellitus type 2 is preventable through the same treatments (exercise, diet, angiotensin-converting enzyme inhibitors [41,42], and statins [43]) aimed at treating other vascular risk factors, bringing the provocative question of whether diabetes itself represents a vascular condition [44]. Recommendations for treatment of diabetes and its associated conditions from the 2003 American Diabetes Association recommendations [23] are summarized in Table 5.

IV. OBESITY, GLUCOSE INTOLERANCE, INSULIN RESISTANCE, AND THE METABOLIC SYNDROME Obesity has been correlated with cardiovascular disease, as have other vascular risk factors like hypertension, diabetes, glucose intolerance, and physical inactivity. The diﬀerent criteria for obesity and its diﬀerent measurements makes a clear relationship to stroke more diﬃcult to establish. It appears that abdominal obesity rather than elevated body mass index is more strongly related to stroke incidence [45]. More recently, obesity has been strongly connected with other signiﬁcant metabolic problems including abnormal glucose and insulin metabolism that renders obesity a key risk identiﬁer for stroke within this group. Glucose intolerance and insulin resistance [46], particularly when associated with other risk factors under the ‘‘Metabolic Syndrome’’ (MetS) [47], are emerging as independent risk factors for cardiovascular disease and stroke. There are two deﬁnitions of MetS from the National Cholesterol Education Program (NCEP), adult treatment panel (ATP-III) [48], and the World Health Organization WHO [49], deﬁnitions both of which feature glucose metabolism dysregulation or hyperinsulinemia as the diagnostic cornerstone, in association with obesity, dyslipidemia, and hypertension as the remaining criteria. MetS is being increasingly recognized as a major epidemic because of the projected growing prevalence of obesity, hypertension, and sedentary lifestyles [50]. In a small study of patients with stroke or TIA, the prevalence of impaired insulin sensitivity was 60% [51]. The individual components of the syndrome are known independent risk factors for cardiovascular disease, but it appears that the combination of these factors together in the same person adds up to a higher total risk than the sum of the risks from each individual risk factor [47]. According to NHANES, the U.S. age-adjusted prevalence of the MetS according the ATP-III deﬁnition is 24% [52]. Cardiovascular death and stroke rates were found to be signiﬁcantly higher in patients with MetS in the Botnia study [53], the Kuopio Ischemic Heart Disease study [54], and the Helsinki Policeman Study [55]. MetS was found also to be associated with progression of carotid atherosclerosis [56]. The increased risk of vascular disease associated with hyperinsulinemia may be related to impaired ﬁbrinolysis and hypercoagulability with increased serum plasminogen activator inhibitor-1 and other hemostatic factors, even in patients with normal glucose tolerance [57], hyperhomocysteinemia and albuminuria [58], or inﬂammation [59,60]. The hopeful aspect about MetS is its potential preventability with diet, physical activity, weight loss, hypertension control, and ﬁnally, medications such as oral hypoglycemics [61]. Treating MetS may also prevent the onset of diabetes and its complications [62].

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V. BLOOD LIPIDS Dyslipidemias have been extensively studied and are now well characterized, their risks well known, and their treatments well established. The recently released guidelines from the National Cholesterol Education Program (NCEP) and its Third Adult Treatment Panel (ATP III) provide an extensive review about the knowledge, evaluation, classiﬁcation, and treatment of dyslipidemias that represent a distillation of our current knowledge. An executive summary was published in 2001 [63], and the full recommendations were published in 2002 [48]. The key recommendations as to screening, classiﬁcation, and management are summarized in Tables 6, 7, and 8. Low-density cholesterol (LDL) elevations are directly related, and high-density cholesterol (HDL) are inversely related, to an increased risk of atherosclerosis and cardiovascular disease [63]. While elevated LDL is now well established as a risk factor for coronary disease, the relationship to stroke has been more ambiguous. Many studies failed to ﬁnd a relationship between ischemic stroke and elevated total cholesterol, including a meta-analysis of 450,000 persons from 45 prospective cohorts [64]. Two observational prospective studies found a positive relationship between ischemic stroke and elevated serum cholesterol levels [65,66]. In the MRFIT study, ischemic stroke deaths were associated with the highest levels of serum cholesterol [65]. The recent Bezaﬁbrate study found also a correlation between ischemic stroke and LDL [67]. There has been a consistent correlation between extracranial carotid atherosclerosis and cholesterol mainly with elevated LDL, or low HDL, particularly in association with hypertension and cigarette smoking [56,68]. The HDL levels were inversely correlated to the risk of ischemic stroke in the Northern Manhattan Stroke Study [69]. The relationship between cholesterol and stroke seems to follow a U-shaped curve where elevated cholesterol levels raise the risk of ischemic stroke, while very low cholesterol levels correlate with an increased risk of hemorrhagic stroke [65]. The association between low cholesterol and hemorrhagic stroke was found in several series, including some from Asia where the prevalence of hemorrhagic stroke is higher [70,71]. While the correlation between cholesterol levels and ischemic stroke is less than certain, the clinical response and reduction in stroke demonstrated in several trials using

Table 6 ATP III Classiﬁcation of LDL, Total, and HDL Cholesterol Cholesterol type

Cholesterol level (mg/dL)

Interpretation

Total cholesterol

<200 200–239 z240 <100 100–129 130–159 160–189 z190 z60 <40

Desirable Borderline high High Optimal Near/Above optimal Borderline high High Very high High (desirable) Low (undesirable)

LDL cholesterol

HDL cholesterol

LDL = low-density lipoprotein; HDL = high-density lipoprotein. ATP III recommends that all adults aged 20 or older undergo a complete lipoprotein proﬁle (total, LDL, and HDL cholesterol and triglycerides) every 5 years as the preferred initial test, rather than screening for total cholesterol and HDL alone. Source: Adapted from Ref. 48.

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Table 7 Categories of Risk that Modify LDL Cholesterol Goals, Risk Category, LDL Goal, and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Diﬀerent Risk Categories

CHD risk category CHD & CHD Risk Equivalents Multiple (2+ risk) factors Multiple (2+ risk) factors 0–1 risk factorsb

LDL level at which to consider drug therapy (mg/dL)

Target LDL (mg/dL)

LDL level at which to initiate TLC (mg/dL)

>20

<100

z100

10–20

<130

z130

z130 (100–129: drug optional)a z130

10

<130

z130

z160

<10

<160

z160

z190 (160–189: LDL-lowering drug optional)

10-year CHD risk Framingham Projections (%)

Abbreviations: LDL = low-density lipoprotein; CHD = coronary heart disease; TLC = Therapeutic Lifestyle Changes. a Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol level of <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL, e.g., nicotinic acid or ﬁbrate. Clinical judgment may also call for deferring drug therapy in this subcategory. b Almost all people with 0–1 risk factor have a 10-year risk < 10%; thus, 10-year risk assessment in people with 0–1 risk factor is not necessary. Notes: 1. 10-year risk of coronary heart disease (CHD) is based on the Framingham Risk proﬁle 2. CHD risk equivalents carry a risk for major coronary events equal to that of established CHD, i.e., >20% per 10 years (i.e., more than 20 of 100 such individuals will develop CHD or have a recurrent CHD event within 10 years). It includes other clinical forms of atherosclerotic disease, peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease such as diabetes and multiple risk factors that confer a 10-year risk for CHD >20%. Risk factors that modify the LDL goal are listed in Table 9. Source: Adapted from Ref. 48.

statins solidify the role not only of cholesterol as a risk of ischemic stroke, but the clinical relevance of its reduction. Several studies using various drugs from the statin family of drugs (HMG coreductase inhibitors) including lovastatin, simvastatin, and pravastatin in patients with acute or chronic coronary disease and elevated or even average levels of LDL consistently demonstrated a relative risk reduction of stroke compared to the nontreated group, varying between 19% and 35% [72–74]. A study with atorvastatin in patients with Table 8 Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goala Cigarette smoking Hypertension (BP z 140/90 mmHg or on antihypertensive medication) Low HDL cholesterol (<40 mg/dL)b Family history of premature CHD (CHD in male ﬁrst-degree relative <55 years; CHD in female ﬁrst-degree relative <65 years) Age (men z 45 years; women z 55 years) a

In Ref. 48, diabetes is regarded as a CHD risk equivalent. HDL cholesterol z 60 mg/dL counts as a ‘‘negative’’ risk factor; its presence removes one risk factor from the total count. Source: Adapted from Ref. 48. b

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hypertension and average or lower-than-average cholesterol also found a signiﬁcant reduction in stroke rate of 27% [75]. The beneﬁt of stroke reduction is not limited to statins; stroke rate was reduced by 31% with gemﬁbrozil in patients with coronary disease and low HDL [76]. These beneﬁcial eﬀects were over and above stroke risk reductions with the standard therapies related to the use of antiplatelet and antihypertensive therapy. Therefore, in patients with coronary heart disease, even with average LDL levels, these agents are indicated for primary stroke prevention. This beneﬁt encourages the use of statins for secondary stroke prevention in patients with stroke, particularly when associated with ischemic atherosclerotic disease, in spite of the lack of data from clinical trials to support such use in this speciﬁc situation. A trial with atorvastatin in patients with stroke and no coronary heart disease is ongoing and could shed light on such an important treatment opportunity [77].

VI. AORTIC ARCH ATHEROSCLEROSIS An autopsy study from Hisayama, Japan, showed aortic arch atherosclerosis (AAA) to be more severe than cerebral atherosclerosis and correlates with the presence of systolic hypertension, age over 79, and serum cholesterol [78]. Attention to the association of AAA with stroke came a decade ago from another autopsy study involving 500 patients with cerebrovascular disease, this time from France [79]. It showed a higher prevalence of aortic arch ulcerated plaques in patients with ischemic stroke as compared to hemorrhagic stroke. It also showed that ulcerated plaques were statistically more common in patients with stroke of undetermined etiology and were not correlated with carotid atherosclerosis. A transesophageal echocardiography study conﬁrmed that this association was particularly stronger with larger plaques (z4 mm) [80], which are predictors of recurrent brain infarction and other vascular events [81]. AAA is equally present among diﬀerent ethnic groups, and its presence also correlates with cryptogenic stroke [82]. Protruding AAA may also predict perioperative stroke risk in patients undergoing heart surgery [83]. Hyperhomocysteinemia [84] is associated with AAA and may predict atherosclerosis progression. It is also associated with elevated peripheral white count [85]. More recently, aortic stiﬀness, as determined by transesophageal echocardiography, was also found to be independently associated with increased stroke risk [86] or even as a predictor of fatal stroke [87]. The treatment of AAA remains controversial in the absence of prospective randomized trials evaluating the options. Initially, anticoagulation was advocated because of the risk of atheroembolism, but a recent retrospective series analysis showed statins to be associated with a decreased risk of stroke, but not antiplatelets or anticoagulants [88].

VII. INFLAMMATION AND INFECTIONS Inﬂammation and infections have risen over the past decade to become part of the important risk factors for atherosclerosis [89,90]. They additionally modulate the traditional risks (hyperlipidemia, physical inactivity, obesity) making them even more pathogenic [91,92]. Several studies have demonstrated the association between recent infections and stroke [93– 96]. Periodontal disease was found to have a modest association with an increased risk of stroke [97] and with subclinical carotid atherosclerosis [98]. An association between cerebrovascular disease and speciﬁc infectious agents, including Chlamydia pneumoniae and Helicobacter pylori, has not been consistently found [99–102]. Several trials have been initiated and some were completed in patients with coronary disease with the intent of

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lowering the risk of myocardial infarction through antibiotic use [103]. There is still no proof that antibiotics lower the risk of cardiovascular events. In a nested case-control study of elderly hypertensive individuals with stroke in Quebec, the use of various antibiotics was not associated with a protective eﬀect from stroke except for the use of penicillin [104]. There are several markers of systemic inﬂammation (Table 9). Few of these markers are sensitive, practical, available, and reliable enough to play the role of a universal marker for the risk of cardiovascular disease and stroke. Of those markers, ﬁbrinogen was the ﬁrst one to be studied, but after a reﬁnement of its assay, C-reactive protein emerged recently as one of the markers that could play such a predominant role [91]. Serum ﬁbrinogen is a powerful and independent risk factor for stroke and cardiovascular disease [105,106]. A meta-analysis of six prospective studies conﬁrmed that association and demonstrated a dose–response relationship that more than doubles the risk of cardiovascular events in those with the upper tertile of serum ﬁbrinogen levels compared to the lowest tertile [107]. In a large Swedish study, elevated cholesterol levels were not signiﬁcantly associated with an increased risk of stroke unless inﬂammation-sensitive proteins including ﬁbrinogen were also elevated [108]. On the other hand, it is associated with the presence of many other major risk factors of stroke, including smoking, physical inactivity, and hypercholesterolemia. Fibrinogen can be reduced through control of smoking, exercise, alcohol intake, and estrogens. Fibrate drugs are also very eﬀective. C-reactive protein (CRP) is an acute phase reactant and a nonspeciﬁc marker for systemic inﬂammation. Several studies have conﬁrmed a strong association of CRP with myocardial infarction (MI), ischemic stroke, and peripheral vascular disease [109–111]. In the Framingham study, CRP was found to be an independent risk factor for stroke in the elderly [112]. Similar association was found in NHANES III [113]. It was also a stronger predictor of vascular events than LDL cholesterol in women participating in the Women’s Health Study [114]. Plasma CRP levels are associated with the extent and severity of atherosclerotic disease. On the other hand, CRP is associated with several other risk factors, including smoking, hypertension, hypercholesterolemia, obesity, and diabetes. Whether decreasing these inﬂammatory-sensitive markers can result in decreased risk of stroke needs further evaluation.

Table 9 Potential Inﬂammatory Markers for Cardiovascular Risk 1. Soluble adhesion molecules E-selectin P-selectin Intracellular adhesion molecule-1 (ICAM-1) Vascular adhesion molecule-1 2. Cytokines Interleukins 1h, 6, 8, 10 Tumor necrosis factor-a 3. Acute-phase reactants Fibrinogen Serum amyloid A protein (SAA) C-reactive protein (CRP) 4. White blood cell count 5. Others (e.g., erythrocyte sedimentation rate) Source: Adapted from Ref. 91.

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VIII. PHYSICAL ACTIVITY Regular, moderate, or vigorous physical activity provided a lower risk of stroke in men, but not in women from the Framingham cohort [115]. Other studies, however, demonstrated a similar beneﬁt in women [116,117]. The Atherosclerosis in Risk Communities study found only a weak eﬀect of physical activity in reducing the risk of stroke [118]. While some studies showed a dose-dependent relationship in stroke risk reduction [117,119], others suggest that any level of activity may equally decrease that risk [120,121]. Even in patients with a known stroke risk factor, i.e., increased left ventricular mass (LVM), physical activity attenuated the risk of ischemic stroke, reducing it to the risk of persons without the cardiac ﬁnding [122]. A recent meta-analysis of all studies involving physical activity conﬁrmed a beneﬁcial eﬀect of moderate and high physical activity in decreasing the risk of both ischemic and hemorrhagic stroke by about 25% as compared with physically low active or inactive persons [123]. The exact mechanism through which exercise decreases the risk of stroke remains unclear, but there are many potential candidate metabolic eﬀects: decreased LDL, increased HDL, decreased weight, decreased insulin resistance, increased endogenous ﬁbrinolysis, decreased ﬁbrinogen, decreased serum homocysteine, and therefore decreased hypercoagulability. Even low-level physical activity, consisting of more than 3 h a week of leisure time activity, halved the risk for developing metabolic syndrome, a newly identiﬁed risk factor for stroke, as compared to sedentary persons [124]. A recent study suggests that physical activity decreases the risk of stroke though upregulation of endothelial nitric oxide synthase activity in the vasculature [125]. Recommendations from the Centers for Disease Control [126] and the National Institutes of Health Consensus Development Panel on Physical Activity and Cardiovascular Health [127] aim for at least 30 min of moderateintensity physical activity on a daily basis or most days of the week.

IX. HOMOCYSTEINE AND MTHFR GENE MUTATION Elevated serum homocysteine (hyperhomocysteinemia) has emerged over the past decade as an independent risk factor for cardiovascular disease in general, and stroke in particular [128]. On the other hand, elevated homocysteine levels are associated with several cardiovascular risk factors, including male sex, increasing age, cigarette smoking, hypertension, hyperlipidemia, renal failure, physical inactivity, and markers of inﬂammation such as C-reactive protein. The methylene tetrahydrofolate reductase (MTHFR) gene is an important regulator of homocysteine metabolism. Mutations of this thermolabile gene with MTHFR 677C!T polymorphism has received major attention as a contributor to hyperhomocysteinemia and therefore a potential genetic risk factor for cardiovascular disease. Homozygous persons for the gene mutation with decreased folate intake have higher homocysteine levels. Those heterozygous do not have hyperhomocysteinemia in spite of low folate intake [129]. Hyperhomocysteinemia was found to be an independent risk factor for stroke in the British Regional Heart Study [130], in elderly individuals from the Framingham study [131], the Rotterdam study [132], and in NHANES-III [133]. It was also found to be associated with an increased risk of stroke in patients with coronary disease [134] and with a risk of recurrent stroke in a hospital-based population [135]. There is a dose–response eﬀect from increasing levels of homocysteine, with the highest levels raising the stroke risk fourfold [130]. Furthermore, fasting levels of homocysteine have been correlated with

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intimal–medial carotid wall thickness [136] and with thoracic aortic atherosclerosis [84]. Additionally, hyperhomocysteinemia substantially increases the cardiovascular risk associated with smoking and hypertension. The initial observational and case-control studies suggested that hyperhomocysteinemia was a strong risk factor for cardiovascular disease. More recent studies and metaanalytic reviews suggest the risk to be modest at best. A recent meta-analysis looking at 30 studies of homocysteine showed that a 25% decrease in serum homocysteine lowers the risk of stroke by 19% and that of ischemic heart disease by 10% [137]. Another metaanalysis distinguishing between genetic and prospective studies suggests that lowering homocyteine levels by 3 Amol/L reduces the risk of stroke by 24% [138]. One potential reason for the inconsistencies may be the variablility in homocysteine levels, acutely and chronically, after a stroke [139]. A recent meta-analysis from studies of the MTHFR gene polymorphism suggests that in persons homozygous for the gene mutation, the risk of cardiovascular disease is increased by 16% [140]. Serum levels of homocysteine can be reduced by increasing dietary folic acid to 0.4 mg/ day. One milligram of cyanocobalamin is generally added to overcome the concerns about masking vitamin B12 deﬁciency. In patients with renal failure, much higher doses of folate (up to 20 mg) could be needed to achieve a reduction in serum homocysteine. Eﬀectiveness in reversing the risk of stroke through lowering serum homocysteine, however, was evaluated through a randomized clinical trial, the Vitamins in Stroke Prevention Trial (VISP) [141]. The study was stopped before completion by the Safety Monitoring Committee after a clear demonstration of the eﬀectiveness of high doses of vitamins in decreasing serum homocysteine without decreasing the risk of stroke. Other ongoing prospective randomized trials in patients with systemic cardiovascular disease may shed further light on this interesting risk factor in the coming years. In the meantime, it does not appear warranted to routinely measure homocysteine in patients at risk of stroke [142].

X. EXOGENOUS OVARIAN HORMONES Female hormones can be administered either in the form of oral contraceptives (OC) or in the form of postmenopausal hormone-replacement therapy (HRT). OC most frequently combine an estrogen and a progestin. HRT can use an estrogen alone or in combination with a progestin. The estrogen and progestin compounds used in OC and HRT can be natural or synthetic products, estrogen agonists or antagonists, and used in diﬀerent doses and combinations. There have been continuous changes in OC and HRT over the past few decades in both dosing and nature of components. Several generations of progestins have been produced. The estrogen dose in OC has decreased from the original 150 Ag to 20–35 Ag. All of these factors render an accurate assessment of beneﬁts and risks of these products incredibly complicated. Despite these complicating factors, the cumulative evidence associates exogenous ovarian hormones, whether used as OC or for HRT, with an increased risk of ischemic stroke and cerebral venous thrombosis. There is growing and consistent evidence that OC are associated with a small increase in risk of stroke as demonstrated in meta-analyses and cohort studies. OC additionally impart a high risk of cerebral venous thrombosis in patients with hereditary coagulaopathies [146] but do not appear to increase the risk of hemorrhagic stroke [143]. The controversy as to whether newer OC preparations with lower estrogen dosage are less risky continues, with some studies showing similar risks for older and newer preparations [145], while others showed a lower stroke risk with low-estrogen OC [143] and no increased

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risk if other vascular risk factors are taken into consideration [147]. The stroke risk associated with OC is small since women of childbearing age uncommonly have other vascular risk factors. The presence of other vascular risk factors, such as hypertension, smoking, and older age, signiﬁcantly increases the risk of ischemic stroke [143]. Estrogen-replacement therapy has been touted as an eﬀective treatment for many of the conditions that complicate menopause. Because of its beneﬁcial eﬀects on serum lipids and vascular endothelium and smooth muscles, estrogen was presumed to be helpful in preventing stroke and cardiovascular disease [148]. Experimental research demonstrated estrogen’s beneﬁcial eﬀects as a neuroprotective agent in reducing the size and improving the outcome from acute experimental stroke [149]. The trophic eﬀects on brain cells led to advocacy for its use in preventing neurodegenerative disease and dementias. Its known beneﬁts in treating osteoporosis and preventing colon cancer appeared overwhelmingly beneﬁcial on top of the vascular and neuroprotective eﬀects that could overcome the risk of breast and uterine cancer. Prospective cohort and case-control studies presented conﬂicting data on the beneﬁts of HRT in reducing stroke risk [150–153]. It took years before large randomized trials were able to adequately address some of these questions. The Heart and Estrogen–Progesterone Replacement Study (HERS) was a randomized study of 2763 postmenopausal women with known cardiac disease showed no signiﬁcant eﬀect on stroke [154], but an increased risk of cardiovascular disease in the ﬁrst year of treatment [155]. That continued to be true in the HERS II study with an additional follow-up of 2 years [156]. The Women’s Estrogen Stroke (WEST) randomized 664 postmenopausal women after TIA or minor stroke to receive estradiol or placebo and showed no reduction in the risk of death or recurrent stroke, but rather an increased risk of fatal stroke [157]. Finally, the largest study to date, the Women’s Health Initiative Study, randomized 16,608 mostly healthy postmenopausal women to receive estrogen– progestin combination or placebo [158]. It showed a signiﬁcantly increased risk of ischemic stroke, with an odds ratio of 1.44, with the hormone-replacement therapy. Similarly, an increased risk of myocardial infarction was found. In summary, HRT not only does not prevent stroke in postmenopausal women, but increases the risk of ischemic stroke and other cardiovascular events, particularly in the ﬁrst few years of treatment [159]. The beneﬁts in regard to osteoporosis and colorectal cancer do not compensate for such increased risks, and while better understanding of what causes hormones to increase the risk is needed [160,161], HRT should not be recommended [162].

XI. TOBACCO SMOKING Tobacco smoking is well established as an independent risk factor for coronary and vascular disease in general, and with stroke in particular, in both sexes and at all ages. The cardiovascular risks associated with cigarette smoking are the best and most widely studied, but cigar or pipe smoking, which more recently had a trend in replacing cigarette smoking, is not devoid of risks [163]. While the cardiovascular risks from cigar and pipe smoking seem to be intermediate between light cigarette smoking and never-smokers, the risk of lung cancer is similar [164]. Smoking raises the risk of all major stroke groups: ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage. The eﬀect follows a dose–response relationship, raising the risk up to 10-fold in those smoking over a pack per day. The relative risk of stroke is one and a half times controls according to a meta-analytic review [165], being highest for subarachnoid hemorrhage (almost three times the risk), intermediate for ischemic stroke (close to double), and lowest for cerebral

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hemorrhage (close to controls). There is some evidence to suggest that smoking enhances atherosclerosis through chronic infections [166]. The presence of additional risk factors beyond smoking such as diabetes and hypertension raise the toll of smoking even further [167]. On the positive side, smoking cessation decreases the acquired elevated risk of stroke, which is substantially reduced within 2–5 years [168]. In the Framingham study, stroke risk leveled oﬀ after 5 years in former smokers, closely approaching that of nonsmokers [169]. The British Regional Heart Study [170] found a considerable and rapid beneﬁt in smoking cessation, particularly in light smokers, while in heavy smokers the risk was never completely reversed. The absolute beneﬁt of quitting smoking on stroke risk was most marked in hypertensive patients [170]. The Atherosclerosis Risk in Communities found that pack-years of smoking but not current smoking, as compared to past smoking, was associated with progression of atherosclerosis, suggesting that some adverse eﬀects of smoking may be cumulative and irreversible [167]. Even passive smoking, shown to impair endoltheium-dependent arterial dilation [171], seems to independently increase the risk of stroke [172]. Smoking cessation is estimated to reduce the annual risk of stroke by 61,500 and save $3.08 billion in stroke-related health care [173].

XII. ALCOHOL CONSUMPTION The relationship between alcohol and stroke remains ambiguous, as there are diﬀerential eﬀects according to type of stroke, sex, and the presence or absence of other risk factors. The eﬀect seems to be dependent on the type, dose, and consistency of alcohol used [174– 176]. There is a dose-dependent response with alcohol as far as increasing the risk of hemorrhagic stroke [177–179]. Light or moderate alcohol consumption is associated with lower risk of stroke [180–182]. Paradoxically, heavy chronic or binge alcohol drinking raises the risk of stroke [183]. A recent meta-analysis of published studies showed that heavy alcohol consumption increases the relative risk of stroke, while light or moderate alcohol consumption may be protective against total and ischemic stroke [184]. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, with an odds ratio (OR) of 1.69 for ischemic stroke, and OR 2.18 for hemorrhagic stroke, while consumption of less than 12 g/day was associated with a reduced relative risk of total stroke (OR 0.83) and ischemic stroke (OR 0.80), and consumption of 12–24 g/day was associated with a reduced relative risk of ischemic stroke (OR 0.72). The metaregression analysis revealed a signiﬁcant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke. The mechanisms of actions through which alcohol increases or decreases the risk of stroke remains unclear but is possibly related to dehydration, hemoconcentration and cardiac rhythm disturbances, and eﬀects on blood lipids and the ﬁbrinolytic and coagulation systems [183].

XIII. CONCLUSIONS Stroke prevention is being transformed from a personal style or belief into the realm of evidence-based medicine. The cumulative information collected over the past decades has been crucial in increasing our understanding of atherosclerosis and how it interacts with

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various risk factors and lifestyles. Further advances in the coming years will no doubt continue to build on knowledge and increase our abilities in diminishing the toll of atherosclerosis. The publication of this distilled information speciﬁcally regarding stroke prevention helps identify the major eﬀective strategies that need to be pursued [183,186,187]. Unfortunately, translating such knowledge to where it matters, into the general population and in patients with stroke or TIA, remains slow [188–190]. The responsibility of treating physicians in identifying those risks and treating and monitoring patients at risk for stroke according to the continuously changing information is essential to enhancing our eﬀectiveness at reducing stroke beyond the limitations of pharmacologic and surgical therapies.

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11 Rehabilitation After Stroke Udo Kischka and Derick T. Wade Rivermead Rehabilitation Research Centre, Oxford Centre for Enablement, Oxford, England

I. INTRODUCTION The therapeutic approach to stroke has until relatively recently been characterized by fatalism and hopelessness. This attitude has pervaded the expectations and actions of the patients themselves, their family members, and even of the physicians in charge of their treatment. Fortunately, things have changed gradually over the last 10 years or so, and cautious optimism as well as a growing conﬁdence have crept into the ﬁeld of rehabilitation. Solid research evidence has been accumulated showing that rehabilitation after stroke is eﬀective, particularly if it is well organized. We will discuss in this chapter what ‘‘well organized’’ means. Several countries such as the United States, Germany, and the United Kingdom [1–3] have developed national guidelines for the clinical management of stroke that often include the organization of rehabilitation services. Rehabilitation medicine has expanded the traditional medical model of the treatment of illness to a greater extent than most other medical disciplines. Rehabilitation physicians do not simply focus on the diagnosis and treatment of a disease. Rather, rehabilitation services aim to prioritize the patients’ wishes and needs, consider their social situation, and involve nurses and therapists as partners, utilizing their speciﬁc knowledge and competence. The rest of this chapter is divided into three parts. The ﬁrst part covers basic concepts of rehabilitation in general, and stroke rehabilitation in particular. Although the models described may, at ﬁrst sight, appear rather abstract, we will attempt to demonstrate that they actually have great practical value for the daily clinical work of professionals working with stroke survivors. The second part describes the therapy of some speciﬁc conditions after stroke, and the third part summarizes evidence regarding the eﬀectiveness of stroke rehabilitation.

II. BASIC CONCEPTS OF STROKE REHABILITATION A. The WHO Model of Functioning, Disability, and Health A comprehensive model of rehabilitation should aid in understanding the illness and its consequences on several levels: physiological, psychological, and social. The model 231

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should comprise not only bodily structures and functions, but also the eﬀects of the illness on the patients’ everyday lives, including their ability to care for themselves as well as its impact on their social roles. The World Health Organization (WHO) proposed an International Classiﬁcation of Impairment, Disability, and Handicap (ICIDH), which has more recently been revised and renamed the International Classiﬁcation of Functioning, Disability, and Health (ICF) [4–6]. This classiﬁcation framework can also be interpreted as a model. Although the model is simple, it has provided clinicians and researchers with a powerful framework for understanding and managing the consequences of illness on diﬀerent levels. The model makes the following distinctions: Pathology: The underlying disease, an abnormality of structure and/or function aﬀecting an organ or organ system. In the traditional medical model, this refers to the diagnosis. Impairment: The symptoms and signs, the manifest abnormalities of function evident to an external observer. Activity (called disability in the earlier model): The behavioral consequences on activities that are meaningful to the patient. In particular, this comprises activities of daily living (ADL) such as washing, dressing, feeding, continence and walking. Participation (called handicap in the earlier model): Changes in the patients’ social roles within their environment as a consequence of the illness. The model also takes into account contextual factors: Personal domain: The patient’s attitudes, beliefs, and expectations. Physical domain: Local physical structures such as the house, local shops, and carers; Social domain: The legal and cultural setting, such as laws and expectations from important others. To illustrate this model we use a hypothetical 53-year-old male patient, Mr. Smith, who has been admitted to the hospital after waking up with a weakness his left arm and leg, which also feel numb. The computed tomography (CT) scan of his brain shows an ischemic stroke in the right middle cerebral artery territory (MCA) and Doppler ultrasound examination gives evidence of a high-grade stenosis of the right internal carotid artery (ICA). In his case, the right MCA ischemic cerebral infarction and the right ICA stenosis are the pathologies. If he had an underlying hypertension or hypercholesterolemia, these would also be pathologies. The symptoms of left arm and leg weakness and sensory loss are the impairments. He probably also had mild dysarthria, another impairment. The weakness and sensory loss aﬀect or limit his activities: it results in an inability to wash, dress, and feed himself unaided. If the arm does not recover, he will probably be made redundant from his job as an electrician, causing him to lose his role as breadwinner of his family. As he was a keen sportsman previously, he will likely have to give up his memberships in his sport clubs. All these changes in his social roles within his family, his work environment, and his circle of friends and acquaintances are referred to as changes in participation. The precise nature and extent of the changes in participation may well be inﬂuenced by the attitude of his employer and relevant legislation, his social context. His expectations and past experiences (i.e., his personal context) may well also inﬂuence his outcome. In his case the nature of his home may not aﬀect outcome, but he may need to adapt his car (i.e., his physical context).

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B. Definition of Stroke Rehabilitation A useful deﬁnition of stroke rehabilitation needs to do justice to its complexity. It is generally recognized that rehabilitation can be regarded under three diﬀerent aspects: structure, process, and outcome. Each individual rehabilitation service can be described according to these categories. Structure refers to the operational characteristics and resources of a rehabilitation service, process describes how a certain rehabilitation service works, and outcome focuses on the aims of a rehabilitation service. Based on these distinctions, one can formulate a set of deﬁnitions that takes the complexity of stroke rehabilitation into account [7]. 1. Structure A service that specializes in rehabilitation comprises a multidisciplinary team of people who: Work together towards common goals for each patient Involve and educate the patient and family in the process Have relevant expertise and experience (knowledge and skills) Can, between them, resolve most of the problems faced by their patients 2. Process Rehabilitation is a reiterative active, educational, problem-solving process, focused on a patient’s behavior (activity) and well-being, with the following components: Assessment—the identiﬁcation of the nature and extent of the patient’s problems and the factors relevant to their resolution Goal setting Intervention—which may include either or both of (1) treatments, which aﬀect the process of change, or (2) support (care), which maintains the patient’s life and safety Evaluation—to check on the eﬀects of any intervention 3. Outcome The aims of the rehabilitation process are to: Maximize the participation of the patient in his or her social setting Minimize the risk of medical complications, such as recurrent strokes, contractures, etc. Minimize the pain and distress experienced by the patient (maximize quality of life) Minimize the distress of and stress on the patient’s family and/or caregivers

C. Assessment Assessment is the collection and interpretation of the data needed to identify the main areas of the patient’s diﬃculties, to formulate sensible goals, and to monitor changes in the patient’s impairment, activity, and participation. Assessment in rehabilitation is best carried out using standardized measures, and a wide range of suitable measures exist that are short and simple enough to be used by any busy clinician [8]. The widely used National Institutes of Health Stroke Scale (NIHSS) [9] is a brief stroke-speciﬁc measure comprising motor, sensory, visual and speech impairments but some

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aspects are unreliable and probably not necessary, and the battery of tests below are probably more informative without taking much more time. We recommend the following measures of impairments: For motor deﬁcits, the Motricity Index and Trunk Control Test [10,11] For hemineglect, Star Cancelation [12] For aphasia, the Frenchay Aphasia Screening Test [13] For brief cognitive screening, the Short Orientation Memory Concentration Test [14]. The two most widely used measures of disability (activity) are the Barthel Activities of Daily Living (ADL) index [15] and the Functional Independence Measure (FIM) [16]. We prefer the Barthel because it is much shorter and simpler than the FIM and just as sensitive [17], reliable, and valid. For mobility, the three best measures are the Rivermead Mobility Index (RMI) [18], 10-meter walking time, and 2-minute walk test [19]. Many other assessments exist, some of which are time-consuming and complicated. They are generaly used by therapists to gain more detailed insight into the causes and underlying mechanisms of a patient’s problems. While identifying the major areas of impairment and disability, it is also important to look for information that will help give a prognosis. The best prognostic factors for predicting functional recovery after stroke indicating a less optimistic outcome (death or severe disability) are the presence of urinary incontinence, previous stroke, loss of consciousness at onset, disorientation, severe motor loss, loss of sitting balance, low ADL score on admission, and low level of social support. In other words, it is as one would expect: the more severe the stroke, the worse the outcome [20–22]. The general rule that the level of disability at 6 months is closely related to the level at one week not only applies to overall disability, but also to speciﬁc abilities such as speech. Only a few prognostic items are known for speciﬁc disabilities. For example, the absence of any active grip in the hand at 3 weeks makes it likely that no useful function will return, and the inability to recognize nonspeech sounds (e.g., a telephone) soon after stroke is associated with severe long-term aphasia. Unfortunately, items that predict a speciﬁc (good or bad) response to therapy (general or speciﬁc) are unknown; in other words, there is no evidence to help select patients for speciﬁc interventions. The dangers of using public selection criteria have been demonstrated [23]. After the initial assessment of the patient, the doctor should be able to answer the following questions: What are the main diﬃculties, and how severe are they? What improvement can potentially be expected within the next few weeks or months? What interventions migh help, and how much?

D. Principles of Therapy and Goal Planning The rehabilitation team for stroke patients usually comprises physical therapists (called physiotherapists in the United Kingdom), occupational therapists, speech and language therapists, clinical neuropsychologists, social workers, nurses, and doctors. Eﬀective teamwork requires that all team members work towards common goals; this is a working deﬁnition of a team. Therefore, one deﬁning characteristic of rehabilitation is that it has a procedure for identifying, agreeing, setting, and monitoring goals.

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The process of goal setting in rehabilitation has been reviewed in detail elsewhere [24,25] and so will not be covered again here. It is important to recognize that good rehabilitation practice should: Set meaningful, challenging, but achievable goals Involve the patient, and the family if appropriate, in goal setting Set both short-and long-term goals Set goals both at the team level and at the level of an individual clinician Avoid using the progress of individual patients against goals set (goal attainment scaling) as the sole or major means of determining further rehabilitation in individual patients A multidisciplinary rehabilitation team that works according to these principles is referred to as an interdisciplinary team. Whereas multidisciplinary means simply that several diﬀerent disciplines are involved, the term interdisciplinary refers to a process in which the team members from the diﬀerent disciplines coordinate their eﬀorts to work towards jointly agreed goals. Let us assume that Mr. Smith has stated that his main goal is to return to living at home with his wife and children without depending on care. To achieve this, several short- and medium-term objectives will have to be met: for instance, he needs to relearn to wash and dress himself, to get in and out of bed alone, to walk inside the house, to feed himself, to use the toilet alone. Diﬀerent members of the rehabilitation team will focus on speciﬁc objectives. The physical therapists will help him to learn to walk again, which may require that he ﬁrst learn to sit safely, then stand alone, and ﬁnally start walking. It may be up to the occupational therapists together with the nurses to work on his ability to dress himself. Each of these objectives will be tackled in graduated steps, and the size of these steps forward will depend on several factors, such as the severity of his impairments, the speed of his natural recovery, and his mood and motivation. Classiﬁcation of rehabilitation treatment interventions is diﬃcult, and no logically consistent framework that has been used successfully yet exists. A partial classiﬁcation of the main approaches is outlined here. Four diﬀerent contrasts can be made. One can identify approaches that are driven by theory (with or without evidence behind the theory) in contrast to pragmatic approaches. Next, one can separate therapy that focuses on impairment from that that focuses on activities. Third, one can contrast therapy directed at the patient to attempts made to alter the environment (or the context). Lastly, one can contrast therapy that attempts to reestablish an activity undertaken in the way it used to be with therapy that may attempt to help the patient to achieve the goal in a diﬀerent way (i.e., compensatory techniques). Considering the content of therapy, it is primarily a problem-solving and educational approach, with practice being a major component. Practice of an impaired function, limited activity, or restricted role is likely to reduce the impairment, activity limitation, or role restriction, and the skill of the rehabilitationist is to facilitate the practice. Practice is usually characterized by repetition, starting with simple tasks and slowly increasing the level of diﬃculty. For example, Mr. Smith, who has completely lost the use of his left arm, is likely to be trained in compensating for this loss of function by doing as much as possible with his right arm alone. If he later regains some functional movement in his left arm, he can subsequently be trained to use it to assist in functional tasks, such as holding a jar while opening the lid with his right hand. Another example would be the rehabilitation of memory deﬁcits using

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assistive devices such as diaries and alarms to support the impaired function (i.e., act as an orthosis). Recent years have seen a gradual shift in focus of stroke rehabilitation from exercising isolated impairments towards task oriented therapy, with treadmill gait retraining being the best example.

III. THERAPY OF SOME COMMON CONDITIONS AFTER STROKE A. Rehabilitation of Motor Deficits The most common motor dysfunction after stroke is spastic hemiparesis. This is characterized by muscle weakness, fatigue, clumsiness (due to reduced coordination of synergists and antagonists), slow contraction/decontraction, increase of muscle tone, enhanced tendon reﬂexes, clonus, and spasms (which can be ﬂexor or extensor). The recovery from the hemiparesis typically occurs in stages [26]. Initially, muscle tone of the aﬀected limbs is ﬂaccid. During the following weeks, spasticity develops and is accompanied or followed by slowly increasing voluntary movement. Usually, active movements start to return in proximal muscles ﬁrst, and later more and more distally. Voluntary movement in the early stage of recovery is characterized by so-called mass movements, both ﬂexor synergies and extensor synergies. Only later does the patient regain the ability to selectively activate isolated muscles. The speciﬁc therapeutic techniques need to be adapted to the patient’s current stage of motor recovery. Therapies employed in the treatment of these deﬁcits aim at improving limb function, posture, and gait, reducing spasticity, alleviating pain, and preventing complications such as contractures. For therapeutic intervention, several diﬀerent theoretical approaches have been developed, which shall be described brieﬂy. Proprioceptive neuromuscular facilitation (PNF) [27] uses exercises of mass movements to strengthen muscle groups by stimulating the proprioceptors through resistance. The neurodevelopmental treatment (NDT) developed by Bobath [28] attempts to reduce spasticity by inhibiting abnormal reﬂex mechanisms and, at the same time, to facilitate normal, selective voluntary motor control. It therefore puts the quality, rather than quantity, of movement ﬁrst. The emphasis of Brunnstrom’s approach [29], in contrast, is on using the synergistic mass movements in therapy in order to increase muscle strength and motor function. The Motor Relearning Programme for Stroke [30] focuses on task-speciﬁc exercises, during which the therapist gives feedback to the patient to avoid unnecessary muscle activity and to achieve selective control of speciﬁc muscles. In addition to the active training of movements, passive therapies are used. They include positioning the patient in side-lying, sitting, or standing in a support frame and tonic stretching exercises, which are performed in a proximo-distal sequence. The main aim of these techniques is to achieve a reduction in spasticity. Serial casting of a spastic limb can prolong the tonic stretching. Adaptive equipment frequently used includes ankle-foot orthoses to keep the foot in a physiological position, arm or leg splints to support a weak muscle group or counter spasticity, and canes and frames of diﬀerent shapes to aid walking. Several additional therapeutic techniques have been developed, which can be used in conjunction with the methods described above. For active therapy of motor functions, treadmill training with partial body weight support [31] is a method whereby the patient is strapped into a harness hanging above a treadmill on which he or she practices walking with help from a therapist. This therapy has several advantages because gait training can start

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earlier than in the conventional setting, many repetitions of a physiological gait cycle can be performed, and the gait pattern trained is more symmetrical. Constraint-induced movement therapy [32,33], also called forced-use therapy, immobilizes the patient’s unaﬀected arm in a sling or a splint for several hours per day, forcing him or her to use the aﬀected arm for all activities. This method is obviously only applicable to patients who have quite signiﬁcant residual motor control in their aﬀected arm. Functional electrical stimulation (FES) and therapeutic electrical stimulation (TES) both elicit muscle contractions, but while FES aims at assisting during a functional activity such as lifting the foot, TES is employed to try to improve motor control even after the end of the therapy sessions. TES is mostly used for the treatment of forearm muscles. Speciﬁc treatments to reduce spasticity include drugs such as tizanidine or baclofen orally and injections with botulinum toxin or phenol. In severe cases, surgical treatments such as the implantation of a baclofen pump or transsections of muscles or tendons can be considered. B. Pain Pain in the shoulder of the aﬀected side is very common after stroke. It is probably related to an inﬂammation of the shoulder capsule and to repeated trauma of the subluxed glenohumeral joint. The treatment aims at avoiding such trauma by reducing the vertical pull of the arm by positioning it on an armboard on the wheelchair, by supporting the arm manually when the patient is being repositioned, by range-of-motion exercises, and by strengthening the supraspinatus and deltoid muscles (for review, see Ref. 34). No speciﬁc approach has been shown to be eﬀective. C. Neuropsychological Deficits The nature of typical neuropsychological deﬁcits after stroke, including the diﬀerent types of aphasia, have been described elsewhere in this book. For the treatment of aphasia, several general principles have been described: focusing on general abilities to communicate rather than on speciﬁc verbal responses; using tasks with material that is relevant, simple, but challenging; starting sessions with a familiar task; gradually adding new tasks, which are related to the familiar tasks; getting the patient to produce a large number of responses; giving frequent feedback to the patient regarding his or her performance and progress in therapy [35]. Most therapists work with verbal and non-verbal material and techniques, such as pronouncing and repetition, sentence completion, gestures, pictures and photographs. Hemineglect therapy typically involves the whole rehabilitation team. Techniques employed are training the patient to visually scan the neglected side of space (with frequent reminders to do so), encouraging the patient to perform voluntary movements with the limbs on the same side as the neglect, and increasing the patients’ awareness of the problem by showing them videotapes of themselves performing everyday tasks. More recent approaches are trying to improve hemineglect by partial visual occlusion or by applying vibration to the neck muscles on the same side as the neglect [36].

IV. EVIDENCE REGARDING EFFECTIVENESS OF STROKE REHABILITATION Rehabilitation after stroke undoubtedly works, although the evidence for speciﬁc rehabilitation interventions is largely absent or weak. A meta-analysis of data from trials of stroke

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unit rehabilitation has shown that rehabilitation services are eﬀective at reducing both mortality and morbidity. Stroke units resulted in (compared to conventional hospital setting) a 19% reduction in death rates, a 25% reduction in rates of institutionalized care, and a 29% reduction in dependency (Stroke Unit Trialists’ Collaboration) [37,38]. Furthermore, there is evidence that these beneﬁts can be achieved in actual practice in unselected hospitals [39], and they may last for many years [40]. The meta-analysis was especially important because it helped characterize the probable important elements of eﬀective rehabilitation: coordination, expertise, and education. These three factors relate to the structure and process of rehabilitation, emphasizing the need for dedicated, interdisciplinary expert teams in stroke rehabilitation. The evidence concerning each part of the process of rehabilitation is much more diﬃcult to identify and evaluate. The evidence would suggest that a process of formal structured assessment of patients with a disability by a team of people specialized in rehabilitation does improve outcome, although (obviously) only when taken as part of the whole process. Assessment in isolation is not helpful, and it is important that more than one profession is involved [41]. The evidence relating to goal planning has been reviewed recently [24,25], and, although it is not amenable to meta-analysis and is diﬃcult to review systematically, there is reasonable support for a systematic approach to setting goals for stroke patients participating in rehabilitation. The evidence concerning speciﬁc interventions is very extensive, with more than 80 randomized studies of rehabilitation intervention for acute stroke [2]. Unfortunately, because rehabilitation covers a huge range of treatments, it is diﬃcult to construct an analytic framework [42]. However, recent research does support various hypotheses. There is now evidence that even quite small levels of intervention can have quite powerful and speciﬁc eﬀects [43], and there is some evidence of a dose-response relationship between therapeutic input and outcome [44]. There is strong evidence that provision of simple equipment is extremely costeﬀective [45]. There is some evidence that even the simple provision of information may be eﬀective [46]. Regarding speciﬁc treatments for motor deﬁcits (PNF, Bobath, Brunnstrom, MRP), no individual method has been proven more eﬀective than the others [47–49]. Treadmill training with partial body weight support has been shown to improve gait [31]. Arm and hand mobility has been shown to be improved by constraint-induced therapy [32,33] and by therapeutic electrical stimulation (for review, see Ref. 50). Drugs can have both beneﬁcial and harmful eﬀects upon a patient’s performance. Reports that amphetamine coupled with physical therapy may increase neurophysiological recovery after stroke [51] could not be replicated in a more recent larger study [52]. There is evidence that levodopa in combination with physiotherapy may enhance motor recovery [53]. Poststroke depression can eﬀectively be treated with tricyclic antidepressants and serotonine reuptake inhibitors, but it is yet unclear whether they also improve disability [54]. Some drugs, such as benzodiazepines, barbiturates, phenytoin, clonidine, prazosine, and neuroleptics, probably impede neurophysiological recovery after stroke [55]. It is important to review whether the drugs taken are still giving more beneﬁt than harm. Too frequently, drugs are started for sound reasons but are

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continued without further thought. Patients should be encouraged to seek a review of their medication at regular intervals. Drugs that may need reviewing include antispastic drugs, anticonvulsant drugs, antidepressant drugs, and minor and major tranquilizers. Anyone interested in a detailed evaluation and listing of the evidence should review the U.K. National Clinical Guidelines for Stroke, which are reviewed and updated regularly; they can be found at http://www.rcplondon.ac.uk/pubs/books/stroke/index.htm.

V. CONCLUSION Referral of a stroke patient for rehabilitation has more evidence to support it that any other action taken by the doctor from the moment of stroke onset. Moreover, the beneﬁcial eﬀects are greater that any that follow from any other action. Unfortunately, we do not yet know how stroke rehabilitation achieves its large beneﬁts, but a similar situation arises in much of medicine. For example, digitalis was used for centuries before anyone knew how it worked. Research suggests that the key principles are related to the process and organizational aspects of rehabilitation rather than any speciﬁc action, but much more research is needed to investigate this. This lack of detailed understanding should not, however, inhibit referral.

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13. Enderby PM, Wood VA, Wade DT, Hewer RL. The Frenchay Aphasia Screening Test: a short, simple test for aphasia appropriate for non-specialists. Int Rehabil Med 1987; 8:166–170. 14. Wade DT, Vergis E. The Short Orientation-Memory-Concentration Test: a study of its reliability and validity. Clin Rehabil 1999; 13:164–170. 15. Collin C, Wade DT, Davis S, Horne V. The Barthel ADL Index: a reliability study. Int Disabil Stud 1988; 10:61–63. 16. Granger CV, Hamilton BB, Sherwin FS. Guide for the use of the uniform data set for medical rehabilitation. Uniform data set for medical rehabilitation project oﬃce. Buﬀalo, NY: Buﬀalo General Hospital, 1986. 17. Van der Putten JJ, Hobart JC, Freeman JA, Thompson AJ. Measuring change in disability after inpatient rehabilitation; comparison of the responsiveness of the Barthel index and the Functional Independence Measure. J Neurol Neurosurg Psychiatry 1999; 66:480–484. 18. Forlander DA, Bohannon RW. Rivermead Mobility Index: a brief review of research to date. Clin Rehabil 1999; 13:97–100. 19. Rossier P, Wade DT. Validity and reliability comparison of 4 mobility measures in patients presenting with neurologic impairment. Arch Phys Med Rehabil 2001; 82:9–13. 20. Kwakkel G, Wagenaar RC, Kollen BJ, Lankhorst GJ. Predicting disability in stroke—a critical review of the literature. Age Ageing 1996; 25:479–489. 21. Paolucci S, Antonucci G, Pratesi L, Traballesi M, Lubich S, Grasso MG. Functional outcome in stroke inpatient rehabilitation: predicting no, low and high response patients. Cerebrovasc Dis 1998; 8:228–234. 22. Patel AT, Duncal PW, Lai SM, Studenski S. The relation between impairments and functional outcomes poststroke. Arch Phys Med Rehabil 2000; 81:1357–1363. 23. Wade DT. Selection criteria for rehabilitation services. Clin Rehabil 2003; 17:115–118. 24. Wade DT. Evidence relating to goal planning in rehabilitation. Clin Rehabil 1998; 12:273–275. 25. Wade DT. Goal planning in stroke rehabilitation: evidence. Top Stroke Rehabil 1999; 6:37–42. 26. Twitchell T. Restoration of motor function following hemiplegia in man. Brain 1951; 74:443– 480. 27. Knott M, Voss DE. Proprioceptive Neuromuscular Facilitation: Patterns and Techniques. New York: Harper & Row, 1956. 28. Bobath B. Adult Hemiplegia. Evaluation and Treatment. 2d ed. London: Heinemann, 1970. 29. Brunnstrom S. Movement Therapy in Hemiplegia. New York: Harper & Row, 1970. 30. Carr JH, Shepherd RB. A Motor Relearning Programme for Stroke. London: William Heinemann Medical Books, 1982. 31. Hesse S, Bertelt C, Schaﬀrin A, Malezic M, Mauritz KH. Restoration of gait in nonambulatory hemiparetic patients by treadmill training with partial body-weight support. Arch Phys Med Rehabil 1994; 75:1087–1093. 32. Wolf SL, Lecraw DE, Barton LA, Jann BB. Forced use of hemiplegic upper extremities to reverse the eﬀect of learned nonuse among chronic stroke and head-injured patients. Exp Neurol 1989; 104:125–132. 33. Taub E, Miller NE, Novack TA, Cook EW, Fleming WC, Nepomuceno CS, Connell JS, Crago JE. Technique to improve chronic motor deﬁcit after stroke. Arch Phys Med Rehabil 1993; 74:347–354. 34. Turner-Stokes L, Jackson D. Shoulder pain after stroke: a review of the evidence base to inform the development of an integrated care pathway. Clin Rehabil 2002; 16:276–298. 35. Brookshire RH. An Introduction to Neurogenic Communication Disorders. 4th ed. St. Louis: Mosby International, 1992. 36. Karnath HO, Christ K, Hartje W. Decrease of contralateral neglect by neck muscle vibration and spatial orientation of trunk midline. Brain 1993; 116:383–396. 37. Stroke Unit Trialists’ Collaboration. Collaborative systematic review of the randomised trial of organised inpatient (stroke unit) care after stroke. Br Med J 1997; 314:1151–1159. 38. Stroke Unit Trialists’ Collaboration. Organised inpatient (stroke unit) care for stroke (Cochrane Review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2002.

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39. Rudd AG, Irwin P, Rutledge Z, Lowe D, Morris R, Pearson MG. The national sentinel audit of stroke: a tool for raising standards of care. J Roy Coll Phys 1999; 33:460–464. 40. Indredavik B, Bakke F, Slordahl SA, Rokseth R, Haheim LL. Stroke unit treatment improves long-term quality of life. A randomised controlled trial. Stroke 1998; 29:895–899. 41. Cunningham C, Horgan F, Keane N, Connly P, Mannion A, O’Neil D. Detection of disability by diﬀerent members of an interdisciplinary team. Clin Rehabil 1996; 10:247–254. 42. Wade DT. A framework for considering rehabilitation interventions. Clin Rehabil 1998; 12:363–368. 43. Kwakkel G, Wagenaar RC, Koelman TW, Lankhorst GJ, Koetsier JC. Eﬀects of intensity of rehabilitation after stroke. A research synthesis. Stroke 1997; 28:1550–1556. 44. Kwakkel G, Wagenaar RC, Twisk JWR, Lankhorst GF, Koetsier JC. Intensity of leg and arm training after primary middle-cerebral-artery stroke: a randomised trial. Lancet 1999; 354:191– 196. 45. Mann WC, Ottenbacher KJ, Fraas L, Tomita M, Granger CV. Eﬀectiveness of assistive technology and environmental interventions in maintaining independence and reducing home care costs for the elderly. Arch Family Med 1999; 8:210–217. 46. Mant J, Carter J, Wade DT, Winner S. The impact of an information pack on patients with stroke and their carers: a randomised controlled trial. Clin Rehabil 1998; 12:465–476. 47. Dickstein R, Hochermann S, Pillar T, Shaham R. Stroke rehabilitation. Three exercise therapy approaches. Phys Ther 1986; 66:1233–1238. 48. Basmajian JV, Gowland CA, Finlayson MA, Hall AL, Swanson LR, Stratford PW, Trotter JE, Brandstater ME. Stroke treatment: comparison of integrated behavioural-physical therapy vs traditional physical therapy programs. Arch Phys Med Rehabil 1987; 68:267–272. 49. Wagenaar RC, Meijer OG, van Wieringen PC, Kuik DJ, Hazenberg GJ, Lindeboom J, Wichers F, Rijswijk H. The functional recovery of stroke: a comparison between neuro-developmental treatment and the Brunnstrom method. Scand J Rehabil Med 1990; 22:1–8. 50. de Kroon JR, van der Lee JH, Ijzerman MJ, Lankhorst GJ. Therapeutic electrical stimulation to improve motor control and functional abilities of the upper extremity after stroke: a systematic review. Clin Rehabil 2000; 16:350–360. 51. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Stroke 1995; 26:2254–2259. 52. Sonde L, Nordstrom M, Nilsson CG, Lokk J, Viitanen M. A double-blind placebo-controlled study of the eﬀects of amphetamine and physiotherapy after stroke. Cerebrovasc Dis 2001; 12:253–257. 53. Scheidtmann K, Fries W, Muller F, Koenig E. Eﬀect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomized, doubleblind study. Lancet 2001; 358:787–790. 54. Turner-Stokes L, Hassan N. Depression after stroke: a review of the evidence base to inform the development of an integrated care pathway. Part 1: Diagnosis, frequency and impact. Clin Rehabil 2002; 16:231–247. 55. Goldstein LB. Common drugs may inﬂuence motor recovery after stroke. The Sygen in Acute Stroke Study Investigators. Neurology 1995; 45:865–871.

12 Cognitive Impairments After Stroke: Diagnosis and Treatment R. D. Jones and Daniel Tranel University of Iowa, Iowa City, Iowa, U.S.A.

I. INTRODUCTION In many if not most cases of stroke, cognitive impairments are the most salient manifestations of the poststroke clinical presentation. For nearly 150 years it has been recognized that focal brain lesions due to stroke can cause highly selective cognitive impairments. In fact, much of the knowledge base gained in the past century in behavioral neurology and functional neuroanatomy in humans is based on the assessment of patients following stroke. This is due in part to the prevalence of stroke in the general population, but also to the fact that stroke produces a relatively focal lesion, as opposed to tumor, trauma, and other brain diseases, which may result in more generalized brain dysfunction and associated behavioral deﬁcits. In fact, the ‘‘golden age’’ of neurology, since the groundbreaking reports of Broca (1865) and Wernicke (1874), has been largely based on patients with stroke (Benton, 1988; Damasio and Damasio, 1992). Our aim in this chapter is to describe some of the more common or scientiﬁcally interesting cognitive sequelae of stroke as well as some current means of treatment of these conditions.

II. COGNITIVE SYNDROMES A. Amnesia The term amnesia refers to a memory deﬁcit. Current thinking in the study of amnesia began in the 1950s with patient HM, who developed amnesia following bilateral mesial temporal lobe resection for seizure control (Scoville and Milner, 1957). Following surgery, it was observed that HM was unable to acquire new factual information, whereas memories acquired prior to the lesion onset were relatively preserved. Subsequent research has demonstrated other brain areas related to memory, as discussed below. To some extent, these brain areas overlap with diﬀerent memory dichotomies proposed by researchers (Kopelman, 2002). Amnesia can be divided into multiple subtypes, but is most commonly divided into anterograde and retrograde types, verbal and visual types, and declarative and nondeclarative types. Anterograde amnesia denotes an inability to acquire new information, 243

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such as facts, skills, or other types of knowledge. The necessary feature to merit the term anterograde amnesia is that the memory impairment is for information presented after the onset of the lesion. Memory for older information is often normal or at least relatively preserved. It is important to assure that there is no defect in perception or sensation that can explain the memory impairment. This is the most common type of memory impairment following stroke and can be associated not only with mesial temporal (and speciﬁcally hippocampal) dysfunction, as in patient HM, but also with many of the socalled midline amnesias, associated with dysfunction of mammillothalamic and/or basal forebrain regions (Damasio et al., 1985; Bauer et al., 2003). Retrograde amnesia, on the other hand, refers to an inability to recall factual knowledge or information that was acquired prior to the onset of the lesion or neurological condition. For example, some patients following stroke may not be able to recall facts associated with their childhood, such as the names of individuals they knew well, events that happened, or places they frequented. This is a more unusual type of amnesia and is almost never observed in the absence of anterograde amnesia unless it is due to psychiatric factors. When present, retrograde amnesia is often ‘‘temporally graded,’’ meaning that events or facts acquired closer to the time of the onset of the lesion are more likely forgotten, whereas events or facts acquired further in time from the onset of the lesion are less likely to be forgotten. Although understanding of the neuroanatomical underpinnings of retrograde memory is still rapidly developing, current knowledge suggests that nonmesial sectors of the temporal lobe, including polar and inferotemporal regions, are likely involved (Kapur et al., 1993; Jones et al., 1998). Some evidence indicates that bilateral lesions result in greater deﬁcits. Also, damage to the midline structures may result in a retrograde amnesia with associated anterograde amnesia. In such cases, there is some suggestion that the retrograde defect in distinguished by confabulation (in some cases) and an inability to identify the temporal sequences in which past events occurred. Another distinction that can be made is between verbal and nonverbal memory. Verbal memory refers to memory for words, stories, or other information presented verbally. A typical ﬁnding in a patient with a verbal memory defect is that the patient will not remember information presented aurally (e.g., instructions, lists), but is able to remember information in nonverbal presentation normally (e.g., faces, geographic routes). The memory impairment in such cases is material-speciﬁc in the sense that verbal material is the only type of information aﬀected or is aﬀected disproportionately. The usual lesion associated with a material-speciﬁc verbal amnesia is the left mesial temporal lobe, and the left hippocampus plays a particularly critical role. Strokes in the distribution of the left posterior cerebral artery can result in lesions that include mesial temporal cortices. Signs commonly associated with such lesions include visual ﬁeld defects, particularly acutely, and some form of language impairment can be observed. Verbal amnesia is also common following stroke in the areas of the aforementioned midlines structures (dorsal thalamus, mammillary bodies, and particularly basal forebrain), but in such cases there is usually an associated visual amnesia (see below). Ruptures of the aneurysms of the anterior communicating artery are a common etiology for this type of memory defect. It is important to distinguish between a language impairment or aphasia, on the one hand, and a verbal memory impairment, on the other hand. The examiner should ensure that amnesia is not due to aphasia. The counterpart to verbal memory is nonverbal or visual memory. Nonverbal memory refers to memory for information that is not necessarily presented or stored verbally to be remembered. For example, in some patients following stroke, memory for a word list will be normal or nearly normal, whereas memory for a series of faces will be

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defective. Nonverbal amnesia is not as readily apparent at bedside as verbal amnesia and may require speciﬁc neuropsychological assessment to establish the diagnosis. In the clinic, patients may complain that they have diﬃculty learning new faces, places, or routes, and they may use verbal cues to aid them in such tasks (e.g., by relying on written directions rather than internal recall of a route). Isolated visual memory defects are associated with damage to the right mesial temporal lobe, and particularly the right hippocampus. Furthermore, a visual memory defect can be observed with strokes in the areas of the thalamus, mamillary bodies, and basal forebrain, but as noted above, in these cases both verbal and visual memory defects are likely to co-occur. The clinician should assure that sensory deﬁcits (e.g., visual ﬁeld defects) do not account for the impairment. There is also a distinction between declarative memory and nondeclarative memory. Declarative memory refers to facts, events, faces, or other knowledge and information that can be inspected and recalled consciously (i.e., information that can be ‘‘declared’’ and brought to the mind’s eye). Nondeclarative memory refers to skills, priming, or conditioning that need not be brought to mind. In many amnesics, for example, it can be shown that new learning of motor skills is normal, whereas new learning of facts, word lists, or faces is defective. This dissociation between the acquisition and retrieval of declarative (facts, words, faces) and nondeclarative (skills, preferences) knowledge supports the distinction and suggests that there may be two distinct memory systems. Declarative memory is usually thought to be associated with the aforementioned mesial temporal lobe and midline structures, whereas nondeclarative memory is often associated with the basal ganglia (Tranel et al., 1994; Tranel and Damasio, 1998).

B. Aphasia Aphasia is an acquired impairment in language. This impairment can be broken down into several subcomponents, including impairments in repetition, naming, comprehension, the production of words, and other components. Current knowledge of aphasia dates back approximately 150 years, but modern linguistic theory and new ﬁndings using the lesion method and functional neuroimaging (and combined approaches) have resulted in a rapidly changing knowledge base regarding aphasia in the past 15 years. Aphasia is a common consequence of stroke in the territory of the middle cerebral artery of the left hemisphere, resulting in lesions in perisylvian cortices. Recently, research has demonstrated that other areas of the left hemisphere, such as inferotemporal cortices or anterior temporal cortex, are involved in certain types of linguistic processing, most notably lexical retrieval (see Damasio and Damasio, 2000, for review). From a practical and clinical perspective, there is widespread agreement on the nomenclature of the aphasias. Several of the subcomponents of impaired linguistic capacity (e.g., deﬁcits in repetition, comprehension, and word ﬁnding) occur with diﬀerent frequencies and patterns in diﬀerent types of aphasia. Furthermore, these types are commonly associated with speciﬁc neural underpinnings. Following is a review of the major subtypes of aphasia. 1. Broca’s Aphasia The speech pattern of patients with a Broca type of aphasia is nonﬂuent. Such patients have diﬃculty producing words, and their production of words is sparse and agrammatic. Paraphasias (or substitutions of incorrect words) are common, particularly of the phonemic type. That is, the paraphasic errors of patients with Broca’s asphasia tend to

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sound like the intended word (e.g., ‘‘redorder’’ for ‘‘recorder’’). Repetition, naming, and writing are impaired, whereas comprehension of language is relatively preserved in both auditory and written forms. Some forms of speech are often preserved, for example, automatic speech, such as verbal automatisms (reciting the alphabet, counting to 10), as are expletives and singing. Such forms of preserved speech likely represent overlearned material or verbal expressions that are mediated by structures other than the neural structures associated with Broca’s aphasia. Broca’s aphasia is associated with damage to Brodmann’s area 44 on the left or the frontal operculum. This area abuts the motor strip, and it is common to ﬁnd a contralateral (right) hemiparesis, particularly in the face and arm. In the acute epoch, particularly with lesions that extend into subcortical white matter, patients may present with a global aphasia (see below), but this syndrome eventually evolves into a Broca type of aphasia. 2. Wernicke’s Aphasia In the years following Paul Broca’s discovery of a focal area of brain lesion associated with aphasia in the 1860s, Carl Wernicke (1874) described a diﬀerent type of aphasia associated with a diﬀerent area of left hemisphere dysfunction. As opposed to Broca’s aphasia, which is characterized by nonﬂuent speech and relatively good comprehension, Wernicke’s aphasia is characterized by ﬂuent speech with impaired comprehension. Articulation and prosody are preserved. However, the ﬂuent, and sometimes hyperﬂuent, speech of the patient with Wernicke’s aphasia is punctuated by numerous paraphasic errors, both of the semantic type (in which a word related by meaning is substituted, e.g., ‘‘truck’’ for ‘‘car’’) and the phonemic type (e.g., ‘‘klar’’ for ‘‘car’’). Speech is often devoid of nouns, particularly proper nouns, and is often dominated by nonspeciﬁc words (e.g., ‘‘thing,’’ ‘‘person’’). The comprehension deﬁcit seen in patients with Wernicke’s aphasia pertains to both written and aural communication. Repetition of sentences is defective, and paraphasic errors and nonspeciﬁc words dominate the naming of objects. The lesion associated with Wernicke’s aphasia is restricted to posterior Brodmann’s area 22 on the left in the posterior superior temporal gyrus. It is not uncommon to observe some neurological signs such as a right homonomous hemianopia and, occasionally, particularly in the acute epoch, hemisensory deﬁcits. However, there may be no neurological signs apart from the language disturbance. In a patient with an isolated but profound aphasia who demonstrates no other clinical signs, the misdiagnosis of psychiatric disease is possible. The incidence of misdiagnosis in this way has likely decreased since the advent of neuroimaging in the 1970s. However, clinicians must still consider the background of the patient in developing diﬀerential diagnoses for the etiology of a language defect, including such factors as age, risk factors for stroke, and the presence of prior psychiatric disease. 3. Conduction Aphasia Before ever having seen a case, Wernicke predicted that a lesion that disconnected the area described by Broca and the area that had been recently described as being associated with comprehension (a.k.a. Wernicke’s area) would result in a disruption of repetition. Wernicke was largely correct apart from precise anatomical location, and this was proved some years later. The core of conduction aphasia is a repetition defect. Comprehension is, by deﬁnition, spared, and speech is ﬂuent and may or may not be paraphasic. Spontaneous writing may be relatively preserved, but writing from dictation is typically impaired.

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Conduction aphasia is often mistaken for aphasia of the Wernicke type, particularly when speech is paraphasic. In such cases, preserved comprehension is the distinguishing characteristic of conduction aphasia. Conduction aphasia is typically associated to damage to the supramarginal gyrus (Brodmann’s area 40) on the left. Posterior area 22, or Wernicke’s area, is spared. Visual ﬁeld defects (right homonomous hemianopia) may be present, and there may be contralateral sensory loss, but other neurological signs may be absent. A lesion to the arcuate fasciculus on the left had been predicted by Wernicke to be suﬃcient to cause this type of aphasia. Although patients with conduction aphasia often have disruption of this pathway, there is no current evidence that lesions to this pathway alone are suﬃcient to cause the syndrome. 4. Global Aphasia Following a large middle cerebral artery stroke on the left, patients may present with defects in almost all aspects of language. Formal neuropsychological assessment in such patients reveals deﬁcits in reading, writing, naming, comprehension, repetition, and most other linguistic abilities. Speech is nonﬂuent, poorly articulated, and sparse. Neurological signs typically include a right hemiparesis, right hemisensory loss, and often right homonymous hemianopia. Like those periods with Broca’s aphasia, patients with global aphasia may retain some rudimentary linguistic abilities, such as repetition of automatisms and, in some cases, singing of familiar songs. The lesion usually associated with global aphasia reﬂects a large stroke in the middle cerebral artery territory. The lesion typically spans from the frontal operculum, or Broca’s area, to the posterior superior temporal gyrus on the left, or Wernicke’s area. Accordingly, patients in almost all cases have right hemisensory loss and right hemiparesis. There have been a few cases described of global aphasia without hemiparesis, and in those cases there were two distinct lesions: one in Wernicke’s area and one in Broca’s area (Tranel et al., 1987). 5. Transcortical Aphasia The unique feature of transcortical aphasias is the preservation of repetition. Unlike the other aphasias described above, patients with transcortical aphasia are able to repeat sentences normally, or with only a mildly impaired performance. These aphasias are rare relative to other types. Two primary types of transcortical aphasia, motor and sensory, are commonly recognized, and a number of researchers describe a mixed type. Patients with transcortical motor aphasia have nonﬂuent, eﬀortful production of speech, with normal, or near normal, comprehension and repetition. The lesion associated with transcortical motor aphasia is in the surround of area 44 of Broca’s area, usually superior and/or anterior to this area. The prognosis is favorable with a circumscribed lesion, but when underlying white matter is compromised, the recovery is not as good. Transcortical sensory aphasia is similar to Wernicke’s aphasia, but with preserved repetition. Output of speech is ﬂuent, with good articulation and prosody. Comprehension is impaired, but as is true of all transcortical aphasias, repetition is at normal or near normal levels. Paraphasias are common and there are typically diﬃculties with naming. The lesion associated with transcortical sensory aphasia is usually in the surround of Wernicke’s area, situated near or in the angular gyrus on the left. A type of transcortical aphasia recognized by some authors is termed mixed transcortical aphasia. Like other transcortical aphasias, repetition is preserved. However, apart

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from repetition, mixed transcortical aphasia resembles a global aphasia, with nonﬂuent sparse output, paraphasic errors, and defects in comprehension. The lesion is typically outside of traditional perisylvian language areas, and sometimes in border zones between MCA distribution and both posterior and anterior cerebral artery distributions. We have seen rare cases in which lesions that would normally produce both transcortical motor aphasia and transcortical sensory aphasia are present in one patient, and in those rare cases the patient presents with a mixed transcortical-type aphasia. 6. Subcortical Aphasia Subcortical aphasia is associated with lesions in the left basal ganglia (especially the head of the candate and the putaman) and can be distinguished from other aphasias by the prominence of severe dysarthria. Variable linguistic impairments can be seen in subcortical aphasia, and the overall proﬁle does not conform to any of the above-noted ‘‘classic’’ aphasia subtypes. Speech may be paraphasic and accompanied by poor auditory comprehension, but may simultaneously be nonﬂuent. Repetition impairments are variable, but right hemisensory and/or motor impairments are a frequent neurological sign. Lesions to left thalamic nuclei may also produce subcortical aphasias, although these thalamic aphasias have been studied less frequently than other types of language disorder. 7. Anomic Aphasia Naming defects are a prominent feature of many types of aphasia syndromes, but when such defects occur in isolation, the term ‘‘anomic aphasia’’ is applied. In some cases, patients may have normal comprehension and ﬂuency, but may have defects in naming certain types of stimuli (e.g., actions or names). Also, with certain lesions there may be greater diﬃculty with word retrieval as the necessary word becomes increasingly speciﬁc. For example, a patient may be able to say that a picture of Abraham Lincoln is a ‘‘person,’’ ‘‘man,’’ or ‘‘president,’’ but may not be able to retrieve the speciﬁc name of Abraham Lincoln. Research has shown that the neural correlates of such naming impairments are commonly outside the traditional perisylvian language areas, and include the temporal pole and inferotemporal regions on left. C. Apraxia Apraxia is an acquired inability to execute skilled or purposeful movements in a ﬂuid manner (see Maher and Rothi, 2001, for a recent review). The term apraxia has been used in a number of ways and in association with a number of rather distinct impairments, including constructional apraxia, dressing apraxia, gait apraxia, gaze apraxia, and apraxia of speech. Despite these multiple uses of the term, in common use among neuropsychologists and neurologists the term apraxia is generally understood to mean an inability to carry out a purposeful movement on command. To merit the term apraxia, the patient’s impaired motor movements should not be referable to aphasia or lack of understanding of a command, nor should they be due to a primary sensorimotor defect. Ideomotor apraxia is the proper term for the most often observed type of apraxia. Ideomotor apraxia is an inability to carry out a simple, purposeful motor movement on command, despite normal comprehension of the command, and adequate motor and sensory functions. Ideomotor apraxia is often distinguished from ideational apraxia. The latter term is used to refer to a condition in which patients fail to execute a command because they have lost basic the understanding or idea or concept of the movement. In

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contrast, in ideomotor apraxia the basic understanding of the concept of the movement is presumed to be maintained, but skilled execution is lacking. Ideomotor apraxia is associated with left hemisphere dysfunction and is most often seen when the lesion is in the left inferior parietal lobule (Brodmann’s areas 40 and 39). Associated signs may include acalculia, alexia, and agraphia.

D. Gerstmann Syndrome The presence of Gerstmann syndrome is deﬁned by the concurrence of four signs, including right-left disorientation, acalculia, agraphia, and defective ﬁnger localization and identiﬁcation (Benton, 1992). The validity of the syndrome has been questioned, since it may be diﬃcult to ﬁnd these signs when the defects are not attributable to sensory loss, aphasia, dementia, or a combination of these. Nonetheless, the syndrome has been associated with lesions in the left parietal lobe and particularly in the area of the left angular gyrus. When these signs coalesce in a patient, sometimes each to a greater of lesser degree, the clinician should consider the possibility of lesions in this general area.

E. Alexia Alexia refers to an acquired impairment in reading (Coslett, 2003). There are two primary forms of alexia, termed pure alexia and alexia with agraphia. Pure alexia is deﬁned as an inability to read with the preserved ability to write (see Sec. II.G). Alexia with agraphia denotes a condition in which a patient acquires an inability to read and to write. A patient with alexia with agraphia is often able to copy letters, but is unable to determine the meaning of a string of letters and is unable to read words phonetically. Acquired alexia with agraphia should be distinguished from impairments in reading not associated with an acquired lesion in which the term dyslexia or development dyslexia is preferred. Alexia with agraphia is associated closely with the left parietal lobe. The condition often presents with coexisting aphasia, usually of a ﬂuent type (transcortical sensory aphasia or Wernicke’s aphasia).

F. Acalculia An acquired deﬁcit in mathematical calculation is referred to as acalculia (Denburg and Tranel, 2003). At least three types can be distinguished. The ﬁrst of these types is acalculia with alexia and agraphia, which is thought to be related to a disturbance in the reading and writing of numbers. The lesion in such cases is generally associated with lesions in the left hemisphere, and especially in the paretal lobe. The second type of acalculia is the spatial type, which denotes an impairment in the spatial organization of numbers when manipulating calculations on paper. This type of acquired calculation impairment is most often seen in right hemisphere lesions, in keeping with the primarily spatial diﬃculties underlying this disorder. Finally, acalculia of the anarithmetric type involves a loss of the ability to manipulate numbers not due to spatial diﬃculties or due to aphasia. In anarithmetria, there is an essential acquired lack of understanding of the relationship between numbers, the meaning of numbers, and the manipulation of numbers. Similar to acalculia with alexia and agraphia for numbers, anarithmetria is typically associated with left parietal stroke.

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G. Visual Disorders 1. Sensory Impairment Disorders of vision are common following stroke and are usually associated with posterior cerebral artery territories (Brodmann’s areas 17, 18, and 19) (Jones and Tranel, 2002). Perhaps the most prevalent visual impairment following stroke is a visual ﬁeld defect, which represents a primary sensory loss rather than a higher visual function (see below). Based on the well-established anatomy of the visual system, the site of many lesions may be placed with relative precision based on the nature of the corresponding visual ﬁeld cut. For example, a lesion in primary visual cortex on the left will result in a homonymous hemianopia in the right visual ﬁeld. Similarly, a lesion in the infracalcarine primary visual cortex on the right will result in a homonymous left superior quadrantanopia. 2. Disorders of Higher Visual Function a. Visual Agnosia—Prosopagnosia. Agnosia is deﬁned as a normal percept stripped of its meaning (Teuber, 1968). In the visual realm, this refers to the phenomenon whereby a patient can perceive an object normally or near normally as reﬂected by normal description of the visual features of the object, but is unable to identify the object. The inability to identify the object must not be due to a language or naming defect. Two broad types of visual agnosia are of primary clinical and theoretical interest. The ﬁrst of these is prosopagnosia, derived from the Greek words prosop (face) and gnosis (knowledge). The central clinical manifestation of prosopagnosia is an inability to recognize familiar faces and, in some cases, an inability of the patient to recognize even his or her own face. The identity of an individual can be ascertained by nonfacial features, such as voice, gait, context, or other cues. Associated neurological signs often include an upper ﬁeld homonymous quadrantanopia. In order to justify the term prosopagnosia, visual acuity and visual perception must be relatively spared, although detailed and highly sensitive testing will usually demonstrate some anomaly in the abilities (see below). In any case, the patient should not have a defect in naming that can account for the face identiﬁcation defect, nor should there be evidence of dementia. A valuable distinction in considering visual agnosia generally, and prosopagnosia in particular, has been made between visual recognition defects of the apperceptive type and the associative type (Lissauer, 1890). In apperceptive prosopagnosia, a perceptual impairment is suﬃcient to explain the face recognition defect. In contrast, in associative prosopagnosia any perceptual defect is insuﬃcient to cause the visual recognition impairment. It is this latter type that most closely corresponds to Teuber’s classic deﬁnition of a normal percept stripped of its meaning. Careful examination in patients with prosopagnosia usually shows that the recognition defect does not apply only to faces, but may extend to other objects as well. Speciﬁcally, patients with prosopagnosia may have diﬃculty recognizing objects that are visually similar, particularly in shape, in a category of which there are numerous members when the patient is asked to identity a particular object at an unique level. For example, some patients with prosopagnosia have diﬃculty recognizing speciﬁc cars and speciﬁc dairy cows in addition to human faces. Several lines of research during the past 20 years suggest that the recognition defect in prosopagnosia is at the conscious level, while there may still be unconscious recognition, or recognition without awareness (Bauer, 1984; Tranel and Damasio, 1985, Jones and Tranel, 2001). Several investigators have demonstrated, that patients with prosopagnosia show normal skin conductance and other autonomic responses in the presence of a picture of a

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familiar individual. Also, it has been demonstrated that patients with acquired prosopagnosia are able to identify normal features such as facial expression, gender, and age based on their perception of faces. Finally, in a recent study it was demonstrated that in at least one patient with developmental prosopagnosia, or a face recognition defect in the absence of an acquired lesion, there is normal nonconscious recognition of familiar faces as reﬂected in autonomic responses in the absence of conscious recognition. Taken as a whole, these ﬁnding suggest that patients with acquired prosopagnosia retain a number of features of the face recognition process, including nonconscious recognition and normal perception and recognition of nonfacial features. However, conscious recognition eludes them. The lesion associated with prosopagnosia typically involves occipital temporal cortex. In most cases, true associative prosopagnosics have bilateral lesions, and apperceptive prosopagnosia has typically been associated with unilateral right-sided lesions (Damasio et al., 1982). Given the location of these lesions, in posterior cerebral artery territory, associated signs may include achromatopsia, pure alexia, and upper ﬁeld homonymous quadrantanopia. With larger lesions, particularly on the right, constructional impairments may be present and there may be left hemispatial visual neglect. b. Visual Object Agnosia. Visual object agnosia refers to a recognition defect at the basic object level rather than a unique level of identiﬁcation (Damasio et al., 2000). For example, a patient with visual object agnosia may not know that a car is a car. Thus, a patient with visual object agnosia will not only be unable to identify a speciﬁc car (e.g., ‘‘my car’’), but will also be unable to say that a given object is a car. Such patients can readily identify objects by touch, sound, or sometimes smell. For example, a patient may feel the windshield wiper blades and the rearview window of a car and identify it as a car, but will not be able to do so in visual modality. In some cases of visual object agnosia, patients have been reported as being able to draw objects accurately on command, but are not able to identify or recognize such objects in visual modality. Such patients, by deﬁnition, do not have aphasia, general amnesia, or dementia. The lesions associated with visual object agnosia are usually extensive, not only involving occipital temporal cortex bilaterally, but often extending dorsally into visual association cortex. Underlying white matter is almost always involved in these cases. This is a rare condition, often associated with color recognition and naming defects and impairments in reading. 3. Disorders of Color Processing a. Achromatopsia. Achromatopsia refers to a loss of color vision at a perceptual level due to an acquired brain disorder. The usual clinical presentation is a patient’s complaint that colors appear to be gray or dirty. This may be in one hemiﬁeld or may be so-called full-ﬁeld achromatopsia. Milder versions of achromatopsia may involve color desaturation or dyschromatopsia rather than complete lack of color perception, and such milder deﬁcits may occur either in hemiﬁeld or full ﬁeld. Associated lesions are usually found in the medial infracalcarine occipital lobe, typically involving the lingual and fusiform gyri. Unilateral lesions aﬀect the contralateral visual ﬁeld, whereas bilateral lesions result in full-ﬁeld achromatopsia. Associated neurological signs often involve visual ﬁeld cuts, usually in the superior quadrants, and may include other neuropsychological disorders such as pure alexia (Damasio et al., 1980). b. Color Anomia. A patient with color anomia is able to match colors and is able to generate colors accurately. For example, such patients can say that a banana is yellow or that a ﬁre truck is red, but they are unable to name colors normally, for example, when shown chips of diﬀerent colors. The lesion is typically in the left occipital lobe, is often

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associated with a right homonomous hemianopia, and may be associated with pure alexia. Given the site of this lesion, a disconnection syndrome has been hypothesized, whereby color perception is normal in entering the right primary visual cortex, but this perception is unable to cross the corpus collosum due to a retrosplenial lesion, thereby blocking generation of the name of the color that is perceived. c. Color Agnosia. Often coexisting with visual object agnosia, color agnosia is a rare condition that refers to the inability to retrieve color information in the context of normal perception and language. For example, a patient with color agnosia will be unable to remember the colors of common objects. When asked the color of a banana, a patient with color agnosia will not be able to say yellow and will not be able to provide a list of objects that come in a certain color (e.g., ‘‘Tell me things that are red’’). Based on a limited number of cases, the neural substrates of color agnosia appear to include either unilateral or bilateral occipital temporal regions. Functional imaging studies suggest that areas associated with color agnosia are probably anterior and lateral to those associated with achromatopsia. 4. Pure Alexia The term pure alexia denotes an acquired inability to read, with the preserved ability to write. Such a disorder is distinct from a developmental disability in reading, known as developmental dyslexia, and is also distinct from alexia with agraphia. The inability to read with the preserved ability to write is, at ﬁrst glance, an apparently bizarre dissociation that in the past has been mistaken for psychiatric disease. The patents are neither demented nor aphasic, nor is there an impairment in memory or basic visual perception. A number of well-studied cases have been reported, and the syndrome is now well understood from a neurological standpoint. To demonstrate dissociation, patients are asked to both read and write. In this context it is useful to have patients copy written material, write a sentence from dictation, and write a sentence spontaneously. Writing from dictation and spontaneously is relatively easily completed by such patients; however, writing to copy will be slow and laborious. Interestingly, although such patients are unable to read, if the examiner asks the patient to trace letters with the patient’s ﬁnger, the patient will be likely to be able to discern the meaning of written words. It is common for such patients to write more ﬂuently with their eyes closed or when looking away from their written production. The lesion associated with pure alexia is in the left occipital lobe and underlying white matter (Damasio and Damasio, 1983). Such lesions often produce a right homonomous visual ﬁeld defect. The lesion usually abuts the splenium, blocking visual information registered by the right primary visual cortex from passing to the left hemisphere and thereby precluding decoding of the written material into lexically meaningful words by association areas in the left paretal cortex. When the patient is asked to trace letters with the hand, this disconnection no longer exists. Speciﬁcally sensory and motor cortices on the left, receiving input from the right hand, are able to provide information to left parietal cortices, and this sensorimotor input is subsequently decoded into lexically meaningful information. In essence, use of the sensorimotor system bypasses the visual system, thus providing access to decoding of lexical stimuli. 5. Disorders of Spatial Analysis a. Balint’s Syndrome. Three clinical features are necessary to make the diagnosis of Balint’s syndrome: simultanagnosia (also known as visual disorientation), optic ataxia, and ocular apraxia (Rizzo, 1993).

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Simultanagnosia is the inability to synthesize distinct features from a visual scene into a meaningful whole or gestalt. This is often viewed as an essential and deﬁning feature of Balint’s syndrome. Patients with simultanagnosia will describe objects as ‘‘shattered,’’ ‘‘coming in and out of view,’’ or ‘‘sometimes there and sometimes not.’’ Patients with simultanagnosia will often report that they see a small part of a given object. For example, a patient studied in our laboratory, when shown a drawing of a Christmas wreath, reported that she saw a bow. The bow was situated on the wreath, but the patient did not apprehend the whole picture. It is common to observe patients describe parts of objects and attribute the parts seen to other objects. Another patient recently studied in our laboratory, when shown a rake, reported that he saw a comb. In this case, the patient saw individual tines of the rake and interpreted them to be the teeth of a comb. The second feature in the diagnosis of Balint’s syndrome is optic ataxia. This term refers to an inability to point to or reach for targets under visual guidance. Examination of this ability consists of simply asking the patient to touch the ﬁnger of the examiner. The patient is to reach out and touch the ﬁnger in a rapid and ballistic movement, but patients with optic ataxia will often miss the target entirely or will reach for the object slowly. Optic ataxia can be observed at the bedside when patients reach for other objects as well, such as pencils or food utensils, and it is common to see such patients ‘‘crawl’’ with their ﬁngers as they approach the desired object. The defect must be established under visual guidance, and such patients perform like normals with eyes closed. The defect in reaching must not be due to a sensorimotor impairment. The third sign seen in Balint’s syndrome is called ocular apraxia. This term denotes an inability to shift gaze normally toward a new visual stimulus. When a patient is asked to ﬁxate on various objects in the room, the examiner will note that patients with ocular apraxia will show eye movements that reﬂect ineﬃcient localization of the object in space. The saccades of such patients in ﬁnding new objects may be completely inaccurate, of greater duration than normals, or both. The lesion associated with Balint’s syndrome has been consistently reported to be bilateral occipital parietal cortices or the superior areas of Brodmann’s area 18 and 19. This is a watershed zone between the MCA and PCA distribution, and the onset of the lesion is often associated with sudden hypotension, such as in cardiac arrest. In some cases, an inferior visual ﬁeld defect has been reported. 6. Cortical Blindness and Anton’s Syndrome Bilateral lesions of occipital cortex, and speciﬁcally of primary visual cortex or Brodmann’s area 17, result in a condition called cortical blindness. A behavioral consequence of this is Anton’s syndrome, in which a patient with cortical blindness denies all visual diﬃculties. As we have noted previously (Jones and Tranel, 2002), Anton’s syndrome is considered a special case of anosognosia and is seen frequently only within the ﬁrst several weeks following bilateral PCA strokes. H. Cognitive and Behavioral Deficits Associated with the Right Hemisphere 1. Neglect Neglect is deﬁned as the failure to respond to a stimulus presented contralateral to a brain lesion, which cannot be accounted for by either sensory or motor impairments (Heilman et al., 2003). Neglect can be seen in visual, tactile, or auditory modalities and is often seen in two or more of these senses. Left hemispatial neglect following right hemisphere stroke is

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far more common than right hemispatial neglect, although right hemispatial neglect following left hemisphere lesions can be seen in some cases, particularly in the acute epoch. In the context of stroke, hemispatial neglect is most often associated with lesions in the occipital parietal temporal border zone, but can be seen in surrounding areas of the right hemisphere. In the assessment of neglect, it is important to conﬁrm that the patient does not have a primary motor or sensory defect. For example, when assessing for left hemispatial visual neglect, it is important to conﬁrm that the patient does not have a left homonomous hemianopia. Similarly, when assessing for tactile or auditory neglect, it is important to conﬁrm that the patient has normal sensory, motor, and auditory functions bilaterally. The assessment of neglect can be undertaken in several ways. At the bedside, visual neglect can be assessed by line bisection tasks or drawing tasks (e.g., ‘‘draw a clock’’). At the bedside or in the examination room, a component of neglect called extinction can be assessed by the method of double simultaneous stimulation in visual, tactile, and auditory modalities. Using this method in the visual modality, for example, the examiner introduces a visual stimulus to the left visual ﬁeld, the right visual ﬁeld, and then to both visual ﬁelds simultaneously, and asks the patient to report in which visual ﬁeld the stimulus occurred. Several trials of unilateral and bilateral stimulation should be completed. Evidence of visual extinction is derived when the patient will identify stimuli in each ﬁeld reliably when presented unilaterally, but when the stimulus is presented to both sides simultaneously the patient will identify only the stimulus presented in the ﬁeld ipsilateral to the lesion. Similar methods can be employed in the tactile modality (e.g., by touching the hands of the patient) or in the auditory modality (e.g., by presenting auditory stimuli individually to each ear or simultaneously to both ears). 2. Anosognosia The term anosognosia refers to a condition in which a patient is unable to recognize a disease process. In severe cases, asomatognosia, or denial of one’s own body part (contralateral to the lesion), may be present. Such severe forms of neglect are typically seen only in the acute epoch following stroke and are associated with hemispatial neglect. In asomatognosia, recognition of body parts ipsilateral to the lesion is preserved. However, milder forms of anosognosia can be seen in the chronic epoch and may be demonstrated in relation to cognitive or behavioral deﬁcits (Schacter, 1990). Whereas the acute and severe forms of anosognosia (e.g., asomatognosia) are associated almost exclusively with right hemisphere lesions, milder forms of anosognosia are not restricted to the right hemisphere, nor are they only seen in the acute epoch. In broad terms, the term anosognosia can be used whenever there is a signiﬁcant discrepancy between a patient’s self-report and objective evidence of disease state or an impaired level of functioning. The underlying source of the recognition problem must not be psychological denial, however, and is presumed to have a neurological, structural basis. The phenomenon may be seen in patients with memory disorders who do not recognize their memory defect or in cases of frontal lobe lesions in which the patient is unaware of changes in their behavior that are readily apparent to others. Also, in keeping with the association with the right hemisphere, it is highly unusual to observe anosognosia in some conditions that are strongly lateralized to the left, such as in strokes producing language defects or aphasia. 3. Aprosody Prosody refers to the melodic contour of speech and is one of many so-called paralinguistic aspects of communication. Depending on the melody of speech, a given sentence

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can take on markedly diﬀerent meanings. For example the sentence, ‘‘your dog is named Baseball,’’ with an uplift of tone at the end of the sentence, would indicate a question, perhaps with an incredulous tone. However, the same sentence uttered with a ﬂat tone would indicate a statement of fact and would call for a diﬀerent response from the listener. Thus, apart from language per se, paralinguistic aspects of speech, and in particular prosody, are important to normal social communication. Ross (1981, 1985, 2000) has proposed a classiﬁcation of diﬀerent types of aprosodia. In this scheme, defects in prosody associated with right hemisphere lesions in some senses mirror linguistic defects in left hemisphere. For example, the counterpart to Broca’s aphasia is a expressive aprosodia, characterized by ﬂat, monotone speech, impaired repetition of prosody, but normal comprehension of aﬀective prosody. Ross suggests that the underlying neural correlate for this type of prosodic defect is the homologue to Broca’s area, in the right frontal operculum. Similarly, a sensory aprosodia serves as a counterpart to a Wernicke-type aphasia. In sensory aprosodia, patients may express prosody normally, but comprehension, as well as repetition of aﬀective prosody, is impaired. This type of prosodic defect, according to Ross, is associated with lesions in Brodmann’s area 22 on the right, in the posterior superior temporal gyrus, corresponding to Wernicke’s area in the opposite hemisphere. Global aprosodia is characterized by defects both in expression and understanding of aﬀective prosody, and the underlying neural correlate is purported to be homologous to the lesion associated with global aphasia in the opposite hemisphere. As a general rule, the underlying neural correlate for aprosodia is typically in the middle cerebral artery distribution on the right. The defect is most prominent in the acute epoch after stroke and may resolve largely or completely in the chronic epoch. 4. Visual Perceptual and Visual Spatial Functions Substantial research suggests that deﬁcits in visual spatial skills and visual perceptual abilities may be acquired with strokes in the right hemisphere. More speciﬁcally, the dorsal visual stream bilaterally, and in particular in the right hemisphere, appears to be associated with deﬁcits in spatial judgment, whereas the ventral visual stream, again particularly in the right hemisphere, is associated with visual perception and identiﬁcation of objects (Farah, 2003). In general, visual perceptual and spatial diﬃculties are observed in patients with posterior parietal and temporal lesions and are associated with other syndromes such as anosognosia, neglect, and to a lesser extent aprosodia. Spatial deﬁcits may be observed in perception of line orientation, guided reaching, drawing and building, and topographic knowledge. Visual perceptual defects, associated generally with the ventral visual stream and with occipital temporal lesions, may be demonstrated on tests of ﬁne visual discrimination, such as Benton’s facial recognition test. I. Executive Functions Executive function is a term used to refer to a loosely deﬁned collection of behaviors and abilities such as judgment, social behavior, decision making, and ‘‘working memory.’’ Although executive functions are clearly linked to frontal cortices and their connections, the terms ‘‘frontal dysfunction’’ and ‘‘executive dysfunctions’’ should not be used interchangeably. In fact, a number of executive functions may be entirely normal in patients with documented frontal lobe lesions, and tests of executive function may be impaired in patients with nonfrontal lesions (Damasio and Anderson, 2003). One of the most clearly identiﬁable syndromes associated with executive dysfunction is akinetic mutism, which is associated with strokes in the cingulate gyrus or the

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supplementary motor area. Bilateral lesions usually result in a more profound and clear clinical picture, but the syndrome may be observed in unilateral lesions, particularly in the acute epoch. Patients with akinetic mutism are alert and awake, but produce no speech when spoken to or prompted. Movement is limited in such patients, as are facial expressions. Patients may orient to sound, but will not produce verbal or nonverbal responses to questions. Following recovery, patients report that they recall being asked questions, and may recall speciﬁc instances or scenarios. However, such patients report that they simply did not want to respond. This is a disorder of motivation. Most patients recover well, particularly those with unilateral lesions. A core feature of executive dysfunction associated with the frontal lobes, and in particular the ventromedial sector, involves change in personality, increased impulsivity, and social dysfunction. This has been termed ‘‘acquired sociopathy,’’ a clear case of which can be seen in one of the earliest cases described of frontal lobe dysfunction and personality change. A railroad worker in the mid-nineteenth century, Phineas Gage, was noted by his physician to have a dramatic personality change following an accident that resulted in frontal lobe damage. Harlow (1868) characterized the personality change as ‘‘Gage was no longer Gage,’’ speciﬁcally that Gage was irritable, impulsive, obstinate, and prone to profanity. Subsequent to this description many such cases have been described, and these patients have a number of commonalties, including acquired deﬁcits in organizational capacities, an inability to hold gainful employment, and an inability to respond to punishment and inappropriate emotional responses. Intellect is typically normal and, in some cases, well above average (see Eslinger and Damasio, 1985). The ventral medial prefrontal sector of the frontal lobes appears to be preferentially aﬀected in such patients. The term ‘‘acquired sociopathy’’ calls to mind the well-known characteristics of developmental sociopaths, including poor or risky decision making and behaviors that have repeated negative consequences. Patients with this acquired form of social conduct disorder due to frontal lobe damage are usually not predatory, as can be developmental sociopaths, and in this sense the disorders are diﬀerent. Substantial recent research has shown that decision making is manifestly defective in such patients, particularly when they must use ‘‘hunches’’ to make decisions. Models of decision making in our laboratory rely on the idea that somatic states assist in advantageous decision making, and the connection between somatic states and execution of decisions is lacking in such individuals.

III. TREATMENT OF COGNITIVE IMPAIRMENTS AFTER STROKE As a rule, cognitive impairments following a stroke improve dramatically in the acute epoch, virtually regardless of the speciﬁc type of impairment. For example, irrespective of the type of stroke (e.g., embolic, hemorrhagic), the site of the lesion (middle cerebral artery, posterior cerebral artery, anterior cerebral artery), or the resultant deﬁcit (e.g., in memory, language, vision, or executive functions), the cognition of stroke patients can be expected to improve. This is in keeping with resolution of the eﬀects of edema and associated diaschesis. The usual course of recovery is quite rapid at ﬁrst and continues for at least several months. At approximately 1–2 years, recovery of cognitive functions following stroke is generally considered to be complete, and any residual cognitive defects are presumed to be largely stable and permanent. In recent years a number of researchers and clinicians have investigated the value of rehabilitation of patients with acquired cognitive impairments due to stroke. Similar to the well-established profession of speech therapy, specialists in cognitive rehabilitation or

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neuropsychological rehabilitation focus on treatment of acquired cognitive deﬁcits associated with stroke and on improving functional capacities in relation to those impairments (see Eslinger, 2002, for a recent summery of rehabilitative treatments for diﬀerent conditions and syndromes). New models for intervention for speciﬁc impairments have been recently described in relation to neurologically based social disturbances, memory, and apraxia. In most cases such interventions are not aimed at ‘‘curing’’ any neurologically based cognitive disorders, but rather are aimed at accommodating such disorders through the use of environmental manipulations, prostheses, or other means. Memory aides, personal data assistants, timers and pagers, and mnemonic devices can be useful in helping with memory disorders. Similarly, computer-based practice may help patients with left visual hemispatial neglect to learn to intentionally attend to the left hemiﬁeld. Finally, traditional psychological interventions and medications can be used to alleviate aﬀective disturbances and depression following stroke, and neurologically based social disturbances can be addressed through psychotherapeutic interventions and social skills training. The aim of such interventions, without exception, is to attain the most advantageous functioning for a given patient following the onset of a cognitive or neuropsychological impairment. This is a new area of research, but the few empirical studies available appear to support such interventions. There is general consensus that such interventions should be driven by empirically demonstrated methods. A second broad class of treatments in the context of cognitive impairments following stroke includes medication interventions. Similar to neuropsychological or behavioral interventions, medication treatment of cognitive sequelae of stroke is in its infancy. Although symptomatic treatment of psychological conditions following stroke is generally accepted (e.g., treatment with antidepressant medications in the setting of depression following stroke), it is probably fair to say that treatment of more cognitively based impairments has yet to be fully proven or accepted. It may well be, for example, that certain medications are helpful in certain types of memory disorder following stroke or in acquired attentional impairments. Similar to research in neuropsychological interventions, the models for such medical interventions are in their infancy, and the methodological challenges for rigorous empirical studies are great. However, the potential beneﬁt of such research is tremendous, given the rate of disability and suﬀering due to cognitive impairment following stroke.

IV. CONCLUDING REMARKS Cognitive impairments are a core feature of the clinical presentation of stroke patients and are important in understanding acquired disability associated with stroke. Such impairments can involve single or multiple cognitive domains depending on the underlying lesion, and may not only aﬀect traditional constructs such as memory and language, but result in deﬁcits in executive functions such as social regulation and decision making. Neuropsychological assessment in the acute epoch following stroke can help to guide placement and rehabilitation emphasis and, in the chronic epoch, help to delineate residual cognitive impairments associated with stroke and help to guide focused rehabilitation strategies. Neuropsychological and medical treatment strategies for the cognitive impairments associated with stroke are in their infancy, but early empirical studies suggest that both behavioral interventions and certain medical interventions may be helpful in speciﬁc poststroke cognitive and neuropsychological conditions.

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REFERENCES Bauer RM. Autonomic recognition of names and faces in prosopagnosia: a neuropsychological application of the Guilty Knowledge Test. Neuropsychologia 1984; 22:457–469. Bauer RM, Grande L, Valenstein E. Amnesic disorders. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology. 4th ed. New York: Oxford Press, 2003:495–573. Benton AL. Neuropsychology: past, present, and future. In: Boller F, Grafman J, eds. Handbook of Neuropsychology. Vol. 1. Amsterdam: Elsevier Science, 1988:1–27. Benton AL. Gerstmann’s syndrome. Arch Neurol 1992; 49(5):445–447. Broca P. Sur la faculte du langage articule. Bull Soc Anthropol 1865; 6:337–393. Coslett HB. Acquired dyslexia. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology. 4th ed. New York: Oxford Press, 2003:108–125. Damasio AR, Anderson SW. The Frontal Lobes. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology. 4th ed. New York: Oxford Press, 2003:404–446. Damasio AR, Damasio H. Anatomical basis of pure alexia. Neurology 1983; 33:1473–1583. Damasio H, Damasio AR. The lesion method in humans. In: Damasio H, Damasio AR, eds. Lesion Analysis in Neuropsychology. New York: Oxford Press, 1989:7–82. Damasio AR, Damasio H. Aphasia and the neural basis of language. In: Mesulam MM, ed. Principles of Behavioral and Cognitive Neurology. 2d ed. New York: Oxford Press, 2000:294–315. Damasio AR, Yamada T, Damasio H, Corbett J, Mckee J. Central achromatopsia: behavioral, anatomic and physiologic aspects. Neurology 1980; 30:1064–1071. Damasio AR, Damasio H, Van Hoesen GW. Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology 1982; 32:15–20. Damasio AR, Graﬀ-Radford NR, Eslinger PG, et al. Amnesia following basal forebrain lesions. Arch Neurol 1985; 42:263–271. Damasio AR, Tranel D, Rizzo M. Disorders of complex visual processing. In: Mesulam MM, ed. Principles of Behavioral and Cognitive Neurology. 2d ed. New York: Oxford Press, 2000:332– 372. Denburg NL, Tranel D. Acalculia and disturbances of the body schema. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology. 4th ed. New York: Oxford Press, 2003:161–184. Eslinger PJ, ed. Neuropsychological Interventions: Clinical Research and Practice. New York: Guilford Press, 2002. Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 1985; 35:1731–1741. Farah MJ. Disorders of visual-spatial perception and cognition. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology. 4th ed. New York: Oxford Press, 2003:146–160. Harlow JM. Recovery from the passage of an iron bar through the head. Publications of the Massachusetts Medical Society 1868; 2:327–347. Heilman KM, Watson RT, Valenstein E. Neglect and related disorders. In Heilman KM, Valenstein E, eds. Clinical Neuropsychology. 4th ed. New York: Oxford Press, 2003:296–346. Jones RD, Tranel D. Severe developmental prosopagnosia in a child with superior intellect. J Clin Exp Neuropsychol 2001; 23:265–273. Jones RD, Tranel D. Vision disorders. In: Ramachandran VS, ed. Encyclopedia of the Human Brain. New York: Academic Press, 2002. Jones RD, Grabowski TJ, Tranel D. The neural basis of retrograde memory: evidence from position emission tomography for the role of non-mesial temporal lobe structures. Neurocase 1998; 4:471–479. Kapur N, Ellison D, Parkin AJ, Hunkin NM, Burrows E, Sampson SA, Morrison EA. Bilateral temporal lobe pathology with sparing of medical temporal lobe structures: lesion proﬁle and pattern of memory disorder. Neuropsychologia 1993; 32:23–38. Kopelman MD. Disorders of memory. Brain 2002; 125(pt 10):2152–2190. Lissauer H. Ein Fall von Seelenblindheit nebst einem Beitrage zur Theorie derselben. Arch Psychiatr Nervenkr 1890; 21:222–270.

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Maher LM, Rothi LG. Disorder of skilled movement. In: Berndt RS, ed. Handbook of Neuropsychology. 2d ed. Vol. 3. Amsterdam: Elsevier Science, 2001:269–283. Rizzo M. ‘‘Balint’s syndrome’’ and associated visuospatial disorders. In: Kennard C, ed. Bailliere’s International Practice and Research. London: Saunders, 1993:415–437. Ross ED. The aprosodias: functional-anatomic organization of the aﬀective components of language in the right hemisphere. Arch Neurol 1981; 38:561–569. Ross ED. Modulation of aﬀect and nonverbal communication by the right hemisphere. In: Mesulam MM, ed. Principles of Behavioral Neurology. Philadelphia: FA Davis, 1985:239–257. Ross ED. Aﬀective prosody and the aprosodias. In: Mesulam MM, ed. Principles of Behavioral and Cognitive Neurology. 2d ed. New York: Oxford Press, 2000:316–331. Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. Neurol Neurosurg Psychiatry 1957; 20:11–21. Schacter DL. Toward a cognitive neuropsychology of awareness: implicit knowledge and anosognosia. J Clin Exp Neuropsychol 1990; 12(1):155–178. Teuber HL. Alteration of perception and memory in man: Reﬂections on methods. In: Weiskrantz L, ed. Annals of Behavior Change. New York: Harper & Row, 1968:274–328. Tranel D, Anderson SW. Knowledge without awareness: an autonomic index of facial recognition by prosopagnosics. Science 1985; 228:1453–1454. Tranel D, Damasio AR. Disorders of higher brain functions. In: Rosenberg RN, Pleasure DE, eds. Comprehensive Neurology. 2d ed. NewYork: Raven Press, 1998:435–453. Tranel D, Biller J, Damasio H, Adams HP, Cornell S. Global aphasia without hemiparesis. Arch Neurol 1987; 44:304–308. Tranel D, Damasio H, Brandt JP. Sensorimotor skill learning in amnesia: additional evidence for the neural basis of nondeclarative memory. Learn Memory 1994; 1:165–179. Wernicke C. Der aphasische Symptomencomplex. Breslau: Cohn und Weigert, 1874.

13 Neuropsychiatric Disorders Following Stroke Robert G. Robinson and Ricardo Jorge, M.D. The University of Iowa, Iowa City, Iowa, U.S.A.

I. INTRODUCTION The association of neuropsychiatric disorders with cerebrovascular disease has been recognized by clinicians for over 100 years, but it is only within the past 20 years that systematic studies have been conducted. The vast majority of studies, however, have focused on neuropsychiatric disorders observed in patients with ischemic or hemorrhagic stroke associated with atherosclerosis, cardiac embolism, or hypertension rather than patients with cerebral aneurysms, arteriovenous malformations, vasculitis, cerebral venous thrombosis, or other rare diseases such as amyloid angiopathy or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This chapter will focus on neuropsychiatric disorders observed among the ﬁrst group of patients.

II. POSTSTROKE DEPRESSION A. Epidemiology Early reports of depression after brain injury (usually caused by cerebrovascular disease) were based on anecdotal case reports of neurologists and psychiatrists. More recent prevalence studies, however, have shown that depression is among the most common neuropsychiatric disorders that occur after stroke. The frequency of poststroke depression depends upon whether patients are examined in hospital or in community surveys and whether they are studied during the acute poststroke period or many months following stroke (Table 1). In addition, the use of cutoﬀ scores to deﬁne the existence of poststroke depression (PSD), rather than the ‘‘gold standard’’ of structured interviews in combination with established diagnostic criteria, has also contributed to reported diﬀerences in the prevalence rates of PSD. Based on pooled data from all studies, the mean prevalence in hospitalized acute stroke patients was 22% for major depression and 17% for minor depression. In outpatient populations, the mean prevalence was 23% for major depression, and 35% for minor depression, while in community samples the mean prevalence for major depression was 13% and for minor depression 10%. 261

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Table 1 Prevalence Studies of Poststroke Depression Investigators [Ref.]

Patient population

n

Criteria

Wade et al., Community 379 Cutoﬀ score 1987 [38] House et al., Community 89 PSE-DSM-III 1991 [68] Burvill et al., Community 294 PSE-DSM-III 1995 [69] Kotila et al., Community 321 Cutoﬀ score 1998 [70] Pooled data means for community studies, total n = 1083 Robinson et al., 1983 [71] Ebrahim et al., 1987 [72] Fedoroﬀ et al., 1991 [73] Castillo et al., 1995 [74] Starkstein et al., 1992 [75] Astrom et al., 1993 [11] Herrmann et al., 1993 [20] Singh et al., 2000 [86] Andersen et al., 1994 [76] Gainotti et al., 1999 [77]

Major Minor Total % % % 30 11

12

23

15

8

23 44

14.1

20

31.8

Acute hosp.

103

PSE-DSM-III

Acute hosp.

149

Cutoﬀ score

Acute hosp.

205

PSE-DSM-III

22

19

41

Acute hosp.

291

PSE-DSM-III

20

18

38

Acute hosp.

80

PSE-DSM-III

16

13

29

Acute hosp.

80

DSM-III

25

NR

25a

Acute hosp.

21

RDC

24

14

38

Acute hosp.

81

Cutoﬀ score

285

HDRS cutoﬀ

153

PSDRS

Acute hosp. or outpatient Acute or rehab. hosp. <2 months 2–4 months >4 months Rehab. hosp.

27

9.1

23

36 10

11

21 31

27% 27% 40% 20

Folstein et al., PSE & items 1977 [78] Finklestein et al., Rehab. hosp. 25 Cutoﬀ score 1982 [79] Sinyor et al., Rehab. hosp. 35 Cutoﬀ score 1986 [27] Finset et al., Rehab. hosp. 42 Cutoﬀ score 1989 [80] Eastwood et al., Rehab. hosp. 87 SADS-RDC 1989 [25] Morris et al., Rehab. hosp. 99 CIDI-DSM-III 1990 [10] Schubert et al., Rehab. hosp. 18 DSM-III-R 1992 [81] Rehab. hosp. 91 DSM-III Schwartz et al., 1993 [26] Pooled data for all acute and rehab. hospital studies, total n = 1865

47

45 48 36 36 10

40

50

14

21

35

28

44

72 40a

40 19.3

18.5

35.5a

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Table 1 Continued Investigators [Ref.]

Patient population

Pohjasvaara et al., 1998 [28] Feibel et al., 1982 [82]

Outpatient

Robinson et al., 1982 [83] Herrmann et al., 1998 [29]

Outpatient (6 months 10 y) Outpatient (3 months) (1 y) Outpatient (3 months) Outpatient

Vataja et al., 2001 [84] Collin et al., 1987 [85] Astrom et al., 1993 [11]

Outpatient (6 months)

n

Criteria

277

PSE-DSMIIIR

Major Minor Total % % % 26

14

40

91

Nursing evaluation

26

103

Cutoﬀ score

29

150 136 275

Cutoﬀ score Cutoﬀ score PSE-DSMIIIR

27 22 40

111

Cutoﬀ score

Outpatient (3 months) 77 (1 y) 73 (2 y) 57 (3 y) 49 Castillo et al. Outpatient 1995 [74] (3 months) 77 (6 months) 80 (1 y) 70 (2 y) 67 Pooled data for outpatient studies, total n = 1300

26

14

42

DSM-III DSM-III DSM-III DSM-III

31 16 19 29

NR NR NR NR

31a 16a 19a 29a

PSE-DSM-III PSE-DSM-III PSE-DSM-III PSE-DSM-III

20 21 11 18 23.3

13 21 16 17 15.0

33 42 27 35 32.9a

PSE=Present State Examination; RDC = Research Diagnostic Criteria; HDRS = Hamilton Depression Rating Scale; SADS = Schedule for Aﬀective Disorders and Schizophrenia; CIDI = Composite International Diagnostic Interview; PSDRS = Poststroke Depression Rating Scales; NR = not reported. a Because minor depression was not included, these values may be low.

B. Diagnosis The diagnosis of PSD may be diﬃcult or impossible to establish in some groups of patients with stroke. For instance, the presence of language comprehension disorders and/or signiﬁcant cognitive impairment may prohibit the reliable assessment of symptoms of depression [1]. The DSM-IV-TR [2] criteria for ‘‘mood disorders due to stroke or cerebrovascular infarction’’ are applicable to the diagnosis of PSD. Some investigators, however, have suggested that several symptoms used by DSM-IV for the diagnosis of major depression, such as loss of energy, poor appetite, and insomnia, are also found among stroke patients with no mood disturbance due to their hospital environment, use of medications, associated medical conditions, or the stroke itself [3]. Investigators of depression associated with physical illness have debated the most appropriate method for the diagnosis of these disorders when some symptoms (e.g., sleep or appetite disturbance) could result from the physical illness. Four approaches used to assess depression in the physically ill include the inclusive approach, in which depressive diagnostic symptoms are counted regardless of whether they may be related to physical illness, the

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etiological approach, in which a symptom is counted only if the diagnostician feels that it is not caused by the physical illness, the substitutive approach, in which other psychological symptoms of depression replace the vegetative symptoms, and the exclusive approach, in which symptoms are removed from the diagnostic criteria if they are not found to be more frequent in depressed than nondepressed patients. Paradiso et al. [87] examined the utility of these methods in the diagnosis of depression during the ﬁrst 2 years following stroke. Among 142 patients who were examined in the hospital and followed up for examination at 3, 6, 12, or 24 months following stroke, 60 (42%) reported the presence of a depressed mood (depressed group) while they were in hospital, and the remaining 82 patients were nondepressed. There were no signiﬁcant diﬀerences in the background characteristics between the depressed and nondepressed groups except that the depressed group was signiﬁcantly younger ( p = 0.006) and had a signiﬁcantly higher frequency of personal history of psychiatric disorder ( p = 0.04). Throughout the 2-year follow-up, depressed patients showed a higher frequency of both vegetative and psychological symptoms compared with the nondepressed patients (Table 2). The only symptoms that were not more frequent in the depressed compared to nondepressed patients were (1) weight loss and early awakening at the initial evaluation; (2) weight loss and early morning awakening at 6 months; (3) weight loss, early morning awakening, anxious foreboding, and loss of libido at 1 year; and (4) weight loss and loss of libido at 2 years. The depressed patients had a higher frequency of most psychological symptoms throughout the 2-year follow-up. The only psychological symptoms that were not signiﬁcantly more frequent in the depressed than in the nondepressed group were (1) suicidal

Table 2 Number of Patients with Vegetative Depressive Symptoms at Each Poststroke Evaluationa Initial evaluation

Autonomic anxiety Anxious foreboding Morning depression Weight loss Delayed sleep Subjective anergia Early awakening Loss of libido a

3-Month follow-up

6-Month follow-up

1-Year follow-up

2-Year follow-up

Dep. Mood

Nondep. Mood

Dep. Mood

Nondep. Mood

Dep. Mood

Nondep. Mood

Dep. Mood

Nondep. Mood

Dep. Mood

Nondep. Mood

23 (39)

4.(5)b

15.(52)

5.(11)b

18.(58)

7.(15)b

9.(45)

6.(12)b

16.(64)

8.(20)b

21 (36)

8.(10)b

13.(46)

3.(6)b

9.(29)

7.(15)

4.(20)

4.(8)

11.(44)

2.(5)b

38 (63)

4.(5)b

17.(67)

2.(4)b

20.(65)

2.(4)b

11.(55)

2.(4)b

17.(68)

0.(0)b

20 (34)

16.(20)

6.(22)

3.(6)

10.(32)

11.(24)

4.(20)

2.(4)

7.(28)

6.(15)

24 (40)

12.(15)b

10.(36)

9.(19)

15.(48)

7.(15)b

8.(40)

5.(10)b

11.(44)

2.(5)b

35 (58)

16.(20)b

17.(61)

12.(28)b

19.(61)

10.(22)b

10.(50)

8.(16)b

15.(60)

10.(24)b

16 (27)

13.(16)

9.(32)

8.(17)

4.(13)

7.(15)

3.(15)

3.(6)

11.(44)

5.(12)b

16 (27)

7.(9)b

12.(46)

12.(11)b

12.(39)

6.(14)b

5.(25)

7.(14)

11.(44)

10.(24)

Number and percentage (in parentheses) of patients with or without depressed mood presenting deﬁnite symptoms. Signiﬁcant at the 0.05 level. Source: Ref. 87.

b

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plans, simple ideas of reference and pathological guilt at 3 months, (2) pathological guilt at 6 months, (3) pathological guilt, suicidal plans, guilty ideas of reference, and irritability at 1 year, and (4) pathological guilt and self-depreciation at 2 years. The eﬀect of using each of the proposed alternative diagnostic methods for poststroke depression using DSM-IV criteria was examined. Compared to gold standard diagnoses based solely on the existence of ﬁve or more speciﬁc symptoms (i.e., symptoms that were signiﬁcantly more common in depressed than nondepressed patients for the diagnosis of DSM-IV major depression), diagnoses based on unmodiﬁed symptoms (i.e., early awakening and weight loss included) had a speciﬁcity of 98% and a sensitivity of 100%. Similar results were found at 3-, 6-,12-, and 24-month follow-up. The sensitivity of unmodiﬁed DSM-IV criteria consistently showed a sensitivity of 100% and a speciﬁcity that ranged from 95 to 98% compared to criteria only using speciﬁc symptoms. Thus, one could reasonably conclude that modifying DSM-IV-TR criteria because of the existence of cerebrovascular disease is unnecessary. The phenomenology of poststroke major depression was found by Lipsey et al. [4] to be similar to those found in elderly patients with primary (i.e., no brain injury) depression. DSM-IV criteria for depression due to stroke with major depressive-like episode requires the presence of either depressed mood or loss of interest during 2 or more weeks following a stroke accompanied by at least four of the following symptoms: decreased or increased appetite or weight, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy, feelings of worthlessness or inappropriate guilt, loss of concentration, and recurrent suicidal ideation. Minor depression is a DSM-IV research diagnosis that requires the presence of more than two but fewer than ﬁve major depressive symptoms including either a depressed mood or loss of interest. Although it excludes depressions ‘‘due to a general medical condition,’’ we have used this diagnosis to identify stroke patients with milder (subsyndromal) forms of depression. Several studies have provided some validation for this diagnosis by identifying diﬀerences between major and minor depression in the frequency of past personal history of depression [5], the association with cognitive impairment [6,7], and association with lesion location [8]. C. Duration The duration of depression has been examined in several longitudinal studies. In a prospective study of mood disorders in 65 acute stroke patients [9], we found that 9 patients (14%) had an in-hospital symptom cluster of major depression, while 12 patients (18%) had a symptom cluster of minor depression. All of the patients with major in-hospital depression no longer had a depression diagnosis by 2 years, whereas only 3 patients (30%) with inhospital minor depression were without a diagnosis of major or minor depression at 2-year follow-up. Morris et al. [10] found that the mean duration of poststroke major depression was 34 weeks while the mean duration of minor depression was only 13 weeks. Astro¨m et al. [11] also found that the majority of major depressions remitted by 1-year follow-up. However, 30% of patients with in-hospital major depression remained depressed at 1-year follow-up, 25% were depressed at 2-year follow-up, and 20% were still depressed at 3-year follow-up. Thus, although the mean duration of major depression appeared to be about 9 months, there were about 20% of patients with major or minor depression in-hospital who remained depressed for at least 3 years following stroke.

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D. Anatomical Correlates Over the last two decades there has been a growing interest in whether there is a reproducible correlation between lesion location and PSD. This interest in lesion location is stimulated by the hope that the lesion locations associated wit PSD might delineate an anatomical circuitry that could establish structural basis for this disorder. In one of the earliest studies that examined the relationship between PSD and lesion location, we found that 14 of 22 patients with left hemisphere lesions and no risk factors for depression (i.e., prior personal history, family history) suﬀered either major or minor depression, while these disorders occurred in only 2 of 14 patients with right hemisphere lesions [12]. We later compared 13 patients with PSD and predominantly left-sided lesions to a group of stroke patients without depression matched for age, sex, lesion size, and lesion location [13]. We found that subcortical atrophy (as evidenced by increased ventricular to brain ratios) was associated with the presence of PSD. In a separate study of 93 patients with right-sided lesions, both right frontal (i.e., 6 of 17 depressed patients and 1 of 25 nondepressed patients had a frontal lesion) and right parietal lesions (i.e., 11 of 17 depressed and 9 of 25 nondepressed had a parietal lesion) were associated with PSD [14]. Although the association of depression with left hemisphere lesions has been replicated by other authors [11,15], other studies have not found lateralized eﬀects [16]. We have recently shown that these laterality eﬀects are present only during the acute stroke period (i.e., up to 2 months following stroke) Furthermore, we have undertaken two metaanalyses of all data that test the hypothesis that within 2 months after stroke, major depression is more frequent following left frontal or left basal ganglia stroke than following comparable lesions of the right hemisphere or posterior lesions of the left hemisphere. A meta-analysis of seven studies (only two were independent samples of ours) including 128 patients showed that the relative risk of major depression following left anterior versus left posterior lesions was 2.29 (95% Cl 1.6–3.4) ( p < 0.001) and for left anterior versus right anterior lesions was 2.18 (% Cl 1.4–3.3)( p <0.001) [17]. Thus, there appear to be strategic lesion locations that lead to depression, but the mechanism by which this occurs needs to be elucidated.

E. Mechanism While the mechanism of PSD remains unknown, we hypothesize [18] that the depletion of neuronal monoamines occurring after lesions in the frontal lobe or basal ganglia of the brain may play a role in PSD. Norepinephrine and serotonin nuclei send ascending projections from their location in the brain stem to the frontal cortex through the median forebrain bundle. These ascending axons then arc posteriorly, running through the deep layers of the cortex where they arborize and send terminal projections into the superﬁcial cortical layers. Lesions of the frontal lobe or basal ganglia have been shown in animal models to disrupt these pathways [18]. Furthermore, using positron emission tomography (PET) and following injection of the 5HT2 receptor ligand N-methyl-spiperone, higher 5HT2 receptor binding was found in ipsilateral, noninjured, temporal, and parietal cortex of patients following right as compared with left-sided lesions. Among patients with left hemisphere stroke, there was a signiﬁcant correlation between severity of depression and decreasing amount of 5HT2 receptor binding [19]. Disruptions of dopaminergic pathways ascending from the ventral tegmental area have also been implicated in the pathogenesis of PSD [20].

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F. Poststroke Depression and Activities of Daily Living Examining the association between poststroke depression and activities of daily living (ADL) is a complicated task because there are many variables that may inﬂuence this association. Nevertheless, we have reported that the severity of depressive symptoms as measured by the Zung self-rating depression scale (SDS) [2], the Hamilton Depression Rating Scale (HDRS) [22], or the Present State Examination (PSE) [23] were signiﬁcantly correlated with severity of impairment in ADL (i.e., the patients’ ability to dress and feed themselves, walk, ﬁnd their way around, express needs, read and write, and keep their room in order) [24]. Other investigators have also reported that severity of poststroke depression was correlated with severity of impairment in ADL [11,25–28]. Several investigators have studied the eﬀect of poststroke depression on recovery in ADL [27–31]. Parikh et al. in 1990 prospectively followed 63 stroke patients and compared the 28 patients with poststroke depression to the 35 patients without depression [31]. The two groups were initially comparable in neurological and functional impairments and demographic features. The depressed group, however, was signiﬁcantly more impaired at 2year follow-up than the nondepressed group in both physical activities and language functions (Fig. 1). The 2-year recovery curve in ADL for the depressed group showed signiﬁcantly less recovery than the nondepressed group. A logistic regression analysis showed that depression was a signiﬁcant independent factor in ADL recovery even after other factors such as age, education, lesion volume, hours of rehabilitation therapy, and type of stroke were taken into account. If poststroke depression impairs recovery in ADL, recovery from poststroke depression would be expected to improve recovery in ADL. Twenty-one depressed patients whose mood improved between in-hospital evaluation and 3–6 months after stroke had signiﬁcantly greater recovery in ADL at follow-up than 34 patients whose mood did not improve (Fig. 2) [32]. Interestingly, patients with either major or minor depression showed the same amount of recovery in ADL when their depression improved (i.e., Hamilton Depression score improved by 50% of initial score). This ﬁnding that major and minor depression did not diﬀer in their relationship with recovery in ADL suggests that the eﬀect may not be

Figure 1 Johns Hopkins functioning inventory (JHFI) scores among patients with an acute inhospital diagnosis of poststroke major or minor depression or no mood disorder. Higher scores (mean F SEM shown) indicate greater impairment. There was a signiﬁcant group-by-time interaction, demonstrating that depressed patients had less recovery in terms of activities of daily living than nondepressed patients. (From Ref. 31.)

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Figure 2 Poststroke patients with remission of depression showed signiﬁcantly greater recovery in ADL than nonremitted patients at 3- or 6-month follow-up (F = 6.37; df = 1; 53; p = 0.015). (From Ref. 32.)

mediated by biological or physiological mechanisms but rather by psychological mechanisms such as poor motivation or social withdrawal. We have also conducted a merged analysis of patients who were treated in one of our double-blind trials of nortriptyline versus placebo for poststroke depression. There were 10 patients whose depression responded to treatment and who were matched in severity of ADL impairment to another 10 patients who failed to respond to treatment. At a dose of 100 mg/day, the patients who responded to treatment had signiﬁcantly lower (i.e., less impaired) ADL scores at 6 or 9 weeks of treatment compared to the 10 patients who failed to respond at the same time and dose [33]. G. Poststroke Depression and Cognitive Impairment Cognitive impairment is one of the most common consequences of stroke. In addition, however, depression among patients with no known brain injury has been shown to produce cognitive impairment. Whether depression in patients with stroke can also lead to a greater degree of cognitive impairment than stroke alone has been a focus of our research. Starkstein et al. compared 13 patients who developed major depression within 2 years following stroke with 13 patients who did not become depressed in the same period but who were matched for both size and location of lesion as the depressed group [13]. In this study, the depressed group showed a signiﬁcantly lower mean Mini-Mental State Examination (MMSE) [34] score and higher frequency of abnormal MMSE scores (i.e., MMSE score of 23 or below) than the lesion-matched nondepressed group. This ﬁnding suggested that poststroke depression might produce an intellectual impairment independent of the stroke lesion itself. The eﬀect of poststroke depression on the recovery from cognitive impairment has been examined in several studies [6,35,36]. Downhill et al. examined 309 patients with acute stroke and assessed the longitudinal course of cognitive impairment associated with inhospital major poststroke depression among 142 patients who were prospectively studied over 2 years [6]. Patients with in-hospital major depression following a left hemisphere stroke were signiﬁcantly more cognitively impaired than initially nondepressed patients at 3-, 6-, and 12-month follow-up. At 24 months, however, there was no diﬀerence in cognitive

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function between major depressed and nondepressed patients with either right or left hemisphere injury. Using a merged analysis of our prior treatment studies, we examined 47 patients with poststroke depression (major n = 33; minor n = 14), divided into those who responded (i.e., had a greater than 50% reduction in Ham-D score) (n = 24, major = 15, minor = 9) and those who failed to respond (n = 23, major = 18, minor = 5) [37]. Although there was no signiﬁcant diﬀerence between the responder group and nonresponder group in their baseline Ham-D scores, repeated-measures ANOVA of the MMSE scores demonstrated a signiﬁcant time-by-response interaction (i.e., MMSE scores in the responder group improved more over the course of double-blind treatment than MMSE scores in the nonresponder group) (Fig. 3). The responder group improved in both attention-calculation and recall items more than the nonresponder group. H. Poststroke Depression and Mortality Wade et al. [38] studied 976 patients with acute stroke. They found that patients with depression assessed at 3 weeks poststroke using the Wakeﬁeld self-assessment depression inventory [39] had 50% higher mortality at 1 year compared to nondepressed patients and concluded that early depression correlated with early death. We have also examined this association among 103 acute stroke patients followed for 10 years [40]. Although the inhospital background characteristics were not signiﬁcantly diﬀerent between depressed and nondepressed patients, major or minor depression during in-hospital evaluation was signiﬁcantly associated with an increased mortality rate over the next 6–7 years. Mortality rate among patient with major or minor depression (i.e., 71% and 70%) was signiﬁcantly higher than in patients without depression (i.e., 41%). The relative risk of depression for mortality was 3.4 (CI 1.4–8.4; p = 0.007). Using a logistic regression to assess the contribution of depression, social function, medical illness, age, sex, social class, physical and cognitive impairment, and size and location of stroke, we found that depression remained an independent risk factor (odds ratio 3.7; CI 1.1–12.2; p = 0.03) (Fig. 4).

Figure 3 Change of MMSE scores in patients with poststroke major depression during treatment study. Treatment responders (n = 13) showed signiﬁcantly greater improvement in cognitive function than nonresponders (n = 18) (F3; 126 = 4.98, group-by-time interaction; p = 0.002 at 25 mg group, diﬀ p = 0.036, at 100 mg group, diﬀ p = 0.024). Error bars represent standard errors on the mean (SE). (From Ref. 37.)

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Figure 4 Survival curves over 10 years for 37 patients with major or minor depression at the time of in-hospital poststroke evaluation compared to 54 patients without an in-hospital diagnosis of depression. By 10 years follow-up, 14 of the 20 patients with major depression and 12 of the 17 with minor depression had died compared to only 22 of 54 nondepressed. (From Ref. 40.)

Preliminary ﬁndings from a 6-year follow-up of our poststroke depression treatment study [41] found that active treatment with nortriptyline or ﬂuoxetine over 12 weeks among 104 patients within the ﬁrst 3 months following stroke resulted in increased probability of survival (Kaplan Meier log rank m2 = 7.3; df = 1; p = 0.006). A logistic regression examining the eﬀects of age, existence of diabetes, severity of ADL impairment, and volume of stroke lesion found that antidepressant use was independently associated with increased survival [42].

I. Treatment Five double-blind placebo-controlled studies have examined the eﬃcacy of antidepressant medication in PSD. The ﬁrst controlled treatment trial of poststroke depression was reported in 1984 [43]. In this study 39 patients with stroke who met the diagnostic criteria for major or minor depressive disorder were enrolled in a double-blind placebo-controlled study of the eﬃcacy of nortriptyline among this population. Of the 39 patients entered in the study, 5 dropped out within 1 week. Of the 34 remaining patients, 14 received nortriptyline and 20 received placebo. Repeated-measures analysis of variance of depression scores and post-hoc tests demonstrated that the nortriptyline group had signiﬁcantly greater improvement than the placebo group at 4 and 6 weeks of treatment. All 11 patients who completed the course of nortriptyline treatment responded, while only 5 of the 15 placebo patients responded ( p V 0.001). In a controlled study by Reding et al. [44], 7 PSD patients with an abnormal dexamethasone suppression test (DST) treated with trazodone had a signiﬁcantly greater improvement in activities of daily living at 2–3 months following stroke measured using the Barthel ADL scale compared to 9 comparable patients treated with placebo. Andersen et al. [45] assessed the eﬃcacy and tolerability of the selective serotonin reuptake inhibitor antidepressant citalopram in a controlled study of 66 patients with stroke. The HAM-D and the Melancholia Scale (MES) were signiﬁcantly better at both 3 and 6 weeks after starting treatment among patients who received citalopram compared to patients given placebo.

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Figure 5 Intention-to-treat analysis. Change in (28-item) Hamilton Rating Scale for Depression score over 12 weeks of treatment for all patients who were entered in the study. A repeated-measures ANOVA demonstrated a signiﬁcant time by treatment interaction (F = 3.45; df = 8; 212; p = 0.004) with nortriptyline-treated being signiﬁcantly better than ﬂuoxetine or placebo. * Post hoc tests with Duncan’s statistic; p < 0.05. (From Ref. 41.)

We recently compared nortriptyline and ﬂuoxetine in the treatment of depression using an entirely diﬀerent socioeconomic population than our original study [41]. A total of 104 patients with acute stroke were randomized to receive either nortriptyline, ﬂuoxetine, or placebo over 12 weeks of treatment [41]. Patients treated with nortriptyline (25 mg week 1, 50 mg week 2, 75 mg weeks 3–6, 100 mg weeks 7–12) had a signiﬁcantly greater decline in HDRS scores than either ﬂuoxetine (10 mg weeks 1–3, 20 mg weeks 4–6, 30 mg weeks 7–9, 40 mg weeks 10–12) or placebo-treated patients at 12 weeks of treatment (F = 3.73; df = 2,53; p V 0.031) (Fig. 5). There were no signiﬁcant diﬀerences between ﬂuoxetineand placebo-treated patients. The response rate for nortriptyline was 77% for patients who completed the study, while the response rate for ﬂuoxetine was 14% (Fisher Exact Test; p V 0.0018). Thus, nortriptyline was superior to ﬂuoxetine in treating poststroke depression. Gastrointestinal side eﬀects, insomnia, and headache were more frequent in the ﬂuoxetine-treated group. In addition, ﬂuoxetine led to an average 14 pound weight loss over 12 weeks that was not seen with other treatments.

III. POSTSTROKE ANXIETY DISORDER A. Epidemiology A signiﬁcant comorbidity exists between poststroke anxiety and PSD. In a study of 98 acute stroke patients, only 6 patients met modiﬁed DSM-III criteria for generalized anxiety disorder (GAD) (i.e., excluding the 6-month duration criteria) in the absence of any mood disorder, while 23 of 47 patients with major depression also met criteria for GAD [46]. Similar results were reported by Astro¨m [47] in a 3-year longitudinal study of 80 patients with acute stroke. In this study, the prevalence of GAD in the acute stage was 28% with no signiﬁcant decrease through the 3-year follow-up. Criteria for major depression were met by 85% of those poststroke GAD patients at some time during the 3-year followup period.

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B. Diagnosis The DSM-IV categorizes poststroke GAD as ‘‘anxiety disorder due to stroke with generalized anxiety.’’ The criteria for primary GAD requires the presence of sustained worrying associated with at least three anxiety symptoms, including restlessness, decreased energy, diﬃculties in concentration, irritability, muscle tension, and sleep disturbance, for a period of at least 6 months. In order to study patients in the acute poststroke stage, most studies of poststroke GAD have not required the 6-month duration. Using our overall population of 309 stroke patients, we examined the frequency of symptoms of GAD among patients who acknowledged the symptoms of anxiety or worry. With the exception of decreased energy, all the individual symptoms of GAD were signiﬁcantly more frequent among patients with the symptom of anxiety or worry compared to those stroke patients who denied anxiety or worry [18]. Thus, since anxiety symptoms are not associated with the stroke itself, poststroke generalized anxiety disorder can be diagnosed using DSM-IV symptom criteria. C. Clinical and Anatomical Correlates Our original population of 98 stroke patients was divided into those with generalized anxiety only, those with anxiety plus depression, those with depression only, and those with no mood disorder [46]. Examination of CT scans among these patients showed that anxiousdepressed patients had a signiﬁcantly higher frequency of cortical lesions than did either the depression-only group or the control group (Fig. 6). Moreover, the depression-only group showed a signiﬁcantly higher frequency of subcortical lesions than did the anxiousdepressed group. In the 3-year longitudinal study of stroke patients by Astro¨m [47], similar ﬁndings were reported. In the acute poststroke period, pure GAD was signiﬁcantly associated with right hemispheric lesions, whereas comorbid anxiety/depression was signiﬁcantly associated with left-hemispheric lesions. Another important ﬁnding of this study was that, at 3 years after stroke, GAD was signiﬁcantly associated with both cortical and subcortical atrophy.

Figure 6 Comparison of basal ganglia and cortical lesions among patients with major depression only (Dep only) major depression plus generalized anxiety disorder (Dep + An), and no mood or anxiety disorder (No Dep or Anx). Major depression alone was associated with basal ganglia lesions, while major depression plus generalized anxiety disorder was associated with cortical lesions. * p < 0.05 compared to other groups. (From Ref. 46.)

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Astro¨m suggested that this atrophy might play a role in the prolonged maintenance of GAD after stroke. Longitudinal studies of poststroke GAD have shown that functional recovery of patients with stroke was negatively aﬀected by the presence of GAD. For example, in her 3year longitudinal study, Astro¨m [47] found that ADL impairment was associated with GAD not only in the acute period but at all time periods after discharge from the hospital. Thus, anxiety was more than an immediate reaction to loss of function. In another study of 142 patients, we found that patients with GAD (n = 18) and depression had signiﬁcantly greater impairment in ADL at a 2-year follow-up than patients with PSD alone (n = 9) [48]. We suggested that one possible explanation was that the comorbidity of PSD and GAD produced a longer duration of depression than PSD alone, and this prolonged depression might lead to more profound adverse physical and social functioning outcomes.

D. Treatment Benzodiazepines are the most commonly prescribed medications for the treatment of GAD but tend to accumulate in older people. Given the fact that stroke patients constitute an older population, benzodiazepines should be used as a time-limited treatment. Buspirone, an anxiolytic medication with partial serotonin agonist properties, has been reported [49] to have a similar eﬃcacy of diazepam in the treatment of GAD but with a more tolerable side eﬀects proﬁle. The utility of buspirone in this population has not been examined. We have examined the eﬃcacy of nortriptyline treatment for patients with comorbid GAD and depression after stroke [50]. Patients receiving nortriptyline treatment (n = 13) showed signiﬁcantly greater improvement on their Hamilton anxiety symptoms than patients receiving placebo (n = 14), demonstrating that poststroke GAD can be eﬀectively treated with nortriptyline (Fig. 7). In addition, the Hamilton anxiety score declined signiﬁcantly more than the Hamilton depression score during the ﬁrst 2 weeks of treatment, suggesting that the response of anxiety symptoms is both independent of depression and more rapid than the response of depressive symptoms in poststroke patients.

Figure 7 Mean Hamilton Anxiety Scale scores in patients with generalized anxiety disorder and comorbid depression after stroke following double-blind treatment with nortriptyline or placebo. The data are based on a merged analysis of three prior double-blind treatment trials. (From Ref. 50.)

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IV. MANIA A. Epidemiology Mania occurs much less frequently than depression following stroke (only 3 cases were identiﬁed among a consecutive series of more than 300 acute stroke patients, including 143 patients with longitudinal assessment). Although numerous case reports and empirical studies document that stroke is associated with mania, there are no epidemiological studies that document the incidence or prevalence of this condition. About half of the reported cases involve single or repeated manic episodes without major depression. B. Pathological Correlates A study of 17 patients with secondary mania (mood disorder due to stroke, with manic features) found that 12 had unilateral right-hemisphere lesions. The frequency of righthemisphere lesions was signiﬁcantly higher compared to 28 patients with major depression, who tended to have left frontal or basal ganglia lesions or patients with no mood disorder following stroke (Table 3). Lesions associated with mania were either cortical (basotemporal cortex or orbitofrontal cortex) or subcortical (frontal white matter, basal ganglia or thalamus). A PET study using [18F]ﬂuorodeoxyglucose (FDG) showed a focal hypometabolic area in the right basotemporal cortex in three patients with right subcortical lesions not seen in seven age-comparable, normal controls [18].

Table 3 Anatomical Findings in Patients with Mania Secondary to Brain Injury and Patients With and Without Depression After Stroke Poststroke patients Mania 2j to brain injury (n = 17) Characteristic Kind of lesion Ischemic lesiona Hemorrhagic lesion Brain tumor Closed head injury Lesion volume (mean % of total volume + SD) Location of lesion Left hemisphere Right hemisphereb Other (bilateral, midline, or posterior fossa) a

Major dep. (n = 31)

Nondep. (n = 28)

n

%

n

%

n

%

8 1 6 2 7.1 F 9.2

47 6 35 12

25 6 0 0 7.6 F 5.9

81 19 0 0

26 2 0 0 4.7 F 4.1

93 7 0 0

1 12 4

6 71 23

19 7 5

61 23 16

9 10 9

32 36 32

Signiﬁcant diﬀerence between the patients with secondary mania and the depressed and nondepressed poststroke patients (m2 = 13.0; df = 2; p < 0.01). b Mania was signiﬁcantly more frequently associated with right compared with left or other lesion locations ( p = 0.0001), and major depression was signiﬁcantly more frequently associated with left compared with right or other lesion locations ( p = 0.0001).

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The symptoms of mania were examined in a series of 25 consecutive patients who met DSM-IV criteria for an mood disorder due to brain injury with manic features. These patients, who developed mania after a stroke, traumatic brain injury, or tumors, were compared to 25 patients with primary mania (i.e., no known neuropathology). Both groups of patients showed similar frequencies of elation, pressured speech, ﬂight of ideas, grandiose thoughts, insomnia, hallucinations, and paranoid delusions.

V. APATHY Marin [51] deﬁned apathy as the absence or lack of feeling, emotion, interest, concern, and motivation. He has proposed diagnostic criteria for apathy based on the overt behavioral, cognitive and emotional concomitants of goal-directed behavior. A. Epidemiology Few studies have examined the prevalence of apathy in stroke patients. Starkstein et al. found apathy in 18 out of 80 patients (22%) with acute stroke lesions [52]. In 9 of these patients apathy coexisted with a depressive syndrome. Among depressed patients, apathy was signiﬁcantly more frequent in those with major depression compared with those who have minor depression. This suggests that while depression and apathy can occur independently, apathy is signiﬁcantly associated with major but not minor depression. Marin et al. [53] studied the prevalence of apathy among patients with chronic stroke lesions. Apathy was diagnosed in 7 out of 40 stroke patients (17.5%). There was no signiﬁcant comorbidity with depression, suggesting that apathy and depression may be related early after stroke but not in the chronic stage. B. Pathological Correlates Several studies have examined the association between apathy and lesions in speciﬁc brain regions. Bogousslavsky et al. reported apathy in patients with bilateral lesions to ventrolateral and dorosmedial thalamic nucleus [54]. Andersson et al. found a higher frequency of apathy in patients with either subcortical or right hemisphere lesions compared with patients with left hemisphere damage [55]. Other studies have found a higher frequency of apathy in patients with lesions involving the posterior limb of the internal capsule and adjacent globus pallidus [56]. Cummings proposed that apathy in poststroke patients may result from dysfunction of cortico-subcortical circuits involving the prefrontral cortex, basal ganglia, and thalamus [57]. To our knowledge, there have been no controlled treatment studies of poststroke apathy. Marin et al. suggested the use of dopamine agonists for patients with basal ganglia and frontal lobe lesions, whereas patients with multiple infarcts or with comorbid depression may obtain beneﬁts from stimulant drugs or antidepressants with a more stimulant proﬁle like bupropion [58].

VI. CATASTROPHIC REACTION In 1939 Goldstein [59] ﬁrst used the term ‘‘catastrophic reaction’’ to describe a series of symptoms (i.e., anxiety, aggressiveness, refusal, and renouncement) that may occur in

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patients with brain injury and appear to be due to the ‘‘inability of the organism to cope with physical or cognitive deﬁcits.’’ A. Diagnosis Starkstein et al. [60] developed a scale (the Catastrophic Reaction Scale) for the assessment of the existence and severity of catastrophic reactions. Using this scale, we reported that a catastrophic reaction was present in 19% of a consecutive series of 62 patients with acute stroke. Moreover, since catastrophic reactions were signiﬁcantly associated with both major depression and basal ganglia lesions, we suggested that this phenomenon might represent the disinhibited release of depressive emotions provoked by anterior subcortical damage. B. Treatment The preferred treatment for the catastrophic reaction is prophylactic [61]. Since this condition appears frequently in patients with nonﬂuent aphasia, speech therapists and physical therapists should be careful to not stress patients who are known to display catastrophic reactions.

VII. PATHOLOGICAL CRYING OR LAUGHING A. Epidemiology Pathological emotion is characterized by frequent and easily provoked episodes of crying and/or laughing that are not appropriate to the situation or are in excess of the underlying emotion. Several studies [62,63] have reported that approximately 15% of acute stroke patients manifest this condition.

Figure 8 Comparison of pathological laughter and crying scale (PLACS) scores over 6 weeks of double-blind treatment with nortriptyline or placebo using parametric analysis (repeated-measures ANOVA)—there was a signiﬁcant treatment (i.e., nortriptyline vs. placebo) by time interaction ( p = 0.0001). The active treatment was superior to placebo at both 4 and 6 weeks of treatment. A nonparametric analog of repeated-measures ANOVA conﬁrmed that there was a signiﬁcant treatment by time interaction ( p < 0.001) and signiﬁcantly greater improvement in the active treated group at 4 and 6 weeks. * p < 0.002. (From Ref. 64.)

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B. Assessment and Treatment Quantiﬁcation of severity can be determined by using the Pathological Crying and Laughing Scale (PLACS) [64] for the assessment of emotional lability. The reliability and validity of this scale was determined in 54 patients with acute stroke [64]. Furthermore, in a doubleblind drug trial of nortriptyline versus placebo, patients receiving nortriptyline (n = 14) showed a signiﬁcantly greater decrease in PLACS scores (i.e., less pathological aﬀective

Table 4 Prevalence Studies of Psychiatric Disorders After Stroke Disorder Vascular dementia

Major depression

Mania Anxiety

Psychosis Apathy

Catastrophic reaction Pathological emotions

Anosognosia

Prevalence rate 1.5/100; women 75–79 years, USA 16.3/100 men >80 years, Italy 10/100 dementia cases in US 15/100 strokes in community 20/100 strokes in acute hospital <1/100 strokes in acute hospital 6/100 strokes in acute hospital 27/100 anxiety F depression acute 28/100 anxiety F depression acute 3.5/100 anxiety neurosis in community <1/100 strokes in acute hospital 11/100 apathy only-acute hospital 11/100 apathy F depression acute hospital 19/100 strokes in acute hospital 15/100 acute stroke in community 21/100 6 month poststroke 14/100 ﬁrst stroke, community 18/100 rehabilitation hospital 24/100 strokes in acute hospital

Studies

[Ref.]

Rocca et al., 1991

88

Rocca et al., 1991

88

Katzmen et al., 1988

89

Burville et al., 1995

70

Robinson, 1998

18

Robinson and Starkstein, 1997

90

Castillo et al., 1993

91

Castillo et al., 1993

91

Astrom et al., 1996

47

House et al., 1991

69

Robinson and Starkstein, 1997

90

Starkstein et al., 1993

52

Starkstein et al., 1993

52

Starkstein et al., 1993

60

House et al., 1991

69

House et al., 1991

69

Andersen, 1995

92

Morris et al., 1993

63

Starkstein et al., 1992

76

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symptoms) at 4–6 weeks of treatment compared to patients receiving placebo (n = 14) (Fig. 8). In another double-blind drug trial using a crossover design, Andersen et al. [65] reported that all 13 patients treated with the selective serotonin reuptake inhibitor (SSRI) citalopram responded to treatment as measured by a reduction in the number of crying episodes by at least 50% as compared to 2 of 13 who responded to placebo. Although signiﬁcant improvement in Hamilton depression scores was also seen in this nortriptyline versus placebo treatment study, when the data were analyzed to exclude the eﬀect of depression, nortriptyline was shown to be an eﬀective treatment for pathological emotions.

VIII. POSTSTROKE PSYCHOSIS A. Frequency, Clinical Correlates, and Treatment Delusions or hallucinations are rare complications of stroke. Rabins et al. [66] screened all individuals z60 years who were admitted to a geriatric unit during a 9-year period and identiﬁed 5 patients with poststroke psychosis. All of them had right frontoparietal lesions and showed a signiﬁcantly greater degree of subcortical atrophy compared to 5 stroke patients matched for age, gender, and lesion size and location but without psychosis. Moreover, 3 of the 5 patients with poststroke psychosis had seizures, while no seizures were seen in any of the 5 nonpsychotic patients. Generally, patients respond to treatment with neuroleptic medications, although some treatment-resistant cases have been reported [67]. In treatment-resistant cases, anticonvulsant medications have been reported to be useful [67].

IX. SUMMARY Numerous neuropsychiatric disorders may occur following stroke (Table 4). Depression and anxiety disorder are two of the most common poststroke neuropsychiatric disorders, and they frequently occur as comorbid conditions. In addition to producing a signiﬁcant degree of psychological distress, depression and anxiety disorder have been shown to be associated with particular lesion locations and to adversely aﬀect both the physical and cognitive recovery from stroke, as well as increasing mortality. Similarly, apathy, catastrophic reactions, pathological aﬀect, and post-stroke psychosis are disorders that may occur following stroke and probably inﬂuence the course of recovery as well as quality of life following stroke. Given the frequent occurrence of these disorders and the magnitude of the public health problems produced by stroke, it is remarkable how few treatment studies have been conducted. Apart from the early treatment interventions to limit cerebral infarction, treatment of the neuropsychiatric disorders following stroke appears to have the greatest potential to improve the outcome and quality of life for people who have suﬀered a stroke.

REFERENCES 1. Gustafson Y, Olsson T, Eriksson S. Acute confusional states in stroke patients. Cerebrovasc Dis 1991; 1:257–264. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder-DMIV-TR. Washington, DC: American Psychiatry Association, 2000.

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3. Harrington C, Salloway S. The diagnosis and treatment of post-stroke depression. Med Health 1997; 80(6):181–187. 4. Lipsey JR, Spencer WC, Rabins PV, Robinson RG. Phenomenological comparison of functional and post-stroke depression. Am J Psychiatry 1986; 143:527–529. 5. Morris PLP, Robinson RG, Raphael B, Samuels J, Molloy P. The relationship between risk factors for aﬀective disorder and post-stroke depression in hospitalized stroke patients. Aust N Z J Psychiatry 1992; 26:208–217. 6. Downhill JE Jr, Robinson RG. Longitudinal assessment of depression and cognitive impairment following stroke. J Nerv Ment Dis 1994; 182:425–431. 7. Spalletta G, Guida G, De Angelis D, Caltagirone C. Predictors of cognitive level and depression severity are diﬀerent in patients with left and right hemispheric stroke within the ﬁrst year of illness. J Neurol 2002; 249(11):1541–1551. 8. Paradiso S, Robinson RG. Minor depression after stroke. An initial validation of the DSM-IV construct. Am J Geriatr Psychiatry 1999; 7(3):244–251. 9. Robinson RG, Bolduc P, Price TR. A two year longitudinal study of post-stroke depression: diagnosis and outcome at one and two year follow-up. Stroke 1987; 18:837–843. 10. Morris PLP, Robinson RG, Raphael B. Prevalence and course of depressive disorders in hospitalized stroke patients. Int J Psychiatr Med 1990; 20:349–364. 11. Astrom M, Adolfsson R, Asplund K. Major depression in stroke patients: a 3-year longitudinal study. Stroke 1993; 24:976–982. 12. Robinson RG, Kubos KL, Starr LB, Rao K, Price TR. Mood disorders in stroke patients: importance of location of lesion. Brain 1984; 107:81–93. 13. Starkstein SE, Robinson RG, Price TR. Comparison of patients with and without post-stroke major depression matched for size and location of lesion. Arch Gen Psychiatry 1988; 45:247–252. 14. Starkstein SE, Robinson RG, Honig MA, Parikh RM, Joselyn P, Price TR. Mood changes after right hemisphere lesion. Br J Psychiatry 1989; 155:79–85. 15. Morris PLP, Robinson RG, Raphael B, Hopwood MJ. Lesion location and post-stroke depression. J Neuropsychiatry Clin Neurosci 1996; 8:399–403. 16. Carson AJ, MacHale S, Allen K, Lawrie SM, Dennis M, House A, Sharpe M. Depression after stroke and lesion location: a systematic review. Lancet 2000; 356(9224):122–126. 17. Robinson RG. The controversy over post-stroke depression and lesion location. Psychiatric Times 2003; 20:39–40. 18. Robinson RG. The Clinical Neuropsychiatry of Stroke. Cambridge: Cambridge University Press, 1998. 19. Mayberg HS, Robinson RG, Wong DF, Parikh RM, Bolduc P, Starkstein SE, Price TR, Dannals RF, Links JM, Wilson AA, Ravert HT, Wagner HN Jr. PET imaging of cortical S2serotonin receptors after stroke: lateralized changes and relationship to depression. Am J Psychiatry 1988; 145:937–943. 20. Herrmann M, Bartles C, Wallesch C-W. Depression in acute and chronic aphasia: symptoms, pathoanatomical-clinical correlations and functional implications. J Neurol Neurosurg Psychiatry 1993; 56:672–678. 21. Zung WWK. A self-rating depression scale. Arch Gen Psychiatry 1965; 12:377–395. 22. Hamilton MA. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62. 23. Wing JK, Cooper JE, Sartorius N. The Measurement and Classiﬁcation of Psychiatric Symptoms: An Instructional Manual for the PSE and CATEGO Programs. New York: Cambridge University Press, 1974. 24. Parikh RM, Lipsey JR, Robinson RG, Price TR. Two-year longitudinal study of post-stroke mood disorders: dynamic changes in correlates of depression at one and two years. Stroke 1987; 18:579–584. 25. Eastwood MR, Rifat SL, Nobbs H, Ruderman J. Mood disorder following cerebrovascular accident. Br J Psychiatry 1989; 154:195–200. 26. Schwartz JA, Speed NM, Brunberg JA, Brewer TL, Brown M, Greden JF. Depression in stroke rehabilitation. Biol Psychiatry 1993; 33:694–699.

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27. Sinyor D, Amato P, Kaloupek P. Post-stroke depression: relationship to functional impairment, coping strategies, and rehabilitation outcome. Stroke 1986; 17:112–117. 28. Pohjasvaara T, Leppavuori A, Siira I, Vataja R, Kaste M, Erkinjuntti T. Frequency and clinical determinants of poststroke depression. Stroke 1998; 29:2311–2317. 29. Herrmann N, Black SE, Lawrence J, Szekely C, Szalai JP. The Sunnybrook stroke study. A prospective study of depressive symptoms and functional outcome. Stroke 1998; 29:618–624. 30. Kotila M, Waltimo O, Niemim L, Laaksonen R, Lempinen M. The proﬁle of recovery from stroke in factors inﬂuencing outcome. Stroke 1984; 15:1039–1044. 31. Parikh RM, Robinson RG, Lipsey JR, Starkstein SE, Fedoroﬀ JP, Price TR. The impact of post-stroke depression on recovery in activities of daily living over two year follow-up. Arch Neurol 1990; 47:785–789. 32. Chemerinski E, Robinson RG, Kosier JT. Improved recovery in activities of daily living associated with remission of post-stroke depression. Stroke 2001; 32(1):113–117. 33. Chemerinski E, Robinson RG, Arndt S, Kosier JT. The eﬀect of remission of poststroke depression on activities of daily living in a double-blind randomized treatment study. J Nervous Mental Dis 2001; 189(7):421–425. 34. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198. 35. Robinson RG, Bolla-Wilson K, Kaplan E, Lipsey JR, Price TR. Depression inﬂuences intellectual impairment in stroke patients. Br J Psychiatry 1986; 148:541–547. 36. Kahn RL, RGoldfarb AI, Pollack M, Peck A. Brief objective measures for the determination of mental status in the aged. Am J Psychiatry 1960; 117:326–328. 37. Kimura M, Robinson RG, Kosier T. Treatment of cognitive impairment after poststroke depression. Stroke 2000; 31(7):1482–1486. 38. Wade DT, Legh-Smith J, Hewer RA. Depressed mood after stroke, a community study of its frequency. Br J Psychiatry 1987; 151:200–205. 39. Snaith RP, Ahmed SN, Mehta S, Hamilton M. Assessment of the severity of primary depressive illness. Wakeﬁeld self-assessment depression inventory. Psychol Med 1971; 1(2):143–149. 40. Morris PLP, Robinson RG, Andrezejewski P, Samuels J, Price TR. Association of depression with 10-year post-stroke mortality. Am J Psychiatry 1993; 150:124–129. 41. Robinson RG, Schultz SK, Castillo C, Kopel T, Kosier T. Nortriptyline versus ﬂuoxetine in the treatment of depression and in short term recovery after stroke: a placebo controlled, doubleblind study. Am J Psychiatry 2000; 157:351–359. 42. Jorge RE, Robinson RG, Arndt S, Starkstein SE. Mortality and post-stroke depression: a placebo controlled trial of antidepressants. Am J Psychiatry 2003; 160:1823–1829. 43. Lipsey JR, Robinson RG, Pearlson GD, Rao K, Price TR. Nortriptyline treatment of poststroke depression: a double-blind study. Lancet 1984; i(8372):297–300. 44. Reding MJ, Orto LA, Winter SW, Fortuna IM, DiPonte P, McDowell FH. Antidepressant therapy after stroke: a double-blind trial. Arch Neurol 1986; 43:763–765. 45. Andersen G, Vestergaard K, Lauritzen L. Eﬀective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 1994; 25:1099–1104. 46. Starkstein SE, Cohen BS, Fedoroﬀ P, Parikh RM, Price TR, Robinson RG. Relationship between anxiety disorders and depressive disorders in patients with cerebrovascular injury. Arch Gen Psychiatry 1990; 47:785–789. 47. Astrom M. Generalized anxiety disorder in stroke patients: a 3-year longitudinal study. Stroke 1996; 27:270–275. 48. Shimoda K, Robinson RG. Eﬀect of anxiety disorder in impairment and recovery from stroke. J Neuropsychiatry Clin Neurosci 1998; 10:34–40. 49. Rickels K, Schweizer EE. Current pharmacotherapy of anxiety and panic. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987:1193– 1203. 50. Kimura M, Robinson RG. Treatment of poststroke generalized anxiety disorder: a double blind trial of nortriptyline. Am J Geriatr Psychiatry 2003; 11:320–327.

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51. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991; 3: 243–254. 52. Starkstein SE, Fedoroﬀ JP, Price TR, Leiguarda R, Robinson RG. Apathy following cerebrovascular lesions. Stroke 1993; 24:1625–1630. 53. Marin RS, Firinciogullari S, Biedrzicky RC. The sources of convergence between measures of apathy and depression. J Aﬀect Disord 1993; 28:117–124. 54. Bogousslavsky J, Regli F, Assal G. The syndrome of unilateral tubero-thalamic artery territory infarction. Stroke 1986; 17:434–441. 55. Andersson S, Krogstad J, Finset A. Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 1999; 29:447–456. 56. Helgason C, Wilbur A, Weiss A, Redmond KJ, Kinsbury NA. Acute pseudobulbar mutism due to discrete bilateral capsular infarction in the territory of the anterior choroidal artery. Brain 1988; 111:507–519. 57. Cummings J. Frontal-subcortical lesions and human behavior. Arch Neurol 1993; 50:873–880. 58. Marin RS, Fogel BS, Hawkins J, Duﬀy J, Krupp B. Apathy: A treatable syndrome. J Neuropsychiatry Clin Neurosci 1995; 7:23–30. 59. Goldstein K. The Organism: A Holistic Approach to Biology Derived from Pathological Data in Man. New York: American Books, 1939. 60. Starkstein SE, Fedoroﬀ JP, Price TR, Leiguarda R, Robinson RG. Catastrophic reaction after cerebrovascular lesions: frequency, correlates, and validation of a scale. J Neurol Neurosurg Psychiatry 1993; 5:189–194. 61. Benson DF. Aphasia, Alexia, and Agraphia. New York: Churchill Livingstone, 1979. 62. Andersen G. Treatment of uncontrolled crying after stroke. Drugs Aging 1995; 6:105–111. 63. Morris PLP, Robinson RG, Raphael B. Emotional lability following stroke. Aust NZ J Psychiatry 1993; 27:601–605. 64. Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughing and crying following stroke: validation of measurement scale and double-blind treatment study. Am J Psychiatry 1993; 150:286–293. 65. Andersen G, Vestergaard K, Riis J. Citalopram for post-stroke pathological crying. Lancet 1993; 342(8875):837–839. 66. Rabins PV, Starkstein SE, Robinson RG. Risk factors for developing a typical (schizophreniform) psychosis following stroke. J Neuropsychiatry Clin Neurosci 1991; 3:6–9. 67. Levin DN, Finkelstein S. Delayed psychosis after right temporoparietal stroke or trauma: relation to epilepsy. Neurology 1982; 32:267–273. 68. House A, Dennis M, Mogridge L, Warlow C, Hawton K, Jones L. Mood disorders in the year after ﬁrst stroke. Br J Psychiatry 1991; 158:83–92. 69. Burvill PW, Johnson GA, Jamrozik KD, Anderson CS, Stewart-Wynne EG, Chakera TMH. Prevalence of depression after stroke: the Perth Community Stroke Study. Br J Psychiatry 1995; 166:320–327. 70. Kotila M, Numminen H, Waltimo O, Kaste M. Depression after stroke. Results of the FINNSTROKE study. Stroke 1998; 29:368–372. 71. Robinson RG, Starr LB, Kubos KL, Price TR. A two year longitudinal study of post-stroke mood disorders: ﬁndings during the initial evaluation. Stroke 1983; 14:736–744. 72. Ebrahim S, Barer D, Nouri F. Aﬀective illness after stroke. Br J Psychiatry 1987; 151:52–56. 73. Fedoroﬀ JP, Starkstein SE, Parikh RM, Price TR, Robinson RG. Are depressive symptoms non-speciﬁc in patients with acute stroke? Am J Psychiatry 1991; 148:1172–1176. 74. Castillo CS, Schultz SK, Robinson RG. Clinical correlates of early-onset and late-onset poststroke generalized anxiety. Am J Psychiatry 1995; 152:1174–1179. 75. Starkstein SE, Fedoroﬀ JP, Price TR, Leiguarda R, Robinson RG. Anosognosia in patients with cerebrovascular lesions. A study of causative factors. Stroke 1992; 23:1446–1453. 76. Andersen G, Vestergaard K, Riis JO, Lauritzen L. Incidence of post-stroke depression during the ﬁrst year in a large unselected stroke population determined using a valid standardized rating scale. Acta Psychiatr Scand 1994; 90:190–195.

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77. Gainotti G, Azzoni A, Marra C. Frequency, phenomenology and anatomical-clinical correlates of major post-stroke depression. Br J Psychiatry 1999; 175:163–167. 78. Folstein MF, Maiberger R, McHugh PR. Mood disorder as a speciﬁc complication of stroke. J Neurol Neurosurg Psychiatry 1977; 40:1018–1020. 79. Finklestein S, Benowitz LI, Baldessarini RJ, Arana GW, Levine D, Woo E, Bear D, Moya K, Stoll AL. Mood, vegetative disturbance, and dexamethasone suppression test after stroke. Ann Neurol 1982; 12:463–468. 80. Finset A, Goﬀeng L, Landro NI, Haakonsen M. Depressed mood and intra-hemispheric location of lesion in right hemisphere stroke patients. Scand J Rehabil Med 1989; 21:1–6. 81. Schubert DSP, Taylor C, Lee S, Mentari A, Tamaklo W. Physical consequences of depression in the stroke patient. Gen Hosp Psychiatry 1992; 14:69–76. 82. Feibel JH, Springer CJ. Depression and failure to resume social activities after stroke. Arch Phys Med Rehabil 1982; 63:276–278. 83. Robinson RG, Price TR. Post-stroke depressive disorders: a follow-up study of 103 outpatients. Stroke 1982; 13:635–641. 84. Vataja R, Pohjasvaara T, Leppavuori A, Mantyla R, Aronen HJ, Salonen O, Kaste M, Erkinjuntti T. Magnetic resonance imaging correlates of depression after ischemic stroke. Arch Gen Psychiatry 2001; 58(10):925–931. 85. Collin SJ, Tinson D, Lincoln NB. Depression after stroke. Clin Rehabil 1987; 1:27–32. 86. Singh A, Black SE, Herrmann N, et al. Functional and neuroanatomic correlations in poststroke depression: the Sunnybrook Stroke Study. Stroke 2000; 31:637–644. 87. Paradiso S, Ohkubo T, Robinson RG. Vegetative and psychological symptoms associated with depressed mood over the ﬁrst two years after stroke. Int J Psychiatry Med 1997; 27:137–157. 88. Rocca WA, Hofman A, Brayne C, Breteler MM, Clarke M, Copeland JR, Dartigues JF, Engedal K, Hagnell O, Heeren TJ. The prevalence of vascular dementia in Europe: facts and fragments from 1980–1990 studies. Ann Neurol 1991; 30:817–824. 89. Katzman R, Lasker B, Bernstein N. Advances in the diagnosis of dementia: accuracy of diagnosis and consequences of misdiagnosis of disorders causing dementia. In: Terry RD, ed. Aging and the Brain. New York: Raven Press, 1988:17–62. 90. Robinson RG, Starkstein SE. Neuropsychiatric aspects of cerebrovascular disorders. In: Yudofsky SC, Hales RE, eds. Textbook of Neuropsychiatry. 3rd ed. Washington, D.C.: American Psychiatric Press, 1997:217–229. 91. Castillo CS, Starkstein SE, Fedoroﬀ JP, Price TR, Robinson RG. Generalized anxiety disorder following stroke. J Nerv Ment Dis 1993; 181:100–106. 92. Andersen G, Vestergaard K, Ingemann-Nielsen M, Lauritzen L. Risk factors for post-stroke depression. Acta Psychiatrica Scandinavica 1995; 92(3):193–198.

14 Evaluation and Treatment of Asymptomatic Carotid Artery Disease Patricia H. Davis University of Iowa, Iowa City, Iowa, U.S.A.

I. INTRODUCTION Carotid atherosclerosis is the underlying cause of approximately 10–20% of ischemic strokes [1]. In asymptomatic patients it is usually detected by the presence of a carotid bruit, in a preoperative work-up before general, cardiovascular, or peripheral vascular surgery, or during the investigations for symptomatic cerebrovascular disease in the contralateral carotid artery or the vertebrobasilar system. Patients with multiple cardiovascular risk factors, prior radiation therapy to the neck, symptomatic coronary artery disease (CAD), or peripheral vascular disease (PVD) have increased risk of carotid stenosis. While patients with carotid bruits or asymptomatic stenosis do have an increased risk of stroke, the stroke may not occur in the territory of the carotid artery with the stenosis, and these patients are also at high risk for subsequent cardiovascular events. Most strokes are not preceded by a warning transient ischemic attack (TIA) in these patients, so interventions to avert stroke are important. Novel methods to select asymptomatic patients who are at the highest risk of having a stroke are being developed including use of blood tests, carotid and transcranial ultrasound, and magnetic resonance imaging (MRI) of carotid plaque. In addition, there has been increased interest in identifying those at the highest risk of vascular disease at a younger age so that primary preventive measures can be instituted sooner. Increased intimal-medial thickness (IMT) of the carotid artery wall occurs earlier in the atherosclerotic process than carotid plaque or stenosis. Measurement of carotid IMT has been shown to provide incremental information to traditional cardiovascular risk factor assessment in predicting those at highest risk for myocardial infarction and stroke. It also has been used as a noninvasive method to assess the eﬀects of therapies directed at prevention of the progression of carotid artery atherosclerosis. Once asymptomatic carotid stenosis has been identiﬁed, the appropriate diagnostic work-up and management of disease remains controversial. Medical therapies to avert stroke include strict control of risk factors (blood pressure, cholesterol, obesity, smoking, and diabetes) including use of statins and antihypertensives, close monitoring for symptoms of CAD, and aspirin therapy. There is no clear consensus on the indications for carotid endarterectomy (CEA) in asymptomatic patients. The published guidelines vary from an endorsement in selected cases [2] to a recommendation that this surgery is not 283

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appropriate in asymptomatic patients [3]. Currently markers that will identify a group that would beneﬁt most from surgery among those with asymptomatic disease are being sought [4]. Surgery for asymptomatic disease is not beneﬁcial if the morbidity and mortality rate is greater than 3%, and complication rates associated with CEA have been shown to vary widely among medical centers and surgeons. Knowledge of the local complication rate is an important factor in the decision to proceed with CEA. With increasing experience and expertise in carotid artery angioplasty and stenting (CAS), this procedure may be a consideration for patients with asymptomatic carotid disease in the future, although no randomized trials comparing the outcomes of CEA and CAS are currently completed in asymptomatic patients. This chapter will address the issues outlined above to provide an approach to evaluating and managing patients with asymptomatic carotid disease.

II. EPIDEMIOLOGY OF ASYMPTOMATIC CAROTID DISEASE A. Carotid Bruits Auscultation of an asymptomatic carotid bruit is one of the ways to identify asymptomatic carotid disease. The prevalence of asymptomatic carotid bruits in a large community-based study was 4.4% in those over age 45 years. The prevalence increased with age from 2.3% at age 45–54 years to 8.2% in those over 75 years [5]. Other studies have conﬁrmed the increased risk of bruit with age [6–8], and incidence data from the Framingham Study suggest that the risk of developing a bruit in those 65 years or older is about 1% per year [6]. Carotid bruits may be due to causes other than internal carotid artery stenosis including venous hum, transmitted heart murmur, hyperdynamic states, or external carotid artery disease [9]. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the sensitivity of a carotid bruit for high-grade (70–99%) stenosis was 63% and speciﬁcity was 61% [10]. In another study, the positive predictive value of a carotid bruit for signiﬁcant carotid stenosis increased with age from 48% at<55 years to 75% in persons 55 and older [11]. Agreement among physicians about the presence of a bruit is generally high (n = 0.67) [12]. Several studies have evaluated the prognostic signiﬁcance of a carotid bruit. There is an increased risk of stroke, which ranges from 1–2% per year [12,13] but also an increased risk of cardiac events and death [12,14]. Risk of stroke is increased with severity of stenosis and progression of stenosis. In one study of patients with asymptomatic carotid bruits, the yearly rate of unheralded ischemic stroke was 4.2% in those with at least 80% stenosis and 1.4% in those with less than 80% stenosis ( p< 0.001). However, even in those with at least 80% stenosis, only 66% of TIAs or stroke were ipsilateral to the carotid stenosis [14]. Studies of elderly patients have not found carotid bruit to be a predictor of stroke. In a study of nursing home residents (mean age of 86 years), the presence of a carotid bruit did not predict subsequent stroke [15]. In a population of 4442 noninstitutionalized persons 60 years or older with isolated systolic hypertension, there was a trend toward increased risk of stroke in those 60–69 years of age with a relative risk (RR) of 2.05 (95% CI 0.92–4.68), but not among those older than 70 years (RR 0.98; 95% CI 0.55–1.76) [8]. Variable recommendations for the auscultation for neck bruits in asymptomatic subjects range from (1) against by the Canadian Task Force on Periodic Health Examination, to (2) a ‘‘C’’ grade recommendation by the U.S. Preventive Services Task Force, to (3) an endorsement in those over 40 years with cardiovascular risk factors by the American Academy of Family Physicians [8]. Once a bruit is detected, a carotid ultrasound should be performed to determine if there is signiﬁcant carotid stenosis.

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B. Asymptomatic Carotid Stenosis The prevalence of signiﬁcant carotid stenosis in asymptomatic older populations is low using data from population-based studies. In the 5,201 participants, all over age 65 years, in the Cardiovascular Health Study (CHS), the prevalence of carotid stenosis of z50% as measured by carotid ultrasound was 7% in men and 5% in women. However, only 2.3% of men and 1.1% of women had at least 75% stenosis [16]. The 5-year risk of ipsilateral fatal or nonfatal stroke was 5% in those with stenosis of at least 70% [17]. In the Framingham cohort, with ages ranging from 66 to 93 years, the prevalence of z50% carotid stenosis was 7% in women and 9% in men. Risk factors for carotid stenosis included age, smoking, systolic blood pressure, homocysteine level, and cholesterol [18,19]. Mineva et al. reviewed the literature concerning the prevalence of z50% carotid stenosis in older populations with results ranging from 4 to 8% and found that carotid stenosis was associated with smoking, CAD, and PVD [20]. In the CHS, carotid stenosis was strongly related to 5-year mortality with a 5-fold increased risk in those with 50–99% stenosis and an 11-fold risk in those with carotid occlusion [21]. Other studies looking at the prognosis associated with carotid stenosis have included patients referred to a vascular laboratory [13,22,23] those included in clinical trials of CEA for symptomatic disease on the contralateral side [24,25], those receiving medical therapy in trials of CEA for asymptomatic stenosis [26–28], and a group of patients referred with carotid occlusion [29]. Table 1 illustrates the risk of stroke in patients with asymptomatic carotid stenosis with a range from 0.7 to 3.3% per year. Although the risk of stroke is increased, the stroke was ipsilateral to the stenosis in only 75% of those with high-grade (>75%) stenosis in one series [22]. Using data from NASCET, Barnett et al. noted that in asymptomatic patients with 70–99% stenosis, 43.5% of strokes were cardioembolic or lacunar and may be unrelated to the carotid stenosis [30]. The percentage of patients with

Table 1 Risk of Stroke with Asymptomatic Carotid Stenosis

Study [Ref.]

n

Toronto [22]

696

Toronto [23] 10-year follow-up

106

Montreal [33]

715

Germany [13] CHS [17] ECST [25] Contralateral to symptomatic NASCET [24] Contralateral to symptomatic

339 5441 2295 1820

Degree of stenosis (%)

Risk of stroke (% per year)

Risk of cardiac event/mortality (% per year)

<75 >75 0–49 50–99 <50 z50 >50 >70 70–99 <70 Occluded 60–99 <60

1.3 3.3 0.57 0.93 1.3 2.2 1.2 1 1.9 0.7 1.9 3.2 1.9

8.3a 6.5b 1.1a 0.6a 1.1a 7b

4.2b 3.5b

ECST = European Carotid Surgery Trial; NASCET = North American Symptomatic Carotid Endarterectomy Trial. a Cardiac event. b Mortality.

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asymptomatic stenosis experiencing a warning TIA rather than an unheralded stroke varies from 25 to 78% [13,22,24]. Data from the Asymptomatic Carotid Atherosclerosis Study (ACAS) suggest that patients do not immediately report the onset of TIA symptoms with less than 40% of new events reported within 3 days [31]. In several studies, the risk of stroke increased with the degree of stenosis [14,32]. In addition, the frequency of silent cerebral infarcts seen on computed tomography (CT) scans increases with the degree of stenosis [33]. The presence of silent infarction on a CT scan may increase the risk of becoming symptomatic [24]. Progression of stenosis with serial ultrasounds predicted an increased risk of stroke in some studies but not others [22,34]. In two studies of serial carotid ultrasounds performed regularly in patients with asymptomatic stenosis over 3–4 years, 70% of patients remained stable, 15–20% progressed, and 10–15% regressed [28,34]. These studies concluded that serial carotid ultrasounds performed to monitor the progression of asymptomatic carotid disease were not cost-eﬀective [28,34]. Once the internal carotid artery occludes, if the patient remains asymptomatic the risk of stroke is very low. In a study of 30 patients with asymptomatic carotid occlusion, Powers et al. found that there was a low incidence of hemodynamic compromise and none suﬀered an ipsilateral stroke in a mean of 32 months of follow-up [29]. Similarly, results from NASCET demonstrated that stroke rates were low in those patients with asymptomatic occlusion (Table 1) [24]. Nadareishvili et al. looked at the long-term risk of ipsilateral stroke in patients with 50–99% stenosis, and this appears to remain stable over time with a 10-year risk of ipsilateral stroke of 9.3% (95% CI 1–18%) [23]. Carotid stenosis is also associated with an increased risk of cardiac events as well as overall mortality, which in some studies has exceeded the risk of stroke (Table 1). In patients enrolled in clinical trials of CEA for asymptomatic stenosis, the estimated 10-year risk of mortality due to CAD ranged from 19 to 51% so that in the Third Report of the National Cholesterol Education Program (NCEP III), carotid stenosis (>50%) was considered a CAD equivalent [35]. Several studies have examined the cost-eﬀectiveness of using carotid ultrasound to screen older populations for asymptomatic carotid stenosis. Whitty et al. predicted that in order to see a signiﬁcant beneﬁt from screening with carotid ultrasound, the prevalence of signiﬁcant stenosis (>50%) must be greater than 20%, and then it would only be beneﬁcial in centers with a high test sensitivity and speciﬁcity and low surgical risks [36]. In another decision analysis model, screening would only be feasible if the population had a 50% prevalence of >50% stenosis and the perioperative stroke or death rate was <2.5% [37]. The strategy that was eﬀective in this decision analysis was CEA for a stenosis of >70% on ultrasound. However, this strategy would only prevent 3–12% of the total number of strokes in the population screened [37]. At present, we cannot identify a population with a prevalence of carotid stenosis that is more than 20%. The Canadian Stroke Consortium published a consensus statement advising against routine screening for asymptomatic carotid stenosis even in patients with risk factors or PVD [3]. C. Carotid Intimal-Medial Thickness In older adults, measurement of carotid artery IMT using carotid B-mode ultrasound has gained acceptance as a noninvasive, inexpensive method to assess the extent of atherosclerosis. Carotid IMT can be measured in the near and far wall of the common carotid, bifurcation and internal carotid to produce a composite measure over 12 sites (Fig. 1). In some studies, carotid IMT is measured only in the far wall of the common carotid artery, as this is the site which is easiest to image. Several pieces of evidence support the validity of

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Figure 1 B-mode ultrasound is used to measure the intimal medial thickness of the near and far wall (arrows) of the common carotid artery (CCA), bifurcation (BIF), and internal carotid artery (ICA) to produce a composite measure of IMT at 12 sites (6 measurements on each side). The small arrows demonstrate the borders used to measure intimal medial thickness.

using carotid IMT as a marker of atherosclerosis. Measurements of carotid IMT with ultrasonography in vivo correlate well with pathological measurements [38] and are reproducible [39]. Increased carotid IMT and the rate of change of carotid IMT over time are signiﬁcantly related to known cardiovascular risk factors in population-based epidemiological studies including elevated low-density lipoprotein (LDL) cholesterol, decreased high-density lipoprotein (HDL) cholesterol, systolic blood pressure, plasma homocysteine, smoking, and body mass index (BMI) [40–42]. Diabetes, smoking, and a history of hypertension cause an IMT increase of 5–12% in comparison to control subjects [43]. In a study of young and middle-aged adults, the strongest predictor of carotid IMT was LDL cholesterol, and childhood cholesterol levels measured as early as age 11 years predicted adult IMT [40]. In older adults, carotid IMT is positively associated with incident myocardial infarction [44–47] and stroke [46,48], and this association persists after adjustment for known cardiovascular risk factors. In a case-control study, Touboul et al. found that odds ratio per standard deviation of increase in common carotid IMT was 1.73 (95% CI 1.45–2.07) for brain infarction after adjustment for cardiovascular risk factors [49]. Increased carotid IMT has also been shown to correlate with the presence of coronary artery calciﬁcation, another marker of the atherosclerotic process [50,51]. Similarly, increased carotid IMT is related to a decreased ankle-arm index (AAI), a marker of PVD [52,53]. Progression of carotid IMT using serial measurements has been used as an endpoint in clinical trials of therapies to slow the atherosclerotic process. The average progression rate is 0.02–0.05 mm/y [54]. Regression or slowing of progression of carotid IMT has been demonstrated in clinical trials of statins [55–57] and other lipidlowering therapies [58], angiotensin-converting enzyme (ACE) inhibitors [59], metoprolol [60], and troglitazone (insulin sensitizer), with variable results for calcium channel blockers [54,61]. The Writing Group II of the American Heart Association Prevention Conference V concluded that measurement of carotid IMT in asymptomatic persons over 45 years of

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age adds additional information to traditional risk factor assessment [62]. However, it is important that this diagnostic test be performed in an experienced laboratory with good reproducibility [63]. The NCEP III recommends that if performed under proper conditions, carotid IMT be used to identify patients at higher risk of vascular disease than revealed by risk factors alone for the purpose of increasing the intensity of LDL-lowering therapy [35]. While measurement of carotid IMT is still primarily used as a research tool, translation into clinical practice is beginning to take place.

III. PATIENTS AT HIGH-RISK FOR ASYMPTOMATIC STENOSIS A. Patients Undergoing Coronary Artery Bypass Grafting The risk of stroke in patients undergoing coronary artery bypass grafting (CABG) ranges from 1 to 5%, making it the most common cause of iatrogenic stroke in the United States [64]. Carotid bruit and asymptomatic carotid stenosis have been identiﬁed in some studies as a risk factor for stroke after CABG [64,65], but not in others [66,67]. In one recent systematic review of the literature, the risk of stroke was<2% without carotid disease, 3% with 50–99% unilateral asymptomatic carotid stenosis, 5% with bilateral stenoses, and 7– 11% with carotid occlusion. However, 60% of the strokes could not be attributed to the presence of carotid disease [65]. Increasing attention has been paid to aortic atherosclerosis as a risk factor for stroke following CABG [67,68]. The prevalence of aortic atherosclerosis increases with age and is correlated with the presence of a carotid bruit [65]. Patients with combined carotid and aortic arch atherosclerosis had a perioperative risk of stroke of 14% in one series [68]. Controversy exists concerning the need for asymptomatic patients with carotid stenosis of at least 60% stenosis to undergo combined or staged CABG and CEA. The American Heart Association (AHA) guidelines recommended as an acceptable indication (Grade C) unilateral CEA for asymptomatic stenosis >60% with simultaneous CABG if surgical risk is<3%. However, once surgical risk exceeded 3%, the indication for CEA combined with CABG became uncertain [2]. Patients who undergo combined CABG and CEA have high complication rates, which exceed the recommended cutoﬀ of 3%. In one series of Medicare patients, the stroke and death rate for the combined procedures was 17.7% [69]. It remains to be determined whether the risk of stroke in patients with asymptomatic carotid disease can be reduced by pre-operative CAS or by performing CABG without cardiopulmonary bypass. B. Patients Undergoing Noncardiac Surgery The risk of stroke in patients undergoing general surgery with an asymptomatic bruit has been estimated to be less than 1% [70]. Evans and Wijdicks [71] found the risk of stroke in patients undergoing general surgery with at least 50% carotid stenosis to be 3.6%. They were unable to identify any risk factors that identiﬁed those at the highest risk, including degree of stenosis. Prophylactic CEA does not appear to be indicated in these patients. C. Patients with Peripheral Vascular Disease Patients with peripheral vascular disease have an increased prevalence of asymptomatic carotid disease. In studies of patients referred for evaluation of PVD, the prevalence of carotid stenosis (>50%) was 25–33% with high-grade (>70%) stenosis in 9–13.5% [72–75]. Factors associated with increased probability of ﬁnding signiﬁcant carotid stenosis

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included presence of a bruit, age, diabetes, and AAI< 0.4 [73,75]. In a Swedish male cohort followed for 10 years, PVD (identiﬁed by an abnormal AAI) was a stronger predictor of subsequent stroke than carotid stenosis identiﬁed by carotid ultrasound [76]. There is no consensus about performing screening carotid ultrasound studies in this population [3,73], but it may be considered if multiple risk factors are present as the prevalence of asymptomatic stenosis may approach the level where screening is cost-eﬀective. D. Patients with Prior Radiation Therapy to the Neck Patients receiving high-dose external radiotherapy to the head and neck are at increased risk of stroke, with a 5-year actuarial risk estimated at 12% [77]. These patients have accelerated carotid atherosclerosis [78]. In a small study of patients who had received radiation a mean of 6.5 years previously, the prevalence of 70–99% carotid stenosis was 21.7% [78]. It has been suggested that these patients undergo yearly carotid ultrasound screening [78], but further studies are needed to support this recommendation.

IV. NOVEL METHODS TO IDENTIFY HIGH-RISK PATIENTS WITH ASYMPTOMATIC CAROTID STENOSIS A. Hematological Markers Several studies have looked for markers using blood tests to identify those with asymptomatic stenosis who are at risk for future cerebrovascular events. Measurement of highsensitivity C-reactive protein (hs-CRP) is an inexpensive blood test, which has been shown in many large epidemiological studies of healthy men and women to be a strong predictor of subsequent stroke, myocardial infarction, and PVD. Measurement of hs-CRP added information beyond that obtained by measuring standard risk factors alone including lipids [79]. In a small cross-sectional study, hs-CRP was elevated in those with symptomatic compared to asymptomatic carotid disease [80]. A prospective study is needed to conﬁrm this observation. Another marker, elevated levels of prothrombin fragment 1.2, which indicates activation of the coagulation system, was predictive of time to subsequent cerebral or cardiovascular ischemic event in asymptomatic individuals with carotid bruits [81]. B. Transcranial Ultrasonography In the setting of high-grade asymptomatic carotid stenosis, stroke mechanisms include artery-to-artery embolization and hemodynamic compromise with insuﬃcient collateral blood supply. Transcranial Doppler ultrasonography (TCD) has been used to study both of these mechanisms in an attempt to select those at highest risk of becoming symptomatic. Molloy and Markus [82] recorded the number of embolic signals (ES) per hour in the ipsilateral middle cerebral arteries in patients with >60% asymptomatic carotid stenosis. The presence of ES was an independent predictor ( p = 0.01) of subsequent TIA or stroke during follow-up. Other studies have used TCD to assess whether the ipsilateral middle cerebral artery distal to an asymptomatic carotid stenosis will dilate in response to hypercapnia. Lack of response to this stimulus demonstrates the presence of hemodynamic compromise as the vessel is already maximally dilated with no reserve. Silvestrini et al. used breath-holding to induce hypercapnia, and those patients who had impaired cerebral vasoreactivity ipsilateral to a 70–99% carotid stenosis had a 13.9% annual ipsilateral

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ischemic event risk compared to 4.1% in those with normal reactivity [83]. In another study using 8% inhaled carbon dioxide to induce vasodilatation, exhausted cerebral reactivity also signiﬁcantly predicted ipsilateral ischemic stroke [84], but both of these studies were based on small numbers of events and need to be conﬁrmed before TCD can be recommended as tool to identify high-risk patients. C. Plaque Characteristics Carotid ultrasound studies have been used to classify the characteristics of carotid plaque which are associated with symptomatic disease. Hypoechoic tissues in the plaque correlate with areas of necrosis or plaque hemorrhage [62]. Hypoechoic plaques and heterogeneous plaques are associated with an increased probability of having symptoms in cross-sectional studies [85]. Other studies have found that echolucent plaque morphology is predictive of stroke in patients with symptomatic but not asymptomatic carotid stenosis [86]. In the Atherosclerotic Risk in Communities Study, acoustic shadowing, a marker of calciﬁcation of the carotid artery, found on the ultrasound examination was predictive of subsequent stroke in women but not men [87]. In the future, use of 3-D carotid ultrasound may allow reﬁnement of techniques to characterize plaque. MRI can also be used to evaluate the components of carotid plaques and the results of MRI in vivo correlate well with the pathological ﬁndings in carotid endarterectomy specimens [88]. MRI characteristics may also predict stability of carotid plaque. In one cross-sectional study, the presence of ﬁbrous cap rupture on MRI was highly associated with a recent history of symptoms [89]. This requires conﬁrmation in a prospective study of asymptomatic subjects with carotid stenosis.

V. EVALUATION OF ASYMPTOMATIC CAROTID DISEASE A. Assessment of Risk Factors and Other Atherosclerotic Disease A careful assessment of risk factors should be performed in all patients with asymptomatic carotid stenosis, including a history of hypertension, diabetes, smoking, elevated lipids, and sedentary lifestyle. Patients should be questioned concerning symptoms suggestive of cardiac disease and PVD. General physical examination should include measurement of blood pressure, body mass index, auscultation for bruits, a cardiac examination, and an evaluation to look for evidence of PVD and abdominal aortic aneurysm. Neurological examination should include funduscopy to look for asymptomatic retinal cholesterol emboli, which may increase the risk of developing stroke [90]. Laboratory testing should include a fasting lipid proﬁle, fasting blood sugar, EKG, and AAI if peripheral vascular disease is suspected. In selected cases, measurement of hs-CRP and plasma homocysteine might be useful. B. Noninvasive Methods to Assess Carotid Stenosis Several noninvasive methods have been developed to assess carotid stenosis. Carotid Duplex, a combination of B-mode ultrasound and Doppler (Fig. 2), is the least expensive, but it is less reproducible than digital subtraction angiography [91]. Moneta et al. [92] determined the criteria that oﬀered maximal accuracy in identifying at least 60% stenosis using carotid Duplex. A peak systolic velocity of greater than 290 cm/s and end diastolic velocity of z80 cm/s gave a positive predictive value of 95%. These values may need to be individualized for each laboratory, and there is great variation in the quality of vascular

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Figure 2 Carotid ultrasound showing B-mode (above) and Doppler images. B-mode shows a large protruding plaque, and Doppler indicates about 60% stenosis.

laboratories [93]. Other noninvasive modalities include noncontrast MRA (Fig. 3) [94], contrast-enhanced MRA [95], and CT angiography (CTA) [91,96]. MRA tends to overestimate the degree of stenosis, while CTA underestimates it when compared to conventional angiography [91,96]. All of these modalities have similar sensitivity and speciﬁcity but when used alone are associated with a signiﬁcant error rate [91,94–96]. In one study, if carotid Duplex was used alone, there was a 28.1% misclassiﬁcation rate, while for noncontrast MRA alone, the error rate was 18.2%, but if both were concordant, the error rate was 7.9% [97]. In another study, carotid ultrasound had a sensitivity of 88% and a speciﬁcity of 76% for identifying a 70–99% stenosis, while the results for MRA were 92% and 76%, respectively. When both were combined, the sensitivity rose to 96% and the speciﬁcity to 80% [94]. Similar results have been found for contrast-enhanced MRA, which has the advantage of a more rapid acquisition time [95]. Carotid ultrasound and MRA rarely misclassify total occlusion as high-grade stenosis [95]. It is clear that the use of two imaging modalities will reduce the misclassiﬁcation rate [94–96], and the AHA guidelines suggest screening with carotid ultrasound with conﬁrmation by MRA and use of conventional angiography only if the results are discordant [98]. CT angiography may be useful for those patients who cannot undergo MRA. Some authors would still advocate the use of conventional angiography in all patients, but in ACAS, half the morbidity in the surgical group was due to angiography [26]. C. Evaluation of Concurrent Cardiac Disease In a clinical trial of CEA for asymptomatic carotid stenosis in male veterans, patients with no history of CAD had a similar risk of cardiac events as those with CAD if they had coexistent intracranial occlusive disease, diabetes, or PVD. The ﬁrst cardiac event was

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Figure 3 Magnetic resonance angiography showing large ulcerated plaque (left), which was conﬁrmed on conventional angiography (right).

myocardial infarction or sudden death in 56% of these patients [99]. However, data from NASCET suggests that the risk of unheralded severe cardiac events was low (3.3%) in patients with symptomatic carotid stenosis. Only those patients with multiple cardiovascular risk factors had a substantially increased risk of coronary events, and routine cardiac investigations were not recommended [100]. Careful monitoring for cardiac symptoms and management of risk factors seems appropriate for patients with asymptomatic stenosis without symptomatic CAD.

VI. THERAPY FOR ASYMPTOMATIC CAROTID DISEASE A. Medical Therapy 1. Lifestyle Modiﬁcation Careful attention needs to be paid to controlling risk factors in these patients. In the placebo group of a trial of lipid-lowering therapy, reduction of BMI by 5 kg/m2, quitting a 10 cigarette/day smoking habit, and reducing dietary intake of cholesterol by 100 mg/day signiﬁcantly reduced the progression of carotid IMT by 0.13 mm/y [101]. 2. Statin Therapy The NCEP III guidelines consider >50% carotid stenosis to be a CAD equivalent and the recommendation is for a target LDL cholesterol of <100 mg/dL with initiation of drug therapy at 130 mg/dL [35]. For those with LDL cholesterol between 100 and 129 mg/dL, therapeutic lifestyle changes are recommended, with drug therapy initiated if there is no improvement in the lipid proﬁle after 3 months. In addition to the eﬀects on cholesterol, statins have been shown to reduce the progression of carotid IMT [55] and may have a

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stabilizing eﬀect on carotid plaque. In a randomized trial of patients undergoing bilateral CEA, patients received either placebo or atorvastatin in between surgical procedures. Histological analysis of the carotid endarterectomy specimens showed less evidence of inﬂammatory markers and less thrombogenecity (as measured by the levels of hemostatic markers) in the plaques of those receiving atorvastatin compared to placebo [102]. 3. Blood Pressure Control Blood pressure control should be closely monitored with a target of 140/90 mmHg except in those with diabetes where the target is 130/85 mmHg [1]. ACE inhibitors [59] and betablockers [60] might be the most appropriate choices for antihypertensive therapy, as they have been demonstrated in clinical trials to prevent progression of carotid IMT. In the SECURE trial, there was a reduction in progression of carotid IMT with ramipril as well as a signiﬁcant reduction in the risk of stroke during follow-up [59]. The beneﬁcial eﬀect of the ACE inhibitor in preventing stroke could not be explained by blood pressure reduction alone, and other postulated eﬀects include increase in endothelial bradykinin, enkephalin, prostacyclin, and nitric oxide, which might act to stabilize plaque. Trials of a calcium channel blockers demonstrated more variable results in preventing progression of carotid IMT [54,61,103]. 4. Aspirin There is only one small controlled trial of aspirin in patients with asymptomatic carotid stenosis of at least 50%. The trial did not show any reduction in annual rate of vascular events, but patients with CAD were excluded [104]. One trial of CEA for asymptomatic carotid stenosis was terminated early because of the high risk of coronary events in the surgical group who were not treated with aspirin [105]. Since patients with asymptomatic carotid disease are at high risk for subsequent cardiovascular events, use of aspirin seems prudent.

B. Surgical Therapy 1. Carotid Endarterectomy The recommendation concerning CEA for a patient with asymptomatic carotid stenosis is aﬀected by carefully weighting the beneﬁt for the patient of the surgery compared to the risk of morbidity and mortality as a result of the CEA. The results from clinical trials of CEA will be discussed under these two headings. a. Beneﬁt of CEA. There are ﬁve trials comparing best medical therapy to CEA in asymptomatic patients [26,27,105–107]. The ﬁrst randomized trial included only 29 patients and was too small to produce any conclusions [108]. A second trial in France (L’AURC) was completed in 1989 but never published. It was included in one metaanalysis of CEA for asymptomatic stenosis [109] but not a second one because of a lack of available details [107]. In the third trial, patients with high-grade stenosis (>90%) were excluded, and 44% of those in the medical group, subsequently crossed over and underwent CEA. There was no diﬀerence in outcome in the two groups, but the design has been strongly criticized [108]. The fourth trial was terminated after 71 patients were enrolled because of an excessive rate of myocardial infarction and TIA in the surgical group who were not treated with antiplatelet therapy [105]. In the next trial published, which included 444 male veterans with at least 50% stenosis measured by conventional

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angiography, there was a signiﬁcant reduction in ipsilateral cerebrovascular event rate (TIA, stroke, or stroke death) of 8.0 vs. 20.6% ( p < 0.001) but not a signiﬁcant reduction in ipsilateral stroke rate or in any stroke or death rates [106]. This led reviewers to comment that surgery was inappropriate if it was only eﬀective in preventing TIAs. The ﬁnal trial, ACAS, was terminated prematurely because statistical signiﬁcance was achieved after an average of 2.7 years of follow-up. There were 1662 patients enrolled who had at least 60% carotid stenosis on carotid ultrasound or angiography. The results were extrapolated to estimate the 5-year event rate. This showed a signiﬁcant reduction in ipsilateral stroke or perioperative stroke or death rates from 11% for the medical group to 5.1% for the surgical group ( p = 0.004). There was not a statistically signiﬁcant reduction in any major ipsilateral stroke or death or in any stroke or death rates [26]. There has been much controversy about the clinical signiﬁcance of these results. Estimates of number needed to treat to prevent one stroke have ranged from 48 to 83 at 2 years [110] to 19 at 5 years [26]. While the study did not have suﬃcient power to look at subgroups, there were several interesting observations. First, the beneﬁt of surgery was not seen in women who had an absolute risk reduction of 1.4% vs. 8.0% for men. Second, there was no diﬀerence in beneﬁt according to the degree of stenosis, although there were small numbers of patients with 90–99% stenosis. Finally, in a post hoc analysis, the subgroup of patients with asymptomatic stenosis on one side and contralateral occlusion had an absolute increase in risk of stroke with surgery of 2.0% (95% CI, 9.3% to 5.2%) because of low long-term risk for medically managed patients [111]. Table 2 illustrates the results from the two largest randomized trials of CEA in asymptomatic patients as well as the results of two systematic reviews of all these trials [107,109]. The absolute risk reduction is small compared to the results for symptomatic carotid stenosis. In NASCET, the absolute risk reduction at 2 years of CEA for 70–99% carotid stenosis was 12.8% with a number needed to treat of 8 [110]. A second rationale for performing CEA in asymptomatic patients is to prevent cognitive impairment due to embolic events, which may be silent. In ACAS, there was no diﬀerence in the Mini Mental Status Examination (MMSE) at follow-up between the surgical and medical groups. However, impaired MMSE did predict higher mortality [112]. Another trial, the Asymptomatic Carotid Surgery Trial (ACST) randomized 1850 patients who did not have ipsilateral symptoms for 6 months and had a degree of stenosis felt to be suitable for CEA. The 5-year follow-up is continuing, and hopefully this will allow analysis to identify a high-risk subgroup [28]. b. Risk of CEA in Asymptomatic Patients. The risk of perioperative morbidity and mortality following CEA is less for patients with asymptomatic than symptomatic disease, but there is a great deal of variation among diﬀerent centers (Table 3). The complication

Table 2 Rate of Perioperative Stroke or Death or Ipsilateral Stroke in Trials of Carotid Endarterectomy versus Medical Therapy for Asymptomatic Carotid Stenosis Study [Ref.] VA [107] ACAS [107] Cochrane Systematic Review [107] Meta-analysis [109]

Medical (%)

Surgical (%)

NNT over time

RR (95% CI)

10.3 6.2 6.8

8.1 4.0 4.9

45 over 4 years 45 over 2.7 years 53 over 3 years

0.77 (0.40–1.46) 0.63 (0.41–0.98) 0.73 (0.52–1.02)

6.4

4.4

50 over 3 years

0.62 (0.44–0.86)

NNT = number needed to treat; VA = Veterans Aﬀairs; ACAS = Asymptomatic Carotid Atherosclerosis Study.

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Table 3 Risk of Perioperative Stroke or Death in Patients Undergoing Endarterectomy for Asymptomatic Stenosis Study [Ref.] VA trial [106] CASANOVA [27] ACE trial [136] ACAS [26] Systematic review [137] Edmonton, Canada [116] Academic medical centers [115] Multistate Medicare Data [138] Ohio Medicare [114] Georgia Medicare [139] Oklahoma Medicare [140] Toronto, Canada [141]

Perioperative stroke or death (%) 4.7 3.0 4.6 2.3 (M 1.7; F 3.6) 3.35 2.5 (1999/2000) 4.2 (1994–2000) 2.8 (M 1.6; F 5.3) 3.7 (range 2.3–6.7) 2.4 3.0 3.7 4.0

Mortality rate (%) 1.9 1.2 0.4 1.31

1.1 1.1

n 211 334 1512 825 2421 222 946 463 3891 167 1002 350 350

VA=Veterans Aﬀairs; CASANOVA=Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin; ACE= Aspirin and Carotid Endarterectomy study; ACAS=Asymptomatic Carotid Atherosclerosis Study.

rate was notably low in ACAS. The AHA guidelines recommend CEA in patients with asymptomatic stenosis only if perioperative morbidity and mortality is less than 3% [2], and some centers clearly will not meet this requirement. Because the margin between risk and beneﬁt is so small, monitoring of the complication rate locally is important for the referring neurologist. This information may be diﬃcult to determine, particularly if the surgeon has a low volume of cases. Factors that inﬂuence the complication rate include number of procedures per year [113,114], age of the patient, gender (higher risk in women), and the presence of heart failure [115]. In ACAS, surgeons had to perform at least 12 CEAs per year and have a perioperative morbidity and mortality rate of<3% in their last 50 cases. Feasby et al. recently suggested that regional centers of excellence should be set up so that surgeons doing this procedure maintain a suﬃcient volume to maintain their expertise [113]. A Canadian study demonstrated that regular audits of CEA with feedback to the surgeons can reduce the complication rate over time [116]. c. Recommendations. The results of these clinical trials have sparked a great deal of controversy regarding the role of CEA in patients with asymptomatic carotid stenosis [3,108,117–126]. Guidelines vary greatly because of the small risk-to-beneﬁt margin. The AHA Stroke Council endorses CEA for asymptomatic patients with at least 60% internal carotid artery stenosis and a surgical risk of less than 3% as well as a life expectancy of at least 5 years [2]. Guidelines from the Canadian Neurosurgical Society consider asymptomatic carotid stenosis of greater than 60% as an uncertain indication for CEA [127], while the Canadian Stroke Consortium States that there is insuﬃcient evidence to recommend CEA for asymptomatic patients [3]. Guidelines from the European Stroke Initiative do not generally recommend CEA but agree that it may be reasonable in individual cases, and those from South Africa recommend CEA for asymptomatic stenosis of >80% with<4% surgical morbidity and mortality [127]. The economic impact of performing CEA for asymptomatic stenosis may be considerable. After the publication of

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ACAS, there was a 63% increase in the number of CEAs done per year in the state of Florida at an estimated cost of $56 million dollars per year [128]. Since the entry criteria for ACAS excluded those over 79 years of age, some have suggested that age should be a criteria for patient selection for CEA [1]. In a decision analysis model, Sarasin et al. demonstrated that if the predicted stroke incidence is 3% per year in asymptomatic patients, the maximum tolerable surgical morbidity and mortality that produces a beneﬁcial 5-year outcome dropped from 5% at age 55 years to 2% for those 85 years of age [129]. Life expectancy may be a better variable to consider in judging whether to take the increased immediate risk of surgery to decrease the long-term future risk of stroke [107]. Until we have suﬃcient data to identify those patients who are most likely to beneﬁt from CEA, decisions have to be made on an individual basis. Factors such as the predicted survival of the patient, comorbidities, including cardiac and pulmonary disease, that increase surgical risk, patient preference concerning risk-taking that is front-loaded, compliance with risk factor modiﬁcation, and local surgical complication rates should be taken into account. Hopefully, in the future more data will allow delineation of those groups who will beneﬁt the most and have the lowest risk. 2. Angioplasty and Stenting Carotid angioplasty and stenting has been available for approximately one decade, and with growing experience and the use of distal protection devices to prevent embolization, procedural morbidity and mortality has declined. In a large global registry, the 1361 asymptomatic patients had a 30-day minor or major stroke- or procedure-related death rate of 3.38%. Operators who performed more than 50 procedures had a signiﬁcantly lower complication rate than those who performed fewer [130]. Long-term follow-up has demonstrated a low rate of restenosis and recurrent stroke, which is similar to CEA [131]. Preliminary results from a single randomized trial, which included asymptomatic patients, of CAS with a neuroprotective device compared to CEA (SAPPHIRE Study) are available. There were 307 patients randomized (202 asymptomatic patients with >80% stenosis and 87 symptomatic patients with at least 50% stenosis), and all patients had at least one high-risk comorbidity (congestive heart failure, severe chronic obstructive pulmonary disease, severe coronary artery disease, radical neck surgery, or radiation therapy). At 30 days the risk of death, stroke, or MI was 5.8% with CAS and 12.6% with CEA ( p < 0.05). The results of follow-up at one year are pending [132]. However, the need for carotid revascularization in high-risk patients with asymptomatic stenosis has not been proven, and medical therapy may be a better option [133]. The AHA guidelines support the use of CAS only in the setting of a clinical trial [134], although this is a source of controversy [133,135].

VII. CONCLUSIONS Asymptomatic carotid stenosis does confer a small increased risk of stroke estimated at 3% per year overall and 2% per year for an ipsilateral event. It is also a marker of generalized atherosclerosis and identiﬁes patients at high risk for cardiovascular events. Screening of older populations with carotid ultrasound is not cost-eﬀective and may result in an increased number of strokes due to complications from angiography and surgery. A group with a prevalence of at least 20% of signiﬁcant (>50%) carotid stenosis would be

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needed to justify screening. Such a group has not been identiﬁed, although patients with prior neck radiation or with PVD and multiple risk factors may approach these levels. For detection of an earlier stage of the atherosclerotic process, measurement of carotid IMT has become an accepted noninvasive method, which may allow better targeting of patients for aggressive risk factor control at a younger age. Patients with asymptomatic carotid stenosis warrant intense risk factor reduction eﬀorts, including cessation of smoking, tight control of blood pressure, preferably with ACE inhibitors or beta-blockers, maintenance of an LDL cholesterol of<100 mg/dL using statin therapy or dietary modiﬁcation (if LDL cholesterol is<130 mg/dL), weight loss, if appropriate, and use of prophylactic aspirin to reduce their risk of coronary events. While more than 140,000 CEA were performed in 1997 in the United States and about half of these were for asymptomatic carotid stenosis [24], consensus among neurologists about appropriate indications has not been reached. Important considerations include comorbid conditions, life expectancy, patient preference, and local perioperative complication rates. Prophylactic CEA cannot be recommended in asymptomatic patients prior to general surgery, peripheral vascular surgery, or CABG. While morbidity and mortality due to CAS is declining with increased experience, improved stents, and the use of neuroprotective devices, its use in asymptomatic patients should be conﬁned at present to patients enrolled in clinical trials. In making the decision whether to treat asymptomatic patients surgically, there is agreement that identifying factors that confer a high risk for stroke would be useful. Factors that have been suggested for stratiﬁcation of risk include age, gender, degree of stenosis, progression of stenosis, presence of a silent infarct on the CT scan, presence of contralateral occlusion, and number of cardiovascular risk factors, but these are unproven. Other potential factors currently being investigated included measurement of hs-CRP or hemostatic factors, detection of unstable plaque using carotid ultrasound or MRI scanning, and use of TCD to detect hemodynamic compromise in the territory of the stenotic carotid artery and number of microemboli in the ipsilateral middle cerebral artery. Completion of the European trial of CEA in asymptomatic patients (ACST) [28] will increase the number of patients enrolled in clinical trials of CEA and allow subgroup analyses to identify a high-risk group that might most beneﬁt from surgical intervention.

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15 Antithrombotic Therapies for Prevention of Ischemic Stroke Harold P. Adams, Jr. University of Iowa Carver College of Medicine, Iowa City, Iowa, U.S.A.

I. INTRODUCTION Prevention is the most cost-eﬀective strategy for treatment of patients with ischemic cerebrovascular disease. Besides avoiding human suﬀering and disability that accompany stroke, eﬀective preventive therapies also reduce the costs of acute hospitalization, rehabilitation, and long-term care. Thus, while some of the individual medical therapies are relatively expensive, their costs are less than those that accompany stroke care. Identiﬁcation and treatment of risk factors associated with accelerated atherosclerosis are fundamental for prevention of stroke. Public health organizations devote considerable eﬀort to public education and awareness of leading controllable risk factors such as hypertension, diabetes mellitus, smoking, and hypercholesterolemia. Interventions of proven utility are available. For example, the risk of stroke drops dramatically within 2–5 years of stopping smoking [1]. In addition, there is increasing evidence that speciﬁc cholesterol-lowering medications and antihypertensive agents are useful in forestalling stroke or recurrent stroke [2–13]. These agents, which may slow progression of an atherosclerotic plaque or protect the endothelium, can be prescribed in conjunction with antithrombotic medications. Agents that aﬀect insulin resistance and secondarily reduce blood pressure and increase high-density lipoprotein (HDL) cholesterol levels might be helpful in preventing stroke in nondiabetic patients who have accelerated atherosclerosis [14–17]. Although the impact of these eﬀorts to help individual patients might appear to be limited, measures to control these widely prevalent conditions can have a dramatic eﬀect on a national or worldwide basis. In addition, the eﬀects of these agents in reducing the likelihood of stroke among high-risk persons are as great as antithrombotic medications. For example, the reduction of stroke among persons receiving the new angiotensinconverting enzyme (ACE) inhibitors is considerable [8–12]. These measures can be supplemented by medical and surgical therapies for treatment of persons judged to be at highest risk for stroke. The conditions listed in Table 1 are arranged in an escalating order of risk, with those individuals already having had a stroke at much greater risk than persons with an asymptomatic carotid bruit detected or those who have atrial ﬁbrillation without neurological symptoms. Table 1 does not include another important variable in predicting the 305

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Table 1 Persons at Highest Risk for Ischemic Stroke Symptomatic atherosclerosis in other parts of the body Myocardial infarction Claudication Asymptomatic carotid bruit Atrial ﬁbrillation not accompanied by neurological symptoms Amaurosis fugax Transient ischemic attack Ischemic stroke

chances of stroke—the interval from the most recent neurological symptoms. There is evidence that the ﬁrst few days and weeks after the event are the period of highest risk. In one recent study, the risk of a stroke was approximately 10% within 90 days of a transient ischemic attack (TIA), but one-half of that risk was concentrated in the ﬁrst 48 hours [18]. Thus, there is a sense of urgency in starting treatment. Patients should be evaluated and the most likely cause of the ischemic symptoms determined promptly so that decisions about long-term medical therapy can be made quickly. In addition, patients should be assessed for potential surgical or endovascular therapy. If these interventions are prescribed, these procedures should be considered as adjuncts to the medical measures. In addition, management of these high-risk patients must include measures to lower the risk of myocardial infarction or cardiac death [19]. In the long term, patients with ischemic neurological symptoms are more likely to die from cardiac disease than from recurrent stroke. Prescription of medications to prevent thromboembolism is the cornerstone of management to prevent stroke among high-risk patients. While these agents may not treat the underlying vascular or cardiac pathology, they are instrumental in lessening the likelihood of a secondary thromboembolism. As a result, the probability of arterial occlusion or embolization of a piece of a clot is lessened. The antithrombotic medications are categorized into two large groupings: anticoagulants and antiplatelet agents (Table 2). The pharmacological actions of the former medications are primarily on individual clotting proteins (factors). The antiplatelet agents primarily aﬀect the ability of platelets to aggregate in response to humoral or cellular stimuli. There may be additional eﬀects of

Table 2 Anticoagulant and Antiplatelet Agents Anticoagulants Heparin Low-molecular weight (LMW) heparins and danaparoid Thrombin inhibitors Warfarin Antiplatelet agents Aspirin Dipyridamole Ticlopidine Clopidogrel Glycoprotein IIb/IIIa receptor blockers

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these medications, which are important in preventing stroke and which are independent of their actions on coagulation. For example, heparin might have anti-inﬂammatory activity that might be critical in an acute ischemic situation, and aspirin is known to be a potent anti-inﬂammatory medication, and some of its eﬃcacy in preventing ischemia might be on this basis [20–22].

II. HEPARIN AND LOW-MOLECULAR WEIGHT HEPARINS OR HEPARINOID Heparin, a glycosaminoglycan derived from biological sources, is used to treat patients at risk for arterial or venous thromboembolism [23]. The routes of administration are subcutaneous or intravenous injections, and adequate levels of anticoagulation [as determined by prolongation of the activated partial thromboplastin time (aPTT)] can be achieved when the agent is given via either route. However, there is a time lag of up to 24 hours to achieve therapeutic aPTT levels if heparin is administered subcutaneously. Heparin binds to plasma proteins and proteins derived from endothelial cells or platelets, and diﬀerences in concentrations of these proteins among patients might partially explain disparities in clinical responses to the medication [24]. The primary action of heparin is its high-aﬃnity binding to antithrombin, which increases the ability of antithrombin to inactivate thrombin and activated factors IX and X [24]. Secondary eﬀects of heparin include inactivation of thrombin via heparin cofactor II, endothelial modulation of coagulation factors, and interaction with platelet factor IV [24,25]. The dosage of heparin that might be eﬀective in preventing ischemic stroke among high-risk patients is not known. Although the optimal level of anticoagulation as measured by the aPTT is not established, the presumed therapeutic dose is approximately 1.5 times control levels. Most patients receive 24,000–30,000 units of heparin daily. The low-molecular weight (LMW) heparins and heparinoid have more selective antithrombotic eﬀects than conventional unfractionated heparin. They act primarily by inhibitation of activated factor X [24,26]. These agents have a longer duration of action and appear to be safer than heparin [27]. The pharmacological actions of the several diﬀerent LMW heparins diﬀer, and thus information about the eﬀectiveness of one agent should not be ascribed to another LMW heparin. A. Safety Unfortunately, the diﬀerence between a dose that is safe and eﬀective and one that is associated with a high rate of bleeding complications is relatively narrow [25]. Bleeding is the most common serious side eﬀect. Intracranial bleeding, including hemorrhagic transformation of an infarction, is the most common life-threatening complication [28]. Other potentially serious bleeding complications include gastrointestinal or genitourinary hemorrhage, retroperitoneal or intra-articular hemorrhage, epistaxis, and ocular hemorrhage. Among patients receiving heparin for treatment of a recent TIA or ischemic stroke, the risk of bleeding has been calculated to be 0.3/100 patient-days [29]. While the route of administration (intravenous or subcutaneous) appears not to correlate with the likelihood of hemorrhage, larger dosages are associated with increased bleeding risks [30]. Continuous intravenous infusions of heparin appear to be safer than intermittent intravenous bolus injections. The use of a weight-based nomogram to administer heparin and adjustments in the dosage in response to the levels of aPTT might improve the safety of heparin [31–33].

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Bleeding usually prompts discontinuance of heparin, and in more serious situations protamine sulfate is given. Approximately 1 mg of protamine sulfate counteracts the anticoagulant eﬀects of 100 units of heparin. The amount of protamine sulfate should approximate the dosage of heparin given in the preceding 1½ hours [24]. When protamine sulfate is given intravenously, it should be administered over at least 10 minutes because it can lead to hypotension. Anaphylaxis is a potential complication. Because the LMW heparins and danaparoid act primarily on activated factor X, protamine sulfate is not eﬀective in reversing the eﬀects of these agents. Clotting agents can be administered in an emergent situation. Heparin also might be associated with thrombocytopenia. Ramirez-Lassepas et al. [34] reported a >40% drop in platelet count in 21 of 137 patients treated with heparin for symptomatic ischemic cerebrovascular disease. In most cases the decline in platelet count was asymptomatic. However, in some patients, a severe autoimmune-mediated thrombocytopenia can lead to the white clot syndrome, myocardial infarction, or stroke [35–38]. Prior use of heparin may predispose to development of autoimmune thrombocytopenia shortly after starting treatment. Thrombocytopenia is less frequent with the LMW heparins than with the unfractionated compound [39,40]. Digital ischemia and purple toe syndrome also can complicate heparin therapy [41,42]. In addition, long-term administration of heparin can induce osteoporosis. The risk of osteoporosis is less with LMW heparins [39]. B. Efficacy Because of a perceived high risk of recurrent stroke, heparin is often prescribed to patients with recent ischemic stroke or TIA [18]. In an uncontrolled study, Putnam and Adams evaluated the utility of heparin given to 74 patients with recent TIA [43]. Despite treatment, recurrent TIA was diagnosed in 12 patients (16.4%) and strokes were found in ﬁve patients (6.8%). One patient died of heparin-associated thrombocytopenia. A small, randomized study found no diﬀerence in events when aspirin or heparin was given to patients with recent TIA [44]. No trials have tested the utility of LMW heparins for treatment of patients with recent TIA. At present there is no evidence that intravenous anticoagulants are superior to antiplatelet aggregating agents for preventing stroke among high-risk patients, including those with recent or crescendo TIA. Prevention of early recurrent thromboembolism (recurrent stroke) is one of the potential indications for emergent anticoagulation among patients with recent stroke. Recent studies have demonstrated that the risk of early recurrent stroke is approximately 1–2% within 1 week or 2–3% within 2 weeks following stroke [45,46]. In a Spanish study, intravenous heparin was administered with the goal of preventing recurrent stroke to 231 patients with recent cardioembolic stroke; ﬁve patients had recurrent events [47]. This rate is similar to that reported among the control groups in the recent large trials. In the International Stroke Trial, the utility of subcutaneous heparin (in two doses) alone or in conjunction with aspirin was compared to aspirin alone or no intervention [45]. Although the risk of early recurrent stroke was reduced with heparin, the beneﬁt was largely negated by an increased risk of bleeding complications. No trend in favor of anticoagulants was noted in the recent trials of LMW heparins and heparinoids [46,48]. In one study enrolling patients with atrial ﬁbrillation who had recent stroke, the rate of early recurrent embolism was higher among patients treated with the LMW heparin than among those receiving aspirin [49]. Overall, there is no strong evidence to show that intravenous anticoagulants are successful in treatment of patients with recent stroke.

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C. Conclusions Current data do not show eﬃcacy of parenterally administered anticoagulants for prevention of ischemic stroke among persons with recent TIA or stroke. Based on currently available data, the potential utility of heparin, LMW heparins, and danaparoid for preventing recurrent ischemic stroke is limited [28,50–54]. None of the agents have been shown to be superior to the other anticoagulants. The utility of parenteral anticoagulants as an interim measure to prevent thromboembolism during the initiation of treatment with oral anticoagulants has not been determined. These agents are associated with an increased risk of bleeding complications, especially among patients with recent ischemic stroke. In particular, patients with large strokes have an increased chance of hemorrhagic transformation of the infarction [28,46]. The primary role for heparin or the LMW heparins or danaparoid in prevention of stroke appears to be as an alternative to warfarin when long-term prophylaxis against thromboembolism is needed. There are situations, such as prevention of stroke during pregnancy, when warfarin cannot be administered [55].

III. DIRECT THROMBIN INHIBITORS The potential usefulness of the direct thrombin inhibitors is being assessed in a number of ischemic vascular diseases, including stroke [56,57]. At present, data are insuﬃcient to provide guidance about their use.

IV. ORAL ANTICOAGULANTS Oral anticoagulants limit conversion of vitamin K through blocking of hepatic vitamin K reductases and depletion of dependent clotting factors including prothrombin, factor VII, factor IX, and factor X [58]. The primary antithrombotic eﬀect is the lowering of concentrations of prothrombin and thrombin. In addition, these agents inhibit the production of proteins C and S. Overall, the antithrombotic eﬀects of the oral anticoagulants are delayed approximately 72 hours following initiation of therapy. Similarly, the antithrombotic eﬀects of warfarin persist for up to 3 days following stopping the medication. The time lags reﬂect the half-life of prothrombin. Warfarin is the most commonly prescribed oral anticoagulant. It has several advantages, including predictable pharmacological eﬀects. Warfarin is available in several oral dosages, and it can be given in a parenteral form. Parenterally administered warfarin can be given to patients with gastrointestinal disease, but the parenteral formulation does not achieve antithrombotic eﬀects more rapidly than the oral form. The delay in antithrombotic eﬀects of the oral anticoagulants means that their role in acute treatment is limited. The antithrombotic actions of warfarin are measured by the prothrombin time, which assesses declines in concentrations of prothrombin, factor VII, and factor X [58]. The ratio of the prothrombin time obtained from the patient is compared to the value of a control. Because laboratories around the world use diﬀerent thromboplastin reagents that diﬀer in their response to the anticoagulant eﬀects of warfarin, the ratios vary considerable between hospitals. As a result, one patient can be undertreated and another can be overdosed, although their prothrombin times are the same. Standardization of prothrombin times using the international normalized ratio (INR) aims at increasing the safety and eﬃcacy of oral anticoagulant therapy [59]. The INR is based on the ratio of the patient’s

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and control prothrombin times as adjusted by the factor of the thromboplastin reagent. The INR has greatly simpliﬁed the administration of oral anticoagulants. For most indications, the desired INR levels are 2–3 (Table 3). Physicians often prescribe a higher dose (10 mg of warfarin) for 2 or 3 days to initiate anticoagulation. Unfortunately, this strategy is not eﬃcient because it can result in frequent adjustments in dosage in response to levels of INR [60]. In addition, the rapid administration of warfarin might lead to a reduction in concentrations of proteins C and S before the levels of the pro-thrombotic clotting factors decline. Theoretically, this diﬀerence could induce a transient pro-thrombotic state. Initiation of warfarin at lower doses might avoid this potential adverse experience and treatment could be started on an outpatient basis [60–62]. Patients should be carefully instructed about the use of the medication. They should not miss doses. However, if they forget to take their medication for 1 or 2 days, they should not try to compensate by taking additional medication because inadvertently high levels of anticoagulation might occur. The responses to warfarin vary considerably between patients. In general, older persons are more sensitive to warfarin than are younger patients [63]. A number of medical conditions alter the eﬀects of oral anticoagulants (Table 4). Bowel or hepatic disease could impair absorption of warfarin or alter metabolism of vitamin K. A stable diet is important in sustaining the antithrombotic eﬀects of warfarin. Patients should be informed about foods that are high in vitamin K. While avoiding these foods is not necessary, patients should be advised to consume them regularly so that the dosage of warfarin can be adjusted accordingly (Table 4). If a patient wishes to take a multiple vitamin as a dietary supplement, multiple vitamin formulations that exclude vitamin K are available for use. Consumption of some ﬁsh oils can potentiate the anticoagulant actions of warfarin. Alcohol consumption also aﬀects anticoagulation. While patients can consume modest amounts of alcohol (1–2 ounces/day), binge drinking should be avoided. Because of concerns about compliance with the treatment regimen and the interactions with alcohol, warfarin usually is not prescribed to patients with a history of alcohol or drug abuse. Several medications alter the antithrombotic eﬀects of warfarin; some can prolong the INR, while others curtail the level of anticoagulation. Listings of the medications that most commonly aﬀect the INR are included in Table 5. Some medications are available in over-the-counter formulations; in particular, a large number of medications contain

Table 3 Desired Levels of Anticoagulation in Prevention of Stroke in High-Risk Patients Condition Recent (<6 months) myocardial infarction Dilated cardiomyopathy Mitral stenosis (with atrial ﬁbrillation) Nonvalvular atrial ﬁbrillation Mitral valve repair Bioprosthetic aortic valve Bioprosthetic aortic valve (with atrial ﬁbrillation) Bioprosthetic mitral valve Mechanical aortic valve Mechanical mitral valve a

Followed by aspirin 325 mg/day.

Desired INR 2–3 2–3 2–3 2–3 2.5 for 3 monthsa 2.5 for 3 monthsa 2.5 2.5 F aspirin 81 mg 2.5–3.0 F aspirin 81 mg 3.0–3.5 F aspirin 81 mg

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Table 4 Conditions or Foods That Alter the Eﬀects of Oral Anticoagulants Conditions that increase the eﬀects of warfarin: Malignancy Autoimmune diseases Diarrhea Malabsorption syndrome Bowel disease Hepatic disease Hyperthyroidism Malnutrition Vitamin K deﬁciency Conditions that decrease the eﬀects of warfarin: Inherited resistance to warfarin Hyperlipidemia Hypothyroidism Nephrotic syndrome Foods that decrease the eﬀects of warfarin (high in vitamin K):a Green leafy vegetables Soybean products (oil or tofu) Canola oil Herbal or Japanese green teas Ginseng Garlic a

Alcohol consumption can alter eﬀects of warfarin.

aspirin or other nonsteroidal agents. The potential for interactions with warfarin should be considered when initiating or withdrawing treatment with any medication. Follow-up measurements of the INR should be performed, and adjustments in the dosage of warfarin might be needed. Some patients are treated with the combination of warfarin and aspirin [64]. The addition of aspirin might increase the risk of serious bleeding complications [65]. Oral anticoagulants are discontinued prior to most surgical procedures. Yet the risks of stopping the anticoagulant need to be weighed against the potential for serious bleeding complications if the operation proceeds. The operation might need to be delayed if the patient’s vascular status is unstable, and halting the warfarin could lead to ischemic complications. However, if the patient’s status is stable or the operation needs to be done promptly, the warfarin should be halted approximately 3–4 days before the scheduled procedure [66]. If there are concerns about the risk of recurrent thromboembolism during this period, an interim course of treatment with heparin or a LMW heparin could be prescribed. In this situation, the parenteral anticoagulant could be withdrawn 4–12 hours before the operation. In cases of surgical emergencies, the antithrombotic eﬀects of the oral anticoagulants can be reversed using strategies employed when treating serious bleeding complications. The surgeon should be asked about the timing of reinstitution of anticoagulant treatment, but the goal should be to restart therapy as soon as possible. A. Safety A transient pro-thrombotic state, which leads to skin necrosis or purple-toe syndrome, could occur during the initiation of treatment with warfarin [42,67–71]. Fortunately, this

312 Table 5 Medications That Alter INR Medications that prolong INR: Acetaminophen Allopurinol Amiodarone Anabolic steroids Cimetidine Cisapride Cloﬁbrate Disulﬁram Erythromycin Fluconazole Fluorouracil Fluoxetine Isoniazid Methronidazole Metrolazone Nalidixic acid Phenylbutazone Propafenone Propoxyphene Propranolol Quinidine Statins Sulfonamides Tamoxifen Tetracycline Theophylline Thyroid medications Tricyclic antidepressants Medications that shorten INR: Azathioprine Barbiturates Benzodiazepines Carbamazepine Cholestyramine Cyclosporine Dicloxacillin Griseofulvin Nafcillin Phenytoin Propylthiouracil Rifampin Sucralfate

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rare complication most commonly occurs among persons with acquired or inherited deﬁciencies of protein C or protein S. A brief course of treatment with heparin or a LMW heparin might prevent this complication during the initiation of warfarin therapy. However, the utility of this approach is not clear, and most patients probably do not need an interim course of parenteral anticoagulation. Because vitamin K is a critical cofactor for the formation of bone matrix proteins, warfarin can lead to decreased bone density, osteopenia, or compression fractures [72]. Oral anticoagulants are associated with a very high risk of teratogenicity, and their use during pregnancy must be avoided [73]. A woman with childbearing potential should be advised about the potential risks of warfarin if she becomes pregnant. If a woman requires long-term anticoagulation during pregnancy, heparin or a LMW heparins should be prescribed [55,73,74]. Hemorrhage is the most frequent complication. With the advent of the INR to monitor the degree of anticoagulation and more uniform dosing regimens aimed at achieving INR levels of 2–3 for most indications, the risk of major bleeding is less than was reported in the past. Still, Gullov et al. [75] reported bleeding complications in 41.1% of patients treated with adjusted-dose anticoagulants over a 3-year period. Based on a study of patients treated in Minnesota, Petty et al. [29] calculated the bleeding complication rate with warfarin therapy to be approximately 7.9/100 person-years. A Dutch study estimated the risk of major bleeding complications to be 2.7/100 person-years [76]. Another study found that the risk of major bleeding complications was approximately 1.6% during the ﬁrst month of treatment [77]. During subsequent months, the risk of hemorrhagic events declines, with an accumulative risk of 3.3% during the ﬁrst 3 months and 5.3% within 1 year. The estimated risk of warfarin-related mortality secondary to bleeding is approximately 1% at 6 months, 5% at 1 year, and 7% by 2–3 years [78]. Presumably, the chances of bleeding are less with low-dose ﬁxed warfarin regimens than with adjusted dose therapy. In general, the risk of bleeding increases when the INR exceeds 3–4. Bleeding can occur anywhere in the body. The most common serious bleeding complications include gastrointestinal or genitourinary hemorrhages. Bleeding into the eye, retroperitoneal space, or joints can also be a cause of serious morbidity. Less serious complications include microscopic hematuria, epistaxis, gingival bleeding, bruising, or rectal bleeding. While these events may not be serious in themselves, they portend an excessively high level of anticoagulation and patients should be advised to seek medical attention if these events occur. The development of bleeding also should prompt an evaluation for an underlying pathology, particularly if the INR is not prolonged. For example, minor gastrointestinal or genitourinary bleeding might unmask a tumor. Patients should also be warned to see a physician if headache, new focal neurological impairments, or changes in consciousness or cognition appear. While the new symptoms might be secondary to brain ischemia, intracerebral hemorrhage or a subdural hematoma might be the result of the medical treatment. Intracranial bleeding is the hemorrhagic complication most likely to lead to a patient’s death. Several clinical variables present in a population of persons at high risk for stroke predict an increased risk of serious bleeding complications during treatment with oral anticoagulants (Table 6). For example, stroke may cause cognitive or gait disturbances that could portend an increased risk of bleeding. The risk of serious hemorrhages is greatest among elderly patients with systolic hypertension, past myocardial infarction, or previous bleeding [30,79]. Leukoaraiosis is an independent risk factor for warfarin-related intracranial hemorrhage among persons who have had ischemic stroke [80]. While caution should be exercised about prescribing oral anticoagulants to persons older than 75, ad-

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Table 6 Clinical Factors Predicting a High Risk of Serious Hemorrhagic Complications During Treatment with Oral Anticoagulants General Advanced age Prior bleeding History of poor compliance with medications Alcohol or drug abuse Nonavailability of laboratory or clinical monitoring Cancer Peptic ulcer or colon disease Hepatic or renal failure Terminal illness Neurological Past history of stroke, especially hemorrhagic stroke Poor balance or incoordination Dementia

vanced age is not a contraindication per se [81]. Many older persons can be treated safely with anticoagulants. On the other hand, demented patients, those with a history of drug or alcohol abuse, persons with chaotic social situations, and individuals with a track record of poor compliance with medications should not be treated with oral anticoagulants. Depending upon the severity and type of bleeding, the changes in management vary. The relative risks of recurrent ischemic events if the anticoagulants are withdrawn should be measured in response to the hemorrhagic complications. There may be situations, such as minor hematuria or recurrent epistaxis, when the anticoagulants do not need to be stopped. In mild bleeding, the warfarin can be withheld and the patient’s coagulation parameters allowed to return to baseline values without any additional intervention. When the bleeding is in conjunction with an excessively elevated INR, the best response might be a temporary suspension of treatment or a reduction in dose. In situations when serious bleeding is occurring in combination with a prolonged INR, administration of vitamin K—the antidote to warfarin—is indicated. In particular, intracranial bleeding usually mandates this response. The usual dosage of vitamin K is 1–10 mg given as a slow intravenous infusion. Vitamin K should be administered slowly because rapid infusions can be complicated by anaphylaxis. The vitamin also can be given orally, but subcutaneously administered vitamin K is not well absorbed [82,83]. A large dose of vitamin K can lead to a state of resistance to further treatment with warfarin that can last up to 1 week or longer. This resistance could complicate reinstitution of oral anticoagulant therapy. In life-threatening situations, such as symptomatic intracranial hemorrhage, fresh frozen plasma or clotting factors can be given to immediately reverse the eﬀects of the anticoagulant [84]. While slightly higher levels of anticoagulation are recommended for patients with mechanical prosthetic valves (particularly mitral) or pro-thrombotic states, the desired INR for most indications is approximately 2–3. Many patients will have a pertubation in INR during a course of treatment. Often the best responses are to not make a change in the treatment regimen or to make a modest adjustment in dosage; this tactic is most commonly used when the patient has no evidence of hemorrhage. A temporary suspension of treatment often is recommended when the INR level is in the range of 4–6 [59,83]. After

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missing one or two doses, the patient could restart warfarin at a slightly lower maintenance dose. In addition to stopping the warfarin, a small dose of vitamin K (0.5–1 mg intravenously or 1–2.5 mg orally) can be administered in conjunction to halting the warfarin when the INR is approximately 6–10 [59]. A larger dose of vitamin K (3–5 mg) is usually needed when the INR is >10. Replacement of clotting factors is usually not needed for treatment of a prolonged INR unless serious bleeding is also occurring.

B. Efficacy Oral anticoagulants are usually administered to prevent thromboembolism among patients with congenital or acquired pro-thrombotic disorders, including the presence of antiphospholipid antibodies [79,85]. Although clinical trials have not established the utility of any level of anticoagulation, in general the desired level of anticoagulation is an INR of >3 [86]. Most of the pro-thrombotic conditions are relatively uncommon, and thus, conducting trials to test for eﬃcacy of anticoagulants will be diﬃcult. Oral anticoagulants are of established utility in preventing stroke among patients with a number of serious structural diseases of the heart. The high-risk cardiac lesions that usually mandate long-term anticoagulant treatment are listed in Table 7. Many of the structural cardiac lesions are complicated by atrial ﬁbrillation. Atrial ﬁbrillation appears to be an important contributing factor for a high rate of embolization, and many of the recent trials of anticoagulation for prevention of stroke have focused on treating patients with the cardiac arrhythmia. The patients with atrial ﬁbrillation who are at the highest risk are those with prior ischemic neurological symptoms [87]. Thus, patients referred to a neurologist are a particularly high-risk group. Other factors among patients with atrial ﬁbrillation that portend a high risk of embolization are listed in Table 7. Patients under the age of 65 with atrial ﬁbrillation but with no other evidence of heart disease do not have a particularly high risk for emboli [88]. Several clinical trials tested the potential utility of

Table 7 High-Risk Cardiac Diseases Prompting Long-Term Anticoagulation Acute myocardial infarction (anterior wall) Dilated cardiomyopathy Rheumatic mitral stenosis Nonbacterial thrombotic endocarditis Libman-Sacks endocarditis Mechanical prosthetic cardiac valve Thrombus—left ventricle, left atrium, left atrial appendage Atrial ﬁbrillation with structural heart disease: Advancing age (>75 years) Women (especially >75 years) History of hypertension Systolic blood pressure >160 mmHg Diabetes mellitus History of coronary artery disease History of congestive heart failure Left ventricular dysfunction on echocardiography Left atrial spontaneous contrast on echocardiography

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oral anticoagulation for prevention of ischemic stroke or other embolic events among patients with nonvalvular atrial ﬁbrillation [89–102]. One trial tested anticoagulants among patients with atrial ﬁbrillation and previous neurological symptoms [103]. The trials compared adjusted doses of warfarin to aspirin, low-dose warfarin, or placebo. The results of these trials are compatible; in all cases adjusted-dose warfarin (desired INR 2–3) was superior to the other therapies in preventing thromboembolic events, including stroke. Other than patients<65 of age who did not have structural heart disease (lone atrial ﬁbrillation), the adjusted-dose warfarin was shown to be the most eﬀective preventive medical therapy. The likelihood of major bleeding complications was not increased dramatically. The European study is of particular importance to physicians dealing with stroke because enrolled patients had had prior ischemic neurological symptoms and this group of persons has the highest risk of recurrent thromboembolism [103]. The trial demonstrated that warfarin was superior to aspirin in preventing recurrent embolization. Meta-analyses demonstrate that oral anticoagulants are associated with an approximately 67% relative risk reduction (from 12% to 4%) among persons with atrial ﬁbrillation [104–106]. Despite a considerable decline in thromboembolic events of cardiac origin, patients with atrial ﬁbrillation can have ischemic stroke from arterial diseases as well. The eﬃcacy of warfarin in preventing noncardioembolic events among patients with atrial ﬁbrillation is not established. Still, based on the consistent data for eﬃcacy and reasonable degree of safety, oral anticoagulants can be recommended as the primary antithrombotic therapy for preventing stroke among patients with atrial ﬁbrillation. Patients with a pacemaker and atrial ﬁbrillation should also be treated with oral anticoagulants [107]. Cardioversion of a patient with atrial ﬁbrillation is associated with a high risk of thromboembolism. Anticoagulants should be given to most patients with sustained atrial ﬁbrillation who will be treated with pharmacological or electrical cardioversion [108]. If there is strong evidence that atrial ﬁbrillation is of new onset (<48 hour) and if an echocardiogram does not demonstrate an intra-atrial thrombus, the cardioversion could be performed without anticoagulant prophylaxis [109–111]. However, for most patients the recommended regimen is 3 weeks of treatment (therapeutic INR level) prior to the cardioversion followed by 4 weeks of therapy after the procedure [112]. Administration of anticoagulants after the procedure is advised because intra-atrial thrombi can develop following cardioversion [113]. Stroke is the major noncardiovascular complication of acute myocardial infarction. Overall, the risk of stroke is approximately 1%, with chances highest among patients with anterior wall myocardial infarction [114–116]. In this group, the risk of stroke may be as high as 2–6% because of the association with an akinetic ventricular segment or the presence of left ventricular thrombi [117,118]. Patients with complicating atrial ﬁbrillation, congestive heart failure, or poor left ventricular function also have a high risk of embolization [119]. A strong time relationship exists; the ﬁrst few days after the myocardial infarction is the period of highest risk [120]. Moore et al. [121] calculated the daily risk of ischemic stroke to be approximately 9/10,000 during the ﬁrst 4 weeks following myocardial infarction. The time relationship is not surprising because this is the period of the acute myocardial and endothelial injury when secondary intraventricular or mural thrombosis develops. Unless other cardiac complications develop, the risk of cerebral embolism drops by 6 months after the cardiac event. Anticoagulants are a key treatment to prevent cardioembolism following myocardial infarction [122]. A brief course of heparin is usually followed by oral anticoagulation to achieve an INR of 2–3. Anticoagulants are stopped approximately 6 months after the myocardial infarction because the period of high risk has passed.

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Oral anticoagulants are the usual therapy for preventing thromboembolism among patients with rheumatic mitral stenosis, especially if atrial ﬁbrillation is present. These medications also are prescribed to most patients with mechanical or biological prosthetic valves, especially for mitral valve replacements [123–125]. The presence of atrial ﬁbrillation, severe left ventricular dysfunction, pro-thrombotic state, or prior neurological symptoms is associated with an increased risk of thromboembolism among patients with artiﬁcial valves [126]. Because of the extraordinarily high risk of thromboembolic events among patients with mechanical valves who have not been treated with anticoagulants, randomized trials have not been done. Thus, evidence of eﬃcacy of the medications is anecdotal but accepted. The desired level of anticoagulation is higher for patients with mitral valve replacements than for those patients with other cardiac causes of embolism; the usual range is an INR of 2.5–3.5. Among patients with prosthetic mitral valves, the risk of embolization increases dramatically when the INR is<2. Some high-risk patients will require the addition of an antiplatelet agent to the warfarin. Oral anticoagulants are often prescribed during the ﬁrst 3 months following placement of a bioprosthetic valve, particularly if it is an aortic valve replacement. Thereafter, aspirin is substituted for the warfarin unless the patient has a history of thromboembolic events. Patients with dilated cardiomyopathies are often treated with oral anticoagulants, although the evidence of eﬃcacy of this therapy is not established [127]. A clinical trial is testing the utility of oral anticoagulants in preventing thromboembolic events among patients with cardiomyopathies, including those with congestive heart failure [119]. Although oral anticoagulants are prescribed to other patients potentially at high risk for stroke, their utility in these situations is not established (Table 8). Oral anticoagulants are administered to patients with a number of cardiac lesions that are of moderate or indeterminate risk for embolic events, including those with patent foramen ovale (PFO) [51,128,129]. One of the reasons for prescribing oral anticoagulants for patients with PFO is the presumed venous origin of the clots that would cause paradoxical embolism. However, a recent trial did not demonstrate the superiority of warfarin over aspirin in preventing recurrent ischemic events [130]. In the trial, patients with PFO did not have a

Table 8 Potential or Uncertain Indications for Long-Term Oral Anticoagulant Therapy Prevention of cardioembolic stroke Patent foramen ovale Atrial septal aneurysm Left atrial turbulence Prevention of arterial thromboembolism Atherosclerotic disease of the aorta Mobile plaques Extracranial or intracranial atherosclerosis Severe stenosis Posterior circulation Intracranial disease Nonatherosclerotic vasculopathies Arterial dissection Radiation induced vasculopathy ‘‘Failure’’ to respond to antiplatelet aggregating agents Adjunct to antiplatelet-aggregating agents

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higher risk of stroke than did those with the cardiac ﬁnding. These results correspond to the ﬁndings of a French study that found a lower rate of embolism among patients with PFO than among controls [131]. In the trial reported by Homma et al. [130], the rate of recurrent stroke among patients prescribed warfarin was similar to that noted among patients treated with aspirin. Although the French study found a higher rate of embolic events among patients with PFO and atrial septal aneurysm, this relationship was not conﬁrmed in the recent trial [130,131]. Despite the results of this large trial, experts still recommend oral agents as stroke-preventive therapy for patients with PFO [132]. Additional research will be needed to conﬁrm this opinion. Until such information becomes available, physicians should assume that aspirin and warfarin are approximately equal in eﬃcacy in preventing embolization among patients with PFO. Patients with severe atherosclerotic disease of the ascending aorta often receive anticoagulants to prevent thromboembolism. Presumably, large mobile plaques could be the nidus for thrombosis. In a small study, Dressler et al. [133] reported that no ischemic events occurred among a group of patients with atherosclerotic disease of the aorta given warfarin, while events happened in 27% of those not treated with anticoagulation. In another trial that included patients with both severe disease of the thoracic aorta and atrial ﬁbrillation, the annual risk of embolism was 5.9% among patients treated with adjusteddose warfarin (INR 2–3) and 17.3% among patients given low-dose warfarin and aspirin [134]. While these results imply a beneﬁt for anticoagulation among patients with aortic atherosclerosis, the reduction in risk may be due to preventing cardioembolic strokes secondary to the heart disease. No other trials have tested the potential usefulness of oral anticoagulants among patients with other cardiac lesions that have an undetermined risk for embolization. Warfarin can be given as an alternative or adjunct to antiplatelet agents, including treatment of patients who have ischemic symptoms despite previous antithrombotic management. In addition, anticoagulants are often given to patients with arterial lesions perceived as especially dangerous. For example, patients with severely stenotic disease of the posterior circulation or the intracranial vasculature are often given anticoagulants despite the absence of deﬁnitive data [135]. The strongest support is from a retrospective, nonrandomized study by Chimowitz et al. [136] that reported rates of recurrent ischemic events of 3.6/100 patient-years among patients taking warfarin and 10.4/100 patient-years among patients receiving aspirin. The results of this study serve as an impetus to perform a trial testing the utility of the two forms of therapy [137]. Pending the results of this trial, deﬁnitive data showing the superiority of warfarin for treatment of patients with arterial lesions are lacking. Some physicians recommend warfarin for treatment of patients with arterial dissections or radiation-induced vasculopathy [138]. However, deﬁnitive information about the usefulness of warfarin for this indication is lacking. Current evidence suggests that the risk of recurrent ischemic symptoms among patients with arterial dissections is relatively low, and the need for oral anticoagulants, which have a greater inherent risk for bleeding that found with antiplatelet agents, is not clear [139–141]. Although oral anticoagulants are prescribed commonly to patients with ischemic symptoms secondary to atherosclerotic cerebrovascular disease, information about their utility is limited [135,142]. A European trial tested the utility of low-dose aspirin or warfarin in prevention of stroke among patients with ischemic stroke and no high-risk cardiac lesion [142,143]. The trial was stopped prematurely because of a high risk of serious bleeding, including brain hemorrhage, among those persons given the anticoagulant (8.1% vs. 0.9%). The high rate of hemorrhage might be secondary to the high level

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of INR (3–4.5). No diﬀerences in the rates of ischemic events were noted. The same investigators are doing another trial testing warfarin (INR f 2–3), aspirin, or aspirin and dipyridamole in preventing stroke among patients with TIA or ischemic stroke. The Warfarin–Aspirin Recurrent Stroke Study is a randomized, double-blind trial that enrolled patients with recent ischemic stroke and no major cardiac lesions to adjusted-dose warfarin (INR 1.4–2.8; mean approximately 2.2) or aspirin 325 mg/day [144]. Recurrent ischemic stroke or death occurred in 196 patients given warfarin (17.8%) and 176 patients given aspirin (16.0%); no net beneﬁt was seen from anticoagulant treatment. No relationship between the level of anticoagulation and the risk of recurrent stroke was found. This large trial does not demonstrate utility for anticoagulants in preventing death or ischemic stroke among persons with arterial diseases causing stroke. At present, anticoagulants cannot be recommended as a primary therapy for preventing recurrent stroke among patients with atherosclerosis.

C. Conclusions Evidence about the usefulness of long-term oral anticoagulant therapy for preventing stroke or recurrent stroke among high-risk patients is mixed. There is strong evidence for the utility of these medications for prevention of thromboembolism among patients with high-risk cardiac lesions, including most patients with atrial ﬁbrillation. These agents are the medications of choice for prevention of ischemic events among patients with a heart disease that is associated with a high risk for embolization. Besides reducing the frequency of stroke, the use of oral anticoagulants also may reduce the severity of ischemic events [145]. Despite the hassles of warfarin therapy and its potential bleeding complications, a study has demonstrated that patients with atrial ﬁbrillation greatly value the eﬃcacy of the medication for prevention of stroke [146]. For most patients, the desired level of INR is 2– 3. On the other hand, oral anticoagulants are not established for forestalling ischemic stroke among persons with heart diseases of intermediate or undetermined risk for embolization. Trials provide no compelling evidence for the use of oral anticoagulants in these situations. In particular, there are no data showing the superiority of warfarin over aspirin for prevention of thromboembolism among patients with a PFO. Additional research will be needed to determine the eﬃcacy of warfarin in preventing thromboembolism for these cardiac conditions. While warfarin can be given to patients with a number of arterial causes of stroke, there are no data to show that this medication is superior to antiplatelet therapy alone. The potential usefulness of anticoagulants for treating patients with intracranial arterial disease is underway. Warfarin could be given as an adjunct to aspirin among patients who have had recurrent symptoms despite treatment.

V. ASPIRIN Aspirin is the most extensively tested and widely used medication for the prevention of ischemic events, including stroke. Aspirin is also a mainstay of the primary prevention of myocardial infarction or vascular death. Aspirin has several advantages; it is easy to administer, relatively inexpensive, and its side eﬀects are relatively well known. Most importantly, aspirin is eﬀective. It is eﬀective over a broad range of doses ranging from 30 to 1500 mg/day [147]. Despite aspirin’s status as an over-the-counter medication, it is potent and has side eﬀects including bleeding (Table 9).

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Table 9 Leading Side Eﬀects of Commonly Prescribed Antiplatelet-Aggregating Agents Aspirin Epigastric distress, erosive gastritis, gastric ulcer Gastrointestinal hemorrhage Bleeding at other sites (including intracranial) Allergic reactions (nasal polyps) Dipyridamole Headaches Bleeding Ticlopidine Allergic reactions (urticaria, skin eruptions) Bleeding Epigastric distress, diarrhea Neutropenia (agranulocytosis) Thrombotic thrombocytopenia purpura (TTP) Hemolytic–uremic syndrome Aplastic anemia Cholestatic hepatitis/jaundice Interstitial pulmonary disease Interstitial nephritis Arthritis Clopidogrel Allergic reactions Epigastric distress, diarrhea Neutropenia (rare) Thrombotic thrombocytopenia purpura (rare) Aplastic anemia (rare) Hepatic disease

Aspirin is an inhibitor of prostaglandin function by irreversibly blocking the eﬀects of cyclooxygenase in platelets and endothelial cells [148–151] (Table 10). The primary antiplatelet action of aspirin is through its inhibition of thromboxane A2 synthase [150,152,153]. Besides its eﬀects on platelet aggregation, thromboxane A2 is a potent vasoconstrictor. Aspirin also inhibits the production of the vasodilator prostacyclin from endothelial cells. Aspirin is absorbed rapidly in the stomach and proximal small intestine. Maximal blood levels are achieved within 20 minutes [154]. Platelet function is inhibited within 1 hour of taking 325 mg of aspirin [150]. While low doses of aspirin (30 mg/day) inhibit platelet function, the eﬀects do not become apparent until 3–7 days following initiation of therapy [153,155]. Enteric-coated preparations of aspirin are associated with slower absorption and onset of action. While blood levels of aspirin decline rapidly, the eﬀects persist for the 7- to 10-day life of the platelet. Because aspirin also aﬀects megakaryocyte function, new platelets also are inhibited. Daily administration of low doses of aspirin (30 mg) can maintain platelet inhibitory eﬀects [156]. Alternate-day aspirin (325 mg) also sustains the eﬀects on platelet aggregation. However, because approximately 10% of platelets are replaced daily, the eﬀects of aspirin are reversed at approximately 1 week following stopping the medication. Helgason et al. [157,158] described a relationship between platelet inhibition and the dose of aspirin. They also noted that the eﬀects of aspirin could vary considerably between patients and that some

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Table 10 Mechanisms of Action and Daily Dosages of Commonly Prescribed Antiplatelet-Aggregating Agents Aspirin (30–1500 mg/day) Block cyclooxygenase Inhibit thromboxane A2 synthase Inhibit prostacyclin Dipyridamole (400 mg/day) Inhibit phosphodiesterase Ticlopidine (500 mg/day)/clopidogrel (75 mg) Block platelet response to ADP-induced aggregation Block interaction between ﬁbrinogen and IIb/IIIa receptor

patients would develop some degree of resistance. These observations were based on the results of platelet aggregation tests, and clinical correlations are not known. Grotemeyer et al. [159] described a group of patients as secondary aspirin nonresponders based on the inability to maintain the inhibition of platelet aggregation with long-term use of the medication. Presumably, a larger dose of aspirin might be eﬀective in such a situation. However, no data are available about the usefulness of high doses of aspirin when a patient has had ischemic symptoms despite treatment of a lower dose of aspirin. There is a possibility that other inhibitors of cyclooxygenase 2, such as nonsteroidal anti-inﬂammatory agents, might dampen the antiplatelet eﬀects of aspirin and increase the chances of thromboembolism [160]. A. Safety Gastric irritation, erosive gastritis, peptic ulcer disease, and gastrointestinal bleeding are the major adverse experiences from the long-term use of aspirin [161] (Table 9). The increase in gastrointestinal bleeding or severe peptic ulcer disease is estimated as approximately 350% [162]. The antiplatelet eﬀects of aspirin cannot be divorced from the agent’s actions on the gastric mucosa. While data are mixed, a relationship between the dosage of aspirin and the rate of serious gastrointestinal side eﬀects is present [163–165]. The chances of gastrointestinal complaints with aspirin use are increased among persons older than 60, with prolonged use, or if the patient has had prior epigastric problems [166]. There appears to be no relationship between aspirin use and Helicobacter pylori infections among patients with peptic ulcer bleeding [165]. Patients often do not tolerate doses greater than 325 mg/day. In a study testing the utility of carotid endarterectomy for treatment of asymptomatic carotid artery stenosis, aspirin was initially prescribed in a daily dose of 1300 mg; most patients could not tolerate the dose [167]. The likelihood of major gastric complaints is reduced with a daily dose of 81–160 mg of aspirin, and this relationship is a major advantage of low doses of aspirin (Table 11). In addition, entericcoated preparations lessen the gastrointestinal side eﬀects [168]. Many physicians now prescribe 81–325 mg enteric-coated aspirin tablets because of the gastrointestinal side eﬀects of larger doses. The doses of aspirin that are used to prevent vascular disease are not suﬃcient to lead to renal dysfunction [151]. Aspirin can be complicated by serious allergic reactions including nasal polyps or asthma. Because aspirin is a potent antiplatelet-aggregating agent, serious bleeding can occur. The risk of hemorrhage is estimated to be 3.5/100 person-years [29]. While gas-

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Table 11 Methods to Reduce Gastrointestinal Side Eﬀects of Aspirin Take medication with food Reduce dose of aspirin (81–325 mg day) Concomitant medications: Antacids Cimetidine Ranitidine Famotidine Lansoprazole Omeprazole Carafate

trointestinal hemorrhage is the most common bleeding complication, hemorrhage in other locations can occur. Intracerebral hemorrhage is a potential side eﬀect. He et al. [169] concluded that the risk of hemorrhagic stroke among persons taking aspirin is 12/10,000. Aspirin may augment the risk of intracranial bleeding complications [170]. Among patients with recent stroke, aspirin modestly increases the likelihood with hemorrhagic transformation of the infarction [45,171]. The risk of intracranial hemorrhage is lower with aspirin than with oral anticoagulants [143]. The dosage of aspirin is not associated with the risk of intracranial hemorrhage or other cases of serious bleeding [163,172]. The lack of dosage relationship with nongastrointestinal bleeding is not surprising because of the broad range of doses that alter platelet function. The risk of all bleeding complications, including gastrointestinal hemorrhage, is more than compensated for by the reduction in the risk of ischemic complications [173]. B. Efficacy Aspirin is eﬃcacious for the primary and secondary prevention of myocardial infarction and vascular death [147,150,174,175]. Aspirin also reduces the likelihood of stroke by approximately 25–30% among persons with symptomatic atherosclerosis. The beneﬁt of aspirin in primary prevention of stroke among asymptomatic persons has not been established, probably because of the higher rates of cardiac ischemic events in such a cohort of persons. Aspirin is eﬀective in preventing vascular events among men and women, older (>65) and younger (V65) patients, hypertensive or nonhypertensive patients, and diabetic and nondiabetic persons. During the last 30 years, several trials tested the utility of aspirin for prevention of stroke among high-risk patients, including those with transient ischemic attacks or prior ischemic stroke. While some studies are inconclusive, the trend in favor of treatment with aspirin is consistent. The ﬁrst trials tested doses of aspirin >1000 mg, and the more recent studies evaluated lower doses [176–182]. Because of the prolonged time period and changes in ancillary care, direct comparisons between these trials for any dosage-related eﬃcacy should be done with caution. Still, some trials have compared two diﬀerent doses of aspirin. A British trial found that 300 mg of aspirin was comparable to a daily dose of 1200 mg [183]. A Dutch study compared a daily dose of approximately 300 to 30 mg; the lower dose was as eﬀective as the larger dose [184]. More recently, Taylor et al. [172] found that low doses of aspirin (81–325 mg/day) were superior to larger doses (650–1300

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mg/day) in preventing ischemic events following carotid endarterectomy. In general, the data suggest that lower doses (81–325 mg/day) of aspirin are at least as eﬀective as larger doses (>325 mg/day). Because of the reduced risk of major gastrointestinal side eﬀects with lower doses of medication, a comparison of risks and beneﬁts would support administration of aspirin in a dosage of 81–325 mg/day [185,186]. Aspirin is an important adjunctive intervention for treatment of patients who undergo cerebrovascular operations including carotid endarterectomy [172,176]. In the study by Taylor et al. [172], the rates of serious ischemic events in the period following carotid endarterectomy were fewer among patients treated with 81–325 mg of aspirin than for those persons taking 650–1300 mg of the medication daily. Several years ago, Grotta et al. [187] suggested that aspirin might also lessen the neurological sequelae of any strokes. Wilterdink et al. [188] investigated the eﬀects of the previous use of aspirin, including tractions, on inﬂammation among patients entered in a clinical trial testing acute stroke therapy. They found that the severity of stroke was reduced among patients who had taken aspirin within 7 days. Conversely, other investigators have not been able to correlate a reduction in the stroke severity with previous use of aspirin [189–191]. The potential neuroprotective eﬀect of aspirin is of interest [192]. However, additional research is needed to determine if aspirin does provide a beneﬁt in lessening brain injury during ischemia. There is no evidence that aspirin lowers the likelihood of vascular dementia [193]. Because of the widespread use of aspirin for prevention of ischemic cerebrovascular disease, physicians often see patients who have had recurrent symptoms despite treatment with the medication. The recurrent events are often described as ‘‘aspirin failures.’’ There is no evidence that increasing the dose of aspirin is eﬃcacious if a patient has ischemic symptoms while taking a low dose of medication. Chimowitz et al. [194] speculated that aspirin might not be as eﬀective as other medications in preventing thromboembolism among patients with advanced atherosclerosis of the internal carotid artery. If this assertion is correct, there may be a reason to replace aspirin with another medication or add another agent to aspirin. However, this situation has not been tested in clinical trials. There is no evidence that other medications would be more eﬀective than aspirin among patients with severe stenosis of the extracranial arteries. Because of the success of aspirin in preventing arterial thromboembolism, the agent is often prescribed to patients who have cardiac diseases that are the potential source for emboli. However, evidence of eﬃcacy is limited. Aspirin is not eﬀective in forestalling formation of an intraventricular thrombus following myocardial infarction [195]. It is not useful as a monotherapy for prevention of stroke among patients with mechanical prosthetic valves [125]. However, aspirin can be used to treat most patients with bioprosthetic valves, particularly those in the aortic position [125]. One small study found no diﬀerence in the thromboembolic rates between patients initially treated with antiplatelet agents and those who ﬁrst received anticoagulants for 3 months and were subsequently treated with aspirin [196]. If these results are conﬁrmed by other studies, the interim course of warfarin might not be needed. Aspirin provides some beneﬁt in lowering the risk of thromboembolism among patients with atrial ﬁbrillation. The eﬀective dose is 325 mg/day. The average reduction in risk (approximately 21%; range 18–44%) is much less than that found with warfarin [93,94,101]. One group looked at the potential utility of aspirin or warfarin in subgroups of patients with atrial ﬁbrillation [91,197]. They found that the risk of stroke was slightly higher with aspirin than with warfarin among patients younger than 75 years but that the beneﬁt from anticoagulation was negated by an increase in bleeding risk. Among older

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patients, the risk of ischemic stroke was considerably higher with aspirin use, but this risk was counterbalanced by a high rate of bleeding with anticoagulants. The net result was a marginal beneﬁt from warfarin. In general, patients considered to have a low risk for thromboembolism, such as those with lone atrial ﬁbrillation, can be treated with aspirin [87,197]. The recent trial performed by Homma et al. [130] found that aspirin was equal in eﬃcacy to warfarin in preventing ischemic events among patients with PFO and prior stroke. The success of aspirin in this situation raises the possibility that the medication might be equally eﬀective in preventing cardioembolic events among patients with other heart diseases judged to be at low or intermediate risk for embolization. The relative utility of warfarin or aspirin for preventing thromboembolic events among persons with complex atherosclerotic disease of the aorta has not been tested. Aspirin might be eﬀective. Aspirin has been tested in several clinical trials enrolling patients with acute ischemic stroke [45,48,49,171,198–200]. In some of these trials aspirin was used as the control to which an anticoagulant was compared. The interval from onset of stroke until treatment was up to 48 hours. In general, these trials found that aspirin was associated with a modest increase in the risk of neurological bleeding complications. On the other hand, the results suggest that aspirin can be started with a reasonable degree of safety to most patients with recent (<48 hours) ischemic stroke. Aspirin is associated with a modest reduction in the risk of early recurrent stroke [200]. In a Norwegian study that recruited patients with acute stroke and atrial ﬁbrillation, aspirin was as eﬀective as low-molecular weight heparin in preventing early recurrent stroke [49]. C. Conclusions Aspirin is an important option for the primary or secondary prevention of ischemic stroke. Besides being eﬀective in lowering the risk of ischemic stroke, aspirin has demonstrated eﬃcacy in preventing myocardial infarction or vascular death. Aspirin has many attributes that make it an ideal medication for stroke prophylaxis. Contraindications to aspirin are active peptic ulcer disease and allergies. Still, aspirin is underused in the treatment of patients at risk for stroke [201]. For most patients, aspirin is the usual ﬁrst choice as an antithrombotic medication to prevent ischemic events. With the exception of persons with heart diseases at a high risk for embolism and those with pro-thrombotic states, aspirin remains a preeminent treatment option [175]. Aspirin appears to be eﬀective in patients with intracranial or extracranial atherosclerotic disease. Aspirin lowers the risk of thromboembolic events among patients undergoing reconstructive vascular operations. Although the utility of aspirin has not been tested in the treatment of patients with noninﬂammatory, nonatherosclerotic vasculopathies, such as arterial dissection, the medication probably is eﬀective in these situations. Aspirin has a secondary role for prevention of stroke among persons with atrial ﬁbrillation or other heart disease with a high risk for embolization [202]. The medication can be prescribed if warfarin cannot be given to a patient [203]. Aspirin also can be given as an adjunct to warfarin [204]. The usual daily dose of aspirin for prevention of stroke is 81–325 mg. Enteric-coated aspirin usually is used because of the lessened risk of gastric complications. Antacids, H2 receptor blockers, proton-pump inhibitors, or sucralfate can be prescribed as adjuncts to aspirin if a patient develops gastric distress from the medication. Some of these medications are expensive, and their use could lessen the economic advantages of treatment of aspirin.

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VI. DIPYRIDAMOLE Dipyridamole is a vasodilator that also aﬀects platelet function by inhibition of cyclic nucleotide phosphodiesterase activity and prevention of adenosine uptake in the platelet [150,205,206] (Table 10). Dipyridamole also increases the antithrombotic actions of the vascular endothelium [207]. The inhibitory actions on platelet function are reversible. Dipyridamole is available in conventional and sustained-release formulations; the latter was developed in order to improve bioavailability of the medication. The half-life of dipyridamole in the extended release formulation is approximately 10 hours. Thus, patients need to take medication twice a day to maintain the antiplatelet eﬀects. While the conventional formulation of dipyridamole is available as a generic medication, the sustained-release dipyridamole currently is available only in a patented compound in combination with low-dose aspirin. The latter medication is considerably more expensive. On the other hand, laboratory monitoring is not required for patients taking aspirin and dipyridamole and the combination medication is easy to give. A. Safety Dipyridamole has an excellent safety proﬁle (Table 9). Headaches are the most common side eﬀect. An exacerbation of headaches probably is secondary to the vasodilatory eﬀects. Presumably, the sustained-release formulation should be associated with fewer headaches than the conventional medication. Still, patients with a history of migraines might not tolerate dipyridamole. Because of the vasodilatory eﬀects of dipyridamole, there has been concern that the medication might increase the risk of ischemic cardiovascular events. However, a recent trial of dipyridamole did not demonstrate an increase in the rate of myocardial infarction among persons with stroke [208]. The risk of major bleeding complications directly attributed to dipyridamole is low. B. Efficacy The eﬃcacy of dipyridamole in prevention of ischemic events, including stroke, has been debated [209,210]. While there is evidence that dipyridamole is eﬀective in lowering the risk of stroke when used as a monotherapy, the medication usually is prescribed in combination with aspirin [182]. Trials performed during the 1970s and 1980s in France and North America did not demonstrate a beneﬁt from the addition of dipyridamole to aspirin [211,212]. Subsequently, a large placebo-controlled European trial found that the combination of dipyridamole 225 mg/day and aspirin 900 mg/day produced an approximately 30% reduction in the risk of stroke [213,214]. Critics of the study concluded that much of the beneﬁt could be ascribed to aspirin [215]. Therefore, a second study was conducted. This placebo-controlled trial tested aspirin 50 mg/day, extended-release dipyridamole 400 mg/day monotherapy, or a combination [182]. Either aspirin or dipyridamole alone lowered the risk of ischemic vascular events by approximately 13– 15%, but the combination had a risk reduction of approximately 24% [182,216,217]. Baseline factors, such as age, did not inﬂuence the eﬀects of treatment [218]. Despite a beneﬁt in lowering the chances of a recurrent stroke, Sivenius et al. [191] found that the combination of dipyridamole and aspirin did not reduce the severity of strokes that did occur despite treatment. Dipyridamole has also been given as an adjunct to warfarin to prevent stroke among persons with very high risk cardiac lesions [219]. The combination was shown to be highly eﬀective. Evidence also shows that the combination of aspirin and

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dipyridamole is cost-eﬀective [220,221]. Additional trials are testing the usefulness of dipyridamole and aspirin in preventing recurrent stroke [142]. C. Summary While some controversy remains about the utility of dipyridamole in prevention of stroke, the evidence suggests that the agent is an option for treatment of high-risk patients [210,222]. The medication is relatively safe. Although the second large European trial found that dipyridamole was eﬀective in lowering the risk of stroke when given as a monotherapy, the primary role of dipyridamole appears to be as an adjunct to aspirin. Overall, the addition of dipyridamole appears to increase the eﬀectiveness of aspirin by approximately 15–23% [223–225]. The combination of extended-release dipyridamole and aspirin is an important option for treatment of patients with recurrent ischemia despite management with aspirin. The current regimen is a tablet containing 25 mg of aspirin and 200 mg of sustained-release dipyridamole taken twice a day. Independent analyses conclude that aspirin and extended-release dipyridamole is a cost-eﬀective alternative when compared to treatment with aspirin alone [220,221,226]. Dipyridamole can be added to warfarin for prevention of embolism among patients with high-risk cardiac lesions, such as mechanical prosthetic valves. Dipyridamole might be given as a monotherapy if a patient cannot tolerate aspirin, clopidogrel, or ticlopidine.

VII. TICLOPIDINE Ticlopidine was the ﬁrst medication developed primarily for its eﬀects on platelet aggregation. Its primary action involves blocking responses to adenosine diphosphate (ADP)–induced aggregation and signal transduction [150,152,227–230] (Table 10). Indirectly, the medication aﬀects interactions between the platelet’s glycoprotein IIb/IIIa receptor and ﬁbrinogen, and as a result the bleeding time is prolonged [150,227,231]. The medication is rapidly absorbed following oral administration. The usual daily regimen is a 250 mg tablet taken twice daily. The half-life of ticlopidine is approximately 24–36 hours following a single dose [150]. Still, the antithrombotic eﬀects of ticlopidine do not appear for approximately 1 week following initiating therapy [232]. Because of the lag in therapeutic eﬀect, ticlopidine is not an optimal intervention for treatment of patients who are unstable, and some physicians have prescribed concomitant aspirin during the introduction of ticlopidine treatment in order to provide protection against thromboembolism. The necessity for this tactic is not apparent. A. Safety The use of ticlopidine is associated with relatively high rates of adverse experiences (Table 9). The most common or serious side eﬀects involve allergic reactions (skin eruptions), gastrointestinal-hepatic side eﬀects, or hematological complications. Generally, the adverse reactions become overt during the ﬁrst days or weeks after starting treatment with ticlopidine. Ticlopidine does prolong the bleeding time, and surgeons usually request that medication be stopped prior to elective surgery. Still, the frequency of major hemorrhagic complications, including serious intracranial bleeding, is relatively low. In comparison to aspirin, the rate of serious gastrointestinal bleeding is low [233]. A physician can anticipate that bleeding complications will be more frequent if ticlopidine

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and aspirin are given in combination than when either medication is prescribed as a monotherapy. Diarrhea and gastrointestinal distress are the most common side eﬀects [233–235]. Patients often complain of an upset stomach or epigastric distress following ingestion of ticlopidine. These symptoms can be alleviated if the medication is taken with food. Sheikh et al. [236] recently reported that upper gastrointestinal mucosal changes were relatively common among persons taking ticlopidine, and the rate of gastric changes is almost as high as among patients taking nonsteroidal anti-inﬂammatory agents, including aspirin. While the use of ticlopidine is associated with a change of bowel habits in a large number of patients, some people will have a severe diarrhea that necessitates stopping the medication. For others, a reduction in the dose of ticlopidine can ease the gastrointestinal symptoms. Rare cases of cholestatic hepatitis, jaundice, interstitial pulmonary disease, interstitial nephritis, or arthritis have been attributed to ticlopidine [237–243]. Severe skin eruptions, including generalized urticaria, can complicate the medication. These allergic reactions will mandate stopping the medication. The most worrisome adverse eﬀects of ticlopidine are hematological and include neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura (TTP), and the hemolytic–uremic syndrome [244–249]. Most hematological reactions occur within 3 months of starting therapy, with the highest risk period being at approximately 2–4 weeks. Although mild declines in white blood cell count often follow the onset of ticlopidine treatment, more severe reductions occur in<1% of patients [233,234]. The neutropenia can progress to agranulocytosis. The cause of neutropenia is not known, but it may be related to an idiosyncratic arrest in the maturation of white blood cell precursors in the bone marrow. A potential relationship may exist between the formation of thiophene-S-chloride by activated neutrophils and the development of agranulocytosis [250]. Although secondary opportunistic infections can unmask the neutropenia, most patients are asymptomatic. Because of the risk of neutropenia, patients prescribed ticlopidine should have their white blood cell count checked every 2 weeks during the ﬁrst 3–4 months after starting the medication. If the neutrophil count declines, the ticlopidine should be discontinued. In most cases, the white blood cell count recovers over the next few days. Some patients will need to be hospitalized to treat the infection. Seriously ill patients with ticlopidine-induced agranulocytosis can be treated with granulocyte colony-stimulating factor as an interim measure [251]. The frequency of ticlopidine-associated TTP is <0.5%. Steinhubl et al. [252] estimated a frequency of 0.02% among patients receiving ticlopidine as an ancillary therapy for treatment of patients undergoing coronary endovascular procedures. In general, the complication appears within 1 month of starting the medication [245]. Ticlopidine-associated TTP appears to be secondary to the development of an antibody to von Willebrand factor metalloprotenase that leads to circulation of large von Willebrand factor proteins [253,254]. Direct interaction with circulating platelets with dysfunctional endothelial cells leads to a microangiopathy [255]. The symptoms of TTP include purpura, skin ischemia, hemolysis, fever, and neurological impairments, especially confusion or encephalopathy. The hemolytic–uremic syndrome can be associated with the TTP [255–257]. Bennett et al. [245] found that mortality of ticlopidine-associated TTP is approximately 50%. Some patients may be asymptomatic, and the decline in platelet count will be found during hematological monitoring. Patients should have their platelet count assessed every 2 weeks during the ﬁrst 3–4 months after starting treatment. Still, the decline in platelet count can be precipitous, and regularly scheduled hematological assessments might miss the drop. The ticlopidine should be stopped if thrombocytopenia develops, and if the patient is seriously ill, plasma exchange should be performed [258,259].

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B. Efficacy Several clinical trials tested the eﬃcacy of ticlopidine in preventing ischemic events in a variety of clinical settings. It was found to be superior to aspirin in treatment of patients with unstable angina pectoris, intermittent claudication, and diabetic retinopathy [232,235,260,261]. An Italian study that enrolled patients with a recent myocardial infarction did not ﬁnd a superiority of ticlopidine over aspirin [262]. Another trial found a decline in ischemic events when ticlopidine was given prior to coronary artery stenting [263]. Machraoui et al. [264] reported that monotherapy with ticlopidine was as eﬀective as the combination of ticlopidine and aspirin in preventing ischemic events following coronary artery stenting. Ticlopidine is eﬀective in reducing periprocedural complications of coronary artery angioplasty; in this setting, it is often combined with aspirin [265–270]. Two large stroke-prevention trials tested the utility of ticlopidine [233,234]. In a placebocontrolled trial that enrolled patients with recent stroke, Gent et al. [234] reported 106 events among 525 patients treated with ticlopidine and 134 of 528 patients treated with placebo. In a direct comparison with aspirin (1300 mg/day), Hass et al. [233] found an approximately 12–18% relative risk reduction with ticlopidine. The diﬀerences were most dramatic within the ﬁrst year of treatment [271]. Identiﬁed subgroups in which ticlopidine appeared to be particularly eﬀective include women, African–Americans, patients with carotid stenosis, and those with more prolonged ischemic events or vertebrobasilar symptoms [272–274,274–277]. The Antiplatelet Trialists Collaboration concluded that ticlopidine was associated with an overall 34% relative risk reduction in ischemic events [147]. Several studies have evaluated the potential eﬃcacy of the combination of ticlopidine and aspirin in contradistinction to aspirin alone. They have demonstrated a reduction in the risk of thrombosis following coronary artery or cerebrovascular endovascular procedures. C. Conclusions The clinical trials demonstrate the eﬃcacy of ticlopidine in presenting ischemic events, including stroke, in patients with a variety of high-risk diseases. The agent is eﬀective when given as a monotherapy, in which case it appears to be superior to aspirin. It also is eﬃcacious when given in combination with aspirin. Despite its strong record of eﬃcacy, safety-related issues are a major impediment to the use of ticlopidine. Because of the relatively high rate of serious side eﬀects and because of the development of alternative medications, physicians often prescribe other antiplatelet-aggregating agents in lieu of ticlopidine. In particular, the high risk for hematological complications, which can be severe, and the subsequent need for frequent monitoring limit the usefulness of ticlopidine. Patients and their families need to be aware of the risks of this medication and the steps needed to assure safety. On the other hand, patients that tolerate the medication and do not develop serious side eﬀects within the ﬁrst 3–4 months seem to tolerate the medication very well on a long-term basis. Although ticlopidine should not be considered as the primary antiplatelet medication to prevent stroke, it is indicated for patients who continue to have ischemic symptoms despite treatment with other agents.

VIII. CLOPIDOGREL Clopidogrel is structurally and pharmacologically similar to ticlopidine [150,228,278]. Like ticlopidine, it produces an irreversible dose-dependent eﬀect on platelet aggregation and

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prolongation of the bleeding time [279]. Clopidogrel appears to work by the development of a disulﬁde bridge between thiol components of its metabolite with a cysteine residue of the platelet ADP receptor [280] (Table 10). The agent is readily absorbed, and some inhibition of platelet aggregation occurs within hours of starting the medication [150,281,282]. While the usual daily dose is 75 mg, initiating therapy with a dose of 300–600 mg can accelerate the antithrombotic eﬀects of clopidogrel [281,283,284]. This eﬀect was the impetus for a clinical trial that tested the utility of adding clopidogrel to aspirin for treating patients with unstable cardiac disease [284,285]. The antithrombotic eﬀects of clopidogrel recover over approximately 7 days following stopping the medication [286]. A. Safety The safety proﬁle of clopidogrel is superior to that found with ticlopidine (Table 9). Gastrointestinal distress, diarrhea, and skin eruptions can occur [229,287,288]. The risk of serious hemorrhage, including gastrointestinal bleeding, is low [287,289]. An interaction between clopidogrel and celecoxib has been associated with a propensity for bleeding [290]. Neutropenia seems uncommon, although aplastic anemia has been reported [291,292]. Like ticlopidine, clopidogrel has been implicated in cases of thrombocytopenia or TTP [248,293–297]. Cases of hemolytic–uremic syndrome and TTP have followed treatment with clopidogrel [298–300]. The risk of TTP seems much lower than with ticlopidine. Still, the cases have been serious, and some patients have required prolonged courses of treatment with plasma exchange. Hepatic dysfunction has also been correlated with the use of clopidogrel [301]. B. Efficacy Several trials evaluated clopidogrel alone or in combination with aspirin. The key study was a direct comparison of clopidogrel (75 mg/day) or aspirin (325 mg/day) in a very large trial that enrolled patients with coronary artery disease, cerebrovascular disease, or peripheral artery disease [302]. The overall results of the trial demonstrated a modest superiority of clopidogrel over aspirin in preventing myocardial infarction, stroke, or vascular death, but the beneﬁt was conﬁned largely to those patients who initially had symptoms of peripheral vascular disease. A trend in favor of clopidogrel was noted among patients whose qualifying symptoms were either a TIA or ischemic stroke. Bhatt et al. [303] found that clopidogrel was superior to aspirin in preventing ischemic events among patients with a history of coronary bypass graft surgery. Since then, clopidogrel has been tested primarily in combination with aspirin, often as a substitute for ticlopidine. Most of the research has involved patients with acute cardiovascular disease, including those who are having endovascular procedures. The trials have demonstrated that the combination of medications is more eﬃcacious than monotherapy with aspirin [285,304]. Emergent administration of clopidogrel (300 mg initial dose) in combination with aspirin was eﬀective in preventing death, recurrent cardiac events, or stroke among patients with unstable heart disease. Another trial conﬁrmed the utility of a loading dose of clopidogrel in treatment of patients with acute coronary artery syndromes [288]. In other trials, the eﬀectiveness of the combination of clopidogrel and aspirin appears to be similar to that achieved with ticlopidine and aspirin [305–312]. Based on a meta-analysis of the studies testing therapies following stenting, Bhatt et al. [313] concluded that clopidogrel should replace ticlopidine as the adjunct to aspirin. The combination of aspirin and clopidogrel can be associated with an increased

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risk of perioperative bleeding if a patient having an endovascular procedure needs a subsequent vascular operation [314]. Albers and Amarenco [315] have cautioned that the results of some of these cardiovascular trials cannot be extrapolated to treatment of patients with ischemic cerebrovascular disease because of the diﬀerences between persons with heart disease and those with recent stroke.

C. Conclusions The eﬃcacy and safety of clopidogrel appear to be similar to that achieved with aspirin. While some experts have emphasized the potential superiority of clopidogrel among patients with symptomatic atherosclerotic disease, others have questioned whether monotherapy with clopidogrel is better than treatment with aspirin alone [287,316]. In general, clopidogrel can be considered as equal to aspirin in preventing stroke among patients with ischemic cerebrovascular disease [229,317]. Two analyses have been unable to demonstrate the cost-eﬀectiveness of clopidogrel in comparison to aspirin [220,318]. Although a number of adverse experiences have been attributed to clopidogrel, the widespread use of the medication and the relatively few reports suggest that clopidogrel is relatively safe. There seems to be a relationship between clopidogrel and TTP, but the frequency of this complication seems to be much less than with ticlopidine. Because the two medications aﬀect platelet aggregation in diﬀerent ways, the combination of aspirin and clopidogrel is particularly interesting. The results of the studies testing the combination for treating patients with unstable heart disease show reasonable safety and improved eﬃcacy. Planned or ongoing trials are testing the combination of clopidogrel and aspirin versus clopidogrel alone or clopidogrel and aspirin versus aspirin alone among patients with recent TIA or ischemic stroke. Clopidogrel is an important therapeutic alternative for prevention of stroke. It would be the ﬁrst treatment to prevent stroke among some highrisk patients, such as those with an intolerance or allergy to aspirin. The combination of clopidogrel or aspirin could also be prescribed to patients who have had recurrent symptoms despite treatment with aspirin or clopidogrel alone.

IX. OTHER ANTIPLATELET AGENTS The Canadian Cooperative Trial found that sulﬁnpyrazone was not eﬀective in preventing ischemic events among patients with a recent TIA or ischemic stroke [179]. In a clinical trial, indobufen was found not to be as eﬀective in preventing stroke as was ticlopidine [319]. No data are available about the potential utility of ibuprofen or the newer cyclooxygenase 2 inhibitors. The utility of the new glycoprotein IIb/IIIa receptor blocking agents in treating acute stroke is being assessed in clinical trials [320,321]. These agents given alone or in conjunction with aspirin have not been demonstrated as eﬀective [322,323].

X. PENTOXIFYLLINE Pentoxifylline can aﬀect the deformability of erythrocytes, shear stress, ﬁbrinogen concentrations, viscosity, and platelet aggregation [324]. Although the medication is pre-

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scribed frequently to persons with peripheral artery disease, its utility in preventing stroke has not been tested extensively. A small clinical trial, which tested pentoxifylline in combination with ticlopidine, suggested that the medications might be useful [325]. No additional data are available.

XI. COMBINATIONS OF MEDICATIONS Because several medications aﬀect platelet aggregation by diﬀerent mechanisms, combining these agents could provide better protection against serious ischemic events than would each of the medications when administered alone. For example, Harker [279] found that aspirin augments the antiplatelet eﬀects of clopidogrel. The combinations also could be associated with an increased risk of serious bleeding complications. Because ticlopidine and clopidogrel are similar pharmacologically, the simultaneous use of both medications is not indicated. On the other hand, clopidogrel, ticlopidine, or dipyridamole has been tested in combination with aspirin. A medication that consists of aspirin and extended-release dipyridamole is already being used as stroke prophylactic therapy. In addition, physicians now are prescribing the combination of clopidogrel and aspirin. While there are sensible reasons to prescribe this combination, it is not clear that concomitant aspirin and clopidogrel should be the initial therapy for most high-risk patients. The combination could be reserved for treatment of those patients who have recurrent symptoms despite monotherapy. However, this strategy has not been tested either. Antiplatelet agents can be used in conjunction with oral anticoagulants. A British trial found that aspirin combined with low-intensity warfarin was more eﬀective than aspirin given alone for preventing death or myocardial infarction [326]. Hurlen et al. [327] tested adjusted-dose warfarin (INR 2.5–4.2) or warfarin (INR 2.2–2.8) and aspirin 150 mg/day in a very large trial. No signiﬁcant diﬀerences in the rates of bleeding were noted. Still, the combination of aspirin and low-dose warfarin was not as eﬀective as adjusteddose warfarin in preventing ischemic events among patients with nonvalvular atrial ﬁbrillation [90,99]. Additionally, Lechat et al. [328] found that the combination of aspirin and an anticoagulant (ﬂuindione) was associated with an increased rate of bleeding complications among patients with atrial ﬁbrillation. Still, the addition of aspirin or dipyridamole to warfarin is recommended for treatment of patients with prosthetic cardiac valves, especially in circumstances when a patient has neurological symptoms despite adequate levels of anticoagulation [65]. Most trials tested aspirin and warfarin. To date there is no information about the usefulness of warfarin with either clopidogrel or ticlopidine. Presumably, the issues related to both eﬃcacy and safety will be raised if these combinations are evaluated.

XII. SELECTION OF ANTITHROMBOTIC MEDICATIONS TO PREVENT STROKE Clinical trials on antithrombotic medications cannot provide information about the safety and eﬃcacy of speciﬁc therapies for patients with all types of ischemic cerebrovascular disease. The diversity of causes, clinical symptoms, concomitant medical problems, and other treatments means that the trials can provide only a framework on which to make decisions for medications to prevent ischemic stroke or recurrent ischemic stroke. Some basic principles do apply. These medications are additions to the therapies that are aimed

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at controlling risk factors that lead to accelerated atherosclerosis. These medications can be supplemented by local interventions, including vascular or cardiac operations or endovascular procedures. In addition, responses to prior treatment, the patient’s overall health and personal preferences, and the presence of speciﬁc contraindications (such as allergies) will inﬂuence decisions about treatment (Table 12). Patients with cardiac diseases judged to be at high risk for cardioembolism, including most structural heart diseases complicated by atrial ﬁbrillation, should be treated with long-term oral anticoagulant therapy unless a speciﬁc contraindication is present. The evidence to support this recommendation is exceedingly strong (Table 13). The adjusteddose warfarin regimen should attempt to achieve an INR of 2–3, with the exception of patients with mechanical prosthetic valves who need a slightly higher level of anticoagulation (INR 2.5–3.5). The level of anticoagulation should be checked if a patient develops ischemic symptoms despite treatment with warfarin. If the INR is below therapeutic levels, the dosage of medication should be increased. At present there are no data to support a recommendation of ﬁxed, low-dose warfarin therapy for prevention of ischemic stroke. Similarly, there is no information to support the widespread recommendation to give warfarin to patients with low- to intermediate-risk cardiac lesions or advanced atherosclerotic disease of the aorta. An antiplatelet agent, usually aspirin 81 mg/ day or dipyridamole 400 mg/day, can be added to warfarin if a patient with a high-risk cardiac lesion has ischemic symptoms despite a therapeutic INR. While clopidogrel could be added to warfarin in lieu of aspirin, there are insuﬃcient data to support this combination of medications. Patients with high-risk cardiac lesions who are judged to have a great risk of serious complications from anticoagulation usually are treated with aspirin 325 mg/day. Patients with an inherited or acquired pro-thrombotic cause of stroke usually are treated with anticoagulants. However, the utility of anticoagulation has not been tested, and in the future, antiplatelet therapies might increase in importance. In addition, patients with platelet disorders (thrombocytosis) are usually treated with aspirin. Antiplatelet agents are the preferred therapy for patients with arterial causes of stroke, including large artery atherosclerosis or small artery disease, or for patients who have no deﬁnitive cause of stroke identiﬁed (Table 14). At present, the choices are aspirin

Table 12 Clinical Factors That Inﬂuence Decisions for Prescribing Antithrombotic Agents Presumed cause of symptoms Plans for surgical interventions Previous antithrombotic treatment Complications from previous antithrombotic treatment Contraindications (i.e., allergies) for speciﬁc medications Clinical variables: Age Overall health Other conditions that require antithrombotic treatment Issues related to compliance (dementia, alcoholism) High risk for complications (falls, trauma) Other medications that could interact with treatment Availability of clinical and laboratory follow-up Wishes of the patient

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Table 13 Interventions for Prevention of Cardioembolic Stroke Patient has a high-risk cardiac lesion? Yes: Treatment with warfarin (INR 2–3) No: Treatment with antiplatelet agent or warfarin Patient has mechanical prosthetic heart valve? Yes: Treatment with warfarin (INR 2.5–3.5) No: Treatment with warfarin and aspirin (81 mg/day) Patient has neurological symptoms despite treatment with warfarin? Yes: INR is subtherapeutic—increase dose of warfarin Yes: INR is therapeutic—add aspirin (81 mg/day) or dipyridamole (400 mg/day) Patient also has atherosclerotic disease? Yes: Possibly add antiplatelet agent Patient has a contraindication for treatment with warfarin? Yes: Aspirin 325 mg/day

(81–325 mg/day), aspirin and extended-release dipyridamole (50 mg/400 mg/day), or clopidogrel (75 mg/day). Because of the side eﬀects, ticlopidine (500 mg/day) probably has become a second-line option. Antiplatelet agents are an important component of management of patients who are having cerebrovascular operations including carotid endarterectomy. For patients who have neurological symptoms and who have not had any prior therapy, aspirin is a very reasonable ﬁrst choice. Aspirin is usually prescribed to patients having surgery. However, treatment with either clopidogrel or the aspirin/extended-release dipyridamole is a reasonable alternative. These medications are particularly indicated if a patient has recurrent symptoms despite aspirin. There is no reason to increase the dose if a patient has recurrent symptoms during treatment with 81–325 mg of aspirin. A combination of clopidogrel and aspirin can be prescribed if a patient has recurrent symptoms despite treatment with either agent alone. The combination of medications is not a ﬁrstline treatment option for most patients. The exception would be management of patients

Table 14 Interventions for Prevention of Stroke in Patients with Arterial Disease Patient has symptoms secondary to large artery atherosclerosis? Yes: Antiplatelet agent [(aspirin 81–325 mg/day), (aspirin/extended-release dipyridamole 50/400 mg/day), (clopidogrel 75 mg/day), (ticlopidine 500 mg/day)] Yes: Surgical reconstruction and antiplatelet agent Yes: Endovascular treatment and combination of aspirin 81–325 mg/day and clopidogrel 75 mg/ day Patient has symptoms secondary to small artery disease? Yes: Treat similar to those persons with large artery atherosclerosis Patient has symptoms secondary to noninﬂammatory vasculopathy? Yes: Treat similar to those persons with large artery atherosclerosis Patient has stroke of undetermined etiology? Yes: Treat similar to those persons with large artery atherosclerosis Patient has a contraindication for treatment with aspirin? Yes: Clopidogrel 75 mg/day Patient has recurrent symptoms despite treatment with aspirin? Yes: Aspirin/extended-release dipyridamole 50/75 mg/day or clopidogrel 75 mg/day or add clopidogrel to aspirin

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who have had endovascular procedures. In this situation, a short course of clopidogrel (approximately 6 weeks of treatment) is added to the aspirin. The results of future clinical trials likely will change these recommendations. The roles of both anticoagulants and antiplatelet agents will likely grow. The use of varying combinations of medications will probably expand. The regular use of antihypertensive or cholesterol-lowering therapies as adjuncts to antithrombotic agents may change the indications for individual medications.

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16 Surgical Management Options to Prevent Ischemic Stroke Brian E. Snell and Robert J. Wienecke University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, U.S.A.

Christopher M. Loftus The University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, U.S.A.

I. CAROTID ARTERY ATHEROSCLEROTIC DISEASE Stroke resulting from atherosclerosis is a common cause of death in the United States. It results in approximately 150,000 deaths per year [1,2]. Approximately 400,000–500,000 new strokes are reported annually, among which there is a 20–50% recurrence rate within 5 years [1,3]. Stroke is also the leading cause of long-term physical and intellectual disability among adults [4]. Race, gender, and vascular risk factors may inﬂuence the distribution of atherosclerosis. Premenopausal women and Japanese, Chinese, Thai, and African-American populations are more likely to develop intracranial disease, whereas Caucasians and those with hypercholesterolemia are more likely to develop extracranial disease [5]. The most common extracranial sites for atherosclerotic disease are the carotid bifurcation, the subclavian arteries, and the proximal vertebral arteries [6,7]. The process of atherosclerosis is thought to occur at these sites secondary to the combined eﬀects of turbulence, blood stagnation, hemodynamic sheer stress, and boundary separation [8]. The ratio of internal carotid artery area to common carotid artery area and the bifurcation angle result in a geometry at the bifurcation which produces vortex ﬂow and increased contact of atherogenic substances and platelets with the site of maximal plaque development [9]. This view of atherogenesis is referred to as the ‘‘response-to-injury’’ hypothesis [10,11]. According to this hypothesis, a variety of forces injure the endothelium, and the inﬂammatory response to this injury results in plaque development. Factors that may cause endothelial injury include hypercholesterolemia, cigarette smoking, hypertension, oxidative stress, advanced glycation end products, and possibly infection [12]. Injury induces endothelial gene expression of platelet and leukocyte adhesion molecules and molecules involved in growth factor, cytokine, and coagulation protein synthesis [13,14]. Increased permeability secondary to endothelial injury allows monocytes and low-density lipoprotein to enter the intima. Monocyte-derived macrophages secrete mitogens, which induce smooth muscle cell egress into the intima, with subsequent proliferation and extracellular collagen and proteoglycan synthesis. Oxidized lipoproteins ﬁll macrophages, 351

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turning them into foam cells, which may rupture and release lipid and cytotoxic enzymes. This increases the ﬁbroproliferative response of the smooth muscle cells [15]. Also, injured endothelium is more thrombogenic secondary to decreased expression of nitric oxide, prostacyclin, and ﬁbrinolytic and antithrombotic glycoproteins [14]. Stroke is deﬁned as a sudden, nonconvulsive, focal neurological deﬁcit. It is characterized by a speciﬁc temporal proﬁle, which includes abrupt onset of a neurological deﬁcit, followed by subsequent arrest, and then regression in all but the most severe strokes. The type of neurological deﬁcit is dependent upon the involved vascular territory, but can include hemiplegia, mental confusion, varied sensory deﬁcits, aphasia, visual ﬁeld defects, diplopia, dizziness, or dysarthria [16]. Atherosclerotic narrowing and ulceration at the carotid bifurcation is a major cause of thromboembolic stroke. The results of several prospective, randomized trials for symptomatic and asymptomatic carotid occlusive disease have provided evidence-based data for treatment of same. By 1990, seven trials were planned or in progress. Four of these trials addressed asymptomatic carotid occlusive disease [Carotid Artery Stenosis Asymptomatic Narrowing Operation Versus Aspirin (CASANOVA) study, Mayo Asymptomatic Carotid Endarterectomy (MACE) study, Veterans Administration Asymptomatic Stenosis Trial (VAAST), and Asymptomatic Carotid Atherosclerosis Study (ACAS)]. Study subjects could not have symptoms from ipsilateral cerebral ischemia secondary to carotid occlusive disease, although contralateral symptoms were permitted in VAAST and ACAS. The four trials used similar exclusion criteria. Patients with neurological (e.g., seizures, dementia), cardiac (e.g., atrial ﬁbrillation, severe valvular disease), or general medical conditions (e.g., diabetes, renal failure) that might aﬀect stroke outcome were also excluded [17]. There is one ongoing asymptomatic carotid surgery randomized trial in the United Kingdom and Europe, the ACST trial [55]. No results are available from this trial at the present time. The CASANOVA study randomized patients from the general population to immediate surgery versus antiplatelet therapy alone and best medical management. Stenosis criteria was 50–90% by noninvasive testing or angiography. Both arms received best medical management including aspirin (1000 mg/d) and dipyridamole (225 mg/d). The follow-up was 3 years, and the study size was 410 patients. Endpoints were death and stroke. Two hundred and six patients were randomized to immediate surgery, and 204 patients were randomized to antiplatelet therapy alone. One hundred and eighteen of the 204 patients in the nonsurgical arm had delayed endarterectomy during the follow-up period secondary to transient ischemic attack (TIA), progressive severe stenosis (>90%), bilateral stenosis (>50%), or contralateral stenosis (>50%). The study found no statistically signiﬁcant diﬀerence in outcome between the surgical and nonsurgical arms (10.7% and 11.3%, respectively) [18]. The unusual study design of CASANOVA limits its statistical validity. The MACE study enrolled 71 patients with >50% stenosis by noninvasive testing. The planned follow-up was 2 years. The nonsurgical arm received best medical management and aspirin (80 mg/d). The surgical arm did not receive aspirin. Only Mayo Clinic patients were randomized to the treatment arms. The study was terminated prematurely because of increased frequency of myocardial infarction in the surgical arm that did not receive aspirin. At termination, too few patients were enrolled to assess statistical signiﬁcance. It was concluded that aspirin was appropriate for the perioperative and postoperative period unless contraindicated [19]. The VAAST enrolled only men from VA centers and randomized them to surgical and nonsurgical arms, both of which received best medical management and aspirin

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(1300 mg/d). Stenosis criteria was >50% by angiography. The follow-up was 5 years, and the study population was 444 patients (211/444 surgical and 233/444 nonsurgical). Participating centers were screened for perioperative morbidity and mortality of <3%. At 4-year follow-up the combined incidence of ipsilateral TIA or stroke was 8% and 20.6% for the surgical and nonsurgical arms, respectively ( p < 0.001). The sample size was not large enough to show statistical signiﬁcance for stroke alone [20]. The ACAS randomized 1662 patients with >60% stenosis (by angiography or Doppler ultrasound) to surgery versus best medical management. All patients received daily aspirin (325 mg). Nonwhite populations comprised only 5% of the study group. The projected risk of ipsilateral stroke at 5 years (mean follow-up of 2.7 years) was 5.1% for the surgical group and 11% for medical management. This represented an overall relative risk reduction of 53%. This risk reduction was more apparent for men and independent of degree of stenosis or contralateral disease. The calculated stroke risk for the medical management arm was 2.2% per year. The perioperative risk of stroke and death was 2.3% plus an additional risk of 1.2% for arteriography. Surgical beneﬁt was noted at 10 months postrandomization and remained statistically signiﬁcant at 3 years [21]. Three trials focused on symptomatic carotid occlusive disease [North American Symptomatic Carotid Endarterectomy Trial (NASCET), Veterans Administration Symptomatic Stenosis Trial (VASST), and European Carotid Surgery Trial (ECST)]. All three trials were terminated early. NASCET and VAAST maintained that participating centers must have surgical morbidity rates of <6%. Inclusion criteria were relatively similar among the trials and included transient retinal ischemia, transient cerebral ischemia, or minor completed stroke within 120 days of randomization in the distribution of the carotid lesion [22]. The ECST stenosis criteria was 0–99%. The trial randomized 3018 patients: 1807 to surgery and 1211 to best medical management. The trial was terminated early at an interim analysis of 2200 patients. Follow-up was 5 years, with a mean of 2.7 years for those <30% stenosis and 3.0 years for those >70% stenosis. Sample size was 374 for the <30% group and 395 for the >70% group. The primary endpoint was ipsilateral stroke. The mild stenosis group (<30%) revealed no statistically signiﬁcant diﬀerence between surgical and nonsurgical arms with respect to stroke incidence. The severe stenosis group (>70%) revealed a beneﬁt to the endarterectomy arm with a 10.3% total risk of stroke (i.e., 7.5% risk of stroke or death within 30 days plus an additional 2.8% risk of stroke) versus a 16.8% risk in the nonsurgical arm. The total 3-year risk of disabling or fatal stroke was 6.0% versus 11.0% in the surgical versus nonsurgical arms, respectively. Surgical beneﬁt outweighed best medical management risk in patients with 70–80% stenosis. This beneﬁt was realized 2–3 years status postrandomization [23]. ECST data reanalysis using NASCET criteria revealed a signiﬁcant surgical beneﬁt for patients with 70% stenosis. The NASCET was terminated early secondary to signiﬁcant risk reduction in patients with >70% stenosis in the surgical arm. Six hundred and ﬁfty-nine patients with symptomatic carotid stenosis between 70% and 99% were randomized to surgical (328 patients) and nonsurgical (331 patients) treatment arms. Ipsilateral stroke risk at 2-year follow-up was 9% for the surgical group versus 26% for the nonsurgical group. This represented a 71% relative risk reduction ( p < 0.001). According to same, one stroke could be prevented for every six to seven endarterectomies performed. A signiﬁcant correlation was noted between severity of stenosis and surgical beneﬁt. The protective eﬀect of endarterectomy was durable over time and independent of age, gender, and stroke risk factors [24]. At 5-year follow-up for 2226 patients with 50–69% stenosis randomized to nonsurgical and surgical arms, the ipsilateral stroke rate was 22.2% versus 15.7%

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(nonsurgical vs. surgical, p = 0.045). Author estimates were that 15 endarterectomies would have to be performed to prevent one stroke in a 5-year period. Those individuals with <50% stenosis did not beneﬁt from endarterectomy. Contralateral occlusion was a strong risk factor for stroke, though contralateral stenosis was not [25]. Timing of surgery did not aﬀect surgical risk. The VASST was terminated early secondary to preliminary results from the two aforementioned trials. Although 5000 patients were screened at 16 participating VA centers, only 193 men were randomized to best medical management (98 men) and surgical (91 men) treatment arms [26]. Angiography was performed on all patients and more than two thirds of the population had >70% stenosis. There was a mean follow-up of 11.9 months. Risk of stroke or crescendo TIA was 7.7% versus 19.4% (surgical versus nonsurgical; p = 0.028). Surgical beneﬁt in patients with >70% stenosis was 7.9% versus 25.6% (surgical vs. nonsurgical). Sample size at 50–69% stenosis was too small to draw any statistically signiﬁcant conclusions. Surgical beneﬁt was appreciated as soon as 2 months status postrandomization and was maintained throughout follow-up. Total perioperative risk was 5.5% (perioperative morbidity of 2.2% plus perioperative mortality of 3.3%). The above studies provide convincing evidence for the surgical treatment of carotid occlusive disease in asymptomatic patients with >60% stenosis and symptomatic patients with >50% stenosis. Note, however, that surgical beneﬁt for women in ACAS was not apparent and nonwhite patients comprised only 5% of the study population. Also, ACAS and VAAST surgeons and patients were speciﬁcally selected for low surgical risk. In the symptomatic carotid stenosis trials beneﬁt of endarterectomy was observed in the setting of low surgical risk. Surgical beneﬁt in nonselected populations may be less predictable. Endovascular techniques including angioplasty and stenting are alternatives to carotid endarterectomy for the treatment of carotid occlusive disease. At the present time endovascular techniques are indicated for patients who are not candidates for conventional open reconstruction. This may include patients with extremely high lesions and patients with medical contraindications to general anesthesia (pulmonary or cardiac). Some experts feel that recurrent carotid stenosis and patients with contralateral carotid occlusion are better treated by endovascular techniques; the senior author (CML) feels that in most cases these patients remain excellent surgical candidates and can be operated without undue risk in our experience. Several studies have demonstrated acceptable morbidity and mortality data for the use of carotid angioplasty and stenting in carotid stenosis. Diethrich et al. [27] reported on 110 patients (117 vessels), 79 of whom were asymptomatic and 31 of whom were symptomatic with stenosis greater than or equal to 70%. Two major and ﬁve minor neurological events resulted from the procedure, together representing 6.4% of the study population. TIAs were reported in ﬁve patients, with a 1.8% mortality. Asymptomatic occlusion occurred in 1.8% and 2.7% ultimately required endarterectomy for failure or restenosis. Yadav et al. [28] reported on 107 patients, with 189 stents placed into 126 carotid arteries. Mean stenosis was 78% preoperatively and 2% postoperatively. Eightytwo percent of these patients met NASCET criteria. There was a 10.8% complication rate for symptomatic patients and a 4% neurological event rate for asymptomatic patients. In follow-up, 4.9% experienced restenosis. The experience of Iyer [29] in 352 patients undergoing 384 procedures revealed a 0.7% major stroke rate, a 6% minor stroke rate, and 0.8% mortality. Nonneurological death occurred in 1.4%. Guterman and Hopkins [30] relayed their experience with 96 high medical risk patients with unstable angina or restenosis after endarterectomy. Patients with long stenotic segments or high carotid

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bifurcations were also included. Angioplasty and stent placement was undertaken in 62 patients, with the remainder receiving angioplasty alone. Two deaths of cardiac origin, two minor strokes, and no major complications were reported. The experience of Rosenwasser and Shanno [31] with 47 patients treated with angioplasty (45 of whom also had stents placed) revealed one major stroke 5 days postoperatively and one ‘‘cold foot,’’ which resolved with heparin therapy. Sixty-three percent required temporary pacing during inﬂation (29/47 patients). Their indications for endovascular treatment of carotid occlusive disease were radiation-induced stenosis, recurrent stenosis, medically unstable patients (with cardiac or pulmonary risk factors), and lesions at C1-2 or long lesions extending into the petrous segment. Complications of carotid endarterectomy include infection, bleeding, damage to local tissue structures (vessels, nerves, muscle), restenosis, myocardial infarction, stroke, and death. Complications applicable to endovascular techniques include pseudoaneurysm, arterial dissection or rupture, aberrant placement of prosthesis, infection, stroke, myocardial infarction, and death. In conclusion, there is convincing evidence for the surgical treatment of carotid occlusive disease in asymptomatic patients with >60% stenosis and symptomatic patients with >50% stenosis. Though more studies need to be performed to deﬁne long-term beneﬁt and durability of endovascular therapies for carotid occlusive disease, current studies are promising. For selected indications, e.g., radiation-induced stenosis, recurrent stenosis, medically unstable patients (with cardiac or pulmonary risk factors), and lesions at C1-2 or long lesions extending into the petrous segment, endovascular therapy is a viable alternative to surgical endarterectomy in selected centers with experienced teams.

II. VERTEBRAL ARTERY ATHEROSCLEROTIC DISEASE Atherosclerosis of the vertebral artery may produce vertebrobasilar insuﬃciency (VBI) or stroke by way of embolism, hypoperfusion, or both. The diagnosis of VBI requires two or more of the following: bilateral sensory and/or motor symptoms occurring during the same event, diplopia, dysarthria, or homonymous hemianopsia. ‘‘Dizziness’’ not explained by orthostasis or inner ear pathology may be a symptom of VBI. Because the vertebral arteries exist as a pair, hypoperfusion typically results from bilateral vertebral atherosclerosis or unilateral atherosclerosis in combination with unilateral congenital hypoplasia or atresia. The vertebral arteries arise from their respective subclavian arteries with the left vertebral artery being dominant in approximately 50–60% of cases [32]. The vertebral arteries begin their ascent through the transverse foramina at C6, and at the level of C2 break laterally to ascend through the transverse foramina of C1. Once through the transverse foramina of C1 the vertebral arteries course posteriorly along the atlas before turning superiorly and medial to pierce the atlanto-occipital membrane and dura. The intracranial vertebral arteries give rise to the posterior inferior cerebellar arteries and the anterior spinal artery before joining as the basilar artery. The left vertebral artery has an aortic arch origin in approximately 5% of cases, and in some 40% of cases the vertebral artery is hypoplastic [33]. A commonly used system for naming the vertebral artery was developed by Krayenbuhl and Yasargil [34]. The vertebral artery is divided into four portions, V1V4. V1 describes the ﬁrst portion of the vertebral artery extending from its origin to the C6 transverse foramen. The second portion, V2, is intraosseous, extending from the

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transverse foramen of C6 to that of C2. V3 portends to that portion of the vertebral artery between the transverse foramen of C2 and the point of posterior fossa entry by way of the foramen magnum. The fourth portion, or intracranial portion of the vertebral artery (V4), travels a short distance before joining its homologue to become the basilar artery. The above-described system of vertebral artery nomenclature facilitates discussion regarding anatomy and pathology and, germane to this chapter, areas of atherosclerosis and surgical treatment. In western society atherosclerosis is ubiquitous. The atherosclerotic lesion begins as an intimal fatty streak, which evolves over time to become a ﬁbrous plaque. The ﬁbrous plaque may grow to occlude or stenose the arterial lumen, or the plaque may rupture causing thrombosis or embolization. Risk factors for the development of atheromatous disease include hyperlipidemia, cigarette smoking, diabetes, hypertension, obesity, and a sedentary lifestyle. As noted by Fisher et al. [4], atherosclerosis seems to aﬀect the V1 segment primarily, but distal V4 segment disease is more commonly symptomatic. Subclavian steal of vertebral blood ﬂow may occur if a ﬂow limiting atherosclerotic plaque extends into the proximal subclavian artery. Very few published studies address the natural history of extracranial vertebral artery atherosclerotic occlusive disease. In 1984 Moufarrij et al. [35] published their data after following 96 patients with greater than 50% vertebral artery stenosis for approximately 4 years. They concluded that proximal vertebral artery atherosclerotic stenosis was a relatively benign condition when not associated with basilar artery atherosclerosis. Surgical treatment of extracranial vertebral artery atherosclerotic disease consists of endarterectomy, bypass grafting, or transposition. These surgical procedures are typically reserved for those individuals suﬀering from persistent vertebrobasilar insuﬃciency or transient ischemic attacks attributable to the vertebral artery. These procedures are made diﬃcult by the relative inaccessibility and small size of the proximal vertebral artery, and as such are fraught with a relatively high morbidity and mortality. Published morbidity and mortality data for proximal vertebral artery reconstruction varies greatly ranging between 1.9% and 20% [36–38]. Five-year patency rates vary between 75% and 80% [36,37]. Balloon angioplasty and stent-supported angioplasty are now being used with increasing frequency to treat symptomatic extracranial vertebral artery disease. Stentsupported angioplasty utilizes the intraluminal rigidity of a stent to prevent elastic recoil and early restenosis. In 1996 a review of 268 vertebral balloon angioplasties performed by Kachel [39] reported an overall success rate of 95%, no mortality, and 0.7% morbidity. Although no long-term outcome studies exist for vertebral stent-supported angioplasty, the short-term results are promising. Those patients with vertebrobasilar insuﬃciency or transient ischemic attacks attributable to the extracranial vertebral arteries are candidates for open surgical or endovascular revascularization procedures. Although no randomized prospective trial has compared the therapeutic eﬃcacy of medical (platelet inhibitors and systemic anticoagulation) versus surgical versus endovascular treatment of symptomatic vertebral disease, the Warfarin-Aspirin Symptomatic Intracranial Disease Study [40] found that patients with a symptomatic stenosis of a major intracranial vessel had fewer strokes when taking warfarin than when taking aspirin, and the results from this study are extrapolated to justify systemic anticoagulation in those with symptomatic extracranial atherosclerotic disease of the vertebral arteries. Certainly, surgical or endovascular procedures should be considered in those patients with a symptomatic stenosis of an extracranial vertebral artery who fail to respond to medical management.

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Patients who are too medically ill to undergo general anesthesia may be better candidates for long-term systemic anticoagulation or endovascular revascularization. There are no absolute contraindications to endovascular treatment of a symptomatic vertebral artery stenosis; however, a recent posterior circulation stroke associated with a tight vertebral artery stenosis is a temporary contraindication to surgical or endovascular revascularization secondary to concern of reperfusion hyperemia and the potentially disastrous consequence of hemorrhagic stroke conversion. The diagnosis of vertebral artery stenosis or occlusion is conﬁrmed with conventional angiography. Contrast-enhanced magnetic resonance angiography is constantly improving with the use of new pulse-sequences and software [41]; however, conventional angiography remains the deﬁnitive test in those patients suspected to have stenotic vertebral arteries. Duplex ultrasound screening of the proximal vertebral arteries is relatively unreliable [42]. As mentioned above, the therapeutic options for symptomatic stenosis of the vertebral artery include medical, surgical, and endovascular management. The modality of choice should be tailored to individual patient needs and expectations, and typically even with endovascular and surgical revascularization procedures antiplatelet drugs or anticoagulants are used in the short-term. Obviously, long-term systemic anticoagulation with warfarin is associated with signiﬁcant morbidity and mortality, and the risks and beneﬁts of any treatment modality must be discussed thoroughly with the patient. A longterm, multicenter, prospective, randomized trial is needed to establish reliable data and scientiﬁcally based recommendations regarding the treatment of extracranial vertebral artery atherosclerotic disease. Potential complications of surgical revascularization include death, damage to soft tissues, infection, bleeding, stroke, and early restenosis or occlusion. Endovascular revascularization carries similar risks, but complications related to arterial access (hematoma, infection, pseudoaneurysm) are included. Iatrogenic dissection has been described with endovascular techniques, but if evident at the time of treatment, placement of additional stents across the dissection is usually curative [38].

III. CAROTID AND EXTRACRANIAL VERTEBRAL ARTERY DISSECTION Carotid and vertebral artery dissection occurs either spontaneously or following trauma and is characterized by bleeding into the tunica media. Carotid dissection is more common than vertebral artery dissection [43]. Arterial dissection is a relatively common cause of stroke in the young, although dissections may occur at any age. Both vertebral and carotid dissection may be associated with headache (commonly ipsilateral), transient ischemic attack, stroke, or a palpable pulsatile mass in cases of pseudoaneurysm formation. Dissection may be asymptomatic and found incidentally on radiographic studies or it may be symptomatic. Vessel stenosis and thromboembolism typically results from bleeding between the intima and media, or alternatively, pseudoaneurysm formation may follow bleeding between the media and adventitia. Spontaneous dissection occurs more commonly in those predisposed by various disease states including ﬁbromuscular dysplasia [44], Marfan’s syndrome, atherosclerosis, and various arteritides. Dissections may also follow relatively innocuous trauma such as sneezing, coughing, or shaving. Iatrogenic dissection following arterial catheterization is well described [38].

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The natural history of extracranial carotid and vertebral dissection is largely unknown because those with asymptomatic lesions rarely seek medical attention, and those with symptomatic dissections are treated via a medical, surgical, or endovascular route. It is generally held that thrombus within the tunica media resolves over several weeks and that the arterial lumen returns to its normal size spontaneously. Dissection of the vertebral artery should be suspected in those complaining of severe spontaneous or posttraumatic neck pain associated with signs and symptoms of posterior circulation stroke or transient ischemia. A history of whiplash, a blow to the back of the neck, chiropractic manipulation, or cervical spine fracture should trigger suspicion of vertebral artery dissection. Vertebral artery dissection-induced pseudoaneurysms may produce a cervical radiculopathy, as described by Fournier et al. [45]. As mentioned above, carotid artery dissection may be associated with signs and symptoms of stroke or transient ischemia. A patient with Horner’s syndrome complaining of headache should be considered to have carotid artery dissection until proven otherwise. Arch and four-vessel cerebral angiography is the diagnostic modality of choice, but duplex ultrasound, magnetic resonance imaging, and computed tomography are reasonable alternatives if contraindication exists to conventional angiography. Duplex ultrasonography should not be relied upon in cases of potential vertebral dissection, as the proximal vertebral artery is not well visualized with ultrasound [42]. Angiography classically reveals an area of severe narrowing or occlusion following a gradually tapered lumen. Extracranial carotid artery dissections usually begin distal to the carotid sinus and extend for a variable distance before ending proximal to the petrous carotid [44]. Vertebral artery dissections most commonly occur between the C2 vertebral body and the skull base (V3 segment). In cases of vertebral or carotid artery dissection, medical management consisting of systemic anticoagulation should be started on an emergent basis. Typically, heparin provides immediate anticoagulation, while oral anticoagulants are allowed to take eﬀect. Systemic anticoagulation is contraindicated in those with stroke. Three to 6 months of anticoagulation is usually suﬃcient prophylaxis against propagation of intramural thrombus and distal embolization. Endovascular and surgical therapeutic modalities are reserved for those patients with dissection who remain symptomatic despite systemic anticoagulation. In cases of carotid dissection or pseudoaneurysm unresponsive or partially responsive to maximal medical therapy, attempts at open surgical bypass, external carotid to internal carotid bypass (ECIC bypass) combined with internal carotid ligation, or internal carotid ligation alone may be made. Most of these surgical procedures are treacherous given the relative inaccessibility of the high cervical carotid artery and the friable nature of pseudoaneurysms. Muller et al. [46] reviewed 50 surgeries performed for symptomatic carotid artery dissection or pseudoaneurysm formation. Forty-nine surgeries were performed for chronic symptomatology despite at least 6 months of anticoagulation, and one surgery was performed on a semi-emergent basis of ﬂuctuating neurological symptoms. In their series one patient died of intracranial bleeding, ﬁve patients suﬀered the development of recurrent minor strokes, and 58% developed cranial nerve deﬁcits, which, in most cases, were temporary. Medically intractable vertebral dissections and pseudoaneurysms may also be treated surgically [36,37]. Ligation of the vertebral artery may be performed with or without bypass. Test balloon occlusion may help predict which patients have adequate collateral blood ﬂow to withstand ligation of the carotid or vertebral arteries. Surgical ligation of the vertebral artery should take a common-sense approach with regard to the posterior inferior cerebellar artery (PICA). If the PICA takes oﬀ distal to the problematic area, then

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the dissection or pseudoaneurysm may be trapped between two ligatures. If the PICA originates within the area of dissection or pseudoaneurysm, one ligature may be placed just proximal to the PICA origin. In both of the above cases, the posterior inferior cerebellar artery will ﬁll in a retrograde fashion from the contralateral vertebral artery. Endovascular treatment of carotid and vertebral artery dissection and pseudoaneurysm has become feasible with the advent and optimization of coils and stents [47–49]. Recently described by Saito et al. [48] is the endovascular treatment of a spontaneous carotid artery dissection with symptomatic pseudoaneurysm formation. In their report, a self-expanding stent was used to cover the pseudoaneurysm neck while coils were passed through the stent into the pseudoaneurysm. Arteriography performed 4 months later conﬁrmed thrombosis of the pseudoaneurysm with preservation of internal carotid artery blood ﬂow. The patient reported symptomatic improvement. In 1999, Liu et al. [47] reported their 8-year experience of treating seven patients with symptomatic carotid artery dissections or pseudoaneurysms with stents. Four patients received stents for large, nonhealing pseudoaneurysms, and three patients received stents for severe preocclusive stenosis. In their series no deaths or signiﬁcant morbidity occurred, but one patient developed asymptomatic occlusion of the treated carotid artery, and one patient required coil embolization of a persistent pseudoaneurysm. Use of stent-supported angioplasty is also well described in the treatment of noncarotid extracranial cerebrovascular disease [39,50] and dissection [38]. Again, no long-term, prospective, randomized study has compared the eﬃcacy and complication rates for the surgical and endovascular treatment of carotid and vertebral artery dissection and dissection-induced pseudoaneurysm, but the seemingly good results and low complication rates associated with endovascular treatment modalities are impressive and should warrant strong consideration for endovascular treatment to be the modality of choice.

IV. ADDITIONAL LESIONS OF THE EXTRACRANIAL VERTEBRAL AND CAROTID ARTERIES Fibromuscular dysplasia (FMD) is an idiopathic angiopathy that may aﬀect the extracranial vertebral and carotid arteries. Pathologically, FMD is characterized by ﬁbrous thickening of the arterial tunica media. FMD aﬀects the arterial wall intermittently, giving on angiogram the classic ‘‘string-of-beads’’ appearance, and like carotid artery dissections, FMD typically aﬀects the internal carotid artery at least 2 cm distal to the common carotid bifurcation. The carotid artery is aﬀected in approximately 75% of cases, and the vertebral artery is aﬀected in up to 25% of cases. Bilateral involvement occurs in 60–75% of all cases [51]. FMD of the extracranial carotid and vertebral arteries predisposes to dissection, pseudoaneurysm formation, stenosis, and thromboembolic phenomena. Cases of symptomatic stenosis secondary to ﬁbromuscular dysplasia have traditionally been treated surgically with the graduated internal dilation technique [52], but in recent times endovascular stent-supported angioplasty has proven to be eﬀective in cases of simple stenosis and in cases of FMD-induced pseudoaneurysms [53]. Carotid artery injury secondary to penetrating neck wounds is a signiﬁcant cause for morbidity and mortality in the urban young. Carotid artery laceration or transection may be accompanied by exsanguination, or lesser injury may cause thrombosis, dissection, or pseudoaneurysm formation. Those patients who are hemodynamically unstable from a carotid artery injury should be taken immediately to the operative suite for repair,

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reconstruction, or ligation of the damaged artery. Patients with no neurological deﬁcit, or with a noncoma deﬁcit, should preferentially undergo carotid repair or reconstruction instead of ligation [54]. Comatose individuals may have the carotid artery ligated, and hemodynamically stable patients suspected to have a carotid injury should undergo angiography prior to neck exploration. Head and neck neoplasms that aﬀect the extracranial carotid or vertebral arteries should be, if possible, removed by dissecting the tumor oﬀ the vessel. If tumor invasion of the arterial wall has occurred, then various reconstructions may be employed. Preoperative test balloon occlusion of the extracranial vessels coupled with intraoperative monitoring may provide invaluable information in diﬃcult cases when sacriﬁce of an artery is considered. Carotid body tumors arise from paraganglion cells and are typically benign and slow growing. Surgical resection of these tumors classically is associated with a relatively high morbidity and mortality.

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17. Harrison GS, Mayberg MR. Prospective randomized studies for carotid endarterectomy. Neurosurg Clin North Am 2000; 11:225–227. 18. CASANOVA Study Group. Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke 1991; 22:1229–1235. 19. Weibers DO. Eﬀectiveness of carotid endarterectomy for asymptomatic carotid stenosis: design of a clinical trial. Mayo Clin Proc 1989; 64:897–904. 20. Hobson RW, Weiss DG, Fields WS, Goldstone J, Moore WS, Towne JB, Wright CB. Eﬃcacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 1993; 328:221– 227. 21. Asymptomatic Carotid Atherosclerosis Study Group. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421–1428. 22. Harrison GS, Mayberg MR. Prospective randomized studies for carotid endarterectomy. Neurosurg Clin North Am 2000; 11:227–232. 23. 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. 24. 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. 25. Barnett HJ. Status report on the North American Symptomatic Carotid Surgery Trial. J Mal Vasc 1993; 18:202–208. 26. Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991; 266:3289–3294. 27. Diethrich EB, Ndiaye M, Reid DB. Stenting in the carotid artery: initial experience in 110 patients. J Endovasc Surg 1996; 3:42–62. 28. Yadav JS, Roubin GS, Iyer S, Vitek J, King P, Jordan WD, Fisher WS. Elective stenting of the extracranial carotid arteries. Circulation 1997; 95:376–381. 29. Iyer S. Carotid angioplasty. Presented at the New York University Cerebrovascular Conference, New York, 1999. 30. Guterman L, Hopkins N. Carotid Angioplasty and Stenting. Philadelphia: American Association of Neurological Surgeons, 1998. 31. Rosenwasser RH, Shanno GB. Angioplasty and stenting for carotid atherosclerotic disease. Neurosurg Clin North Am 2000; 11:323–330. 32. Osborn AG. Diagnostic Neuroradiology. St. Louis: Mosby-Year Book, 1994:142–143. 33. Arnold V, Lehrmann R, Kursawe HK. Hypoplasia of the vertebrobasilar arteries. Neuroradiology 1991; 33(suppl):426–447. 34. Krayenbuhl H, Yasargil MG. Die vaskularen Erkrankungen im Gebiet der Arteria vertebralis und Arteria basilaris. Stuttgart: Thieme, 1957:1–170. 35. Moufarrij NA, Little JR, Furlan AJ, Williams G, Marzewski DJ. Vertebral artery stenosis: long-term follow-up. Stroke 1984; 15:260–263. 36. Berguer R, Flynn LM, Kline RA, Caplan L. Surgical reconstruction of the extracranial vertebral artery: management and outcome. J Vasc Surg 2000; 31:9–18. 37. Berguer R, Morasch MD, Kline RA. A Review of 100 consecutive reconstructions of the distal vertebral artery for embolic and hemodynamic disease. J Vasc Surg 1998; 27:852–859. 38. Fessler RD, Wakhloo AK, Lanzino G, Qureshi AI, Guterman LR, Hopkins LN. Stent placement for vertebral artery occlusive disease: preliminary clinical experience. Neurosurg Focus 1998; 5:41–45. 39. Kachel R. Results of balloon angioplasty in the carotid arteries. J Endovasc Surg 1996; 3:22– 30. 40. Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S, Pessin MS, Weichel E, Sila CA, Furlan AJ, Kargman DE, Sacco RL, Wityk RJ, Ford G, Fayad PB. The WarfarinAspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488–1493.

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41. Leclerc X, Gauvrit JY, Nicol L, Pruvo JP. Contrast-enhanced MR angiography of the craniocervical vessels: a review. Neuroradiology 1999; 41:867–874. 42. Ackerstaﬀ RG, Grosveld WJ, Eikelboom BC, Ludwig JW. Ultrasonic duplex scanning of the prevertebral segment of the vertebral artery in patients with cerebral atherosclerosis. Eur J Vasc Surg 1988; 2:387–393. 43. Leys D, Lesoin F, Pruvo JP, Gozet G, Jomin M, Petit H. Bilateral spontaneous dissection of extracranial vertebral arteries. J Neurol 1987; 234:237–240. 44. Anson J, Crowell RM. Craniocervical arterial dissection. Neurosurgery 1991; 29:89–96. 45. Fournier JY, Amsler U, Weder B. Extracranial vertebral artery dissection causing cervical root lesion. J Neuroimaging 2000; 10:125–128. 46. Muller BT, Luther B, Hort W, Neumann-Haefelin T, Aulich A, Sandmann W. Surgical treatment of 50 carotid dissections: indications and results. J Vasc Surg 2000; 31:980–988. 47. Liu AY, Paulsen RD, Marcellus ML, Steinberg GK, Marks MP. Long-term outcomes after carotid stent placement for treatment of carotid artery dissection. Neurosurgery 1999; 45:1368– 1373. 48. Saito R, Ezura M, Takahashi A, Yoshimoto T. Combined neuroendovascular stenting and coil embolization for cervical carotid artery dissection causing symptomatic mass eﬀect. Surg Neurol 2000; 53:318–322. 49. Simionato F, Righi C, Scotti G. Post-traumatic dissecting aneurysm of extracranial internal carotid artery: endovascular treatment with stenting. Neuroradiology 1999; 41:543–547. 50. Phatouros CC, Higashida RT, Malek AM, Meyers PM, Leﬂer JE, Dowd CF, Halbach VV. Endovascular treatment of noncarotid extracranial cerebrovascular disease. Neurosurg Clin North Am 2000; 11:331–350. 51. Goldberg HI. Angiography of extra- and intracranial occlusive cerebrovascular disease. Neuroimag Clin North Am 1992; 2:487–507. 52. Starr DS, Lawrie GM, Morris GC. Fibromuscular disease of the carotid arteries: long-term results of graduated internal dilation. Stroke 1981; 12:196–199. 53. Manninen HI, Koivisto T, Saari T, Matsi PJ, Vanninen RL, Luukkonen M, Hernesniemi J. Dissecting aneurysms of all four cervicocranial arteries in ﬁbromuscular dysplasia: treatment with self-expanding stents, coil embolization, and surgical ligation. Am J Neuroradiol 1997; 18:1216–1220. 54. Weaver FA, Yellin AE, Wagner WH, Brooks SH, Weaver AA, Milford MA. The role of arterial reconstruction in penetrating carotid injuries. Arch Surg 1988; 123:1106–1109. 55. Halliday AW, Thomas D, Mansﬁeld A. The Asymptomatic Carotid Surgery Trial (ACSI). Rationale and design. Steering Committee. Eur J Vasc Surg 1994; 8:703–710.

17 Thrombolysis for Acute Stroke John Marler National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.

I. INTRODUCTION Life is short, and Art long; the crisis ﬂeeting; experience perilous, and decision diﬃcult. The physician must not only be prepared to do what is right himself, but also to make the patient, the attendants, and externals cooperate. —Hippocrates [1]

Thrombolysis is directed at the immediate cause of 80% of acute strokes: brain artery occlusion by a blood clot. The concept of dissolving blood clots to treat stroke has been tested since the 1950s. Before 1990 most trials of thrombolyis used either urokinase or streptokinase. No beneﬁt was demonstrated. In 1996 the U.S. Food and Drug Administration (FDA) approved treatment of acute stroke with tissue plasminogen activator (rt-PA) after publication of the results of two trials performed by the National Institute of Neurological Disorders and Stroke. Treatment was approved for patients with ischemic strokes in whom treatment could be started within 3 hours of stroke onset. Thrombolysis can make a real diﬀerence to patients with acute stroke if given soon enough resulting in a signiﬁcant reduction in disability. However, there is a 6% risk of intracerebral hemorrhage attributed to rt-PA. This risk is thought to be even greater in patients who do not meet strict eligibility criteria. This risk reduces the likelihood that rt-PA will be used. In addition, few patients who have stroke recognize the symptoms and seek emergency medical treatment soon enough to be eligible for rt-PA. The result is that only 2% percent of patients with acute stroke actually are treated with rt-PA. Therefore, the challenge for the physician specializing in the treatment of stroke is to increase the success of treatment for those treated and to increase the number of patients treated. This requires many changes in the usual care for stroke patients and a clear understanding of the risks and beneﬁts. The investment of time and eﬀort early on in the emergency room has long-term payoﬀs in reduced disability and less rehabilitation and nursing home care. The changes required to gain these beneﬁts are not simple. Rapid treatment of patients soon after stroke onset requires a complex system involving many people with diﬀerent training who must work together and prepare ahead of time if their eﬀorts are to make a signiﬁcant diﬀerence. Successful eﬀorts will 363

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be rewarded by an increasing number of patients who return home after a stroke with minimal or no disability.

II. BACKGROUND Stroke is extremely common. Divided equally among the 4000 or so U.S. emergency departments, the estimated 750,000 strokes that occur each year in the United States would give each emergency department 175 strokes per year, or 3–4 per week. If 10–25% of stroke patients arrived within one hour of stroke onset, one to three acute stroke patients would potentially be eligible for thrombolytic treatment per month. Currently only 2% of stroke patients, or approximately 15,000 per year, are treated with rt-PA. If community use of rt-PA were to result in a 12% absolute increase in the number of patients with minimal or no disability at 3 months, as it did in clinical trials, then treating 2% of all stroke patients would increase the number of patients with minimal or no disability by 1800 U.S. patients per year.* Lesser beneﬁts would accrue to more patients. The estimated cost savings for this would be signiﬁcant, approximately $4000 per patient treated [2]. Increasing patient awareness and physician ability to use thrombolytic treatment could raise the treatment rate to 10–20%, resulting in signiﬁcantly improved outcomes with minimal or no disability for 9000–18,000 patients per year. Wider use of thrombolysis will require that more patients and their families recognize stroke when it happens and know to seek emergency medical care and that more physicians treat the patients who do arrive soon enough to be eligible to receive the treatment. Public and professional education campaigns by a number of diﬀerent voluntary and government organizations are ongoing. Other diﬃculties reduce the extent to which thrombolysis is used to treat acute stroke. For some physicians the risk of intracerebral hemorrhage seems too high, even though there are well-documented beneﬁts that outweigh the consequences of intracerebral hemorrhage. While tissue plasminogen activator is only the ﬁrst thrombolytic treatment for stroke, other agents or approaches to reperfusion may be safer and easier to use. Regardless of how thrombolysis is done, extensive changes in the current medical system are required to expedite the care of stroke patients. These systemic changes are very diﬃcult for a physician acting alone to eﬀect. Later sections in this chapter will address these diﬀerent problems.

III. THROMBOLYTIC AGENTS Clinical trials have evaluated or are currently evaluating several thrombolytic agents for treatment of acute ischemic stroke. These include streptokinase, urokinase, prourokinase, tissue plasminogen activator, tenecteplase, and reteplase. Two other agents are considered thrombolytic to some extent: ancrod, which lyses ﬁbrinogen, and abciximab, a monoclonal antibody that inhibits platelet function. Of these drugs, only tissue plasminogen activator has been approved for stroke treatment, and then only for very carefully selected patients. Tenecteplase, reteplase, and abciximab have been approved for coronary artery disease. The diﬀerent agents are discussed below in alphabetical order by their generic name.

* 600,000 ischemic strokes 2% 12% = 1440.

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A. Alteplase (Recombinant Tissue-Type Plasminogen Activator) Alteplase is the only thrombolytic drug approved for treatment of acute ischemic stroke. It was ﬁrst approved for treatment of acute myocardial infarction. There are two doses for myocardial infarction. One dose is a 3-hour 100-mg infusion beginning with 60 mg over one hour, with 10% given as an initial bolus over 1–2 minutes. The rest of the dose is given by continuous infusion at 20 mg per hour for 2 hours. The dose is reduced for patients who weigh less than 65 kg. An accelerated 90-minute dose regimen is also used for myocardial infarction. A 15 mg bolus is followed by a dose of 0.75 mg/kg (maximum 50 mg) infused over 30 minutes and then 0.50 mg/kg (maximum 35) infused over 60 minutes. Total dose for a 70 kg patient in the accelerated regimen would be 15 + 0.75 70 + 0.50 70 = 15 + 50 + 35 = 100 mg. The dose of alteplase for stroke is lower than that given for myocardial infarction. Prior to the larger stroke clinical trials, dose determination studies were performed to determine a best dose for treatment of acute stroke. The dose used for stroke was lower than the dose approved for myocardial infarction. The total dose approved for acute stroke treatment is 0.9 mg/kg up to a maximum of 90 mg, the ﬁrst 10% given as a bolus, followed by a 60-minute infusion. There have been six major randomized placebo-controlled trials of intravenous rtPA for use in acute stroke [3–7] (Table 1). Because these trials used a similar dose and similar outcome measures, it is possible to perform a combined analysis of data from all of the 2775 patients randomized within 6 hours of stroke onset in the six trials [8]. The median age of the 2775 patients was 68 years, the median baseline NIH Stroke Scale was 11, and median time from stroke onset to treatment was 4 hours. The odds ratios for favorable outcome ranged from 2.8 at 0–90 minutes to 1.2 at 271–360 minutes in favor of the rt-PA group (Table 2). Parenchymal hemorrhage II (PH2), deﬁned as a dense blood clot exceeding 30% of the infarct volume with signiﬁcant space-occupying eﬀect, occurred in 5.9% of rt-PA–treated patients and 1.1% of placebo-treated patients. The incidence of parenchymal hemorrhage was increased in older patients, but was not clearly related to the time from onset of stroke symptoms to treatment. It is clear from this analysis and a separate analysis of the NINDS-sponsored trials [9] that the sooner rt-PA is given following stroke, the greater the beneﬁt. Because it has been approved for use in the treatment of acute stroke within 3 hours since 1996, numerous reports on case series of patients given rt-PA are available. Intracerebral hemorrhage rates are similar to those reported in trials. The drug is given less

Table 1 Six Comparable Randomized Controlled Clinical Trials Testing rt-PA for Treatment of Acute Ischemic Stroke Study NINDS Part 1 NINDS Part 2 ECASS I ECASS II ATLANTIS A ATLANTIS B All

Patients

Baseline median NIHSS

Onset to treatment median (Min)

290 333 612 791 142 607 2775

14 15 12 10 11 10 11

109 104 270 265 268 274 243

Dose (mg/kg) 0.9 0.9 1.1 0.9 0.9 0.9

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Table 2 Odds Ratios for a Favorable Outcome at 3 Months Poststroke by Time Interval from Onset to Treatment for Six Randomized Trials of rt-PA for Acute Stroke Time interval (min) 0–90 91–180 181–270 271–360

Odds ratio for favorable outcome at 3 monthsa 2.81 1.55 1.40 1.15

(1.75, (1.12, (1.05, (0.90,

4.50) 2.15) 1.85) 1.47)

95% conﬁdence limitsb 2.81 1.55 1.40 1.15

(1.75, (1.12, (1.05, (0.90,

4.50) 2.15) 1.85) 1.47)

a

3-month favorable outcomes include Rankin (0–1 = favorable), Barthel (95–100 = favorable), and NIH Stroke Scale (0–1 = favorable). 1, 8, 9, and 6 patients from NINDS Part I, ECASS I, ECASS II, and ATLANTIS B, respectively, were excluded from this analysis as they were randomized after 360 minutes or OTT was not reported. b Odds ratios computed from global statistical approach [9] using intention-to-treat analysis. 12, 11, 33, 37, 83, and 47 patients from NINDS Part 1, NINDS Part 2, ECASS I, ECASS II, Atlantis A, and Atlantis B, respectively, were missing one or more outcomes at 3 months based on the ITT algorithm used in this report and were given the worst outcomes for those that were missing. In the original article on the NINDS trial only 1 patient in Part 1 and 4 patients in Part 2 are reported as missing outcomes. For the other 18 patients, a more complex algorithm was used to include data close to the missing 3-month visit as the ﬁnal outcome. Odds ratios were computed adjusting for age, baseline glucose level, baseline NIH Stroke Scale, baseline diastolic blood pressure, prior hypertension, and the interaction, between age and baseline NIH Stroke Scale.

often than would be desired, and when it is, more patients are probably treated close to the 3-hour deadline in practice than in the clinical trials where half the patients were treated within 90 minutes. Therefore, depending on the eﬀect of time, the beneﬁt may not be as much as predicted by the NINDS trials. In those studies looking for compliance with recommendations for use, the hemorrhage rate was higher when patients were treated who had one or more of the conditions speciﬁed in the contraindications or warnings for use in stroke. After an educational eﬀort to increase guideline compliance, a second study demonstrated a lower rate of intracerebral hemorrhage, 6.4%, compatible with what was observed in the trials [10]. In addition, a higher percentage of patients were treated after the training. In summary, it would seem that rt-PA is performing as predicted in trials, that there is unnecessary delay in treatment, and that the drug is not being oﬀered to all eligible patients. B. Ancrod Ancrod, which is similar to thrombin, is produced from the venom of the Malayan pit viper. It has three major systemic eﬀects promoting reperfusion: deﬁbrinogenation and decreased blood viscosity, clot lysis resulting from the deﬁbrinogenation, and anticoagulation. Ancrod has been tested for stroke in clinical three trials. The Ancrod in Stroke (AIS) study [11] was a randomized double-blind comparison of intravenous ancrod with placebo in 132 patients within 6 hours of stroke onset. The dose of ancrod was 0.5 IU/kg given over 6 hours followed by daily 30-minute infusions to keep the ﬁbrinogen in the range of 70–100 mg/dL for 7 days. The primary outcome was the Scandinavian Stroke Scale (SSS). There was no signiﬁcant diﬀerence in overall mean scores on the SSS in the primary analysis that adjusted for center. Subsequent analysis of the study showed a beneﬁcial eﬀect if the results were not stratiﬁed by center. The dosing

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used in the trial did not have the desired eﬀect on ﬁbrinogen levels: ﬁbrinogen levels were reduced below 100 mg/dL in only 23% of the ancrod-treated patients. The 48-center Stroke Treatment with Ancrod Trial (STAT) [12] was a randomized double-blind trial comparing intravenous ancrod to placebo in 500 stroke patients within 3 hours of stroke onset. A more complicated dosing regimen was utilized in order to attain a target ﬁbrinogen level of 40–69 mg/dL for 5 days. A favorable outcome on the Barthel Index at 90 days was attained by 42.2% of the patients treated with ancrod and 34.4% of the patients treated with placebo. For this primary outcome, there was a statistically signiﬁcant diﬀerence between the two groups ( p = 0.04). There was a trend toward more hemorrhage in the ancrod group, which had a 5.2% rate of symptomatic intracranial hemorrhage compared to the placebo group, which had a 2.0% rate. The European Stroke Treatment with Ancrod Trial (ESTAT) enrolled 1222 patients up to 6 hours following stroke onset. So far the study has not been published. Ancrod is not yet approved for use in the treatment of acute ischemic stroke. C. Prourokinase (Recombinant Urokinase Prodrug) The thrombolytic drug prourokinase (proUK) is a proenzyme precursor of urokinase manufactured with recombinant technology. It is administered intra-arterially where it is activated to UK at the thrombus surface by ﬁbrin-associated plasmin. There is some evidence that the thrombolytic eﬀect of proUK is enhanced by heparin [13]. There have been two studies of this drug in stroke patients, PROACT I [14] and PROACT II [13]. The ﬁrst was a phase II study of recanalization. The second was a randomized, controlled clinical trial to determine eﬃcacy using clinical outcomes at 90 days. PROACT I randomized 40 patients in a 2:1 ratio to receive either 6 mg of recombinant (r)-proUK or placebo. All patients received heparin. Patients were carefully selected for the presence of an appropriate TIMI grade 0 or 1 occlusion of an M1 or M2 middle cerebral artery segment. Of the 46 randomized patients, 26 received r-proUK and 14 received placebo. The primary outcome of the trial was recanalization rate. The r-proUK group had a 57.7% recanalization rate compared to 14.3% of the placebo patients ( p = 0.17). Symptomatic intracerebral hemorrhage occurred in 15.4% of the r-proUK patients compared with 7.1% of the placebo patients. Although there was no statistical signiﬁcance, there was a trend toward better clinical outcome at 90 days for the r-proUK group. PROACT II was a randomized, controlled, open-label clinical trial that tested eﬃcacy of proUK in 180 stroke patients treated within 6 hours of acute stroke following arteriography to conﬁrm the presence of a middle cerebral artery occlusion. There was unequal 2-to-1 randomization in the trial. A total of 121 patients received 9 mg of r-proUK plus heparin; 59 received heparin alone. The primary outcome was the proportion of patients with slight or no neurological disability at 90 days as deﬁned by a modiﬁed Rankin score of 2 or less. In the primary intent to treat analysis, 40% of the r-proUK patients and 25% of the control patients had a modiﬁed Rankin score of 2 or less. This was a statistically signiﬁcant diﬀerence with p = 0.04. Mortality was similar for both groups. Symptomatic intracranial hemorrhage within 24 hours of treatment occurred in 10% of the r-proUK patients and 2% of the control patients. Although both of these trials had positive outcome by prospectively planned analyses, prourokinase is currently not available since the U.S. Food and Drug Administration (FDA) has not approved it for use for the treatment of any disease. Further conﬁrmatory trials have not yet been started. The results of the PROACT studies are used to justify to some extent the intra-arterial use of other thrombolytic agents. The value of this has not been proven in clinical trials.

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Selecting patients using angiography does not account for the inconvenience and possible risk of angiography for the large number of patients who are excluded for the lack of an appropriate lesion and who presumably do not receive thrombolytic treatment. The delay in starting treatment due to the additional procedures required for intra-arterial therapy needs to be considered. Any delay in treatment must lead to signiﬁcantly more rapid recanalization or reduction of risk compared to intravenous therapy. This may be possible because of the application of the drug directly to the clot surface and any beneﬁts of clot manipulation on time to recanalization. However, these hypothetical beneﬁts are unproven and the procedures require heparin, which may increase the risks on intracerebral hemorrhage. At this time the beneﬁt of intra-arterial therapy compared to intravenous therapy is unproven. One or more trials are underway to address this question. D. Reteplase Reteplase is a variant of tissue plasminogen activator that promotes the cleavage of endogenous plasminogen to plasmin. Plasmin degrades the ﬁbrin matrix of blood clots. Fibrin stimulates the plasminogen cleavage. In vitro, reteplase has lower ﬁbrin speciﬁcity than alteplase (rt-PA). Reteplase is cleared from the circulation by the liver and the kidney. The circulation half-life is 13–16 minutes. In the GUSTO III trial [15], reteplase was compared to alteplase for treatment of myocardial infarction. The results of the trial showed that alteplase was superior to reteplase, but the investigators reported the ﬁndings as equivalence. Bleeding rates were 0.95% for reteplase and 1.2% for alteplase. The reteplase dose used for myocardial infarction was two 10 unit bolus intravenous injections given 30 minutes apart. Another trial demonstrated earlier reperfusion when reteplase was compared to alteplase using coronary angiography (60% reperfusion at 90 minutes for reteplase compared with 45% for alteplase). The drugs have more similarities than diﬀerences in their eﬀects. Reteplase is much easier to administer than alteplase for treatment of myocardial infarction. Evaluation of reteplase for acute ischemic stroke is moving forward in small studies investigating dose, safety, and indications of activity. E. Streptokinase Streptokinase (SK) for acute stroke has been tested in four relatively recent trials [16–19]. The investigators from the trials have published an analysis using data from 1292 randomized patients who received either a placebo or a dose of 1.5 million units of SK given intravenously within 4 or 6 hours of stroke onset [20]. Three of the trials were terminated early because of safety concerns. Concomitant aspirin was given to 330 patients in the SK group and to 319 in the control group. Heparin was administered within 48 hours of randomization to 404 (31%) patients. The average time from onset to start of treatment was 3.86 hours. There was a trend toward better outcomes in patients who received therapy within 3 hours compared with those who received therapy later. This diﬀerence was statistically signiﬁcant in the Australian Streptokinase Trial (ASK). The antigenic properties of SK experienced in myocardial infarction trials were also experienced in the stroke trials. Hemorrhagic conversion was 1.82 times more frequent in the SK compared to the control group. In the MAST-E trial, the symptomatic hemorrhage rate with SK was a very high 21.2% compared to 2.6% in the placebo group. The bottom line is that, in the four trials, the relative risk of early death for the SK group was 1.94. The disappointing results of these trials have discouraged further testing of SK for acute stroke.

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F. Tenecteplase Tenecteplase (TNK-TPA, TNK) is rt-PA genetically modiﬁed at three sites to have longer half-life, increased ﬁbrin speciﬁcity, and increased resistance to inhibition by plasminogen activator inhibitor 1 (PAI-1). Preclinical laboratory studies have demonstrated a trend toward reduced intracerebral hemorrhage in a rabbit model of stroke; hemorrhage was observed in 66% of rt-PA–treated animals compared to 55% of TNK-TPA–treated animals [21]. The diﬀerence between TNK-TPA and control was not statistically signiﬁcant, while the comparison between TPA and control showed a signiﬁcantly higher hemorrhage rate. The drug has already been shown to be eﬀective for treatment of myocardial ischemia in clinical trials. In these cardiac trials, TNK was co-administered with heparin and aspirin. One pivotal trial, the ASSENT-2 trial, compared a 5–10 second 30–50-mg bolus of TNK to an accelerated infusion of rt-PA given as a 15-mg bolus followed by a 30-minute 0.75-mg/kg infusion and a 30-minute 0.50-mg/kg infusion. The dose of TNK was based on the patient’s weight; 30 mg of TNK if body weight was less than 60 kg, 40 mg if body weight was 60–70 kg, and 50 mg if body weight was z70 kg. Over 16,000 patients were randomized at 1021 hospitals in 13 months (1.28 patients per month per hospital). The rate of intracranial hemorrhage was 0.93% and 0.94% in each group. Over 90% of patients received heparin and aspirin as well. There were signiﬁcantly more total (28.95% vs. 26.43%) and major (5.94% vs. 4.66%) hemorrhages as well as more patients requiring blood transfusions (5.49% vs. 4.25%) in the rt-PA compared to the TNK treatment group. The conclusion of the ASSENT-2 trial for myocardial infarction treated within 6 hours was that single bolus TNK was equivalent to an accelerated infusion of rt-PA. Thirty-day mortality in the TNK and TPA groups was 6.179% and 6.151%, respectively, with a p-value for equivalence of 0.0059. The lower severe hemorrhage rate for TNK used for myocardial infarction compared to rt-PA may predict a lower rate of intracerebral hemorrhage for stroke patients treated with TNK. Like reteplase, tenecteplase is much easier to give than alteplase. The fact that TNK can be given as a single bolus has several potential advantages, including earlier start of treatment and decreased likelihood of medication errors. Dose-ﬁnding and safety studies are currently underway in stroke patients.

G. Urokinase Urokinase is a protein enzyme obtained from cultured human neonatal kidney cells. It is produced in the kidney and can be found in normal urine. It acts systemically in the endogenous ﬁbrinolytic system by converting plasmin to plasminogen. The half-life of urokinase is approximately 12 minutes. However, following treatment, decreased levels of plasma ﬁbrinogen and increased levels of ﬁbrin and ﬁbrin-degradation products may persist for 24 hours. Urokinase has been approved by FDA for use in treating pulmonary embolus. Recent stroke is listed as a contraindication for use of urokinase. However, because it is available and because there are many case reports of its use, urokinase is used at some centers to speed the lysis of clots. It is administered intra-arterially through a catheter. Often the operator will pass the catheter through the clot as the drug is injected in order to speed reperfusion. There are no large randomized trials demonstrating any beneﬁt for acute stroke. Case series conﬁrm that lysis does often occur. Unfortunately, clinical results are diﬃcult to evaluate and compare to the normal course of acute stroke. The intra-arterial procedures involved limit the use of urokinase to hospitals with special expertise and equipment. The procedures for catheterization delay the time from

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stroke onset to start of treatment. It is not known whether the intra-arterial approach shortens the time to recanalization when compared to intravenous therapy. A few studies comparing intravenous to intra-arterial therapy are ongoing. Some approaches combine the two routes of administration, starting early with intravenous administration of a thrombolytic followed by intra-arterial therapy if there is no clinical evidence of reperfusion with intravenous therapy.

IV. RISKS AND BENEFITS The real possibility of intracerebral hemorrhage is a major deterrent to wider use of thrombolysis for acute stroke. Clearly, thrombolysis would be even more beneﬁcial without this serious and often fatal complication. From the physician’s point of view, giving a treatment that can cause serious harm to patients is very stressful. When perceiving a greater risk, a physician will generally be more careful when making a diagnosis and classifying a patient. With thrombolysis for stroke, the situation is even more stressful because the time to evaluate a patient is very limited. Overlooking a small hemorrhage on a computed tomography (CT) scan or failing to obtain the prothrombin time before starting treatment can have disastrous results. A physician has to ask whether the risk is worth the beneﬁt. Many treatments used in modern medicine can cause harm to patients. Chemotherapy for cancer, coronary artery bypass surgery, and aortic bypass grafting are obvious examples. For suspected acute appendicitis, the rare surgical or anesthetic complication can result in death or serious disability, even though the appendix may eventually be found to be normal. For stroke, since it is fatal only about 20% of the time, and since some patients do recover without treatment, it may be diﬃcult for the treating physician to feel the same urgency that impels action when the possibility of death or serious disability is an absolute certainty. In the light of these serious risks, it is diﬃcult to sense the full scope of the impact of the disease. It is from the patient’s vantage point that the beneﬁts of thrombolysis carry more weight. If a physician cannot tell whether a patient will have an intracranial hemorrhage or not, then for the patient the decision to take a risk depends on how a group of similar patients has done when treated compared to a similar group that was not treated. Despite the increased rate of intracranial hemorrhage, the death rate is the same and the disability is much less in stroke patients treated with rt-PA within 3 hours. To a patient, it is clear which group they would prefer. A similar situation is carotid endarterectomy. This procedure is routinely recommended to patients with recent transient ischemic attack and z70% stenosis. These are patients who have had a transient or mild stroke but who are minimally disabled or normal at the time the decision is made to perform surgery. The absolute beneﬁt from surgery over 2 years is estimated to be a 17% reduction in stroke. The rate of death and stroke from the surgery itself is estimated to be 5.8%. The initial risk of surgery is not balanced until approximately 3 months after the surgery is performed. If the risk of surgery is kept lower, then the beneﬁt is even greater. However, even with the risk as high as 5.8% for stroke and death, most physicians will recommend surgery without much reservation. The situation is not that much diﬀerent in the use of rt-PA. One diﬀerence with rt-PA is that the patient is currently experiencing a signiﬁcant and potentially reversible stroke that has a high likelihood of producing serious disability or death at 3 months. The risk of intracranial hemorrhage as a complication of rt-PA treatment is

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Table 3 Outcomes at 3 Months for Patients with Baseline NIHSS Greater than 20 in the Two Trials of the NINDS TPA Stroke Study Treatment group for patients with NIHSS >20 rt-PA Placebo

Deaths at 3 months (%)

Rankin 4 or 5 at 3 months (%)

Rankin 0 or 1 at 3 months (%)

48 38

21 38

10 4

Source: Ref. 27.

similar to the 5.8% risk of surgery, except that a fatal hemorrhage after rt-PA may be more common than a fatality following surgery. The absolute beneﬁt estimated for thrombolysis is 12% compared to 17% for endarterectomy. However, the thrombolysis beneﬁt accrues over 3 months and is durable for at least a year in the case of thrombolysis. The 17% beneﬁt of endarterectomy accrues over 2 years. The risk of surgery is not equalled by subsequent prevention of stroke and death events until approximately 3 months after the surgery is performed. Until that time, the endarterectomy group is actually doing worse that the medically treated group. In the NINDS rt-PA stroke trials, there were not more deaths in the rt-PA group than in the placebo group at any time. One way to reduce the incidence of symptomatic intracranial hemorrhage is to select patients. Although they have not been tested in a conﬁrmatory trial, a secondary analysis of data from the two NINDS TPA stroke study trials provides some interesting insights. A carefully constructed multivariate model showed that only baseline NIH Stroke Scale and edema or mass eﬀect on the baseline CT scan were signiﬁcantly associated with an increased risk of intracerebral hemorrhage in the ﬁrst 36 hours after rt-PA treatment. Three percent of the 110 patients with a baseline NIHSS of <10 had symptomatic intracerebral hemorrhages in the ﬁrst 36 hours after rt-PA administration; however, 17% of patients with a baseline NIHSS of >19 had symptomatic hemorrhages within 36 hours. For patients with edema or mass eﬀect on baseline CT scan before treatment, 31% had symptomatic hemorrhages compared with 6% for those who did not have baseline CT ﬁndings. For example, more patients with stroke scales >20 did well after treatment with rt-PA (Tables 3 and 4). This is also true for those with edema and mass eﬀect at baseline. Both of these results were statistically signiﬁcant. When they were tested, the best models that could be developed using the data from the two NINDS trials correctly predicted the incidence of symptomatic hemorrhage only 57% of the time. However, death rates, although not statistically signiﬁcant, were higher for rt-PA–treated patients in these two groups. Larger prospective studies would be required for more accurate estimates of rates

Table 4 Outcomes at 3 Months for Patients with Edema or Mass Eﬀect on Baseline CT Scan in the Two Trials of the NINDS TPA Stroke Study Treatment group for patients with NIHSS >20 rt-PA Placebo

Death or Rankin 4 or 5 at 3 months (%)

Rankin 0 or 1 at 3 months (%)

56 52

25 16

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of disability and death in these two groups. Time from stroke onset to treatment, even within the 3-hour window, also becomes important. As discussed earlier, another concern may be that the actual use of rt-PA in practice may vary considerably from its use in very carefully monitored clinical trials (Table 5). A number of case series have been reported from locations across the world (Table 6). Case series are prone to errors. However, they do provide the only data we have on hemorrhage rates after approval of rt-PA for use. Suﬃce it to say that when the hemorrhage rates for these studies are averaged together, the result is approximately 6%, almost exactly the rate experience in the two pivotal NINDS trials. In Cleveland, after an initial study showing a high 15.7% incidence of intracranial hemorrhage, a stroke quality improvement program to increase compliance with guidelines resulted in an increased number of patients being treated and a lower, 6.4%, incidence of symptomatic intracerebral hemorrhage. Future reﬁnements of thrombolytic therapy may reduce the initial risk of treatment. Drugs could be coadministered which reduce the rate of hemorrhage. One possibility that has been tested in the laboratory is metalloproteinase inhibitors [22]. Another approach would be to try diﬀerent doses or dosing schedules. One of the alternate thrombolytic drugs such as tenectoplase could be signiﬁcantly safer than rt-PA. All of these possibilities depend upon the organization and completion of large-scale trials comparing two active treatments.

Table 5 Selection Criteria for Intravenous rt-PA for Acute Ischemic Stroke Starting Within 3 Hours of Onset Inclusion Ischemic stroke with a clearly deﬁned time of onset within three hours or less of the earliest time intravenous infusion can be started Deﬁcit measurable on the NIHSS CT scan of the brain showing no evidence of intracranial hemorrhage Exclusion Another stroke or serious head trauma within the preceding 3 months Major surgery within 14 days History of intracranial hemorrhage Systolic blood pressure consistently above 185 mmHg or diastolic blood pressure consistently above 110 mmHga Rapidly improving or minor symptoms Symptoms suggestive of subarachnoid hemorrhage Gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 21 days Arterial puncture at a noncompressible site within the previous 7 days Seizure at the onset of stroke Taking anticoagulants or has received heparin within the 48 hours preceding the onset of stroke and had an elevated partial-thromboplastin time Prothrombin times greater than 15 seconds Platelet counts below 100,000 per cubic millimeter Glucose concentrations below 50 mg per deciliter (2.7 mmol per liter) or above 400 mg per deciliter (22.2 mmol per liter) Aggressive treatment was required to reduce their blood pressure to the speciﬁed limits. a

Patient not excluded if there is one or more readings below maximum limits for diastolic and systolic blood pressure.

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Table 6 Summary of Case Series Reporting Rate of Intracerebral Hemorrhage with rt-PA Treatment of Stroke in Practice at Diﬀerent Locations Study [Ref.]

Year

Cologne [28] Multicenter survey [29] Indianapolis [30] STARS [31] Cleveland [32] Vancouver [33] Calgary [34] Houston [35] Bethesda [36] Helsinki [37] Melbourne [38] Berlin [39] Santiago [40] Peoria [41] Overall

1998 1999 2001 2000 2000 2000 2000 2001 2003 2003 2003 2001 1999 2000

a

Number of stroke patients

Rate of symptomatic intracerebral hemorrhage (%)

100 189 50 389 70 46 68 269 44 75 30 75 20 57 1482

5 6 10 3 16 2 9 6 7 8a 7 3 5 5 6

Parenchymal hematoma reported approximates symptomatic intracerebral hemorrhage.

V. DEVELOPING THE SYSTEMS TO DELIVER THROMBOLYTIC THERAPY RAPIDLY Guidelines for treating acute stroke have been established (Table 5). The need to treat rapidly and the risk of hemorrhage increase the need to have stroke expertise readily available in emergency departments. This, in turn, requires a system to be in place to rapidly diagnose stroke and to treat those that are eligible for thrombolysis. After treatment, appropriate management requires careful monitoring of blood pressure and neurological status. The decision to use thrombolytic therapy for stroke involves a lot more than knowing whether or not the drug is eﬀective and oﬀers beneﬁt to patients. It involves more than knowing the risks and beneﬁts for each individual patient. The U.S. healthcare system has changed fundamentally since the introduction of thrombolytic therapy for acute myocardial infarction. The emergency department, a safety net for the healthcare system, has become a busy, crowded, pressured, and cramped facility as health maintenance organizations, medical liability costs, and the Medicare system have limited the care available for an increasing number of patients. In the nihilistic approach of the past, stroke was a disease usually requiring little or no time from the emergency department staﬀ. Introducing new and complex procedures for diagnosing and treating stroke into the current environment encounters predictable resistance. There are few, if any, motivations provided in the current healthcare system for physicians to lead the change required to oﬀer the best care for stroke patients. The reimbursement system currently discourages rather than encourages the rapid treatment of acute stroke despite good evidence that an initial investment in acute treatment actually reduces total cost of care for stroke patients. The current healthcare system does not allow the savings from decreased rehabilitation and nursing home costs to oﬀset the cost of acute care in accounting for total care. The

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only pathway provided for introducing a new treatment that requires signiﬁcant changes in the emergency care system requires years to have an eﬀect on reimbursement schedules. Therefore, these eﬀorts to improve stroke care must be supported by physicians and hospitals that are highly motivated to provide the best possible care despite considerations of cost.

VI. STROKE CENTERS Many hospitals are not yet prepared to consistently deliver thrombolytic therapy for stroke because the necessary trained personnel, procedures, and equipment are not available. Most U.S. hospitals currently do not have special stroke-treatment protocols and do not have procedures in place for rapid diagnosis of stroke [23]. Delays in the emergency department can add signiﬁcantly to delay in patient arrival and further reduce the number of patients who receive thrombolytic therapy. One solution to these problems is the creation of acute stroke treatment centers similar to trauma centers. The Brain Attack Coalition has established guidelines for primary acute stroke centers [24]. The coalition recommended two levels of stroke center: primary stroke centers and comprehensive stroke centers. A primary center would stabilize and provide emergency care for acute stroke. Depending on the resources available at the primary center, the patient could either receive complete treatment at the primary center or be transferred to a comprehensive center. A comprehensive stroke center would care for patients experiencing strokes that require specialized testing and treatment. An acute stroke team at a primary stroke center responds rapidly when a patient with suspected acute stroke is identiﬁed. Team members are specially trained healthcare professionals, including those with expertise in diagnosing and treating patients with cerebrovascular disease. The team should include at least one other healthcare professional, such as a nurse. The team should be available 24 hours a day, 7 days per week. It is not reasonable to expect emergency department staﬀ to care for acute stroke. Emergency department staﬀ is usually overloaded with high volumes of patients and many competing priorities that make it impossible for them to spend the time required for adequate evaluation and treatment of acute stroke. Ideally, the emergency department staﬀ will activate the stroke team when notiﬁcation is received prior to arrival at the emergency department that a patient with possible stroke is en route. The stroke team can perform the initial evaluation of the patient if they arrive before the patient, or, while the stroke team assembles, emergency department physicians can begin the initial evaluation, including blood pressure, NIH Stroke Scale, laboratory tests, electrocardiogram, and CT scan. A member of the stroke team should be able to see the patient within 15 minutes of being called. Cellular telephones and pagers are fallible. Batteries fail; pagers are forgotten. A backup, second-call system should ensure the availability of a stroke team leader if the primary leader does not respond within a speciﬁed brief time. After the ﬁrst stroke team member has seen the patient, the determination can be made as to whether further assistance is needed. For instance, if the ﬁrst team member to arrive determines that the patient does not have a stroke or that ischemic stroke onset was more than 3 hours earlier, then full activation of the team may not be required. Acute stroke does not occur frequently enough to require a full-time acute stroke team, even if one team covers several hospitals in the same metropolitan area. Stroke team members would typically have other ongoing patient care responsibilities. They would be

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on call as part of a stroke team, carrying a special pager on an alternating basis. A special salary supplement may be provided. To be successful, the stroke team must be supported by a larger administrative structure. A formal written document delineating the administrative support for the stroke team is very important. Issues addressed should include the amount and extent of administrative support, staﬀ reimbursement, stroke team notiﬁcation plans, expected and required response times, quality improvement procedures, record keeping, and priority of access to imaging and laboratory resources. The stroke team should maintain a log that documents call times, response times, patient diagnoses, treatments, and outcomes, in both the short and long term. The acute stroke patient is cared for by a series of diﬀerent healthcare providers. The emergency medical transport system, the emergency department staﬀ, the acute stroke team, the intensive care unit teams, and the hospital ward staﬀ all see the acute stroke patient separately. Written care protocols are required for continuity of care and maintenance of the highest possible standards of care. The availability of such protocols for the use of rt-PA in acute stroke has been shown to be a key step in reducing rt-PA–related complications [25,26]. At a stroke center, there should be a process for periodic review and reﬁnement of the protocol as the stroke team gains experience and new treatments for stroke are developed. Many patients are not eligible for thrombolytic therapy for one reason or another. Signiﬁcant beneﬁts may accrue to patients from protocols that maximize care for patients who come late after ischemic stroke, transient stroke patients, and patients with subarachnoid and intracerebral hemorrhage. Preprinted physician orders and laboratory request sheets augment protocols. Successful implementation of the protocols by a stroke team will reduce delays and increase the quality of care once the patient arrives at the hospital. Further improvements in care derive from eﬀective emergency medical services (EMS) that have their own protocols for diagnosis and rapid triage of potential stroke victims. Since there is no national system, each stroke center and stroke team must form its own links to the local EMS. These links include joint participation in educational programs, sharing of protocols, and combined reviews of quality measures. Rapid transport enabling the start of intravenous thrombolysis requires special eﬀorts in rural settings where distances are greater and population is less dense. EMS for trauma patients in rural settings have been successful. Success treating rural trauma suggests same success is possible treating rural stroke. One diﬃcult problem to resolve while establishing EMS protocols for acute stroke is whether to bypass nearby hospitals that have not established themselves as primary stroke centers. Transport to a hospital that is not fully prepared to deliver thrombolytic therapy can cause unnecessary delay and potentially preclude thrombolytic therapy despite adequate EMS training and response. The primary stroke center hospital emergency department (ED) is where most of the action takes place (Table 7). Coordination between emergency medical services, emergency department medical personnel, and the acute stroke team are focused here. Wellplanned open lines of communication of emergency medical services allow for early notiﬁcation of ED personnel prior to arrival of stroke patients at the hospital. Information gathered during transit of the patient can speed initial evaluation and activation of the acute stroke team. Usually the acute stroke team is not drawn entirely from ED staﬀ on duty, but comes in to augment the eﬀorts of ED staﬀ when a stroke is diagnosed. This allows ED staﬀ to focus on initial diagnosis and activation of the stroke team while maintaining smooth patient ﬂow through the ED. The stroke team takes responsibility for the eﬀort required to evaluate and treat stroke patients, as much as 1 or 2 hours’ work for

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Table 7 Major Elements of a Primary Stroke Center Patient care areas Acute stroke teams Written care protocols Emergency medical services Emergency department Stroke unita Neurosurgical services Support services Commitment and support of medical organization; a stroke center director Neuroimaging services Laboratory services Outcome and quality improvement activities Continuing medical education a

A stroke unit is only required for those primary stroke centers that will provide ongoing hospital care for patients with stroke.

two or more people. Coming as infrequently as four times a week or less, an eﬀort this extensive could be quite disruptive of the usual patient ﬂow in many EDs. The availability of an acute stroke team that is responsive and eager to accept responsibility for care of stroke patients will have a positive eﬀect on the responsiveness of ED physicians and staﬀ. The result can be increased interest resulting in better diagnostic accuracy, earlier completion of laboratory and radiological testing, and better care of patients. Written protocols maintain consistency of ED care with established guidelines for patients experiencing an acute stroke and eligible for thrombolytic therapy. The result is an increased use of rt-PA for acute stroke, with 11–13% more patients having a good neurological outcome at 90 days. In addition, treating stroke patients with rt-PA increases from 36–48%, relatively, the odds ratio of being discharged home. Because stroke patients do not present frequently, training is needed to maintain familiarity with protocols and procedures to triage and treat stroke. Emergency department staﬀ should be trained in the diagnosis and treatment of stroke twice a year. The training should include policies and statements about how the ED is integrated with the entire stroke center, along with treatment algorithms and ﬂow charts. ED eﬀectiveness can be evaluated in terms of performance and outcomes. The bottom line for evaluating ED acute stroke care performance is the ‘‘door-to-needle’’ time for thrombolysis, ideally 60 minutes or less—the ‘‘golden hour’’ of stroke when the eﬀorts of a coordinated stroke care can make signiﬁcant diﬀerences in long-term patient outcomes. Important outcome measures include patient status at 3 months and compliance with established protocols. Thrombolysis starts in the ED but is completed in a hospital stroke unit. If a hospital does not provide special inpatient care for stroke patients, stabilization and transfer to another hospital better equipped for stroke patient care is possible. Stroke units are not always in separate rooms within a hospital, but are in areas where special care can be given to stroke patients by hospital staﬀ with special training and experience in treating patients after a stroke. Neurological status and blood pressure need to be monitored carefully after thrombolytic treatment. Other supportive and diagnostic measures are instituted as well.

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Clearly, organizing an acute stroke response team, enabling an emergency department, support a stroke unit, and training emergency medical services all takes commitment and investment from healthcare systems. As mentioned earlier, there is evidence to suggest that investment is justiﬁed in terms of better patient outcomes and lower lifetime healthcare costs.

VII. FUTURE DIRECTIONS Reperfusion therapy can make a signiﬁcant diﬀerence in the treatment of acute ischemic stroke. The treatments are only in their earliest stages of development. Future directions will tackle two main problems with the current treatment using rt-PA: the low therapeutic index and the small number of patients being treated. The low therapeutic index reﬂects a small diﬀerence between the dose that causes serious hemorrhage and the dose required to restore perfusion. Eﬀorts to reduce the hemorrhage rate will include looking at diﬀerent thrombolytic agents and diﬀerent doses

Figure 1 Graph of model estimating OR for favorable outcome at 3 months in recombinant tissuetype plasminogen activator (rt-PA)–treated patients compared to placebo-treated patients by time from stroke onset to treatment [onset-to-treatment time (OTT)] with 95% conﬁdence intervals, adjusting for OTT, age, baseline glucose level, baseline NIH Stroke Scale, baseline diastolic blood pressure, prior hypertension, and interactions between OTT and treatment as well as between age and baseline NIH Stroke Scale. OR > 1 indicates greater odds that rt-PA–treated patients will have a favorable outcome at 3 months compared to the placebo-treated patients. ITT analysis was performed with data from all 2775 patients. Twelve, 11, 33, 37, 83, and 47 patients from NINDS Part 1, NINDS Part 2, ECASS I, ECASS II, Atlantis A, and Atlantis B, respectively were missing one or more outcomes at 3 months and were given the worst outcomes for those that were missing. In the original article on the NINDS trial only 1 patient in Part 1 and 4 patients in Part 2 are reported as missing outcomes. For the other 18 patients, a more complex algorithm was used to include data close to the missing 3-month visit as the ﬁnal outcome [8].

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of rt-PA. Dosing of rt-PA could be individualized based on diﬀerent patient characteristics, or a lower ﬁxed dose could be compared to the currently approved 0.9-mg/kg dose of rt-PA. Another possibility is that thrombolytic agents could be combined with drugs that increase the brain’s resistance to hemorrhage. For instance, preliminary data have already been published that suggest a metalloproteinase inhibitor can reduce hemorrhage in an animal model without reducing clot lysis. The rates of hemorrhage are already small (6%), and small changes in these rates, e.g., 1 or 2%, could make important changes in the therapeutic trials involving hundreds of centers treating stroke early after onset. A recent trial in myocardial infarction randomized 16,949 patients over 13 months early after onset of chest pain. The number of patients treated at each center was just a little over 1 per month. The main determinant of the rapid recruitment rate was the large number of centers—over 1000. Future trials of reperfusion therapy will require numbers approaching this magnitude with participation of a large percentage of stroke specialists. A rough estimate of the size of a trial designed to detect a reduction of hemorrhage rate from 6% to 4% would be 5200 patients: 300 emergency departments treating patients V2.5 hours after stroke onset would have to treat 1 patient per month for 17 months to complete the trial. Each of these centers would need the availability of stroke and radiological expertise to ensure careful evaluation and diagnosis prior to inclusion in a trial. The infrastructure to maintain this trial organization would be large. Increased eﬃciency would be available if several trials were conducted at once on diﬀerent types of neurological emergency conditions. The large clinical trials focused on increasing the beneﬁt from thrombolytic therapy will themselves be important tools for advancing the state of the stroke response infrastructure. Participation in trials and the eﬀort of voluntary organizations and the government to promote better stroke care will have major impact on increasing the number of patients who receive appropriate reperfusion therapy (Fig. 1).

VIII. CONCLUSION Thrombolysis can work to improve outcomes from acute stroke. However, thrombolytic treatment is still in the early stages of development, and its full potential has not been developed. Safer protocols need to be developed and the medical system needs to implement means for getting patients to recognize stroke and increasing the rapidity of the medical response. This development will require the cooperation and participation of the emergency medicine and neurological communities as a whole.

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Marler with wild-type tissue plasminogen activator in a rabbit embolic stroke model. Stroke 2001; 32:748–752. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)–induced hemorrhage after thromboembolic stroke. Stroke 2000; 31:3034–3040. Goldstein L. North Carolina stroke prevention and treatment facilities survey. Stroke 2000; 31:66–70. Alberts MJ, Hademenos George, Latchaw Richard E, Jagoda Andrew, Marler John R, Mayberg Marc R, Starke Rodman D, Todd Harold W, Viste Kenneth M, Shephard Meighan GirgusTim, Shwayder Marian EmrPatti, Walker Michael D. Recommendations for the establishment of primary stroke centers. JAMA 2000; 283:3102–3109. Adams H, Brott T, Furlan A, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. Stroke 1996; 27:1711–1718. Albers G, Bates V, Clark W, Bell R, Verro P, Hamilton S. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 2000; 283:1145–1150. NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997; 28:2109–2118. Grond M, Stenzel C, Schmulling S, Rudolf J, Neveling M, Lechleuthner A, Schneweis S, Heiss WD. Early intravenous thrombolysis for acute ischemic stroke in a community-based approach. Stroke 1998; 29(8):1544–1549. Verro P, Kasner SE, Binder JR, Patel SC, Mansbach Hypoglycemia, Daley S, Schultz LR, Karanjia PN, Scott P, Dayno JM, Vereczkey-Porter K, Benesch C, Book D, Coplin WM, Dulli D, Levine SR. Initial clinical experience with IV tissue plasminogen activator for acute ischemic stroke: a multicenter survey. The t-PA Stroke Survey Group. Neurology 199; 53(2):424–427. The Balance of Risk and Beneﬁts. Lopez-Yunez AM, Bruno A, Wiliams LS, Yilmax E, Zurru C, Biller J. Protocol violation in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke 2001; 32:12–16. Albers GW, Bates VE, Calrk WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA 200; 283(9):1145–1150. Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hichey JA, Hammel JP, Qu A, Sila CA. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000; 283(9):1151–1158. Chapman KM, Woolfenden AR, Graeb D, Johnston DC, Beckman J, Schulzer M, Teal PA. Intravenous tissue plasminogen activator for acute ischemic stroke. Stroke 2000; 31(21):2920– 2924. Buchan AM, Barber PA, Newsommon N, Karbalai HG, Demchuk AM, Hoyte KM, Klein GM, Feasby TE. Eﬀectiveness of t-PA in acute ischemic stroke: outcome relates to appropriateness. Neurology 2000; 54(3):679–684. Grotta JC, Burgin WS, El-Mitwalli A, Long M, Campbell M, Morgenstern LB, Malkoﬀ M, Alexandrov AV. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996-2000. Arch Neurol 2001; 58(12):2009–2013. Loaatimore SU, Chalela J, Davis L, DeGraba T, Ezzeddine M, Haymore J, Nyquist P, Baird AE, Hallenbeck J, Warach S. NINDS Suburban Hospital Stroke Center. Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy: the NINDS Suburban Hospital Stroke Center experience. Stroke 2003; 34(6):e55–57. Epub 2003, May 15. Lindsberg PJ, Soinne L, Roine RO, Salonen O, Tatlisumak T, Kallela M, Happola O, Tianinen M, Haapaniemi E, Kuisma M, Kaste M. Community-based thrombolytic therapy of acute ischemic stroke in Helsinki. Stroke 2003; 34(6):1443–1449. Epub 2003, May 08.

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38. Szoeke CE, Parsons MW, Butcher KS, Baird TA, Mitchell PJ, Fox SE, Davis SM. Acute stroke thrombolysis with intravenous tissue plasminogen activator in an Australian tertiary hospital. Med. J Aust 2003; 178(7):309–310. 39. Koennecke HC, Nohr R, Leistner S, Marx P. Intravenous tPA for ischemic stroke team performance over time, safety, and eﬃcacy in a single-center, 2-year experience. Stroke 2001; 32(5):1074–1078. 40. Feuerhake W, Chamorro H, Araya F. Article in Spanish. Data taken from PubMed abstract in English. Rev Med Chil 1999; 127(7):814–819. Intravenous tissue plasminogen activator in the treatment of acute ischemic stroke: feasibility, safety, and eﬃciency in the 2 ﬁrst years of the clinical practice. 41. Wang DZ, Rose JA, Honings DS, Garwacki DJ, Milbrandt JC. Treating acute stroke patients with intravenous tPA; The OSF Stroke Network experience. Stroke 2000; 31(1):77–81.

18 Anticoagulant and Antiplatelet Treatment of Acute Ischemic Stroke Eivind Berge Ulleva˚l University Hospital, Oslo, Norway

Peter Sandercock Western General Hospital, Edinburgh, Scotland, UK

I. ANTITHROMBOTIC TREATMENT Ischaemic stroke results in a most signiﬁcant health burden for patients, their caregivers, and society. It is estimated that there will be 8.5 million patients with acute ischemic stroke in Europe and the United States over the next decade [1–3], and of these, about one half will die within 6 months of stroke onset [4]. Of those who survive, about one third will depend on other people for help with their activities of daily living [5]. If some widely practicable therapies could be shown to prevent death or dependence for ‘‘just’’ 10 or 20 of every 1000 patients, it would, for every million stroke patients so treated, ensure that an extra 10,000 would survive and become independent. If such beneﬁts exist, they must not, therefore, be overlooked. Antithrombotic agents, such as heparin and aspirin, are inexpensive, easy to administer, and could be widely used in the management of acute ischemic stroke. This chapter reviews the evidence on their clinical beneﬁts in acute ischemic stroke. Ischemic strokes are the result of arterial thromboembolic occlusion and cerebral infarction [6]. The rationale for antithrombotic agents in acute ischemic stroke is therefore to suppress or halt any underlying thrombotic process to reduce the volume of infarcted cerebral tissue (and hence reduce the degree of neurological deﬁcit and consequent disability). Antithrombotic agents are also given to prevent stroke recurrence (secondary prophylaxis) and to prevent (or treat) deep vein thrombosis and pulmonary embolism in patients who have had a stroke (tertiary prophylaxis). However, antithrombotic agents can increase the risk of intracranial and extracranial hemorrhage, which might oﬀset any beneﬁts. Antithrombotic agents can be broadly divided into anticoagulants and antiplatelet agents. Agents that act primarily to inhibit coagulation include unfractionated heparin, low molecular weight heparin, heparinoids, and oral anticoagulants such as warfarin. Antiplatelet agents, such as aspirin, dipyridamole, ticlopidine, clopidogrel, and glycoprotein IIb/IIIa antagonists (e.g., abciximab), act by inhibiting platelet aggregation. Agents with 383

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thrombolytic properties are usually not deﬁned as antithrombotic agents, and agents such as prostacyclin and pentoxifylline have major vascular eﬀects other than antiplatelet actions. A. Risk of Intracranial Hemorrhage One of the risks of antithrombotic therapy in the acute phase of stroke is that it might exacerbate any tendency to hemorrhagic transformation of the infarct. It is therefore unwise to assume that the balance of harm and beneﬁt will be the same in the acute phase of stroke as when these agents are used for long-term secondary prevention. The clinical impact of hemorrhagic transformation is diﬃcult to assess in an individual patient. Minor degrees of transformation can occur without any clinical deterioration, whereas the development of a large parenchymatous hematoma may be fatal. In a review of the trials of thrombolytic therapy within 6 hours of stroke onset, 1.0% of the patients allocated control had a fatal intracranial haemorrhage [7]. However, even if a speciﬁc category of patients was at especially high risk of symptomatic hemorrhagic transformation with antithrombotic treatment, this does not necessarily mean that the net result will be adverse for this group of patients. By analogy with carotid endarterectomy for carotid stenosis, some patients may be at high risk of stroke with surgery, but at even higher risk without it, so that the balance of adverse and beneﬁcial eﬀects of surgery in such patients is still favorable. In addition to increasing the risk of hemorrhagic transformation, antithrombotic agents could both increase the risk of symptomatic intracranial hemorrhage arising de novo (as intracerebral, subarachnoid, or subdural bleeding) and the risk of bleeding at other, extracranial sites. The key question is, therefore, whether or not the beneﬁts of treatment outweigh the adverse outcomes. This aim of this chapter is to assess the eﬀects of anticoagulants and antiplatelet agents on the major outcomes after stroke (death and dependency in activities of daily living) and on the risk of vascular events, such as recurrent stroke (ischemic or hemorrhagic), deep vein thrombosis, and pulmonary embolism. We emphasize the evidence from randomized-controlled trials (and systematic reviews of trials) of antithrombotic agents given within 48 hours of stroke onset and continued for about 2 weeks.

II. ANTICOAGULANT AGENTS A. Evidence from Randomized-Controlled Trials and Systematic Reviews A recent systematic review identiﬁed 21 randomized-controlled trials comparing anticoagulants with control among patients with acute ischemic stroke [8]. The included trials tested standard unfractionated heparin, low molecular weight heparin, heparinoid, direct thrombin inhibitors, and heparin given for 24 hours followed by oral anticoagulation. Most of the data came from trials in which unfractionated heparin was administered by subcutaneous injection in high (12,500 IU twice daily) or low dose (5,000 IU twice daily). In total, the trials included 23,427 patients with acute presumed ischemic stroke [8]. The results are dominated by the data from a single trial, the International Stroke Trial (IST), which included 19,435 patients [5,8]. In the IST, patients were allocated, in an open factorial design, to treatment policies of aspirin 300 mg daily, subcutaneous unfractionated heparin, the combination, or to ‘‘avoid both aspirin and heparin’’ for 14 days. A systematic review of trials exclusively comparing low molecular weight heparins with

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control is also available [9], and since that review appeared, a further trial comparing low molecular weight heparin with control has been published [10]. A recent review also compared anticoagulants with antiplatelet agents [11]. There are only a few trials directly comparing one anticoagulant agent with another or comparing diﬀerent doses of the same agent [12–14]. The results of these reviews will be presented when appropriate. 1. Recurrent Ischemic Stroke During the Treatment Period Immediate anticoagulation signiﬁcantly reduced the relative odds of recurrent stroke of ischemic or unknown type (referred to as recurrent ischemic stroke for simplicity) within the ﬁrst 2 weeks by 24% [95% conﬁdence interval (CI) 12–35%], from 3.6% in controls to 2.8% in treated patients, i.e., avoiding 9 recurrences for every 1000 patients treated. The eﬀects of the diﬀerent regimens tested were broadly consistent with this overall estimate of eﬀect. 2. Symptomatic Intracranial Hemorrhage During the Treatment Period Immediate anticoagulation signiﬁcantly increased the relative odds of symptomatic intracranial haemorrhage by 152% (95% CI 92–230%), from 0.5% in controls to 1.4% in treated patients, i.e., causing 9 symptomatic intracranial haemorrhages for every 1000 patients treated. Each of the regimens tested, when compared to controls, appeared to increase the risk of symptomatic intracranial hemorrhage. The relative increase was consistent across the diﬀerent regimens, although (because of small numbers) it was only statistically signiﬁcant for unfractionated heparin. Indirect comparisons of diﬀerent dosing regimens showed consistently higher bleeding risks with higher dose regimens. In the IST [5], patients allocated to subcutaneous unfractionated heparin were randomized to a high-dose (12,500 IU twice daily) or to a low-dose regimen (5,000 IU twice daily), and the proportions of patients who developed symptomatic intracranial hemorrhage were 1.8% and 0.7%, respectively—a highly signiﬁcant 11 per 1000 excess with the higher dose (2p < 0.00001). A systematic review of all trials directly comparing high- with low-dose anticoagulants in acute stroke supports the dose dependency of the bleeding risks [13,14]. 3. Recurrent Stroke of Any Type During the Treatment Period This combined endpoint encompasses both the beneﬁcial and adverse eﬀects of anticoagulants and provides the best estimate of the net eﬀect of anticoagulants on recurrent stroke events. Anticoagulation was not associated with a net reduction in the odds of this event (OR 0.97; 95% CI 0.85–1.11) (Fig. 1). 4. Major Extracranial Hemorrhage During the Treatment Period Hemorrhages into the gastrointestinal tract and elsewhere were reported in 0.4% of controls and 1.3% of treated patients, a signiﬁcant threefold increase, i.e., for every 1000 patients treated with anticoagulants, 9 have a major extracranial hemorrhage. The indirect comparisons of diﬀerent agents show that the bleeding risks are higher with higher-dose regimens. In the IST, the risk of major extracranial bleeds was 2% among patients allocated high dose and 0.6% among those allocated low dose, a highly signiﬁcant 14 per 1000 excess with the higher doses (2p < 0.00001) [5]. A systematic review of all trials directly comparing high- with low-dose anticoagulants conﬁrmed this dose dependency [13,14].

Figure 1 Anticoagulants in acute ischemic stroke: proportional eﬀects on recurrent stroke of any type (ischemic, unknown, or hemorrhagic) during the scheduled treatment period. Results of a systematic review of randomized-controlled trials comparing heparin with control in patients with acute ischemic stroke. The estimate of treatment eﬀect is expressed as an odds ratio (solid square for individual trials; solid diamonds for groups of trials) and its 95% conﬁdence interval (horizontal line or width of diamond). The size of the solid square is proportional to the amount of information available. An odds ratio of 1.0 corresponds to a treatment eﬀect of zero, an odds ratio less than 1 suggests treatment is better than control, and an odds ratio greater than 1 suggests treatment is worse than control. The ﬁgures given to the right are relative odds ratios with 95% conﬁdence intervals. (Adapted from Ref. 8.)

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5. Deep Venous Thrombosis and Pulmonary Embolism During the Treatment Period Data on the eﬀects of anticoagulants on deep venous thrombosis were available for only 916 patients. There was heterogeneity of treatment eﬀect between the trials, which makes it harder to interpret the overall estimate of treatment eﬀect. Overall, symptomatic or asymptomatic deep vein thrombosis occurred in 43% of controls and 15% of treated patients, a highly signiﬁcant 79% reduction in relative odds with anticoagulants (95% CI 61–85%), i.e., for every 1000 patients treated, 280 avoid deep vein thrombosis. Fatal or nonfatal pulmonary embolism was not systematically sought in the trials. It was reported in only 0.9% of controls and 0.6% of treated patients, a signiﬁcant 39% reduction in relative odds with anticoagulants (95% CI 17–55%), i.e., for every 1000 patients treated, 3 avoid pulmonary embolism. It is diﬃcult to judge whether the reductions in deep vein thrombosis or pulmonary embolism are dose-dependent from the indirect comparisons. In the IST, fatal or nonfatal pulmonary embolism occurred in 0.4% of those allocated highdose and 0.7% of those allocated low-dose heparin, a nonsigniﬁcant diﬀerence [5]. A systematic review of all of the direct randomized comparisons conﬁrmed the greater reduction in pulmonary embolism with higher doses, but the absolute beneﬁt was very small [13,14]. Underascertainment of events in both groups may mean that the absolute beneﬁt has been underestimated (the proportional reduction is not likely to be aﬀected by underascertainment); if the true rate of pulmonary embolism was 3% in the controls, and the same 39% proportional reduction were applied (i.e., from 3% to 1.85%), for every 1000 patients treated about 12 might avoid pulmonary embolism. However, even if the beneﬁt is that large, it will still be substantially oﬀset, since an extra 9 patients will have a major extracranial haemorrhage associated with anticoagulants (estimate of control pulmonary embolism risk [15]). 6. Death During the Treatment Period and at the End of Follow-Up There was no signiﬁcant eﬀect on deaths during the treatment period; 8.7% of controls died compared with 8.5% of treated patients (95% CI 10% reduction in relative odds to 10% increase). By the end of the scheduled follow-up at 3–6 months, 20.6% of controls had died compared with 21.4% of treated patients, a nonsigniﬁcant 5% increase in the relative odds of death (95% CI 2% reduction to 12% increase) (Fig. 2). 7. Death or Dependency at the End of Follow-Up The most important measure of outcome is the proportion of patients at the end of follow-up who are either alive, but need help for everyday activities, or are dead. Overall, 60.1% of controls were dead or dependent compared with 59.7% of treated patients, a nonsigniﬁcant diﬀerence (95% CI 6% reduction to 5% increase in the odds of death) (Fig. 3).

B. Effects of Anticoagulants in Various Categories of Patients 1. Suspected Cardioembolic Ischemic Stroke Anticoagulants have often been advocated for the treatment of acute cardioembolic stroke, and in many centers in the United States such patients are treated routinely with intravenous heparin [16–18]. However, there is no evidence to support the use of intravenous heparin in such circumstances [19]. Subgroup analyses of patients with acute

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Figure 2 Anticoagulants in acute ischemic stroke: proportional eﬀects on death from all causes at end of follow-up. Results of a systematic review of randomized-controlled trials comparing heparin with control in patients with acute ischemic stroke. Same conventions as Figure 1. (Adapted from Ref. 8.)

ischemic stroke of suspected cardioembolic origin in all available randomized-controlled trials did not show net beneﬁt from anticoagulants compared with control [8,20] or aspirin [11]. 2. Progressing Hemispheric Stroke Likewise, many textbooks and reviews recommend immediate intravenous heparin for patients with progressing stroke. However, there have not been any trials of intravenous

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Figure 3 Anticoagulants in acute ischemic stroke: proportional eﬀects on death of dependency at end of follow-up. Results of a systematic review of randomized-controlled trials comparing heparin with control in patients with acute ischemic stroke. Same conventions as Figure 1. (Adapted from Ref. 8.)

heparin for progressive stroke, and anticoagulants have not been shown to prevent neurological deterioration after stroke better than aspirin [10,21,22]. 3. Basilar Thrombosis The IST included over 2000 patients with posterior circulation infarcts, and there was no evidence that the eﬀects of treatment in this subgroup were any diﬀerent from those seen in the trial overall [5]. However, it is likely that only a small proportion had occlusion of the basilar artery. A trial focused on patients with proven basilar occlusion might be justiﬁed, but trials that seek to recruit a type of patient only rarely encountered in clinical practice are notoriously diﬃcult to do. 4. Carotid or Vertebral Artery Dissection There is no randomized evidence of the eﬀect of anticoagulants in patients with ischemic stroke due to arterial dissection [23], and the limited nonrandomized data show no evidence of an advantage of anticoagulants over aspirin [23].

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5. Intracranial Venous Thrombosis Two trials have evaluated heparin as a treatment for the whole spectrum of intracranial venous thrombosis [24,25], and a Cochrane systematic review of the randomized trials of anticoagulants has recently been completed [26]. Although the evidence is not strongly in favor of anticoagulants, they do appear safe in these patients. 6. Acute Myocardial Infarction Patients with full-thickness anterior myocardial infarction have a higher than average risk of developing left-ventricular thrombus. Some trials have shown that medium-dose subcutaneous unfractionated heparin or low molecular weight heparin reduce the frequency of left ventricular thrombus formation [27,28], but an overview of the 26 trials of anticoagulants in acute myocardial infarction (including 73,000 patients) found little evidence of any signiﬁcant net clinical beneﬁt (in terms of major clinical events) from adding either subcutaneous or intravenous heparin to the treatment of patients given aspirin [29,30]. The value of anticoagulants in a patient with an acute myocardial infarction complicated by acute ischemic stroke is also unclear [29,30]. Ischaemic stroke in patients with acute coronary syndromes may also be iatrogenic, due to particulate emboli reaching the brain as a complication of some invasive cardiological procedure, such as coronary angiography or angioplasty. The value of anticoagulants in these patients is not clear, as the embolic material is often atheromatous debris from the large arteries rather than fresh thrombus or platelet aggregates.

C. Use of Anticoagulants for Acute Ischemic Stroke Despite the lack of evidence from randomized-controlled trials, there are still occasions when clinicians may feel compelled to use anticoagulants in patients with acute ischemic stroke. In a survey of U.S. and Canadian neurologists, a large proportion reported that they would use intravenous heparin for stroke in evolution (U.S. neurologists 51% vs. Canadian neurologists 33%), vertebrobasilar stroke (30% vs. 8%), carotid territory stroke (31% vs. 4%), and atrial ﬁbrillation (88% vs. 84%) [17]. These practises are surprisingly variable and divergent from current recommendations [19,31]. 1. High Risk of Deep Vein Thrombosis Guidelines vary in their recommendations about whether or not heparin should be used routinely for deep vein thrombosis prophylaxis [32–36], and the criteria for selective use are not based on ﬁrm evidence. Patients at high risk of deep vein thrombosis, e.g., immobile patients with predisposing factors for deep vein thrombosis, may beneﬁt from graded compression stockings or, alternatively, from low-dose heparin. However, there is no evidence as to the beneﬁt of these preventive measures or whether any beneﬁt is additive to the eﬀect of aspirin [11]. 2. Atrial Fibrillation Patients with atrial ﬁbrillation who have had a stroke or transient ischemic attack are likely to beneﬁt from long-term oral anticoagulants as secondary prevention [37], but the best time to start anticoagulant therapy is not known [22]. In the occasional circumstance

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where we do feel compelled to use anticoagulants in the acute phase, the decision must be based on the likely risk of recurrent ischemic stroke events without treatment and the risk of symptomatic hemorrhagic transformation with treatment. The risk of early recurrent ischemic stroke is relatively low (estimates range from 1 to 8% during the ﬁrst 14 days) [22,38]. Symptomatic hemorrhagic transformation of the infarct occurs most commonly during the ﬁrst 2 weeks, and the risk is highest in patients with large infarcts or uncontrolled hypertension or in patients given more intensive heparin regimens [5,8,39]. Based on the available evidence [11], the oﬃcial recommendation is now that all patients with acute ischemic stroke and atrial ﬁbrillation should be started on aspirin as soon as possible [19,31]. Patients with minor ischemic strokes or transient ischaemic attacks can be started on oral anticoagulants immediately, and aspirin should be stopped once the International Normalized Ratio is in the therapeutic range. Patients with large infarcts can be started on oral anticoagulants after a week or two, when the risk of hemorrhagic transformation of the infarct is lower. When oral anticoagulants are started in this way, some time after the acute event, concomitant heparin (to overcome any transient prothrombotic state associated with the start of warfarin) is probably not needed [31,34]. 3. Intracranial Venous Thrombosis There is no ﬁrm evidence in favor of anticoagulants for intracranial thrombosis, although they appear to be safe [24–26]. Believers recommend anticoagulation with heparin, especially if the patient is deteriorating, and some even suggest local thrombolysis if all else fails [40]. In the collaborative European trial [25], after 3 weeks patients allocated anticoagulants were put on oral anticoagulants for 3 months (analogous to the treatment of deep venous thrombosis in the leg), which seems sensible. 4. Agent Most trials of anticoagulant agents in acute ischemic stroke have used unfractionated subcutaneous heparin [8], and systematic reviews have not provided evidence that any one agent is better than this regimen [8,12]. Trials of low molecular weight heparin for the prevention and treatment of venous thromboembolism in patients with conditions other than acute stroke [41] and for the treatment of acute coronary heart syndromes [42] strongly suggest that subcutaneous low molecular weight heparin is superior to intravenous unfractionated heparin, with no excess risk of bleeding [41,43]. The situation is diﬀerent in acute stroke: only one small trial suggested that low molecular weight heparin (fraxiparine) is beneﬁcial [44], but this ﬁnding was not conﬁrmed by subsequent, larger trials [10,22,45] and a systematic review [12]. At present, therefore, there is no clear evidence that low molecular weight heparins are superior to unfractionated heparin in acute ischemic stroke. 5. Dose and Route of Administration Oral anticoagulants achieve therapeutic plasma levels only after several days of therapy, and hence are of little value in the setting of acute stroke. Anticoagulants must therefore be given by intravenous or subcutaneous injection of heparin (or heparin-like agents) if they are to achieve a rapid eﬀect. The risk of bleeding with heparin is clearly dosedependent—the higher the dose, the higher the risk of intracranial and extracranial hemorrhage—and there is no evidence to support the use of full-dose adjusted regimens

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with intravenous unfractionated heparin or heparinoid [5,8,19,21,39]. The use of full-dose intravenous heparin must therefore be regarded as an experimental treatment, only to be used in the context of randomized-controlled trials [19]. Low-dose subcutaneous regimens are preferable (e.g., 5000 IU unfractionated heparin twice daily), since they are simpler, do not require complex monitoring, and are likely to be associated with lower bleeding risks [8].

D. Adverse Effects and Complications During Anticoagulant Treatment Table 1 lists the most important adverse eﬀects of heparins. The most life-threatening risks are intra- or extracranial hemorrhage. Management of severe hemorrhage caused by unfractionated heparin consists of stopping any administration of anticoagulants, estimation of the clotting time, and reversal with intravenous protamine sulfate or vitamin K and clotting factor concentrates (with or without fresh frozen plasma) according to local protocols and preferably in consultation with the local hematology specialist [34]. For reversal of low molecular weight heparin or heparinoids, consult the manufacturer’s data sheet. Reversal of warfarin therapy is often best done in consultation with the local hematology specialist. If an ischemic stroke occurs in a patient already receiving oral anticoagulants, the reason for the infarction must be sought. The cause is often inadequate dose of anticoagulants [37], but infective endocarditis must be ruled out. Recurrent ischemic stroke despite an adequate International Normalized Ratio may necessitate the addition of lowdose aspirin, though this is likely to double the risk of intracranial hemorrhage [46,47].

Table 1 Adverse Eﬀects of Heparin Local minor complications of subcutaneous heparin at injection site Discomfort Bruising Local complications of intravenous heparin at cannula site (or elsewhere) Pain at cannula site Infection at cannula (sometimes with severe systemic infection) Reduced patient mobility because of infusion lines and pump Intracranial bleeding Hemorrhagic transformation of cerebral infarct (potentially disabling or fatal) Intracerebral hematoma Subarachnoid hemorrhage Subdural hematoma Extracranial hemorrhage Subcutaneous (can sometimes be massive) Visceral (hematemesis, melaena, hematuria) Thrombocytopenia Type I: Dose and duration related, reversible, mild, usually asymptomatic, not serious and often resolves spontaneously Type II: Idiosyncratic, allergic, severe (may be complicated by arterial and venous thrombosis) Osteoporosis Skin necrosis Alopecia

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E. Suggestions for Future Research 1. Combination of Aspirin and Low-Dose Anticoagulant Treatment As part of a systematic review of anticoagulants versus antiplatelet agents for acute ischemic stroke, we sought to assess whether the addition of anticoagulants to antiplatelet agents oﬀers any net advantage over antiplatelet agents alone [11]. The data from this review suggested that the combination of low-dose unfractionated heparin and aspirin might be associated with net beneﬁts over aspirin alone, and this might be worth testing in further large-scale randomized-controlled trials. 2. Very Early Anticoagulation A further trial is planned to randomize 1000 patients with non-lacunar ischemic stroke within 12 hours of onset to full doses of intravenous unfractionated heparin or to aspirin 300 mg daily [the Rapid Anticoagulation Prevents Ischaemic Damage (RAPID) trial] [48]. Until the RAPID trial is complete, there is no indication to use anticoagulants (either unfractionated heparin, low molecular weight heparin, or heparinoid, given either subcutaneously or intravenously) as routine treatment in patients with acute ischemic stroke in general or, in particular, etiological subtypes.

III. ANTIPLATELET AGENTS: ASPIRIN A. Rationale for Aspirin in Acute Ischemic Stroke Antiplatelet agents are widely used for the treatment and prevention of atherothrombotic vascular disease, and the majority of the randomized-controlled trials comparing antiplatelet agents with control are of aspirin. Antiplatelet agents taken for 2 years after an ischemic stroke or transient ischemic attack typically avoid about 36 serious vascular events (myocardial infarction, stroke, and vascular death) per 1000 patients treated [49]. More speciﬁcally, long-term antiplatelet use results in a signiﬁcant reduction in the absolute risk of recurrent ischemic stroke (24 prevented per 1000), while the risk of intracranial hemorrhage with long-term antiplatelet use remains low, with an excess of 1 hemorrhage for every 1000 patients treated over an average of 2 years [49]. In patients with ischemic stroke or transient ischemic attack, long-term antiplatelet therapy avoids 36 serious vascular events for every 1000 patients treated for 3 years [50]. In the venous circulation, among patients at high risk of venous thrombo-embolism (chieﬂy as a result of general or orthopaedic surgery), antiplatelet drugs also reduce deep venous thrombosis by 39% and pulmonary embolism by 64% [51]. Aspirin is also eﬀective in the treatment of acute myocardial infarction, preventing about 38 serious vascular events per 1000 patients treated for just one month [50]. In acute stroke there is substantial platelet activation [52,53], and aspirin therapy might therefore also be beneﬁcial for this disease. Until a few years ago, there was no reliable evidence on the eﬀects of aspirin therapy for acute ischemic stroke, and clinical practice in the use of aspirin still varies considerably around the world. In the United Kingdom, a 1995 survey showed that 50% of physicians who routinely treated patients with acute stroke started antiplatelet therapy within 48 hours of the onset of stroke if they thought that it was likely to have been a cerebral infarct [54]. An updated survey in 1998 found that this number had increased to 77% [55]. In the United States, aspirin is less frequently used in acute ischemic stroke, and physicians more often use anticoagulant therapy with heparin [16–18,56].

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B. Evidence from Randomized-Controlled Trials and Systematic Reviews 1. Data Available The lack of data in the 1980s about the eﬀects of antiplatelet drugs as a treatment for the acute phase of stroke led to two large-scale randomized-controlled trials of aspirin, the IST and the Chinese Acute Stroke Trial (CAST), which together randomized over 40,000 patients [5,57]. In CAST, patients were allocated, in a double-blind design, to one month of 160 mg daily aspirin or matching placebo. Two reviews of these data are available [58,59]. The Cochrane systematic review includes all the completed randomized trials of any antiplatelet drug in acute stroke and examines their eﬀects on a variety of clinical outcomes [58]. The second review includes a meta-analysis of individual patient data from CAST and IST to examine the eﬀects of aspirin in particular categories of patient during the scheduled treatment period [59]. Both reviews report the frequency of events during the scheduled treatment period (2–4 weeks), and the Cochrane review also reports events and outcomes at the end of scheduled followup (6 months in IST, one month in CAST). 2. Recurrent Ischemic Stroke During the Treatment Period Aspirin signiﬁcantly reduced the odds of recurrent ischemic stroke during the treatment period by 30% (95% CI 20–40%), from 2.3% in controls to 1.6% in treated patients, i.e., avoiding 7 events per 1000 patients treated [59] (Fig. 4). 3. Symptomatic Intracranial Hemorrhage During the Treatment Period There was a small excess of symptomatic intracranial hemorrhages with aspirin (including symptomatic transformation of an infarct). It occurred in 0.8% of controls versus 1.0% of treated patients, a nonsigniﬁcant 21% relative increase in odds (95% CI 1% reduction to 49% increase)—an excess of about 2 per 1000 patients treated [59] (Fig. 4). 4. Death During the Treatment Period Aspirin signiﬁcantly reduced the relative odds of death from all causes during the treatment period by 6% (95% CI 1–16%), from 6.5% in controls to 6.1% in treated patients, i.e., avoiding 4 deaths for every 1000 patients treated [59] (Fig. 4). 5. Further Stroke or Death During the Treatment Period This outcome event cluster conveniently summarizes the overall balance of beneﬁts and adverse events within the treatment period: recurrent ischemic stroke, recurrent stroke of unknown type, symptomatic intracranial hemorrhage, symptomatic hemorrhagic transformation of the infarct, and death from any cause. We refer to this composite outcome event as ‘‘further stroke or death.’’ Aspirin signiﬁcantly reduced the relative odds of further stroke or death by 11% (95% CI 5–15%), from 9.1% to 8.2%; for every 1000 patients treated, 9 avoid further stroke or death during the treatment period [59] (Fig. 4). 6. Deep Venous Thrombosis and Pulmonary Embolism During the Treatment Period Two trials including only 136 patients reported data on deep venous thrombosis. Thirtyﬁve patients developed ‘‘symptomatic or asymptomatic deep vein thrombosis’’ during the treatment period, 29% of those allocated to control and 24% of those allocated to

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Figure 4 Aspirin in acute ischemic stroke: absolute eﬀects on diﬀerent events during the scheduled treatment period. Results of an individual patient meta-analysis of 40,000 patients with acute ischemic stroke in the IST [5] and CAST [57]. Numbers and percentages of patients are shown for the various events by allocated treatment. The percentages are plotted as bars with the standard deviation of each bar plotted at the top. The diﬀerence between aspirin (A) and control (C) is given as the beneﬁt per 1000 patients treated, along with its standard deviation and statistical signiﬁcance (SD and 2p); a negative beneﬁt indicates an apparent hazard. The numbers who suﬀered the relevant event but survived are marked with an asterisk at the foot of each bar. (Adapted from Ref. 59.)

treatment. There was a nonsigniﬁcant 22% relative reduction in the odds of deep vein thrombosis (95% CI 64% reduction to 67% increase), but it is potentially important. If conﬁrmed, it would imply that for 1000 patients treated, about 50 would avoid deep vein thrombosis [58]. Data from over 40,000 patients were available for the eﬀects of aspirin on pulmonary embolism (although fatal or nonfatal pulmonary embolism was not systematically sought in these trials). Aspirin signiﬁcantly reduced the relative odds of pulmonary embolism by 29% (95% CI 4–47%), from 0.5% in controls to 0.3% in treated patients, i.e., for every 1000 patients treated, 2 avoided pulmonary embolism. If we allow for the likely underascertainment of pulmonary embolism in these trials, and assume that the true rate in the controls was perhaps 3%, and then apply the same proportional reduction, then for every 1000 patients given aspirin, 12 might avoid pulmonary embolism. These data therefore strengthen the rationale for the routine use of aspirin in the acute phase of a stroke and continuing it long term; aspirin is likely to be adequate for thrombosis prophylaxis for patients at low and moderate risk of deep vein thrombosis and pulmonary embolism. For patients at high risk of deep vein thrombosis, perhaps because

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Figure 5 Aspirin in acute ischemic stroke: proportional eﬀects on death from all causes at end of follow-up. Results of a systematic review of randomized-controlled trials comparing aspirin with control in patients with acute ischemic stroke. Same conventions as Figure 1. (Adapted from Ref. 58.)

of a history of a previous episode of venous thromboembolism or the presence of thrombophilia, the question is what to add to aspirin. Graded compression stockings are one option and low-dose subcutaneous heparin another; both are supported by reasonable evidence (chieﬂy from trials in higher-risk patients, but not from trials in stroke patients). The SIGN guidelines on prevention of deep vein thrombosis have recently been updated and provide a useful reference work (www.show.scot.nhs.uk/sign/ home.htm) [35]. 7. Death at the End of Follow-Up The beneﬁt seen during the treatment period was still evident, so the diﬀerence in deaths from all causes at the end of follow-up at least a month later was about 8 deaths for every 1000 patients treated (Fig. 5) [58]. 8. Death or Dependency at the End of Follow-Up Aspirin signiﬁcantly reduced the odds of being dead or dependent at ﬁnal follow-up by 5% (95% CI 2–9%), from 47.1% in controls to 45.8% in treated patients, i.e., an additional 13 patients alive and independent for every 1000 patients treated (Fig. 6). Aspirin also signiﬁcantly increased the odds of making a complete recovery by 6% (95% CI 1–11%), an extra 10 patients making a complete recovery for every 1000 patients treated [58].

Figure 6 Aspirin in acute ischemic stroke: proportional eﬀects on death of dependency at end of follow-up. Results of a systematic review of randomized-controlled trials comparing aspirin with control in patients with acute ischemic stroke. Same conventions as Figure 1. (Adapted from Ref. 58.)

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C. Effect of Aspirin in Various Categories of Patients The beneﬁts of aspirin are consistent with those seen when antiplatelet therapy is used in long-term secondary prevention after a stroke [50]. The individual patient data metaanalysis, based on over 40,000 patients with acute ischemic stroke, did not identify any group in which the beneﬁts—or the adverse outcomes—were signiﬁcantly greater than or less than the averages reported above [59]. For the one-third reduction in recurrent ischemic stroke, the overall treatment eﬀect (2p < 0.0000001) was large enough for the subgroup analyses to be informative. The recurrence rate among control patients was similar in all 28 subgroups, so the absolute reduction of 7 per 1000 did not diﬀer substantially with respect to age, sex, conscious level, atrial ﬁbrillation, computed tomography (CT) ﬁndings, blood pressure, stroke subtype, or concomitant heparin use. There was also no good evidence that death without further stroke was reversed in any subgroup or that in any subgroup the increase in hemorrhagic stroke was much larger than the average, and there was no heterogeneity between the reductions in further stroke or death during the scheduled treatment period (Fig. 7). Among the 9000 patients randomized without a prior CT scan in the IST and CAST, aspirin appeared to be of net beneﬁt, with no unusual excess of hemorrhagic stroke, and among the 800 who had inadvertently been randomized after a hemorrhagic stroke, there was no evidence of net hazard (further stroke or death: 67 allocated control vs. 63 allocated aspirin) [59]. These data are reassuring in that they establish that patients inadvertently entered in the trials with a hemorrhagic stroke were not, on average, harmed as a result. However, they do not establish the safety of continued aspirin treatment in patients with primary intracerebral hemorrhage, nor do they establish the safety of giving aspirin in patients who are not CT scanned at all. There is little point in CT scanning after a week or so, since, at that stage, CT is increasingly unable to diﬀerentiate infarction from hemorrhage.

D. Use of Aspirin for Acute Ischemic Stroke Early aspirin is of beneﬁt for a wide range of patients, so all patients with suspected acute ischemic stroke should receive it unless there is a clear contraindication [19]. There was no clear evidence of a ‘‘time window’’ for the beneﬁt of aspirin; the relative beneﬁts among those randomized late (24–48 hours after stroke onset) were as great as among those randomized early (within the ﬁrst 0–6 hours) [59]. The IST and CAST trials tested a policy of ‘‘start aspirin immediately.’’ Aspirin should therefore be started as soon as a CT or magnetic resonance imaging (MRI) scan has been performed and has excluded intracranial hemorrhage. If CT scanning is not immediately available and the clinician feels, on clinical grounds, that the patient is unlikely to have a hemorrhagic stroke (i.e., no ‘‘apoplectic onset,’’ with early headache or vomiting, fully conscious, etc.), then aspirin can be started while the CT or MRI scan is being organized. This policy does not appear to reduce the beneﬁts from aspirin [59]. There has long been a controversy whether patients with acute ischemic stroke and atrial ﬁbrillation should be treated with heparin or aspirin. The IST and CAST trials included 4500 patients who had atrial ﬁbrillation at the time of randomization [59]. In these patients, the risk of recurrent stroke in hospital was 2.9% in the controls and 2.0% in patients allocated aspirin. The one-third reduction in the relative odds of recurrent ischemic stroke with aspirin was no diﬀerent from that seen in patients without atrial ﬁbrillation [59]. The Heparin in Acute Embolic Stroke Trial compared low molecular

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weight heparin with aspirin in 449 patients with acute ischemic stroke and atrial ﬁbrillation and showed no evidence of an advantage for low molecular weight heparin over aspirin [22]. All such patients should therefore be started on aspirin in the acute phase and continued on oral anticoagulant therapy when the risk of hemorrhagic transformation of the infarct is decreased (after a week or so) [11,31]. Implementation of a hospital policy or guideline of ‘‘immediate aspirin for all patients with acute ischaemic stroke’’ is a part of a well-organised stroke service. Several diﬀerent strategies may be required to maintain a high level of compliance with the policy [34,60,61]. 1. Who Should Not Be Given Aspirin? It should go without saying that patients with a history of deﬁnite aspirin sensitivity and patients with primary intracranial hemorrhage should not have antiplatelet drugs as a treatment for their stroke. However, patients with intracranial hemorrhage who have a very clear and pressing indication to continue aspirin (e.g., unstable angina) and are thought to have a low risk of further intracranial bleeding may need to resume aspirin therapy at a later stage. Patients receiving thrombolytic treatment for acute ischemic stroke may be at an increased risk of intracranial haemorrhage if aspirin is given concomitantly [7,62]. Starting aspirin the next day, probably around 24 hours after thrombolytic treatment, is unlikely to increase the risk of hemorrhage and should not reduce the beneﬁt of aspirin treatment [59]. 2. Dose and Route of Administration Based on the available randomized evidence, the appropriate dose of aspirin for use in acute ischemic stroke is between 160 and 300 mg/day. The lowest dose shown to be eﬀective in acute myocardial infarction is 160 mg/day [50,63]. Lower doses of aspirin (75–150 mg/day) are eﬀective for long-term prevention of serious vascular events [49] but have not been evaluated in acute stroke. There is some (but not abundant) evidence that at least 120 mg of aspirin is needed to acetylate all circulating platelets within a short period of time [64,65]. There is also some experimental evidence that a dose of 160–300 mg of aspirin daily is required in the acute phase of an ischemic cerebral or cardiac event in order to achieve rapid inhibition of thromboxane biosynthesis [52,63,66]. For patients who can not swallow safely, aspirin can be given rectally by suppository, by nasogastric tube, or by intravenous injection (as 100 mg of the lysine salt, infused over 10 minutes).

Figure 7 Aspirin in acute ischemic stroke: proportional eﬀects on further stroke or death in diﬀerent subgroups during the scheduled treatment period. Results of an individual patient metaanalysis of 40,000 patients [59] with acute ischemic stroke in the IST [5] and CAST [57]. For each particular subgroup the number of events among aspirin- and no-aspirin–allocated patients, and the odds ratio (black square, with area proportional to the total number of patients with an event) are given. A square to the left of the solid vertical line suggests beneﬁt, signiﬁcant at 2p < 0.01 only if the whole 99% conﬁdence interval (CI) (horizontal line) is to the left of the solid vertical line. The overall result and its 95% CI is represented by a diamond. Here and elsewhere, results for those with missing information on particular characteristics are not listed separately (except for CT ﬁndings), but numerators and denominators for them can be obtained by subtraction of the subgroup results from the total (e.g., the numbers with no prognostic index calculated were 16/638 aspirin versus 18/638 control). (Adapted from Ref. 59.)

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E. Adverse Effects and Complications During Aspirin Treatment Major extracranial haemorrhage (deﬁned as bleeding serious enough to cause death or require transfusion) is the most frequent serious adverse event. In the trials, the relative increase in odds with aspirin was large (68%; 95% CI 34–109%), but the absolute excess was small—four additional major extracranial hemorrhages for every 1000 patients treated [58]. The excess of extracranial hemorrhage was greater among patients allocated heparin than among other patients (heparin plus aspirin 1.8%; heparin alone 0.9%; aspirin alone 0.7%; no heparin/aspirin 0.5%) [59]. The risk of adverse events with aspirin can therefore be kept to a minimum by avoiding anticoagulants. Some patients have an ischemic stroke while already using aspirin, and in the IST, 4000 patients were already on aspirin or other antiplatelet drugs at randomization; the beneﬁts of continuing aspirin in this group of apparent ‘‘aspirin failures’’ was as great as in those not on aspirin at stroke onset. What to do for long-term secondary prevention in patients who have a stroke while already on aspirin is discussed elsewhere in this book. F. Suggestions for Future Research 1. Other Antiplatelet Agents The overall treatment eﬀect of aspirin in acute ischemic stroke is not large, and the search for better acute antithrombotic therapies in acute ischemic stroke should continue. There are no reliable data as yet on whether other antiplatelet regimens look more promising than aspirin in the treatment of acute ischemic stroke. The data from the Cochrane Review showed no signiﬁcant diﬀerences between aspirin alone, ticlopidine alone, or the combination of aspirin and dipyridamole [58], but the data from the nonaspirin regimens were extremely limited, and such indirect comparisons are subject to bias [50]. 2. Combination of Aspirin and Other Antiplatelet Agents There are many diﬀerent pathways involved in the aggregation of platelets, and a combination of two eﬀective antiplatelet agents working through diﬀerent mechanisms might be more eﬀective than a single agent. However, particularly large trials will be needed to test whether the addition to aspirin of ticlopidine, dipyridamole, or clopidogrel can produce signiﬁcantly greater clinical beneﬁt than aspirin alone [67]. 3. Combination of Aspirin and Low-Dose Heparin One systematic review suggests that the combination of low-dose unfractionated heparin and aspirin is more beneﬁcial than aspirin alone [11]. This might be worth testing in further large-scale randomized-controlled trials.

IV. OTHER ANTITHROMBOTIC AGENTS Antithrombotic agents other than anticoagulants and aspirin have been insuﬃciently studied in cerebrovascular disease. A Cochrane systematic review of antiplatelet therapy for acute ischemic stroke identiﬁed a small number of studies testing agents other than aspirin, including the Gp IIb/IIa inhibitor abciximab, ticlopidine, the combination of aspirin and dipyridamole, and the antiplatelet agent OKY 046 [58]. Some small trials have compared a variety of diﬀerent agents with inconclusive results [68–70], but there has been

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no large-scale trial that has randomly allocated patients between diﬀerent antiplatelet regimens. The indirect comparisons of the diﬀerent agents in the Cochrane Review showed no evidence of signiﬁcant heterogeneity of eﬀect between the diﬀerent agents. However, since the data from the non-aspirin regimens were extremely limited and such indirect comparisons are fraught with diﬃculties, no ﬁrm conclusion can be reached [50]. A. Gp IIb/IIIa Inhibitors Intravenous abciximab, an antibody Fab fragment directed against platelet IIb/IIIa receptors that inhibit platelet aggregation, has been recently introduced to reduce the rate of thrombotic complications of angioplasty and stent placement in coronary atherosclerotic disease [71]. There is some evidence that abciximab may be useful in the treatment of acute ischemic strokes [72,73] and in strokes complicating endovascular procedures on the coronary and cerebral circulation [74,75]. Placebo-controlled trials in the hyperacute phase of stroke and trials testing whether abciximab can be given instead of, or in addition to, intravenous thrombolysis with recombinant tissue plasminogen activator are either underway or recently completed but not fully reported [76–78]. Until new larger studies are completed, there is no indication to use these agents routinely. B. Ticlopidine Ticlopidine in acute ischemic stroke has been studied in a small pilot study with mainly nonclinical outcome measures [79]. This agent awaits further research. C. Fibrinogen Depleting Agents There are several deﬁbrinogenating agents. Ancrod is a 234-amino-acid glycosylated serine protease derived from the venom of the Malayan pit viper. During Ancrod therapy there is a fall in plasma ﬁbrinogen, plasminogen, plasminogen activator inhibitor, and antiplasmin levels [80], which might improve perfusion in the ischemic brain and so have a beneﬁcial eﬀect, provided its use is not associated with a substantial excess of major bleeding. There have been 10 small studies of Ancrod, of which three studies (including a total of 182 patients) met the methodological criteria of a Cochrane systematic review [81]. These three studies showed promising eﬀects, but the number of outcome events was far too small for reliable conclusions [81]. Since the review was published, the STAT trial including 500 patients has reported promising results [82]. A further trial with 600 patients (ESTAT) has been completed, but the results have not been published in full [83]. At present, though the data are promising, there is not enough evidence to justify the use of deﬁbrinogenating agents in routine clinical practice. D. Suggestions for Future Research It seems likely that the future direction of research will be to evaluate the newer agents, especially the Gp IIb/IIa inhibitors. For patients presenting within the ﬁrst few hours of onset, trials may compare directly a Gp IIb/IIIa inhibitor (plus or minus aspirin) and a thrombolytic agent. Trials recruiting with a wider time window, e.g., up to 48 hours, may compare GpIIb/IIIa inhibitor alone with GpIIb/IIIa inhibitor plus aspirin, and with aspirin alone. However, as with acute myocardial infarction, trials that seek to provide

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reliable estimates of diﬀerences in eﬀects of diﬀerent antithrombotic regimens will need to recruit tens of thousands of patients.

V. SUMMARY A. Anticoagulants There is no evidence that anticoagulants given within 48 hours of onset of acute ischemic stroke have any eﬀect on death, or death or dependency after follow-up of at least one month. Anticoagulants reduce the risk of recurrent ischemic stroke and venous thromboembolism during the treatment period, but this beneﬁcial eﬀect is oﬀset by a similar-sized increase in the risk of intracranial hemorrhage. The increased risk of intraand extracranial haemorrhage is dose-dependent. The data do not identify any category of patient in which there is clear net beneﬁt and do not support the routine use of high-dose intravenous or subcutaneous anticoagulants in any form for patients with acute ischemic stroke. Low-dose subcutaneous regimens will prevent deep vein thrombosis, but with a small but deﬁnite increased risk of major haemorrhage. It may therefore be advisable to consider safer alternatives for deep vein thrombosis prophylaxis in high-risk patients (such as aspirin, compression stockings, or early mobilization). B. Aspirin Aspirin 160–300 mg daily started within 48 hours of onset of presumed ischemic stroke reduces the risk of early recurrent ischemic stroke without a major risk of early hemorrhagic complications and improves long-term outcome. Patients with acute stroke in whom intracranial hemorrhage has been excluded or is thought to be unlikely should therefore receive aspirin as soon as is practicable, provided no deﬁnite contraindications exist. In those who cannot tolerate aspirin, an alternative antiplatelet agent should be considered, although the evidence for other agents is inadequate at present. Aspirin is eﬀective in the long-term prevention of recurrent ischemic stroke and other major vascular events and should therefore be continued after hospital discharge. The beneﬁts of treatment with anticoagulants, aspirin, and thrombolytic agents given within 6 hours of stroke onset are given in Table 2.

Table 2 Eﬀects of Anticoagulants, Aspirin, and Thrombolytic Agents in Acute Ischemic Stroke Beneﬁt per 1000 patients

Harm per 1000 patients

Anticoagulants

9 avoid early recurrent ischaemic stroke

Aspirin

12 avoid death or dependency

Intravenous thrombolytic drugs (<3 hours of stroke onset)

60–120 avoid death or dependency

9 symptomatic intracranial haemorrhage 1 symptomatic intracranial haemorrhage 50 fatal intracranial haemorrhage

Treatment

Indication to Use No indication to use routinely Use routinely

Selective use within 3 hours: more trials needed

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C. Other Antiplatelet Agents Antithrombotic agents other than anticoagulants and aspirin have been insuﬃciently studied in cerebrovascular disease. There is no indication to use these agents routinely for the treatment of acute ischemic stroke.

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19 Neuroprotective Agents and Other Therapies for Acute Stroke Nils Gunnar Wahlgren and Niaz Ahmed Karolinska University Hospital, Stockholm, Sweden

I. INTRODUCTION Sudden occlusion of an artery leading to the brain is the most common cause of stroke. Nerve cells within the occluded part of the brain may survive for some time depending on collateral blood ﬂow from surrounding vascular territories. Unless blood circulation is restored, energy-dependent electric polarity cannot be maintained over the cell membranes. Depolarization leads to release of excitatory amino acid transmitters such as glutamate, inﬂux of calcium into the cells, increase of nitric oxide, formation of free radicals, lipid peroxidation, and cell death [1–3]. Lysis of an occluding blood clot, either by endogenous activation of ﬁbrinolysis or by thrombolytic drugs, interrupts these events. Since lysis does not occur in many patients early enough to avoid irreversible ischemic lesions, interest has focused on factors that may delay cell death until reperfusion is established. Hyperthermia, hyperglycemia, and reduced diastolic blood pressure have been found to increase infarct size and to be related to poor clinical outcome [4–10]. Numerous attempts have been made to develop a pharmacological agent that protects the brain cells from pathophysiological events following ischemia, but so far no such drug is proven beneﬁcial in randomized controlled trials (RCT). In this chapter we will discuss some of the classes of agents available that may protect ischemic brain.

II. THE ISCHEMIC CASCADE Following occlusion of a cerebral artery, a blood ﬂow reduction to about 40% of the normal value is compensated for by increased extraction of oxygen and glucose from blood. If blood ﬂow is decreased further, energy use is reduced by suppression of neuronal ﬁring activity. Heiss and coworkers [11] showed that individual neurons ceased spontaneous ﬁring activity at a level of 18 mL/100 g/min, although a high interneuronal variability was found between 22 mL/100 g/min and 6 mL/100 g/min. Some neurons seem to be particularly vulnerable, with a reduced ﬁring even at moderately reduced blood ﬂow [12]. 409

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With a blood ﬂow between about 10 and 20 mL/100 g/min, brain cell function is potentially recoverable, although neurotransmission is severely reduced or discontinued [13,14]. Anaerobic metabolism of glucose results in lactate accumulation and acidosis, leading to failing energy-dependent ion homeostasis over cell membranes. Within minutes or a few hours, or more immediately if blood ﬂow is below 10 mL/100 g/min, cell damage becomes irreversible [15,16]. Consequently the degree of ischemia as well as its duration determines whether brain cells will survive. Anoxic depolarization leads to release of excitatory neurotransmitters, primarily glutamate [17]. Glutamate stimulates inﬂux of calcium and sodium through NMDA, AMPA, and metabotrophic receptors. Entry into cells of sodium and water causes cytotoxic edema. Increase of intracellular calcium causes damage to metabolic functions and eventually leads to cell death through formation of free radicals (Fig. 1). In contrast, genetically regulated cell death, apoptosis, may continue around the infarct zone hours to days after onset of ischemia, as a consequence of induction of immediate early genes and expression of heat shock proteins [18]. Reperfusion terminates pathophysiological events caused by ischemia, but may also exacerbate ischemic injury by oxygen delivery to cells with damaged mitochondrial function and subsequent free radical formation, migration of leucocytes into the injured tissue, and increased cytokine release [19].

III. NEUROPROTECTIVE AGENTS TESTED IN HUMAN STROKE TRIALS TO DATE A large number of pharmacological agents with evidence from preclinical studies to modulate the eﬀect of receptor- or voltage regulated ion channels, stabilize membrane polarity, scavenge the eﬀect of free radical generators, or inhibit leukocyte adhesion to vessel walls have been subjected to RCTs in acute stroke patients [30–132]. Although several of the candidates have been shown to reduce infarct size and/or improve neurological function in animal stroke models, none has survived clinical evaluation. In the following, we will discuss the classes of neuroprotectants evaluated in completed and ongoing randomized controlled trials of acute stroke (Table 1). A. Calcium Channel Blockers The most extensively evaluated calcium antagonist, nimodipine is a dihydropyridine derivative, which acts on voltage dependent L-type calcium channels. Fifteen clinical trials [30– 44] involving 5320 patients showed no beneﬁt with nimodipine treatment, although in 1994 a meta-analysis of 9 major RCTs of nimodipine (n = 3719) suggested a potential beneﬁt with early nimodipine treatment (within 12 hours) [45]. The VENUS (Very Early Nimodipine Use in Stroke) trial with 445 patients treated within the ﬁrst 6 hours was terminated prematurely because an interim analysis did not suggest a beneﬁcial role of early administration of oral nimodipine [41]. Hypotensive eﬀects, particularly with intravenous nimodipine treatment, may outweigh any neuroprotective properties [9,33]. Other calcium antagonists tested with neutral result in acute stroke were nicardipine [46], ﬂunarizine [47], [48], isradipine [49], and darodipine (PY 108-068) [50]. A Cochrane systematic review of calcium antagonists in acute stroke involving 28 trials with 7521 patients found no eﬀect of calcium antagonists on poor outcome at the end of follow-up (OR 1.07, 95% CI 0.97– 1.18) or on death (OR 1.10, 95% CI 0.98–1.24) [51].

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Figure 1 The ischemic cascade and reperfusion injury. CBF = cerebral blood ﬂow, ATP = adenosine triphosphate; AMPA = D-amino-3-hydroxyl-5-ethyl-4-isoxazole propionate; NMDA= N-methyl-D-aspartate; NO = nitric oxide.

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Table 1 Putative Neuroprotective Agents, Evaluated or Under Evaluation in Acute Stroke Patients Mechanism of action Ion channel blockers Calcium channel blockers

Number of clinical trials

Drugs Nimodipine (voltage-dependent Ca2+ channels) Flunarizine Isradipine

Result

15

No beneﬁt

No beneﬁt No beneﬁt

Nicardipine PY 108-068 Fosphenytoin 619C89 BMS-204352

2 (1 pilot) 2 (1 pilot, I discontinued) 1 (Ph II) 1 1 RCT 2 Ph II 1trial

YM872 ZK-200775 (MPQX)

2 1 ph IIa

Competitive NMDA antagonists

CGS 19755 (Selfotel)

1 Ph II, 2 RCT

Noncompetitive NMDA antagonists

Aptiganel (Cerestat) CP-101,606

1 RCT 1 Ph III trial in hemorrhagic stroke 1 Ph II 2 pilot completed, 2 ongoing

Sodium channel blockers Potassium channel opener Glutamate antagonists AMPA antagonists

Dextrorphan Magnesium (voltage-gated Ca2+ channels) MK-801 (Dizocilpine Neurogard) Remacemide Glycine site antagonists

Polyamine site antagonists GABA agonists

GV150526 (Gavestinel) ACEA 1021 Eliprodil

Ongoing Abandoned due to side eﬀects RCT abandoned due to no beneﬁt and increased mortality Abandoned Ongoing

No beneﬁt Ongoing

No RCT

Abandoned

1 Ph II, current status unknown 2 (GAIN Americas and international) 1 ph II Ph III—abandoned

CNS side eﬀects

Clomethiazole Diazepam Bay x 3072

2 completed 1 (EGASIS) Serotonin agonist 1 Ph II completed, 1 Ph III ongoing Free radical scavengers (antioxidants and nitric oxide inhibitor) Antioxidants Ebselen 2 completed, 1 ongoing Tirilazad

No beneﬁt No beneﬁt No beneﬁt No beneﬁt No beneﬁt, another trial is considered

1 completed, 1 terminated prematurely

No beneﬁt Safe with low dose Results not published No beneﬁt Ongoing Beneﬁcial outcome in Ph II No beneﬁt on primary end point No beneﬁt

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Table 1 Continued Mechanism of action

Drugs

NXY-059 (CPI-22) Nitric oxide inhibitor, Lubeluzole Na+ channel blockers, unknown mechanism Multiple or unknown mechanism of action Non-NMDA antagonists Gangliosides-GM1 Phosphatidylcholine Citicoline precursor (CDP-choline) Mechanism unknown or Piracetam uncertain Others Calcium chelator DP-b99 Growth factors Fibroblast growth factor (bFGF) Leukocyte adhesion Anti-ICAM antibody inhibitor (Enlimomab) Hu23F2G Adenosine transport Propentophylline inhibitor Opioid antagonists Nalmefene Apoptosis inhibitors Calpain and caspase inhibitors

Cerebrolysin

Number of clinical trials

Result

1 Ph II 4 RCT

Well tolerated No beneﬁt

4 completed 1 Ph II, 3 RCT, 1 in ICH ongoing 1 completed, 1 ongoing

No beneﬁt Mixed results

1 Ph II 1 ph III trial abandoned 1 RCT abandoned

Ongoing High mortality

1 RCT abandoned 1 small RCT 2 trials (1 Ph II, 1 Ph III) 1 Ph II study completed

No beneﬁt on primary end point

Treatment worsened outcome No beneﬁt Trend but nonsigniﬁcant No beneﬁt

Beneﬁt in Ph II

Ph = phase; AMPA = D-amino-3-hydroxyl-5-ethyl-4-isoxazole propionate; NMDA = N-methyl-D-aspartate; RCT = randomized controlled trial; CNS = central nervous system; ICH = intracranial hemorrhage.

B. Sodium Channel Blockers Sodium inﬂux through Na+ channels can lead to the release of glutamate and may also directly stimulate a rise in free intracellular Ca2+. Fosphenytoin, an anticonvulsant, glutamate release inhibitor, and sipatrigine (BW619C87), a derivative of the anticonvulsant lamotrigine, are Na+ channel blockers, and both have selectivity for neuronal Na+ channels compared with cardiac Na+ channels. Although animal models showed positive results [52,53], trials in ischemic stroke patients failed to prove eﬃcacy of these drugs [54–56].

C. Glutamate Antagonists There are three main types of glutamate receptors. NMDA and AMPA receptors are part of ligand-gated cation channels, and the third is a metabotrophic receptor belonging to a seven-transmembrane domain G-protein–coupled receptor group. The main glutamate receptor responsible for Ca2+ inﬂux is of the NMDA type.

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1. NMDA Antagonists There are two main types of NMDA antagonists—noncompetitive and competitive. A considerable number of NMDA antagonists have been synthesized and shown to be active neuroprotectants in animal models, but none have been shown to be beneﬁcial in clinical trials. A general problem with NMDA antagonists has been marked psychotomimetic side eﬀects. a. Competitive NMDA Antagonists. Competitive NMDA antagonists, such as selfotel (CGS 19755), bind reversibly at the NMDA binding site. They compete with glutamate for binding at this site, thereby reducing the eﬀects of glutamate. Many competitive antagonists are highly polar and cross the blood-brain barrier poorly. The initial phase IIa study of selfotel (CGS 19755) in patients with acute ischemic stroke (n = 32) showed beneﬁt [57], but a subsequent phase III study was abandoned (n = 567) after an interim analysis showed no therapeutic beneﬁt in primary outcome and increased mortality in the selfotel group [58]. b. Noncompetitive NMDA Antagonists. Noncompetitive antagonists bind to the phencyclidine recognition site on the ionophore and alter the way in which it responds to glutamate at the NMDA-binding site. Aptiganel (Cerestat), Dextrorphan, MK-801, and NPS 1506 are glutamate antagonists, non-competitive NMDA channel blockers. Clinical trials with these drugs in patients with acute stroke were halted because of insuﬃcient evidence of positive clinical impact or signiﬁcant side eﬀects [59,60]. CP-101,606 is a postsynaptic antagonist of NMDA receptors bearing the NR2B subunit. Phase III stroke trials with CP-101,606 in hemorrhagic stroke are ongoing since a phase II trial suggested improved outcome [61]. Remacemide is a low-aﬃnity NMDA receptor antagonist, which also interacts with voltage-dependent sodium channels. In a pilot study the drug revealed central nervous system–related adverse events [62]. Current phase of development is not known. Magnesium is regarded as a noncompetitive NMDA antagonist and voltage-gated calcium channel blocker. Magnesium exerts a blocking action on the cation channel of NMDA receptors at normal membrane potentials that prevents the inﬂux of calcium ions. When the sodium/potassium pump fails, the membrane potential disappears and the blocking action of magnesium dissolves, allowing calcium inﬂux [63,64]. Initial pilot RCT (n = 60) within 12 hours of symptoms showed that magnesium was well tolerated, with no signiﬁcant adverse eﬀects and no change in blood pressure or pulse rate [65]. FAST-MAG (Field Administration of Stroke Therapy—Magnesium) is a recently completed pilot study (n = 20) where paramedics identiﬁed stroke patients and administered magnesium sulfate by infusion. It took an average of 29 minutes (compared to 191 minutes in hospital) to reach the scene and administer the drug. Symptoms improved in 20%, worsened in 7%, and were unchanged in 73% of patients [66]. A phase III, multicenter study (FAST-MAG) is ongoing, with an expected enrollment of 1270 patients [54]. IMAGES (Intravenous Magnesium Eﬃcacy in Stroke—Magnesium) is a recently published study with 2589 patients within 12 hours of stroke onset which did not show any diﬀerence in primary outcome (death or disability at 90 days) between magnesium and placebo. However, there was an indication that magnesium could be beneﬁcial in patients with lacunar stroke. MR (magnetic resonance) IMAGES is an ongoing substudy of the main IMAGES trial to determine whether intravenous magnesium sulfate (within 12 hours) will reduce the frequency of infarct growth. Primary outcome measure is the frequency of DWI lesion growth from baseline to day 90 T2-weighted MRI [54]. c. Glycine Site Antagonists. Glycine is an inhibitory transmitter in the central nervous system (CNS). The NMDA glutamate receptor–ionophore complex carries a glycine-

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binding site. Glycine must be bound to this site before the cation channel will open in response to glutamate [68]. GV150526 (Gavestinel) is a glutamate antagonist and NMDA receptor blocker at the glycine site. GAIN (Glycine Antagonist in Neuroprotection)– Americas (n = 1367) and GAIN–International (n = 804) in patients with acute stroke (ischemic or hemorrhagic) found no statistically signiﬁcant diﬀerence between treatment groups on primary outcome and on mortality at 3 months [69,70]. Later the sponsoring company halted development of GV 150526 for stroke. Licostinel (ACEA 1021; 5-nitro-6, 7-dichloro-2,3-quinoxalinedione) is a competitive antagonist of glycine at the NMDA receptor. Clinical development of licostinel in stroke has been halted due to adverse eﬀects [71]. d. Polyamine Site Antagonists. Eliprodil is a glutamate antagonist at the NMDA polyamine site. A phase III stroke trial was abandoned, but the trial results have not been reported [72]. 2. AMPA Antagonists (Glutamate Antagonists) AMPA receptors are usually not a major contributor to glutamate-induced excitotoxicity, but inhibiting NMDA receptors may increase their relative contribution [73]. Other factors may also contribute to the downregulation of NMDA receptors (e.g., extracellular proton accumulation) and upregulation of AMPA receptors (e.g., increased permeability to calcium due to changes in subunit composition) [74]. YM872 is a glutamate blocker, AMPA receptor antagonist. It is currently evaluated in ARTIST (AMPA Receptor Antagonist Treatment in Ischemic Stroke Trial), an ongoing RCT (n = 600, planned) to compare the clinical therapeutic eﬀects of YM872 versus placebo in patients with ischemic stroke who are treated with thrombolysis [75]. ARTIST MRI is an ongoing substudy of ARTIST (n = 260 planned) to evaluate the eﬀects of YM872 on stroke lesion volume. Primary outcome is lesion volume at day 28 (+/ 5) as measured by FLAIR MRI [76]. K-200775 (MPQX) is a glutamate antagonist (competitive AMPA blocker). A phase IIa trial was halted due to excessive sedation at therapeutic levels. No further development is planned [54].

D. Monogangliosides (GM1) Exogenous gangliosides have a multiple mode of action with trophic activity, glutamate antagonism, and membrane stabilization. Several studies with GM1 in cerebral ischemia failed to show beneﬁcial eﬀect over placebo in the primary eﬃcacy analyses. However, in a few studies, secondary and post hoc analyses showed improvement in the GM1 group patients compared with the placebo patients [77–80]. In a Cochrane systematic review, 12 trials of exogenous GM1 in acute ischemic stroke (n = 2265) were analyzed, and no signiﬁcant diﬀerence in mortality was found (odds ratio 0.91, 95%, CI 0.73–1.13) at the end of follow-up and no diﬀerence between early (within 48 hours) and delayed treatment. The reviewers concluded that there is not enough evidence that gangliosides are beneﬁcial in acute stroke. Caution is warranted because of reports of sporadic cases of GuillainBarre´ syndrome after ganglioside therapy [81].

E. GABA Agonists GABA is the major inhibitory neurotransmitter in the brain. Its inhibitory eﬀects are mediated through the opening of chloride channels that form part of the GABA receptor-

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ionophore complex. The whole complex is known as the GABAA receptor. The resulting increase in chloride conductance leads to hyperpolarization of neurons, including those that release glutamate. 1. Clomethiazole Clomethiazole is neuroprotectant in animal models of ischemic stroke [82–86]. The exact mechanism of action of clomethiazole is not fully understood, but it is known to bind to a nonbenzodiazepine site on the GABAA receptor, causing an increase in chloride conductance and subsequent hyperpolarization [87]. Clomethiazole augments the eﬀects of endogenous GABA and can also directly activate the GABAA receptor at a site separate from the GABA recognition site. Clomethiazole was ﬁrst tested in a RCT (n = 1360) in hemispheric stroke (within 12 hours), which showed no overall adverse or beneﬁcial eﬀect on long-term outcome but produced sedation [88,89]. In a predeﬁned subgroup classiﬁed as total anterior circulation syndrome (TACS) (n = 545, or 40% of all randomized patients), 40.8% on the clomethiazole versus 29.8% on the placebo reached relative functional independence [90]. The drug was also found to be safe in hemorrhagic stroke [91]. A subsequent study with 1198 TACS patients failed to show any beneﬁt over placebo. The target population was selected, and suﬃcient drug was given to produce the expected pharmacological eﬀect in the brain. The ﬁnal conclusion was that clomethiazole does not improve outcome in patients with major ischemic stroke [92]. 2. Diazepam Diazepam is a GABA agonist. A phase III, multicenter trial of diazepam in acute stroke (EGASIS = Early GABA-ergic Activation Study In Stroke) is ongoing [93].

F. Serotonin Agonists Activation of neural 5HT1A receptors by speciﬁc agonists results in the induction of potassium current through the inward rectiﬁer channels that causes hyperpolarization and inhibition of neural activity. Repinotan (Bay x 3702) is a serotonin agonist (5HT1A receptor subtype), clinically evaluated in BRAINS (Bayer Randomized Acute Ischemia Neuroprotectant Study), a phase II RCT (n = 240) within 6 hours of symptom onset with 3 doses of intravenous Bay x 3702 or placebo for 72 hours (60 patients in each group). This pilot study found an improvement in neurological and functional outcome at 4 weeks and 3 months in those patients receiving a dose of 1.25 mg/day for 3 days [94]. RECT (Repinotan Exposure Controlled Trial) is an ongoing phase III RCT with a planned enrollment of 660 patients (within 6 hours of stroke onset) [95].

G. Potassium Channel Opener Neuronal membrane potential is the result of a concentration gradient between sodium and potassium ions. Stabilization of membrane potential may be achieved by opening potassium channels. BMS-204352 activates neuronal potassium channels, which may result in neuronal hyperpolarization or decreased neurotransmitter release. POST-010 and POST-011 were phase III RCT involving 1978 patients (within 6 hours) with the doses

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of 1.0 or 0.1 mg or placebo. BMS-204352 failed to show superior eﬃcacy compared to placebo [96].

H. Free Radical Scavengers 1. Antioxidants During oxidative stress, there is excessive production of highly reactive, neurotoxic free radicals, which are involved in the pathophysiology of cerebral ischemia as well as in reperfusion [97]. Transgenic mice that overexpress human superoxide dismutase (SOD) suﬀer less ischemic neuronal damage in ischemic stroke models than do normal mice [98,99]. Conversely, SOD knockout mice are more susceptible to neuronal damage than normal mice [100]. Agents with a capacity to scavenge their action have been evaluated in stroke. Ebselen is a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action. One RCT (n = 300) revealed that ebselen treatment signiﬁcantly improved outcome compared with placebo at 1 month ( p = 0.023) but not at 3 months ( p = 0.056) [101]. Another RCT found a nonsigniﬁcant good outcome ( p = 0.129) in the ebselen group [102]. A multicenter RCT with a planned enrollment of 390 patients is ongoing [54]. Tirilazad mesylate is a lipid peroxidation inhibitor. RANTTAS (Randomized Trial of High Dose Tirilazad in Acute Stroke) involving 556 patients (within 6 hours) was terminated prematurely because of no signiﬁcant diﬀerence in primary outcome between the two treatment groups [103]. RANTTAS II [104] was stopped after 126 patients had been enrolled, when questions regarding safety emerged from a parallel study in Europe. A Cochrane systematic review of 6 trials (4 published, 2 unpublished) involving 1757 patients with acute ischemic stroke found that tirilazad does not alter case fatality but increased the odds of being dead or dependent [105]. The current phase of development of the drug is not known. NXY-059 (CPI-22) is a nitrone-based free radical– trapping agent in development for acute stroke. Early studies indicate that plasma concentrations that are neuroprotective in rats can be achieved in humans without producing unacceptable adverse eﬀects. A phase IIa RCT evaluated the safety and tolerability of two doses of NXY-059 regimens (n = 48 in lower-dose, n = 49 in higher-dose) compared with placebo (n = 50) within 24 hours of acute stroke. NXY-059 was well tolerated in patients with acute stroke, and it also improved neurological scores [106]. A large pivotal trial is in preparation.

2. Nitric Oxide Inhibitors Lubeluzole has at least two mechanisms of action. It is a sodium channel blocker and therefore reduces the increase in extracellular glutamate concentration. Its main mechanism of action appears to be inhibition of glutamate-induced damage mediated through the formation of nitric oxide [107]. Clinical trials of lubeluzole have produced equivocal results. Lub (U.S. and Canadian Lubeluzole Ischemic Stroke Study) found that (n = 721) the overall mortality rate at 12 weeks was lower for lubeluzole-treated patients compared to placebo (20.7% vs. 25.2%) [108]. A subsequent study, LUB-INT-13 (n = 1786), was unable to conﬁrm the previous positive trend over placebo [109]. A metaanalysis of all lubeluzole trials concluded that the drug has no neuroprotectant eﬀect [110].

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I. Growth Factors Trafermin is a ﬁbroblast (trophic factor) growth factor (bFGF) [111]. A multicenter, acute stroke trial (n = 302) was stopped due to higher mortality compared to placebo [54]. J. Adhesion Molecules/Neural Inflammation Blockers/Leukocyte Adhesion Inhibitor Enlimomab is a mouse monoclonal antibody against intercellular adhesion molecule (ICAM)-1 that is required for leukocyte attachment and migration through cerebral endothelium. Rovelizumab (Hu23F2G) is a humanized monoclonal antibody directed against the neutrophil CD11b/CD18 cell adhesion molecule. EAST (Enlimomab Acute Stroke Trial) (n = 625) (within 6 hours) showed that patients treated with enlimomab had a worse primary outcome at 90 days than with placebo ( p = 0.004) [112]. HALT (Hu23F2G Phase 3 stroke trial) in acute stroke (n = 310) was terminated because it failed to meet predeﬁned criteria for success [54]. K. Opioid Antagonists Nalmefene (Cervene) is an opioid antagonist with relative selectivity for kappa opiate receptors. A phase II trial (n = 312) in patients with acute ischemic stroke (within 6 hours) found no signiﬁcant diﬀerence in primary outcome but suggesting beneﬁt for patients younger than 70 years [113]. A subsequent phase III trial (n = 368) found no signiﬁcant diﬀerence in primary and secondary analysis (in patients less than 70 years old) for nalmefene treatment compared with placebo [114]. L. Phosphatidylcholine Precursor (Citicoline) The exact neuroprotective mechanism of citicoline is unknown. It may promote new membrane repair and preserve cells during ischemia since it ampliﬁes the biosynthesis of phosphatidylcholine, the primary component of neural membrane. Trials with citicoline in patients with acute stroke showed mixed results. A phase II trial (Citicoline 010) found no diﬀerence in infarct size or neurological function with 500 mg citicoline compared to placebo [115]. An initial multicenter randomized (3 doses of citicoline and 1 placebo), vehicle-controlled trial (Citicoline 001) involving 259 patients showed beneﬁt of 500 and 2000 mg doses (but not 1000 mg) compared to placebo [116]. A subsequent trial (Citicoline 007) involving 394 patients (within 24 hours) failed to show beneﬁt of citicoline over placebo in a primary analysis. However, post hoc analyses found that patients with baseline NIHSS score 8 or more treated with citicoline were more likely to have a full recovery (placebo 21% vs. citicoline 33%; p = 0.05) [117]. A subsequent trial with 899 patients (within 24 hours) showed no beneﬁt in patients with NIHSS score of 8 or more in primary or secondary endpoints [118]. RICH (Role of Intravenous Citicoline for Supratentorial Hemorrhage) is an ongoing RCT of citicoline in patients with intracranial hemorrhage [119]. M. Multiple or Unknown Mechanism of Action The mechanism of action of piracetam is not known; it may increase cerebral blood ﬂow, and it inhibits platelet aggregation. PASS (Piracetam in Acute Stroke Study) involving 927

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supratentorial acute ischemic patients within 12 hours showed no diﬀerence in primary outcome between treatment groups. Post hoc analyses found a diﬀerence favoring piracetam relative to placebo in patients presenting within 7 hours of stroke onset and with moderate and severe stroke in the early treatment group ( p < 0.02) [120]. PASS II (Piracetam Acute Stroke Study II) is an ongoing phase III randomized trial in patients older than 50 years, with a clinical diagnosis of stroke (presenting within 7 hours of onset) deﬁned as a middle cerebral artery infarction score between 20 and 50 and without sequelae of a previous stroke. The primary outcome is Frenchay Aphasia Screening Test at 4 weeks and complete recovery from aphasia at 12 weeks [121]. ONO-2506 is a neuroprotective candidate that modulates uptake capacity of glutamate transporters and expression of GABA receptors and various astrocytic factors. A phase II/III trial is ongoing in patients with cortical stroke within 6 hours of symptom onset [122]. N. Adenosine Transport Inhibitor (Propentofylline) Propentofylline was tested in 30 patients with acute ischemic stroke (within 48 hours) to measure the eﬀect on regional brain glucose metabolism (rCMRglu) using repeated PET (positron emission tomography). After 14 days rCMRglu was increased in the infarct area, and there was a trend in clinical improvement in the propentofylline-treated patients that was not statistically signiﬁcant [123]. O. Apoptosis Inhibitors Apoptosis (programmed cell death) contributes to the development of full-blown infarction in addition to necrosis, which is the dominating cause of cell death [124–126]. Activation of caspase-3, one of a family of aspartate-speciﬁc cysteine proteases, is a key step in apoptosis in mammals. Recently neuroprotection against apoptosis has attracted increasing attention [127,128]. Several candidates have been successful in the experimental model of ischemia in signiﬁcantly reducing infarct size [125,126]. They have been reported to be able to protect even when given many hours after the ischemic insult [129]. It is therefore possible that caspase inhibitors may protect mildly hypoxic neurons in the periphery of the ischemic penumbra against apoptotic death. Inhibition of caspase action, blocking proapoptotic gene expression, and stimulation of antiapoptotic gene overexpression are some of the successful mechanisms. In the future, antiapoptotic neuroprotective drugs, alone or in combination with antinecrotic neuroprotective agents, may achieve good outcome in clinical trials [18]. Cerebrolysin (CERE) is a peptide preparation with neuroprotective (calpain and caspase inhibitor) and neurotrophic action, produced by a standardized enzymatic breakdown of lipid-free brain proteins. A placebo-controlled trial of an adjuvant administration of CERE in patients suﬀering from acute ischemic stroke within 24 hours (n = 68 in placebo, n = 78 in CERE) showed that patients in the CERE group had a signiﬁcant improvement in motor functions at 21 days (CNS, section A1) ( p < 0.05) compared to the placebo group. However, large clinical trials are needed to conﬁrm these results [130]. P. Combination Studies—Neuroprotection + Thrombolysis Combining a neuroprotectant with thrombolysis may augment the beneﬁcial eﬀects of the two agents. CLASS-T was a pilot RCT of clomethiazole versus placebo (within 12 hours)

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in patients treated with thrombolysis within 3 hours. There was no diﬀerence in death or adverse events between clomethiazole and placebo. In the TACS subgroup, clomethiazole patients score nonsigniﬁcantly higher functional outcome than placebo (52.9% vs. 44.7%) [131]. LUB-USA-6 was a phase II, multicenter RCT combination therapy trial with Lubeluzole and t-PA in acute ischemic stroke (within 3 hours). Target enrollment was 200 patients, but the study was halted after lack of eﬃcacy was demonstrated for lubeluzole alone [132]. ARTIST is a RCT (detailed earlier) to compare the clinical therapeutic eﬀects of YM872 versus placebo in patients with ischemic stroke treated with thrombolysis [75].

IV. OTHER THERAPIES FOR ACUTE STROKE A. Neuroprotective Effects of Cooling High body temperature (>37.5jC) is an independent predictor of unfavorable outcome in patients with acute stroke. Temperatures below 36.5jC improved outcome compared to normothermic patients [133–136]. In experimental stroke models, it has been demonstrated that moderate or even slight hypothermia decreases ischemic damage. The exact mechanism by which hypothermia exerts its neuroprotective eﬀect is not known, but experimental studies have shown that the release of neurotoxic excitatory amino acids and free oxygen radicals are reduced during hypothermic ischemia. Recently a human stroke study has demonstrated that hypothermia decreases glutamate, glycerol, lactate, and pyruvate in the ‘‘tissue at risk’’ area of the infarct but not within the infarct core [137]. Pharmacological treatment alone (paracetamol, metamizol) usually fails to lower core body temperature below 37jC and did not alter outcome after acute stroke [138,139]. Several physical devices are now available by which mild to moderate hypothermia can be attained such as by cooling mattress [140], surface cooling with ‘‘forced air’’ [141], and by the use of cooling blankets as well as alcohol and ice bags, by circulating temperatureadjusted normal saline in a closed-loop system [142]. Previous pilot studies have shown that mild (1–2jC below normal) [140], modest (35.5jC) [141], and moderate hypothermia (33jC) of core body temperature [143,144] may be safely attained without severe side eﬀects. However, a recent study showed that hypothermia below 33jC is associated with several adverse eﬀects such as thrombocytopenia (70%), bradycardia (62%), and pneumonia (48%). Deaths occurred (8%) during hypothermia as a result of severe coagulopathy, cardiac failure, or uncontrollable intracranial hypertension. Additional deaths (30%) occurred during or after rewarming because of rebound increase in intracranial pressure (ICP) and fatal herniation. A shorter (<16 hours) rewarming period was associated with a more pronounced rise of ICP [145]. However, Steiner and coworkers showed that slow, controlled rewarming is feasible and may be used for ICP and CPP control after moderate hypothermia for space-occupying infarction [146]. Current evidence shows that even moderate hypothermia (33jC) requires invasive procedures. Stroke patients do not tolerate such hypothermia without sedation or light anesthesia, which increases the risk of hypotension and respiratory complications. However, lowering body temperature by 1–2jC may suﬃce to improve functional outcome in acute stroke patients, and such mild hypothermia should be tested in randomized controlled clinical trial [147]. There is currently no evidence from randomized trials to support the routine use of physical or chemical cooling therapy in acute stroke [148]. A large, randomized-controlled clinical trial is needed to test the possible beneﬁcial eﬀect of induced modest hypothermia in unselected patients with stroke.

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B. Elevated Intracranial Pressure and Brain Edema Brain edema is deﬁned as an abnormal accumulation of ﬂuid in the brain tissue accompanied by an increased volume of the brain. Brain edema is intracellular (cytotoxic) or extracellular (vasogenic). Cytotoxic edema is caused by the impairment of cell metabolism resulting in an increase in tissue sodium ions and water content. Cytotoxic edema occurs during the early phase of infarction (within minutes) before any structural damage is evident. Vasogenic edema results from the extravasation of serum proteins due to increased permeability and breakdown of the blood-brain barrier (BBB), a phenomenon augmented by reperfusion. Both intracellular and extracellular edema are involved in cerebral ischemia. Clinically signiﬁcant brain edema develops during the ﬁrst 24–48 hours after ischemic infarcts. In younger patients with complete MCA infarction, brain edema and elevated ICP may become a major complication and may lead to herniation and death. Outcome is fatal in the majority of these patients, with a mortality of about 80% with standard treatment [149,150]. 1. Medical Therapy There is no evidence-based medical therapy for brain edema and elevated intracranial pressure, but osmotherapy, i.e., glycerol (hyperosmolar agent), and intravenous mannitol (osmotic diuretic) are widely used. Hypotonic and glucose-containing solutions should be avoided as replacement ﬂuids. Dexamethasone and other corticosteroids are not used for brain edema treatment after stroke. In an acute crisis, short-acting barbiturates such as thiopental can be given as a bolus, which reduces ICP quickly and signiﬁcantly. It requires monitoring of ICP, EEG, and hemodynamic parameters since signiﬁcant blood pressure drop may occur. Usually adrenergic substances must be given to counteract this side eﬀect [151]. Hyperventilation lowers the ICP, and stroke patients with increased ICP may be treated conservatively with continuous mandatory ventilation. However, this treatment is not based on evidence from RCTs. The eﬀects of hyperventilation do not last longer than 12–36 hours.

2. Surgical Therapy (Decompressive Surgery) a. In Malignant Middle Cerebral Artery Infarction. Decompressive surgery involves removal of a large part of the hemi-cranium to allow space for expansion of edematous brain tissue. The rationale is to reduce intracranial pressure and prevent fatal brain herniation, increase perfusion pressure to the part of the brain that is still salvageable, and preserve cerebral blood ﬂow by preventing further compression of the collateral vessels. In a nonrandomized study, surgical decompressive therapy in a hemispheric space-occupying infarction lowered mortality rate to 30% compared with 80% of historical controls [149,150,152]. A prospective multicenter study protocol has been recently developed and is now underway [153]. b. In Cerebellar Infarction. Decompressive surgery is considered the treatment of choice of a large space-occupying cerebellar infarction with brain stem compression, although the data from a controlled, randomized trial are lacking. Comatose patients with large space-occupying cerebellar infarctions have a mortality rate of about 80% if treated conservatively. This high mortality rate can be lowered to<30% if decompressive surgery is performed [154].

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V. THE FUTURE OF NEUROPROTECTION TREATMENT AFTER STROKE A. Ongoing Trials The striking discrepancy between positive results in animal stroke models and the negative outcome in human stroke trials has resulted in skepticism as to whether these models are all relevant for evaluation of neuroprotective agents. Is this skepticism justiﬁed? Obviously positive outcomes in stroke models do not guarantee success in clinical trials. On the other hand, there are few alternatives. Most researchers would probably require a positive outcome in stroke models a prerequisite for continuing a development program into the clinical phase. Although many trials have been neutral or negative, several trials are still ongoing. Some of these ongoing studies have a short time window from 3 to 6 hours [75,76,95,122,155], but some have a longer time window of 12 [67,93] and 24 hours [54]. Only the ARTIST MRI study used baseline diﬀusion-perfusion mismatch MRI (z20%) for patient selection [76]. Sample sizes of these studies are small to moderate (n = 390– 700). Only IMAGES has a relatively large sample size (n = 2700) [67]. ARTIST is a combination study with thrombolysis. None of these ongoing studies are testing more than one neuroprotective candidate [75,76]. Have we learned from previous failures of neuroprotective trials? B. Lessons from Previous Failures One major uncertainty in the design of acute ischemic stroke trials is how late after stroke onset a neuroprotective drug could be expected to exert a clinically meaningful eﬀect. Most stroke model studies of neuroprotective candidates have administered the drug either before or very soon after ischemia was induced. A treatment window used for thrombolysis treatment at most 3 hours after stroke onset has not been used in any published neuroprotective trial [156,157]. In studies published between 1995 and 1999, the delay between stroke onset and treatment ranged between 4 hours and 12 days (median 12 hours) [158]. Furthermore, previous neuroprotection trials might not have targeted the optimal study population, since patients were selected without imaging evidence of salvageable tissue. Stroke trials include several etiological subtypes, while underlying experimental studies are often homogeneous. Small trials with heterogeneous stroke etiology may also suﬀer the risk that a potential eﬀect in a stroke subgroup may be diluted by lack of eﬀects in other subgroups. Imbalance in the distribution of prognostically important baseline variables, such as stroke severity and age, between treatment and control arms has caused diﬃculties in the interpretation of study outcomes. There is increasing concern that conclusions of lack of beneﬁt of some neuroprotective candidates may have been premature and that a working concept may have been neglected because of suboptimal trial size and design and too generous time windows for treatment intervention [20–29]. It is indeed possible that power calculations should include more modest eﬀects of neuroprotective agents than previously expected and that sample sizes consequently should be extended considerably. Larger trials aiming to detect modest beneﬁts from a neuroprotective agent might have yielded a positive outcome. Some clinical trials have been terminated because of problems with safety, which were not detected in experimental settings. Human stroke patients have received lower doses of the drug than proven eﬃcacious in a preclinical model. An important aspect of drug acting under ischemia is whether it reaches the occluded target area in suﬃcient concentrations. There is limited knowledge about the comparability between animal experiments and human stroke on this point.

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C. Improved Quality of Basic Experimental Data One explanation for the failure to translate positive results from animal experiments into humans may be that stroke models are representative for only a minority of stroke patients. Most clinical trials include cortical as well as lacunar stroke, and sometimes hemorrhagic as well as ischemic stroke, in elderly patients with comorbidity and polypharmacy, while the typical stroke model includes proximal middle cerebral artery occlusion in young, healthy animals. Physiological parameters such as body temperature, oxygenation, blood pressure, heart rate, and blood glucose in stroke patients vary considerably, while these factors are tightly controlled and standardized in experimental stroke models. Preclinical testing of neuroprotective candidates should be standardized. Results in conventional stroke models with young and healthy animals could be repeated in old animals with common comorbidity such as atherosclerosis [156]. Putative neuroprotective agents in animal models given before or immediately after ischemic insult that successfully reduced infarct size should also be investigated several hours after ischemic insult.

D. A Wider Concept of Neuroprotection The usual concept of neuroprotection in stroke is that a drug inhibits pathophysiological events under ischemia, i.e., when the main arterial supply is occluded by a thromboembolic process. The introduction of thrombolysis treatment in stroke requires a neuroprotective agent that is safe and eﬀective after reperfusion. From this perspective, scavengers of free radical reactions would attract increased interest since they are involved in reperfusion injury as well as ischemic injury.

E. Improved Clinical Trial Methodology Future clinical trials should adhere to the conditions in which animal experiments were successful. A drug eﬀect may be modest, so that the study must be large enough to show a diﬀerence between active treatment and control. 1. Patient Selection Patient selection should aim to create a homogeneous population for initial stroke trials. Patients should be standardized with regard to stroke severity (not too severe and not too mild) and to stroke subtype in early trials (mimicking the experimental setting, e.g., cortical stroke). New randomization methods may be used to minimize baseline imbalances. DWI/PI mismatch MRI can be used to select patients with potentially salvageable tissue (corresponding to penumbra). Patients lacking this mismatch could be excluded from the study. 2. Criteria for Agent Selection 1. Safe and tolerable: One reason for neuroprotective trials to be terminated prematurely is severe or intolerable adverse eﬀects. Stroke patients are vulnerable since many suﬀer severe comorbidity. Any agent that aggravates comorbidity, such as hypertension, brain edema, and fever, is unlikely to be successful, even with neuroprotective properties. A potential neuroprotective eﬀect may be masked by adverse eﬀects [33].

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2. Short time window: The time window should be short (at least within 3 hours). However, if studies select the patients with evidence of salvageable tissue from imaging techniques, the time window may be extended beyond 3 hours. 3. Highly eﬀective with potential to be co-administered with other neuroprotective agents: A drug proven highly eﬀective in stroke models should be selected (80% or more reduction of infarct volume). If no single agent is found suﬃciently eﬀective, a combination therapy with multiple sites of action should be considered. A minimum dose with documented eﬀect in stroke models should be selected. 4. Rapid onset of action and availability of the drug in the tissue at risk: Since the ischemic cascade starts at stroke onset, an ideal drug would have a rapid onset of action to protect the brain. Intravenous formulation is preferable to an oral route. Even with intravenous administration a challenge is to cross the bloodbrain barrier. Although it has been demonstrated in rats that disruption of the BBB occurs 3–5 hours after MCA occlusion, this has not been shown in humans. Therefore, an ideal neuroprotective agent would be a small molecule that can readily may cross the BBB and reach the ischemic area without delay. 5. Capability to be co-administered with thrombolytic agent: Combination of neuroprotection with reperfusion may be considered since neuroprotective therapy is more eﬀective in reversible ischemia stroke models than in permanent occlusion. The neuroprotective agents must be safe to be co-administered with thrombolytic therapy. 6. Outcome measures: Surrogate markers like change of lesion volume measured by DWI/PI MRI can by useful in early studies to guide the design of large clinical trials. In pivotal trials, the primary endpoint should be clinically relevant and sensitive [159–161]. F. Hopes for the Future All negative results from neuroprotective trials may discourage investigators to continue their search for an eﬀective agent. However, it would be a mistake to give up the eﬀorts since too many methodological errors have been done over the years and promising approaches may have been abandoned prematurely. Study sample sizes in many clinical trials have been too small, particularly in the early years. It is possible that the eﬀect of a neuroprotective treatment will be more modest than expected, if it exists.

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20 Balloon- and Stent-Assisted Percutaneous Transluminal Angioplasty of Cerebrovascular Occlusive Disease for the Prevention of Stroke John C. Chaloupka, Niranjan Ganeshan, and Ali Elahi University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

John B. Weigele Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Walter S. Lesley St. Louis University School of Medicine, St. Louis, Missouri, U.S.A.

I. INTRODUCTION Stroke remains among the leading causes of major morbidity and mortality within the United States, with approximately 800,000 new or recurrent cases encountered annually [3,125]. It is the third most common cause of death (behind cardiovascular disease and cancer), in which over 70% of cases are caused by thromboembolic ischemia. Stroke also has become the leading cause of serious, long-term disability in the United States, accounting for more than half of all patients hospitalized for acute neurological disease [3]. Although there are numerous etiologies of thromboembolic stroke, up to a third of cases may be attributable to atherosclerosis of the common carotid bifurcation and internal carotid bulb [40]. Furthermore, intracranial cerebral atherosclerotic occlusive disease is believed to account for at least another 8–10% of thromboembolic strokes [31], although its true incidence likely has been underestimated. In certain ethnic (e.g., Asians, African Americans) and geographic (southeastern United States) populations, the incidence of intracranial occlusive disease appears to be considerably higher than this estimate (28,32,59,60), thereby substantially increasing its overall impact on ischemic stroke. Interestingly, during the rising availability of endovascular techniques for revascularization of the brain, several tertiary referral centers, including ours, that specialize in the diagnosis and treatment of intracranial occlusive disease have experienced a dramatic rise in caseload over the last few years. 433

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Considerable eﬀorts have been made to precisely deﬁne the epidemiology, pathogenesis, natural history, and optimal management of ischemic stroke related to both intracranial and extracranial cerebrovascular occlusive disease. These eﬀorts can be traced to the classic works of C. M. Fisher [50,51], who ﬁrst elegantly demonstrated the relationship between an atherosclerotic plaque forming in various locations of the cerebrovascular circulation and the resultant ischemic injury of the brain that would occur from either a downstream artery to artery embolus or regional hypoperfusion. Establishing this pathoetiological linkage was crucial for establishing medical and surgical therapeutic interventions aimed at stroke prevention. Considerable time and eﬀort has subsequently gone into evaluating the merits and limitations of various treatment paradigms, which has been largely driven by advances in biomedical science and technology. Eventually such interventions required validation by large-scale, evidence-based clinical trials, in which some, such as carotid endarterectomy, were found to be eﬃcacious in properly selected patients. Despite the successes of certain therapies in preventing ischemic stroke, there remains considerable room for improvement and reevaluation. For example, although large-scale randomized clinical trials have shown that carotid endarterectomy (CEA) is clearly eﬀective (compared to best medical management) in preventing ischemic stroke in symptomatic patients, this beneﬁt is only achievable if very low perioperative complications are maintained and if patients have relatively ‘‘low-risk’’ preoperative factors and/or comorbidities. In patients with asymptomatic carotid stenosis, the absolute and relative beneﬁts over best medical management are overall modest at best (and not even measurable in certain subpopulations such as women), and again are exquisitely dependent upon a very low perioperative complication rate. Outside the highly controlled (and consequently somewhat contrived) realm of clinical trials, many patients with either symptomatic or asymptomatic carotid occlusive disease are also routinely considered for CEA, but are likely at higher risk for serious perio-operative morbidity or mortality, owing to such risk factors as contralateral carotid occlusion, severe coronary artery disease, unstable neurological status, and recurrent stenosis after CEA. This risk escalation has been diﬃcult to accurately quantify, but may at least in some patient subgroups be in excess of the relative beneﬁts of intended stroke prevention. Furthermore, several types of extracranial occlusive lesions present serious diﬃculties related to limited access by open approaches (e.g., stenoses of the internal carotid artery distal to the bulb, proximal common carotid artery (CCA), and entire vertebral artery), For all intracranial occlusive lesions, the situation is worse, whereby surgical access and techniques for direct revascularization are either impossible or associated with excessive risk of major neurological morbidity or mortality. ‘‘Indirect’’ surgical revascularization techniques (typically via extracranial to intracranial bypass operations) were shown to be of no signiﬁcant beneﬁt in a large clinical trial [12,44]. Finally, best medical management, including systemic anticoagulation and antiplatelet therapy, is still associated with a very high cumulative risk of stroke. For example, data from the EC/IC Bypass Study estimated this risk to be as high as 8% per year [44]. Owing to the above-mentioned shortfalls in both medical and surgical management of cerebrovascular occlusive disease, there has been growing interest and eﬀort in expanding the role of endovascular surgery for revascularization of both extracranial and intracranial occlusive lesions using balloon- and/or stent-assisted percutaneous transluminal angioplasty (PTA). As techniques and technology have evolved, these therapeutic modalities appear to be increasingly useful for the management of many types of cerebrovascular occlusive disease, although more evidence of eﬃcacy is still needed through the conduct of larger-scale clinical trials. In this chapter we review the current status of these cumulative eﬀorts.

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II. BACKGROUND Although the natural history of both extracranial and intracranial occlusive disease has been studied for nearly half a century, the risk of stroke from such lesions has been clearly deﬁned only recently. These data permit both historical and direct comparison of outcomes for various medical and surgical therapeutic interventions in the past and currently serve as a foundation for assessing the rationale and eﬃcacy of endovascular surgical techniques for cerebral revascularization. Extracranial carotid atherosclerotic disease characteristically aﬀects the common carotid bifurcation and/or the proximal 2 cm of the internal carotid artery (ICA). This anatomical predilection likely is related in part to the peculiar ﬂuid mechanics (e.g., slip stream separation and reattachment zones, countercurrent recirculation zones, regional shear/strain gradients) and consequent cellular/molecular events that are related to the unique anatomical conﬁguration of the carotid bifurcation and bulb [11,53,79]. The same vascular risk factors associated with both coronary and peripheral vascular atherosclerotic disease (e.g., smoking, hyperlipidemia, diabetes, hypertension, family history) are strongly correlated with carotid occlusive disease, and therefore result in a high degree of comorbidity in aﬀected patients. Artery-to-artery embolism is by far the most common pathoetiological mechanism of stroke arising from extracranial carotid occlusive disease. As an atherosclerotic plaque progresses and becomes hemodynamically more signiﬁcant, ﬁbrin and platelet thrombus often accumulates in recirculation zones of low shear that are characteristically present between the distal end of the stenosis and the proximal region of the ﬂuid jet. These aggregates can be sheared away from various ﬂow disturbances and reversals that commonly occur within the carotid sinus. Plaque rupture and ulceration may also be a source of downstream cerebral emboli by serving either as an excellent substrate for thrombus accumulation or as an independent source of detritis. Unfortunately, many patients with extracranial carotid artery atherosclerotic disease do not have ‘‘sentinel’’ signs or symptoms (e.g., transient monocular blindness, transient ischemic attacks) preceding their index cerebrovascular event (i.e., clinical stroke or imaging evidence of cerebral infarction) [3,125]. It has been estimated that preceding transient ischemic attacks (TIAs) may occur in no more than 50% of patients with subsequent documented carotid territory stroke [31]. Based upon both retrospective longitudinal studies and recent clinical trials comparing best medical management to surgical intervention, the natural history of extracranial carotid occlusive disease, permits direct comparison of risk of stroke in patients receiving no treatment or medical management versus those receiving open surgical revascularization [124]. The risk of ipsilateral stroke for asymptomatic carotid atherosclerotic disease is well established from clinical trials that have evaluated the relative eﬃcacy of surgical revascularization. The European Carotid Trialists Collaboration Group evaluated nearly 2300 patients with asymptomatic carotid stenoses of varying severity over a mean follow-up period of approximately 54 months [46]. Stroke risk in lesions of 70–99% stenosis was approximately 1% per year. The Asymptomatic Carotid Atherosclerosis Study (ACAS) showed in 1662 patients with z60% stenosis a 2.2% annual risk of stroke in the medical treatment arm and a 1% annual risk of stroke in the CEA treatment arm [8]. The average risk reduction was approximately 50% over a 5-year period, although interestingly there was only a 17% (insigniﬁcant) risk reduction in women. More importantly, subsequent analysis of the ACAS results have raised serious questions regarding the actual beneﬁts of CEA, in that no beneﬁt of intervention was found in women and no signiﬁcant reduction in major strokes occurred [8]. Finally, the Veterans Aﬀairs Cooperative Group [70] showed an

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annual stroke rate of 2.3% in men with z50% carotid stenosis who also were treated with aspirin alone, as well as an approximately 5% annual rate of all ipsilateral neurological events (mostly TIAs). The risk of ipsilateral stroke for symptomatic carotid occlusive disease is better established by well designed clinical trials. The European Carotid Surgery Trial (ECST) enrolled symptomatic patients with carotid occlusive disease over a 10-year period, in which 2200 patients had a mean follow-up of 3 years. In almost 800 patients with stenoses in the 70– 99% range, there was an annual stroke risk of 5.6%. Furthermore, for patients already experiencing TIAs, the annual ipsilateral stroke rate increased to 13% within the ﬁrst year and nearly 33% over a 5-year period (6.6% average annual rate). Patients with signiﬁcant stenoses who had already experienced one ipsilateral stroke had the highest annual rates of a subsequent stroke (5–9%). The North American Symptomatic Carotid Endarterectomy Trial (NASCET) prospectively randomized 2926 patients in over 100 centers with symptomatic carotid artery stenosis to endarterectomy or medical management with aspirin [109]. One component was halted in 1991 because of proven beneﬁt for surgery in symptomatic patients with carotid artery stenosis greater than 70%. The cumulative risk for stroke over 2 years for patients with a stenosis of 70–99% was 26% (13% annual risk) in aspirin-treated patients versus 9% in surgically treated patients. The 30-day perioperative risk of CEA for any stroke and death was approximately 6%; the 30-day risk of major stroke or death was 2.1% (0.6% death). Perioperative nonfatal myocardial infarction occurred in approximately 1%. Wound problems (hematoma, infection) were observed in 9%, and cranial nerve injuries occurred in 8%. The 2-year incidence of ipsilateral major or fatal stroke was reduced from 13.1% in the aspirin-treated group to 2.5% in the surgically treated group. For patients with a stenosis of 70–99%, there was 13% annual risk of stroke, compared to a 9% annual rate in patients randomized to the surgical arm [109]. Further subgroup analysis showed increasing risk of stroke with severity of stenosis (those with 90–94% stenosis had a 35% annual rate of stroke), except for critical or nearly occluded ‘‘string-like’’ lumens, in which the annual risk of stroke decreased to approximately 11% [124]. Interestingly, less than 2% of patients with a nearly occluded carotid artery treated with medical management only developed a stroke within the ﬁrst month from onset of symptoms. The American Heart Association recently published indications for CEA that are stratiﬁed by an estimate of surgical risks as follows:<3%, 3–5%, and 5–10% for asymptomatic disease, and V6% or 6–10% for symptomatic disease [94]. A detailed review of these indications is beyond the scope this chapter, but a few salient points from this publication should be emphasized. First and foremost, according to the AHA recommendations, the only scientiﬁcally proven indication for CEA is in symptomatic patients with z70% ICA stenosis (based upon NASCET criteria), and an operative risk of <6% [33,94]. However, subgroup analysis of the NASCET trial also shows a strong trend towards beneﬁt in symptomatic patients with stenoses of 50–70% or greater [33], except for women. Second, as suggested earlier, the magnitude of beneﬁt of stroke reduction (i.e., absolute risk reduction) in asymptomatic patients undergoing CEA is very modest at best. Furthermore, this applies only to patients in the lowest operative risk category (i.e., <3%). Based upon this latter fact, many have advocated using stricter inclusion criteria for asymptomatic patients, consisting of a higher threshold of stenosis (z80%), lowest operative risk for CEA based upon published criteria, and special consideration to comorbidities (particularly those needing surgical intervention under general anesthesia). Since the beneﬁts (both relative and absolute) of CEA in stroke prevention are strongly dependent upon the risks of peri-operative complications (including both neurological and cardiovascular morbidity), some comment on operative risks is warranted to provide the

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proper context and goals of endovascular surgical approaches to cerebral revascularization. This topic has been controversial (particularly with the recent increasing interest in competing endovascular techniques), due to a combination of a paucity of objective data and frequent misinterpretation or misunderstanding of the few published studies that have attempted to provide objective evaluation of the issue. Many of these problems center around the use of outcomes reported from NASCET, which was a highly controlled and selective study for both patients and surgeons. Not surprisingly, NASCET results are often overgeneralized and inappropriately applied to a broader population of ‘‘real world’’ situations. For example, studies evaluating the complications of CEA in broad cross sections of community and academic practice have shown much higher rates of perioperative morbidity and mortality. Brott and Thalinger [24] showed that lower volume institutions in the greater Cincinnati metropolitan area had combined morbidity and mortality rates over 10%, with a perioperative stroke rate of 8.6% and a mortality rate of 2.8%. A meta-analysis of 51 studies showed an average perioperative risk of mortality of aproximately 2% and combined morbidity and mortality of almost 6% [122]. Of greater interest and importance, this study showed that there has been considerable variation in reported outcomes, with increased complication rates appearing to be positively correlated with third-party adjudication (i.e., neurologist) of perioperative morbidity and mortality. A study aimed at speciﬁcally quantifying risk of CEA was reported by Sundt et al. over two decades ago [126]. They hypothesized that certain angiographic, medical, and neurological factors may portend a higher operative risk in aﬀected patients. The ‘‘higher-risk’’ angiographic factors included contralateral CCA and/or ICA occlusion, a tandem skull base stenosis of the ICA (typically involving the siphon), a high carotid bifurcation, extensive plaque distal (>3 cm) or proximal (>5 cm) to the CCA bifurcation, and the presence of ‘‘soft’’ plaque (i.e., thrombus) occurring on an ulceration. Higher-risk medical factors included several cardiovascular comorbidities (e.g., recent myocardial infarction within 6 months of surgery, ongoing myocardial ischemia, congestive heart failure, and poorly controlled hypertension), as well as morbid obesity, chronic obstructive pulmonary disease, and advanced age (>70 years). The neurological risk factors were referred to as ‘‘instability,’’ being deﬁned as follows: progressive neurological deﬁcits, frequent transient ischemic attacks, and multiple strokes. Based upon these risk factors patients were classiﬁed into four groups as follows: group 1, no risk factors; group 2, only angiogaphic risk factors; group 3, medical risk factors F angiographic risk factors; and group 4, neurological risk factors only. In 331 patients reviewed using this classiﬁcation scheme, total morbidity and mortality rates were calculated: group 1, 1%; group 2, 2%; group 3, 7%; and group 4, 10%. The natural history of intracranial atherosclerotic occlusive disease is less well deﬁned because of a combination of probable underreporting of cases and overemphasis within past decades of the more readily correctable extracranial carotid occlusive disease. A large tertiary hospital cooperative study of almost 5000 patients undergoing cerebral angiography showed an incidence of intracranial occlusive lesions of approximately 23% [63]. This surprisingly high incidence of intracranial disease may very well occur in blacks and Asians [48,59,60,66] but is likely an overestimation of the general North American population due to selection bias. On the other end of the spectrum, some studies aimed at identifying the pathoetiological origin of TIAs have estimated that intracranial occlusive disease is clearly causitive in less than 10% of cases [31]. Again, the true incidence of clinically signiﬁcant intracranial occlusive disease detected by these studies could easily be underestimated by misclassiﬁcation of acute thrombotic strokes that are mistakenly attributed to an extracranial embolic source. This is because, unlike extracranial carotid disease, intracranial atherosclerosis has a higher predilection to ﬁrst present with a major apoplectic stroke (i.e., not preceded by any prodromal symptoms) [31]. In the case of middle cerebral arterial

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stenosis, data obtained from the EC-IC Bypass Study Group [44] and a smaller case series report [21] suggest that there is approximately an 8% annual cumulative risk of stroke in patients undergoing medical management. Although medical therapy has been shown to have some beneﬁcial eﬀect in stroke reduction, there remains a signiﬁcantly high failure rate [34,44,139]. Even among patients who are fortunate to suﬀer reversible neurological deﬁcits upon initial presentation, many will subsequently develop a major stroke within a relatively short time (one week to a few months [28,146]. The previously advocated convention of ‘‘waiting for the next event’’ has been challenged by preemptively considering these patients for therapeutic revascularization through the increasing availability and use of intracranial PTA and stenting. Craig et al. found the medium-term risk of stroke in asymptomatic patients was 36% with a 45% mortality rate, while in symptomatic patients the respective ﬁgures were 45% and 42%. This may reﬂect the hemodynamic rather than thromboembolic consequences of intracranial stenosis [34]. As in the case of extracranial carotid occlusive disease, intracranial atherosclerosis characteristically aﬀects certain anatomical sites of the circle of Willis, including the petrous and cavernous segments of the ICA, terminal ICA, M1 segment of MCA, distal vertebral artery (post-PICA segment > pre-PICA segment), vertebrobasilar junction, and basilar artery (proximal and middle portions most commonly). Although still unproven, it is believed that the peculiar geometric conﬁguration of the basal arterial circulation of the brain may produce blood ﬂow disturbance similar to those noted within the carotid sinus that predispose to plaque formation and thromboembolism. It is of particular interest that these same ﬂow disturbance may also lead to berry aneurysm formation in patients with certain genetic predispositions (e.g., mutations in extracellular matrix proteinases).

III. RELATIVE MERITS OF PTA AND STENTING A. Advantages There are hypothetical and real advantages for adopting endovascular surgical techniques for the treatment of cerebrovascular occlusive disease. Most obvious is the minimally invasive nature of these operations, which typically can be performed by a simple percutaneous transfemoral arteriotomy. Such operations inherently should be associated with less overall iatrogenic morbidity (owing to less tissue dissection and manipulation, risk of injury to surrounding normal organs, wound infection, etc.), resulting in more rapid recoveries and convalescence. For example, stent-assisted percutaneous transluminal angioplasty (SAPTA) of cervical carotid disease obviates the risks of cranial nerve injury, neck hematoma, wound infection, and unrecognized hemodynamic ischemia during cross clamping associated with CEA, as well as eliminating the need for general anesthesia. However, it must be emphasized that although minimally invasive, endovascular surgical techniques for cerebral revascularization are not automatically safer than open operative techniques with regards to neurological morbidity and mortality. Major catastrophic complications are possible, and in certain cases (e.g., PTA and stenting of intracranial stensoses) are not infrequent. For endovascular procedures to be useful, these risks of major catastrophic morbidity and mortality must be considerably less than the natural history of the disease and must remain substantially lower than comparable operations. Finally, cerebrovascular PTA and stenting oﬀers access to various atherosclerotic lesions that are either extremely diﬃcult or essentially impossible to approach by conventional open surgical techniques. This includes all skull base and proximal circle of Willis

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locations, as well as high and/or long cervical lesions of the carotid and much of the extracranial course of the vertebral artery. Even very proximal disease of the great vessels (e.g., subclavian artery, vertebral artery origin, CCA, and innominate) is likely better approached by endovascular techniques because of the often underestimated higher perioperative morbidity of conventional vascular surgical techniques developed for these lesions. B. Disadvantages Despite incentives of utilizing endovascular surgical techniques for cerebral revascularization, there are real and hypothetical risks, limitations, and unresolved questions regarding relative safety and eﬃcacy. Despite meticulous technique and care, both thromboembolic and hemorrhagic complications may still occur. Acute complications such as vasospasm, perforation, dissection, stent thrombosis, and rebound stenosis, are particularly signiﬁcant, owing to their likely devastating sequelae. Correction of these complications is a considerable challenge because of the combination of the inherent limitations of remote access to the lesion by endovascular navigation and available technology. Fortunately, experience suggests that these complications are not as frequent as was once originally feared. It is also likely that with improvements in both technology and technique, such complications will diminish. Access to targeted extracranial and intracranial lesions remains a problem as well, because of a variety of anatomical, pathological, and technological factors. For example, the combination of certain unfavorable peripheral and/or brachiocephalic vascular anatomy, such as peripheral occlusive disease, abdominal aortic aneurysm, dolicoectasia of the aortic arch and great vessels, and excessive tortuousity, loops, and/or kinks of the carotid and vertebral arteries, may essentially preclude safe and eﬃcious navigation of a variety of PTA and stent-delivery systems commonly used for extracranial carotid and vertebral occlusive disease. These limitations are further compounded by the added demands of navigating coronary devices into inherently tortuous smaller arteries at a considerable distance from an inserted guiding catheter. Technological innovations in which devices speciﬁcally are designed for cerebrovascular applications promise to overcome at least some of these barriers. The long-term eﬃcacy or durability of cerebral revascularization using PTA and stenting remains unproven, which likely will aﬀect the overall rate of future development and eventual magnitude of adoption of this therapeutic modality. There is concern that short-term restenosis rates similar to those observed with both coronary and peripheral vascular PTA and stenting may occur in both the extracranial and intracranial circulations, leading to a negating of any long-term beneﬁts of stroke reduction.

IV. TECHNIQUES Dramatic improvements in both technique and technology have facilitated safe and eﬀective endovascular surgical revascularization of the brain. These improvements are likely to continue with the increasing interest and utilization of such an approach to carotid occlusive disease. Lower proﬁle and more ﬂexible delivery systems are on the horizon, which may be augmented by downstream embolic capturing devices. A. General Preparations Prior to commencing a revascularization procedure, a detailed evaluation of the patient’s history, physical, and imaging is performed. A recent history of completed stroke may be a

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relative contraindication for acute revascularization, because of the combination of increased risk of hemorrhage into ischemic brain tissue that can occur from either ‘‘breakthrough’’ perfusion hemorrhage (typically in a large, acute infarct) or hemorrhagic conversion associated with anticoagulants, antiplatelets, and occasionally ﬁbrinolytics that are often used as adjuncts to SAPTA. If a patient experiences a recurrent or crescendo pattern of transient ischemic attacks, conﬁrmation of complete reversibility of transient neurological deﬁcit may minimize the risks associated with irreversible ischemic brain injury. Imaging evidence of a recent infarct may also represent a relative contraindication to acute revascularization. A careful review of a patient’s medical comorbidities exclude attention to the presence of uncontrolled hypertension, cardiac arrhythmias, angina, or congestive heart failure. Although not representing contraindications to therapy, these comorbid conditions usually need to be optimally managed medically or surgically to minimize the risk of perioperative morbidity and mortality. Prior to commencement of the operation, several preparative steps need to be addressed. First, a detailed, independent baseline neurological examination is done immediately before performing SAPTA. This practice ensures that the operators are thoroughly familiar with the patient’s neurological function, to increase the level of sensitivity and accuracy of detecting possible perioperative deﬁcits resulting from thromboembolic or hemodynamic events. Although typically a routine battery of preoperative tests (ECG, CBC, electrolytes, and coagulation proﬁle) is obtained during our initial clinic encounter with the patient, these studies are again reviewed to ensure that predisposing factors for perioperative complications are either corrected or minimized. All patients must have adequate intravenous access for perioperative ﬂuid management and medication administration. Transurethral catheterization of the bladder is recommended to ensure patient comfort during potentially prolonged operations, for monitoring ﬂuid balance, and for minimizing risks of hemodynamic instability that may arise from overdistention of the urinary bladder. When possible, patients are premedicated with two antiplatelet medications for 1–2 days prior to the procedure. Enteric-coated aspirin (ASA 325 mg qd) in combination with clopidogrel (Plavix 75 mg qd) is given to minimize the risks of periprocedural thromboembolism. In the event of an acutely indicated procedure, an initial dose of Plavix (375 mg) is administered. All patients undergoing carotid PTA and stenting receive intravenous heparin. For patients with thrombus accumulation suspected within a stenosis on catheter angiography, revascularization may be postponed by placing the patient on an extended period of systemic anticoagulation (ﬁrst systemic heparin, followed by warfarin) lasting approximately 3–4 weeks. The rationale for this approach is to allow time for the patient’s native ﬁbrinolytic system to slowly clear the thrombus, thus minimizing the risk of iatrogenic thromboembolic stroke during the endovascular operation. Currently, we are not routinely employing IIb/IIIa glycoprotein inhibitors in patients requiring extracranial carotid revascularization, since the added expense and risk of use of this drug does not appear to be outweighted by either a perceived or real enhancement of outcome. The most notable exceptions to this practice are in cases of long segmental stenoses requiring extensive endoluminal reconstruction and the presence of large ulcerated plaques. In contrast, owing to the well-recognized increased risk of early thrombotic occlusion that may occur shortly after PTA and/or SAPTA of intracranial arteries, we routinely administer Aggrastat (0.8. Ag/kg/min IV bolus over 15 min) or Reopro (0.25 mg/kg/min IV bolus over 15 min) immediately before the ﬁrst dilatation of a lesion. Selective catheterization of appropriate arteries is performed ﬁrst to assess the primary lesion for location, length, severity, and morphology. The presence of additional ‘‘tandem’’

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stenoses within the aﬀected vessel or collateral vessels is documented to determine appropriate prioritization of both endovascular surgery and overall management. Both downstream transit time and overall collateral circulation are hemodynamic parameters that assess a given patient’s risks for signiﬁcant neurological morbidity in the presence or absence of endovascular surgery. As such, therapeutic decision making should not be based exclusively upon the anatomical severity of a stenosis observed on angiography, but rather on the overall clinical signiﬁcance of the cerebrovascular occlusive disease. For example, a patient with only a moderate degree of stenosis (50–70%), yet is symptomatic, and with poor collateral reserve is an attractive candidate for endovascular surgery; conversely another patient with a ‘‘string’’ sign (nearly completed occlusion), who is neurologically stable, and with excellent collateral circulation may not need to undergo revascularization owing to the relatively good prognosis of this scenario. For extracranial SAPTA, all patients receive an initial intravenous bolus infusion of 3000 units of heparin following placement of a diagnostic femoral sheath. An additional 2000 units (totaling 5000 units) of heparin is administered following placement of the appropriate guiding catheter or sheath. An additional 1000 units is administered as a bolus or continuous infusion each subsequent hour throughout the duration of the procedure. We administer these doses empirically in most patients, with a goal of maintaining activated clotting time (ACT) greater than 2.5 the baseline value (>250 sec).

B. Extracranial PTA and Stenting 1. Access There are two basic techniques commonly employed for carotid SAPTA. In both cases a large inner diameter guiding catheter or sheath is positioned into the common carotid (or occasionally the innominate artery). It has been our experience that placement of a long arterial sheath from a percutaneous common femoral artery puncture is preferable from multiple perspectives, including enhanced stability, ease of coaxial delivery of PTA and stent catheters, and minimization of the size of arteriotomy. This technique is performed as follows. A standard 6 Fr arterial sheath is inserted into the common femoral artery after single wall percutaneous puncture and guide wire insertion. A 5 Fr diagnostic catheter is carefully positioned within the appropriate great vessel (usually the external carotid artery origin during internal carotid artery SAPTA), for subsequent placement of an exchange length (260 cm) 0.035 or 0.038 in. (e.g., Amplatz regular or extra-stiﬀ) wire. The diagnostic catheter and sheath are carefully removed, while maintaining the distal purchase of the guide wire. For extracranial stent cases where a 0.018 in. SmartStent (O.D. = 2.3 mm) or Wallstent (O.D. = 2.4 mm) will be deployed, a 7 Fr, 90 cm Shuttle Sheath (I.D. = 0.10 in., O.D. = 0.131 in.) is carefully advanced over the stiﬀ exchange wire, until a stable position within the parent lesion vessel (distal common carotid artery) is obtained. We prefer the ﬁnal sheath position to be at least 1–2 cm below the lowest planned stent placement to minimize potential stent deployment diﬃculty. We also ﬁnd that placing a wide arcing curve on the Shuttle inner dilator and distal sheath, as well as removal of the intervening rotating hemostatic valve, facilitates navigation of tortuous aortic arches and brachiocephalic vessels. Care must be taken to hold both components (dilator and sheath) together during initial advancement. Subsequently, the outer sheath is independently advanced into position over the dilator and guide wire within the proximal brachiocephalic vessels. This latter maneuver is critical, since the dilator is poorly seen on ﬂuoroscopy (without a marker band), and therefore

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may be inadvertently advanced too far distally into the stenotic lesion if both components are advanced in tandem. An alternative approach that may be employed requires a coaxial technique utilizing a diagnostic catheter (5 Fr, 120 cm) and guide wire (0.035 or 0.038 in.) within the 90 cm Shuttle sheath and subsequent staged advancement of each into the appropriate position. The diagnostic catheter and its associated curves may assist in distal navigation, while also minimizing wire/catheter/sheath transitions. Following stabilization, the sheath is then connected to a large bore rotating hemostatic valve and continuous pressurized heparinized saline infusion. In some cases, smaller delivery devices may be utilized, such as coronary PTCA and stent microcatheters, in which case a 6 or 7 Fr thin-walled guiding catheter with larger internal diameters (e.g., Envoy, Cordis Neurovascular or Guider, Boston Scientiﬁc) may be placed primarily or over an exchange guide wire. Appropriate testing of device/catheter compatibility is recommended before attempting therapy. 2. Lesion Crossing For many higher-grade stenoses (>80%), a stiﬀer and more torquable 0.014 in. microguidewire (e.g., Transend 14 EX, PT Graphix, Boston Scientiﬁc) is used to navigate across the lesion under ﬂuoroscopic road-mapping. A key to success in is to minimize the amount of probing and torquing of the microguidewire when entering the lesion. In extremely tight (>90%) and or irregular lesions, it is often necessary to obtain multiple DSA projections or three-dimensional reconstructed rotational DSA to obtain the most optimal working projection. A braided microcatheter (e.g., Prowler Plus, Cordis Neurovascular) is then slowly advanced beyond the stenotic segment. The 0.014 in. wire is removed and replaced with an exchange length (300 cm) 0.018 in. (SV5) or 0.014 in. (Luge) guide wire. The microcatheter is then exchanged with a carefully prepared (i.e., purged of air and preinfused with 50/50 saline-contrast) semi-compliant PTA microballoon (e.g., Maverick, Ninja, Photon, Slalom). On rare occasions a 0.035 in. guide wire (e.g. Terumo Glidewire) is needed for additional support and pushability of a stent-delivery system (e.g., excessive brachiocephalic tortuosity). Usually this maneuver is accomplished by sequential coaxial upsizing the devices used to ﬁrst cross and subsequently predilate an atherosclerotic lesion. 3. PTA Accurate measurements of the length of the stenosis and the parent vessel proximal and distal to the stenosis should be made. Standard measuring techniques using either an external standard, internal catheter reference, or quantitative angiography (QA) postprocessing software may be utilized eﬀectively. If an internal catheter reference is used, careful manual measurements should be performed (calipers or other precise measuring tool). Automated calculations utilizing a small reference point may grossly miscalculate scales of reference. We have found that the most recent versions of QA included on at least some of the contemporary biplane or single plane DSA systems generally provide surprisingly accurate automated measurements. Predilatation of the lesion is often needed before attempting stent deployment. In such cases a balloon with a nominal inﬂation diameter that is undersized to the native vessel diameter (in most cases a 4 20 mm balloon) is used to provide suﬃcient restoration of the inner diameter of the artery to permit safe passage of the stent delivery catheter. The length of the balloon is selected to closely match the total length of the targeted stenosis. Inﬂations are performed under continuous ﬂuoroscopic visualization, initially with a moderate degree of speed (approximately 30 sec) until a well-deﬁned ‘‘balloon waist’’ is

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observed. Subsequently, a more rapid surge of pressure is applied (typically requiring approximately a one-half to three-quarters turn on the balloon inﬂator), which typically equates to the approximate nominal pressure rating of the balloon. We try to use the lowest possible inﬂation pressure to eliminate the stenotic waist as our endpoint, at which time we rapidly deﬂate the balloon. Recurrent waisting (ﬁbrotic postendarterectomy lesions) or densely calciﬁed plaques requiring higher inﬂation pressures (up to 20 atm) may be encountered and should be approached with caution. These patients may have a higher frequency of complications, including prolonged bradycardia and hypotension, vessel dissection, vessel perforation, or balloon rupture–related air embolus. Appropriate balloon selection and judgment for the task at hand is of paramount importance (e.g., balloons of a rated burst pressure of 10–12 atm should not be inﬂated to 20 atm, especially in a poorly purged balloon). For cases requiring PTA alone, incremental larger balloon diameters should be exchanged across the lesion and slowly inﬂated as described above. No more than three balloon exchanges (and preferably only two) are recommended in larger parent arteries, with the maximal balloon diameter approaching, but not exceeding, the smallest parent artery diameter (usually distal to the stenosis). The ﬁnal desired angiographic appearance in extracranial cases should approach the native vessel diameter and geometry. For patients in whom a signiﬁcant residual stenosis is observed, endovascular stenting should be seriously considered secondary to the signiﬁcant rate of restenosis in these suboptimally treated lesions. Once a lesion has been crossed, maintaining an exchange wire across the lesion is highly recommended. In the event of a complication during PTA (i.e., vessel dissection, distal embolization, vessel occlusion), emergent ‘‘rescue’’ stenting or intra-arterial thrombolysis may be required. 4. Stent-Assisted Angioplasty In other vascular systems (such as the heart, pelvis, and lower extremities) conventional doctrine has suggested that primary SAPTA is preferable whenever feasible. Such an approach maximizes eﬃciency, minimizes thromboembolic complications associated with multiple catheter exchanges, and likely minimizes certain additional risks/complications, such as acute occlusion (from excessive plaque fracture and/or iatrogenic dissection) and ‘‘rebound’’ restenosis from elastic recoil (negative remodeling). Theoretically, deployment of a stent within a stenotic lesion may ‘‘trap’’ or compress soft/friable thrombus/plaque between the vessel wall and strut stents, minimizing the risk of distal embolization. As a rule, self-expanding stents are preferred within the extracranial vessels, especially at the level of the common carotid bifurcation. A variety of self-expanding stents are now available for carotid SAPTA, which have various technical advantages and disadvantages that are beyond the scope of this work. We currently use a 5.5 Fr sheath–compatible nitinol self-expanding stent delivered by conventional coaxial exchange guide wire technique (Precise stent, Cordis Endovascular), which has a relatively low proﬁle and excellent precision in deployment without signiﬁcant foreshortening. As in PTA, appropriate measurements of the parent vessel and stenosis are required. We prefer to use a stent of 1–3 mm greater diameter than the parent vessel (e.g., a 6 mm ICA would receive a 8–9 mm diameter stent), since this slight oversizing ensures adequate radial tension and approximation of the device to the endoluminal surface. This likely reduces the risk of complications such as stent migration and early thrombosis from poor endoluminal apposition. The intentional slight oversizing may also promote a delayed mechanical and biological remodeling of the diseased segment through gradual continued dilatation and stimulation of various growth factors and extracellular matrix proteinases (occurring over days to weeks). However, it must also be

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emphasized that excessive oversizing of these self-expanding stents must be avoided, since this may cause serious complications such as vessel wall necrosis and protracted carotid body stimulation. We also use a stent that is at least 1.0 cm longer than the lesion to ensure adequate coverage of both the distal and proximal stenotic segments. It is often necessary to cross the external carotid artery with a stent, owing to extension of disease into the common carotid bifurcation that needs revascularization. This can be done with relative impunity, since the ECA in most cases remains patent on follow-up examination. In the rare cases when the ECA does occlude (usually from severe coexistent atherosclerotic disease), patients usually remain asymptomatic secondary to the presence of abundant collaterals. If a second stent is required, a self-expanding stent of equal or greater diameter is overlapped with the primary stent and appropriately deployed. If a selfexpanding stent of a smaller diameter is positioned within a larger self-expanding stent, the risk of delayed dilatation and subsequent stent migration arises. On occasion, selfexpanding coronary stents (e.g., Radius) or balloon-expandable coronary stents (e.g., NIR, Multilink Duet, S670, Penta) may be required in smaller vessels (e.g., vertebral artery) or diﬃcult anatomical locations. On postdeployment angiography, the stent margins should approximate the luminal diameter and geometry of the parent vessels, proximal and distal to the stenosis. If a residual stenosis is present or poor approximation of the stent margins is observed, poststent dilatation or ‘‘ﬂaring’’ using PTA balloons is recommended. C. Intracranial Revascularization Unfortunately, despite the increasing interest in and use of PTA and stenting of intracranial cerebrovascular occlusive disease, development of appropriately designed microcatheter systems compatible with the intracranial vasculature has been considerably lagging. This is particularly the case regarding the commercial development of microballoon PTA and stent technology that speciﬁcally has the appropriate mechanical/physical characteristics for safe and eﬀective application within the intracranial arteries. Because of past limitations in the commercial availability of certain devices designed speciﬁcally for cerebral endovascular procedures, our group and many others have resorted to experimenting with existing devices designed for cardiac and/or peripheral endovascular surgery. Examples of successful oﬀ-label use of such devices has occurred with large-caliber guiding catheters, coaxial PTA balloon catheters, and balloon expandable stent technology. Based on these previous experiences and the increasing demand for endovascular surgical revascularization of the brain, we are ﬁnding ourselves trying ad hoc commercially available coronary microcatheter PTA and stent devices for intracranial cerebrovascular applications. However, to our knowledge, no systematic evaluation of the performance characteristics of these devices for such oﬀ-label use has been performed. 1. Special Preparations As with extracranial revascularization, a history, physical examination, and preoperative tests (e.g., blood work, ECG, imaging studies) are preliminary requirements for deciding upon the best therapeutic strategy that considers optimizing technical and clinical outcomes and minimizing potential peri-operative morbidity or mortality. Premedication with antiplatelet agents (most commonly daily Plavix 75 mg and ASA 325 mg is given to minimize perioperative thromboembolic events. Unlike for extracranial revascularization, we use a glycoprotein (GP) IIb/IIIa receptor inhibitor (tiroﬁban) due to past reports of acute in-stent thrombosis and distal thromboembolism occurring with intracranial PTA alone or in combination with stenting. This synthetic competitive GP

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receptor inhibitor can be infused as a loading dose in 15 minutes to achieve peak systemic antiplatelet action and is self-reversible in 2–3 hours after discontinuation of a maintenance infusion. It should be emphasized that great caution should be exercised when using tiroﬁban or other intravenous GP IIb/IIIa inhibitors because of their propensity to cause hemorrhage. When using such antiplatelet medications, it is crucial to reduce systemic anticoagulation with heparin. It is useful to monitor the activated clotting time (ACT) in such scenarios, in which intraoperative values should not exceed 300 seconds, and postoperative values at the time of arteriotomy closure should be below 250 seconds. 2. Access Usually either a standard thin-walled or reinforced extended-length (24 cm) 6 Fr arterial sheath is placed by percutaneous single-wall puncture into the common femoral artery, which will accommodate most of the commonly used diagnostic and guiding catheters for intracranial PTA and stenting. Usually a 5 Fr diagnostic catheter is then carefully positioned within the appropriate distal vessel circulation for subsequent placement of an exchange length (260 cm) 0.035 or 0.038 (Terumo Glide, Amplatz regular or extra-stiﬀ) wire. The diagnostic catheter is removed, while maintaining the distal purchase of the exchange length guide wire. We use the smallest possible outer diameter guiding catheter that will accommodate the coronary PTA and stent devices commonly used for intracranial lesions. This usually means selecting the larger lumen 6 Fr brided guiding catheters, such as the Envoy (Cordis) or Guider (BSC). The guiding catheter is placed within the safest distal segment of the extracranial artery (typically skull base for the ICA) and the mid-cervical portion of the vertebral artery. It is important to conﬁrm the compatibility of the PTA balloon or stent outer diameter with the selected guiding catheter I.D. prior to placement. After conﬁrming atraumatic placement of the guiding catheter, an O-ring rotating hemostatic valve is applied, permitting continuous pressurized heparinized saline infusion through the catheter. 3. Lesion Crossing As with extracranial stenoses, we use a conventional soft-tip 0.014 in. microguidewire (e.g., FasDasher 14, Transcend 14 Floppy, Boston Scientiﬁc) to navigate across the targeted stenosis. In some situations a slightly stiﬀer and more torquable microguidewire (e.g., Transend 14 EX, Boston Scientiﬁc) is required. We prefer using conventional exchange guide wire techniques to maintain constant access across an intracranial stenosis during intervention. The next step is to use a low-proﬁle braided microcatheter (e.g., Prowler 14, Excel 14) for catheterization of the normal arterial segment just beyond the lesion. The 0.014 in. microguidewire is then removed and replaced with a stiﬀer, exchange length (300 cm) 0.014 in. (e.g., Luge, PT Graphix, Balance). The microcatheter is then withdrawn and exchanged for one of many co-axial type (double lumen) 0.014 in. coronary PTA catheters that are available. The key to successful navigation of these devices is smooth and steady advancement, relying on the use of momentum for gaining purchase around the tight curvatures and tortuosity frequently encounted within the intracranial arteries. Excessive pushing should be avoided because of the risk of guiding catheter migration and arterial wall dissection. On occasion the exchange method of intracranial access with a PTA balloon is not possible, in which case primary crossing with the balloon microcatheter and a stiﬀer 0.014 in. microguidewire (e.g., PT Graphix) is performed. Again, for added safety and capability, an exchange length wire should be inserted before withdrawal of the balloon in case repeat angioplasty and/or stenting is required.

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D. PTA A variety of coronary PTA devices are available for intracranial applications. We have had particular success with low-proﬁle, semicompliant coronary PTA systems, such as the Open Sail (Guidant), Maverick (Boston Scientiﬁc), and Ninja (Cordis). In many intracranial stenosis, PTA alone is often suﬃcient to achieve adequate luminal diameter to alleviate or prevent clinical symptomatology. The balloon selected should be undersized by at least 0.5 mm and very slowly inﬂated under direct ﬂuoroscopic visualization. Inﬂations are be terminated when the stenotic waist is ﬁrst eliminated or when the nominal pressure (<6 atm) is achieved (Figs. 3,4). Gradual incremental times for initial inﬂation range from 20 to 30 seconds, while total inﬂation times are commonly in the range of 90–120 seconds. Rarely additional inﬂations may be performed utilizing the existing balloon or after exchanging for a slightly larger PTA device. The balloon diameter should never exceed the calculated diameter of the parent vessel distal to the stenosis. A mild angiographic improvement in the arterial lumen is a safe endpoint for intracranial lesions, minimizing the risks of arterial perforation. Minor arterial dissections may be created and safely observed for a period of 15–45 minutes to preclude acute thrombotic occlusion (Figs. 3,4). In many cases, subsequent long-term angiographic follow-up may demonstrate endothelial repair and beneﬁcial remodeling of the residual intimal tear and stenosis.

E. SAPTA Intracranial stenting is usually reserved for the following situations: (1) major iatrogenic dissection and or residual stenosis occurring immediately following PTA, (2) recurrent stenosis/failed PTA, and (3) aneurysm remodeling. It is essential to maintain a 0.014 in. exchange length microguidewire to ensure safe recrossing of the stenosis with a stent. Although from a technical perspective it is preferable to primarily stent/angioplasty a given intracranial stenosis, unfortunately in actual practice this is often very diﬃcult or impossible to accomplish because of the frequent severity of stenosis encountered in our patient population. Stent selection should be been based upon the following variable: (1) technical diﬃculty of access (e.g., increased tortuosity), (2) native arterial diameter, (3) length of stenosis, and (4) special application requirements. For example, atherosclerotic lesions within more distal locations (e.g., M1 segment) require the shortest and most ﬂexible stent, typically having a small number of unit cells, fewer crown linkages, and a low percentage surface area coverage. In contrast, stents selected for aneurysm remodeling at the skull base may require more scaﬀolding and a larger number of unit cells, which is associated with a commensurate decrease in stent ﬂexibility. As with intracranial PTA, correct sizing is of paramount importance. We have found that it is preferable to slightly undersize the diameter of the stent (Figs. 3,4). Although this may increase the risk of distal stent migration from insuﬃcient approximation, the greater risk of arterial wall dissection and/or perforation (with its usually catastrophic results) is greatly reduced. It is always possible to reinﬂate the delivery balloon to a higher pressure (past nominal) to better apply the stent to the intima. Another important guiding principle is to always try to deploy an intracranial stent with the lowest inﬂation pressure. Again, slow inﬂations are preferred over rapid ramping. If a residual waist persists, poststent dilatation may be carefully performed with either the same delivery balloon or a slightly upsized PTA catheter (typically no more than 0.5 mm above the original sizing) (Fig. 3). Delayed control

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angiography at least 15–20 minutes after initial stent deployment is mandatory to evaluate for early stent thrombosis, stent margin dissections, and rebound stenosis. Removal of the delivery balloon should be done slowly and carefully, avoiding prolonged traction on the deployed stent. It is not uncommon to have initial diﬃculties with balloon extraction after intracranial stenting. This usually can be overcome by either initial partial advancement of the device through the stent before withdrawal or low-pressure (1 atm) partial reinﬂation of the balloon. Finally, it should be emphasized that a less than perfect control angiogram after stent deployment often results in good clinical outcome (because of neointimalization and beneﬁcial remodeling) and therefore may represent a suitable endpoint for the endovascular operation.

V. COMPLICATIONS Some complications universal to any type of percutaneous transarterial angiographic and therapeutic procedure include groin hematoma, retroperitoneal hemorrhage, iatrogenic arteriovenous ﬁstula and/or pseudoaneurysm formation, limb ischemia from arterial thrombosis, nephrotoxicity, and various types of contrast media hypersensitivity reactions. Fortunately, with the exception of groin hematomas, the incidence of these complications is under 1%. Other complications are related to the speciﬁc artery targeted for therapeutic intervention. Although most of these complications are essentially the same generic mechanical traumas and sequelae encountered in other arteries throughout the body, their clinical signiﬁcance (i.e., both thrombotic and hemorrhagic stroke) is often markedly ampliﬁed by the relatively unforgiving nature of the aﬀected end organ (i.e., the brain). This realization of the intrinsically higher risks/stakes of neuroendovascular surgery cannot be overemphasized to physicians and patients alike. Obviously an overriding emphasis on preventing or minimizing perioperative neurological morbidity is necessary through meticulous attention to both the clinical status of the patient and the technical performance of the operation, since relatively minor deviations often translate into a major catastrophe. Clearly, cerebral revascularization demands a higher standard of technical and clinical outcome performance by the operator compared to any of the other organ systems approached by endovascular operations. Examples of such complications for both extracranial and intracranial endovascular operations can be broken down into two broad categories: hemorrhagic versus thromboembolic. Common etiologies for hemorrhagic complications include pinhole perforations, larger arterial wall tears or transections, dissecting aneurysms, and breakthrough and/or reperfusion hemorrhages in downstream microvascular beds (‘‘downstream hemorrhagic complications’’). The former mechanical complications may arise from a variety of technical errors, such as aggressive microguidewire manipulations, excessive stiﬀness of microguidewires and/or microcatheters, excessive pushing of delivery systems, oversizing of PTA balloons and/or stents, overinﬂation of PTA balloons, and inadvertent placement of a microguidewire into a small perforating branch. Clearly the best means of preventing such problems is to avoid these technical transgressions, although the precise demarcation between a technical error versus a scrupulous technical maneuver is often blurred or undeﬁned. Unfortunately, even when the most meticulous and orthodox endovascular surgical technique is utilized, such complications still occur. Obviously, the gravity of these mechanical complications is greatly increased for intracranial PTA and stenting because of the more serious consequences of subarachnoid, intraventricular, and intraparenchymal

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hemorrhage of the brain. Management of such complications is achieved mostly by conventional principles of neurosurgical practice. As for so-called downstrem hemorrhagic complications, predisposing etiological factors are mostly responsible. In particular, recent or ongoing ischemic injury to a relatively large region of cerebral cortex and/or white matter may lead to dysfunctional autoregulation and direct injury to the microvascular bed. A sudden rise in perfusion pressure from revascularization may lead to a reperfusion injury and/or so-called breakthrough perfusion edema and hemorrhage within the aﬀected regions of the brain. Therefore, as a general guideline, cerebral revascularization should be avoided in the setting of a recent (3–6 weeks) stroke aﬀecting more than 25% of a particular intracranial arterial territory. There should also be some reluctance to intervene early in patients with unstable neurological signs and symptoms for the same reasons, although frequently this is not practical if the patient has not stabilized on maximal medical management and is at risk for a completed infarction. Patients with very poor cerebrovascular collateral reserve, as documented on cerebral blood ﬂow studies obtained before and after administration of Diamox, may also be at higher risk of a perfusion breakthrough hemorrhage. Common etiological origins of infarction include vasospasm, intimal ﬂap production, frank dissection, plaque rupture, rebound restenosis, and acute thrombotic occlusion of the angioplasty/stent site. Again, as with hemorrhagic complications, technical misadventures may be responsible. However, even more so than in the former category, thromboembolic complications can occur without any obvious or subtle technical error. This latter problem has led to attempts at technical modiﬁcation to minimize intimal trauma (e.g., slower balloon inﬂations, undersizing, lower inﬂation pressures), as well as implementation of increasingly aggressive adjunctive anticoagulation regimens using various combinations of indirect and direct antiplatelet agents and systemic intravenous heparin. Unfortunately, our experience with these modiﬁcations is too incomplete to determine their true eﬀectiveness at this time. Certain complications are unique to the targeted artery when dealing with the cerebrovascular system. The most prominent and occasionally very serious complication peculiar to PTA and stenting of the extracranial carotid is both transient and persistent bradycardia and/or hypotension from stimulation of the carotid sinus. These cardiovascular complications have been variably reported in association with dilatation of stenoses at or near the carotid bulb, although the frequency, duratin, and magnitude of these problems remain poorly deﬁned. Iatrogenic dissection from PTA or stenting of either the distal vertebral or internal carotid arteries (both extracranial and intracranial portions) can also produce Horner’s syndrome by either thromboembolic ischemic injury to the posterior inferior cerebellar artery territory or injury to the periadventitial carotid sympathetic plexus.

VI. REVIEW OF CLINICAL EXPERIENCE: THE UIHC EXPERIENCE Our group has had considerable experience with both extracranial and intracranial cerebral revascularization using endovascular PTA and stenting. In particular, within the last 24 months there has been a dramatic rise in caseload stemming from a combination of enhanced technical and technological capabilities and an increasing willingness to consider endovascular surgical revascularization in patients with poor alternative therapeutic options. In reviewing our last 250 consecutive extracranial carotid PTA and stenting cases, we have achieved the following short-term technical and clinical results with the techniques described [29] earlier. Our technical success rate remains at approximately

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98%. There was one death (0.4%) and two major (0.8%) and eight minor (3.2%) strokes/ TIAs. It must be emphasized that these results have been achieved without the use of distal protection devices designed to minimize downstream embolization and have all undergone third-party adjudication of neurological outcomes (as a result of our multidisciplinary eﬀort to provide this type of endovascular operation). Representative cases are illustrated in Figures 1 and 2. It has been previously noted that extracranial carotid PTA and stenting (particularly in the ICA bulb region) can be associated with certain cardiovascular complications, such as

Figure 1 Archetypal stent-assisted angioplasty of a symptomatic ICA stenosis. Lateral views from selective left CCA injections. (A) Severe stenosis (85%) of LICA bulb conﬁrmed on catheter angiography in a patient with recurrent episodes of transient right hemiparesis and word-ﬁnding diﬃculties. (B) and (C) Lesion is ﬁrst crossed (B) and then dilated with a 4 mm 20 mm semicompliant PTA balloon catheter. No distal protection device is utilized. (D) Control angiogram left CCA injection shows improved diameter of lesion, although there remains signiﬁcant residual narrowing, as well as the potential for worsening rebound re-stenosis or occlusion (so-called negative vessel wall remodeling). (E) A self-expanding nitinol stent is positioned across the lesion over an exchange length guide wire. (F ) The deployed stent appears well-positioned across the lesion, although there remains a hemodynamically signiﬁcant residual stenosis. (G) A larger, semicompliant PTA balloon catheter (6 20 mm) is subsequently positioned and inﬂated across the residual stenosis. (H) Final control angiogram shows an excellent technical result with restoration of luminal diameter of the ICA (compared to the cervical segment distal to the bulb). No clinical complications were encountered.

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Figure 1 Continued.

bradycardia, hypotension, arrhythmia, and myocardial infarction. Although many practitioners expressed concern about these types of complications, the frequency and magnitude of these problems remain poorly deﬁned. This led us to retrospectively review our case series experience of carotid stenoses treated with PTA and stenting in 61 patients. Our cardiovascular monitoring routine includes measurement of heart rate continuously, blood pressure periodically (q 2 min), and ECG continuously, before, during, and after PTA and stenting. Prior to endovascular surgery, patients are evaluated for preexisting ischemic cardiac disease and/or arrhythmias by screening history and ECG. For patients with suspected coronary occlusive disease, a stress thalium perfusion study is also obtained, which is possible prompts further work-up by a cardiologist (typically leading to a cardiac catheterization study). In this case series we avoided prophylactic use of both temporary cardiac pacemakers and pressor infusions. In our series of 70 PTA and stent operations, major cardiovascular events occurred only in three cases (4.3%), consisting of persistent hypotension (4.3%) alone or in combination with persistent bradycardia (2.9%) that required extended hospitalization. One myocardial infarction (1.4%) also occurred in association with persistent hypotension/bradycardia without major sequelae. Although severe bradycardia and hypotension were rarely encountered in this series, transient or rapidly reversible hypotension and bradycardia were observed in 40% of cases. Persistent hypotension and bradycardia in the three cases were treated successfully with either a

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Figure 1 Continued.

continuous intravenous infusion of dopamine or intermittent intravenous boluses of glycopyrrolate. There were no deaths, and no patient required cardiac pacemaker placement. Based upon this experience we believe that clinically signiﬁcant cardiovascular complications (deﬁned as events either potentially life threatening or requiring an extension of hospitalization) are very uncommon and typically can be managed medically without the use of prophylactic pacemaker placement. It is also our impression that cardiovascular complications may be reduced by a combination of preemptive measures, including hypervolemic hydration, glycopyrrolate premedication, and certain technical modiﬁcations (e.g., slow balloon inﬂations, avoidance of high inﬂation pressures or excessive oversizing of selfexpanding stents). Our most recent experience with intracranial PTA and/or stentin has also been very favorable. In reviewing our last 90 consecutive cases of elective stent-assisted angioplasty (SAPTA), we have achieved the following short-term technical and clinical results with techniques that have been previously outlined. Our overall technical success rate was 95%, in which one lesion intended for revascularization could not be crossed for PTA or stenting. Our technical success rate speciﬁcally for ‘‘intention to stent’’ was slightly lower at approximately 90%. There have been one death (1%) and two perioperative major strokes (2%). There have been only three (3%) recurrent ipsilateral symptoms in the remaining

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Figure 1 Continued.

patients for variable follow-up intervals of 1–28 months. Five (5%) angiographic restenoses have been thus far detected in the same time interval of follow-up. Two typical cases of intracranial SAPTA are illustrated in Figures 3 and 4.

VII. REVIEW OF CLINICAL OUTCOMES A. Extracranial Carotid Circulation The value of endarterectomy for symptomatic carotid artery stenosis and the success of PTA in coronary, renal, iliac, and peripheral arteries led to interest in carotid artery angioplasty as a less invasive alternative to surgical endarterectomy. Enthusiasm was tempered, however, by concerns for the risks of acute thrombosis, arterial dissection, distal emboli, and delayed restenosis, which could be more catastrophic and less salvageable in the target organ (brain) than in other vascular beds. The possible beneﬁts of carotid angioplasty or stenting compared to endarterectomy might include lower periprocedural morbidity/mortality, equal or better stroke prevention, lower costs, and better patient acceptance [16].

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Figure 2 Emergent stent-assisted angioplasty of a symptomatic, functionally occluded left ICA. (A) A 79 year-old man presented with progressive hemiparesis and hypesthesia. A CT scan of the brain shows areas of watershed ischemic injury aﬀecting the left frontal and parietal lobes. (B) A critical (99%), long segmental stenosis of the cervical LICA just beyond the bulb is noted on catheter angiography (CCA injection; lateral projection). Note the initial lack of downstream ﬁlling of the ICA compared to the ECA. (C) and (D) Delayed pre-treatment angiogram from left CCA injection (left anterior oblique projection) shows very sluggish antegrade ﬂow downstream from the stenosis. (E) Lesion is ﬁrst crossed and then dilated with a relatively longer semi-compliant PTA balloon catheter (4 40 mm). No distal protection device could be utilized owing to the severity of the stenosis. (F) Control angiogram, left CCA injection shows dramatically improved restoration in the diameter of the cervical ICA, as well as restoration of antegrade blood ﬂow. However, owing to the potential for rebound re-stenosis or occlusion, stent-assisted angioplasty was performed. (G) A long, self-expanding nitinol stent (8 40 mm) is positioned across the lesion over an exchange length guide wire. (H) Final control angiogram after stent deployment shows an excellent technical result with good restoration of luminal diameter of the ICA (a small residual stenosis persists), and excellent re-establishment of antegrade ﬂow downstream into the left anterior circulation. Note the continued positive remodeling of the stented segment resulting from the strong radial force of the self-expanding stent.

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Figure 2 Continued.

In 1980 a study of percutaneous angioplasty of atherosclerotic stenosis of common carotid artery origin was published [77]. Several case reports and small series followed, including angioplasty of carotid bifurcation atherosclerotic stenosis [20,136,140,150]. The ﬁrst large case series was published in 1986. Twenty-seven patients underwent carotid angioplasty for atherosclerosis, ﬁbromuscular disease, and Takayasu’s disease. All of the procedures were successful, without morbidity or mortality. No recurrent symptoms occurred during 3-month to 4-year follow-up [141]. A large single institution study in 1996 reported percutaneous angioplasty of 85 high-grade symptomatic carotid stenoses over a 4-year period. The technical success rate was 92% (<50% residual stenosis). The 30-day mortality was 0% and 30-day morbidity was 4.9% [55]. In spite of the favorable results obtained with carotid angioplasty, theoretical advantages of vascular stents have held a strong appeal for endovascular surgeons. These include the prevention of elastic recoil, arterial dissections, and distal emboli, as well as possible lower restenosis rates. Supporting the concept, coronary artery stents were reported

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Figure 2 Continued.

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Figure 2 Continued.

to result in higher technical success rates, lower rates of acute occlusions, and lower restenosis rates than coronary angioplasty. For these reasons, most recent series on carotid endovascular intervention have reported primary stenting of the carotid artery, although these advantages compared to angioplasty remain unproven [16,35]. Although numerous studies are conducted to evaluate the safety and eﬃcacy of carotid SAPTA, They diﬀer signiﬁcantly in deﬁning and measuring outcomes, which makes interpretation and comparison diﬃcult and/or misleading. A few of the problems with these studies in general include: 1. Varying inclusion and exclusion criteria for patient selection: The degree of risk factors for death and stroke such as smoking, diabetes mellitus, hypertension, other organ failure vary greatly between enrolled patients in each study, making head-to-head comparisons diﬃcult. 2. Unreliable and varying operator skill and experience for performing carotid SAPTA: The experience with CEA has been much more extensive than the current experience with the performance of CAS. The proﬁciency and experience of investigators studying CAS vary widely.

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3. Varying methodologies in the performance of CEA and SAPTA: The use of stents versus angioplasty alone, administration of heparin and heparinoids and the extent of their use during and after CAS procedures, timing and use of antiplatelet agents also vary among diﬀerent investigators. Similarly, the use of shunting and EEG monitoring also vary among those performing CEAs. 4. Varying deﬁnition of outcomes: Such designations as ‘‘major’’ vs. ‘‘minor,’’ or ‘‘disabling’’ vs. ‘‘nondisabling’’ neurological deﬁcits frequently have not been precisely deﬁned or are deﬁned in conﬂict with other previous works. For example, some authors have deﬁned major stroke in terms of its impact on disability, while others emphasize the persistence of symptoms beyond a set time period as the distinguishing threshold between a ‘‘major’’ and ‘‘minor’’ stroke. Standardized metrics of disability, such as the Rankin or modiﬁed Rankin Scale, frequently have not been used in many studies, in which reviewers are left to interpret outcomes derived from rather arbitrary measures such as ‘‘independence’’ with activities of daily living. 5. Potential conﬂicts of interest by various investigators that could result in both intentional and unintentional bias of the studies. A number of large carotid artery stent series were published between 1996 and 1999 [4,9,18,19,22,37,41,64,90,117,123,130,138,143,144,148,151]. Phatouros et al. [115] summarized the results of 11 of these studies, which included a total of over 800 patients. They noted that comparison of studies was complicated by inconsistencies in the sample populations, lesion characteristics, endovascular techniques, and outcome data. The overall reported technical success rate was >95%. Procedure-related mortalities ranged from 0.6 to 4.5%, major stroke rates from 0 to 4.5%, minor stroke rates from 0 to 6.5%, and 6 month restenosis rates were <5%. The stroke and death rates compared favorably with the NASCET and ECST data. This is particularly notable since in 5 of the studies, 80% of 574 patients would have failed to be included in the endarterectomy trials because of comorbidities [115]. The reported <5% 6-month restenosis rate compared well with the reported postendarterectomy carotid artery restenosis rate of 10% in the ﬁrst year, 3% in the second year, and 2% in the third year [54]. Wholey et al. [149] surveyed the global status of carotid artery stent deployment. Between February and June 1997, surveys were sent to 29 major carotid stent centers throughout the world identiﬁed by publications, presentations, and discussions at meetings. There were 24 respondents (86%). As of June 1997, a total of 2048 patients had undergone carotid stent deployment at those centers. The average percentage of symptomatic patients was 66.4% (range 47–100%). The overall technical success rate (<30% residual stenosis) was 98.6%. The rate of major strokes was 1.32% (0–3.85%). The rate of minor strokes was 3.08% (0–7%). The average perioperative (30-day) mortality rate was 1.37% (0–6.9%). The combined average major and minor stroke and death rate was 5.77%. The most commonly used stents were the Palmaz (53%), Wallstent (39%), and Strecker (8%). Stent deformations were exclusively reported with the Palmaz stent (1.4 % at 6 months). Only two centers used cerebral protection. The overall restenosis rate (>50% stenosis) was 4.8% at 6 months [149]. In contradistinction, there have been two recent reports with less favorable carotid stent complication rates. A prospective consecutive, randomized trial of endarterectomy versus carotid stenting in a single institution was stopped because of unacceptable morbidity after 17 patients. Five of 7 stent patients had periprocedural strokes. Three strokes were disabling at 30 days. None of the 10 endarterectomy patients had a neurological deﬁcit or

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Figure 3 Emergent, stent-assisted angioplasty of a symptomatic, critical stenosis of the intracranial right vertebral artery. A 51 year-old man presented with abrupt onset of vertigo, double vision, limb ataxia and incoordination, which would reproducibly worsen when his head was placed in an upright position. An MRI of the brain showed multifocal punctuate infarcts in the cerebellum (A), pons, and right occipital lobe (B), best seen on diﬀusion weighted images. An MRA (not shown) suggested bilateral occlusion of the vertebral arteries, as well as possible occlusion of the lower basilar artery. Catheter angiography from selective left vertebral (C) and right vertebral artery (VA) injections shows an acute thrombotic occlusion of the left VA (D), and a critical stenosis (>90%) of the distal intracranial segment of the right VA. Note the very poor downstream ﬁlling of the basilar artery, which ﬁlled only sluggishly retrograde from the right posterior communicating artery (not shown). Owing to the severity and length of the stenosis (E), primary stent-assisted PTA (SAPTA) was not possible. The lesion was therefore ﬁrst crossed with a 0.014W microguidewire and a 1.9 Fr. microcatheter to permit placement of an exchange 0.014W guide wire. Pre-stent dilatation (F ) was then performed with a semi-compliant coronary PTA balloon catheter (3 10 mm). Immediate (G) and ten minute delayed (H) control angiograms after the PTA shows initially very good restoration of antegrade vertebrobasilar ﬂow, although the dilated lesion shows a intimal ﬂap with residual stenosis. The delayed angiogram shows rapid restenosis and deteriorating antegrade ﬂow, which would almost certainly progress to complete occlusion without any additional intervention. This illustrates the common problem of negative remodeling occurring immediately after intracranial PTA. (I) Consequently, a 3.5 9 mm balloon expandable stent was positioned across the distal portion of the lesion and expanded to a slightly sub-nominal pressure (5 atm). (J) The immediate control angiogram shows excellent anatomic restoration of the distal portion of the lesion, which is associated with excellent return of antegrade vertebrobasilar ﬂow. However, there remains a hemodynamically signiﬁcant marginal stenosis just proximal to the stent, which will require SAPTA as well. (K) Using telescoping technique, a second 3.5 9 mm balloon expandable stent was positioned partially overlapping the proximal ﬁrst stent and then deployed, again through a slightly subnominal inﬂation pressure (5 atm). (L) Final control angiogram after telescoping stent deployment shows an excellent technical result with excellent restoration of luminal diameter of the VA, as well as excellent restoration of antegrade ﬂow into the entire vertebrobasilar system. There were no clinical complications, and the patient’s symptoms completely resolved.

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perioperative death [102]. This study suﬀered from a critical ﬂaw in that the endovascular operator had no prior experience or training with carotid stenting, raising serious doubts concerning the validity of the study. Jordan et al. [76] performed a retrospective comparison of carotid stenting in 312 patients and endarterectomy with local anesthesia in 121 patients. There were 11 TIAs (4.1%), 23 strokes (8.6%), and 3 deaths (1.1%) in the stent group versus 2 TIAs (1.8%), 1 stroke (0.9%), and no deaths (0%) in the endarterectomy group [76]. The suggestion that carotid stenting may be more cost-eﬀective than endarterectomy has been challenged. Jordon et al. [75] compared the total hospital charges for carotid balloon angioplasty and stenting to endarterectomy. During a consecutive 14-month period, 239 carotid artery stenoses were electively treated, 109 by stenting and 130 by endarterectomy. In the stent group, there were 8 total strokes (7.7%) (6 minor, 2 major) and one death (0.9%). In the endarterectomy group, there were 2 strokes (1.5%) (1 minor, 1 major) and 2 neurological deaths (1.5%). Total hospital charges per admission were $30,140 for the stent group and $21,670 for the endarterectomy group. Excluding the charges for care of complications, the respective hospital charges were $24,848 for stenting and $19,247 for endarterectomy. Catheterization lab charges averaged $12,968 versus $4263 for operating room charges. The details of the catheterization lab charges were not provided [75]. Kilaru et al. [78] also found a signiﬁcant cost saving for CEA versus carotid artery stenting (CAS). They found this to be predominantly related to the higher rate of stroke in the later group. The CEA data were obtained from in-house cases while the CAS data were obtained from the literature. They calculated an immediate procedural cost of $7,871 and $10,133 for CEA and CAS respectively. The CAS costs included a $1,600 embolic protection device not routinely used at all institutions. Additionally, their estimated stroke rates of 0.9% and 5% for CEA and CAS, respectively, are not necessarily representative of all institutional experience. There is limited validity in directly comparing the results of carotid stent series and endarterectomy data, because there are often signiﬁcant diﬀerences in the age and medical

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Figure 4 Attempted balloon angioplasty alone of a symptomatic, critical stenosis of the left middle cerebral artery, which required bail-out stent-assisted PTA. (A) A 45 year old man with multiple cardiovascular risk factors presented with crescendo TIAs consisting of right hemiparesis and an expressive aphasia. An MRI and MRA of the brain (not shown) revealed a few small punctuate cortical infarcts in the left frontal lobe, and signal drop out in the left M1 segment of the MCA, consistent with a severe left MCA stenosis. A catheter angiogram from selective left ICA injection showed short, but critical (>90%) stenosis of the proximal M1 segment of the left MCA. Using classical co-axial exchange technique, the critical stenosis was ﬁrst crossed with a 0.014W microguidewire and a 1.9 Fr. microcatheter to permit placement of an exchange 0.014W guide wire (B). A semi-compliant coronary PTA balloon catheter (2 10 mm) was navigated into optimal position and inﬂated very slowly (C) to a sub-nominal pressure (5 atm). (D) An immediate control angiogram after the PTA showed good restoration of antegrade ﬂow into the MCA branches and, although the dilated lesion demonstrated a triangular ﬁlling defect in the mid-portion of the stenosis, which likely represented an intimal ﬂap. As noted in Figure 3, delayed angiograms would almost certainly show progressive restenosis and deteriorating antegrade ﬂow, as the result of post-PTA negative remodeling. A 2.5 9 mm balloon expandable coronary stent is navigated across the lesion (E) and then slowly deployed (F ) by a sub-nominal inﬂation (4 atm). (G) and (H) An un-subtracted view of the expanded stent (G) shows good alignment and lack of residual deformity across the lesion. A subsequent control angiogram from left ICA injection shows excellent restoration of luminal diameter of the MCA, as well as excellent restoration of antegrade ﬂow into the downstream MCA territory. There were no clinical complications, and the patient’s symptoms completely resolved.

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conditions of patients who undergo the two procedures. Many carotid stent patients would not have qualiﬁed for the NASCET, ECST, and ACAS trials because of older age and/or serious medical comorbidities. The endarterectomy clinical trials all rigorously selected relatively young, healthy patients. It is also doubtful that the endarterectomy trial statistics are typical of general endarterectomy results in the United States [33]. Patients with advanced age or with serious additional medical problems who undergo endarterectomy have signiﬁcantly higher perioperative morbidities and mortalities than the NASCET and ESCT trial patients [125,147]. A recent study showed there was a signiﬁcantly higher death rate for unselected Medicare patients undergoing carotid endarterectomy at the same institutions participating in the NASCET and ACAS studies than for the original study participants (NASCET-0.6%, ACAS-0.1%, unselected 1.4%). The perioperative mortality rates for nontrial hospitals were even higher: 1.7% for high-volume institutions, 1.9% for average-volume institutions, and 2.5% for low-volume institutions. These data likely reﬂect diﬀerences in selection criteria (high-risk patients) and surgical expertise [147]. Conners et al. [33] noted that a number of new drugs are available to treat atherosclerosis and prevent strokes since the endarterectomy clinical trials, including new oral antiplatelet agents (e.g., ticlopidine, clopidigrel), lipid-lowering agents (HMG-CoA reductase inhibitors), antiplatelet aggregators (GP IIB/IIIA receptor inhibitors), and treatments for hyperhomocysteinemia. The potential beneﬁts or lack thereof for both endovascular and surgical carotid interventions compared to contemporary medical therapy are unknown [33].

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Beebe [15] points out that the clinical carotid stent literature is largely anecdotal. A peer-reviewed, externally adjudicated, randomized trial comparing carotid stenting and endarterectomy has never been published. The carotid stent articles consist of abstracts, anecdotal reports, and largely anecdotal clinical series. Problems include small number and incomplete data on conditions, selection criteria, and follow-up. Often patients with dissimilar histories, stroke risks, and types of lesions are grouped together. The potential for investigator bias is often present. Although the published data support the premise that carotid stenting can be performed reasonably eﬀectively and safely, they cannot be used to prove the hypothesis that carotid stenting is equal or superior to endarterectomy [15]. Hobson further noted at the time of writing his commentary that the current literature on carotid angioplasty and stenting only qualiﬁes for level IV or level V evidence and grade C clinical recommendations. No level I or II studies have been conducted, and no grade A or B clinical recommendations are available [67]. In a single institution randomized trial, Brooks et al. [23] treated 104 symptomatic carotid stenoses (>70%), with 53 undergoing stenting and 51 CEA. There was one death in the CEA group and one TIA in the CAS group. Overall, the CAS group had shorter hospitalization, but in the presence of complications, CEA patients tended to have shorter hospitalization. They concluded that CAS challenged CEA as the preferred treatment option if a reduction in cost can be achieved. The Carotid and Vertebral Angioplasty Study (CAVATAS) [45] was the ﬁrst large prospective, randomized, multicenter trial comparing carotid PTA (i.e., without stenting) to endarterectomy. The CAVATAS investigators postulated an equivalency performance of PTA (i.e., ‘‘. . . endovascular treatment would have the same major complication rates and less minor morbidity that surgery’’). Twenty-two centers in Europe, Australia, and Canada participated in this randomized, double-blind, prospective study of endovascular versus surgical treatment of primarily carotid stenosis. Each center had a designated ‘‘expert’’ vascular or neurosurgeon, radiologist, and neurologist (or ‘‘physician with an interest in cerbrovascular disease’’). Anatomical inclusion criteria for enrollment was deﬁned as the presence of stenoses aﬀecting the common carotid artery, carotid bifurcation, or internal carotid artery. Both the means of detecting a stenosis and the subsequent calculation of the degree of severity of the lesion were unfortunately not rigorously prescribed in the study, although most centers relied on conventional digital subtraction angiography (DSA) for both diagnosis and quantiﬁcation. However, although a standard basic formula to calculate percent stenosis [% stenosis = 100(1A/C)] was used in this study, the deﬁnition of the reference vessel diameter (C) diﬀered signiﬁcantly compared to NASCET (C = width of disease-free portion of the common carotid artery below the bifurcation, instead of width of the portion of the internal carotid artery distal to disease). This diﬀerence unfortunately created a serious problem in attempting to make any meaningful direct comparisons of outcomes with previous CEA trials. There were also extensive exclusion criteria from randomization, which mostly aﬀected recruitment of patients suitable for CEA, including recent myocardial infarction, poorly controlled hypertension, diabetes mellitus, renal disease, respiratory failure, inaccessible stenosis, and severe cervical spondylosis. Exclusion criteria for angioplasty included severe intracranial stenosis, thrombus, and anatomical inaccessibility. The investigators did not specify the technique used in the procedures, which creates problems with outcome analysis and general applicability. In the CEA arm, the use of general anesthesia, bypass shunts during CEA, and heparinization was entirely left up to the individual operator’s discretion. Similar discretionary freedom was given to the endovascular operators, including use of SAPTA vs. PTA alone, use of various types of stents (Wallstent, Streker, Palmaz), and the use of prestent and/or poststent dilatation. All patients

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undergoing endovascular intervention were given aspirin (or alternative antiplatelet agent) 24 hours prior to the procedure, followed by systemic heparin during and 24 hours after the procedure. A fatal stroke was deﬁned as death resulting as a direct consequence of a perioperative stroke. Disabling stroke was deﬁned as that in which the patient required assistance to do ADLs for >30 days after onset of symptoms. Nondisabling stroke was deﬁned as that in which symptoms lasted longer than 7 days. Symptoms that were transient or lasted less than 7 days were not counted as a stroke. Out of the 505 patients who were enrolled, 240 were treated by endovascular surgery and 246 treated by CEA (many died or had strokes prior to treatment). The rate of death or any stroke was identical in both arms of the trial—10%. There was no signiﬁcant diﬀerence in any of the endpoints: death, disabling stroke, nondisabling stroke, and death or nondisabling stroke within 30 days after treatment. There was a signiﬁcantly greater number of cranial nerve palsies (9% vs. 0), hematomas requiring surgery or extending hospital stay (7% vs. 1%), myocardial infarctions (1% vs. 0), and pulmonary emboli (1% vs. 0) in the surgical group. While all of the deaths in the endovascular group were fatal strokes, only one out of the four deaths in the surgical group was secondary to a stroke; the rest were caused by ruptured aortic aneurysm, respiratory arrest from neck hematomas, and pulmonary embolism. The majority of all strokes in both groups were ischemic. The baseline characteristics were similar in both groups. In comparison to NASCET, CAVATAS was criticized by some for its higher rate of periprocedural complications in CEA. However, a direct comparison cannot be made as there was (1) closer scrutiny for complications in CAVATAS with the monitoring of all postoperative patients by a neurologist, (2) a signiﬁcantly larger number of patients with contralateral carotid occlusion (8% vs. 4%) and ischemic heart disease who underwent CEA in CAVATAS versus NASCET, and 3) greater enthusiasm for referral to surgery given the positive result of NASCET in CAVATAS. The role of angioplasty and stenting versus angioplasty alone could not be assessed from the data provided by CAVATAS. Furthermore, the technical expertise for performance of carotid PTA or SAPTA varied widely, as did the techniques utilized to achieve endovascular surgical revascularization of the carotid, owing to a lack of technical guidelines. The experience with carotid PTA or SAPTA at the time of the study was also its infancy stage compared to the more mature techniques developed for CEA. Although CAVATAS was the only large-scale, randomized, prospective trial to provide comparative safety and eﬃcacy rates of the two competing revascularization interventions, the general applicability of these results to a wider population of patients with carotid occlusive disease is highly questionable because of the extensive exclusion criteria used to enroll patients. Recently an industry-sponsored (Cordis Endovascular, Miami Lakes, FL) randomized clinical trial (SAPPHIRE) comparing the safety and eﬃcacy of SAPTA to that of CEA was completed and presented at the 2002 AHA Meeting. The investigators of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial compared the risks of CEA vs. carotid SAPTA with added protection of an Emboli Protection Device (EPD) in ‘‘patients at high risk for surgical treatment.’’ SAPPHIRE was a randomized prospective trial involving 29 centers. The primary endpoints included (1) composite of death, stroke, and MI at 30 days, (2) major adverse cardiac events at 30 days, and (3) death and ipsilateral stroke at day 31 and up to 12 months after the procedure. Secondary endpoints included (1) the rate of restenosis of more than 50% by ultrasound at 48 hours, 6 months, 1, 2, and 3 years after the procedure, (2) disabling stroke at 30 days and 6 months, (3) composite of major adverse clinical events, and (4) the overall safety assessment of distal protection devices. Interventionalists performed the endovascular procedure and,

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similar to the surgeons, had to meet certain procedural criteria prior to study participation. The surgeons needed an average rate of 30 annual CEAs with a less than 1% complication rate of stroke, death, or MI. The interventionalists needed an average of 64 procedures with a low complication rate of less than 2% for stroke and TIA to participate. Patients were enrolled if they either were symptomatic with a stenosis of 50% or greater of the common or internal carotid artery or, if asymptomatic, had a stenosis of 80% or greater of the same arteries and fulﬁlled one or more ‘‘comorbidity criteria’’ (e.g., coexistent signiﬁcant ischemic coronary artery disease, congestive heart failure). In addition, patients were randomized only if a consensus agreement was met by a team of neurologists, surgeons, and endovascular interventionalists. Those enrolled patients about whom no consensus could be reached were placed into a stent or surgical registry. At the time of this writing, the results of this study have not appeared in a peerreviewed journal. A summary of the outcomes presented at the 2002 AHA Meeting is as follows: 156 patients were randomized to the carotid SAPTA arm and 151 in the CEA arm. Baseline characteristics were similar in both groups, although there was a statistically signiﬁcant larger number of patients enrolled in the carotid SAPTA arm with history of cardiovascular disease and CABG. Interestingly, approximately 70% of the enrolled patients were actually asymptomatic. There was no statistically signiﬁcant diﬀerence in the 30-day periprocedural period in the percentage of patients who experienced a stroke, MI, or died. Of particular note were the combined stroke and death rates, which were 4.5% for SAPTA and 6.6 % for CEA ( p = NS). When the primary outcomes (death, stroke, and MI) were combined, there was a statistically lower rate in the SAPTA arm of the trial (5.8% vs. 12.6%; p = 0.047). The rates of TIA and major bleeding were similar in both arms, while there was a signiﬁcantly greater number of cranial nerve injuries in the CEA arm (5.3% vs. 0; p < 0.01). The investigators contend that there was a numerical trend favoring the carotid SAPTA arm with respect to complications. Moreover, the statistical insigniﬁcance is largely attributed to the low number of patients enrolled in each arm. It is diﬃcult to conclude that carotid SAPTA is a safer procedure than CEA by these preliminary SAPPHIRE results. It is, however, clear that the level of periprocedural risk between carotid SAPTA and CEA in this presumably ‘‘high-risk’’ population is equivalent. The other important question that this trial raised is the appropriateness of intervention in so-called high-risk and asymptomatic carotid stensoses, where it would appear that the complication rates in both arms (4.5% and 6.6%) substantially exceed the natural history of the disease based upon previous randomized clinical trials such as ACAS. SAPPHIRE also excluded many patients thought to have high surgical risk from randomization, as did NASCET and CAVATAS (e.g., those with prior radiation therapy to the neck, prior CEA, high cervical location, intracranial aneurysm). Therefore, the relative beneﬁt of carotid SAPTA patients remains unstudied in a large prospective trial and should be the subject of future studies. CREST is funded by the National Institute of Neurological Disorders and Stroke. It compares the relative eﬃcacy of the two treatments described above in preventing primary outcomes of stroke, acute myocardial infarction, or death during a 30-day periprocedural period or ipsilateral stroke over a 4-year follow-up period. Primary eligibility criteria are a symptomatic (within 180 days) (z50%) carotid stenosis. Two thousand ﬁve hundred randomized patients will be treated by appropriately credentialed surgeons, and periprocedural outcome will be assessed by a masked adjudication committee [68,69,71]. Although there has been resistance in the surgical community to endorse carotid angioplasty and stenting as comparable to endarterectomy, there are some accepted indications. These include surgically inaccessable lesions (intrathoracic, high cervical),

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nonatherosclerotic pathology (ﬁbromuscular disease, postradiation angiitis, postendarterectomy restenosis, dissection), and high–medical risk patients [36,56,120]. In 14 patients with radiation-induced extracranial carotid artery stenosis, stenting was technically successful in 100%, with a reduction in mean stenosis from 77% to 8%. There was one minor stroke with complete recovery in 2 days, no major stroke, and no procedural mortality. There was no restenosis in the 9 patients imaged at 6-month follow-up [6]. In 17 postendarterectomy restenoses, carotid stenting was technically successful in 100%, with no perioperative stroke or death. In comparison, surgical repair of 16 carotid restenoses was technically successful in 100%, with no stroke or death, and one recurrent laryngeal nerve palsy [70]. Lanzino et al. [81] reported angioplasty (n = 7) or angioplasty with carotid stenting (n = 18) for 25 patients with carotid artery restenosis following endarterectomy. There was one TIA, and there was no major stroke or death. Stenting yielded better technical results and a lower restenosis rate (1/18) [81]. New et al. [106] reported on a large multicenter study on the safety, eﬃcacy, and shortterm results of stenting for restenosis. Three hundred and ﬁfty-eight arteries underwent PTA/stenting with a mean duration of 5.5 years from previous CEA. Thirty-nine percent were symptomatic. Thirty-day stroke and death rate was 3.7%, including 1.7% minor, 0.8% major, and 0.3% fatal rate. The 3-year stroke-free rate was 96%. Abu Rahma et al. [1] performed a nonrandomized parallel comparison of outcomes for CEA versus PTA/stenting for restenosis. With the advent of more experience for endovascular techniques, they demonstrated similar major stroke rates of 0% versus 1.7% for stenting versus CEA. Although CEA had signiﬁcantly higher transient (16.3%) and permanent (1.7%) cranial nerve injury rates versus 0% for PTA/stenting, the long-term eﬃcacy was questioned with a 56% 3-year restenosis rate for PTA/stenting deﬁned as >50% stenosis versus 0% for CEA. They concluded that PTA/stenting can be an alternative to reoperation, particularly in marginal surgical risk patients. Liu et al. [85] reported technically and clinically successful stent placement in 7 patients for carotid dissection. All remained asymptomatic and without restenosis at a mean 3.5-year follow-up [85]. Bejjani et al. [17] reported successful treatment of 5 symptomatic carotid dissections with complete long-term recovery. In a study of 42 high–surgical risk patients who underwent PTA/stenting, Fox et al. [52] had a 19% overall stroke/death rate with a 9.5% ipsilateral stroke rate. This compared favorably with the medical and surgical arms of the NASCET trial, which demonstrated a 32.3% and 15.8% major stroke/death rate and 26% and 9% ipsilateral stroke rate, respectively. Importantly, most of the treated patients would have been excluded from NASCET based on medical/angiographic risk factors (n = 24), restenosis (n = 17), and radiation-induced stenosis (n = 4). The technical aspects of carotid stenting are evolving. Ongoing challenges include the development of improved stents optimized for the carotid artery and the prevention of procedure-related cerebral emboli. Mathur et al. [91] reported 14 patients with deformed Palmaz stents on 6-month routine angiographic follow-up. Some patients required repeat intervention. As a result of these and similar observations, there has been a trend toward the use of less deformable, self-expanding stents such as the Wallstent, Smart stent, or lowerproﬁle Precise stent. A new generation of stents optimized for the carotid bifurcation is under development [14]. The current major concern of carotid stenting is the risk of embolic stroke. An ex vivo carotid bifurcation model was developed to quantify the emboli produced by carotid stenting and to correlate the embolic risk with plaque morphology [112]. Human carotid plaques obtained during endarterectomy were dilated and stented in the model. Both the

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Palmaz stent and the Wallstent were studied. Every experimental dilatation and stenting generated emboli, ranging in number from 2 to 126 particles (median = 15) and ranging in size from 120 to 2100 Am (mean = 338 Am). The emboli consisted of atherosclerotic debris, organized thrombus, and calciﬁed material. Sonographically echolucent plaques and stenoses z90% produced more emboli [112]. Manninen et al. [87] compared balloon angioplasty to stent placement in human cadaver carotid arteries in situ. Unexpectedly, both techniques caused the same frequency and severity of embolization. The largest embolic particles were intimal strips measuring up to 5 mm in diameter occuring in all stent deployments and most balloon angioplasties [87]. A cerebral protection device has been described to prevent cerebral emboli during carotid stenting. Theron designed a triple coaxial catheter system for cerebral protection against emboli during angioplasty based on temporary distal internal carotid occlusion [137]. The device was reported to reduce distal embolic complications from 8% in 38 patients undergoing angioplasty without the device to 0% in 43 patients with the distal balloon protection [138]. Few groups have adopted the technique [149]. This has likely been due to the rather cumbersome nature of the system and complications attributed to the device [64]. Additional cerebral protection systems are currently under development and may further improve the safety of carotid stenting [114]. The Imaging in Carotid Angioplasties and Risk of Stroke trial (ICAROS) [135] is an international multicenter registry of carotid stenting designed to determine criteria for stratifying stroke risk and 1-year restenosis rates. It will use a computer elaboration of carotid plaque morphology and echo characteristics to stratify stroke risk. Centers are free to use their own patient-selection criteria and techniques, but rigorous documentation will be required. No results are currently available.

B. Intracranial Circulation Use of PTA in the intracranial arteries was signiﬁcantly delayed. The large, stiﬀ catheters and guide wires were ill-equipped to negotiate tortuous, delicate intracranial arteries. In addition, the risks of complications were formidable, including arterial dissection, embolus, thrombosis, and rupture, potentially resulting in stroke and death. The early intracranial angioplasty literature consisted of scattered pioneering case reports that mostly highlighted the promises and signiﬁcant limitations/risks of the technique. Sundt et al. [127] reported two successful cases of basilar artery angioplasties performed in 1980. Both patients had severe basilar artery stenoses and progressive, intolerable vertebrobasilar neurological symptoms despite maximal medical therapy. One patient had failed multiple surgical bypasses. The relative inﬂexibility of the available catheters and guidewires of that era necessitated an operative exposure of the suboccipital vertebral artery at C1-C2 to gain vascular access. Both patients experienced postprocedural TIAs, but otherwise had good clinical responses [127]. The same group, however, reported a similar case several years later, which resulted in a fatal delayed basilar artery pseudoaneurysm and rupture [128]. Subsequently, Higashida et al. [65] reported an unsuccessful percutaneous, transfemoral attempt to balloon dilate tandem basilar artery stenoses, followed by an angioplasty via operative exposure of the C1-2 vertebral artery, which was technically successful but resulted in a brainstem infarct. The ﬁrst anterior circulation intracranial angioplasty was reported in 1984. A transfemorally placed coronary angioplasty balloon catheter was successfully used to dilate a symptomatic cavernous carotid stenosis [111]. A subsequent report described use of a

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relatively soft silicone elastomer balloon catheter (designed to treat vasospasm) to dilate an atherosclerotic middle cerebral artery stenosis. Following transient vasospasm, there was an enlarged vascular lumen. A Tc-99m HMPAO SPECT cerebral blood ﬂow study showed increased ﬂow to the middle cerebral artery distribution, the ﬁrst direct demonstration of improved cerebral perfusion following intracranial angioplasty [116]. Subsequent successful case reports of petrous carotid and basilar artery angioplasties appeared [4,121]. The petrous carotid artery had undergone progressive remodeling and was widely patent at 2-year angiographic follow-up. The basilar artery was occluded on 6-month angiography, but the patient was asymptomatic. The authors speculated that the angioplasty allowed suﬃcient time for adequate collateral formation. Additional series including from several to 70 patients have been published in the last few years. All of the studies have been historical or uncontrolled. No prospective randomized, controlled trial comparing intracranial angioplasty to medical or open surgical therapy has been published. In spite of these important limitations, the recent literature provides information on a number of key scientiﬁc issues, including appropriate patient selection, operative technique, technical and clinical success, complications, and restenosis. Touho [142] reported a series of 19 attempted intracranial carotid artery angioplasties in symptomatic patients (TIA or prior CVA with unstable neurological symptoms on maximal medical therapy). The procedure was successful in 13 (68.4%). The mean stenosis was reduced from 83.1% before the angioplasty to 35.8% after the procedure. Seven of the 13 patients demonstrated clinical improvement. All of the patient who responded had below-normal cerebral perfusion and abnormal vasodilatory response on preprocedure rCBF SPECT, while most of the nonresponders did not. There was a 38.5% restenosis rate at 6–12 months [142]. Improved microcatheters and microguidewires were used for successful transfemoral percutaneous angioplasty of basilar artery stenoses. One case report described a successful basilar artery angioplasty with no symptoms at 12-month follow-up. The authors suggested complications may be minimized by gentle, short inﬂations [73]. Terada et al. [131] described vertebrobasilar angioplasty in 12 patients, 8 of whom [67%] were successful without complications. There were 2 iatrogenic dissections with permanent infarcts, one ultimately leading to death from a brainstem infarction. There were 2 thromboemboli with TIAs. Mean stenosis decreased from 84% to 44%. Restenosis occurred in 2 [131]. Nakatsuka et al. [105] reported 2 successful basilar artery PTAs with no new neurological deﬁcits at 10 and 13 months after the angioplasties. They emphasized low-pressure submaximal PTA with an undersized balloon diameter to minimize risk. Mori et al. [119] demonstrated the technical feasibility of reopening chronic total MCA occlusions, successful in four occlusions less than 3 months old and unsuccessful in two occlusions more than 3 months old. There were no complications. McKenzie et al. [93] reported intracranial angioplasty for 12 atherosclerotic stenoses and 5 stenoses caused by vasculitis. Although 16 of 17 lesions demonstrated initial improvement, all 5 stenoses caused by vasculitis rapidly recurred and progressed to complete occlusion. Eleven of 12 patients with atherosclerotic lesions were clinically improved at 12 months. The authors suggested that intracranial PTA for vasculitis is not indicated [93]. Callahan and Berger [26] reported a series of 15 patients. Intracranial angioplasty was technically successful in all but one fatal ICA rupture and one brainstem infarct. There was no restenosis or symptom recurrence over more than 24 months [26] Takis et al. [129] reported a small series with a higher complication rate. Eight of 10 intracranial angioplasties were technically successful, but there were 5 cases of vasospasm resulting in 2 infarcts, and dissections causing strokes in 2 patients. Yokote et al. [152] reported 17 cases of intracranial

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PTA. Four followed intra-arterial thrombolysis. Sixteen of 17 were technically successful. One fatal MCA reocclusion was caused by a dissection. Restenosis occurred in 25% during a mean 14-month follow-up [152]. Mori et al. [96] characterized the short- and intermediate-term patency rates in a series of 35 patients undergoing intracranial PTA; 27 procedures were technically successful. There were 3 permanent complications. The 3-month restenosis rate was 29.6%. In patients without signiﬁcant restenosis at 3 months, all remained free of restenosis at 12 months. Restenosis was more common with severe, eccentric lesions, extremely angulated lesions, and total occlusions [96]. Marks et al. [89] reported the 16- to 74-month clinical follow-up in a series of 23 patients, 21 of whom had technically successful intracranial angioplasties. There was one fatal vessel rupture, and one stenosis could not be crossed. There was one stroke in the same vascular territory as the angioplasty during the follow-up period, an annual rate of 3.2%. The authors suggested that intracranial angioplasty reduces the risk of future stroke in patients with symptomatic stenoses [97]. In a diﬀerent study, Mori et al. [90] compared follow-up patency rates with lesion morphology to ﬁnd the attributes of atherosclerotic lesions most amenable to angioplasty. Lesions were assigned to three groups: type A, short (5 mm or less in length, concentric or moderately eccentric, less than totally occlusive); type B (5–10 mm in length, extremely eccentric, or totally occluded less than 3 months); and type C (more than 10 mm in length, extremely angulated, or totally occluded more than 3 months). Clinical success rates for type A, B, and C lesions were 92%, 86%, and 33%, respectively. Cumulative risks of stroke or bypass surgery for type A, B, and C lesions were 8%, 26%, and 87%, respectively. The authors concluded that type A lesions are the most favorable for intracranial angioplasty. Restenosis at 1 year was for type A, 0% (92% follow-up); for type B, 33% (86% follow-up); and type C, 100% (33% follow-up) [97]. Conners et al. [32] retrospectively reviewed a 9-year experience of 70 intracranial angioplasties with special attention to procedural technique. Cases were assigned to three time periods that employed evolving techniques. In the early period, angioplasty was moderately rapid and brief. The balloon was slightly smaller than the vessel diameter. In the middle period, angioplasty was extremely rapid and brief. The balloon was equal to or slightly larger than the vessel diameter. In the last period, the balloon was undersized and inﬂation was extremely slow (several minutes). Clinical improvement occurred in 87.5% of cases in the early period, 83.3% of the cases in the middle period, and 98% of cases in the latest period. Complications including dissection, abrupt occlusion, and death were most common in the middle period (extremely rapid and brief inﬂation, slight oversizing permitted). Extremely slow balloon inﬂation and balloon undersizing yielded the fewest complications and the best clinical results. These authors also advocated the use of a platelet glycoprotein IIb/IIIa receptor inhibitor, such as abciximab, during the procedure, as well as po aspirin, po nimodipine, and IV heparin. The angioplasty site was periodically observed for 1 hour following PTA for possible thrombus formation. After the procedure, patients were maintained on ticlopidine and aspirin [32]. A summary of the literature is presented in Table 1. Since the original report by Sundt et al. [127] in 1980, over 350 cases of intracranial angioplasty have appeared in the literature. All of the published series have selected symptomatic patients experiencing recurrent transient ischemic attacks or prior infarcts with continued neurological symptoms in spite of maximal medical therapy (anticoagulation, antiplatelet medication). Fifty-ﬁve percent of the PTAs have been in the anterior circulation (distal intracranial internal carotid, anterior, and middle cerebral arteries), and 45% have been in the posterior circulation (vertebrobasilar system). The overall reported technical success rate is 87%. Of interest, the technical success rate in cases reported up to 1995 was 74%, while the technical success rate in series

PTA of Cerebrovascular Occlusive Disease

471

reported from 1996 to the present is 95%. This reﬂects greater surgical experience, as well as improving techniques and equipment. The overall clinical success rate mirrors the technical success rate at 82%. This is strong evidence that appropriate candidates have been selected for intracranial angioplasties, therefore, a successful procedure is highly likely to have therapeutic value. Major complications have occurred in 11% (TIA, infarct, vessel occlusion, vasospasm, embolus, symptomatic dissection, rupture). There have been seven reported deaths (2%), and ﬁve reported vessel ruptures (1.4%). Recent improvements in equipment and technique are decreasing complication rates. Long-term patency rates have yet to be determined, but short- and intermediate-term patency rates compare favorably with other vascular systems.

C. Intracranial Stent-Assisted Angioplasty Since the initial clinical introduction of the peripheral arterial Palmaz stent in the late 1980s, there has been a dramatic, continually increasing use of stents in the coronary, renal, and iliac arteries as data accumulate that vascular stents improve the initial angioplasty technical results, can repair angioplasty complications (dissections), and may improve long-term patency rates. The recent introduction of second-generation coronary stents with lower proﬁles, greater ﬂexibility, and improved trackability in the last several years has resulted in preliminary applications in the intracranial arteries. The ﬁrst published report of use of an intracranial stent for atherosclerotic occlusive disease appeared in 1996, in which a patient with a symptomatic 99% stenosis of the petrous segment of the internal carotid artery was treated. The stenosis was initially predilated with a 4 mm diameter Bandit angioplasty balloon. The post-PTA appearance was described as ‘‘better but hazy,’’ prompting use of a 4 mm Palmaz-Schatz coronary stent, which was eventually deployed after ‘‘moderate resistance’’ to advancement was encountered. The patient had no immediate complications and remained symptom-free at a 4-month followup. The authors acknowledged that the indication for stent deployment was controversial, but strongly believed that its use not only created a better angiographic result, but also lowered the risk of an acute arterial occlusion and may have been associated with a lower restenosis rate [47]. Dorros et al. [38] subsequently described the use of a Palmaz-Schatz coronary stent to salvage an angioplasty induced ﬂow-limiting dissection of the petrous carotid artery. They described ‘‘much diﬃculty’’ in advancing the relatively stiﬀ catheter across the site, but the procedure was successful. The artery was widely patent on the poststent angiogram. The patient remained asymptomatic on 5-month follow-up, and there was no restenosis on follow-up angiography [38]. The development of second-generation coronary stents with greater ﬂexibility, lower proﬁles, and superior trackability has increased the feasibility and appeal of intracranial stent deployment. A Cook GRII second-generation coronary stent was used to improve a residual post-angioplasty stenosis in the petrous/precavernous internal carotid artery from 57% to 8% [5]. Phatouros et al. [115] reported a case of acute vertebrobasilar thrombosis superimposed on a severe proximal basilar artery stenosis. The acute clot was successfully lysed with urokinase, but there was a minimal response of the underlying stenosis to angioplasty, raising concern for rethrombosis. A Gianturco-Roubin-2 stent was deployed across the stenosis with an excellent angiographic result. The patient had a good neurological recovery, but unfortunately died of unrelated cardiogenic shock and sepsis soon after the procedure. GFX (AVE) stents have been used in several cases, including: a high-grade,

1/BA

19/ 8 ICA, 9 MCA, 2 ACA

12/ 7 VA, 4 BA, 1 VA&BA

Ahuja et al., 1992 [4]

Touho, 1995 [142]

Terada et al., 1996 [131]

1/1

1/MCA

7/13

8/12

8/12

1/1

1/1

1/1

0/1

1/1

2/2

Clinical success

13/19

1/1

1/1

1/1

1/BA

1/ICA

1/1

1/ICA

O’Leary and Clouse, 1984 [111] Higashida et al., 1987 [65] Purdy et al., 1990 [116]

Rostomily et al., 1992 [121]

2/2

Technical success

2/2BA

Stenoses/ Location

Sundt et al., 1980 [127]

Study [Ref.]

Table 1 Summary of Clinical Reports of Intracranial PTA

1 asymptomatic dissection, 2 transient neurological deﬁcits 2 dissections (1 infarction, 1 death), 2 thromboembolic infarcts, 2 TIAs

Postprocedure TIAs

None

Transient vasospasm

Brainstem infarct

Postprocedure TIAs, minor perforator pontine infarct None

Complications

10/11 clinically asymptomatic at 2 yr, angiographic restenosis 2/7 at 6 mo

Heparin

Heparin

Heparin

Heparin

Angiographic restenosis at 3 d, clinically stable at 2 mo Angiographically patent and clinically stable at 2 yr Angiographically occluded at 6 mo, clinically stable 38.5% angiographic restenosis at 6–11 mo

None

Clinically stable at 1 yr

Clinically stable at 5 mo, 7 wks

Follow-up

Heparin

Heparin

Heparin

LMW dextran, Dipyrid, Verapamil

Meds

472 Chaloupka et al.

4/6

Not reported

4/6

27/35

Nakamaya et al., 1998 [104] Yokote et al., 1998 [152]

Mori et al., 1997b [96]

17/9 ICA, 4 MCA, 4 VA&BA

6/6MCA (chronic total occlusions) 35/9 ICA, 20 MCA, 3 VA, 1 BA, 2 PCA 3/3 VA&BA

Mori et al., 1997a [95]

16/17

5/10

8/10

10/ 3 ICA, 1 MCA, 1 BA, 5 VA

Takis et al., 1997 [129]

16/17

4/6

4/6

3/3

13/15

14/15

3/3

11/12 athero; 0/5 vasculitis

16/17

17/ 8 ICA, 1 ACA, 2 MCA, 4 VA, 2 BA 15/ 9 ICA, 3 MCA, 1 VA, 2 BA 6/ 6 MCA total occlusions

Callahan and Berger, 1997 [27] Mori et al., 1996 [ ]

2/2

2/2

2/ 2 BA

1/1

Nakatsuka et al., 1996 [105] McKenzie et al., 1996 [93]

1/1

1/BA

Houdart et al., 1996 [73]

1 fatal MCA dissection

1 symptomatic dissection, 1 abrupt occlusion, 1 vessel rupture 3 small CVA

5 vasospasm-2 CVA, dissection, perforator occlusion in 2 with CVA None

1 vessel rupture-death, 1 brainstem infarct None

1 symptomatic dissection

None

Transient SAH

Ticlopidine, IV heparin

IV heparin, Ia U.K.

ASA, LMW dextran, heparin, Ia isosorbide

ASA, heparin

IV heparin, Ia TNG, Ia papav, nimodipine

ASA IV heparin

Nifedipine, heparin, ASA

Heparin

Unreported

Heparin

All angiographically patent at 3–6 mo 3/16 at 3 mo, 4/16 at 1 yr

1 restenosis 3 mo, no restenoses in 3 at 3,4,12 mo 8/27 restenosis at 3 mo, no change at 12 mo

1 restenosis at 3 mo, no restenosis in 2 at 1 yr 9 clinically stable 2–30 mo

0/14 restenosis at 24 mo, clinically stable

Clinically stable at 12 mo, no angiographic restenosis at 6 mo Clinically stable at 10 and 13 mo 11/12 atherosclerotic lesions clinically improved at 1 yr

PTA of Cerebrovascular Occlusive Disease 473

Marks et al., 1999 [89]

Nomura et al., 1999 [107] Jiminez et al., 1999 [74]

Eckard et al., 1999 [43]

Mori et al., 1998 [97]

Study [Ref.]

Table 1 Continued

21/23

21/23

23/7 ICA, 3 MCA, 8 VA, 4 BA, 1 PCA

1/1

1/1

1/1 BA

6/6

6/6

7/8

32/42

33/42

7/8

Clinical success

Technical success

6/1 BA, 5VA

42/8 ICA, 21 MCA, 6 VA, 5BA, 2 PCA 8/8 ICA

Stenoses/ Location

Vasospasm— successfully treated 1 MCA rupture-death, 1 abrupt ICA thrombosis— successful lysis

None

1 dissection, TIA

Abrupt closure— CVA, dissection CVA

Complications

Ia U.K., Ia verapamil, heparin, Ia papaverine IV heparin

Low MW dextran, decadron, nimodipine ASA, heparin IV heparin

ASA, LMW dextran, heparin, Ia isosorbide

Meds

20/21 clinically stable at 16–74 mo

2 restenoses at 3 and 4 mo Stable at 7 mo follow-up

1/7 restenosis

9/32 restenosis at 1 yr

Follow-up

474 Chaloupka et al.

70/23 ICA, 20 MCA, 15 VA, 10 BA, 2 PCA

16/6 VA, 3 BA, 5 MCA, 3 ICA

20/14 VA, 6 BA 25/10 VA, 9 VBJ, 6 BA

Conners and Wojak,1999 [32]

Alazzaz et al., 2000 [2]

Nahser et al., 2000 [101] Gress et al., 2002 [61]

18/20 18/25

25/25

12/15

15/16

20/20

66/70

66/70

3 minor, 2 major stroke, 2 deaths— one acute vessel occlusion and 1 basilar artery rupture

1 CVA due to dissection, 2 hemorrhagic strokes, 1 death due to abrupt occlusion, 1 death due to vessel perforation 2 CVA due to thrombosis, 1 dissection needing stent (not symptomatic) 1 TIA, 1 hemiparesis Aspirin, heparin, coumadin Heparin, other not speciﬁed

Not speciﬁed

Abciximab, ticlopidine, ASA, nimodipine, heparin

1 restenosis at 1 mo rest stable at 3 mo to 2 yr f/up. 1 symptom recurrence at 2 yr 12/14 angio patent, 1/15 new symptoms

PTA of Cerebrovascular Occlusive Disease 475

Flex (Cook)

1/BA

Callahan and Berger, 2000 [26]

GFX

1/VBA

GFX

GFX

1/ICA

3/1 ICA, 2 VA

GFX

1/BA

Lanzino et al., 1999 [81] Fessler et al., 1999 [49] Malek et al., 1999 [87]

Morris et al., 1999 [100]

GFX

1/VA

Mori et al., 1999 [98]

GFX, Multilink

Gianturc Roubin-2

1/BA

3/3BA

GR II

1/ICA

Horowitz et al., 1999 [72]

Palmaz-Schatz

1/ICA

Dorros et al., 1998 [38] Al-Mubarak et al., 1998 [7] Phatouros et al., 1999 [115]

Palmaz-Schatz

Stents

1/ICA

Lesions/ Location

Feldman et al., 1996 [47]

Study [Ref.]

1/1

3/3

3/3

1/1

1/1

1/1

1/1

1/1

1/1

1/1

1/1

Technical success

Table 2 Summary of Clinical Reports of Intracranial Stenting

1/1

3/3

3/3

1/1

1/1

1/1

1/1

1/1

1/1

1/1

1/1

Clinical success

Cardiac arrest post-stent day 29

None

2 clinically silent embolic CVA Stent induced dissection, brainstem CVA Pontine infarct, trans hemiparesis

None

Death due to sepsis/cardiogenic shock None

None

None

None

Complications

Heparin, Ia NTG, Ia UK Heparin, clopidogrel, ASA ASA, clopidogrel, heparin Ia U.K. abciximab ASA, clopidogrel, heparin, abciximab Ia U.K., abciximab Ia verapamil Ia NTG, heparin

No restenosis: 3 mo angio in 2, 6 mo angio in 1 None

Improved at 5 mo, minimal hemiparesis None

Stable at 5 mo

No sx. at 5 mo

None

Death on poststent day 10

Heparin, Ia UK

Low MW dextran, heparin, Ia isosorbide Ia UK, heparin

No sx. at 4 mo

No sx. at 5 mo

No sx. at 4 mo

Follow-up

None

ASA, Ticlopidine, Procardia, heparin Heparin

Meds

476 Chaloupka et al.

12/4 ICA, 5 VA, 3 BA

8/4 VA, 4 BA

11/3 VA, 8 BA

6 (individual location not outlined) 1 BA

Mori et al., 2000 [99]

Rasmussen et al., 2000 [119]

Levy et al., 2001 [83]

Ramee et al., 2001 [118]

36/18 ICA, 2 MCA, 14 VA, 2 BA 2/1 ICA, 1 VA

8/4 BA, 4 VA

Nakahara et al., 2002 [103]

Levy et al., 2002 [82]

Lylyk et al., 2002 [84]

Gondim et al., 2002 [58]

12/12 BA

Gomez et al., 2000 [57]

S670 GFX Velocity AVEinr

2/2

4/5

5/7

30/34

1/1

5/5

7/11

7/8

10/12

12/12

2/2

34/36

Velocity, AVE gfx, AVE inx

S670

1/1

5/6

9/11

NIR

S670 Tristar

ACS AVE NIR

7/8

10/12

GFX, Multilink

GFX, Duet

12/12

Micro II, GFX, Multilink Duet

IBA dissection with stroke, 1 technical failure and 1 long stenosis not stented, 1 post angioplasty stenosis not requiring stent

None

2 TIA, 1 AMI, 1 death

None

1 subarachnoid hemorrhage/ death 1 VA+ BA rupture, 1 pontine stroke, 1 brain death None

1 occlude BA at 4 mo, 1 transient brainstem ischemic event None

ASA, ticlopidine, clopidogrel, warfarin, abciximab, eptiﬁbatide

ASA, clopidogrel, ticlopidine, heparin ASA, clopidogrel, heparin abciximab ASA, ticlopidine, heparin, abciximab Ticlopidine, ASA

ASA, clopidogrel, heparin, abciximab ASA, clopidogrel, heparin, abciximab

ASA, clopidogrel or ticlopidine, heparin Ticlopidine, LMW dextran, heparin, Ia isosorbide

7/7 clinic/angio follow-up >12 mo No restenosis or clinical 2 symptoms 3–4 mo 8/8 neuro improved at mean 26 mo follow-up

7/11 no sx., no restenosis 6/7 at mean 5 mo follow-up 5/5 no sx. at 12 mo follow-up

10/10 no restenosis On 3 mo angio, all clinically stable at 11 mo ave. follow-up All w/o sx. at mean 8 mo follow-up

No sx. in 10/12 at 0.5 to 16 mo

PTA of Cerebrovascular Occlusive Disease 477

478

Chaloupka et al.

eccentric intracranial vertebral artery stenosis [98], a severe proximal basilar artery stenosis [80], and a 90% petrous carotid artery stenosis [49], all with good technical and clinical results. Reliable intracranial stents represent a powerful ‘‘bail-out’’ tool for angioplastyrelated failures and complications. Malek et al. [88] reported a delayed iatrogenic dissection of the entire basilar artery 2 days after an initially successful vertebral artery PTA/stent, which was successfully repaired with a second tandem GFX stent positioned to tack down the entry point of the dissection. The patient made a good clinical recovery. In another case, an acute basilar artery occlusion was successfully recannalized with chemical thrombolytic, uncovering an atherosclerotic stenosis. Unfortunately, the artery repeatedly occluded after multiple balloon dilatations. A Cook ﬂex stent was placed successfully restoring antegrade ﬂow [26]. Morris et al. [100] reported three successful cases of intracranial PTA and GFX stent deployment. The ﬁrst case involved a ﬂow-limiting angioplasty-induced dissection of a symptomatic cavernous carotid atherosclerotic stenosis, successfully repaired with a stent deployment. Two intracranial vertebral artery stenoses were successfully treated with PTA and stent placement. There were no complications, and all of the patients were asymptomatic on short-term follow-up [100]. Horowitz et al. [72] reported angioplasty and stenting (GFX, Multilink) of three symptomatic mid-basilar stenoses without complication. This was followed by a larger series by Gomez et al. [57], reporting 12 patients who underwent elective stenting (Microstent II, GFX, Multilink Duet) of symptomatic basilar artery stenoses. All cases were technically successful. Mean stenosis was reduced from 71.4% to 10.3%. There was one case of postprocedural sixth and seventh nerve palsies with diploplia, which resolved within 8 weeks. No other postprocedural complications were noted. Another patient had a recurrent TIA at 4 months. Repeat angiography revealed a proximal basilar artery occlusion, which was successfully recanalized. All of the other patients remained asymptomatic on clinical follow-up at 0.5–16 months (mean 5.9 months) [57]. Mori et al. [99] reported 12 attempted stent (GFX, Multilink) deployments in the intracranial vertebral, carotid, and basilar arteries, technically successful in 10. Two vertebrobasilar cases failed due to proximal arterial tortuosity and inability to advance the stents across the lesions. Mean stenosis was reduced from 80% to 7%. No complications occurred. Three-month angiographic follow-up in all patients demonstrate a mean stenosis of 19%, without a single signiﬁcant (>50%) restenosis. All patients remained asymptomatic on 8- to 14-month clinical follow-up [99]. Rasmussen et al. [119] reported stent-assisted (GFX, Duet) angioplasty of 8 symptomatic intracranial vertebrobasilar stenoses. One patient had a dissection proximal to the stent and died of a massive subarachnoid hemorrhage the evening of the operation. All of the other cases were technically and clinically successful, remaining asymptomatic at up to 8 month follow-up. Mean stenosis decreased from 84% to 7% [119]. Lylyk [84] reported the largest recent single series of intracranial stents. Thirty-four patients with symptomatic intracranial atherosclerotic lesions and dissections that produced 50% stenosis were treated. Eighteen were anterior and 16 posterior circulation. Mean stenosis was 75%. At clinical follow-up, 21 patients improved, 11 were stable, and 2 deteriorated. The transient procedural morbidity rate was 12%, and the transient neurologic morbidity rate was 6%. Twenty-one patients were followed up angiographically for 6 months with none requiring repeat angioplasty. A summary of the current intracranial stent literature is presented in Table 2. One hundred and twenty-one cases have been reported. Thirty-nine (32%) have been placed in the intracranial internal carotid artery, and 64 (53%) have been placed in the intracranial vertebrobasilar arteries, with 6 not identiﬁed in terms of location. Seventy-six percent have

PTA of Cerebrovascular Occlusive Disease

479

been technically and clinically successful. There have been six infarcts (two clinically silent), four TIAs, two ruptures, one acute myocardial infarction, and three procedurally related deaths. There was one four-month arterial occlusion. Short-term follow-up has detected no cases of restenoses.

VIII. PATIENT SELECTION Without adequate statistical evidence documenting the short- and long-term beneﬁts of cerebrovascular PTA and stenting, the indications for selecting those patients most likely to beneﬁt from such intervention will remain variably controversial and contentious. Since the need for good outcomes data is so great, it is presently best to either participate in one of the above-mentioned ongoing or planned clinical trials (at least for extracranial carotid PTA and stenting), or alternatively develop standardized protocols for both patient selection and technical execution of therapy. The latter ideally should be done in a multidisciplinary forum, in which participation and collaboration of practitioners from diﬀerent specialties (e.g., neurology, neurosurgery, interventional neuroradiolgy) is solicited and encouraged. Since the risk of future stroke is generally much higher in symptomatic patients, it is preferable to primarily consider performing both extracranial or intracranial PTA and stenting in this population. Signs and symptoms of cerebral infarction, minor strokes, TIAs, or amaurosis must be referable to the side of a detected occlusive lesion. Based on NASCET data, the appropriate anatomical selection criterion for extracranial carotid disease (in which a reasonable beneﬁt from intervention may be expected) is at least 50% stenosis, although it may be preferable to use the threshold of z70% stenosis, owing to the concordant higher risk-beneﬁt ratio of therapeutic intervention. Owing to the smaller caliber of involved vessels and the increased predilection for rapid progression, intracranial occlusive lesions of lesser severity should be considered (typically at the z50% stenosis threshold using NASCET measurements). For extracranial carotid occlusive disease, the presence of a symptomatic and hemodynamically signiﬁcant stenosis is not suﬃcient at this time to consider patients for PTA and stenting, since a well-studied and validated therapeutic modality (i.e., CEA) is available. Rather, an additional stipulation should be required in that some technical, anatomical, medical, or neurological factor makes a patient either ‘‘less favorable’’ or ‘‘high risk’’ for conventional CEA. This latter stipulation is of course highly controversial and contentious, being open to substantial individual bias and interpretation from both open and endovascular surgeons alike. It has been tremendously disappointing to hear so-called experts in carotid endarterectomy state that there are essentially no high-risk or inoperable carotid lesions, and therefore no real indication for use of endovascular approaches. We believe that the risk factors articulated by Sundt et al. [126,128] can serve as general guidelines for deﬁning patients who may be at higher operative risk for conventional CEA. Accordingly, symptomatic patients with one or more of the following characteristics are considered for PTA and stenting: tandem stenoses, contralateral carotid occlusion, coexistent intracranial occlusive disease, high carotid bifurcation, extensive plaque distal (>3 cm) or proximal (>5 cm), poor surgical access (e.g., above angle of jaw or intrathoracic/neck base CCA disease), cardiovascular comorbidity (myocardial infarction, active or unstable ischemia, severe hypertension, and congestive heart failure), other signiﬁcant medical comorbidities (COPD, morbid obesity), and unstable neurological status. Other selection criteria not mentioned in the Sundt et al. study [129] for extracranial occlusive disease

480

Chaloupka et al.

include failed CEA (i.e., recurrent stenosis) for carotid disease, and subclavian steal, contralateral occlusion, ipsilateral dominance, and persistent symptomatic dissection for vertebral disease. With regards to intracranial atherosclerotic disease, the role of angioplasty and stenting remains not clearly deﬁned. Several ongoing studies may provide useful information. In the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial [145] 806 patients with TIA or minor stroke with angiographic stenosis of 50–99% of a major intracranial artery will be randomized to warfarin or aspirin. The Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA) trial is a nonrandomized, multicenter, phase 1 study to evaluate the safety and performance of stenting in 50 patients with symptomatic extracranial vertebral or intracranial arterial stenosis [30]. For intracranial occlusive disease, our threshold for considering a patient for either PTA alone or in combination with a stent has steadily decreased as our experience and success with these endovascular techniques has increased. In the past we tended to limit oﬀers of treatment to those patients who had unequivocally failed so-called maximal medical management and were without any other therapeutic options that carried a favorable risk-beneﬁt analysis (e.g., high-risk EC-IC or intracranial surgical bypasses). An additional stipulation of this management was that the failure of medical management had to occur after a patient’s ﬁrst or index ischemic event (i.e., recurrent cerebral ischemia). Certainly, this conservative approach cannot be faulted for attempting to cautiously apply an incompletely veriﬁed and evolving therapeutic modality that has considerable potential risks of major morbidity and mortality [83,84]. However, as indicated earlier, our group and others have found that, unfortunately, may patients managed expectantly in this fashion will subsequently present with a catastrophic stroke. Such an event often results in a poor clinical outcome, owing to a combination of time constraints of eﬀectively reversing cerebral ischemia and/or the increased technical diﬃculties often encountered in achieving optimal cerebral reperfusion under emergency circumstances. Consequently, our group is now currently recommending intracranial PTA and stenting in patients with documented clinical or imaging evidence of cerebral ischemia (including stroke, TIAs, and amaurosis) that is clearly referable to a z50% stenosis of an intracranial artery. Although still an important guiding principle, the additional requirement for failure of best medical management is now less rigidly followed, being inﬂuenced by the many other factors. These include severity of stenosis (lesions z70% tend to be considered earlier for revascularization), status of collateral circulation, perceived technical diﬃculty of intervention, complications and risks of long-term anticoagulation, and severity of index symptoms. Final recommendations for management are also a joint eﬀort among the involved clinical services, which also demand considerable input and deference to each individual patient’s needs, concerns, and preferences.

IX. FUTURE DEVELOPMENTS Dramatic technical and technological innovations are likely to occur as operators gain more experience and insight into the best ways to more safely and eﬀectively revascularize the cerebrovascular system using endovascular surgery. The immediate eﬀects of this experience will be in the continuing reﬁnement and standardization of existing conventional percutaneous transarterial access and revascularization applied speciﬁcally to the cerebrovascular system. There has been a considerable lag in properly deﬁning the best technical

PTA of Cerebrovascular Occlusive Disease

481

and technological parameters for cerebrovascular PTA and stenting. These parameters will ﬁrst have to be clearly deﬁned and articulated in a way that will eventually permit their validation through the technical and clinical outcomes achieved in future reports of case series experience. Future enhancements will also be particularly dependent upon technological innovation, largely owing to the medical device industry’s recent realization of the substantial economic implications of this emerging health care market. Newer PTA and stent devices will likely be more streamlined and ﬂexible, permitting safer and more reliable delivery into the cerebrovascular system. Adjunctive downstream embolic protection devices will become widely utilized. Advances in material science and engineering will permit construction of stents with superior mechanical properties and biocompatibility that may overcome many of the current problems and limitations of these devices. With our everincreasing understanding of the cellular and molecular basis of vascular biology, we predict that stent coating with various biologically active molecules (e.g., growth factors, cytokines, recombinant constructs) will be commonly employed to promote a more controlled and predictable neointimalization and possibly to stimulate beneﬁcial arterial wall remodeling. It is also likely that novel technological innovation will bring to clinical practice many unconventional tools such as self-navigating catheters, angioscopy, endovascular atherectomy devices, and biologically active thin ﬁlm–covered stents, all of which will expand the capabilities and indications of endovascular surgical management of cerebrovascular occlusive disease.

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21 Medical and Surgical Management of Intracerebral Hemorrhage Daniel J. Guillaume and Patrick W. Hitchon University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

I. INTRODUCTION Spontaneous intracerebral hemorrhage (ICH) accounts for 10–20% of all strokes [1,2], with an estimated 37,000 patients aﬀected each year in the United States [3]. It is more than twice as common as subarachnoid hemorrhage (SAH) and is more likely to result in death or major disability than ischemic stroke or SAH [4]. Each year, more than 20,000 Americans die from ICH and an estimated 7000 operations are performed in the United States for evacuation of ICH [5]. Despite available guidelines for medical and surgical treatment of ICH [6], management varies greatly throughout the world [5]. An increased risk of ICH with age has been reported in the United States and other countries [7–11]. Incidence increases from 6/100,000 in those aged 40–47 years to 25/100,000 in those 60–69 years old to 350/100,000 in those over 80 years of age [12]. Hypertension is the single most signiﬁcant and prevalent modiﬁable risk factor for spontaneous ICH. It is slightly more frequently among men than women and is signiﬁcantly more common among young and middle-aged blacks than whites of similar ages [13–15]. Incidence among Asians is also higher than those reported for whites in the United States and Europe. In the computed tomography (CT) era, the 30-day mortality for ICH has been reported at 35– 52%, with half of the deaths occurring within the ﬁrst 2 days [7,16–18]. Pathophysiological alteration in small arteries and arterioles due to sustained hypertension is normally regarded as the most signiﬁcant cause of ICH [16,19–23]. ICH that originates in the putamen, external capsule, thalamus, internal capsule (Fig. 1), pons, or cerebellum (Fig. 2) is generally linked with hypertension. Anticoagulants increase the relative risk of ICH by 6- to 11-fold overall [24–27]. It may also occur following cerebral infarct. Low molecular weight heparin has been found to increase the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors [28]. Drugs, including amphetamines, pseudoephedrine, phenylpropanolamine (contained in many over-the-counter nasal decongestants and appetite suppressors), and cocaine have been known to induce ICH. In 50% of cases, a sudden increase in blood pressure above recent baseline is the trigger. Another mechanism is hypersensitivity or direct toxic eﬀect of the drug on cerebral blood vessels, giving an arteritis-like vascular change characterized 489

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Figure 1 This 74-year-old male with prior history of lacunar infarcts was found unresponsive at his home. On exam, he was able to open his eyes to noxious stimulation and localized with the right upper extremity. He withdrew his left upper extremity on the left. The head CT shown reveals a left thalamic hemorrhage with extension into the internal capsule and corona radiota and with intraventricular extension into the lateral, third and fourth ventricles. Also noted are old lacunar infarcts involving the left internal capsule and atrophy involving the right basal ganglia. Despite emergent placement of right frontal ventriculostomy, the patient failed to improve. Support was withdrawn and he subsequently died.

angiographically by beading. This is reversible with discontinuation of the drug abuse and administration of steroids [29,30]. Cerebral amyloid angiopathy (Fig. 3) is one of the most common causes of lobar ICH in those over age 70 [31–35]. This condition results from the deposition of amyloid protein predominantly in the cortical arterioles of the brain. Abrupt, dramatic increase in blood pressure (BP) in normotensive patients has been documented to precipitate ICH. Arteriovenous malformations (AVMs) (Fig. 4) are important causes

Figure 2 This 60-year-old male was found unresponsive at his home. On exam, he was unresponsive to verbal commands, had equal and sluggishly reactive pupils and demonstrated decorticate posturing bilaterally. A noncontrast head CT scan (A) shows a large left posterior fossa hemorrhage with compression of the fourth ventricle and cerebral aqueduct and subsequent obstructive hydrocephalus. He underwent emergent ventriculostomy followed by posterior fossa craniectomy and hematoma evacuation (B). One month later, he required placement of ventriculoperitoneal shunt. Upon discharge to a rehabilitation facility, he was following commands with all extremities.

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Figure 3 This 64-year-old female presented with a severe headache, which progressed to unresponsiveness. Upon presentation to the emergency department, she was somnolent and would not open her eyes in response to noxious stimuli. Her pupils were equal and reactive. She localized briskly on the left side and displayed decerebrate posturing on the right. A head CT (A) demonstrates a 4 5 9 cm left frontal lobar hemorrhage with mile eﬀacement of the supracellar cistern and 1.2 cm midline shift. She underwent left frontal craniotomy and clot evacuation with improvement (B). Pathological examination of the clot showed congophilic angiopathy. Upon discharge to a rehabilitation facility, she was able to follow commands with the left side, but remained severely hemiparetic on the right.

of nonhypertensive ICH, occurring primarily in younger patients [36]. Increased risk of hemorrhagic presentation of AVMs is associated with hypertension, small size, and deep venous drainage [37]. Aneurysms (Fig. 5) typically cause SAH, but may also bleed into brain parenchyma and cause ICH [38]. Brain tumors with higher predilection to hemorrhage include glioblastoma multiforme, metastatic melanoma, choriocarcinoma, and renal cell and bronchogenic carcinoma. Other causes of ICH include infectious and noninfectious vasculitis, delayed posttraumatic hemorrhage, venous thrombosis, idiopathic hypereosinophilic syndrome, Zieve syndrome, and hemodialysis [39]. Outcome in ICH is poor overall. Mortality rates for spontaneous ICH are in the 40– 50% range [7–9,14,17,40,41]. Volume of ICH, age, Glasgow coma score on admission, pulse pressure, and blood pressure on admission have been found to be independent predictors of

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Figure 3 Continued.

survival in ICH. The presence and degree of intraventricular extension and hydrocephalus are important predictors of outcome in spontaneous ICH in addition to hemorrhage volume [42–44]. Thrombolysis or coagulopathy-related ICH has a particularly poor outcome, usually due to the greater volume of these hemorrhages [45,46].

II. CLINICAL PRESENTATION Patients with ICH typically present with acute onset of a focal neurological deﬁcit, which progresses over minutes to hours with associated headache, nausea, vomiting, decreased consciousness, and elevated blood pressure. By comparison, ischemic strokes and SAH infrequently have gradual progression of symptoms [46]. One fourth of patients presenting with ICH who present alert deteriorate within 24 hours, particularly those with large hematomas and intraventricular extension [47,48]. The early progression of neurological deﬁcit in many patients with an ICH is most often due to ongoing bleeding and enlargement of the hematoma during the ﬁrst few hours [49]. Worsening cerebral edema can also lead to secondary deterioration within 24–48 hours after the onset of hemorrhage [47]. Patients with large hematomas usually have a decreased level of consciousness as a result of increased intracranial pressure and direct compression of the thalamic and/or brainstem reticular activating system [50].

Figure 4 In 1982, this 10-year-old presented with a generalized tonic clonic seizure. Angiography (A) revealed a large right parietal arteriovenous malformation. He was followed and remained clinically stable. In 1982, he developed acute severe headache and neurological deterioration. A head CT revealed a large hematoma in the region of the AVM (B). He underwent emergent craniotomy and clot evacuation, as well as resection of the AVM. He remained with residual left homonomous hemianopsia and left spastic hemiparesis. In 1995, a small residual AVM was treated with steriotactic radiotherapy, and angiography in 1999 showed obliteration of the malformation.

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Figure 5 This 50-year-old male developed an acute onset of severe headache with progressive decline in mental status. A head CT revealed diﬀuse subarachnoid hemorrhage with blood in the suprasellar cistern, Sylvian ﬁssure, lateral, third and fourth ventricles, and ventriculomegaly (A). He ﬁrst underwent ventriculostomy with improvement in mental status. An angiogram (B) revealed an anterior communicating aneurysm aneurysm, which was coiled with a good result.

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Patients with a supratentorial ICH involving the putamen, caudate, and thalamus usually have contralateral sensorimotor deﬁcits of varying severity due to involvement of the internal capsule. Abnormalities of higher cortical function, including aphasia, neglect, gaze deviation, and hemianopsia, may occur as a result of disruption of connecting ﬁbers in the subcortical white matter and functional suppression of overlying cortex [51]. In those with an infratentorial ICH, signs of brainstem dysfunction and contralateral motor deﬁcits may be present [52]. Ataxia, nystagmus, and dysmetria may occur if the cerebellum is involved. The most worrisome feature with infratentorial hematomas is obstructive hydrocephalus, with symptoms ranging from headache, nausea, and vomiting to severe deterioration in level of consciousness due to increased intracranial pressure. Elevation in blood pressure occurs in up to 90% of patients with ICH. Seizures occur in 6–7% of patients with ICH, more commonly with lobar than with deep hemorrhages [17].

III. DIAGNOSTIC STUDIES Computed tomography should be obtained promptly. It demonstrates the size and location of the clot, presence of herniation, intraventricular hemorrhage, or hydrocephalus and may reveal structural abnormalities such as aneurysms (Fig. 5), arteriovenous malformations (Fig. 4), or brain tumors. Angiography should be considered with presence of subarachnoid or intraventricular blood, abnormal intracranial calciﬁcation, prominent vascular structures, or unusual hemorrhage site (peri-Sylvian). A prospective study of angiography in patients with ICH [53] indicated that cerebral angiography has a low yield in identifying an underlying vascular abnormality in patients >45 years old who have a history of hypertension and a thalamic, putaminal, or posterior fossa ICH. Angiography should be considered for all patients without an apparent cause of hemorrhage who are surgical candidates, particularly young, normotensive patients who are clinically stable. Most elderly patients with deep hemorrhages die or possess severe morbidity related to the hemorrhage and are not candidates for angiography. Timing of cerebral angiography depends on the patient’s clinical state and the neurosurgeon’s judgment concerning the urgency of surgery, if needed. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), if available, are sometimes helpful and may obviate the need for contrast cerebral angiography in selected patients. They should also be considered to look for cavernous malformations in normotensive patients with lobar hemorrhages and normal angiographic results who are surgical candidates. MRI can also provide information concerning the time course of the bleed. Blood work should include a complete blood count, prothrombin time, activated partial thromboplastin time, electrolytes, electrocardiography, and chest radiograph. A platelet function test may be useful in patients taking antiplatelet agents.

IV. MEDICAL MANAGEMENT Intracerebral hemorrhage is an emergency of the utmost importance, as it is frequently associated with early neurological deterioration or death. Patients often possess multiple medical problems, which complicates management. A complete history from prehospital care providers should be obtained, focusing on factors that may predispose to ICH, such as

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hypertension, liver disease, use of anticoagulants or antiplatelet agents, use of illicit drugs, or hematological disorders. Head trauma should be ruled out. Table 1 lists the key issues in the medical management of ICH. A. Initial Management Initial management should focus on airway, breathing, circulation, and detection of focal neurological deﬁcits. Patients who exhibit a decreasing level of consciousness or signs of brainstem dysfunction should have their airway secured immediately. Indications for endotracheal intubation include insuﬃcient ventilation, risk of aspiration, or impairment of arterial oxygenation. Intubation should be performed carefully, following institutional protocols such as maximal preoxygenation and administration of drugs (e.g., atropine, thiopental, midazolam, propofol, and succinylcholine) to avoid reﬂex arrhythmias and/or large blood pressure variations. Precautions should be taken to prevent aspiration of gastric contents. Most patients with endotracheal tubes receive nasogastric or orogastric tubes to prevent aspiration. It is impossible from clinical exam and history to deﬁnitively distinguish between cerebral infarction and ICH. Therefore, a noncontrast head CT should be obtained and interpreted as soon as the patient is stable. Current ACLS guidelines recommend obtaining a head CT within 25 minutes of patient arrival in the ER, with radiologist interpretation within 45 minutes [54]. It should be routine practice for a neurologist or neurosurgeon to see the CT scan immediately. The location and size of hematoma, presence of ventricular blood, hydrocephalus, underlying structural abnormalities, and mass eﬀect should be carefully noted. Initial and ongoing patient management is guided chieﬂy by clinical status; thus neurological examination must be carried out expeditiously and frequently. Signiﬁcant changes in level of arousal or focal neurological deﬁcit should be evaluated promptly with a repeat head CT, as early neurological deterioration is frequently due to clot expansion. Fujii and colleagues [55] reported a study of 627 patients admitted within 24 hours of clinical ICH who underwent admission and 24-hour CT scans. They demonstrated an overall rebleed rate of 14%. Independent predictors of expansion of ICH were time from symptom onset to imaging, alcohol consumption, hematoma shape (with hematomas of irregular shape more likely to grow than those of similar size and round shape), diminished level of consciousness,

Table 1 Medical Management of Acute Spontaneous ICH: Key Issues Problem Insuﬃcient ventilation, risk of aspiration or impaired oxygenation Acute neurological deﬁcits or deterioration Elevated INR or platelet function test Signs of transtentorial herniation, brainstem compression, or mass eﬀect MAP z 130 mmHg

Management strategies Endotracheal intubation, mechanical ventilation Stat noncontrast head CT Stat transfusion of FFP, vitamin K, or platelets as appropriate Hyperventilation and intravenous mannitol, stat neurosurgical evaluation IV antihypertensive agent (tailor to individual patient)

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and ﬁbrinogen level. In another retrospective series of 204 nonsurgically treated patients with spontaneous ICH imaged within 48 hours of symptom onset, Kazui and colleagues [56] observed the highest frequency of hematoma expansion in those patients who were imaged within 3 hours of onset (36%) versus a 0% rebleed rate in those imaged between 24 and 48 hours after onset. Similar results showing a declining rate of rebleeding with the passage of time were encountered in other reviews [49]. Coagulation abnormalities should be corrected rapidly. In patients with heart disease, the administration of diuretics should be considered, while giving large volumes of blood products. In order to prevent ongoing bleeding, fresh-frozen plasma (FFP) is given promptly and rapidly for patients with elevated protime/International Normalized Ratio (INR), along with vitamin K, to correct coagulation abnormalities without delay. Sedating agents, which can mask neurological deterioration, should be avoided. B. Blood Pressure Management Strategies for management of BP following ICH have been controversial. In healthy individuals, cerebral autoregulation protects against a precipitous fall in BP. With chronic hypertension there is a shift in the lower limit cerebral blood ﬂow of (CBF) autoregulation toward a higher pressure to accommodate increased vascular resistance. Disruption of cerebral autoregulation occurs with acute ischemic or hemorrhagic stroke, rendering brain perfusion more susceptible to BP changes [57]. The rationale for lowering BP is to reduce the risk of ongoing bleeding from ruptured small arteries and arterioles, as persistent marked elevation of BP can promote further bleeding, increase cerebral blood ﬂow, and raise intracranial pressure (ICP). Dandapani and colleagues [58] assessed 87 patients who suﬀered ICH with an initial mean arterial pressure (MAP) either greater or less than 145 mmHg. The combined mortality and severe morbidity rate was 65% in the >145 mmHg group and 34% in the V 145 mmHg group. They examined the aﬀects of lowering of MAP to <125 mmHg within the ﬁrst 2–6 hours. Patients with a MAP >125 mmHg had a mortality rate of 43% and combined mortality and severe morbidity rate of 60% compared with 21% and 34%, respectively, in those whose MAP was lowered to V 125 mmHg. An animal study by Qureshi and colleagues suggests that pharmacological reduction of MAP does not adversely aﬀect regional CBF or ICP in experimental ICH [59]. They introduced ICH in 12 anesthetized dogs by injection of blood under arterial pressure in the deep white matter adjacent to the caudate nucleus, and then measured serial regional CBF using radiolabeled microspheres and compared them with control animals. Intravenous labetalol was administered 90 minutes following hematoma formation to experimental and control animals while maintaining cerebral perfusion pressure of >65 mmHg. MAP and ICP were continuously monitored. Despite the presence of elevated ICP, MAP reduction was not associated with changes in regional CBF in the regions around and distant to the hematoma. They observed a decrease in cerebrovascular resistance after administration of labetalol, suggesting that regional CBF was maintained by compensatory vasodilatation. The above studies support early use of antihypertensive agents with ICH. MAP must be tightly controlled, however, as overaggressive treatment of blood pressure may decrease cerebral perfusion pressure and subsequently lead to secondary ischemia, worsening brain injury, particularly in the setting of increased intracranial pressure.The optimal level of a patient’s blood pressure, therefore, should be based on individual factors such as presence of chronic hypertension, elevated ICP, age, presumed cause of hemorrhage, and interval since onset. The authors of the ‘‘Guidelines for the Management of Spontaneous Intracerebral

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Hemorrhage’’ [6] have recommended that blood pressure levels be maintained below a mean arterial pressure of 130 mmHg in persons with a history of hypertension, while in patients with elevated intracranial pressure who have an intracranial pressure monitor in place, cerebral perfusion pressure (MAP ICP) should be kept higher than 70 mmHg. Low blood pressure should be managed with volume replacement and consideration of pressors. Intravenous agents with a smooth and easy titration, including labetalol, enalapril, and nicardipine, are preferable for control of BP. Nifedipine and nitroprusside should be avoided due to their tendency to lower BP too quickly. Nitroprusside, the most commonly used agent for severe elevations of blood pressure, is a vasodilatory agent that theoretically can increase cerebral blood ﬂow and thereby intracranial pressure. This possible disadvantage has not been demonstrated in a clinical study. C. Management of Intracranial Pressure and Cerebral Perfusion Increased ICP is a major contributor to mortality after ICH, hence its control is essential. A stepwise escalation of initial procedures to control ICP can be followed. Optimal head position can be adjusted according to ICP values. The head of the bed is typically kept at 30 degrees. A ﬁnal line of defense against elevated ICP is surgical decompression. This will be discussed in the following section. The fastest way to decrease ICP is with hyperventilation. Hypocarbia leads to cerebral vasoconstriction, with almost immediate reduction of cerebral blood ﬂow, although peak ICP reduction may take up to 30 minutes after pCO2 is changed. Reduction of pCO2 to approximately 30 mmHg, best achieved by raising ventilation rate at constant tidal volume (12–14 mL/kg), lowers ICP 25–30% in most patients [6]. Failure of elevated ICP to respond to hyperventilation indicates a poor prognosis. In general, if hyperventilation is instituted for elevated ICP, partial pressure of carbon dioxide (pCO2) should be maintained between 30 and 35 mmHg until ICP is controlled. When hyperventilation is deemed no longer necessary, gradual normalization of serum pCO2 should occur over a 24- to 48-hour period. The eﬀect of sustained hyperventilation on ICP is controversial. In theory, the reduction of ICP by hyperventilation ceases when the pH of CSF reaches equilibrium. Prolonged hyperventilation may lead to ischemia. Osmotherapy is another ﬁrst-line defense for treatment of elevated ICP. Twenty percent mannitol (0.25–0.5 g/kg every 6 hr) may be given for patients with progressively increasing ICP values or clinical deterioration presumed to be secondary to mass eﬀect. To maintain an osmotic gradient, furosemide (10–20 mg every 6 hr) may be administered simultaneously with mannitol. Serum osmolality and sodium values should be measured prior to each dose. At our institution, osmotics and diuretics are typically withheld if serum osmolality is >320 mOsm/L or serum sodium is >150 mg/dL. Corticosteroids are avoided as no clinical study has shown beneﬁt, and multiple side eﬀects are possible [60]. If elevated ICP cannot be controlled with the above-mentioned treatments, barbiturate coma may be induced. The result is presumably mediated through reduction of CBF and volume. In addition to reducing the volume of the normal brain, barbiturates reduce cerebral edema, perhaps as a result of mild systemic hypotension. They may also act as free radical scavengers. Pentobarbital is the most commonly used barbiturate. Short-acting agents such as thiopental may also reduce elevated ICP. The complications of high-dose barbiturate administration include cardiovascular suppression and hypotension, which is most pronounced at the time of bolus administration. Systemic hypotension chieﬂy results from decreased venous tone, baroreﬂex tone, and sympathetic activity. Cardiovascular suppression may be worsened by associated dehydration promoted by osmotherapy and

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diminished cardiac ﬁlling pressures. Many patients require support from pressors. Patients should be monitored with continuous EEG. Maximal reduction in cerebral metabolism is achieved with burst suppression of 30–60 seconds duration. Longer periods of burst suppression in the dog were not associated with any further reduction in CBF or oxygen metabolism [61]. Since some tolerance develops with continued administration of barbiturate, use of multiple small boluses may be considered (0.3–0.6 mg/kg). Pentobarbitol levels should be checked daily. A goal is usually ICP < 24 mmHg and pentobarbital level < 3–5 mg%. Neurological function may take up to 2 days to return once barbiturates have been removed. Level must be <10 Ag/mL before brain death can be declared. Patients with assumed elevated ICP and deteriorating level of consciousness are candidates for invasive ICP monitoring. The decision to place an ICP monitor should be based on rate of decline and other clinical factors such as unresponsiveness, inability to follow commands, vegetative posturing, and CT evidence of mass eﬀect and hydrocephalus. In general, ICP monitors should be placed in (but not limited to) patients with a GCS score of <9 and all patients whose condition is thought to be deteriorating due to elevated ICP. Intraventricular monitors and intraparenchymal ﬁberoptic ICP devices are two commonly used methods of monitoring ICP. An intraventricular catheter adds the therapeutic ability to drain ﬂuid. This will be discussed further in Sec. V.D. D. Prevention of Seizures Seizure activity can result in neuronal injury and destabilization of a critically ill patient and must be treated aggressively. In patients with ICH, prophylactic anticonvulsants (typically phenytoin) are used, with levels checked frequently. A goal level is 14–23 Ag/mL. This is continued for one to several months. Some clinicians continue the medications until there is an absence of blood on CT. E. Fluid Management The target of ﬂuid management is euvolemia. Optimal central venous pressure (CVP) or pulmonary wedge pressure may vary from patient to patient. If hypovolemia is thought to contribute to hypotension, CVP should be maintained between 5 and 12 mmHg or pulmonary wedge pressure at 10–14 mmHg. Electrolytes (sodium, potassium, calcium, and magnesium) should be checked and repleted as needed. Acidosis and alkalosis should be corrected according to blood gas analysis. F. Management of Body Temperature Body temperature should be maintained at normal levels. Acetaminophen 650 mg every 4 hours or cooling blankets should be used to treat hyperthermia >38.5jC. In febrile patients or those at risk for infection, appropriate cultures and smears (tracheal, blood, and urine) should be obtained and chest radiograph evaluated. If ventricular catheters are present, analysis of cerebrospinal ﬂuid (CSF) should be performed with temperature spikes to detect signs of meningitis. If present, appropriate antibiotic therapy should follow. G. Other Medical Management Issues For patients with acute ICH, admission to a neuro-intensive care unit is associated with reduced mortality rate [62]. Four small, randomized trials of medical therapy for ICH have

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been conducted: steroid versus placebo treatment [60,63], hemodilution versus best medical therapy [64], and glycerol versus placebo [65]. None of the studies showed any signiﬁcant beneﬁt for any of the therapies. In the study by Poungvarin et al. [60] patients who were treated with steroids were more likely to develop infectious complications than those treated with placebo. Pulmonary embolism is a common threat during the recovery period, particularly for bedridden patients with hemiplegia. Pneumatic compression devices decrease the risk of pulmonary embolism during hospitalization. Depending on the patient’s clinical state, physical therapy, speech therapy, and occupational therapy should be initiated as soon as possible.

V. SURGICAL MANAGEMENT The rational for evacuation of ICH is that reduction of clot volume may improve neurological recovery and clinical outcome. Volume of ICH is a substantial predictor of poor outcome irrespective of hematoma location, patient age and neurological condition [66–71]. Larger clots result in more profound and longer-lasting alterations in adjacent brain parenchyma due to mass eﬀect, edema, and prolonged interaction between the hematoma and normal tissue [72]. Removal of mass may improve perfusion of compromised brain parenchyma and prevent intracranial hypertension. It also may augment the clearance of blood breakdown products, preventing secondary edema and other neurotoxicities. Another important phenomenon is the early spontaneous expansion of ICHs discussed earlier. Several factors contribute to the decision to proceed with hematoma evacuation or to provide aggressive medical therapy only. These include hematoma size, age of patient and associated comorbidities, clinical status, location of clot, and presence of hydrocephalus. Important distinctions regarding hematoma location include deep versus lobar, supratentorial versus infratentorial, and dominant versus nondominant hemisphere. Lesions located within the dominant hemisphere can produce more disability by destroying eloquent centers and aﬀecting dominant extremities. Furthermore, surgical evacuation of hematomas within the dominant hemisphere is associated with risk of damage to these expressive and receptive language centers. The goals of surgical evacuation of ICH should be to remove as much blood as possible as quickly as possible with the least amount of brain trauma from the surgery itself. Timely surgery may be the key to success. In some situations surgery should also remove the underlying cause of ICH, such as an arteriovenous malformation, and prevent complications such as hydrocephalus and mass eﬀect of the blood clot. Craniotomy has traditionally been the approach for removal of ICH. Its major advantage is adequate exposure, which may lead to more complete clot removal and subsequent decrease in ICP. The major disadvantage of a more extensive surgical approach is that it may lead to further brain damage, particularly in patients with deep hemorrhages or those involving the dominant hemisphere. It may also expose an already critically ill patient to a lengthy procedure under general anesthesia. Numerous clinical trials comparing surgical evacuation to medical therapy alone have been performed during the last 40 years. Because earlier trials failed to show a signiﬁcant beneﬁt with clot evacuation, many neurologists and neurosurgeons do not recommend clot evacuation for spontaneous ICH. However, most neurosurgeons have witnessed numerous individual patients do extremely well following clot evacuation for ICH, and anecdotal

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reports document frequent dramatic recovery after emergent ICH evacuation in younger patients with impending brain herniation [6,73]. The key to operative success likely lies in proper patient selection and appropriate surgical technique. Following is a review of the key randomized trials to date, succeeded by general recommendations for surgical removal based on data from these studies. General indications for surgical evacuation of ICH are listed in Table 2. A. Surgery Versus Medical Therapy: Randomized Studies The ﬁrst and largest trial was published in 1961 [74]. In this pre-CT study, 180 patients were randomized, with diagnosis of ICH based on exam, cerebral angiography, and lumbar puncture. The study was done when surgical and anesthesiological techniques, as well as monitoring of patients in intensive care units, diﬀered substantially from those used today and before the availability of CT. Most feel it should not be included in modern-day metaanalyses. Auer and colleagues [75] conducted a randomized trial comparing endoscopic clot aspiration with best medical treatment. Patients were between 30 and 80 years old, had a hemorrhage >10 cm3 in volume, received treatment and angiography within 48 hours of onset, had no identiﬁable vascular cause of hemorrhage, and were suitable for surgery from a general medical and anesthesiological point of view. Of 723 patients with ICH, 100 met criteria for study entry. In the 50 patients randomized to surgery, the hemorrhage was evacuated through a burr hole by a neuroendoscope, with continuous rinsing with artiﬁcial CSF at a pressure of 10–15 mmHg. The blood clots and CSF were removed by suction at regular intervals. Oozing vessels were coagulated with a laser built into the system, and the entire procedure was under direct visual control. More than 90% of the clot was evacuated in 15% of patients, between 70% and 90% in 29% of patients, and between 50% and 70% in 56% of patients. At 6 months, the mortality rate of the surgical group (42%) was signiﬁcantly lower than that of the medical group (70%). Surgical beneﬁt was mainly limited to patients with lobar hematomas and patients less than 60 years old. Juvela and colleagues in 1989 [76] reported a randomized study comparing surgery versus best medical therapy for 52 patients with spontaneous supratentorial ICH. Hemorrhage was removed by craniotomy within a mean of 14.5 hours after onset. Batjer and

Table 2 Indications for Surgery Problem Posterior fossa hemorrhage z 3 cm Hydrocephalus Young patient with moderate or large lobar hemorrhage and neurological deterioration Basal ganglionic hemorrhage > 30 mL, expanding or with neurological deterioration Structural lesion (e.g., tumor, AVM) Small hemorrhage or minimal deﬁcit GCS < 4

Management strategies Surgical evacuation, consider ventricular catheter Ventricular catheter drainage Consider evacuation

Consider evacuation

Consider resection and evacuation Medical treatment Medical treatment

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colleagues in 1990 [77] conducted a randomized trial in patients with putaminal hematomas z 3 cm in diameter, evaluating best medical management, best medical management plus ICP monitoring, and surgical evacuation in 21 patients. The study of Morgenstern et al. [78] compared craniotomy to best medical therapy in 34 patients with ICH, with goal time to surgery 12 hours from symptom onset. Patients had supratentorial ICH with a volume z10 cm3 and a Glascow Coma Score (GCS) score of 5–15. The data from the above-mentioned clinical trials have been critically analyzed [79,80]. With exclusion of the data obtained by McKissock and colleagues, the results suggest beneﬁt from surgery overall, with a reduction in the chances of death and dependency after surgical treatment by a factor of 0.63. The International Surgical Trial in Intracerebral Hemorrhage [81] is an ongoing trial comparing the outcomes of early surgical intervention and initial conservative treatment in acute ICH. It is located in Europe, Africa, Asia, North America, South America, and Australia, with a target enrollment of 1000 patients.

B. Surgery Versus Medical Therapy: Nonrandomized Studies A large, nonrandomized, multicenter study from Kanaya [82] in Japan compared medical and surgical treatment of putaminal hemorrhages during the 1980s. Of the 7010 patients studied, 3635 received medical treatment alone and 3375 underwent surgery. Mortality in alert and confused patients was signiﬁcantly lower in medically treated patients compared with surgically treated patients. However, mortality in patients who were stuporous or worse was signiﬁcantly lower in those who were treated surgically. There have been numerous other smaller nonrandomized series comparing craniotomy and best medical treatment of ICH [5,73,83–97] with variable and inconclusive ﬁndings.

C. Minimally Invasive Clot Aspiration Backlund and von Holst [98] in the 1970s reported an innovative surgical method for aspiration of hematoma utilizing a CT-guided stereotactic method and a specially developed cannula. Since then many types of CT-guided stereotactic equipment have been developed. Innovations in devices to break up and remove the clot include modiﬁcations of a screw inside a cannula [98], an ultrasonic aspirator [99], a specially designed endoscope [75], a modiﬁed nucleotome [99,100], a double track aspiration [101], intraoperative CT monitoring [102], and intraoperative ultrasound [103]. As detailed in the previous section, Auer and colleagues demonstrated beneﬁt of surgical endoscopic clot evacuation (signiﬁcantly lower mortality rates and improved clinical outcomes) compared with medical treatment alone for the management of ICH [75]. This study, as well as several subsequent case series evaluating thrombolysis and catheter aspiration of ICH, suggest that minimally invasive interventions may substantially decrease hematoma volume, while avoiding the morbidity of a major craniotomy, especially in elderly and debilitated patients who have suﬀered an ICH [75,104–108]. Although no study has addressed it, this method may prove to be beneﬁcial to craniotomy in evacuation of deep dominant hemisphere clots, with lower risk of injury to cortical structures. Kanaya and Kuroda [103] reported that rebleeding after surgery was seen in 10% of patients who underwent craniotomy, 5% who underwent CT aspiration, and 6% who had undergone ultrasound-guided aspiration. On average, CT-guided aspiration removed 71%

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of the original hematoma, whereas ultrasound-guided aspiration removed 81%. Other investigators using various CT-guided aspiration techniques, including thrombolytic instillation, have reported aspiration of 30–90% of the hematoma over the ﬁrst several days. The rebleeding rate in aspiration studies without thrombolytics ranged from 0 to 16%, while, with instillation of thrombolytics, the rebleeding rate ranged from 0 to 10% [75,85,90,96,97,99–101,103,105,107,109–122].

D. Posterior Fossa Hemorrhage, Intraventricular Hemorrhage, and Hydrocephalus Cerebellar hematomas (Fig. 2) are unique from a surgical perspective because they can be approached without causing substantial damage to higher cortical or primary motor pathways (contrary to hematomas arising in the basal ganglia, thalamus, or pons). Morbidity and mortality are frequently related to brainstem compression or obstructive hydrocephalus and may be decreased by prompt decompression [52,93]. Surgery is favored in patients with cerebellar ICHs who have an initial GCS score of <14 or large hemorrhages (>40 mL) [123]. Those with a GCS >14 and small hematomas (<40 mL) tend to do well without surgery. Early craniotomy is recommended in patients with a cerebellar hematoma because the rate of neurological deterioration after cerebellar hemorrhage is very high and unpredictable. Nonrandomized treatment series of patients with cerebellar hemorrhage report good outcomes for surgically treated patients who have large (>3 cm) cerebellar hemorrhages or cerebellar hemorrhages with brainstem compression or hydrocephalus [92,93,124,125]. In these patients medical management alone often results in poor outcomes, while surgical decompression can yield dramatic improvements. For these reasons, neurosurgeons and neurologists advocate that large cerebellar hemorrhages with compression of the brainstem or obstruction of the fourth ventricle should be surgically removed as quickly as possible. Hydrocephalus is an independent predictor of poor outcome after supratentorial ICH [44]. Patients with symptomatic hydrocephalus should undergo prompt placement of ventricular catheter. This should be done prior to posterior fossa decompression. If a signiﬁcant amount of intraventricular blood is present, a larger lumen-diameter catheter should be used as ventricular drainage following intraventricular hemorrhage is often complicated by blood clots that cause catheter obstruction. To facilitate early and eﬀective clearance of blood in the ventricles, some have instilled intraventricular thrombolytic agents in patients with intraventricular blood in association with spontaneous ICH [126]. Ventricular drainage should be initiated and terminated based on clinical exam, ICP values, and CT ﬁndings. Because of potential infectious complications, CSF should be sampled every 2–3 days for evidence of infection.

VI. PREVENTION OF ICH Given that ICH is associated with high morbidity and mortality and proven eﬀective therapy is lacking in most cases, prevention of ICH is important. The Systolic Hypertension in the Elderly Program Study [127] reported that treatment of isolated systolic hypertension in the elderly decreased the risk of ICH by 50%. Although conclusive evidence is lacking, these intervention studies, in light of the known high prevalence of hypertension in those suﬀering ICH, suggest that treatment of hypertension may be the most eﬀective way to

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prevent ICH. Another important means of preventing ICH is close monitoring of the anticoagulation level in patients treated with warfarin [128,129] and careful choice of patients who are anticoagulated. Careful selection of patients undergoing thrombolysis for myocardial infarction or acute ischemic stroke may also decrease the incidence of ICH [130]. A decrease in the use of cocaine and other sympathomimetic agents would likely result in a decrease in ICH. Data from the Framingham Study [129] indicate that increased daily consumption of fruits and vegetables may decrease risk of both ICH and ischemic stroke. Smoking cessation has not been shown to lower risk of ICH in an interventional or observational cohort study.

VII. SUMMARY: MEDICAL AND SURGICAL MANAGEMENT OF ICH 1. Initial priorities are airway, breathing, circulation, and detection of focal neurological deﬁcits. Those with risk of aspiration or diﬃculty with ventilation or oxygenation should undergo immediate endotracheal intubation. 2. A noncontrast head CT should be obtained and interpreted as soon as patient is clinically stable. 3. Neurological exam should be repeated frequently, and signiﬁcant changes in level of arousal or focal neurological deﬁcit should prompt repeat head CT. 4. Coagulation abnormalities should be corrected rapidly. 5. All patients should be monitored in the intensive care unit. 6. A mean arterial pressure of 110–130 mmHg should be maintained. 7. In patients with elevated ICP who have an ICP monitor, a goal cerebral perfusion pressure is > 70 mmHg. 8. ICP may be managed through patient positioning, osmotherapy, hyperventilation, barbiturate coma, and surgical decompression. 9. Patients with small hemorrhages or minimal neurological deﬁcits may be treated medically as they generally do well with medical treatment alone. 10. In patients with a GCS score of < 4, medical management should be strongly considered, as they tend to do poorly regardless of treatment strategy. This is particularly true in the case of dominant hemisphere hemorrhages. Stereotactic aspiration may have application in moderate-sized hemorrhages. 11. Patients with posterior fossa hemorrhage > 3 cm in diameter who are neurologically deteriorating or who have brainstem compression and hydrocephalus from ventricular obstruction should undergo prompt surgical clot evacuation. 12. Patients with hydrocephalus should undergo placement of ventricular catheter as quickly as possible. 13. Young patients with large lobar hemorrhages (z 50 cm3) who deteriorate during observation may beneﬁt from surgical removal of the hemorrhage. 14. An ICH associated with a structural lesion such as an aneurysm or a vascular malformation is to be removed where a good outcome is anticipated 15. Hemorrhages involving the dominant hemisphere are more devastating, and this should be considered in the management. 16. Body temperature should be maintained at normal levels. 17. Pneumatic stockings should be applied to decrease the risk of pulmonary embolism.

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22 Management of Subarachnoid Hemorrhage J. van Gijn and G. J. E. Rinkel University Medical Center, Utrecht, The Netherlands

I. INTRODUCTION Subarachnoid hemorrhage (SAH), mostly from aneurysms, accounts for only 3% of all strokes [1] but for 5% of stroke deaths and for more than one quarter of potential lifeyears lost through stroke [2]. The twentieth century saw great advances in diagnosis, starting with the ability to recognize the condition at all during life. Advances in treatment and prevention of complications have also occurred, but until recently these have led to only modest improvement in overall outcome [3]. The gradual substitution of surgical clipping of ruptured aneurysms by endovascular occlusion that has started to evolve in the last decade is a great step forward [4,5]. Nevertheless, there are still formidable challenges ahead for neurologists, neurosurgeons, and radiologists.

II. EPIDEMIOLOGICAL ASPECTS A. Incidence The incidence of subarachnoid hemorrhage has remained stable over the last three decades. In a meta-analysis of relevant studies, the pooled incidence rate was 10.5 per 100,000 person-years [6]. There seemed to be a decline across time, but this was caused by diagnostic bias. That more recent studies reported lower incidence rates than older studies could be entirely explained by the increasing proportion of patients investigated with computed tomography (CT) scanning. In a virtual study where CT is applied to all patients, the incidence would be 5.6 per 100,000 patient-years [6], only slightly lower than the incidence of 6.9 published later for a study spanning a 30-year period of the population in Olmsted, Minnesota [7]. The average age of patients with subarachnoid hemorrhage is substantially lower than for other types of stroke, which peak in the sixth decade [8,9]. Gender, race, and region have a marked inﬂuence on the incidence of subarachnoid hemorrhage. Women have a 1.6 times (95% CI 1.5–2.3) higher risk than men [6], and blacks a 2.1 times (95% CI 1.3–3.6) higher risk than whites [10]. In Finland and Japan the incidence rates are in the order of 20 per 100,000 per year, i.e., more than three times higher than in other parts of the world [6,11,12]. 513

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B. Risk Factors An important but nonmodiﬁable risk factor is familial predisposition to subarachnoid hemorrhage. Between 7 and 20% of patients with subarachnoid hemorrhage have a positive family history [13]. First-degree relatives of patients with subarachnoid hemorrhage have a three- to sevenfold increase in risk of being struck by the same disease [14–17]. In second-degree relatives, the incidence of subarachnoid hemorrhage is similar to that in the general population [16]. The occurrence of subarachnoid hemorrhage is also associated with speciﬁc heritable disorders of the connective tissue, but these patients account for only a minute fraction of all patients with subarachnoid hemorrhage. Autosomal dominant polycystic kidney disease (ADPKD), the most common heritable disorder associated with subarachnoid hemorrhage, is found in at most 2% of patients with subarachnoid hemorrhage [18]. Other genetically determined disorders associated with subarachnoid hemorrhage are EhlersDanlos disease IV and neuroﬁbromatosis type 1, but these associations are weaker than between ADPKD and aneurysms, and these syndromes are seldom found in patients with subarachnoid hemorrhage. Marfan’s syndrome has often been associated with subarachnoid hemorrhage, but in a clinical cohort of 129 patients with Marfan’s syndrome, none had a history of subarachnoid hemorrhage [19]. Modiﬁable risk factors for subarachnoid hemorrhage have been addressed in a systematic review of 8 longitudinal and 10 case-control studies that fulﬁlled predeﬁned methodological criteria; only smoking, hypertension, and heavy drinking emerged as signiﬁcant risk factors, with odds ratios in the order of 2–3 [20]. For the use of oral contraceptives, the risk was signiﬁcantly increased in a later meta-analysis (RR 1.42; 95% CI 1.12–1.80) [21]. In terms of attributable risk, drinking alcohol 100–299 g/wk has been estimated to account for 11% of cases of SAH, drinking alcohol z300 g/wk for 21%, and smoking for 20% [22]. An additional 17% of the cases could be attributed to hypertension, 11% to a positive family history for SAH, and only 0.3% to ADPKD.

C. Outcome Case fatality ranged between 32% and 67% in a review of population-based studies from 1960 onward [3]. The weighted average was 51%. Of patients who survive the hemorrhage, approximately one third remain dependent [3]. Recovery to an independent state does not necessarily mean that outcome is good. In a study on quality of life in patients after subarachnoid hemorrhage, only 9 of 48 (19%) (95% CI 9–33%) patients who were independent 4 months after the hemorrhage had no signiﬁcant reduction in quality of life [23]. Reevaluation of this cohort 18 months after the hemorrhage showed that outcome had considerably improved in terms of handicap and quality of life, but that still only 15 of the 48 patients (31%) (95% CI 19–46%) had no reduction in the quality of life [24]. The improvement in the ﬁrst year and a half shows that long-term follow-up is essential in studies on eﬀectiveness of new treatment strategies on functional outcome after subarachnoid hemorrhage. The sad truth remains that only a small minority of all patients with subarachnoid hemorrhage can continue their life as before. The relatively young age at which subarachnoid hemorrhage occurs and the poor outcome together explain why the loss of years of potential life before age 65 from subarachnoid hemorrhage is comparable to that from ischemic stroke [2].

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III. DIAGNOSIS OF SAH A. Clinical Features The clinical hallmark of subarachnoid hemorrhage is a history of unusually severe headache with sudden onset. A period of unresponsiveness longer than one hour occurs in almost half the patients, and focal signs develop at the time of the headache or soon afterwards in one third of patients [25,26]. In such patients with neurological deﬁcits it is straightforward that they should be referred for further investigation. In those in whom headache is the only symptom, it is often more diﬃcult to recognize the seriousness of the underlying condition. Classically, the headache from aneurysmal rupture comes on in seconds. Therefore, it is important to make speciﬁc inquiries about how quickly the headache developed; patients often complain only about the severity of the headache and do not know that the speed of onset is a pivotal piece of information. But even an accurate history does not reliably distinguish between aneurysmal rupture and innocuous forms of headache, such as benign vascular headache or muscle contraction headache. First, only half of patients with aneurysm rupture describe the onset as instantaneous; the other half describe it as coming on in seconds to even a few minutes [25]. Second, of all patients whose headache comes on within a split second, only one out of 10 has a subarachnoid hemorrhage [27]; innocuous forms of headache are so common that exceptional forms with sudden onset still vastly outnumber episodes of SAH. Other headache features are equally unhelpful in making the distinction: the severity is rated similarly, vomiting occurs in 70% of patients with aneurysmal rupture but also in 43% of patients with innocuous thunderclap headache, and preceding bouts of similar headaches are recalled in 20% of patients with aneurysmal rupture and 15% of patients with innocuous thunderclap headache [25]. Neck stiﬀness is a common sign in SAH of any cause, but it takes hours to develop, and therefore it cannot be used to exclude the diagnosis if a patient is seen soon after the onset of headache (or much later); also, it does not occur if patients are in deep coma. Subhyaloid hemorrhages require experience with fundoscopy and occur in approximately 17% of patients, at least of those who reach the hospital alive [28,29]. Even though the chance of SAH in a patient with explosive headache as the only symptom is only 10% [27], the lack of clinical features that distinguish reliably and at an early stage between SAH and innocuous types of sudden headache necessitates a brief consultation in the hospital for all such patients. The discomfort and cost of referring the great majority of patients with innocuous headache is outweighed by the beneﬁt of not missing a ruptured aneurysm [30]. It is even more diﬃcult to suspect aneurysmal rupture if the patient does not tell a history of sudden headache or if other symptoms seem to prevail over the headache, such as in patients presenting with a seizure or a confusional state, or if there is an associated head trauma. Epileptic seizures at the onset of aneurysmal SAH occur in approximately 10% of patients [31]. Of course, the majority of patients with de novo epilepsy above age 25 will have underlying conditions other than subarachnoid hemorrhage, but the diagnosis should be suspected if the postictal headache is unusually severe. One to 2% of patients with subarachnoid hemorrhage present with an acute confusional state, and in most patients a history of sudden headache is lacking [32]. The diﬀerential diagnosis of acute confusional state is extensive, and subarachnoid hemorrhage accounts for at most a few of all patients seen in an emergency ward because of an acute confusional state [33]. In such patients the diagnosis emerges only if a careful history of an eyewitness reveals the sudden onset of symptoms; also, detection of focal deﬁcits or absence of a psychiatric history should raise the index of suspicion and lead to a brain imaging study.

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Traumatic and spontaneous SAH are sometimes diﬃcult to disentangle. Patients may be found alone after having been beaten up or hit by a vehicle, without external wounds to indicate an accident, with a decreased level of consciousness or with retrograde amnesia, making it impossible to obtain a history and with neck stiﬀness causing the patient to be worked up for SAH. Conversely, patients may be in an accident while riding a bicycle or driving a car at the time of the aneurysmal rupture [34]. The diagnostic conundrum is diﬃcult when patients sustain a skull fracture having fallen down after aneurysm rupture [35] or when head trauma causes an aneurysm to burst [36]. Meticulous reconstruction of traﬃc or sports accidents may therefore be rewarding, especially in patients with disproportionate headache or neck stiﬀness. Some special features of the history may provide a clue about the cause of SAH. Pain at onset in the lower part of the neck (upper neck pain is common also with ruptured intracranial aneurysms) or a sudden and stabbing pain between the shoulder-blades, with or without radiation to the arms, suggests a spinal arteriovenous malformation or ﬁstula as the source of SAH [37]. A history of even minor neck trauma or of sudden, unusual head movements before the onset of headache may provide a clue to the diagnosis of vertebral artery dissection as a cause of SAH. Cocaine ingestion as a risk factor may not immediately be known in the case of an unconscious patient. In cocaine-associated SAH there is often an underlying aneurysm [38,39]. The physical examination provides an indication about the cause of SAH. Monocular blindness may result from an anterior communicating artery aneurysm if it is exceptionally large [40]. Complete or partial third nerve palsy is a well-recognized sign after rupture of an aneurysm of the internal carotid artery at the origin of the posterior communicating artery, less commonly with aneurysms of the basilar bifurcation or the superior cerebellar artery. The pupil may be spared, contrary to conventional wisdom [41]. Sixth nerve palsies, often bilateral in the acute stage, usually result from a nonspeciﬁc and sustained rise of cerebrospinal ﬂuid pressure at the time of rupture or later. A combination of visual and oculomotor deﬁcits should raise the suspicion of a pituitary apoplexy [42,43]. Lower cranial nerve palsies point to dissection of the vertebral artery through direct compression of the ninth or tenth nerve. B. Investigations: Brain Scanning If subarachnoid hemorrhage is suspected, CT scanning is mandatory because of the characteristically hyperdense appearance of extravasated blood in the basal cisterns. The pattern of hemorrhage often suggests the location of any underlying aneurysm, though with variable degrees of certainty [44,45]. A false-positive diagnosis of subarachnoid hemorrhage on CT is possible in the presence of generalized brain edema, with or without brain death, which causes venous congestion in the subarachnoid space and in this way may mimic SAH (Fig. 1) [46]. The CT scan should be carefully scrutinized because small amounts of subarachnoid blood may easily be overlooked (Fig. 2). If after a thorough review no blood is found, aneurysmal subarachnoid hemorrhage cannot be excluded. Even if CT is performed within 12 hours after the hemorrhage and with a modern machine, studies are negative in about 2% of patients with a subarachnoid hemorrhage [47]. Brain CT may also help in distinguishing primary SAH from traumatic brain injury, but the aneurysmal pattern of hemorrhage is not always immediately appreciated in patients admitted with a trauma [48]. If trauma is the cause of SAH, the blood is usually conﬁned to the superﬁcial sulci at the convexity of the brain, adjacent to a fracture or to an intracerebral confusion, which ﬁndings dispel any lingering concern about the possibility of a ruptured aneurysm. Nevertheless, patients with basal-frontal contusions may show a

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Figure 1 Pseudo-subarachnoid hemorrhage. CT scan of a 27 year old man who had a cardiorespiratory arrest after he had injected himself with a high dose of heroin and cocaine. The ventricles and subarachnoid spaces are compressed by diﬀuse ischemic edema, with venous congestion that falsely suggests subarachnoid bleeding.

pattern of hemorrhage resembling that of a ruptured anterior communicating artery aneurysm [35], and in patients with blood conﬁned to the Sylvian ﬁssure or ambient cistern, it may also be diﬃcult to distinguish trauma from aneurysmal rupture by the pattern of hemorrhage alone (Fig. 3) [49]. Magnetic resonance (MR) imaging with gradient echo T2 sequence or ﬂuidattenuated inversion recovery (FLAIR) techniques demonstrates subarachnoid hemorrhage in the acute phase almost as reliably as CT [50–52], but MR is often impracticable because the facilities are less readily available than CT scans, and restless patients cannot be studied unless anesthesia is given. After a few days, however, MR imaging is increasingly superior to CT in detecting extravasated blood, up to 40 days later [53,54] This makes MR imaging a unique method for identifying the site of the hemorrhage in patients with a negative CT scan but a positive lumbar puncture (see below), such as those who are not referred until 1 or 2 weeks after symptom onset [55]. In patients under propofol sedation, FLAIR images may falsely suggest SAH [56]. C. Investigations: Lumbar Puncture Lumbar puncture is still an indispensable step in the exclusion of subarachnoid hemorrhage in patients with a convincing history and negative brain imaging. Lumbar puncture

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Figure 2 A 36-year-old woman with sudden onset headache. CT scan on the same day shows a minute amount of blood in the right Sylvian ﬁssure (on reader’s left).

should not be carried out rashly or without some background knowledge. A ﬁrst rule is that at least 6 and preferably 12 hours should have elapsed between the onset of headache and the spinal tap. The delay is essential, because if there are red cells in the CSF suﬃcient lysis will have taken place during that time for oxyhemoglobin and bilirubin to have formed [57]. The bilirubin pigment gives the CSF a yellow tinge after centrifugation (xanthochromia), a critical feature in the distinction from a traumatic tap; both pigments are invariably detectable until at least 2 weeks later [57]. The ‘three-tube test’ (a decrease in red cells in consecutive tubes) is notoriously unreliable, and a false-positive diagnosis of subarachnoid hemorrhage can be almost as invalidating as a missed one. Spinning down the blood-stained CSF should be done immediately. If the supernatant seems crystal-clear, the specimen should be stored in darkness (daylight breaks down bilirubin not only in newborns but also in test tubes) until absence of blood pigments is conﬁrmed by spectrophotometry [58]. Although the sensitivity and speciﬁcity of spectrophotometry have not yet been conﬁrmed in a series of patients with suspected SAH and a negative CT scan [59], it is the best technique currently available. Keeping patients in an emergency department or admitting them to hospital up to 6–12 hours after symptom onset may be a practical problem. Yet it is unavoidable until a scientiﬁcally sound method has been devised to distinguish a traumatic tap reliably from blood that was previously present. Even the smoothest puncture can hit a vein. Immediately proceeding with CT or MR angiography in all patients with blood-stained CSF is not

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Figure 3 A 60-year-old man with head injury. CT scanning shows extravasated blood in the left suprasellar and ambient cisterns (left). A small amount of blood at the convexity (right) is the radiological clue that the origin of the hemorrhage is traumatic.

a good idea, because a small (<5 mm) aneurysm may well be coincidental and should often be left untreated, while a negative study may require conﬁrmation by catheter angiography. Even then, lingering worries may restrict the patient’s future life—this refers not only to the person in question but to also insurance companies, authorities for driving licenses, etc!

IV. CAUSES OF SAH A. The Main Cause: Saccular Aneurysms Approximately 85% of all spontaneous hemorrhages into the subarachnoid space arise from rupture of saccular aneurysms at the base of the brain [60,61]. Saccular aneurysms are almost never congenital, but develop during the course of life. The frequency with which saccular aneurysms are found in the general population depends on the deﬁnition of size and the diligence with which the search for unruptured aneurysms is performed. In a systematic overview of studies reporting the prevalence of intracranial aneurysms in patients studied for reasons other than subarachnoid hemorrhage, the prevalence ranged between 0.4% in retrospective autopsy studies and 6.0% in prospective angiography studies, resulting in a weighted estimate of 2.3% for adults without risk factors [62].

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B. The Search for a Ruptured Aneurysms: Is Catheter Angiography Still Necessary? The gold standard for detecting aneurysms is conventional angiography, but this procedure can be time consuming and it can be risky. A systematic review of three prospective studies in which patients with SAH were distinguished from other indications for catheter angiography found a complication rate (transient or permanent) of 1.8% [63]. At any rate, the aneurysm may again rupture during the procedure—in 1–2% overall and in 5% if angiography is performed within 6 hours of the initial bleeding [64]. Other imaging modalities include MR angiography (MRA) and CT angiography (CTA). Three-dimensional imaging is now possible with these techniques as well as with conventional angiography (Fig. 4). MRA is safe but less suitable in the acute stage because seriously ill patients are often restless or need extensive monitoring. A review of studies comparing MRA and intra-arterial angiography in patients with recent subarachnoid hemorrhage under blinded-reader conditions showed a sensitivity in the range of 69–100% for detecting at least one aneurysm per patient. For the detection of all aneurysms the sensitivity is 70–97%, with speciﬁcity in the range of 75–100% [65]. Despite its limitations but thanks to its noninvasive nature and because no contrast injection is needed, MRA is a feasible screening tool for detecting aneurysms in people at increased risk, such as relatives

Figure 4 Three-dimensional reconstruction from a catheter angiogram showing an aneurysm in the bifurcation of the left middle cerebral artery in a 37-year-old man with subarachnoid hemorrhage.

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of patients with subarachnoid hemorrhage and patients with polycystic kidney disease [66–68]. CTA (Fig. 5) is based on the technique of spiral (helical) CT. It can easily be obtained immediately after the noncontrast CT on which the diagnosis is ﬁrst made. It is minimally invasive, because it does not require intra-arterial catheterization. Compared with MRA it involves radiation and injection of iodine-based contrast, but it is much simpler to perform, especially in ill patients. After the data acquisition, which can be done within one minute, postprocessing techniques are needed to produce an angiogram-like display. The most practical procedure for daily routine is cine review of the axial source images combined with maximum intensity projection (MIP) of a limited volume of interest [69]. In addition, MIP images derived from CTA can be rotated and studied on a computer screen at every conceivable angle, which is a great advantage over the limited views with conventional angiography. The sensitivity of CTA (compared with catheter angiography) is 85–98%, in the same range as that of MRA [65]. On the other hand, both techniques are still evolving, and sometimes CTA can detect aneurysms that were missed with conventional angiography [70,71]. It is not surprising, therefore, that an increasing proportion of patients with a ruptured aneurysms is successfully treated with CTA as the only imaging method [72–74].

Figure 5 CT scan (left) showing large intracerebral hematoma in the right temporal lobe. An aneurysmal origin can be suspected because it extends towards the inner table of the skull at the branching site of the middle cerebral artery. CT angiography (right) conﬁrms the presence of an aneurysm of the right middle cerebral artery.

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There is no doubt that catheter angiography is on its way out for the pretreatment assessment of cerebral aneurysms, as the techniques of CTA and MRA are still improving and as neurosurgeons and interventional radiologists are growing familiar with it. C. Nonaneurysmal Perimesencephalic Hemorrhage Approximately 15% of subarachnoid hemorrhages are not attributable to saccular aneurysms. It was recognized in the 1980s and subsequently conﬁrmed that two thirds of patients in this group (10% of the total) are characterized not only by a perfectly and consistently normal angiogram but also by a so-called perimesencephalic pattern of hemorrhage, distinct from that in most episodes of aneurysmal bleeding [75–77]. In this strikingly harmless variety of subarachnoid hemorrhage, the extravasated blood is conﬁned to the cisterns around the midbrain, and the center of the bleeding is immediately anterior to the midbrain (Fig. 6) [78,79]. In some cases, the only evidence of blood is found anterior to the pons [80]. For this reason some have proposed the term pretruncal hemorrhage [81], but in other patients the blood is found mainly in the ambient cistern or only in the quadrigeminal cistern [82,83]. There is no extension of the hemorrhage to the

Figure 6 Nonaneurysmal perimesencephalic hemorrhage in a 65-year-old man. The center of the hemorrhage is ventral to the midbrain and pons in the posterior part of the suprasellar cisterns. There is some extension to the basal part of the Sylvian ﬁssue on both sides, but not to the lateral part of the Sylvia ﬁssures, the anterior part of the suprasellar cisterns, or the anterior interhemispheric cistern.

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lateral Sylvian ﬁssures or to the anterior part of the interhemispheric ﬁssure. Some sedimentation of blood in the posterior horns of the lateral ventricles may occur, but frank intraventricular hemorrhage or extension of the hemorrhage into the brain parenchyma indicates arterial hemorrhage and rules out this particular condition [78]. Clinically, there is little to distinguish idiopathic perimesencephalic hemorrhage from aneurysmal hemorrhage. Perimesencephalic hemorrhage can occur in any patient over the age of 20 years, but most patients are in their sixth decade, as with aneurysmal hemorrhage. A history of hypertension was obtained more often than expected in a single study [84] but not in another [85] In one third of patients strenuous activities immediately precede the onset of symptoms, a proportion similar to that found in aneurysmal hemorrhage [25]. The headache onset is more often gradual (minutes rather than seconds) than with aneurysmal hemorrhage [25], but given the relative infrequency of nonaneurysmal hemorrhage, the predictive value of this feature is poor. Loss of consciousness and focal symptoms are exceptional in idiopathic perimesencephalic hemorrhage, and in those cases only transient; a seizure at onset virtually rules out the diagnosis [25]. On admission, all patients are in fact in perfect clinical condition, apart from their headache [85]. Transient amnesia is found in about one third and is associated with enlargement of the temporal horns on the initial CT scan [86]. Typically, the early course is uneventful: rebleeds and delayed cerebral ischemia simply do not occur. Approximately 20% of patients have enlarged lateral ventricles on their admission brain CT scan, associated with extravasation of blood in all perimesencephalic cisterns, which probably causes blockage of the CSF circulation at the tentorial hiatus [87]. Only a few have symptoms from this ventricular dilatation, and even then an excellent outcome can be anticipated [88,89]. The period of convalescence is short, and with appropriate support almost invariably patients are able to resume their previous work and other activities, without a lasting decrease in the quality of life [90,91]. If exceptions to this rule occur, we suspect the attending physician rather than the disease is to blame [92]. Rebleeds after the hospital period have not been convincingly documented thus far [90,93,94]. A perimesencephalic pattern of hemorrhage may occasionally (in 2.5–5%) be caused by rupture of a posterior fossa aneurysm [78,95,96]. The chance of ﬁnding an aneurysm in 5% of patients has to be weighed against the risks of angiography imposed upon the remaining 95% of patients. In recent years, CTA has been studied as method to conﬁrm or exclude the presence of an aneurysm in patients with a perimesencephalic pattern of hemorrhage on CT. The proportion of posterior fossa aneurysms missed by CTA is inﬁnitely small [97]. A formal decision analysis based on these observations indicates that a strategy where CTA is performed as the only procedure results in a better utility than a strategy where conventional angiography is performed if CTA is negative or if all patients are initially investigated by conventional angiography [98]. D. Rare Causes of Subarachnoid Hemorrhage Together these make up 5% of all ﬁrst episodes of SAH (Table 1). Arterial dissection tends to be recognized more often in the carotid than in the vertebral artery, but subarachnoid hemorrhage from a dissected artery occurs mostly in the vertebral artery (Fig. 7) [49,99]. In a postmortem study of fatal subarachnoid hemorrhage, dissection was found in 5 of 110 patients [100]. Rebleeding occurs frequently, in 30–70% [101–103]. The interval can be as short as a few hours or as long as a few weeks. The second episode is fatal in approximately half of the patients. Intracranial dissection in the anterior circulation is much less common than with the vertebral artery. Reported

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Table 1 Causes of Subarachnoid Hemorrhage Cause Ruptured aneurysm Nonaneurysmal perimesencephalic hemorrhage Rare conditions Arterial dissection (transmural)

Frequency (%)

Site of blood on CT

85 10

Basal cisterns or none Basal cisterns

Pattern of hemorrhage on CT

5 Basal cisterns

Cerebral arteriovenous malformation Dural arteriovenous ﬁstula Vascular lesions around the spinal cord

Superﬁcial

Septic aneurysm

Usually superﬁcial

Pituitary apoplexy

Usually none

Cocaine abuse

Basal cisterns or superﬁcial Basal cisterns or superﬁcial

Trauma (without contusion)

Characteristic features

Basal cisterns Basal cisterns

Preceding neck trauma or pain; lower cranial nerve palsy Vascular lesion often visible on CT History of skull fracture Pain in lower part of neck or in back; radicular pain or cord deﬁcit History; preceding lever or malaise Visual or oculomotor deﬁcits; adenoma on CT History History

cases have aﬀected the terminal portion of the internal carotid artery [104,105], the middle cerebral artery [106,107], and the anterior cerebral artery [108]. Arteriovenous malformations (AVMs) of the brain may cause subarachnoid hemorrhage, but only <5% of all ruptured AVMs rupture in the subarachnoid space, usually at the convexity of the brain, without intracerebral hematoma [109]. Saccular aneurysms form on feeding arteries of 10–20% of AVMs, presumably because of the greatly increased ﬂow and the attendant strain on the arterial wall. If bleeding occurs in these cases, it is more often from the aneurysm than from the malformation [110,111]. In those cases the site of the aneurysms is diﬀerent from the classical sites of saccular aneurysms at the base of the brain; this explains why the hemorrhage is more often into the parenchyma itself than into the subarachnoid space [112,113]. Dural arteriovenous ﬁstulae of the tentorium can give rise to a basal hemorrhage that is indistinguishable on CT from aneurysmal hemorrhage [114]. The anomaly is rare and can be found from adolescence to old age. The risk of hemorrhage from dural AVMs depends on the pattern of venous drainage. Patients with direct cortical venous drainage have a relatively high risk; the risk is further increased if a venous ectasia is present. Patients with drainage into a main sinus have a low risk of hemorrhage, whereas the chance of rupture is negligible if no reﬂux occurs into the smaller sinuses or cortical veins [115]. After a ﬁrst rupture, the annual rate of rebleeding is in the order of 8% [116,117].

Figure 7 CT scan (left and center) showing extravasated blood in the prepontine, interpeduncular, ambient and pontocerebellar cistern, and in the 4th ventricle. Catheter angiography (right) shows caliber changes in the left vertebral artery, consistent with arterial dissection.

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Spinal arteriovenous malformations or cavernous angiomas present with subarachnoid hemorrhage in approximately 10%; in more than 50% of these patients, the ﬁrst hemorrhage occurs before the age of 20 years. Clues pointing to a cervical or thoracic origin of the hemorrhage are onset with a sudden and excruciating pain in the lower part of the neck, or pain radiating from the neck to the shoulders or arms [118,119]. Depending on the relationship between the vascular anomaly and the spinal cord, the hemorrhage may be restricted to the CSF spaces or there may be associated hematomyelia [120,121]. In the absence of such symptoms, AVMs of the spinal cord may again become manifest when spinal cord dysfunction develops, after a delay that may be as short as a few hours or as long as a few years—at least with the intradural type, which is most common. Rebleeding may occur, even repeatedly, with extradural AVMs [122]. CT scanning of the brain in patients with a ruptured cervical AVM may show blood throughout the basal cisterns and ventricles [119]. If a cervical origin of the hemorrhage is suspected, MR imaging or MRA are ﬁrst-line investigations [123]; spinal angiography is impractical as well as hazardous if there are no localizing signs or symptoms. Saccular aneurysms of spinal arteries are mostly associated with AVMs [124]. As an isolated source of hemorrhage in the spinal canal they are extremely rare, with approximately 12 patients on record [125,126]. As with AVMs of the spinal cord, the clinical features of spinal subarachnoid hemorrhage may be accompanied by those of a transverse lesion of the cord, partial or complete. Cardiac myxoma is an uncommon lesion that may, in exceptional cases, metastasize to an intracranial artery, inﬁltrate the wall and thus cause an aneurysm to develop, even more than a year after operation of the primary tumor [127]. Septic aneurysms develop if infected tissue debris enters the blood stream and lodges in the wall of cerebral arteries. Most strokes in the context of infective endocarditis are not subarachnoid hemorrhage but (hemorrhagic) infarcts or intracerebral hemorrhages from pyogenic arteritis [128–130]. Sometimes rupture of a septic aneurysm is the initial manifestation of infective endocarditis [128,131]. Aneurysms associated with infective endocarditis are most often located on distal branches of the middle cerebral artery, but approximately 10% of the aneurysms develop at the base of the brain [132]. Therefore, rupture of a septic aneurysm causes an intracerebral haematoma in most patients, but some have a basal pattern of hemorrhage on CT that is very similar to that of a ruptured saccular aneurysm. Septic aneurysms in patients with aspergillosis are usually located on the proximal part of the basilar or carotid artery [133]. Pituitary apoplexy is the traditional name for arterial hemorrhage occurring in a pituitary tumor, probably resulting from tissue necrosis involving one of the hypophyseal arteries. Several contributing factors may precipitate hemorrhagic infarction of a pituitary tumor, such as pregnancy, raised intracranial pressure, anticoagulant treatment, cerebral angiography, or the administration of gonadotrophin-releasing hormone [43,134]. The initial features are a sudden and severe headache, with or without nausea, vomiting, neck stiﬀness, or a depressed level of consciousness [43,135]. The hallmark of pituitary apoplexy is that most patients have a sudden decrease in visual acuity: in one series of 15 patients, only 2 had normal visual acuity. In most patients with pituitary apoplexy, eye movements are disturbed as well, because the hemorrhage compresses the oculomotor, trochlear, and abducens nerves in the adjacent cavernous sinus [42]. Brain CT or MR imaging scanning indicates the pituitary fossa as the source of the hemorrhage and in most instances the adenoma itself is visible [42]. Cocaine abuse leads to subarachnoid hemorrhage mostly via formation of aneurysms, at least in 70% of cases where hydrochloride (crack) cocaine is involved, against 30–40% of those where the alkaloid form was used [38]. The pattern of hemorrhage on

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brain CT is often similar to that of a ruptured saccular aneurysm, and the diagnosis rests on a conﬁrmatory history or on the results of toxicological tests. The source of the hemorrhage in patients without an aneurysm is unknown. Although biopsy-proven vasculitis has been found [136], changes suggestive of vasculitis often fail to show up on angiograms, admittedly a very insensitive test [137]. Anticoagulant drugs are seldom the sole cause for subarachnoid hemorrhage; if patients with a ruptured aneurysm are on anticoagulants, the outcome is relatively poor [138]. Sickle cell disease as the background of subarachnoid hemorrhage involves children in 30% of cases [139]. Adults usually have an associated aneurysm at the base of the brain, but in children CT scanning shows blood in the superﬁcial cortical sulci. In them angiography shows no aneurysm but multiple distal branch occlusions and a leptomeningeal collateral circulation; the hemorrhage is attributed to rupture of these collaterals. E. Patients Without Identifiable Cause of Subarachnoid Hemorrhage If no vascular or other abnormalities can be identiﬁed, it is essential to take into account the pattern of hemorrhage on the initial CT scan. If this pattern is perimesencephalic, the diagnosis of nonaneurysmal hemorrhage is established and no repeat studies are needed given the absence of rebleeds and the invariably good outcome. Such patients need no longer be on an intensive- or medium-care unit, can be transferred to a regular ward, and can usually be discharged home after a few days with the reassurance that no complications will ensue and that they can take up their lives without any restrictions. Patients with an aneurysmal pattern of hemorrhage on CT but a negative angiogram still can develop secondary ischemia and have a 10% risk of rebleeding [90,93]. These patients should therefore remain on the intensive- or medium-care unit. The substantial risk of rebleeding in patients with an aneurysmal pattern of hemorrhage indicates that at least in some patients an aneurysm escapes radiological detection. Apart from technical factors, such as insuﬃcient use of oblique projections, this phenomenon may have several explanations, including narrowing of blood vessels by vasospasm, thrombosis of the neck of the aneurysm or of the entire sac, or obliteration of the aneurysm by pressure of an adjacent haematoma, particularly with aneurysms of the anterior communicating artery [140]. Given the risk of a later rebleed, it is in patients with an aneurysmal pattern of hemorrhage on CT that repeat angiography seems most clearly indicated. MR or CT angiography may in exceptional cases show the expected aneurysm, despite a normal angiogram [55,70,71].

V. EARLY ASSESSMENT OF PATIENTS WITH ANEURYSMAL SAH In the following sections it shall be assumed that the cause of SAH is an aneurysm, unless speciﬁcally indicated otherwise. A. Grading Scales The baseline variable most closely related to poor outcome in aneurysmal SAH is the neurological condition of the patient on admission. Two other important factors are age and the amount of subarachnoid blood on the in initial CT scan [60]. Several grading systems have been developed for this initial assessment, in most cases consisting of approximately ﬁve categories of severity, in hierarchical order. The constituent features

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of these grading systems are not only the level of consciousness, but also headache, neck stiﬀness, and focal neurological deﬁcit. Apart from the lack of validity, these more or less traditional systems show wide variations between observers. A committee of the World Federation of Neurological Surgeons (WFNS) has proposed a grading scale of ﬁve levels, essentially based on the Glasgow Coma Scale (GCS), with focal deﬁcit making up one extra level for patients with a GCS score of 14 or 13 (Table 2) [141]. In other words, the WFNS Scale takes into account the fact that a focal neurological deﬁcit in patients with SAH rarely occurs with a normal level of consciousness and acknowledges that the presence or absence of such a deﬁcit does not add much to the prognosis in patients with a GCS score of 12 or less. Although no formal studies of the validity and reliability of the WFNS Scale have yet been undertaken, its face validity is high, and it is regrettable that obsolete grading systems are still much used [142,143]. B. Causes of Poor Clinical Condition on Admission and Their Treatment It is often tacitly assumed that the initial clinical condition is related only to the impact of the ﬁrst hemorrhage. This is incorrect, since some complications can occur within hours of the original rupture. Only by exclusion it should be assumed that the cause is global brain damage as a result of high pressure and subsequent ischemia. Early rebleeding occurs in up to 15% of patients in the ﬁrst few hours after admission for the initial hemorrhage, at least in those in whom it is associated with a sudden episode of clinical deterioration [144]. As such sudden episodes often occur before the ﬁrst CT scan, or even before admission to hospital, a deﬁnite diagnosis is diﬃcult and the true frequency of rebleeding on the ﬁrst day is invariably underestimated. Patients with rebleeding should be resuscitated and artiﬁcially ventilated if respiratory arrest occurs, because in a substantial proportion spontaneous respiration returns within a few hours. Intracerebral hematomas occur in up to 40% of patients with ruptured aneurysms. Not surprisingly, the average outcome is worse than in patients with purely subarachnoid blood [145]. When a large haematoma is the most likely cause of the poor condition on admission, immediate evacuation of the hematoma should be seriously considered (with simultaneous clipping of the aneurysm if it can be identiﬁed), often with the aneurysm having been demonstrated only by MRA or CTA. Surgical treatment may be life-savng in patients with impending transtentorial herniation, particularly with temporal hematomas. In patients with large Sylvian hematomas (Fig. 5), decompressive craniotomy may obviate the need for removal of the hematoma if immediate clipping is not an option [146].

Table 2 World Federation of Neurological Surgeons (WFNS) Grading Scale for Patients with Subarachnoid Hemorrhage WFNS grade I II III IV V a

Glasgow Coma Scale sum score 15 14 or 13, without focal deﬁcit 14 or 13, with focal deﬁcita 12 to 7 6 to 4

Cranial nerve palsies are not considered a focal deﬁcit for this purpose. Source: Ref. 141.

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Acute subdural haematoma is usually associated with recurrent aneurysmal rupture, but can also occur with the initial hemorrhage. It may be life-threatening, in which case immediate evacuation is called for [147]. Acute hydrocephalus should be suspected in patients with gradual obtundation within 24 hours of hemorrhage, especially if accompanied by slow pupillary responses to light and downward deviation of the eyes [89,148]. If the diagnosis is conﬁrmed by CT, this can be a reason for lumbar puncture or early ventricular drainage depending on whether the site of obstruction is in the subarachnoid space or in the ventricular system (Fig. 8). Nevertheless, it should be kept in mind that some patients improve spontaneously in the ﬁrst 24 hours [149]. If acute hydrocephalus is associated with large amounts of intraventricular blood, the clinical condition is often poor from the outset. If such patients are left alone, more than 90% has a poor outcome. An indirect comparison of observational studies suggests that insertion of an external ventricular catheter is not very helpful in these patients, but that a strategy where such drainage is combined with ﬁbrinolysis through the drain results in a good outcome in half the patients [150]. Also, there is anecdotal evidence of successful surgical removal of an expanding clot in the fourth

Figure 8 Acute hydrocephalus after subarachnoid hemorrhage in an 85-year-old woman. Upper row (day 0): CT scan on admission shows blood in the basal cisterns and enlargement of the ventricular system, with some sedimentation of blood in the 3rd and 4th ventricles. Middle row (day 1): after the patient had lapsed into coma—marked enlargement of the lateral ventricles and third ventricle. A lumbar puncture was performed; within an hour the patient again responded to questions. Lower row (day 4): marked decrease in size of the ventricular system.

Figure 8 Continued.

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Figure 9 A 75-year-old woman with a subarachnoid hemorrhage that was fatal within hours of onset. CT scanning shows abundant blood in all basal cisterns and in superﬁcial sulci.

ventricle causing brain stem compression [151]. This needs to be conﬁrmed in studies with concurrent, randomized controls. Global cerebral ischemia is the most probable cause if neither a supratentorial hematoma nor intraventricular hemorrhage can explain a patient’s poor clinical condition. The most likely explanation is a prolonged period of global cerebral ischemia at the time of hemorrhage, as a result of the pressure in the cerebrospinal ﬂuid spaces being elevated to the level of that in the arteries for as long as a few minutes (Fig. 9). This is quite distinct from delayed ischemia, which is focal or multifocal (see below). Such immediate damage is probably reﬂected by evidence of global cerebral edema on CT scans [152] or by diﬀuse lesions on diﬀusion weighted MR imaging [153]. General measures for nursing and medical management of patients with ruptured aneurysms have been summarized in Table 3. The main purposes are to make the patient as comfortable as possible under the circumstances and at the same time to avoid rebleeding, delayed cerebral ischemia, and medical complications.

VI. PREVENTION OF REBLEEDING Medical, surgical, or endovascular intervention can prevent recurrent hemorrhages in patients who survive the period of initial assessment. After the ﬁrst day, the risk of

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Table 3 General Management of Patients with Aneurysmal Subarachnoid Hemorrhage Nursing Continuous observation (Glasgow Coma Scale, temperature, ECG monitoring, pupils, any focal deﬁcits) Nutrition Oral route preferred, but only with intact cough and swallowing reﬂexes -If nasogastric tube is necessary: - Deﬂate endotracheal cuﬀ (if present) on insertion - Conﬁrm proper placement by x-ray - Begin with small test feeds of 5% dextrose - Prevent aspiration by feeding in sitting position and by checking gastric residue every hour - Tablets should be crushed and ﬂushed down (phenytoin levels will not be adequate in conventional doses) - Total parenteral nutrition should be used only as a last resort - Keep stools soft by adequate ﬂuid intake, restriction of milk content, and administration of magnesium oxide Blood pressure - Do not treat hypertension unless there is evidence of heart failure or progressive organ damage Fluids and electrolytes - Intravenous line mandatory - Give at least 3 L/day (normal saline) - Insert an indwelling bladder catheter if voiding is involuntary - Compensate for a negative ﬂuid balance and for fever - Monitoring of electrolytes (and leukocyte count) at least every other day Pain - Start with acetaminophen and/or dextropropoxyphene; avoid aspirin - Midazolam can be used if pain is accompanied by anxiety (5 mg intramuscularly or infusion pump) - For severe pain, use codeine or, as a last resort, opiates Prevention of deep vein thrombosis and pulmonary embolism - Before occlusion of aneurysm: apply compression stockings - After treatment of the aneurysm: fractionated heparin Medical treatment to prevent secondary ischemia - Nimodipine 60 mg orally every 4 hours, to be continued for 3 weeks

rebleeding (Fig. 10) is more or less evenly distributed over the next 4 weeks, ﬂuctuating around 2% per day for patients still at risk [154]. A. Antifibrinolytic Drugs Medical treatment for preventing rebleeding has not yet been successful; treatment with antiﬁbrinolytic agents does reduce the rebleed rate, but fails to improve overall outcome. A systematic review of antiﬁbrinolytic agents included eight trials published before 2000 that met predeﬁned inclusion criteria and totalled 937 patients [155]. In the meta-analysis antiﬁbrinolytic treatment did not provide any evidence of beneﬁt on outcome. The risk of rebleeding was signiﬁcantly reduced by antiﬁbrinolytic therapy, but this was oﬀset by a similar increase of the risk of secondary cerebral ischemia. In other words, antiﬁbrinolytic drug work, but they do not help. Because all trials in this meta-analysis had been performed before the 1990s, at a time when prevention or treatment of secondary cerebral ischemia had

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Figure 10 Serial CT scans in a 54 year old woman with repeated hemorrhages from an aneurysm of the anterior communicating artery, in whom occlusion of the aneurysm was not possible for medical and surgical reasons. Upper row (day 8): subarachnoid blood in the anterior interhemispheric ﬁssure (left), without intraventricular bleeding (right). Middle row (day 11): increased amount of subarachnoid blood, with intraparenchymal extension (left) and blood in the cavum septi pellucidi (right). Lower row (day 12): new layer of intraparenchymal bleeding (left), with extension into the frontal horn of the right ventricle (right).

yet to be developed, the results of two large new clinical trials on antiﬁbrinolytic therapy were awaited with interest. In one trial, performed in the Netherlands, all 492 patients were maximally protected against ischemia by means of calcium antagonists and a liberal supply of ﬂuids. Tranexamic acid signiﬁcantly reduced the rate of rebleeding, yet the overall outcome was not diﬀerent between the two groups, mainly because of cerebral ischemia [156]. The second trial was performed in Sweden and involved 505 patients; again the overall outcome did not improve in patients treated with tranexamic acid, despite an impressive reduction in the rate of rebleeding [157]. B. Operative Clipping of the Aneurysm Surgical obliteration of the aneurysm has been the mainstay of treatment for decades. Until the 1980s this was deferred until day 10–12, because of the many complications with earlier operations. Since then, many neurosurgeons have adopted a policy of early clipping of the aneurysm, i.e., within 3 days of the initial bleed. The main rationale, of course, is

Figure 10 Continued.

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optimal prevention of rebleeding. The theoretical advantages of early operation have not yet been proven. In the only randomized trial of the timing of operation performed so far, 216 patients were allocated to operation within 3 days, after 7 days, or in the intermediate period [158]. The outcome tended to be better after early rather than after intermediate or late operation, but as the diﬀerence was not statistically signiﬁcant, a disadvantage could not be excluded. The same result—no diﬀerence in outcome after early or late operation— emerged from observational studies [154,159–162]. C. Endovascular Treatment Since the introduction of detachable platinum coils for packing of aneurysms with subsequent local thrombosis [163], endovascular embolization is increasingly used. Numerous observational studies have published complication rates, occlusion rates, and short-term follow-up results, but indirect comparisons between endovascular and surgical treatment are inappropriate because there are many diﬀerences in study design, patients, and aneurysms [164,165]. Also, rerupture of aneurysms may occur even several months after apparently successful coiling [166,167]. Fortunately, in 2002 the results of a randomized comparison between endovascular and surgical treatment in 2143 patients were published after a planned interim analysis had shown a highly signiﬁcant advantage in favor of coiling. An earlier and much smaller clinical trial (109 patients) had been inconclusive [168]. In the large trial, from Great Britain, the proportion of patients who were dead or dependent after one year was 30.6% in patients allocated to surgical clipping versus 23.7% in patients allocated to coiling [4]. This corresponds with an absolute risk reduction of 6.9% and a relative risk reduction of 22.6%. It should be kept in mind that most aneurysms in this trial were at the anterior communicating and carotid artery; most patients with aneurysms at the middle cerebral artery were not randomized because these were not suitable for coiling, whereas most aneurysms in the posterior fossa were preferentially treated by coiling, in keeping with recent observational studies [169–171]. Also, few patients in poor clinical condition were randomized. The results of the trial therefore apply especially to patients in good clinical condition with aneurysms on the carotid artery or anterior communicating artery. Some uncertainty remains about the durability of the occlusion by coiling; the rate of late rebleeding from the same aneurysm after surgical treatment is known to be in the order of 2% after 10 years and 9% after 30 years [172] but at this stage the rate of recanalization followed by rupture after coiling is hardly known beyond 3 years [173]. Surgical clipping remains the preferred option in most aneurysms of the middle cerebral artery, because as a rule these are not suitable for coiling, as well as for aneurysms at other sites in which the anatomical features are unfavorable for coiling. Many posterior circulation aneurysms are suitable for both clipping and coiling; solid evidence from clinical trials is lacking in these patients. For ruptured basilar artery aneurysms a recent study retrospectively compared 44 patients treated by coiling with 44 other patients who were surgically treated [174]; after adjustment for baseline diﬀerences the odds ratio for poor outcome after coiling was 0.28 (95% CI 0.08–0.99), which suggests that coiling is the preferred treatment for patients with ruptured aneurysms of the basilar artery. For patients in poor clinical condition, there is even more uncertainty. The results of the ISAT trial cannot be directly extrapolated to patients with a severely impaired level of consciousness, but given the lack of evidence on the eﬀectiveness of the standard treatment (clipping) in this situation, most treatment teams will prefer coiling for this category of patients.

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Endovascular occlusion with coils is usually performed with the patient under general anesthesia, because any movement of the patient may jeopardize the procedure; in some centers, however, embolization of intracranial aneurysms is performed in awake patients after administration of sedative and analgesic agents [175]; this method has logistical advantages and allows intraprocedural assessment of the patient’s condition, but may be disadvantageous if intraprocedural rebleeding occurs.

VII. PREVENTION OF SECONDARY CEREBRAL ISCHEMIA Delayed cerebral ischemia occurs mainly in the ﬁrst or second week after aneurysmal subarachnoid hemorrhage, in about 2% of unoperated patients at risk per day, with an approximately fourfold increase in risk after early operation [154]. Despite many years of intensive research, the pathogenesis of secondary cerebral ischemia following subarachnoid hemorrhage is only partly understood. It is a generally held belief that after the hemorrhage an unidentiﬁed factor is released from the blood clot into the subarachnoid space, which induces vasoconstriction and thereby secondary ischemia. Several observations argue against this popular notion. First, the presence of subarachnoid blood, though a powerful predictor of delayed cerebral ischemia, is not in itself a suﬃcient factor for the development of secondary ischemia, because secondary ischemia does not occur in patients with a perimesencephalic (nonaneurysmal) subarachnoid hemorrhage [85]. Second, in large series of patients the site of delayed cerebral ischemia does not correspond with the distribution or even the side of subarachnoid blood [176,177]. Third, many patients with vasospasm never develop secondary ischemia [178]. These observations collectively suggest that not only the presence of subarachnoid blood per se but rather the combination with other factors such as the arterial origin of the blood and the existence of a tear in the arterial wall determines whether and where secondary ischemia will develop. Despite this lack of pathophysiological insight, some progress has been made in the prevention of secondary ischemia after aneurysmal SAH by changes in general medical care (notably increased ﬂuid intake and avoidance of antihypertensive drugs) as well as by speciﬁc drug treatment. Transcranial Doppler sonography may suggest impending cerebral ischemia by means of the increased blood ﬂow velocity from arterial narrowing in the middle cerebral artery or in the posterior circulation, but only velocities below 120 mL/min or above 200 mL/min are reasonably accurate in excluding or predicting delayed ischemia, while almost 60% of patients are in the intermediate range [179]. Even then, demonstration of arterial narrowing does not prove in itself that clinical deterioration has been caused by ischemia.

A. Management of Blood Pressure Management of hypertension is a diﬃcult issue in patients with SAH, especially if the blood pressure rises above 200/110 mmHg. Aggressive treatment of high blood pressure entails a deﬁnite risk of ischemia in areas with loss of autoregulation, especially since hypertension after SAH may be a compensatory phenomenon. The empirical evidence for the advice not to administer antihypertensive drugs is sparse. An observational study from the 1980s, in which all events had been documented by means of serial CT scanning, compared patients in whom hypertension had been newly treated with normotensive controls; the rate of rebleeding was lower but the rate of cerebral infarction was higher

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than in untreated patients, despite the blood pressures being, on average, still higher than in the controls [180]. Also, an observational study suggested that intraoperative hypotension had a deleterious eﬀect on outcome [181]. It seems best to reserve antihypertensive drugs (other than those the patients were taking already) for patients with extreme elevations of blood pressure as well as evidence of rapidly progressive end organ deterioration, diagnosed from either clinical signs (e.g., new retinopathy, heart failure) or laboratory evidence (e.g., signs of left ventricular failure on chest x-ray, proteinuria, or oliguria with a rapid rise of creatinine levels).

B. Fluid Balance and Electrolytes Fluid management in SAH is important to prevent a reduction in plasma volume, which may contribute to the development of cerebral ischemia. Nevertheless, the arguments for a liberal (some might say aggressive) regimen of ﬂuid administration are indirect. In approximately one third of the patients plasma volume drops by more than 10% within the preoperative period, which is signiﬁcantly associated with a negative sodium balance; in other words, there is loss of sodium as well as of water [182]. Observational studies with historical controls suggest that a daily intake of at least 3 L of saline (against 1.5–2.0 L in the past) is associated with a lower rate of delayed cerebral ischemia and a better overall outcome [183]. A regimen of prophylactic volume expansion, regardless of ﬂuid balance, has not proved eﬀective in a few clinical trials, though these studies were underpowered [184,185]. Despite the incomplete evidence, it seems reasonable to prevent hypovolemia. We favor giving 2.5–3.5 L/day of normal saline, unless contraindicated by signs of impending cardiac failure. Nevertheless, it appears that many patients need an even greater daily ﬂuid intake to balance the production of urine plus estimated insensible losses (via perspiration and expired air). Fluid requirements may be guided by recording of central venous pressure (directly measured value should be above 8 mmHg) or pulmonary wedge pressures (to be kept above 7 mmHg), but frequent calculation of ﬂuid balance (four times per day until approximately day 10) is the main measure for estimating how much ﬂuid should be given. Fluid intake should be increased proportionally in patients with fever, from whatever cause.

C. Calcium Antagonists Initially, the rationale for the use of calcium antagonists in the prevention or treatment of secondary ischemia was based on the assumption that these drugs reduce the frequency of vasospasm by counteracting the inﬂux of calcium in the vascular smooth-muscle cell. This antispastic eﬀect of calcium antagonists was conﬁrmed by many in vitro studies with intracranial arteries and also by in vivo assessments of arterial lumen changes after experimental subarachnoid hemorrhage. Clinical trials have been undertaken with three types of calcium antagonists—nimodipine, nicardipine, and AT877— of which nimodipine is the most extensively studied and used. A systematic review of all randomized controlled trials on calcium antagonists in patients with subarachnoid hemorrhage showed a signiﬁcant reduction in frequency of poor outcome, which resulted from a reduction in the frequency of secondary ischemia [186]. The nimodipine trials showed a signiﬁcant reduction in the frequency of poor outcome, whereas the nicardipine and AT877 trials did not. On the other hand, nicardipine and AT877 signiﬁcantly reduced the frequency of

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vasospasm, whereas the nimodipine trials showed only a trend towards reduction of vasospasm, despite a larger number of patients included. In brief, administration of nimodipine improves outcome in patients with subarachnoid hemorrhage, but it is uncertain whether nimodipine acts through neuroprotection, through reducing the frequency of vasospasm, or both. Nicardipine and AT877 deﬁnitely reduce the frequency of vasospasm, but the eﬀect on overall outcome remains unproved, which again underlines the weak relation between vasospasm and outcome. The practical implications are that the regimen employed in the dominant nimodipine trial (60 mg orally every 4 hours, to be continued for 3 weeks) is currently regarded as the standard treatment in patients with aneurysmal subarachnoid hemorrhage. If the patient is unable to swallow, the tablets should be crushed and washed down a nasogastric tube with normal saline. There is no evidence for eﬀectiveness of intravenous administration of nimodipine, which carries a risk of inducing hypotension. It is a somewhat uncomfortable thought that almost the entire evidence about eﬃcacy and dosage of nimodipine hinges on a single, large clinical trial [187]. Because the results might be aﬀected by unpublished negative trials, the beneﬁts of nimodipine cannot be regarded as being beyond all reasonable doubt.

D. Neuroprotective Drugs Other Than Calcium Antagonists Tirilazad has been studied in four randomized, controlled trials, totaling more than 3500 patients [188–191]. This drug belongs to the category of 21-amino steroids that inhibit iron-dependent lipid peroxidation. The only beneﬁcial eﬀect on overall outcome was seen in a single subgroup of a single trial, i.e., those treated with 6 mg/kg/day (two other groups received 0.2 or 2 mg/kg/day) [188]. This possible beneﬁt could not be reproduced in the corresponding subgroup from a parallel trial [190], nor in two further trials with an even higher dose (15 mg/kg/day) in women [189,191]. A single trial with another hydroxyl radical scavenger, NV-propylenedinicotinamide (nicaraven), in 162 patients showed a decreased rate of delayed cerebral ischemia but not of poor outcome at 3 months after SAH [192]. Curiously enough, the reverse was found a trial of 286 patients with ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase–like action: improved outcome at 3 months after SAH, but without any reduction in the frequency of delayed ischemia [193].

E. Aspirin and Other Antiplatelet Agents Several studies have found that blood platelets are activated from day 3 after subarachnoid hemorrhage, mostly through increased levels of thromboxane B2, the stable metabolite of thromboxane A2, a substance that promotes platelet aggregation and vasoconstriction [194,195]. The practical question is whether interventions aimed at counteracting platelet activation are therapeutically useful. A retrospective analysis of 242 patients who had survived the ﬁrst 4 days after SAH showed that patients who had used salicylates before their hemorrhage (as detected by history and urine screening) had a signiﬁcantly decreased risk of delayed cerebral ischemia, with or without permanent deﬁcits (RR 0.40; 95% Cl 0.18–0.93) [196]. There is a need for a prospective and randomized study of salicylates or other antiplatelet drugs as a preventive measure against delayed cerebral ischemia, preferably

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after clipping of the aneurysm to avoid rebleeding being precipitated by the antiplatelet and so antihemostatic action. A pilot study of aspirin after early operation in 50 patients has shown that this treatment is feasible and probably safe [197]. Three antiplatelet agents other than aspirin have been tested in separate trials of patients with subarachnoid hemorrhage: dipyridamole, the thromboxane A2 synthetase inhibitor cataclot, and the experimental agent OKY-46. In a systematic overview of these three trials and two small aspirin trials, the rate of poor outcome was not signiﬁcantly diﬀerent between patients treated with antiplatelet agents and controls, but there was a signiﬁcant reduction in the risk of delayed cerebral ischemia [197a].

F. Other Strategies to Prevent Delayed Cerebral Ischemia Magnesium levels are decreased in half the patients with subarachnoid hemorrhage who are admitted within 12 hours, and again in half the patients in the period between days 2 and 10 after the hemorrhage [198]. Hypomagnesemia between days 2 and 10 proved an independent predictor for the development of delayed ischemia [198]. Administration of magnesium sulfate is therefore potentially useful for the prevention or treatment of secondary ischemia. Thus far the clinical experience does not extend beyond safety studies [199,200] and a dose ﬁnding study for long-term administration [201]. Other potentially useful drugs that have not been evaluated beyond the stage of safety testing are endothelin receptor antagonists [202] and intraventricular administration of sodium nitroprusside and thiosulfate [203]. Calcitonin gene–related peptide is a potent vasodilatator, but in a randomized clinical trial no eﬀect of this drug was found [204]. Another strategy aimed at reducing the frequency of vasospasm is lysis of the cisternal blood clot with intrathecally administered recombinant tissue plasminogen activator, but a clinical trial in 100 patients failed to show a reduction in the rate of secondary ischemia or poor outcome [205]. Prophylactic transluminal balloon angioplasty has been advocated [206], but there are no controlled studies to support this.

VIII. TREATMENT OF DELAYED CEREBRAL ISCHEMIA Treatment with hypervolemia, hemodilution, and induced hypertension, the so-called triple H therapy, has become widely used, although evidence from clinical trials is still lacking. The risks of deliberately increasing the arterial pressure and plasma volume include rebleeding of an unclipped aneurysm, increased cerebral edema or hemorrhagic transformation in areas of infarction [207], myocardial infarction, and congestive heart failure. Few centers have experience with the endovascular approach in the treatment of symptomatic vasospasm after SAH [208–211]. These reports document sustained improvement in more than half of the cases (the number of patients in these reports ranged between 20 and 50), but the series were uncontrolled and evidently there must be publication bias. Rebleeding can be precipitated by this procedure, even after the aneurysm has been clipped [212]. Hyperperfusion injury has also been reported [213]. In view of the risks, the high costs, and the lack of controlled trials, transluminal angioplasty should presently be regarded as a strictly experimental procedure. The same caution applies to uncontrolled reports of improvement of ischemic deﬁcits after intra-arterial

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infusion of papaverine, following superselective catheterization [214–216]; moreover, not all impressions about the eﬀect of papaverine are positive [217].

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163. Guglielmi G, Vinuela F, Duckwiler G, Dion J, Lylyk P, Berenstein A, Strother C, Graves V, Halbach V, Nichols D, et al. Endovascular treatment of posterior circulation aneurysms by electrothrombosis using electrically detachable coils. J Neurosurg 1992; 77:515–524. 164. Brilstra EH, Rinkel GJE, van der Graaf Y, van Rooij WJJ, Algra A. Treatment of intracranial aneurysms by embolization with coils—a systematic review. Stroke 1999; 30:470– 476. 165. Johnston SC. Combining ecological and individual variables to reduce confounding by indication: case study—subarachnoid hemorrhage treatment. J Clin Epidemiol 2000; 53:1236– 1241. 166. Manabe H, Fujita S, Hatayama T, Suzuki S, Yagihashi S. Rerupture of coil-embolized aneurysm during long-term observation—case report. J Neurosurg 1998; 88:1096–1098. 167. Horowitz MB, Jungreis CA, Genevro J. Delayed rupture of a previously coiled unruptured anterior communicating artery aneurysm: case report. Neurosurgery 2002; 51:804–806. 168. Koivisto T, Vanninen R, Hurskainen H, Saari T, Hernesniemi J, Vapalahti M. Outcomes of early endovascular versus surgical treatment of ruptured cerebral aneurysms—a prospective randomized study. Stroke 2000; 31:2369–2377. 169. Lempert TE, Malek AM, Halbach VV, Phatouros CC, Meyers PM, Dowd CF, Higashida RT. Endovascular treatment of ruptured posterior circulation cerebral aneurysms—clinical and angiographic outcomes. Stroke 2000; 31:100–110. 170. Tateshima S, Murayama Y, Gobin YP, Duckwiler GR, Guglielmi G, Vin˜uela F. Endovascular treatment of basilar tip aneurysms using Guglielmi detachable coils: anatomic and clinical outcomes in 73 patients from a single institution. Neurosurgery 2000; 47:1332– 1339. 171. Uda K, Murayama Y, Gobin YP, Duckwiler GR, Vin˜uela F. Endovascular treatment of basilar artery trunk aneurysms with Guglielmi detachable coils: clinical experience with 41 aneurysms in 39 patients. J Neurosurg 2001; 95:624–632. 172. Tsutsumi K, Ueki K, Usui M, Kwak S, Kirino T. Risk of recurrent subarachnoid hemorrhage after complete obliteration of cerebral aneurysms. Stroke 1998; 29:2511–2513. 173. Byrne JV, Sohn NJ, Molyneux AJ. Five-year experience in using coil embolization for ruptured intracranial aneurysms: outcomes and incidence of late rebleeding. J Neurosurg 1999; 90:656–663. 174. Lusseveld E, Brilstra EH, Nijssen PC, Van Rooij WJ, Sluzewski M, Tulleken CAF, Wijnalda D, Schellens RL, van der GY, Rinkel GJE. Endovascular coiling versus neurosurgical clipping in patients with a ruptured basilar tip aneurysm. J Neurol Neurosurg Psychiatry 2002; 73:591–593. 175. Qureshi Al, Suri MFK, Khan J, Kim SH, Fessler RD, Ringer AJ, Guterman LR, Hopkins LN. Endovascular treatment of intracranial aneurysms by using Guglielmi detachable coils in awake patients: safety and feasibility. J Neurosurg 2001; 94:880–885. 176. Brouwers PJAM, Wijdicks EFM, van Gijn J. Infarction after aneurysm rupture does not depend on distribution or clearance rate of blood. Stroke 1992; 23:374–379. 177. Hop JW, Rinkel GJE. Secondary ischemia after subarachnoid hemorrhage. Cerebrovasc Dis 1996; 6:264–265. 178. Rordorf G, Koroshetz WJ, Copen WA, Gonzalez G, Yamada K, Schaefer PW, Schwamm LH, Ogilvy CS, Sorensen AG. Diﬀusion- and perfusion-weighted imaging in vasospasm after subarachnoid hemorrhage. Stroke 1999; 30:599–605. 179. Vora YY, Suarez-Almazor M, Steinke DE, Martin ML, Findlay JM. Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 1999; 44:1237–1247. 180. Wijdicks EFM, Vermeulen M, Murray GD, Hijdra A, van Gijn J. The eﬀects of treating hypertension following aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 1990; 92:111–117. 181. Chang HS, Hongo K, Nakagawa H. Adverse eﬀects of limited hypotensive anesthesia on the outcome of patients with subarachnoid hemorrhage. J Neurosurg 2000; 92:971–975.

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182. Hasan D, Wijdicks EFM, Vermeulen M. Hyponatremia is associated with cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Ann Neurol 1990; 27:106–108. 183. Vermeij FH, Hasan D, Bijvoet HWC, Avezaat CJJ. Impact of medical treatment on the outcome of patients after aneurysmal subarachnoid hemorrhage. Stroke 1998; 29:924–930. 184. Feigin VL, Rinkel GJE, Algra A, van Gijn J. Circulatory volume expansion for aneurysmal subarachnoid haemorrhage. The Cochrane Library Issue 3, 2000. 185. Egge A, Waterloo K, Sjoholm H, Solberg T, Ingebrigtsen T, Romner B. Prophylactic hyperdynamic postoperative ﬂuid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 2001; 49:593–605. 186. Feigin VL, Rinkel GJE, Algra A, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage (Cochrane Review). The Cochrane Library, 2000. 187. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al. Eﬀect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 1989; 298:636–642. 188. Kassell NF, Haley EC Jr, Apperson-Hansen C, Stat M, Alves WM, Dorsch NW, Fabinyi G, Matheson J, Reilly P, Siu K, Stokes B, Stuart G, Koos W, Calliauw L, Selosse P, Astrup J, Gjerris F, Mendelow AD, Castel JP, Christiaens JL, Cophignon J, Keravel Y, Lagarrigue J, Mourier K. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 1996; 84:221–228. 189. Lanzino G, Kassell NF, Dorsch NWC, Pasqualin A, Brandt L, Schmiedek P, Truskowski LL, Alves WM. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg 1999; 90:1011–1017. 190. Haley EC Jr, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM. A randomized doubleblind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg 1997; 86:467–474. 191. Lanzino G, Kassell NF. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America. J Neurosurg 1999; 90:1018–1024. 192. Asano T, Takakura K, Sano K, Kikuchi H, Nagai H, Saito I, Tamura A, Ochiai C, Sasaki T. Eﬀects of a hydroxyl radical scavenger on delayed ischemic neurological deﬁcits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled doubleblind trial. J Neurosurg 1996; 84:792–803. 193. Saito I, Asano T, Sano K, Takakura K, Abe H, Yoshimoto T, Kikuchi H, Ohta T, Ishibashi S. Neuroprotective eﬀect of an antioxidant, ebselen, in patients with delayed neurological deﬁcits after aneurysmal subarachnoid hemorrhage. Neurosurgery 1998; 42:269–277. 194. Juvela S, Kaste M, Hillbom M. Platelet thromboxane release after subarachnoid hemorrhage and surgery. Stroke 1990; 21:566–571. 195. Ohkuma H, Suzuki S, Kimura M, Sobata E. Role of platelet function in symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 1991; 22:854–859. 196. Juvela S. Aspirin and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Neurosurg 1995; 82:945–952. 197. Hop JW, Rinkel GJE, Algra A, Berkelbach van der Sprenkel JW, van Gijn J. Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Neurology 2000; 54:872– 878. 197a. Dorhout Mees SM, Rinkel GJE, Hop JW, Algra A, van Gijn J. Antiplatelet therapy in aneurysmal subarachnoid hemorrhage: a systematic review. Stroke 2003; 34:2285–2289. 198. Van den Bergh WM, Algra A, Berkelbach van der Sprenkel JW, Tulleken CAF, Rinkel GJE. Hypomagnesemia after aneurysmal subarachnoid hemorrhage. Neurosurgery 2003; 52:276–281. 199. Boet R, Mee E. Magnesium sulfate in the management of patients with Fisher Grade 3 subarachnoid hemorrhage: A pilot study. Neurosurgery 2000; 47:602–606.

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23 Surgical Management of Ruptured Aneurysms Carlo Bortolotti Bellaria Hospital, Bologna, Italy and University of Illinois, Peoria, Illinois, U.S.A.

Giuseppe Lanzino University of Illinois, Peoria, Illinois, U.S.A.

Neal F. Kassell University of Virginia Health Sciences Center, Charlottesville, Virginia, U.S.A.

I. INTRODUCTION Surgical treatment of ruptured intracranial aneurysms has reached a critical stage. With continuous advances in endovascular management and the recent publication of the International Subarachnoid Aneurysm Trial (ISAT) results in The Lancet in October 2002 [1], indications for surgical treatment of ruptured aneurysms are in continuous evolution.

II. THERAPEUTIC STRATEGIES IN RUPTURED ANEURYSMS: SURGICAL OR ENDOVASCULAR TREATMENT? The natural history of untreated ruptured intracranial aneurysms is so poor that conservative management is indicated only in patients with a very poor grade on admission (Grade V) who fail to improve after hemodynamic and systemic stabilization, control of increased intracranial pressure, and external ventricular drainage [2]. With the availability of endovascular techniques, coiling of ruptured intracranial aneurysms has become a valid alternative to surgical clipping in an increasing number of patients with aneurysmal subarachnoid hemorrhage (SAH) [3]. The decision to proceed with endovascular or surgical aneurysm obliteration takes into account multiple factors. The ISAT trial compared neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms. Clinical outcomes were assessed at 2 months and at 1 year. The primary outcome was the proportion of patients with a modiﬁed Rankin scale score of 3–6 (dependency or death) at 1 year. Trial recruitment was stopped early by the steering committee after an interim analysis showed that 23.7% of patients allocated to endovascular treatment were dependent or dead at 1 year compared with 30.6% of patients allocated to surgical treatment ( p = 0.0019). The results of this trial have raised a heated debate, especially in North America. It is conceivable that with further technical advances, an ever-growing number of patients will 551

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likely beneﬁt from endovascular embolization. Surgical clipping, however, still represents the treatment of choice in a signiﬁcant number of patients with ruptured intracranial aneurysms. In the ISAT study, participating centers evaluated a total 9559 patients with proven aneurysmal SAH during the entire duration of the trial. Of these, only 2143 patients were randomized because they were considered to be amenable to either therapeutic modality. Still, there remain a signiﬁcant number of patients with ruptured intracranial aneurysms who will continue to beneﬁt from surgical treatment of a ruptured aneurysm. It is our policy to prefer surgical treatment over endovascular treatment in young patients with aneurysms of the anterior circulation who are in good clinical condition (WFNS grades 1–3) (Fig. 1). In these patients, surgical clipping still oﬀers the best guarantee of permanent aneurysm occlusion and obviates the need for long-term angiographic controls, thus reducing the psychological stress to the patient and the family. In experienced hands, the risk of surgery in ‘‘good-grade,’’ young (<65 years) patients with ruptured anterior circulation aneurysms is probably not diﬀerent from that of endovascular treatment [4]. Middle cerebral artery aneurysms carry a higher risk of incomplete treatment and higher risk of perioperative complications with endovascular techniques. These aneurysms at our institution are almost uniformly treated surgically since perioperative risk associated with clipping of MCA aneurysms is uniformly low except in the giant variety or in calciﬁed aneurysms. We also feel that very small (<5 mm) ruptured aneurysms, not so unusual in the anterior communicating–anterior cerebral artery complex, are more diﬃcult and riskier to treat by endovascular means. In experienced hands, surgery carries a very small risk after clipping of such lesions. We prefer endovascular treatment in patients with basilar artery aneurysms because of the technical diﬃculties associated with treating aneurysms in this location. Endovascular treatment is also preferred in elderly individuals (>65 years) or in patients with signiﬁcant systemic diseases and in poor neurological condition (grades 4–5). Of course, exceptions to these rules are common. It is therefore important that each patient and aneurysm is evaluated by a neurovascular team with neurosurgical and endovascular capabilities and expertise. In such a manner, each patient is oﬀered the best treatment. In some selected cases, the best

Figure 1 (A) Lateral internal carotid artery angiogram showing an elongated aneurysm at the level of the posterior communicating artery take-oﬀ (arrow). (B) Lateral internal carotid artery angiogram after clipping of the aneurysm. A surgical clip is visualized (double arrow). There is no evidence of residual ﬁlling of the aneurysm and no compromise of the parent vessel.

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results can be achieved by a ‘‘staged approach’’ in which each therapeutic modality is used at diﬀerent times. For example, partial aneurysm embolization can be beneﬁcial in poorgrade patients to achieve partial, temporary protection and allow for a more aggressive treatment of vasospasm. In these cases, the dome of the aneurysm (the site most commonly involved by the rupture) can be packed with coils, leaving the area of the aneurysm neck relatively free of coils. Once patients have recovered from the acute phase following SAH, deﬁnitive surgical clipping can be then safely carried out.

III. TIMING OF SURGICAL TREATMENT The primary reason to treat ruptured intracranial aneurysms is to prevent rebleeding. Numerous studies have shown that the risk of rebleeding is highest in the ﬁrst few days following SAH, particularly during the ﬁrst 24 hours. In the Cooperative Study on Timing of Surgery, the risk of rebleeding during the ﬁrst 24 hours was 4% [5,6]. More recent studies which also take into account rebleeding before or during transfer to tertiary referral centers have observed a much higher incidence of rebleeding than originally reported by the Cooperative Aneurysm Study investigators [7,8]. Thus, if surgery to treat a ruptured aneurysm has to be eﬀective in preventing rebleeding, treatment should be instituted as soon as possible. The issue of whether or not to operate acutely on a patient with a ruptured aneurysm has received a lot of attention in the literature [9–12]. In the past, some surgeons advocated a uniform policy of ‘‘delayed’’ surgery because of concerns regarding the risk and diﬃculty of operating on a tight, swollen brain. However, with this ‘‘delayed’’ philosophy patients often suﬀered death and disability secondary to rebleeding. In addition, without securing the aneurysm, measures to counteract vasospasm, in particular increasing perfusion pressure, could not be eﬃciently implemented for fear of facilitating the aneurysm’s rerupture. In order to answer the question of whether to operate early or in a delayed fashion for ruptured intracranial aneurysms, a large, multicenter observational study, The International Study on Timing of Aneurysm Surgery, was launched worldwide in the early 1980s. In 2 years, the study enrolled 3521 patients in 68 centers in 14 diﬀerent countries. Neurosurgeons were required to indicate their plan of treatment in regard to the timing of treatment at the time of patient admission (0–3, 4–6, 7–10, 11–14, and 15–32 days). The overall results of the study indicated that the outcome of patients undergoing ‘‘early’’ treatment (0–3 days) was not signiﬁcantly diﬀerent from the outcome of patients undergoing ‘‘delayed’’ surgery (>10 days). At 6 months the percentage of patients achieving good results was 63% and 62%, respectively. However, when the subgroup of patients treated in North American centers was considered [13], patients undergoing early surgery had a better outcome than patients undergoing delayed surgery (70.9% and 62.9% had a good result, respectively). These improved results in North American centers were correlated with a more aggressive management of vasospasm after securing the aneurysm in patients undergoing early surgery. Following the International Study on Timing of Surgery, a policy of early surgery has been adopted worldwide by most centers and today most patients with ruptured aneurysms are treated within a few hours after admission to tertiary referral centers [14]. Yet, a cooperative study performed in The Netherlands in the late 1990s [15] showed that rebleeding still remains the main cause of poor outcome even in centers adopting a policy of early surgery. The importance of prompt aneurysm treatment in preventing rebleeding

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was also stressed by a recent observation of the ISAT trial. In that study there was a slight diﬀerence in the time between randomization and the ﬁrst procedure in the two groups (endovascular versus conventional surgery). In patients who were allocated to endovascular treatment, the mean interval from randomization to treatment was 1.1 days, and for those allocated to neurosurgery the mean interval was 1.7 days. Despite this small diﬀerence (0.6 days), there was a signiﬁcant diﬀerence in the number of patients who suﬀered a rebleed while awaiting treatment (14 with 7 deaths in the endovascular treatment and 23 with 16 deaths in the surgical group). These observations suggest that in order to maximize the beneﬁts of surgical clipping of ruptured aneurysms, treatment should be instituted as soon as possible whenever feasible. It is our policy to operate on patients on the day of admission to our hospital. However, patients admitted in the late afternoon hours, especially if technically challenging lesions are present, usually are scheduled for surgery the following day. While waiting for surgery and often before transfer to our hospital, we start intravenous tranexamic acid (1 g every 6 hours) since a recent report from Sweden [16] suggests that intravenous tranexamic acid given to patients immediately after a diagnosis of SAH is made and continued for a few doses until early aneurysm treatment halves the risk of rebleeding without signiﬁcantly increasing the risk of delayed cerebral ischemia from vasospasm.

IV. ANESTHESIA Preparation for surgery and neuroanesthesia of patients harboring ruptured intracranial aneurysms presents numerous challenges. The goals of anesthesia in this situation are to limit the risk of aneurysm rupture, prevent cerebral ischemia and facilitate surgical intervention. During induction of anesthesia, a balance must be achieved between minimizing the transmural pressure (diﬀerence between the mean arterial pressure and intracranial pressure) across the aneurysm wall to avoid rebleeding and maintaining an adequate cerebral perfusion pressure. This balance can be readily achieved in a patient without signiﬁcant neurological compromise, but becomes a great challenge in a patient with a compromised neurological status and with hemodynamic instability. During surgery the goals of anesthesia are to provide adequate analgesia, favor brain relaxation, maintain an adequate cerebral perfusion pressure while reducing transmural pressure across the aneurysm wall during the period of exposure and clipping of the aneurysm, and allow prompt awakening and neurological evaluation of patients after surgery. It is important that patients are in a deep anesthetic state before the pins of the Mayﬁeld device are applied for head ﬁxation. This avoids a pain-induced hypertensive spike, which may facilitate aneurysm rupture. Controlled hyperventilation and osmotic diuretics decrease brain swelling and minimize the need for brain retraction. For this purpose, preoperative insertion of a lumbar drain, whenever safe, facilitates drainage of cerebrospinal ﬂuid increasing brain relaxation. The same goal can be achieved through the placement of a ventricular catheter. Lumbar drainage is contraindicated in patients with intracranial hematomas and mass eﬀect because of the risk of facilitating uncal herniation [17]. During exposure of the aneurysm, mild induced hypotension may help in ‘‘softening’’ the aneurysm and makes intraoperative rupture easier to control. With the availability of temporary clipping, however, we have abandoned the use of induced hypotension as an aid during dissection of the aneurysm because of the risk that even a short period of hypotension

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in the setting of SAH might increase the risk of delayed cerebral ischemia from vasospasm [18]. If temporary clipping of the parent vessel is utilized, it is helpful to artiﬁcially increase the systemic blood pressure with the goal of maximizing perfusion of the ischemic areas through preexisting collateral channels while temporary clipping is maintained. During temporary clipping, administration of ‘‘brain-protective’’ agents such as barbiturates can be helpful in minimizing the risk of brain injury from ischemic insult. The utility of induced intraoperative hypothermia to lower ischemic consequences of aneurysm surgery currently is being tested.

V. OPERATIVE TECHNIQUE A. Skin Incision and Surgical Approach Diﬀerent types of skin incision and approaches can be used for the treatment of saccular ruptured intracranial aneurysms. Most aneurysms, however, involving either the anterior or posterior circulation can be treated using a pterional craniotomy with minor modiﬁcations of this standard approach. The most common modiﬁcations of this approach involve partial or complete removal of the orbitozygomatic rim to minimize brain retraction and increase the angle of exposure. Skull base approaches such as the orbitozygomatic one become of critical importance in the exposure of complex, giant aneurysms of the paraclinoid carotid or the region of the basilar apex. In such cases, the view through which the surgeon operates can be enlarged by extensive bone removal, thus minimizing the need for brain retraction [19,20]. Once the craniotomy is completed and the bone ﬂap elevated, special care is taken to obtain careful hemostasis. Additional space in the standard pterional approach can be gained by drilling the sphenoid ridge. In the case of anterior communicating aneurysms, drilling to ﬂatten the rough surface of the anterior cranial fossa at the level of the orbital roof also improves the aneurysm’s exposure. A clear and clean ﬁeld is a prerequisite for adequate visualization of the aneurysm. After opening the dura, the brain is exposed. The brain surface often appears quite red and swollen because of the presence of subarachnoid blood. Small extravasation of blood through the subarachnoid space with small subdural hematomas at times so small as not to be visualized on the preoperative CT scan are sometimes encountered. B. Intradural Portion Minimizing brain retraction in acute aneurysm surgery is of utmost importance. Careful handling of the brain tissue reduces the risk of additional damage. Drilling of bone or bone removal, administration of osmotic diuretics, hyperventilation, and drainage of cerebrospinal ﬂuid are maneuvers helpful in achieving this goal. However, there is no substitute for careful, delicate microsurgical technique. Once the dura is opened, the remaining portion of the intradural procedure is done with the magniﬁcation and increased illumination provided by the surgical microscope. The introduction and widespread acceptance of microsurgical techniques in the late 1960s for the treatment of intracranial aneurysm as popularized by Yasargil and Drake [21,22] has represented a landmark step in the surgical treatment of intracranial aneurysms. This technical innovation has both increased the safety and dramatically improved the results of this delicate and challenging surgical act.

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After opening the dura, ‘‘splitting’’ of the Sylvian ﬁssure allows for separation of the frontal and temporal lobes reducing the degree of traction/retraction of these structures and facilitating exposure of the middle cerebral artery and the carotid bifurcation. Opening of the subarachnoid cisterns at the base of the brain allows for additional drainage of cerebrospinal ﬂuid, often inducing a signiﬁcant degree of brain relaxation. An additional maneuver that greatly facilitates drainage of cerebrospinal ﬂuid from the ventricular system is the opening of the lamina terminalis. Opening of the lamina terminalis, a thin layer of gray matter covered by pia mater that forms the anterior wall of the third ventricle, during surgery for ruptured intracranial aneurysms also seems to reduce the incidence of shunt dependent hydrocephalus after SAH [23,24]. It is therefore our opinion that this straightforward microsurgical maneuver should be performed whenever possible during aneurysm surgery. Once adequate brain relaxation is achieved, the brain surface is protected and a brain retractor is used to gently retract the brain and increase the working space at the base of the brain. C. Obtaining Proximal Control and Temporary Clipping One of the basic principles underlying aneurysm surgery, especially in the case of a freshly ruptured aneurysm, is to obtain ‘‘proximal control.’’ In other words, the vessel from which the aneurysm is arising is exposed proximally, and, if intraoperative aneurysm rupture occurs, it can be temporarily occluded. This maneuver decreases the amount of blood ﬂowing throuh the ruptured aneurysm facilitating control of the rupture, visualization of the surrounding structures, and safer clipping of the aneurysm. In some cases of aneurysms located in the paraclinoid segment of the carotid artery, it is technically diﬃcult to obtain control of the parent vessel immediately proximal to the aneurysm. In such cases it may be indicated to expose the carotid in the neck and temporarily occlude the vessel in the neck in case of intraoperative aneurysm rupture. An alternative technique, primarily utilized in the case of giant aneurysms of the paraclinoid carotid artery, is to place a balloon catheter in the cervical internal carotid artery while the patient is under general anesthesia. Once the carotid artery distal to the aneurysm is identiﬁed and temporarily occluded, the balloon is inﬂated while blood is simultaneously aspirated through the catheter with consequent aneurysm collapse. This technique facilitates clipping of these challenging lesions but bears the risk of some complications primarily intraoperative thromboembolism from the balloon catheter and vessel wall dissection. Cardiocirculatory arrest, used in some challenging large or giant aneurysms especially involving the posterior circulation as an extreme form of ‘‘proximal control,’’ is rarely employed in the case of a freshly ruptured aneurysm primarily because of the risk that the protracted hypotension adds to the possibility of symptomatic vasospasm. Once proximal control is obtained, the aneurysm is identiﬁed and carefully dissected. Complete dissection of the aneurysm and identiﬁcation of surrounding structures is of paramount importance for an eﬀective and safe exclusion of the aneurysm from the circulation. In the setting of a ruptured aneurysm, this portion of the procedure is complicated by the presence of tenacious clot around the aneurysm, which makes the dissection tedious and the surrounding branches diﬃcult to visualize. In some cases, temporary clipping of the inﬂow and outﬂow vessels is a great aid in facilitating aneurysm dissection in the late parts of this stage. Temporary arterial clipping is a well-established technique in intracranial aneurysm surgery particularly useful in the presence of larger and broad-based aneurysms, which quite often are tenaciously adherent

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to the eﬀerent and/or perforating vessels. Temporary clipping involves temporary occlusion of the feeding vessels in an attempt to ‘‘soften’’ the aneurysm and decrease the amount of bleeding in case of aneurysm’s rupture. At times, when complete arrest of blood ﬂow to the aneurysm is the goal, temporary clipping of the eﬀerent vessels might be used. During temporary clipping, dissection of the aneurysm from the surrounding brain parenchyma and careful separation of the aneurysm from any adjacent vessel often intimately attached to it is ﬁnalized. Particular attention and care is given to separation of the aneurysm from tiny perforating vessels. This is especially critical in particular aneurysm locations such as the basilar bifurcation, the anterior cerebral-anterior communicating complex, the middle cerebral artery, and the carotid bifurcation. Temporary clipping is performed using clips that have less closing force than permanent clips, which are used to permanently occlude the aneurysm. The smaller closing force of temporary clips minimizes the risk of causing damage to the vessel wall while still allowing temporary occlusion of the vessel. Although some surgeons recommend mandatory temporary clipping in any aneurysm case, we use temporary clipping as indicated and required by the particular situations of the operation. There is controversy as to the best technique to use temporary clipping, with some authors advocating continuous periods of temporary occlusion up to a variable period of time and others suggesting that it is safer to perform numerous periods of temporary clipping separated by brief periods of reperfusion. Temporary clipping is not without shortcomings. In addition to creating a temporary situation of decreased regional cerebral blood ﬂow, there is also the danger of fracturing atherosclerotic plaques (often present in proximity to aneurysms in older individuals) and dislodging distal emboli. This might explain why some patients wake up with neurological deﬁcits in the territory of the temporary clipped vessels even after a very short period of temporary clipping. Despite these shortcomings, temporary clipping is an invaluable tool, especially in the case of challenging aneurysms where isolation of the aneurysm from small perforating vessels is critical before proceeding with permanent clipping. Temporary clipping is also critical in the presence of giant aneurysms. In such cases, after temporary clipping of the aﬀerent and eﬀerent vessels, the aneurysm sac often needs to be open, thrombus within the aneurysm evacuated, and the neck freed from any calcium/atherosclerotic plaque before reconstruction of the aneurysm neck and aneurysm occlusion is performed with a variety of clip techniques. Once the aneurysm sac is completely isolated from the surrounding vessels and all of the vessels around the aneurysm are identiﬁed and separated, permanent clipping is then carried out (Fig. 2). D. Intraoperative Angiography The goal of aneurysm surgery is to eﬀectively exclude the aneurysm from the circulation while avoiding any compromise of the surrounding vessels. In the past decade, with improvements in diagnostic capabilities, a number of centers specializing in the treatment of cerebrovascular diseases have proposed the use of intraoperative angiography. The aim of this kind of procedure is to get intraoperative ‘‘feedback’’ of the vascular anatomy and aneurysm degree of exclusion (Fig. 3). In case of compromise of the parent/eﬀerent-vessels complex or aneurysm residual, the clip can be immediately replaced. Although the quality of the image obtained in the operating room environment using C-arm technology is not quite as good as that of a routine angiogram done in the angiography suite, it is usually possible to obtain a picture good enough to make proper intraoperative decisions and to

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Figure 2 (A) Intraoperative view of the aneurysm in Figure 1. The aneurysm (A) arises from the internal carotid artery (ICA). The optic nerve (ON) is also visualized medial to the ICA. (B) Surgical clip and distal portion of a clip-applier. The blades of the clip can be open by applying pressure on the clip head with the applier. (C) Intraoperative view after clipping of the aneurysm.

assess vessel patency and aneurysm exclusion. The resolution of current intraoperative angiograms, however, does not allow assessment regarding possible compromise of small perforating vessels. Recently, two large studies [25,26] have addressed the usefulness, safety, and feasibility of intraoperative angiography. In these studies the intraoperative angiogram disclosed parent vessel and/or branch occlusion requiring clip repositioning in a percentage of patients as high as 12%. The rate of clip revision can be as high as 22–29% if large and giant aneurysms alone are considered. When an eﬃcient team is available, the intraoperative angiogram does not add signiﬁcantly to the operative time. In line with our own experience, in both above-mentioned studies the additional time required to conduct intraoperative angiography was approximately 20 minutes. Although it is not cost-eﬀective to obtain a routine intraoperative angiogram, there are certain locations (AcoA, MCA, paraclinoid internal carotid artery) where this study is more useful, suggesting that a policy of ‘‘selective’’ intraoperative angiography might be indicated when intraoperative diﬃculties are anticipated on the basis of aneurysm location, size, shape, orientation, and relationship to surrounding vascular and bony structures. The complication rate related to this procedure is less than 1%.

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Figure 3 (A) Selective internal carotid artery angiogram of a patient with a giant left ICA bifurcation aneurysm. (B) Immediately after clipping an intraoperative angiogram is obtained to conﬁrm exclusion of the aneurysm and patency of the parent vessels.

VI. SPECIAL SITUATIONS A. Combined Surgical-Endovascular Techniques In selected cases, embolization and surgery can be used as complementary therapeutic techniques. For instance, in poor-grade patients, embolization of the aneurysm can be attempted with the goal of achieving safe and partial aneurysm occlusion. Even partial coil embolization signiﬁcantly decreases the risk of aneurysm rupture in the acute phase. Once partial aneurysm obliteration is accomplished, vasospasm can be aggressively treated if needed by using hyperdynamic therapy and angioplasty if necessary. After the patient’s condition has stabilized, the aneurysm can be treated with surgical clipping if persistent ﬁlling is found on follow-up angiography. A second coil embolization should be considered riskier than surgical treatment. Surgical clipping of previously coiled aneurysms is challenging. However, if the coils are within the aneurysmal sac and not located in the neck portion, surgical clipping usually can be performed safely without the need for opening the aneurysm sac and removing the coils. A ‘‘combined’’ approach is also useful in some cases of wide-neck and/or giant aneurysms. In such a situation, if neither primary embolization or complete surgical exclusion can be safely and eﬀectively achieved, then partial clipping of the aneurysm can be pursued to transform a giant wide-necked aneurysm into a giant aneurysm with a smaller neck. Subsequent coil embolization with complete exclusion of the aneurysm can then be accomplished. B. Ruptured Aneurysms Presenting with Intracranial Hematoma and Mass Effect Aneurysms causing intracranial hematoma with mass eﬀect pose particular problems. In some cases the patient’s neurological status is severely compromised because of the mass eﬀect caused by the hematoma, and emergency surgical evacuation may be needed to release the mass eﬀect (Fig. 4). In such a circumstance, obtaining an angiogram can be

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Figure 4 CT scan of the brain without contrast shows the presence of a large intracerebral hematoma in the right temporal lobe with mass eﬀect and midline shift. The hematoma was caused by a ruptured posterior communicating artery aneurysm.

time consuming, and surgical evacuation is often carried out without a conﬁrmatory angiography even when the presence of an aneurysm is strongly suspected on the basis of the CT scan. Associated SAH, origin of the hemorrhage from the base of the interhemispheric ﬁssure (ruptured anterior communicating aneurysms) or the Sylvian ﬁssure (ruptured middle cerebral artery aneurysms) are CT ﬁndings strongly suggestive of a ruptured aneurysm in a patient with an intraparenchymal hematoma. A CT angiogram done in concomitance with the diagnostic CT scan may, in some of these cases, eliminate the need for a cerebral angiogram by showing a possible underlying aneurysm. In these cases, hematoma evacuation takes priority. An associated aneurysm can be surgically occluded in the same setting. C. Giant Aneurysms Very large aneurysms pose increased technical diﬃculties. Some authors suggest a policy of delayed surgical treatment because of the intrinsic diﬃculties associated with surgical treatment of these lesions in the ﬁrst days following SAH. One report suggested that ruptured giant aneurysms have the same rate of rebleeding as smaller ones [27,28]. However, patients included in that study were all stable enough to be transferred to a tertiary referral center. Our anecdotal observation is that giant aneurysms are more likely to rebleed in the acute phase, probably because of the hemodynamics of these challenging lesions (Fig. 5). It is our policy to treat giant ruptured aneurysms as soon as a patient is medically stable on a semiurgent basis (the following day for patients admitted in the afternoon or evening).

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Figure 5 (A) Right selective carotid artery angiogram showing a giant aneurysm of the paraclinoid carotid artery. The ‘‘jet’’ of blood directed against the aneurysm sac is clearly visualized (arrow). It has been our anecdotal experience that, once ruptured, giant aneurysms have a higher tendency to rebleed than smaller aneurysms. This 74-year old female suﬀered a massive rebleeding while awaiting treatment of her aneurysm. (B) CT scan of the brain without contrast shows the giant aneurysm with diﬀuse subarachnoid hemorrhage and massive hydrocephalus after rebleeding.

D. Wrapping There are a few cases where the aneurysm cannot be satisfactorily and safely clipped. Wrapping of the aneurysm is then achieved by ‘‘coating’’ the sac of the aneurysm with muslin gauze or similar substances. Aneurysm wrapping as primary treatment of the aneurysm has become a less common treatment with better clip design and the availability of endovascular techniques. Yet there are still some situations in which this technique represents a compromise when an aneurysm that has been exposed surgically is deemed not to be ‘‘clippable.’’ Wrapping, although not as eﬀective as clipping, has been shown to reduce the rate of rebleeding in the ﬁrst 6 months after the period of maximal risk (2 weeks) has elapsed [29]. The mechanism by which wrapping reduces the incidence of early rebleeding in the ﬁrst 6 months is probably by triggering a reactive, inﬂammatory reaction that reinforces the aneurysm’s wall. Situations in which wrapping is still useful include dissecting aneurysms and aneurysms that are so small they will not ‘‘accept’’ a clip.

VII. CONCLUSION With continuous advances in neuroendovascular techniques, indications for surgical treatment of ruptured aneurysms are likely to continue to evolve in the near future.

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However, a signiﬁcant number of patients with ruptured intracranial aneurysms still continue to beneﬁt from surgical treatment. In order to optimize the beneﬁts of each type of treatment (surgical or endovascular), patients with ruptured aneurysms should be evaluated by a neurovascular team capable of oﬀering, without any bias, diﬀerent therapeutic options. Treatment should then be tailored to the speciﬁc needs of the individual patient.

REFERENCES 1. Malyneux A, Kerr R, Stratton I, Sandercook P, Clarke M, Shrimpton J, Holman R. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. Lancet 2002; 360:1267–1274. 2. Sundt TM Jr, Kobayashi S, Fode NC, Whisnant JP. Results and complications of surgical management of 809 intracranial aneurysms in 722 cases: related and unrelated to grade of patient, type of aneurysm, and timing of surgery. J Neurosurg 1982; 56:753–765. 3. Lanzino G, Guterman, LR, Hopkins LN. Endovascular treatment of aneurysms. In: Winn HR, ed. Youmans Neurological Surgery. 5th ed. Philadelphia: Saunders, 2003:2057–2078. 4. Brilstra EH, Algra A, Rinkel GJ, Tulleken CA, van Gijn J. Eﬀectiveness of neurosurgical clip application in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 2002; 97:1036– 1041. 5. Kassell NF, Torner JC, Haley EC, Jane JA, Adams HP, Kongable GL, et al. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall management results. J Neurosurg 1990; 73:18–36. 6. Kassell NF, Torner JC, Jane JA, Haley EC, Adams HP, et al. The International Cooperative Study on the Timing of the Aneurysm Surgery. Part 2: surgical results. J Neurosurg 1990; 73:37–47. 7. Brilstra EH, Rinkel GJE, Algra A, van Gijn J. Rebleeding, secondary ischemia, and timing of operation in patients with subarachnoid hemorrhage. Neurology 2000; 55:1656–1660. 8. Ohkuma H, Tsurutani H, Suzuki S. Incidence and signiﬁcance of early aneurysmal rebleeding before neurosurgical or neurological management. Stroke 2001; 32:1176–1180. 9. Lanzino G, Shaﬀrey ME, Shaﬀrey CI, Henson S, Kassell NF. Aneurysm surgery: timing. In: Batjer HH, ed. Cerebrovascular Disease. Philadelphia: Lippincott-Raven, 1997:1093–1102. 10. Lanzino G, Kassell NF. Surgical treatment of the ruptured aneurysm: timing. Neurosurg Clin North Am 1998; 9:541–548. 11. Ross N, Hutchinson PJ, Seeley H, Kirkpatrick PJ. Timing of surgery for supratentorial aneurysmal subarachnoid haemorrhage: report of a prospective study. J Neurol Neurosurg Psychiatry 2002; 72:480–484. 12. Lanzino G, Andreoli A, Limoni P, Tognetti F, Testa C. Vertebro-basilar aneurysms: does delayed surgery represent the best surgical strategy? Acta Neurochir (Wien) 1993; 125:5–8. 13. Haley EC, Kassel NF, Torner JC, et al. The International Cooperative Study on the Timing of the Aneurysm Surgery. The North American Experience. Stroke 1992; 23:205–214. 14. Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002; 97:247–249. 15. Roos YBWEM, de Haan RJ, Beenen LFM, Groen RJM, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in The Netherlands. J Neurol Neurosurg Psychiatry 2000; 68:337– 341. 16. Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002; 97:771–778. 17. Dangor AA, Lam AM. Anesthesia for cerebral aneurysm surgery. Neurosurg Clin North Am 1998; 9:647–660.

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18. Chang HS, Hongo K, Nakagawa H. Adverse eﬀects of limited hypotensive anesthesia on the outcome of patients with subarachnoid hemorrhage. J Neurosurg 2000; 92:971–975. 19. Gonzalez LF, Crawford NR, Horgan MA, Deshm ukh P, Zabramski JM, Spetzler RF. Working area and angle of attack in three cranial base approaches: pterional, orbitozygomatic, and maxillary extension of the orbitozygomatic approach. Neurosurgery 2002; 50:550–555. 20. Andaluz N, Van Loveren HR, Keller JT, Zuccarello M. Anatomic and clinical study of the orbitopterional approach to anterior communicating artery aneurysms. Neurosurgery 2003; 52:1140–1148. 21. Yasargil MG. Intracranial microsurgery. Clin Neurosurg 1970; 17:250–256. 22. Drake CG. On the surgical treatment of ruptured intracranial aneurysms. Clin Neurosurg 1965; 13:122–155. 23. Komotar RJ, Olivi A, Rigamonti D, Tamargo RJ. Microsurgical fenestration of the lamina terminalis reduces the incidence of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery 2002; 51:1403–1413. 24. Tomasello F, d’Avella D, de Divitiis O. Does the lamina terminalis fenestration reduce the incidence of chronic hydrocephalus after subarachnoid hemorrhage? Neurosurgery 1999; 45:827–832. 25. Chiang VL, Gailloud P, Murphy KJ, Rigamonti D, Tamargo RJ. Routine intraoperative angiography during aneurysm surgery. J Neurosurg 2002; 96:988–992. 26. Tang G, Cawley CM, Dion JE, Barrow DL. Intraoperative angiography during aneurysm surgery; a prospective evaluation of eﬃcacy. J Neurosurg 2002; 96:993–999. 27. Khurana VG, Piepgras DG, Whisnant JP. Ruptured giant intracranial aneurysms. Part I. A study of rebleeding. J Neurosurg 1998; 88:425–429. 28. Piepgras DG, Khurana VG, Whisnant JP. Ruptured giant intracranial aneurysms. Part II. A retrospective analysis of timing and outcome of surgical treatment. J Neurosurg 1998; 88:430– 435. 29. Todd NV, Tocher JL, Jones PA, Miller JD. Outcome following aneurysm wrapping: a 10-year follow-up review of clipped and wrapped aneurysms. J Neurosurg 1989; 70:841–846.

24 Management of Patients with Unruptured Intracranial Aneurysms David O. Wiebers, M.D. Mayo Clinic and Mayo Medical School, Rochester, Minnesota, U.S.A.

Intracranial aneurysms usually go undetected until spontaneous rupture results in a clinical picture of subarachnoid hemorrhage (SAH), intracerebral hemorrhage, or both. However, in some cases, an aneurysm is diagnosed before rupture based upon clinical features unrelated to intracranial hemorrhage or unruptured aneurysms are discovered while investigating a patient with SAH from another source. Alternatively, the diagnosis may be fortuitous, often the result of performing cerebral angiography for an unrelated disorder. The question of how patients with unruptured aneurysms should be managed remains controversial, but certain guidelines can be developed based on available data concerning the natural history, pathogenesis, and surgical morbidity and mortality for these lesions. Unruptured intracranial aneurysms (UIAs) constitute a signiﬁcant public health problem. Several autopsy studies have shown a wide range of overall frequency (0.2– 9.9%) [1–6] for intracranial aneurysms in the general population, with the more recent prospective autopsy and angiographic studies indicating an overall frequency of approximately 3–6% [7]. These data imply that UIAs will aﬀect an estimated 12 million persons in the United States at some point during their lives. The mean age of the population is increasing, and intracranial aneurysms appear to develop with increasing age [8]. The incidence of SAH from an intracranial aneurysm also increases progressively with age [9]. In recent years, the wide use of computed tomography (CT) and magnetic resonance (MR) imaging procedures has greatly increased the numbers of aneurysms discovered incidentally, making the management of these patients increasingly relevant. Subarachnoid hemorrhage from ruptured intracranial aneurysm aﬀects an estimated 22,000 patients per year in the United States, and despite signiﬁcant declines in the overall stroke incidence over the past 45 years [10,11], the incidence of SAH has not declined [12,13]. Saccular (berry) aneurysms account for 80–90% of all intracranial aneurysms and normally appear as small rounded dilatations, but other shapes (sessile, pedunculated, multilobed) are also seen. Approximately 20% of patients with saccular aneurysms have a family history of SAH or intracranial aneurysm, and multiple aneurysms are found in 20– 25% of patients [70]. Other medical conditions that have been associated with intracranial aneurysms include polycystic kidney disease (PKD) [14,15], coarctation of the aorta [16,17], Marfan syndrome [18], Ehlers-Danlos syndrome [19,20], ﬁbromuscular dysplasia [21–24], pseudoxanthoma elasticum [25], moyamoya disease [26–30] pituitary tumors [6] and arteriovenous malformations (AVMs) [6,31–35]. 565

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I. PATHOGENESIS The pathogenesis of intracranial aneurysms has long been a subject of great controversy. The medial defect theory was formally introduced by Eppinger [36] and later developed by Forbus [37], who believed that aneurysms were acquired lesions resulting from degeneration of the elastic membrane because of continued overstretching of this membrane, with an underlying congenital defect in the muscularis portion of the arterial wall. Given the relative ubiquity of medical defects in the general population, Glynn [38] later proposed that the most important factor in producing saccular aneurysms was degeneration of the internal elastic lamina, possibly caused by atherosclerosis. He suggested that both congenital medical defects and acquired internal elastic lamina defects had to be present before cerebral aneurysms formed. Subsequently, Stehbens [17] found that the frequency of medical defects increased with age and, consequently, suggested that they were not congenital. He also found that the distribution in nature of these defects was inconsistent with the frequency of distribution of berry aneurysms in humans and other animals. It was his opinion that the defects were involved fortuitously, and that thinning of the arterial wall was an acquired early change associated with degeneration of cells in the elastica as well as of muscle cells in the intracellular matrix. The increase in incidence rates of aneurysmal hemorrhage with increasing age and several other clinical observations suggest that aneurysms are not congenital [8,9], although this does not preclude a congenital predisposition. Several environmental factors have been implicated on intuitive and experimental grounds as playing a signiﬁcant role in the development of intracranial aneurysms. Most of these include increased hemodynamic stress in the form of systemic hypertension [39–42], focal increases in blood ﬂow such as those from contralateral carotid occlusion [43], and atherosclerosis [38]. However, other clinical studies have failed to show a correlation between hypertension and aneurysmal SAH or the discovery of UIAs [8,9,44,45]. Other structural arterial defects have also been proposed, largely on the basis of associated diseases, such as Marfan syndrome, pseudoxanthoma elasticum, and EhlersDanlos syndrome.

II. GROWTH AND RUPTURE OF ANEURYSMS As with the origin of intracranial saccular aneurysms, there is great controversy about the mechanisms involved in their subsequent growth and rupture. The understanding of such mechanisms is necessary to optimize management of patients with unruptured aneurysms. The risk of cerebral angiography has limited serial angiographic studies of unruptured aneurysms. The scant information that is available [46–48] seems to indicate wide variability in the growth rate of individual aneurysms. Angiographic and clinical evidence seems to suggest that, whereas some aneurysms may increase in size over several years, others may enlarge considerably in hours to weeks or may decrease in size or spontaneously obliterate. The increasing quality of noninvasive techniques including CT angiography (CTA) and MR angiography (MRA) provides increasing opportunities to learn more about the growth of intracranial aneurysms without substantial risk to the patient. Several experimental in vitro studies and in vivo clinical observations have implicated intramural hemodynamic factors and, to a lesser extent, extramural physical factors in the growth of intracranial aneurysms.

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Among the intrinsic factors, hemodynamic stresses and pulsatile ﬂow patterns have been implicated [37,49,50]. It has been demonstrated experimentally that hydrostatic pressure is greater at the apices of arterial bifurcations than at other angles of the bifurcation or other places along the artery [37] and that it increases with increasing angles of bifurcation and also with increasing blood pressure and blood ﬂow. Dissipation of energy at the apex of a bifurcation has been thought to be a factor in the origin and growth of aneurysms, because this is the place at which aneurysms often occur in the arterial tree. Some clinical evidence that pulsatile ﬂow is a factor in rupture of an aneurysm can be derived from Jain’s study [49] of 18 instances of rupture when more than one aneurysm was located along the same artery. In these cases, the proximal aneurysm ruptured in 12 patients and was trombosed in the 6 other patients in whom the distal aneurysm ruptured. The importance of turbulence in relation to growth of aneurysms has also been emphasized. Foreman and Hutchison [51] showed that normal blood ﬂow through stenotic arteries induced peaks of vibration that coincided with the natural resonant frequencies of the vessel walls. Musical high-pitched bruits have been recorded at surgery from intracranial aneurysms. Ferguson [52,53] suggested that if vibrations produced by turbulence occur at the resonant frequency of the arterial wall, structural fatigue results. This process could lead to weakening of the wall of an aneurysm, with subsequent enlargement or rupture. Other potential mechanisms for these bruits include aneurysmal oscillation, Helmholtz resonation, or hydrodynamic whistle [54,55]. Experimentally, Scott et al. [56] found that the distensibility curves of cerebral aneurysms changed abruptly after the aneurysm was subjected three times to pressure of 200 mmHg, and the arteries became brittle. Since the walls of large aneurysms are usually thicker, it has been reasoned that these aneurysms are less likely to rupture. This has been countered by more recent clinical evidence demonstrating that larger aneurysms are more likely to rupture [45,57], making less clear the importance of aneurysm wall elasticity for determining future rupture. Another situation that emphasizes the potential importance of hemodynamic stresses on the origin and growth of aneurysms is the coexistence of intracranial aneurysms and AVMs. In this circumstance, the aneurysms tend to form on the arteries feeding the AVM, and higher rates of blood ﬂow through the AVM have been correlated with enlargement of the associated aneurysm [58]. However, recent data involving unruptured AVMs and aneurysms [33,34] showed aneurysms occurring in similar percentages of patients with small, medium, and large AVMs and in similar percentages of patients with high-ﬂow, highshunt, low-ﬂow, and low-shunt AVMs. These data suggest that the mechanism by which AVMs predispose to aneurysm formation within AVM-feeding systems is not simply based on the high blood ﬂow or high shunt in these systems. Certain extrinsic factors in the environment of an aneurysm may also aﬀect its growth. Supporting evidence is anecdotal, such as the case report by Scanarini et al. [59] concerning a patient who had enlargement of a middle cerebral artery saccular aneurysm after removal of part of an adjacent temporal lobe with evacuation of an intracerebral hematoma. It is possible that creation of a space around the aneurysm by temporal lobectomy directly contributes to growth of the aneurysm in such patients. It has also been postulated that ophthalmic and cavernous segment internal carotid aneurysms are more likely to become giant aneurysms because some protection is aﬀorded against rupture by the anterior clinoid process and dura of the cavernous sinus [60]. More recently, increased emphasis has been placed upon the perianeurysmal environment as a predictor of aneurysmal natural history [61–63]. More speciﬁcally, these investigators call attention to various elements bounding the subarachnoid space including bone,

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brain, and dura, as well as elements traversing the subarachnoid space including arachnoid villae, cranial nerves, and blood vessels, and point out that the number and nature of the structures that an aneurysm will encounter and develop contacts with is dependent upon the location of the aneurysm [63]. It is recognized that compact constraints established between an aneurysm and its environment could inﬂuence aneurysm either positively or negatively, oﬀering either protection against rupture or, on the contrary, added propensity to rupture [63]. These authors use this speciﬁc example of posterior communicating artery aneurysms, indicating that this location appears to be one that would, for a variety of reasons, add to the likelihood of rupture on the basis of external factors. Also in recent years, the scientiﬁc and engineering tool of computational ﬂuid dynamics has been proposed as a means of evaluating individual aneurysmal circumstances which could add to predicting propensity for future rupture [65,66]. This technique of mathematical modeling has the potential to investigate and evaluate a number of hemodynamic factors that may lead to aneurysm formation, enlargement thrombosis, and rupture including sheer wall stress, pressure and mural stress, impingement force, ﬂow rate, and residence time. However, additional research will be required to assess the relative importance of these factors as well as how they might interact and relate to other factors such as vessel geometry [65,66]. A postmortem study [64] in which patients died within 3 weeks after hemorrhage from a ruptured aneurysm has shown that a new protective layer with ﬁbrin as its main component is formed soon after the rupture. This newly formed protective layer is relatively weak in the early stage (the ﬁrst 3 weeks), during which time the danger of recurrent bleeding is very high. After 3 weeks the new wall is reinforced and thickened by capillary proliferation and by resorption of recurrent minor bleeding from these capillaries within the new wall. However, capillary proliferation may also lead to the formation of new potential points of rupture. These factors may account for substantial diﬀerences in the potential for growth and rupture between previously ruptured and unruptured aneurysms.

III. NATURAL HISTORY STUDIES The limited clinical data concerning the natural history of unruptured aneurysms should be considered separately for patients without prior SAH and those with prior SAH from a diﬀerent source. A. Patients with Unruptured Intracranial Aneurysms Without Prior Subarachnoid Hemorrhage Locksley et al. [57] studied 34 patients with unoperated unruptured symptomatic aneurysms, but only 19 had long-term follow-up (z5 years or until death). Of the 19 patients, 8 ultimately died of spontaneous SAH, and another died after lumbar puncture. All 8 patients with ruptures had aneurysms that were 7–11 mm in diameter or larger (the precise size of the aneurysms in the 7–11 mm category was not stated). No aneurysm smaller than 7 mm in diameter ruptured, and it was not indicated whether any aneurysm smaller than 10 mm in diameter ruptured. Zacks et al. [67] gathered data on 10 patients with untreated, fortuitously discovered intracranial aneurysms over a follow-up period of 7 weeks to 71⁄2 years. None of the patients had intracranial hemorrhages, but only 2 were followed for 5 years or more after diagnosis or until death. None of the aneurysms exceeded 10 mm in diameter.

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Wiebers et al. [45] gathered data during a mean follow-up period of approximately 8 years on a group of 65 patients who had a total of 81 unruptured saccular aneurysms. A multivariate discriminate analysis assessed the relation of several variables to aneurysmal rupture. The only signiﬁcant variable was aneurysm size. None of the 44 aneurysms smaller than 1 cm in diameter ruptured, whereas 8 of the 29 aneurysms 1 cm or more in diameter eventually ruptured. Aneurysmal symptoms other than rupture and the presence of multiple lobes also showed a positive correlation with eventual rupture. However, multivariate analysis showed that the increased risk of rupture for multilobed aneurysms and aneurysms producing symptoms other than rupture could be attributed solely to the size of the aneurysm. This and other studies [57] have documented that aneurysms 7 mm or smaller in diameter seldom cause symptoms unrelated to rupture. However, many aneurysms larger than 7 mm in diameter, particularly those between 8 and 20 mm, do not cause symptoms. Wiebers et al. [8] subsequently extended their experience with unoperated unruptured saccular aneurysms. Over a mean follow-up interval of 8.3 years, 15 of 130 patients (161 aneurysms) had intracranial hemorrhage. Of the 102 aneurysms smaller than 1 cm in diameter, none ruptured during the follow-up period, whereas of the 51 aneurysms 1 cm or larger in diameter, 15 eventually ruptured. Five of the 15 ruptures occurred within 3 months of the diagnosis of intracranial aneurysm, and 14 of the 15 ruptures were fatal. As with the previous study, the only single variable of unquestionable signiﬁcance for predicting aneurysmal rupture was aneurysm size ( p < 0.0001). However, when combinations of variables were analyzed, the interaction term of aneurysm size and patient age was even more signiﬁcant than aneurysm size alone ( p < 0.00001). Subsequently, a study by Yasui et al. [68] involving 234 patients with and without prior SAH were evaluated during a period of 6.2 years. Overall, 34 patients (14.5%) experienced subsequent SAH with an average annual rupture rate of 2.3%, but it was unclear what rates applied to patients with or without prior SAH. In a separate study, these authors evaluated aneurysm size in 25 patients with or without prior SAH and rupture of a previously unruptured aneurysm [69]. Twenty-two of the newly ruptured aneurysms were less than 9 mm in diameter at initial diagnosis, and 16 were less than 5 mm in diameter. Aneurysm size increased in 19 of 20 patients who were reassessed angiographically after rupture. Again, it was unclear which patients with subsequent SAH did and did not have a history of SAH prior to their identiﬁcation with an unruptured intracranial aneurysm. The International Study of Unruptured Intracranial Aneurysms represents a multicenter collaborative eﬀort organized in 1990 to study the natural history of unruptured intracranial aneurysms and the morbidity and mortality associated with UIA repair. A report from this study group in 1998 [70] included a natural history component based on retrospectively identiﬁed patients using predeﬁned criteria for patient entry and aneurysmal rupture across multiple centers, remeasurement of all aneurysms with hard copy ﬁlms that involved a deﬁned system for magniﬁcation correction, and a published methodology for indepth detection, review, and adjudication of detailed data regarding outcome events. This study also had suﬃcient numbers of patients to allow secondary subgroup analysis according to aneurysm size, location, and history of SAH from a diﬀerent aneurysm. A report included 727 patients with UIAs and no history of SAH from another source and an average of 7.5 years of follow-up. Among patients with UIAs less than 10 mm in diameter, the subsequent rupture rate was very low at less than one tenth of 1% per year. The overall rupture rate for patients with aneurysms greater than or equal to 10 mm in diameter was approximately 1% per year, including rupture rates of approximately 6% in the ﬁrst year among patients with giant (z25 mm) UIAs. Aneurysm location also predicted future rupture (posterior communicating, vertebral basilar/posterior cerebral, and basilar tip UIAs were more likely to rupture). However, aneurysm size was the best predictor of future

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rupture. Multiple other patient demographic characteristics, aneurysmal symptoms other than rupture, aneurysmal characteristics, behavioral factors, and associated medical conditions did not independently predict future rupture. Even more recently, the ISUIA Investigators have reported natural history data based on a prospective cohort involving 1692 patients with 2686 UIAs including 1077 patients in group 1 and 615 in group 2. Prior to this, all natural history studies had been based upon retrospective patient identiﬁcation, which, by the very nature of the cohort, raises some question about the potential for selection bias. Among the prospective cohort, the diagnosis of UIA was made between 1991 and 1997. The mean age of patients was 55 years, approximately three fourths of the cohort was female, and the mean follow-up was 4.1 years, for a total of 6544 patient-years of follow-up. As with the retrospective cohort, larger aneurysmal size predicted greater risk of rupture. Aneurysmal location was also important, with greater risk involving posterior circulation and posterior communicating locations and lesser risk regarding carotid cavernous location. Although the predictors of rupture followed the same patterns as with the retrospective cohort, the rupture rates for the prospective cohort were higher than those of the retrospective cohort for aneurysms 7 mm or greater in diameter. Running averages for successive 3 mm size categories revealed optimal cut points at diameters <7, 7–12, 13–24, and z25 mm. Rupture rates at three locations were statistically diﬀerent and were therefore used in models for predicting rupture. A statistical comparison of patients without (group 1) and with (group 2) a history of SAH revealed signiﬁcantly higher rupture rates among group 2 patients with UIAs <7 mm ( p < 0.0001). Otherwise in this cohort, rupture rates for patients in group 1 and group 2 did not diﬀer. Five-year cumulative hemorrhage rates by aneurysm site (parent artery), size (4 size categories), and group (for aneurysms <7 mm) are shown in Table 1 [71]. B. Patients with Unruptured Intracranial Aneurysms with Prior Subarachnoid Hemorrhage Winn et al. [72] evaluated the long-term outcome (mean follow-up period 7.7 years) of 182 patients with multiple aneurysms who had an SAH; 132 were treated by bed rest and 50 by surgery directed at the unruptured aneurysm. In the bed rest group, 21 patients (16%) had a late hemorrhage, but the investigators concluded that in all 21 patients the late hemorrhage was due to rerupture of the original aneurysm. In the surgically treated group, patients

Table 1 Five-Year Cumulative Rupture Rates According to Size and Location of Unruptured Aneurysm and According to Patient Group Among Patients in Unoperated Cohort Rupture rate (%) Aneurysm location Cavernous (n = 210) AC/MC/IC (n = 1037) Post-P comm (n = 445)

<7 mm, Group 1a

<7 mm, Group 2b

7–12 mm

13–24 mm

z25 mm

0 0 2.5

0 1.5 3.4

0 2.6 14.5

3.0 14.5 18.4

6.4 40 50

Cavernous, Cavernous carotid artery; AC, anterior communicating or anterior cerebral artery; MC, middle cerebral artery; IC, internal carotid artery (not cavernous carotid artery); Post-P comm, vertebrobasilar, posterior cerebral arterial system, or the posterior communicating artery. a Patients had no history of subarachnoid hemorrhage. b Patients had a history of subarachnoid hemorrhage from a separate aneurysm.

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underwent wrapping, clipping, or carotid artery ligation. Ten (20%) of the 50 patients subsequently had intracranial hemorrhage; 3 were believed to have bled from a previously intact aneurysm. No relationship was found between the size of the second-largest aneurysm and the propensity for rupture. However, for the entire patient group, the population with late rebleeding included a signiﬁcantly greater proportion of patients with aneurysms 10 mm or larger in diameter. Heiskanen [73] followed a similar group of 61 patients who had SAH and at least two intracranial artery aneurysms in whom only the ruptured aneurysm had been clipped. During a 10-year follow-up period, 7 patients bled from a previously unruptured aneurysm, and 3 additional patients suﬀered fatal bleeding more than 10 years after the ﬁrst SAH. No aneurysm sizes were noted. Another series involved 142 patients who had harbored 181 UIAs who were followed until death, SAH, or z10 years for a mean of 13.9 years [74]. The large majority (131) of the 142 patients had prior SAH from a separate aneurysm that was repaired. The annual rupture rate from UIAs was 1.4% for the entire group. Aneurysm size was the only variable study that predicted future rupture. However, the strength of the predicted value of aneurysm size was marginal for the entire population ( p = 0.036) and was not statistically signiﬁcant for the 138 patients with prior SAH. Subsequent follow-up of the 57 remaining patients from this cohort yielded similar results [75]. The report by the ISUIA Investigators involving retrospective natural history [70], 722 patients were identiﬁed with a prior history of SAH followed for a mean of approximately 7.5 years. The rupture rates for group 2 patients with UIAs of <10 mm in diameter were 11 times higher than the same size aneurysm among group 1 patients without prior SAH. The only clear predictor of future rupture among these patients was basilar tip location. Size alone did not appear to predict future rupture. In the more recent prospective natural history report from ISUIA [71] as mentioned above, the rupture rates for group 2 patients were only diﬀerent from group 1 patients for aneurysms less than 7 mm in diameter, and therefore rupture rates for group 2 patients (Table 1) are only shown separately for group 2 patients in the various locations for UIAs <7 mm in diameter. The overall pattern and magnitude of rupture rates in the ISUIA prospective natural history series for group 2 patients were virtually identical to those reported for the retrospective series [70].

IV. IMPLICATIONS OF NATURAL HISTORY STUDIES CONCERNING PATHOPHYSIOLOGY OF ANEURYSMAL DEVELOPMENT, GROWTH, AND RUPTURE Over the years many have called attention to patients with small ruptured aneurysms diagnosed following subarachnoid hemorrhage, inferring that small unruptured aneurysms, even in group 1, may have substantial rupture rates. If it were possible to extrapolate the natural history of UIAs by referring to series of patients with ruptured aneurysms, it would not hae been necessary or advisable to perform natural history studies using UIA patients. The ﬁndings of the ISUIA study and other natural history studies emphasize that the natural history of UIAs cannot be extrapolated from patients with ruptured aneurysms. It is important to recognize that there is a major diﬀerence between the following questions: 1. What is the probability of a ruptured aneurysm being a certain size? 2. What is the probability of future rupture of a given-sized aneurysm discovered before rupture?

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The second of these questions is relevant to clinical management of patients with UIAs. A great deal of confusion has been added to the ﬁeld by not recognizing the diﬀerence between these two questions. The bottom line is that one does not learn much about the natural history of unruptured aneurysms by referring to characteristics of patients with ruptured aneurysms. This very graphically applies not only to aneurysm size but also aneurysm location. Available evidence suggests that most aneurysms that are going to rupture do so at the time of, or soon after, they form and that the critical size for rupture is lower for those aneurysms that rupture early. In a study by Wiebers et al. [8], the sizes of the aneurysms that ruptured ranged from 10 to 40 mm in diameter before rupture, with a mean diameter of 21.3 mm. Yet a discrepancy was noted between this observation and the observation that the mean size of ruptured aneurysms, as seen arteriographically over the prior 10 years at the Mayo Clinic, was approximately 7.5 mm in diameter. Similar discrepancies have been replicated in subsequent retrospective [70] and prospective [71] natural history data involving group 1 (no prior SAH) patients. Three possible explanations for this discrepancy were suggested. First, small aneurysms could outnumber large aneurysms to such an extent that a very small percentage of the small aneurysms that rupture still represents a signiﬁcant fraction of all aneurysmal ruptures. It is doubtful that this argument can fully explain the discrepancy. The observation of 102 aneurysms smaller than 10 mm in diameter with 824 person-years of follow-up allowed a calculation with greater than 95% conﬁdence that the ratio of aneurysms smaller than 10 mm in diameter to those larger than 10 mm in diameter would have to be at least 60:1 to fully account for the discrepancy. However, from autopsy and arteriographic data previously provided in the literature by Locksley [76] and McCormick [5], the ratios appear to be approximately 5:1–6:1. A second possible explanation involved a decrease in aneurysmal size following rupture due to partial collapse of the walls at the time of rupture or because of thrombus formation in the aneurysmal sac, which could decrease the arteriographic lumen size without decreasing the overall external size of the aneurysm. Spontaneous decreases in aneurysmal size have been well documented, occurring without rupture in isolated cases, but no data are available on angiographic appearance of aneurysms immediately before and after rupture. The third, and most compelling, explanation oﬀered was that the critical size for aneurysmal rupture is smaller if rupture occurs at the time of or soon after aneurysm formation. On the basis of these considerations, other clinical and natural history data, and prior available data on the pathophysiology of intracranial aneurysms, the authors proposed the following scenario of aneurysm development: Intracranial saccular aneurysms are not congenital lesions; rather, they develop with increasing age. Most intracranial saccular aneurysms that develop probably do so over a relatively short period, measured in terms of hours, days, or weeks, attaining a size that is allowed by the limits of elasticity of the elastic components of the walls of the aneurysm. At this point, the aneurysm either ruptures or, if the limits of elasticity are not exceeded and it maintains itself intact, the walls undergo a process of compensatory hardening, similar to other vascular walls subjected to arterial blood pressures, with the formation of excessive amounts of collagen [77,78]. The tensile strength of collagen is several hundred times that of elastic ﬁbers [78]. With this added tensile strength, which continues accumulating over time, the likelihood of rupture becomes less unless the size of the aneurysm is quite large at the time it initially stabilizes. Aneurysms of 1 cm or larger at the time of the initial stabilization are much more likely to undergo subsequent growth and rupture, since the stress on the wall increases with the square of

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the diameter of the aneurysm, according to the law of Laplace. From these considerations, it follows that the critical size for aneurysmal rupture is smaller if rupture occurs at the time of or soon after aneurysm formation, as would appear to be true for the vast majority of small aneurysms that rupture. Chronic hypertension appears to have little or no eﬀect upon either the prevalence of intracranial aneurysms or their propensity for subsequent rupture. However, sudden elevations of blood pressure may have a greater inﬂuence on aneurysmal rupture and may be identiﬁable only in studies incorporating prospective follow-up. It is important to keep in mind that the above hypotheses have been formulated largely on the basis of data from patients with UIA who had no history of prior SAH and may or may not apply to patients with UIA with prior SAH from a diﬀerent aneurysm. The underlying pathophysiological mechanism that caused an initial aneurysmal rupture likely puts these patients at higher risk for subsequent rupture of UIAs. The hypotheses have also been based upon data involving arteriographic aneurysmal size. There may be considerable discrepancy between CT, MR, and arteriographic aneurysmal size because of thrombus within the aneurysm, calciﬁcation of its walls, or perhaps other factors. Computed tomography or MR imaging parameters, such as aneurysmal wall thickness, may be more valuable than recognized in deﬁning future risk of UIA. Another element that reinforces the inability to predict natural history of unruptured intracranial aneurysms by assessing characteristics of series of patients with ruptured aneurysms involves aneurysm location. This is particularly evident at the anterior communicating artery location where from it is common in ruptured aneurysm series to see 30–35% of ruptured aneurysms emanating. In contrast, among unruptured intracranial aneurysm series, the percentage of such aneurysms is much lower. In ISUIA, only 10–15% of over 5500 patients had anterior communicating artery aneurysms, indicating that these aneurysms are particularly prone to develop and rupture early and that they do not tend to stabilize to make it into studies involving patients with UIAs. In sharp contrast to what one would predict their natural history to be on the basis of ruptured aneurysm series, patients with anterior communicating artery UIAs are at substantially less risk of future rupture than patients with aneurysms in many other locations, including posterior circulation aneurysms and posterior communicating artery aneurysms [71].

V. TREATMENT CONSIDERATIONS Another important component for making management decisions about patients with UIA involves the morbidity and mortality rates associated with aneurysmal treatment, including direct surgery as well as endovascular methods. A. Direct Surgical Treatment Most of the studies involving direct surgical treatment for unruptured intracranial aneurysms have involved case series from one or more neurosurgeons in which their results are evaluated. Overall morbidity and mortality rates have varied from 0 to 7% for death and 4 to 15.3% for complications [69,70,79–87]. In two recently reported meta-analyses [88,89], somewhat discrepant results were reported. The ﬁrst of these involved 733 patients [24] and reported a 1% mortality and 4% morbidity rate. The second, which involved 2460 patients (89), reported a mortality rate of 2.6% and a permanent morbidity rate of 10.9%. The metaanalyses were made more diﬃcult by the lack of uniformity regarding the deﬁnition of good

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versus poor outcomes or even mortality rates, which were variably deﬁned at 30 days, 3–6 months, or 1 year after surgery. None of the individual studies contained a signiﬁcant number of patients to warrant conclusive judgment regarding the predictors of outcome. Surgical morbidity and mortality has been assessed by ISUIA, and this is the only study to systematically assess cognitive status before and after surgery across multiple centers with a teams-evaluation approach [70,71]. All ISUIA assessments of surgical and endovascular morbidity and mortality have been based on prospectively entered patients for the years 1991–1997. In the phase 1 ISUIA report [70], in 798 patients without prior SAH, surgical mortality rates were 2.3% at 30 days and 3.8% at 1 year, whereas in those with prior SAH from a treated aneurysm, mortality rates were 0% at 30 days and 1% at 1 year. The overall rate of surgery-related morbidity and mortality was 17.5% in group 1 and 13.6% in group 2 at 30 days and 15.7% and 13.1%, respectively, at 1 year. Patient age was clearly an important risk factor inﬂuencing surgical outcome. A more recent prospective report [71] from ISUIA included 1917 patients undergoing surgical treatment for UIAs in phases 1 and 2 of the study. In this report, overall surgical morbidity and mortality rates at 1 year were reported at 12.6% for group 1 and 10.1% for group 2. The improved rates observed in the comparison of phase 2 versus phase 1 of ISUIA were attributed largely to operating on younger patients in phase 2. A multivariate analysis revealed that patient age was a strong predictor of outcome (Fig. 1), with a substantial increase in risk occurring at about age 50 years and older, escalating considerably after age 60–70. Other variables predicting poor surgical outcomes were larger size of the aneurysm, location of posterior circulation, history of prior ischemic cerebrovascular disease, and aneurysmal symptoms other than rupture. Figure 2 summarizes 1-year surgical morbidity and mortality rates according to the interactions of patient age and aneurysmal size and location. B. Endovascular Treatment Results of endovascular treatment for patients with UIAs are not as plentiful as the results of patients treated with direct surgery. In a retrospective cohort study of patients with UIAs treated between 1994 and 1997 at 60 university hospitals, Johnston et al. [90] compared treatment results among 255 patients treated with endovascular coils and 2357 treated with

Figure 1 Poor outcomes at 1 year in the surgical cohort by age. Poor outcomes include death, a Rankin score between 3 and 5, or impaired cognitive status. Bars show 95% CI. With permission from The Lancet 2003; 362:103–110.

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Figure 2 Poor surgical outcomes at 1 year by age, site, and size of aneurysm. Poor outcomes include death, a Rankin score between 3 and 5, or impaired cognitive status. Bars show 95% CI. With permission from The Lancet 2003; 362:103–110.

open surgery. Adverse outcomes (deﬁned as in-hospital deaths and discharges to nursing home or rehabilitation hospitals) occurred in 10.6% of endovascular patients and 18.5% of surgical patients. In another retrospective assessment utilizing The University of California at San Francisco (UCSF) Hospital discharge database [91], 118 surgically treated patients with UIA were compared to 98 patients treated by endovascular procedures. These patients had been judged retrospectively to be candidates for either procedure. Overall, 25% of the surgically treated group displayed poor outcomes compared to 8% of the endovascularly treated group. At an average of 3.9 years following treatment, 34% of surgically treated patients displayed persistent or new systems compared to 8% of patients treated with endovascular procedures. In one further retrospective analysis based on patients treated in the state of California between 1990 and 1998, adverse events were deﬁned as in-hospital death or discharge to a nursing home or rehabilitation hospital at any point throughout the treatment course. Adverse outcomes were reported in 10% of the endovascular patient group compared to 25% of the surgical group [92]. In a recent meta-analysis involving 1383 patients treated with endovascular coiling for ruptured or unruptured intracranial aneurysms, Brilstra et al. [93] found a low permanent complication rate (3.7%) but a low rate of complete obliteration (54%). Even more recently, the ISUIA Investigators [71] reported results involving 451 prospectively identiﬁed patients with unruptured intracranial aneurysms treated by endovascular procedures. Overall morbidity and mortality associated with endovascular repair at 30 days was 9.1% and at 1 year was 9.5%. The patient group receiving endovascular treatment was found to be a higher-risk group than those receiving open surgery in the ISUIA cohort because of increased age, increased aneurysm size, and more posterior circulation aneurysms treated by endovascular procedures. A multivariate analysis revealed that increased aneurysm size and posterior circulation location conferred increased risk of endovascular procedure. Patient age was not a signiﬁcant predictor of outcome in contrast to patients treated with open surgery. Figure 3 summarizes 1-year endovascular morbidity and mortality rates according to interactions with patient age, aneurysm size, and location.

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Figure 3 Poor endovascular outcomes at 1 year by age, site, and size of aneurysm. Poor outcomes include death, a rankin score between 3 and 5, or impaired cognitive status. Bars show 95% CI. With permission from The Lancet 2003; 362:103–110.

From a statistical perspective, some of the endovascular cohort analyses were associated with wider conﬁdence intervals than the open surgical cohort analyses because of the smaller sample size in the endovascular cohort data. Another treatment consideration involves the performance of carotid endarterectomy on patients with unruptured aneurysms. Altogether, at least 55 cases involving endarterectomy in patients with intracranial aneurysms have been reported [67,94–97]. Among 51 cases without prior SAH, 4 had subsequent rupture at intervals ranging from 2 days to 10 months after endarterectomy. Among 4 patients with prior SAH, 3 had ruptures following carotid endarterectomy. One further treatment consideration relates to patients with unruptured aneurysms and intracranial AVMs. This is a much more common occurrence than was previously thought [98]. After careful review of the angiograms of 91 patients with unruptured intracranial AVMs, it became apparent that 16 of these patients had 20 coexisting unruptured intracranial aneurysms [33]. The risk of subarachnoid hemorrhage in this group was approximately double that among patients with rupture AVMs alone. Virtually all of the aneurysms occurred within the feeding systems of the AVMs, and the extra risk conferred by the presence of aneurysm did not clearly relate to aneurysmal size.

VI. MANAGEMENT SUGGESTIONS Following the publication of the phase 1 ISUIA data [70], an expert panel convened by the American Heart Association and primarily constructed of neurosurgeons concluded that ‘‘in view of the apparently low natural history risk of group 1 patients with small UIAs, treatment cannot be generally recommended’’ [99]. Two other neurosurgical investigators also concluded in an evidence-based medicine criteria approach that the class 2 evidence from ISUIA ‘‘is diﬃcult to ignore,’’ and recommended conservative management for group 1 patients with UIAs less than 10 mm in diameter as well as all UIA patients under age 64 [100]. Johnston et al. [101] in an extensive cost utility analysis regarding UIAs indicated that ‘‘treatment of small asymptomatic unruptured cerebral aneurysms in patients without a

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history of SAH worsens clinical outcomes and was neither eﬀective nor cost eﬀective.’’ The newest ISUIA information continues to generally support these recommendations but allows a more sophisticated detailed and individualized assessment of the risks of natural history versus the risks of surgical and/or endosvascular repair. In general, for group 1 patients with aneurysms less than 7 mm in diameter, it is very unlikely that one will improve on the natural history of these lesions, particularly in the anterior circulation. We cannot establish that positive family history increases the risk in this group, but we must also keep in mind that we have very few symptomatic patients, particularly those with acute or changing symptoms, and virtually none where we have observed aneurysmal growth, so that these rare circumstances may constitute exceptions to the broader principle. For all other patients, these individuals have more substantial rupture rate according to aneurysmal size and location, but we can now be more sophisticated in doing comparisons on the basis of more than size, and it is important that we look at size/site/group-speciﬁc natural history rates and compare them to size/site/age of treatment morbidity and mortality rates. In many cases, patients with higher natural history morbidity and mortality will be associated with higher treatment morbidity and mortality, but not always. Another concept that has come across as crucial here is that the age of the patient is very important in making management decisions, largely because age has a major impact on operative morbidity and mortality but relatively little impact on natural history. The age range in which impact is greatest starts around 50 years and higher for open surgery and around 70 years and higher for endovascular procedures. For purposes of comparing rupture risks to surgical and endovascular morbidity and mortality, it is useful to look at the risks in Table 1 and compare them with those in Figures 2 and 3. These data provide risks of natural history and treatment morbidity and mortality based on various interactions that appear to be most signiﬁcant. The rupture risk is lowest for asymptomatic group 1 patients with aneurysms less than 7 mm in diameter in the anterior circulation where rates are in the neighborhood of 1/10 of 1% per year. Surgical morbidity and mortality is most favorable for asymptomatic patients under age 50 with UIAs in the anterior circulation less than 24 mm in diameter and no history of ischemic cerebrovascular disease. Endovascular morbidity and mortality may be less age dependent, and this could favor endovascular procedures, particularly between ages 50 and 70. There is also the question of immediate versus long-term risk with regard to treatment eﬀectiveness and durability. This emphasizes the importance of long-term follow-up in patients after open surgery and endovascular procedures to assess not only the immediate and short-term complications, but also long-term eﬀectiveness. Routine screening with noninvasive tests such as CT, MR imaging, or MR angiography would be expected to have a very low yield in the general population, because although aneurysms are quite prevalent at autopsy, they appear to develop with increasing age. Even among patients with predisposing conditions, such as autosomal dominant polycystic kidney disease (ADPKD), the use of routine screening may have a very low yield, particularly in younger patients [102]. In these patients, it seems reasonable to perform noninvasive screening CT or MR imaging studies in certain subgroups of patients, namely those with a family history of intracranial aneurysm or SAH, those who undergo major elective surgery with anticipated hemodynamic instability, those who have indeterminate symptoms that might suggest intracranial aneurysm, those in high-risk occupations, and those who want the reassurance screening can provide. In patients with UIA and AVM combined, it is quite likely that the aneurysm will be located within the feeding system of the AVM. These aneurysms appear to be more prone to future growth and rupture than unruptured aneurysms in general. When repair is contemplated, it seems wise to repair the aneurysm before addressing the AVM, especially in

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patients with large aneurysms since sudden changes in the hemodynamics of the feeding system may predispose to aneurysmal rupture. For carotid endarterectomy in patients with UIAs, the sudden change of hemodynamics in the distal carotid system from correcting a pressure-signiﬁcant stenosis may be a factor predisposing to enlargement or rupture of a previously unruptured intracranial saccular aneurysm. Even endarterectomy for nonpressure-signiﬁcant stensosis could cause substantial distal carotid system pressure alterations with clamping and unclamping. Although the data are too sparse to allow deﬁnitive conclusions, it would appear that carotid endarterectomy should be approached with increased caution in patients with UIAs, particularly for those that are larger than 5 mm in diameter in the ipsilateral carotid system. Overall, optimal management of patients with UIAs clearly needs to involve identifying patients who are at greatest subsequent risk of hemorrhage, particularly in view of epidemiological evidence from multiple vantage points which suggest the large majority of intracranial aneurysms never rupture. Optimal management also involves predicting which patients will have the greatest likelihood of success and lowest complication rates from repairing UIAs. When repair of UIAs is considered, it is important to recognize that available evidence suggests that substantially lower complication rates are associated with institutions and individuals with large numbers of patients with cerebral aneurysms treated on an annual basis [103,104]. It is therefore of great importance to seek out individuals and institutions with substantial ongoing experience with these procedures. When unruptured intracranial aneurysms are left alone and monitored, it seems advisable to suggest that patients avoid smoking (including passive smoke) and heavy alcohol consumption and that they avoid stimulant medications and drugs and excessive straining and Valsalva maneuvers resulting in major acute increases in blood pressure. Daily physical activities need not be altered. While there are many other medical reasons to treat chronic hypertension, data from ISUIA and other studies indicate that chronic hypertension has little or no eﬀect on aneurysmal development or rupture. Unruptured intracranial aneurysms are generally monitored annually with MRA for 3 years and then every 3–5 years thereafter.

REFERENCES 1. Cohen MM. Cerebrovascular accidents. A study of two hundred one cases. Arch Pathol 1995; 60:296–307. 2. Chason JL, Hindman WM. Berry aneurysms of the circle of Willis. Results of a planned autopsy study. Neurology 1958; 8:41–44. 3. Housepian EM, Pool JL. A systematic analysis of intracranial aneurysms from the autopsy ﬁle of the Presbyterian Hospital, 1914 to 1956. J Neuropathol Exp Neurol 1958; 17:409–423. 4. Stehbens WE. Aneurysms and anatomical variation of cerebral arteries. Arch Pathol 1963; 75:45–64. 5. McCormick WF, Acosta-Rua GJ. The size of intracranial saccular aneurysms. An autopsy study. J Neurosurg 1970; 33:422–427. 6. Jakubowski J, Kendall B. Coincidental aneurysms with tumours of pituitary origin. J Neurol Neurosurg Psychiatry 1978; 41:972–979. 7. Rinkel GJ, Djibuti M, Algra A, et al. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998; 29:251–256. 8. Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM. The signiﬁcance of unruptured intracranial saccular aneurysms. J Neurosurg 1987; 66:23–29. 9. Phillips LH II, Whisnant JP, I’Fallon WM, et al. The unchanging pattern of subarachnoid hemorrhage in a community. Neurology 1980; 30:1034–1040.

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10. Garraway WM, Whisnant JP, Drury I. The continuing decline in the incidence of stroke. Mayo Clin Proc 1983; 58:520–523. 11. Broderick JP, Philips SJ, Whisnant JP, O’Fallon WM, Bergstralh EJ. Incidence rates of stroke in the 80s: the end of the decline of stroke? Stroke 1989; 20:577–582. 12. Ingall T, Wiebers D. Natural history of subarachnoid hemorrhage. In: Whisnant JP, ed. Stroke: Populations, Cohorts, and Clinical Trials. Oxford: Butterworth-Heinemann, 1993:174–187. 13. Brown R, Wiebers D. Subarachnoid hemorrhage and unruptured intracranial aneurysms. In: Bougoulasslavsky J, ed. Cerebrovascular Diseases. Malden, MA: Blackwell Science, 1998:1502– 1531. 14. Iglesias CG, Torres VE, Oﬀord KP, Holley KE, Beard CM, Kurland LT. Epidemiology of adult polysystic kidney disease, Olmsted County. Minnesota: 1935–1980. Am J Kidney Dis 1983; 2:630–639. 15. Wiebers DO. Management of unruptured intracranial aneurysms. In: Grantham JJ, Gardner KD, eds. Problems in Diagnosis and Management of Polycystic Kidney Disease. Proceedings of the First International Symposium on Polycystic Kidney Disease. Kansas City, 1985: 145–154. 16. Reifenstein GH, Levine SA, Gross RE. Coarctation of the aorta: a review of 104 autopsied cases of the ‘‘adult type,’’ 2 years of age or older. Am Heart J 1947; 33:146–168. 17. Stehbens WE. Cerebral aneurysms and congenital abnormalities. Australas Ann Med 1962; 11:102–112. 18. Finney HL, Roberts TS, Anderson RE. Giant intracranial aneurysm associated with Marfan’s syndrome: case report. J Neurosurg 1976; 45:342–347. 19. Edwards A, Taylor GW. Ehlers-Danlos syndrome with vertebral artery aneurysm. Proc R Soc Med 1969; 62:734–735. 20. Bannerman RM, Ingall GB, Graf CJ. The familial occurrence of intracranial aneurysms. Neurology 1970; 20:283–292. 21. Palubinska AJ, Perloﬀ D, Newton TH. Fibromuscular hyperplasia: an arterial dysplasia of increasing clinical importance. AJR 1966; 98:907–913. 22. Wylie EJ, Binkley FM, Palubinskas AJ. Extrarenal ﬁbromuscular hyperplasia. Am J Surg 1966; 112:149–154. 23. Belber CJ, Hoﬀman RB. The syndrome of intracranial aneurysm associated with ﬁbromuscular hyperplasia of the renal arteries. J Neurosurg 1968; 28:556–559. 24. Bolander H, Hassler O, Liliequist B, West KA. Cerebral aneurysm in an infant with ﬁbromuscular hyperplasia of the renal arteries. Case report. J Neurosurg 1978; 49:756–759. 25. Dixon JM. Angioid streaks and pseudoxanthoma elasticum: with aneurysm of the internal carotid artery. Am J Ophthalmol 1951; 34:1322–1323. 26. Pool JL, Wood EH, Maki Y. On the cases with abnormal vascular networks in the cerebral basal region in the United States. In: Kudo T, ed. A Disease with Abnormal Intracranial Vascular Networks: Spontaneous Occlusion of the Circle of Willis. Tokyo: Igaku-Shoin, 1967:63–68. 27. Yasargil MG, Smith RD. Association of middle cerebral artery anomalies with saccular aneurysms and moyamoya disease. Surg Neurol 1976; 6:639–643. 28. Kodama N, Suzuki J. Moyamoya disease associated with aneurysm. J Neurosurg 1978; 48:565– 569. 29. Adams JP Jr, Kassell NF, Wisoﬀ HS, Drake CG. Intracranial saccular aneurysm and moyamoya disease. Stroke 1979; 10:174–179. 30. Yabumoto M, Funahashi K, Fuji T, Hayashi S, Komai N. Moyamoya disease associated with intracranial aneurysm. Surg Neurol 1983; 20:20–24. 31. Anderson RM, Blackwood W. The association of arteriovenous angioma and saccular aneurysm of the arteries of the brain. J Pathol Bacteriol 1959; 77:101–110. 32. Suzuki J, Onuma T. Intracranial aneurysms associated with arteriovenous malformations. J Neurosurg 1979; 50:742–746. 33. Brown RD, Wiebers DO, Forbes G, O’Fallon WM, Piepgras DG, Marsh WR, Maciunas RJ. The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 1988; 68:352–357.

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34. Brown RD, Wiebers DO, Forbes GS. The relationship of unruptured intracranial arteriovenous malformations to intracranial aneurysms [abst]. Ann Neurol 1989; 26:127. 35. Brown R, Wiebers D, Forbes G. Unruptured intracranial aneurysms and vascular malformations: frequency of intracranial hemorrhage and relationship of lesions. J Neurosurg 1990; 73:859–863. 36. Eppinger H. Pathogenesis (histogenesis and aetiologie) der Aneurysmen einschliesslich des Aneurysma equi Verminosum: pathologischanatomische Studien. Arch Klin Chir 1887; 35(suppl):1–563. 37. Forbus WD. On the origin of miliary aneurysms of the superﬁcial cerebral arteries. Bull Johns Hopkins Hosp 1930; 47:239–284. 38. Glynn LE. Medial defects in the circle of Willis and their relation to aneurysm formation. J Pathol Bacteriol 1940; 51:213–222. 39. Andrews RJ, Spiegel PK. Intracranial aneurysms: age, sex, blood pressure, and multiplicity in an unselected series of patients. J Neurosurg 1979; 51:27–32. 40. Kwak R, Mizoi K, Katakura R, Suzuki J. The correlation between hypertension in past history and the incidence of cerebral aneurysms. In: Suzuki J, ed. Cerebral Aneurysms: Experience with 1000 Directly Operated Cases. Tokyo: Neuron Publishing, 1979:20–24. 41. Nagata I, Handa H, Hashimoto N, Hazama F. Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg Neurol 1980; 14:477–479. 42. Gonzalez CF, Cho YI, Ortega HV, Moret J. Intracranial aneurysms: ﬂow analysis of their origin and progression. AJNR Am J Neuroradiol 1992; 13(1):181–188. 43. Clark WC, Ray MW. Contralateral intracranial aneurysm formation as a late complication of carotid ligation. Surg Neurol 1982; 18:458–462. 44. McCormick WF, Schmalstieg EJ. The relationship of arterial hypertension to intracranial aneurysms. Arch Neurol 1977; 34:285–287. 45. Wiebers DO, Whisnant JP, O’Fallon WM. The natural history of unruptured intracranial aneurysms. N Engl J Med 1981; 304:696–698. 46. Du Boulay GH. Some observations on the natural history of intracranial aneurysms. Br J Radiol 1965; 38:721–757. 47. Allcock JM, Canham PB. Angiographic study of the growth of intracranial aneurysms. J Neurosurg 1976; 45:617–621. 48. Sarwar M, Batnitzy S, Schechter MM, Liebeskind A, Zimmer AE. Growing intracranial aneurysms. Radiology 1976; 120:603–607. 49. Jain KK. Mechanism of rupture of intracranial saccular aneurysms. Surgery 1963; 54:347–350. 50. Coll AM, Del Corral JF, Yazawa S, Falco´n M. Intra-aneurysmal pressure diﬀerences in human saccular aneurysms. Surg Neurol 1976; 6:93–96. 51. Foreman JEK, Hutchison KJ. Arterial wall vibration distal to stenoses in isolated arteries of dog and man. Circ Res 1970; 26:583–590. 52. Ferguson GG. Turbulence in human intracranial saccular aneurysms. J Neurosurg 1970; 33:485–497. 53. Ferguson GG. Physical factors in the initiation, growth, and rupture of human intracranial saccular aneurysms. J Neurosurg 1972; 37:666–677. 54. Simkins TE, Stehbens WE. Vibratory behaviour of arterial aneurysms. Lett Appl Eng Sci 1973; 1:85–100. 55. Olinger CP, Wasserman JR. Electronic stethoscope for detection of cerebral aneurysm, vasospasm, and arterial disease. Surg Neurol 1977; 8:298–312. 56. Scott S, Ferguson GG, Roach MR. Comparison of elasatic properties of human intracranial arteries and aneurysms. Can J Physiol Pharmacol 1972; 50:328–332. 57. Locksley HB. Report on the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage. Section V, part II. Natural history of subarachnoid hemorrhage, intracranial aneurysms, and arteriovenous malformations: based on 6368 cases in the cooperative study. J Neurosurg 1966; 25:321–368. 58. Tognetti F, Limoni P, Testa C. Aneurysm growth and hemodynamic stress. Surg Neurol 1983; 20:74–78.

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59. Scanarini M, Zuccarello M, Mingrino S, Fiore DL. Enlargement of intracranial saccular aneurysms: a case report. Acta Neurochir (Wien) 1980; 54:101–106. 60. Sekhar LN, Heros RC. Origin, growth, and rupture of saccular aneurysms: a review. Neurosurgery 1981; 8:248–260. 61. Seshaiyer P, Hymphrey JD. On the potentially protective role of contact constraints on saccular aneurysms. J Biomech 2001; 34(5):607–612. 62. Ruı´ z DSM, Tokunaga K, Dehdashti A, Sugiu K, Delavelle J, et al. Is the rupture of cerebral berry aneurysms inﬂuenced by the perianeurysmal environment? Suppl Acta Neurochir 2002; 82:31–34. 63. Ruı´ z DSM, Ru¨fenacht DA. The perianeurysmal environment: a predictor of aneurysm natural history? ASNR 2003; 63:66 (this is from the Proceedings of the ASNR 2003 meeting—a special issue of the Am J Neuroradiol). 64. Suzuki J, Ohara H. Clinicopathological study of cerebral aneurysms. Origin, rupture, repair, and growth. J Neurosurg 1978; 48:505–514. 65. Metcalfe RW. The promise of computational ﬂuid dynamics as a tool for delineating therapeutic options in the treatment of aneurysms. Am J Neuroradiol 2003; 24:533–554. 66. Steinman DA, Milner JS, Norley CJ, Lownie SP, Holdsworth DW. Image-based computational simulation of ﬂow dynamics in a giant intracranial aneurysm. Am J Neuroradiol 2003; 24(4):559–566. 67. Zacks DJ, Russell DB, Miller JDR. Fortuitously discovered intracranial aneurysms. Arch Neurol 1980; 37:39–41. 68. Yasui N, Suzuki A, Nishimura He, et al. Long-term follow-up study of unruptured intracranial aneurysms. Neurosurg 1997; 40:1155–1159. 69. Yasui N, Magarisawa S, Suzuki A, et al. Subarachnoid hemorrhage caused by previously diagnosed, previously unruptured intracranial aneurysms: a retrospective analysis of 25 cases. Neurosurgery 1996; 39:1096–1100. 70. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Engl J Med 1998; 339:1725–1733. 71. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. The Lancet 2003; 362:103–110. 72. Winn HR, Almaani WS, Berga SL, et al. The long-term outcome in patients with multiple aneurysms. Incidence of late hemorrhage and implications for treatment of incidental aneurysms. J Neurosurg 1983; 59:642–651. 73. Heiskanen O. Risk of bleeding from unruptured aneurysms in cases with multiple intracranial aneurysms. J Neurosurg 1982; 55:524–526. 74. Juvela S, Porras M, Heiskanen O. Natural history of unruptured intracranial aneurysms: a longterm follow-up study. J Neurosurg 1993; 79:174–182. 75. Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 2000; 93:379–387. 76. Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms, and arteriovenous malformations. In: Sahs AL, ed. Intracranial Aneurysms and Subarachnoid Hemorrhage. A Cooperative Study. Philadelphia: JP Lippincott, 1969:89–96. 77. Artmann H, Vonofakos D, Mu¨ller H, et al. Neuroradiologic and neuropathologic ﬁndings with growing giant intracranial aneurysm. Review of the literature. Surg Neurol 1984; 21:391– 401. 78. Caro CG, Pedley TJ, Schroter RC, et al. The Mechanics of the Circulation. New York: Oxford University Press, 1978. 79. Moyes PD. Surgical treatment of multiple aneurysms and of incidentally discovered unruptured aneurysms. J Neurosurg 1971; 35:291–295. 80. Jain KK. Surgery of intact intracranial aneurysms. J Neurosurg 1974; 40:495–498. 81. Mount LA, Brisman R. Treatment of multiple aneurysms—symptomatic and asymptomatic. Clin Neurosurg 1974; 21:166–170.

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25 Arteriovenous Malformations and Other Vascular Anomalies J. P. Mohr, Alexander V. Khaw, and John Pile-Spellman Columbia University, New York, New York, U.S.A.

A collection of vascular disorders exist that are suﬃciently diﬀerent from normal variation as to have acquired names, some of which are associated with clinical manifestations. Loosely grouped under the title arteriovenous malformations (AVMs), this group is commonly further subdivided into (1) AVMs per se, i.e., disorders acquired through embryological mechanisms [1]; (2) arteriovenous ﬁstulas (AVFs), acquired during life; (3) cavernous malformations, and (4) capillary telangiectasias. The latter two disorders are histologically distinctive from AVMs and AVFs, smaller in size, and generally pursue a benign clinical course. AVMs and AVFs are commonly mistaken for one another, providing no end of diﬃculties for those hoping that epidemiological studies may point to management outcomes. The other malformations, not easily visualized on an angiogram and only recently diagnosable in some instances by modern imaging such as computed tomography (CT) and magnetic resonance (MR), have yet to have been studied well enough to understand their full range of manifestations and outcomes. The low frequency of well-developed lesions in infancy and the impossibility of reliably distinguishing congenital lesions from those acquired later using angiographic and magnetic resonance imaging (MRI) techniques have brought into question earlier views that AVMs or AVFs grow, remain static, or shrink, and whether their fate is tied to their physiological properties. It is still unknown whether the hypertrophied channels of AVMs or AVFs become independent of autoregulation or can be expected to subside if the venous obstruction is relieved, nor is it understood whether they have certain theoretical limits in size and extent or continue to develop until they hemorrhage. Lastly, it is unclear whether the proper treatment is ligation or neglect [2].

I. CLASSIFICATION OF LESIONS A. Arteriovenous Malformations AVMs are the best recognized among this group of vascular disorders because of their greater frequency, especially in a young to middle-age group. Clinical attention is most often drawn by, in descending frequency, hemorrhage, seizure disorder, headache, or, rarely, progressing focal neurological syndromes. From gross inspection at autopsy or 583

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surgical specimen, they appear as a tangle of vascular channels , comprising twisted and convoluted vascular spaces, which at one or multiple sites link the feeding arteries to the draining veins. These sites, lacking a capillary bed, are known as the nidus [3,4]. Angiogram and inspection at the time of surgery will not always identify the exact margin of the lesion. The lesions vary in size from tiny, so-called cryptic, malformations to massive anomalies that encompass a number of cerebral lobes. 1. Histology Early schemes of classiﬁcation from the nineteenth century originated from gross and histopathological observations, but are giving way to those focused on prognosis. A convenient starting point is the system of classiﬁcation developed by McCormick and Schochet [5] based on pathology, summarizing the main histological features. By microscopy, AVMs demonstrate that the large cavernous components of the malformation are mostly devoid of elastica or signiﬁcant muscularis in the walls [3]. The feeding and draining vessels are histologically recognizable as arteries or veins well away from the nidus, but as they approach the ends linking them together, many are uncharacterizable as either artery or vein and are partially separated by thin islands of sclerotic tissue. In the site(s) of the nidus, vessels inferred to be arteries have considerable amounts of endothelial thickening, medial hypertrophy, thin muscularis, and elastica, thought by some authors to explain poor local autoregulation. Occasionally sites of local thrombosis are found. Vessels assumed to be veins are thin-walled and vary in size, having irregular muscular and elastic components. The distinctive histological feature is an absence of capillaries. AVMs contain little to no functionally important brain tissues within the mass [5]. Cerebral function that would be located in the brain at the site occupied by the malformation is assumed to have been functionally displaced to the margin of the malformation [6,144]. 2. Subtypes Several roughly distinct radiologically identiﬁable subtypes of AVMs have been recognized recently that carry diﬀerent prognostic features. The most common variants occupy a zone of brain and could be considered ‘‘regional’’ lesions. A common variant is the maplike lesion lying across the border zone shared by adjacent cerebral arteries. This is the striking and easily recognized AVM depicted in many texts. In this variant, arterial feeders arise from adjacent cerebral arteries and join together in the nidus that straddles the border zone. Wedge-shaped in appearance when viewed from the coronal plane, the main lesion has its broad base on the cortex and an apex pointed toward the subjacent ventricular wall. Veins draining the nidus may run to the deep venous system in the ventricles or back towards to the cerebral surface or take both. Another variant is located mainly in the immediate subcortical white matter, (i.e., centrum semiovale in the cerebrum, cerebellar white matter in the cerebellum). Its form is less wedge-shaped and is usually cylindrical or globoid in the central white matter. Its arterial supply is typically limited to the immediate adjacent branches of a single cerebral vascular territory, the vein typically draining in one direction, either to the convexity surface or to the deep ventricular system, but usually not to both. Arteries supplying this type of AVM usually send branches to the nidus from the brain surface and often also continue on their usual path to supply healthy brain more distally (so-called vessels en passage). In either type there may be arterial supply from vessels below or adjacent to the deep parts of the lesion. Their angiographic appearance suggests that they have been

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drawn to the ﬁstula by a sump eﬀect of the nidus. These deep vessels usually arise from branches or main trunks of the major cerebral arteries in the lenticulostriate, choroidal, or thalamoperforant arteries, reaching the AVM after passing through healthy tissues. Another form of AVM could be considered ‘‘vascular territory’’ lesions. These less common disorders appear to be a deranged arterial supply through the entire territory of the aﬀected artery. A profusion of small branches, far more and far smaller than normally seen, makes up the distinctive appearance of these lesions. The lesion typically involves virtually the entire arterial supply of a single vessel only, the more commonly aﬀected being the anterior cerebral or the anterior choroidal. These lesions do not penetrate deep into brain tissue and are distinctively diﬀerent from the regional lesions. Finally, some AVMs are so small that discovery by conventional angiogram is the only means of diagnosis. These lesions, usually regional in type, aﬀect such sites as the midbrain, pons, thalamus, a small region of a cerebral lobe, etc., and currently defy exact correlation. 3. Associated Disorders AVMs usually occur in isolation, unrelated to other disease states, but a few have been associated with the Rendu-Osler-Weber syndrome (hereditary hemorrhagic telangiectasia), most of them small [7,8]. In one recent large study [8], 31 of 136 cases from a hereditary hemorrhagic telangiectasia clinic were inferred to have cerebral AVMs on MRI. Eighteen of these patients underwent angiogram; all were positive and 7 had multiple (three or more) AVMs. The AVMs varied in size from 3 to 25 mm in maximal dimension. AVMs have also been described in Wyburn-Mason syndrome [9]. B. Arteriovenous Fistulas No longer properly classiﬁed as AVMs, AVFs are receiving increasing attention. They are inferred to arise from trauma or venous occlusion. Trauma to the brain surface may crush together and join or enlarge the existing arteriovenous shunts roughly 90 Am in size near the superior sagittal sinus, and possibly at other sites [10,11]. Once linked or enlarged, such ﬁstulas would presumably lose their autoregulation and be subject to the same enlargement typical of any arteriovenous link. The assumption that head injury is the cause is often diﬃcult to document with any reliability. Another source of a ﬁstula is the late sequelae of thrombosis of a large vein or sinus, which may create a high enough resistance to normal arterial ﬂow as to force creation of new pathways to reach venous outﬂow [10,12,13]. In such instances, the angiogram usually shows delayed or irregular ﬁlling of the draining veins, with secondary delays in emptying of the ﬁstula, and in severe cases also showing slowing of entry of contrast into the feeding carotid or vertebrobasilar arteries. The locus of the ﬁstula formed secondary to venous occlusion is usually adjacent to the large draining veins, adjacent to the dural sinuses also known as dural ﬁstulas. The feeding arteries and draining veins such as the meningeal and other dural arteries can dilate and convolute in a manner seen in congenital AVMs. These shunts can develop in a fairly short time, possibly months. If sinus thrombosis occurs, a major hemorrhagic lesion may follow. C. Other Malformations Until recent advances in imaging, notably MRI, it was diﬃcult to demonstrate the other groups of vascular abnormalities, namely the cavernous angiomas, telangiectasias, and

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venous malformations, in living humans. These were mainly the purview of the pathologist, found on routine autopsies [14–18]. Cavernous angiomas have become better recognized in the last two decades because of their characteristic appearance on MR scan (less so on CT scan). Cavernous angiomas (malformations) are becoming more and more the subject of reports in the literature [18– 21]. They are composed of cavernous channels with multiple areas of thrombosis. They may occur anywhere including the cortical surface or deep in the brain stem. These lesions rarely occupy a clinically signiﬁcant amount of space in the brain but may be located in clinically important cortical or subcortical regions and are occasionally multiple. Although they are a mass, they do not produce displacements commensurable to that of a neoplasm. The ﬂow through these lesions is minimal, a feature that prevents their being seen on angiograms. They became recognized in recent times on CT scans by their contrast enhancement and their characteristic conﬁguration. While not readily identiﬁed on CT scan without contrast enhancement, the distinctive cat’s eye appearance on MR has made the diagnosis more frequent since the introduction of MR scanning. With evolving experience and larger data sets, the cat’s eye appearance is no longer considered pathognomonic for cavernous angiomas, as it once was, and is shared by any source of minor bleeding, including small AVMs. Clinically, cavernous malformations usually present with a seizure disorder, and the same may be said for venous malformations [22,27]. These lesions may also be seen with headaches, which may or may not be related to the lesion. Clinically manifesting hemorrhage is less frequent than with AVMs [23–26]. MRI has allowed study of family members, which in small case series has suggested a hereditary basis for some instances of multiple cavernous malformations [27,145–147], thus prompting the identiﬁcation of three loci (CCM1-3) and one mutation (KRIT1) [148– 149]. A predominance among hispanics has been suggested. Capillary telangiectasias, as is suggested by their name, are a tiny focal proliferation of what appears histologically to be capillaries. They are rare and occur more often in the brain stem, cerebellum, or diencephalon than in the cerebral hemisphere or subcortical region [18,28]. Little is known of their propensity for hemorrhage, but it is thought to be infrequent. No distinctive syndromes are associated with their occurrence. Although they frequently demonstrate small microhemorrhages on histological examination, the hemorrhage rarely appears to be large enough to create a clinical syndrome [28], although some reports suggest otherwise [8]. Prior to high-ﬁeld MRI, when brain telangiectasias are associated with the Rendu-Osler-Weber syndrome, other telangiectasias are recognized elsewhere in the body. For the autosomal dominant disorder hereditary hemorrhagic telangiectasia, two causative mutations, aﬀecting the activin receptor-like kinase (ALK-1) and endoglin (ENG) have been identiﬁed [29]. The telangiectasias have long been considered curiosities for the pathologist to describe, with only rare clinical signiﬁcance. They were most frequently found only at postmortem. Venous malformations, at one time not considered an entity, are discovered by MR imaging more than by any other technique. Usually small, their typical location is embedded in the wall of a ventricle, draining the local deep cerebral white matter [30], or the deep portions of the cerebellum. They have a characteristic angiographic appearance of vessels

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fanning from the center, giving rise to the term caput medusa [22,30–33]. Arterial ﬁstulazation may occur [30–34]. Few pathological studies have been done on these lesions, but they appear to be abnormally distended veins located in an abnormal location (i.e., deep in the white matter). Some evidence shows that they represent anomalous venous drainage, which compensates for the absence of normal venous conduits. These lesions rarely hemorrhage. Very few have been resected, and intraoperative studies show that they are devoid of arterial blood. Curiously, they appear to be associated with headaches and occasionally with seizures. There remains a low frequency of case reports, but current opinion is that they are usually benign [32]. They present with a lower frequency of hemorrhage than do AVMs [23] and are often considered as the cause of hemorrhage from cryptic malformations [18,33]. D. AVM Epidemiology During the last half of the twentieth century, scarcely more than a dozen publications described more than 100 cases per series [13,35–43]. These early studies suggested a very low prevalence, but the autopsy series of McCormick and Rosenﬁeld [44] found 196 AVMs among 4530 consecutive autopsies, an incidence of 4.3%. No major autopsy series has appeared since then. Given this lack of data, much attention has been paid to the 24 (12.2%) of McCormick’s cases who were symptomatic, 21 of whom had suﬀered hemorrhage, 16 described as ‘‘massive.’’ The remainder had epilepsy or steal phenomena. The distribution of AVMs in cerebral hemispheres was 118 (60%), 28 (14%) aﬀected the brain stem, and the spinal cord was the site in 5 (3%). This distribution closely approximates those in clinically symptomatic series. Other reports are from smaller cohorts. In one report of 100 patients angiogrammed for tandem lesions in a setting of high-grade carotid stenosis, two AVMs were found [45]. One consecutive series of MR found no AVMs among the cases. The largest case series of AVMs is still the one assembled as part of the cooperative study of subarachnoid hemorrhage [46,47]. The lesions were diagnosed by conventional angiogram. Symptomatic AVMs made up 549 of the 6368 cases, representing an incidence of 8.6% of subarachnoid hemorrhages. With the usual frequency of strokes attributed to subarachnoid hemorrhage being roughly 10%, these data provided a basis for considering AVMs to account for approximately 1% of all strokes. Similar ﬁgures have been documented in several small population-based studies in recent decades [48]. Recent work in the New York Islands AVM Study has accumulated over 150 cases from the population of some 9 million in a period of a year and a half, suggesting an incidence of some 1.21/ 100,000 person-years, of which 0.42/100,000 person-years were symptomatic from hemorrhage [49]. A similar incidence was gleaned from the smaller population base in the Northern Manhattan Stroke Study [50]. Estimates of the prevalence of AVMs, separate from the incidence, have been all but impossible to obtain, given the small fraction of total stroke cases that AVMs represent [51,52]. Given current concerns with therapy, the ratio of symptomatic to asymptomatic AVM cases, if known, could well inﬂuence the aggressive management plan for asymptomatic cases discovered by incidental imaging, as appears currently to be the case [53]. The inferred congenital nature of AVMs has been at odds with the very low reported rates of familial inheritance [54–58]. Fewer than 20 families make up the current literature. A mode of inheritance cannot currently be estimated. In contrast to the male preponderance in general for AVMs reported in clinical surgical services, the sexes are equally represented in the scanty family history data.

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II. FEATURES OF AVMs A. Location The wide range of locations for AVMs has defeated simple eﬀorts to characterize their inferred origin. The brain stem and cerebellum are involved slightly more frequently in infants and children [59]. In the adult population, volumetric studies suggest no special predilection for AVMs in any part of the brain [60]. Posterior fossa, at 12% of brain volume, is associated with 12–14% of malformations [60,150]. Location was long considered to have no bearing on the tendency for hemorrhage, growth, regression, vascular complexity, or size, but recent work has indicated that those with predominantly border zone location have a lower incidence of hemorrhage as a presentation and a higher incidence of seizures than do the deeper leasions [61]. Widespread acceptance of these ﬁndings might well impact on management decisions. The great variation in location has also indicated that lesions may be not merely multilobar or lobar—suggesting an anatomical site proclivity—but may also conform to the territory of a given artery, arguing for a vascular etiology separate from an anatomical lobar site. Thus, among the hitherto less well-described locations are the brain stem [62], corpus callosum [63], choroidal artery territory [64], and anterior dura. Some have been diﬀusely located along the course of the aﬀected artery [63] and some in sites remote from the main sensorimotor pathways, such as the occipital lobes (see below) [65]. B. Number The vast majority of AVMs are single, but there has been an increasing frequency of cases of multiple AVMs [9,66]. One series of 203 patients reported a frequency of 19 (9%) [9]. When multiple, the lesions are usually small. For multiple AVM cases, the risk of hemorrhage, seizures, or growth over time has not yet been studied adequately to infer a speciﬁc outcome related to this group. C. Clinical Classification Schemes In the last half of the twentieth century a series of classiﬁcation schemes were developed based on angiographic appearance [41,67–69]. Despite their usefulness in determining the operability of these lesions, most of these schemes have given way to the scale most widely used at present, that of Spetzler and Martin [70], based on surgical approach. Some doubts have been raised regarding the adequacy of grading systems, especially in the assessment of interobserver agreements. However, Hamilton and Spetzler [71] have reported that their 5point AVM grading system has had useful predictive value for neurological morbidity after embolization or surgery; of 120 cases treated overall, grades I–III showed no impairments, whereas those in grade IV had 21.9% and grade V 16.7%. D. Natural History and Clinical Presentation Limited information exists on the natural history of AVMs. Many retrospective studies of AVMs have aﬀorded us some insight into the clinical presentation of these lesions, but no deﬁnitive data are available on the natural history of a large group of avms obtained through prospective studies [13,36–43,72,73]. Experience painstakingly accumulated at a few large centers is the only information available [74].

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1. Hemorrhage This diagnosis was clinically inferred by the onset of stroke or by positive results of spinal ﬂuid examination in the days prior to the current wide availability of MR imaging. It has been the major event bringing an AVM to clinical attention. The main focus of the hemorrhage may be parenchymatous, ventricular, subarachnoid, or any combination thereof, depending on the site of the lesion and its venous drainage. Primarily parenchymatous hemorrhage occurs most often (63% of cases), while subarachnoid occurs in 32% and ventricular, least often, in 6%. A long list of publications indicates that smaller and deeper AVMs appear more prone to hemorrhage than do very large lesions [16,36,37,75–78]. Those straddling arterial border zones have recently been reported as having a lower incidence of presenting as hemorrhage [61]. Estimates of the risk of ﬁrst hemorrhage are highly dependent on the source of the clinical series. The widely quoted series from Crawford et al. [35] reported a 42% risk of rehemorrhage in 20 years and a slightly higher risk for smaller lesions. Ondra et al. [39] reported a mean follow-up time of 23.7 years for 160 of 166 (96%) symptomatic patients who had not undergone operation for a wide variety of reasons. This group of cases had a combined rate of mortality and major morbidity of 2.7% a year. The rate of rebleeding was 4% a year and that of mortality 1%. The rates seemed fairly constant from year to year. Horton et al. [38] estimated a roughly similar risk of 0.031 per patient-year based on the course of 540 patients seen in referral at a major hospital. At least 10% of AVMs show evidence of prior bleeding at surgery in reports dating over the last half century, more often encountered in the smaller AVMs [77,79]. This high prevalence of prior hemorrhage clearly indicates that many are small enough to escape clinical detection. The reason may have to do with high feeding artery pressures in these smaller lesions [78]. Once hemorrhage has occurred from any site, the risk of rehemorrhage is known to increase, but the extent and the timing are uncertain: in 81 cases of rehemorrhage in the Cooperative Study [46], 13 were third hemorrhages and 4 were fourth. In a separate study, Krayenbu¨hl and Yasargil [80] found that 12 of 53 recurrent hemorrhages had occurred more than once. Graf et al. [81] reviewed the records of 191 patients with AVMs, but the mean period of follow-up was a relatively short 2- to 5-year period. Nevertheless, there was a high rate of initial hemorrhage in the 11- to 35-year-old age group, and the rate of rebleeding was about 2% a year. Smaller lesions were more prone to hemorrhage, and approximately 13% of the patients died as a result of the hemorrhage. It is generally accepted that approximately 15% of operated AVMs show evidence of prior but asymptomatic hemorrhage [17]. A similar high rate of recurrence after the initial hemorrhage has also been reported from the Columbia AVM database, a more recent source of information than those cited above [82]. Settings for the rupture are not well correlated with similar exertional states commonly encountered with other causes of hemorrhage [40], a point against advising asymptomatic patients to live a completely sedentary life. Among pregnant women with AVM, bleeding rates of 0.031 per patient-year during pregnancy compare favorably with the 0.031 per patient-year risk for nonpregnant females [38], making avoidance of pregnancy less of an issue than in days where no data existed. Even vaginal delivery appears not notably associated with increased risk of bleeding [38,83]. Although the frequency of AVM hemorrhage approximates that of aneurysms, there is a growing awareness that the severity of the eﬀect of the hemorrhage appears to be much milder. In the large series by Pia et al. [84], among 16 patients with hematomas of 100–250 mL, only 1 died and 14 regained functional capacity. Four had slight to moderate

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hemiparesis, and two were asymptomatic. A prospective study of patients enrolled in the Columbia Presbyterian Medical Center AVM database and those in the larger New York Islands AVM Study who suﬀered a spontaneous recurrent hemorrhage showed a less severe syndrome than has traditionally been assumed to occur. In a one-year census of the NY Islands Study, none of the hemorrhage patients died, and only eight (24%) had disabling neurological deﬁcits. In these case series, those with purely intraventricular or subarachnoid hemorrhages seemed to have the best prognosis. The syndrome of parenchymal hemorrhage is similar to that from other causes, with focal neurological deﬁcits [17,47,52,72,85]. However, stroke from AVMs is diﬀerent from the usual parenchymal hemorrhage; the lesion is embedded in the brain, the bleeding ﬁrst expanding the ﬁstula before displacing healthy tissue, making for a milder syndrome for a given lesion volume than that from hypertensive hemorrhage. Those lesions located in polar regions of the brain may become apparent in the face of massive hemorrhage, with little more than headache and nonfocal symptoms related to the mass eﬀect and rise of intracranial pressure. However, those lesions located in deep structures such as the diencephalon, basal ganglion, or motor, sensory, and speech areas occur in regions with tightly compacted functionally important ﬁber systems, often creating more devastating neurological deﬁcits secondary to involvement of these areas. In some cases the hemorrhagic origin of the symptoms may not be recognized by the patient or the treating physician, but the current low threshold for imaging has led to more of them being discovered than in the past. Multiple hemorrhages associated with untreated AVMs are common [79]. The course of recidivous hemorrhages is unpredictable. The three main types of hemorrhage are: 1. The AVM bleeds mainly into the ventricular system, producing hemocephalus rather than parenchymatous damage. About 10% of patients have this picture. An unrelenting course over minutes from the onset of headache to stupor is the typical presenting picture. 2. The hemorrhage aﬀects the subarachnoid space in a fashion similar to ruptured aneurysm, potentially including severe vasospasm. About 10% of persons have this presentation, some on several occasions. 3. A deﬁcit due to a parenchymatous hemorrhage occurs followed by a satisfactory remission. The opportunity to make such a time-course observation is decidedly uncommon because the diagnosis as hemorrhage is increasingly documented by imaging and because of the great motivation for intervention. Little information can be found in the literature to corroborate our rough classiﬁcation, but examples can be found [86–90]. AVMs are believed to cause as few as 10% in some series of parenchymatous hematomas [88], an impression that may give some comfort to the physician faced with an etiological diagnosis. However, frequencies as high as 35–44% [47] in other series should promptly eliminate any complacency in attempts to make an etiological diagnosis on clinical grounds alone. The prognosis following hemorrhage with or without intervention varies widely. A few reports have detailed patients who made remarkable functional improvements despite hemorrhage and extensive surgery [87,91]. Cases have been described in which deep hemorrhages and the causative AVM have been removed with good results [88]. Others, however, were less fortunate [90,92]. Should AVMs have a better clinical outlook, more eﬀort might be appropriate to deal aggressively with such hematomas than is routinely the case in many institutions.

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2. Vasospasm After Hemorrhage This unwelcome outcome occurs with a far lower frequency compared with that associated with ruptured aneurysm [93,94]. Some reasons for this diﬀerence are that these lesions occur less frequently than do cerebral aneurysms, making a smaller data base for comparison, and they may be more frequently evaluated in the acute stage by arteriography, whereas spasm is generally seen on follow-up arteriography done a few days after the subarachnoid hemorrhage. More likely, however, is that they hemorrhage with less frequency into the large basal cisterns than aneurysms. In subarachnoid hemorrhage from aneurysms well out in the surface vasculature, spasm is also less common than those in the basal cisterns. Although the incidence of spasm is lower with AVMs, some instances of severe spasm can occur. If present, vasospasm should be treated vigorously by whatever techniques are currently preferred. 3. Aneurysms Long ignored, aneurysms are now known to coexist in approximately 10% of cases, in more recent large series up to 23% [93,95,150]. This possibility and the management options attached to aneurysms prompts the recommendation that AVM patients should undergo full angiography as part of their evaluation plan. They may be along arteries feeding the AVM or in separate vascular territories. Some may also be within the nidus itself. Sometimes the aneurysms are multiple. In cases where subarachnoid hemorrhage is the main clinical condition, a question arises as to which lesion has created the hemorrhage. 4. Seizures AVMs were often discovered, in the days prior to CT and MR brain imaging, in the aftermath of seizures. Seizures occur with low frequency, especially following hemorrhage, and the increasing practice of brain imaging for seizures often reveals AVM before rupture [26,67,96,97]. Seizures as the presenting syndrome occur over a remarkable range of incidence, varying from 28% (Cooperative Study) to 67% [46]. The incidence of seizures alone compared with seizures in association with hemorrhage also varies widely. Despite earlier opinions to the contrary in the literature [86,98], the clinical features of seizures are not distinctive for AVM [96]. There is no direct correlation between AVM size and the frequency, severity, or ease of control with medications [99–101]. A high correlation exists with border zone location [87], which has a lower incidence of hemorrhage than deeper lesions. The type of seizure has only rarely been reported. Individual case reports document typical focal epilepsy not associated with loss of consciousness; Jacksonian type, with or without the loss of consciousness; some akinetic events with sudden loss of function; and some generalized tonic–clonic seizures. Focal seizures predominate, varying from 45 to 59% [46]. In the Cooperative Study [46], 102 cases had seizures, 45% of which were focal, 42% generalized, 8% psychomotor, and 7% unspeciﬁed. Few reports describe seizures with occipital AVMs, many events taking the form of migraine aura [102]. 5. Headaches These complaints occur in association with some cases of AVMs, but they appear not to predict or be predicted by AVM. At one time considered to take a distinctive form in AVMs [86,102–104], modern studies have been unable to deﬁne a unique headache syndrome

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[75,104,105]. From the clinical diagnosis point of view, headaches identical to migraine occur [106], sometimes in the same patients who experience atypical migraine in other attacks [40,79,96,103,106]. That recurrent unilateral headache should arouse suspicion of an ipsilateral AVM is a concept put forward by Northﬁeld [24], dating from 1940, a time when the great rarity of angiographic basis for the diagnosis makes his comments an opinion, not a reliable data source. No unilateral predominance was found in the series of 100 cases reported by Parkinson and Bachers [69] or in the 70 cases described by Lees [106]. The yield of AVMs in a workup for headache seems quite low. In a lengthy review, Evans [107], surveying reports on brain imaging done for headache and normal neurological examination in 3026 brain scans, found that 0.2% were associated with AVM. The disappearance of migraine headaches postoperatively is not unusual and may occur following any type of operation. Disappearance of migraine after operation was a common feature of the early literature, which was made up mostly of single case reports. The question is now raised as to whether all patients with migraine should be evaluated for an AVM. At the very least, CT scan with large bolus contrast should be carried out in these individuals. If anything suspicious is noted, then MR scan should be performed. 6. Mass Lesions and Cerebral Steal AVMs commonly occupy a volume of space in the brain suﬃcient to cause symptoms from masses of other cause, yet few symptoms occur prior to the occurrence of hemorrhage. This observation led to assumptions that the AVM lesions displace function usually present at that site to adjacent regions, and the bulk of the lesion itself is clinically silent. Such seems to be the case, save in instances when venous obstruction causes edema in and around the regions of the lesion, creating a symptomatic mass that involves all of the edematous structures. This phenomenon is most commonly noted in those malformations that occupy a site adjacent to the aqueduct of Sylvius. In such instances, the distended veins may block the aqueduct, leading to hydrocephalus. In other instances, there is indirect evidence of a mass eﬀect through the development of a raised intracranial pressure perhaps similar to that seen with otitic hydrocephalus where the venous system is obstructed or carrying a higher pressure than it normally accommodates. Although rare, cases have been reported in which papilledema and raised intracranial pressures are a prominent part of the syndrome. Interestingly, this problem does not regress rapidly following the removal of the shunt. Some large AVMs create syndromes of pressure from enlargement of a draining vein; the pressure applied to the brain bends the nidus of the AVM proper and along the course of the vein only. Several dozen such cases have been reported [108]. Another potential source of symptoms may be attributed to ‘‘cerebral steal.’’ A large literature existed on this subject before the last decade [109–114]. This entity, in most cases actually explained by venous distortion or mass eﬀect, described above [115], has been inferred to exist in a small number of cases. Challenge oﬀered by a deliberately worded title arguing that such steal is an unestablished mechanism of symptoms in AVMs [116] has largely gone unanswered [117]. However, two instances have been described showing major increases in oxygen extraction adjacent to two ‘‘huge’’ AVMs [118], ﬁndings that they argued meant that some form of steal can occur in AVM and may prove reversible.

III. LABORATORY DIAGNOSES Because the clinical syndromes of AVM are not distinctive for the causes like those of subarachnoid hemorrhage from aneurysm, laboratory studies, especially brain imaging,

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play an important role. In approximately 10% of the patients, the diagnosis is discovered in a serendipitous fashion. A. Computed Tomography In 85% of AVMs diagnosis can be made by CT scan [53], contrast showing an enhancing lesion that is usually at the cortical level extending deep, whose margins are irregular, and which, when viewed with the most sophisticated CT scanners, may be associated with serpentine vascular channels. Large hemorrhages from one of these malformations can be recognized on the noncontrast scan, and these may be demonstrated in the ventricular system or in the subarachnoid cisterns at the base of the brain. A hemorrhage may partially obscure the malformation, which, however, should show up as an additional area of enhancement on the enhanced scan. When the malformation contains distended veins related to the aqueduct, hydrocephalus may be present. In patients who have had previous hemorrhages that are now resolved, the CT scan will often show an area of encephalomalacia, a cleavage area between the nidus of the malformation and the normal brain. Calcium may occasionally be present along with the AVM or associated with the encephalomalacia. Such areas of infarction or encephalomalacia may be extensive, with minimal neurological abnormalities. B. Magnetic Resonance Imaging MRI is fast overtaking CT and even conventional angiography in the diagnosis of AVM. Early reports with low ﬁeld magnets [119] showed the high-ﬂow vascular channels of an AVM as dark areas or regions of reduced signal. As opposed to angiogram, which reveals nothing of the brain parenchyma, MRI shows the relationships to the surrounding brain well and has proved superior to angiography in deﬁning the nidus. Evidence of prior hemorrhage and its source, the size of the nidus, the source of ﬂow to the lesion, the course of draining veins, and the relation of the malformation to normal brain structures are now regularly shown. A central focus of high signal surrounded by hypointensity, once thought pathognomonic of cavernous angiomas, has been found due to AVM in ﬁve of nine operated cases [120] and to neoplasm in 18 of 24 patients. Increasing use is being made of functional MR to identify functionally important tissue in or near the AVM. Many clinics now use this information in planning embolization, surgery, or radiotherapy [121–123]. C. Doppler Insonation Transcranial Doppler technology has increased the range of investigations for AVMs because the methodology has easy bedside use. Barely two decades old, the techniques for insonation of the intracranial vessels are now well described [124]. Using this method, investigations have demonstrated the principal sources of ﬂow to the lesion [125]. Doppler has also been used to plan and evaluate embolization therapy [126]. It is being used in investigations of perfusion breakthrough. In our experience, the pattern of low resistance to arterial ﬂow typical of AVMs has successfully predicted all angiographically obvious AVMs involving the cerebrum, missing only a handful of AVMs whose shunts required careful examination of the angiogram for their detection, or whose small feeders were exclusively from the anterior choroidal territory. In a recent report from our center,114 consecutive cases of AVM were compared with 22 non-AVM hemorrhage cases and 52

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normals. Medium- to large-size AVMs were easily detected, but 62% of small ones (most requiring angiogram for documentation) were not. Transcranial Doppler was also highly sensitive (80%) in a group of ﬁve AVM patients with acute hemorrhage. No relationship was found between ﬂow velocities and the occurrence of hemorrhage (mean velocities f110 –114 cm/s in both groups). No support was found for the notion of steal. Impaired CO2 reactivity is typical of vessels feeding AVMs and is not seen in those not feeding the malformation, save for the posterior cerebral arteries. Some cases have been reported in which the posterior cerebral artery not feeding the AVM has also shown impaired reactivity; the reasons are not known [127]. Color-coded transcranial Doppler is only now making an appearance, but some of the experience to date has been encouraging. The larger lesions may actually be imaged as well as insonated [128,151]. D. Angiography In spite of advances in other forms of diagnostic imaging, arteriography remains the foundation of the diagnosis of vascular abnormalities and has proved superior to MR in deﬁning the details of the vascular supply [129]. However, a few examples of thrombosed, nonhemorrhagic AVMs have been found by brain imaging that were not shown by angiogram [19,20]. Angiography plays a major role in preparing the patient for therapy. Full documentation of the lesion involves rapid sequence ﬁlming, magniﬁcation of certain arterial territories, separate injection of the extracerebral vessels, and stereoangiography done in the lateral series. Rapid-sequence ﬁlming at rates of ﬁve to six per second assists in the analysis of arterial supply in terms of number, source, and size of the feeding arteries. This method is being increasingly superceded by digital imaging, using techniques that allow rotation of the image, which formerly required stereoscopic plain ﬁlms. The goal of all such methods is to assess when the artery feeding the malformation also feeds healthy cerebrum in its more distal branches. It is recognized that arterial contributions to an AVM are numerous, and not all may be identiﬁed by angiogram; however, the major ones playing a role in embolization or surgery of an AVM may be identiﬁed by conventional angiography. Modern computer processing is allowing detailed three-dimensional maps of AVMs from multiple images [130,131]. Other techniques that have proved useful are magniﬁcation angiography and large injections of contrast material with a prolonged venous phase. In terms of magniﬁcation angiography, there are disadvantages to be considered. The malformation and its components are visualized in a somewhat distorted view, which makes exact measurements and the study of relationships diﬃcult. However, magniﬁcation angiography will demonstrate small feeders to the malformation, which may not be identiﬁed on standard angiography. All forms of angiography should be as selective as possible. For practical purposes this means injection of the vertebral or internal carotid arteries, since techniques for injection directly into the distal feeding vessels of a vascular malformation are cumbersome and not yet readily available. External carotid injection is essential to document dural feeders, which are found the more they are sought, especially in posterior hemispheral and posterior fossa AVMs. Angiotomography and cineangiography is coming into more widespread use but thus far still remains incompletely developed for AVMs. Digital subtraction angiography, especially with arterial injection, once in its technological adolescence insuﬃcient of giving extensive details of these lesions to be of major help in planning an operation, has advanced to the standard technique now satisfying most

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needs for high-resolution radiography. Although multiple AVMs are infrequent [132], the association with aneurysms is well recognized so that comprehensive four-vessel angiography should be carried out in all patients. If severe arterial vasospasm is present once the lesion has been identiﬁed, the remainder of the arteriographic study should be deferred to a later date. The high-volume injection of contrast agent and a prolonged venous phase are essential in identifying the somewhat ubiquitous and obscure venous malformations. Cavernous malformations rarely show at angiography since their arterial feeders are small and infrequent. In planning embolization it is frequently necessary to use a diﬀerent catheter system for diagnosis than for interventional neuroradiology [76,109,133]. In such cases, angiography will be repeated at the time of embolization once this is selected as the course of treatment. Intraoperative arteriography is a diﬃcult procedure that delays an already long operation and has thus far had limited use.

IV. TREATMENT A. Surgery It has long been assumed that the AVM must be removed in its entirety to prevent regrowth or hemorrhage. Where this dogma arose has not been easy to discover. As far back as 1920, Walter Dandy, one of the preeminent neurosurgeons of his day, expressed the opinion (held as of today by many) that ‘‘the only way to cure an arteriovenous aneurysm [n.b.—his term for AVM] is to ligate the entering artery or excise the vascular tumor. But the radical attempt at cure is attended by such supreme diﬃculties as is so exceedingly dangerous as to be contraindicated except in certain selected cases’’ [75]. It may have been the futility of ligation of feeding arteries in the decades before microsurgery that encouraged the view that any less than full removal was futile. In any event, modern high-quality angiograms done in the immediate postoperative period have left some investigators of diﬀering opinions as to whether any small angiographic signs of residua can be found [134,135], but it was long assumed that an AVM successfully removed as indicated by its absence on postoperative angiogram was a permanent cure. An unsettling emerging literature suggests that recurrence may be more frequent than has long been supposed [136]. Recent imaging has revealed some remarkable examples of relapse years later, some of them appearing as if they had never been removed [136]. Apart from the increasing concerns about recurrence of AVMs postoperatively, the preoperative assessment as to the feasibility of safe removal has led to a number of classiﬁcations, the most common being that derived by Spetzler and Martin [70] based on risks of mortality and morbidity associated with operative intervention. This scale includes an assessment of the site of the lesion as if occurring in an otherwise healthy brain area. Described as ‘‘eloquent,’’ the weighting given to whether operation in a given area is assumed to carry a risk of neurological deﬁcit plays an important role in the SpetzlerMartin scale. Given its presumed importance, it has been somewhat unsettling to ﬁnd that the ‘‘eloquent’’ component had a lower predictive value for operative neurological deﬁcit when tested in our case population [152]. The ﬁgures for morbidity and mortality vary widely by institution, among other factors depending on adjudication of adverse events. In our large series of AVMs for which an operation with complete resection was performed, the treatment risks (with independent adjudication) were <2% for perioperative mortality, 15% for early disabling and 26% for early nondisabling morbidity. At a mean follow-up period of one year, the

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rates for late morbidity attenuated to 6% and 32% for disabling and nondisabling deﬁcits, respectively [152]. B. Interventional Radiology For embolization, the early opinions of Luessenhop and Presper [133] still hold sway— that short of total obliteration of the malformation, embolization provides little protection from recurrent hemorrhage or progressive neurological deﬁcit. They noted that seizures were easier to control following embolization, but this may be a result of closer scrutiny of the patient rather than a direct eﬀect of the embolization, and little current data supports this early impression. It is our clinical impression that embolization aﬀords some protection and amelioration of symptoms when there is a signiﬁcant reduction in the AVM. These unsettling cases have prompted questioning of the former doctrine that any treatments that fall short of total obliteration of the AVM, including embolization [76], radiotherapy [137], and partial surgical procedures [91], are inadequate. Further work is needed, but embolization to anatomical completeness may eventually prove as eﬀective as surgical extirpation. Two recent publications provide incomplete evidence supporting a beneﬁt from embolization [138,139]. This emerging literature is a challenge to conventional surgery and is sure to stimulate more clinical research. C. Radiotherapy Increasingly popular, this approach has been shown to obliterate some of the smaller lesions [137], but higher doses are required for the larger lesions, raising concern for radiation necrosis [140] and uncertainty of success. The course of the lesions has been shown by repeat angiograms in only a few studies. Growth of the AVM has been documented, as has stability and even regression [4,141–143]. Minakawa et al. [142] repeated the angiogram 5–28 years after ﬁrst discovery or treatment in 20 patients, 16 of whom were untreated while the remaining were residual. The AVM was unchanged in eight, larger in four, smaller in four, and had disappeared in four. The AVMs that disappeared were relatively small and fed by a single feeder or a few feeders. It remains to be seen whether such ﬁndings will be reproduced by others, but the possibility of estimation of AVM size by MR should stimulate such studies in the future. One of the major restrictions in published data on obliteration rate has repeatedly been overestimation due to follow-up bias towards those individuals who underwent postradiation arteriography [153]. Reported average obliteration rates after 2 years of approximately 40–50% are reported [153–155], and overall vary between 60.5% and 78.9% [154–157], in pediatric and adolescent populations even more between 35 and 94.7% [158,159]. Both the latency until obliteration and the signiﬁcant proportion of non- or partial responders imply a persistent risk of hemorrhage, estimated as around 1.5–1.8% per year after radiotherapy [159,160]. Moreover, only little data exist on long-term eﬀects of stereotactic radiation [161–164].

REFERENCES 1. Stapf C, Mohr JP. New concepts in adult brain arteriovenous malformations. Curr Opin Neurol 2000; 13(1):63–67.

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135. Solomon RA, Connolly ES Jr, Prestigiacomo CJ, MKhandji AG, Pile-Spellman J. Management of residual dysplastic vessels after cerebral arteriovenous malformation resection: implications for postoperative angiography. Neurosurgery 2000; 46(5):1052–1060. 136. Kader A, Goodrich JT, Sonstein WJ, Stein BM, Carmel PW, Michelsen WJ. Recurrent cerebral arteriovenous malformations after negative postoperative angiograms. J Neurosurg 1996; 85(1):14–18. 137. Kjellberg RN, Hanamura T, Davis KR, Lyons SL, Adams RD. Bragg-peak proton-beam therapy for arteriovenous malformations of the brain. N Engl J Med 1983; 309(5):269–274. 138. Meisel HJ, Mansmann U, Alvarez H, Rodesch G, Brock M, Lasjaunias P. Eﬀect of partial targeted N-butyl-cyano-acrylate embolization in brain AVM. Acta Neurochir (Wien) 2002; 144(9):879–887. 139. Wikholm G, Lundqvist C, Svendsen P. The Goteborg cohort of embolized cerebral arteriovenous malformations: a 6-year follow-up. Neurosurgery 2001; 49(4):799–805. 140. Statham P, Macpherson P, Johnston R, Forster DM, Adams JH, Todd NV. Cerebral radiation necrosis complicating stereotactic radiosurgery for arteriovenous malformation. J Neurol Neurosurg Psychiatry 1990; 53(6):476–479. 141. Mendelow AD, Erfurth A, Grossart K, Macpherson P. Do cerebral arteriovenous malformations increase in size? J Neurol Neurosurg Psychiatry 1987; 50(8):980–987. 142. Minakawa T, Tanaka R, Koike T, Takeuchi S, Sasaki O. Angiographic follow-up study of cerebral arteriovenous malformations with reference to their enlargement and regression. Neurosurgery 1989; 24(1):68–74. 143. Spetzler W, RF C. Enlargement of an AVM documented by angiography: case report. J Neurosurg 1975; 43:767. 144. Alkadhi H, Kollias SS, Crelier GR, Golya X, Hepp-Reymond M-C, Valavanis A. Plasticity of the human motor cortex in patients with arteriovenous malformations: a functional MR imaging study. AJNR Am J Neuroradiol 2000; 21:1423–1433. 145. Rigamonti D, Hadley MN, Drayer BP, Johnson PC, Hoenig-Rigamonti K, Knight JT, Spetzler RF. Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 1988; 319(6):343–347. 146. Horowitz M, Kondziolka D. Multiple familial cavernous malformations evaluated over three generations with MR. AJNR Am J Neuroradiol 1995; 16:1353–1355. 147. Brunereau L, Labauge P, Tournier-Lasserve E, Laberge S, Levy C, Houtteville J-P. Familial form of intracranial cavernous angioma: MR ﬁndings in 51 families. Radiology 2000; 214:209–216. 148. Reich P, Winkler J, Straube A, Steiger HJ, Peraud A. Molecular genetic investigations in the CCM1 gene in sporadic cerebral cavernomas. Neurology 2003; 60:1135–1138. 149. Denier C, Labauge P, Brunereau L, Cave´-Riant F, Marchelli F, Arnoult M, et al. Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 2004; 55:213–220. 150. Khaw AV, Mohr JP, Sciacca RR, Schumacher HC, Hartmann A, Pile-Spellman J, et al. Association of infratentorial brain arteriovenous malformations with hemorrhage at initial presentation. Stroke 2004; 35:660–663. 151. Uggowitzer MM, Kugler C, Riccabona M, Klein GE, Leber K, Simbrunner J, Quehenberger F. Cerebral arteriovenous malformations: diagnostic value of echo-enhanced transcranial Doppler sonography compared with angiography. AJNR Am J Neuroradiol 1999; 20(1):101–106. 152. Hartmann A, Stapf C, Hofmeister C, Mohr JP, Sciacca RR, Stein BM, et al. Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke 2000; 31:2361–2364. 153. Heﬀez DS, Osterdock RJ, Alderete L, Grutsch J. The eﬀect of incomplete patient follow-up on the reported results of AVM radiosurgery. Surg Neurol 1998; 49:373–384. 154. Chang JH, Chang JW, Park YG, Chung SS. Factors related to complete occlusion of arteriovenous malformations after gamma knife radiosurgery. J Neurosurg 2000; 93(suppl 3):96–101. 155. Yamamoto M, Hara M, Ide M, Ono Y, Jimbo M, Saito I. Radiation-related adverse eﬀects

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Mohr et al. observed on neuro-imaging several years after radiosurgery for cerebral arteriovenous malformations. Surg Neurol 1998; 49:385–398. Yamamoto M, Jimbo M, Hara M, Saito I, Mori K. Gamma knife radiosurgery for arteriovenous malformations: long-term follow-up results focusing on complications occurring more than 5 years after irration. Neurosurgery 1996; 38(5):906–914. Schlienger M, Atlan D, Lefkopoulos D, Merienne L, Touboul E, Missir O, et al. Linac radiosurgery for cerebral arteriovenous malformations: results in 169 patients. Int J Radiat Oncol Biol Phys 2000; 46(5):1135–1142. Smyth MD, Sneed PK, Ciricillo SF, Edwards MS, Wara WM, Larson DA, et al. Stereotactic radiosurgery for pediatric intracranial arteriovenous malformations: the University of California at San Francisco experience. J Neurosurg 2002; 97:46–55. Shin M, Kawamoto S, Kurita H, Tago M, Sasaki T, Morita A, et al. Retrospective analysis of a 10-year experience of stereotactic radiosurgery for arteriovenous malformations in children and adolescents. J Neurosurg 2002; 97:779–784. Karlsson B, Lax I, So¨derman M. Risk for hemorrhage during the 2-year latency period following gamma knife radiosurgery for arteriovenous malformations. Int J Radiat Oncol Biol Phys 2001; 49(4):1045–1051. Flickinger JC, Kondziolka D, Lunsford LD, Pollock BE, Yamamoto M, Gorman DA, et al. A multi-institutional analysis of complication outcomes after arteriovenous malformation radiosurgery. Int J Radiat Oncol Biol Phys 1999; 44(1):67–74. Husain AM, Mendez M, Friedman AH. Intractable epilepsy following radiosurgery for arteriovenous malformation. J Neurosurg 2001; 95:888-892. Kihlstrom L, Guo W-Y, Karlsson B, Lindquist C, Lindqvist M. Magnetic resonance imaging of obliterated arteriovenous malformations up to 23 years after radiosurgery. J Neurosurg 1997; 86:589–593. Kaido T, Hoshida T, Uranishi R, Akita N, Kotani A, Nishi N, Sakaki T. Radiosurgeryinduced brain tumor. J Neurosurg 2001; 95:710–713.

26 The Diagnosis and Management of Cerebral Venous Thrombosis David Lee Gordon University of Miami School of Medicine, Miami, Florida, U.S.A.

Cerebral venous thrombosis (CVT) occurs as a consequence of other conditions, in particular hypercoagulable states. Thus, arterial thromboses or noncerebral venous thromboses may coexist in patients with CVT. Patients with CVT have a high incidence of pulmonary embolism due to either direct thromboembolism from the cerebral sinovenous system or a generalized disturbance in coagulation [1]. In the last decade there has been an increase in the diagnosis and survival of patients with CVT due to (1) improved knowledge and appreciation of hypercoagulable states, (2) improved ability to detect CVT with noninvasive testing such as magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) or, more speciﬁcally, magnetic resonance venography (MRV), (3) improved ability to predict outcome using magnetic resonance diﬀusion-weighted imaging (DWI), and (4) improved prognosis of patients with even severe neurological deﬁcits due to the increased use of anticoagulation. CVT, however, remains a diagnostic and therapeutic challenge due to (1) its variable clinical manifestations, (2) its variable MRI ﬁndings, (3) insuﬃcient medical school and postgraduate training regarding cerebral venous anatomy and thrombosis, and (4) persistent controversy regarding its optimal treatment. The keys to diagnosis are clinical suspicion based on the coexistence of a CVT clinical syndrome with a condition known to predispose to CVT and the proper interpretation of MRI and MRV. The keys to management are the use of full-dose anticoagulation—even in the presence of signiﬁcant intracranial hemorrhage—and an appreciation and understanding of hypercoagulable states. CVT aﬀects people of any age, and its incidence is not known. Due to the diﬃculty in diagnosing CVT, retrospective studies underestimate its true incidence. There have been only two prospective autopsy studies with markedly diﬀerent results. In a 1973 study, Towbin found that 17 of 182 (9.3%) autopsied patients had CVT, an incidence that was much higher than previously thought, though it still did not take into account patients with CVT who survive [2]. In a 2003 study, Bienfait and colleagues reported a prospective autopsy series of 102 patients and found only one case of latent CVT [3]. The low postmortem incidence in this study may be due to improved detection and survival of CVT patients in recent years. In 1995, Daif and colleagues estimated the hospital frequency of CVT to be 7 in 100,000 adult patients and the ratio of CVT to arterial strokes to be 1:62.5, though this ratio was only 1:8.5 in patients aged 15–45 [4]. This author’s experience parallels that of other 605

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investigators: a busy academic stroke service will diagnose CVT on average four to seven times per year [4–8]. In children the estimated incidence of CVT is 0.29 per 100,000 per year, accounting for one fourth of pediatric ischemic cerebrovascular cases [9].

I. CEREBRAL SINOVENOUS ANATOMY Since MRI and MRV interpretation is integral to the diagnosis of CVT, clinicians should have at least a rudimentary knowledge of cerebral sinovenous anatomy (Fig. 1) and drainage patterns. Most cerebral veins and sinuses ﬂow in an axial plane (forehead to occiput, the same plane as the long axis of the skull). This is perpendicular to the ﬂow of cerebral arteries, which primarily occurs in the coronal plane (skull base to top of skull). Ultimately, however, all venous blood drains inferiorly via the two internal jugular veins. Knowing the direction of ﬂow assists in the interpretation of MRA. In order to detect ﬂow on MRA, one must acquire the images in a plane perpendicular to the direction of ﬂow. Thus, coronal acquisitions are optimal for MRV. Since cerebral veins and sinuses do not have valves, sinovenous occlusions cause increased venous pressure, the pathophysiological basis for the clinical features of CVT. Increased venous pressure causes (1) increased intracranial pressure, (2) blood–brain barrier disruption, with resultant leakage of ﬂuid (vasogenic edema) and diapedesis (hemorrhage), and (3) decreased capillary perfusion pressure, which in turn leads to arterial ischemia and infarction (cytotoxic edema). A. Superficial Veins and Sinuses The superﬁcial sinovenous system consists of cortical veins and the dural sinuses, including the superﬁcial sagittal sinus, inferior sagittal sinus, torcular Herophili, transverse sinuses, and sigmoid sinuses. Although the straight sinus is a dural sinus and thus anatomically is

Figure 1 Three-dimensional view of the cerebral sinovenous anatomy and its relation to the dura and skull.

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usually included with the superﬁcial sinuses, functionally and clinically it is best included with the deep sinuses because it is the primary outlet for the deep venous system. Several cortical veins (also called cerebral veins) drain the medial and dorsal aspects of the frontal, parietal, and occipital lobes. The cortical veins usually course anteromedially to enter the superior sagittal sinus in the direction opposite the ﬂow of blood within the sinus. The superior sagittal sinus originates at or just superior to the foramen cecum of the frontal bone, occasionally communicating with small nasal veins. It courses posteriorly in the dorsal aspect of the falx cerebri and terminates near the internal occipital protuberance, draining either directly into the right transverse sinus or, less commonly, into the torcular Herophili. Due to its relatively large diameter and midline position, one can often visualize the superior sagittal sinus coursing over the cerebrum on midsagittal MRI. Coronal MRI displays the sinus in cross section. The inferior sagittal sinus courses posteriorly in the ventral aspect of the falx cerebri. It receives veins that drain the corpus callosum, cingulate gyri, and adjacent medial hemispheres and empties into the straight sinus [10]. The inferior sagittal sinus is often so narrow that it is not readily seen on MRI. The torcular Herophili (‘‘the wine press of Herophilus’’) is located at the internal occipital protuberance. It is often called the conﬂuence of the sinuses because it is where the superior sagittal sinus and the straight sinus join the two transverse sinuses. Most often, however, the torcular is not truly a conﬂuence because the superior sagittal sinus drains directly into the right transverse sinus and the straight sinus drains directly into the left transverse sinus. The transverse sinuses are located within the attached margin of the tentorium cerebelli. They course laterally and anteriorly from the occipital protuberance or torcular Herophili to the base of the petrous portion of the temporal bone to form the sigmoid sinuses. The right transverse sinus usually drains the superior sagittal sinus and thus is an important venous outlet for the cerebral cortex. The left transverse sinus usually drains the straight sinus and thus is an important venous outlet for the subcortical cerebral hemispheres. The sigmoid sinuses are adjacent to the mastoid processes of the temporal bones and traverse the jugular foramina where they empty into the internal jugular veins. The term lateral sinus refers to the transverse and sigmoid sinuses together. The superior petrosal sinuses empty into the transverse or sigmoid sinuses, and the inferior petrosal sinuses empty into the sigmoid sinuses or the internal jugular veins. The petrosal sinuses drain the cavernous sinuses and veins from the cerebellum, pons, and medulla. B. Deep Venous System The deep venous system includes the internal cerebral veins, the basal veins of Rosenthal, the great vein of Galen, and, functionally, the straight sinus. The internal cerebral veins drain the corpus callosum and interior cerebral hemisphere, including the thalami, caudate nucleus, and superior aspect of the lentiform nucleus. The basal veins of Rosenthal drain the midbrain, inferior aspect of the lentiform nucleus, and medial temporal lobe. The internal cerebral veins and basal veins join to form the great vein of Galen, which is large in diameter, but is actually quite short and drains posteriorly into the straight sinus. The great vein of Galen is often well seen on midsagittal MRI, but since blood ﬂow in the great vein generally runs in the coronal plane, perpendicular to ﬂow in most other veins, it is often not well visualized on MRV even when patent. The straight sinus courses from the splenium of the corpus callosum to the occipital protuberance, running in the dural fold formed by the juncture of the falx cerebri and the

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tentorium cerebelli. It is an extension of the great vein of Galen as that vein joins the inferior sagittal sinus. The straight sinus usually receives cerebellar veins and drains either directly into the left transverse sinus or, less commonly, into the torcular Herophili. It is often well seen on midsagittal MRI just superior to the cerebellum. C. Cavernous Sinuses The cavernous sinuses lie on either side of the sphenoid bone, superolateral to the sphenoid air sinus, and extend from the superior orbital ﬁssures to the dorsum sellae. They receive blood from facial, ophthalmic, retinal, cerebral, and meningeal veins. The cavernous sinuses communicate with each other across the sella through the circular (intercavernous) sinus. They drain posteriorly into the superior and inferior petrosal sinuses, thus communicating with the lateral sinuses. Passing through the walls of the cavernous sinus are the internal carotid artery (siphon or intracavernous portion); the oculomotor, trochlear, and abducens nerves; and the ophthalmic and maxillary divisions of the trigeminal nerve. Oculosympathetic ﬁbers accompany the internal carotid artery into the sinus and exit with the ophthalmic nerve.

II. CLINICAL PRESENTATION CVT may present acutely, subacutely, or chronically [5]. The most common clinical features of CVT in adult patients, with estimated percent frequency, are headache (75%), papilledema (50%), seizures (50%), focal deﬁcits (50%), and altered consciousness (33%) [4,6,8,11,12]. The symptoms and signs that occur as result of cerebral venous occlusion are due to a combination of the nonfocal syndrome of intracranial hypertension (increased intracranial pressure) and focal neurological deﬁcits due to parenchymal brain lesions. The speciﬁc deﬁcits vary depending on the location of the sinovenous thrombosis (e.g., superﬁcial sagittal sinus, lateral sinus, deep veins). The natural history of CVT is unclear because our knowledge is based on case reports and retrospective series of patients receiving various therapies that likely aﬀect prognosis. Lesion pathology also aﬀects prognosis. Deﬁcits due to water leakage (vasogenic) edema are largely reversible, while those due to cell-death (cytotoxic) edema are largely irreversible. The outcome of patients with intracerebral hemorrhage due to CVT is diﬃcult to predict— their prognosis may actually be quite good, especially if level of consciousness is not signiﬁcantly aﬀected. Table 1 summarizes the four main clinical syndromes of CVT. A. Intracranial Hypertension Approximately 90% of patients with CVT have symptoms consistent with intracranial hypertension, most often with associated focal signs or seizures [7]. Patients with intracranial hypertension due to cerebral venous occlusion commonly present with a persistent diﬀuse or focal headache, often with papilledema. Other related symptoms include nausea, vomiting, visual blurring or obscurations, diplopia (most commonly horizontal diplopia due to the false localizing sign of uni- or bilateral abducens nerve palsies), depressed consciousness, and confusion. The syndrome of intracranial hypertension may occur in patients with thrombosis of the superior sagittal sinus, lateral sinus, or deep cerebral veins. Often the thrombosis extends to more than one sinus. Otitic hydrocephalus is a term used primarily in the otolaryngology

Any cerebral sinus or vein

Pseudotumor cerebri Intracranial mass lesion Hydrocephalus

Thrombus location

Diﬀerential diagnosis

Ischemic stroke Intracerebral hemorrhage Hemorrhagic tumor Vascular malformation

Seizures -partial or generalized Focal deﬁcit(s) -cortical signs, e.g., aphasia -hemiparesis -bilateral, leg > arm (SSS) -cranial nerve palsies (LS) Lobar (uni- or bilateral) -paramedian (SSS) -temporal (LS) Pathology -vasogenic edema -cytotoxic edema/infarction -hemorrhage Superior sagittal sinus (SSS) Lateral sinus (LS) Cortical vein

Superﬁcial CVT

Deep CVT

Subcortical (esp. bilateral) -thalami -basal ganglia Pathology -vasogenic edema -cytotoxic edema/infarction -hemorrhage Straight sinus Great vein of Galen Basal veins of Rosenthal Internal cerebral veins Ischemic stroke (top of the basilar) Toxic-metabolic encephalopathy Creutzfeldt-Jakob disease

Delirium/subacute dementia Depressed consciousness Focal deﬁcits

Any combination of the four syndromes may coexist in an individual patient. Neonates and young infants may also present with behavioral changes and signs of cranial swelling.

Focal lesions

Headache Papilledema Nausea, vomiting Depressed consciousness Visual obscurations Diplopia Tinnitus None

Clinical features

Intracranial hypertension

Table 1 Clinical Syndromes of Cerebral Venous Thrombosis (CVT)

Orbital/retro-orbital mass Tolosa-Hunt syndrome Mucormycosis Aspergillosis

Cavernous sinus -uni- or bilateral

Retro-orbital edema

Swollen eye, eyelid, disk Ophthalmoplegia Pupillary changes Facial sensory loss (V1-2) Ipsilateral carotid stroke Systemic infection

Cavernous thrombosis

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literature; it refers to intracranial hypertension secondary to ear infection and resultant lateral sinus thrombosis but is a misnomer, since the ventricles are not dilated in this condition. Some patients with CVT present only with nonfocal symptoms and signs referable to increased intracranial pressure, resembling the syndrome of idiopathic intracranial hypertension (pseudotumor cerebri), a condition that occurs primarily in young obese women. In one series, 37% of 160 CVT patients had isolated intracranial hypertension (headache or papilledema or abducens nerve palsy without focal signs or altered consciousness) [7]. In another study, investigators found that 10% of patients with chronic daily headache had cerebral venous thrombosis [13]. One should consider the diagnosis of CVT in any patient with persistent headache and no discernible intracranial mass lesion on imaging study, particularly if papilledema is present.

B. Superficial Sinus Thrombosis Focal signs due to thrombosis of the superﬁcial sinovenous system include partial seizures with or without secondary generalization, aphasia and other cortical deﬁcits, hemiparesis, hemisensory loss, and hemianopsia. Vasogenic edema, cerebral infarction, or lobar hemorrhage may occur as a direct result of sinus occlusion or via extension of thrombus to cortical veins. The superior sagittal sinus is the most common location for CVT, occurring in approximately 75% of cases; the lateral sinus is the second most common location, occurring in just over 50% of cases; and cortical vein thrombosis occurs in about 25% of cases [4,6–8,12]. Due to its midline location, thrombosis of the superior sagittal sinus may result in bilateral symptoms involving legs more than arms. Lateral sinus thrombosis may cause lesions in the temporal or occipital lobes or may present with single or multiple cranial nerve palsies, particularly cranial nerves three through eight [14].

C. Deep Vein Thrombosis Thrombosis involving the deep cerebral veins generally results in one of two syndromes, either acute confusion with depressed consciousness or subacute dementia marked by disorientation, attention deﬁcits, abulia, short-term memory loss with confabulation, and dyscalculia [15–22]. The former syndrome commonly leads to rapid coma and death if not treated quickly [16]. Focal deﬁcits (e.g., hemiparesis, hyperreﬂexia) and eye movement abnormalities (e.g., dysconjugate gaze, nystagmus) may also occur with deep CVT. Bilateral thalamic edema may result in compression of the Sylvian aqueduct or third ventricle and resultant superimposed hydrocephalus. Thrombosis of the deep cerebral veins, including the straight sinus, occurs in approximately 25% of CVT cases [4,6–8,12]. One should suspect the diagnosis in any patient with bilateral lesions (edema/infarction or hemorrhage) in the thalami or basal ganglia.

D. Cavernous Sinus Thrombosis Patients with cavernous sinus thrombosis have ocular symptoms and signs. Lesions of the cavernous sinus are manifested by headache or retro-orbital pain, periorbital edema,

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chemosis, proptosis, ptosis, ophthalmoplegia, pupillary abnormalities, and upper face numbness. The pupil may be dilated due to oculomotor nerve palsy or constricted due to Horner’s syndrome. Retinal hemorrhages and a swollen optic disk may be present. Unilateral thrombosis may spread via the circular (intercavernous) sinus to become bilateral. Since infection is the most common cause of cavernous sinus thrombosis—especially sphenoid sinusitis—these patients often present with fever or other signs of sepsis [23]. Involvement of the carotid artery siphon by compression, focal arteritis, or extension of infection may result in carotid occlusion or embolism and ischemic strokes of the ipsilateral hemisphere. Rarely, the carotid wall is suﬃciently weakened to result in a carotid–cavernous sinus ﬁstula. Cavernous sinus thrombosis may extend posteriorly along the petrosal sinuses to the lateral sinus and result in a syndrome of intracranial hypertension. E. Young Children Neonates and young infants with CVT whose cranial sutures have not yet closed may present with a tense fontanelle, dilated scalp veins, and scalp edema as well as depressed consciousness, seizures, respiratory distress, fever, and decreased oral intake [9]. In neonates, both superﬁcial and deep CVT may cause intraventricular hemorrhage [24–26]. Older children with CVT often have seizures and manifest the symptoms of intracranial hypertension as would adults, with headache, papilledema, vomiting, and abducens nerve palsy [9]. Among children with CVT who do not receive anticoagulation, developmental delay is a common long-term sequela; residual focal deﬁcits such as hemiparesis are less common [9].

III. PREDISPOSING CONDITIONS As originally described by Virchow in 1856, thrombosis occurs as a result of changes in (1) the blood, (2) blood ﬂow, or (3) the vessel wall [27]. This rule holds true for thrombosis in cerebral veins as well as peripheral veins. Thus, one may organize the etiologies of CVT into three categories: hypercoagulable states, low-ﬂow states, and vessel-wall abnormalities (Table 2). Very often the presence of more than one condition is necessary before a patient develops CVT [28–32]. Commonly, a subclinical hypercoagulable state becomes apparent only after a second condition occurs, for example, patients with prothrombin G20210A mutation present with CVT only after beginning oral contraceptives or developing otitis media and mastoiditis [29,32], a man with anticardiolipin antibodies develops CVT only after suﬀering neck trauma [33], or a woman with Crohn’s disease and previously undiagnosed free protein S deﬁciency develops CVT only after giving birth to her ﬁrst child (Figs. 2–5). A. Hypercoagulable States Normally, blood is ﬂuid within the arteries and veins in order to transport nutrients and waste products, yet is able to gel quickly in order to plug leaks and prevent blood loss from the vascular system. The blood and vessels balance ﬂuidity and coagulation through the complex interplay of naturally occurring antithrombotic and prothrombotic properties. The normal venous endothelium prevents thrombosis by producing coagulation-factor inhibitors. The liver produces circulating anticoagulants such as protein C, protein S, and

612 Table 2 Etiologies or Predisposing Conditions Associated with Cerebral Vein Thrombosis I.

Hypercoagulable states a. Deﬁciencies of natural anticoagulants i. protein C ii. protein S total iii. protein S free iv. antithrombin III b. Dysfunctional clotting factors i. activated protein C resistance ii. Leiden factor V mutation iii. prothrombin (factor II) G20210A mutation iv. dysﬁbrinogenemia c. Decreased ﬁbrinolysis i. plasminogen activator inhibitor-1 ii. liproprotein (a) d. Elevated coagulation factors i. ﬁbrinogen ii. factor VIII e. Hyperhomocysteinemia f. Antiphospholipid antibodies i. lupus anticoagulant ii. anticardiolipin antibodies (IgG, IgM) iii. anti-beta-2-glycoprotein 1 antibodies (IgG, IgM) g. Estrogen changes i. pregnancy ii. puerperium iii. oral contraceptives h. Inﬂammatory bowel disease i. ulcerative colitis ii. Crohn’s disease i. Nephrotic syndrome j. Disorders of blood elements i. polycythemia vera ii. essential thrombocythemia iii. paroxysmal nocturnal hemoglobinuria iv. sickle-cell disease and trait v. hypereosinophilia vi. immune-mediated heparin-induced thrombocytopenia k. Other hypercoagulable conditions i. disseminated intravascular coagulation ii. androgen therapy iii. L-asparaginase iv. tamoxifen v. paraneoplastic thrombophilia II. Low-ﬂow states a. Dehydration b. Iron-deﬁciency anemia c. Diabetic ketoacidosis d. Left heart failure e. Right heart failure f. Cerebral arterial occlusion g. Hyperviscosity (e.g., secondary polycythemia) h. Compression of cerebral sinus or jugular vein

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Table 2 Continued III. Vessel-wall abnormalities a. Infectious phlebitis i. otitis media ii. mastoiditis iii. peritonsillar abscess iv. sinusitis (frontal, sphenoid, ethmoid, maxillary) v. sepsis vi. bacterial or fungal meningitis vii. orbital or nasal furuncle viii. dental or pharyngeal abscess b. Noninfectious phlebitis i. carcinomatous meningitis ii. intrathecal chemotherapy iii. sarcoid meningitis iv. Behcßet’s disease c. Trauma i. closed head injury ii. neck trauma iii. jugular vein catheter

antithrombin III that interact with endothelial substances (e.g., thrombomodulin and heparan sulfate) to prevent the activation of coagulation factors such as factor V, factor VIII, thrombin, and factor X. When the balance is disrupted in favor of thrombosis, the patient is said to have ‘‘thrombophilia’’ or a ‘‘hypercoagulable state’’ [34]. Hypercoagulable states may be inherited or acquired. Often the presence of one hypercoagulable state is insuﬃcient to cause a thrombotic episode, and it is common for more than one abnormality to be present in the symptomatic patient. 1. Deﬁciencies of Natural Anticoagulants Protein C is a vitamin K–dependent plasma protein that is activated by thrombin in the presence of endothelial thrombomodulin. Activated protein C acts as an anticoagulant by inhibiting factors Va and VIIIa with the assistance of the cofactor, protein S. Protein S, also a vitamin K–dependent plasma protein, is active when free (unbound) and is inactive when bound to C4b-binding protein. C4b-binding protein increases as an acute-phase response during infection or inﬂammation, leading to an increase in bound protein S, a decrease in functional free protein S, and possibly a transient hypercoagulable state. Antithrombin III binds and inhibits thrombin (factor IIa) and factors IXa, Xa, XIa, and XIIa, although it primarily inhibits thrombosis through its eﬀects on thrombin and Xa; it is most eﬀective when in the presence of endothelial heparan sulfate or heparin. Deﬁciencies of protein C, protein S, and antithrombin III may be either inherited or acquired. The inherited conditions are autosomal dominant. Heterozygotes have an increased risk of venous thrombosis, while homozygotes for all three inherited conditions generally do not survive the neonatal period [35]. Acquired protein C or protein S deﬁciencies may occur due to inﬂammation, liver disease, disseminated intravascular coagulation (DIC), L-asparaginase therapy, and vitamin K deﬁciency or antagonist therapy; acquired protein S deﬁciency may also occur due to pregnancy and estrogen therapy [34]. Acquired antithrombin III deﬁciency may occur due to liver disease, DIC, L-asparaginase therapy, pregnancy, estrogen therapy, and nephrotic syndrome [34]. Deﬁciency

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Figure 2 Simultaneous magnetic resonance (MR) images of a 29-year-old postpartum woman with known Crohn’s disease and previously undiagnosed free protein S deﬁciency who developed constant daily headaches after normal vaginal delivery and Wernicke’s aphasia four weeks later. Axial MR images demonstrate a large left temporoparietal lesion. (A) T1-weighted image shows a large hypointense lesion (darker area outlined by white arrows) with mass eﬀect (sulcal and ventricular eﬀacement and slight midline shift) consistent with either vasogenic or cytotoxic edema. (B) The FLAIR image suggests the edema (white area) is vasogenic because it tracks in white-matter areas (ﬁnger-like projections marked by white arrows); the FLAIR image also demonstrates parenchymal hemorrhage (black area marked by black arrows). The simultaneous isointense (gray) appearance on T1 and hypointense (dark) appearance on FLAIR suggests the hemorrhage is relatively recent. (C) The diﬀusion-weighted image (DWI) shows the same parenchymal hemorrhage (black area marked by black arrow) seen on FLAIR, but fails to demonstrate a hyperintense (white) lesion, conﬁrming that the edema is in fact vasogenic, not cytotoxic. Despite the intracerebral hemorrhage, the patient received full-dose intravenous heparin followed by oral warfarin and made a complete recovery.

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Figure 3 More-inferior (caudal) FLAIR images of the patient described in Figure 2 demonstrate lack of normal ﬂow void in the left jugular vein (A), left sigmoid sinus (B), and left transverse sinus (C), consistent with sinovenous thrombosis.

of at least one of these three natural anticoagulants occurs in 2–12% of CVT patients [4,12,28]. 2. Dysfunctional Coagulation Factors Activated protein C resistance (APCR) is a condition with many possible etiologies, both inherited and acquired, that increases the risk of venous thrombosis [35,36]. The most common cause of APCR among Caucasians is the factor V Leiden mutation, in which there is an alteration of a site on factor Va that is normally cleaved by activated protein C. The prothrombin G20210A mutation (substitution of guanine for adenine at nucleotide 20210 of the prothrombin gene) leads to elevated prothrombin levels, which in turn leads to increased thrombin production and resultant impaired inactivation of factor V by activated protein C

Figure 4 Noncontrast sagittal T1-weighted images of the patient described in Figure 2 show normal ﬂow void (black sinus marked by black arrow) in the right transverse sinus (R) and lack of normal ﬂow void (white sinus marked by white arrow) in the left transverse sinus (L), consistent with left transverse sinus thrombosis. The surrounding area of decreased signal is consistent with vasogenic edema.

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Figure 5 MR venography (MRV) of the patient described in Figure 2. (A) The lateral view appears normal. (B) The anteroposterior view, however, shows poor ﬂow in the left transverse and left sigmoid sinuses. Although an atretic left transverse sinus is a normal variant, the MRV and MRI ﬁndings taken together conﬁrm thrombosis of the left transverse and sigmoid sinuses. A = anterior; P = posterior; R = right; L = left; SUP = superior sagittal sinus; COR = cortical veins; INF = inferior sagittal sinus; GAL = great vein of Galen; INT = internal cerebral vein; BAS = basal vein of Rosenthal; STR = straight sinus; TOR = torcular Herophili; TRA = transverse sinus; SIG = sigmoid sinus; JUG = jugular vein.

[35]. The ﬁrst reports of factor V Leiden and the prothrombin G20210A mutation were in 1993 and 1996, respectively [37,38]. In studies of European Caucasians since those reports, factor V Leiden and the prothrombin G20210A mutation have been the most common inherited hypercoagulable states associated with venous thrombosis in general and CVT in particular, each occurring in 10–20% of CVT patients [12,28,29,35,39,40]. By comparison, each of these mutations occurs in about 3% of healthy European controls [29]. Dysﬁbrinogenemia encompasses a diverse group of inherited and acquired defects with varied clinical expressions and is a rare cause of venous thrombosis [41]. 3. Decreased Fibrinolysis Although individual reports suggest a possible link between plasminogen deﬁciency and CVT, larger studies and literature reviews refute the association of plasminogen deﬁciency and tissue-type plasminogen activator (t-PA) deﬁciency with increased risk of thrombosis [39,42]. Excessive or abnormal plasminogen activator inhibitor-1 may lead to excessive clotting, especially in association with other genetic thrombophilic defects, and may be especially important as a cause of CVT in obese young women [25,43]. Recent investigations focus on the role of elevated lipoprotein(a) levels as a hypercoagulable state. Lipoprotein(a) appears to interfere with the normal function of plasminogen in ﬁbrinolysis, thereby promoting thrombosis [44]. One group of investigators attributed isolated deep cerebral vein thrombosis in a neonate to hereditary lipoprotein (a) elevation [26]. 4. Elevated Clotting Factors Elevated levels of ﬁbrinogen and factor VIII occur as part of an acute-phase response, but persistently increased levels are associated with an increased risk of venous thrombosis [35]. Factor VIII elevation is a much more common cause of venous thrombosis. Factor VIII

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circulates in the plasma as a complex with von Willebrand factor and facilitates clotting by accelerating the conversion of factor X to Xa in association with factor IXa [34]. In one study, 8 of 11 patients with CVT had elevations of plasma factor VIII months after the acute event, suggesting the elevations were causative and did not represent an acute-phase response [45]. Elevations in factor VIII may occur during thyrotoxicosis and lead to increased risk of CVT [46]. 5. Hyperhomocysteinemia Homocysteine induces a hypercoagulable environment by enhancing factor V, factor XII, and tissue factor and inhibiting protein C, thrombomodulin, and heparan sulfate [34]. Elevations in serum homocysteine may be inherited or acquired. The inherited forms occur as a result of deﬁciencies in one of three enzymes. One enzyme is vitamin B6 dependent (cystathionine synthase), one is vitamin B12 dependent (methyltetrahydrofolate methyltransferase), and one is folic acid dependent (methylenetetrahydrofolate reductase). Homozygous homocystinuria, with multiple strokes and myocardial infarctions by early adulthood, is due to cystathionine synthase deﬁciency. Mild elevations of homocysteine occur in patients who are homozygous for the C667T mutation in methylenetetrahydrofolate reductase. Acquired causes of hyperhomocysteinemia include folic acid deﬁciency, vitamin B12 deﬁciency, vitamin B6 deﬁciency, renal failure, hypothyroidism, cancer, acute lymphoblastic leukemia, pernicious anemia, certain medications, increasing age, and cigarette smoking [34,35]. In one study, hyperhomocysteinemia occurred in 33 (27%) of 121 patients with CVT, compared to 20 (8%) of 242 healthy controls, accounting for a fourfold increase in the risk of CVT [47]. Other investigators detected hyperhomocysteinemia in 6 (40%) of 15 patients with CVT [12]. 6. Antiphospholipid Antibodies Antiphospholipid antibodies (aPLs) are a heterogeneous group of serum immunoglobulins that bind to either charged phospholipids or lipid-bound proteins and promote thrombosis to varying degrees. The aPLs may occur in association with autoimmune disease or some other condition (e.g., cancer, viral infections, syphilis, migraine, phenothiazine use, and procainamide use) and 40% of patients with systemic lupus erythematosus (SLE) have aPLs [34]. The aPLs, however, most commonly occur in patients without other evidence of autoimmune disease as part of the so-called primary aPL syndrome (serum aPLs and one of three clinical presentations—thrombosis, thrombocytopenia, or recurrent fetal loss) [34]. The most commonly detected aPLs are lupus anticoagulant (LA), anticardiolipin antibodies (aCLs), and anti-h-2-glycoprotein 1 antibodies (ah2GP1s), but many others exist, most with as-yet-undetermined prothrombotic risk [48]. The clinical diagnosis of primary aPL syndrome is often diﬃcult because (1) various types of aPLs commonly coexist in the same patient; (2) currently, no single test is suﬃcient to diagnose all patients with the disorder; and (3) laboratory abnormalities may be isolated, transient, or borderline [48]. In addition, except for LA, aPLs exist in three classes—IgG, IgM, and IgA—that diﬀer in their thrombotic potential. While the details of these diﬀerences have yet to be worked out, IgA aPLs generally do not promote thrombosis, and there may be diﬀerences between IgG and IgM antibodies in terms of venous versus arterial thrombotic risk (e.g., in one study, IgG antibodies promoted venous thrombosis while IgM antibodies promoted arterial thrombosis) [47]. In mainly retrospective series of CVT patients in which the investigators evaluated for the presence of LA or aCLs, aPLs have been detected in 8–53% of patients

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[4,12,28,49,50]. In one study, investigators tested each of 31 CVT patients for aCLs and found 22.6% were positive compared to 3.2% of age- and sex-matched controls; the investigators did not test for LA [49]. In another prospective study, investigators detected aPLs in 14% of 42 patients [12]. None of these series included testing for ah2GP1s or other types of aPLs. 7. Pregnancy, the Puerperium, and Oral Contraceptives Women account for 75–85% of adult patients with CVT [6,8,12,29,39,45,47,49]. Among children with CVT, however, males predominate [9,30,31]. Hormonal changes explain the diﬀerence—approximately 75% of women with CVT present during pregnancy or the puerperium or while taking oral contraceptives [6,8,12,29,39,45,47,49]. During normal pregnancy and the puerperium, protein C and total protein S levels decrease and coagulation factors increase, resulting in increased thrombin production and a relative hypercoagulable state [51]. The risk of CVT is particularly high during the puerperium—in one study, CVT occurred 13 times more often during the puerperium than during pregnancy [6]. Even second- and third-generation oral contraceptives cause decreased levels of protein S and antithrombin III and increased levels of coagulation factors (e.g., ﬁbrinogen, thrombin, and factors VII and X) [52,53]. In one study, the use of oral contraceptives resulted in a 20-fold increase in the risk of CVT [29]. 8. Inﬂammatory Bowel Disease Thrombosis in general, including CVT, occurs with increased frequency in patients with ulcerative colitis and Crohn’s disease, and there is increasing evidence that hypercoagulability plays a major role in the pathogenesis of these conditions [54,55]. Based on evaluation of pathological specimens, one group suggested that Crohn’s disease is a consequence of multifocal gastrointestinal infarction; this same group later detected elevated factor VII:C, lipoprotein(a), and ﬁbrinogen levels in Crohn’s disease patients [56,57]. Another group of investigators found that, compared to healthy control subjects, patients with both types of inﬂammatory bowel disease have a higher prevalence of aCLs and ah2GP1s, higher levels of ﬁbrinogen, lower levels of free protein S, increased activated protein C resistance, and increased homocysteine levels and that patients with Crohn’s disease have increased lipoprotein(a) [58–61]. Thrombosis occurs somewhat more frequently during the active stages of inﬂammatory bowel disease, in patients with ulcerative colitis as opposed to Crohn’s disease, and in patients receiving corticosteroids [54]. Adding to the hypercoagulability theory of inﬂammatory bowel disease, there have been several reports of successful treatment of intestinal symptoms with heparin and low molecular weight heparin, associated with a paradoxical decrease in rectal bleeding, especially in patients with ulcerative colitis [62,63]. There have been reports of successful anticoagulation in adult and pediatric patients with inﬂammatory bowel disease and CVT [54,64,65]. The patient whose images appear in Figures 2–5 is one such patient. 9. Nephrotic Syndrome Nephrotic syndrome is associated with an increased incidence of thromboembolic complications, including CVT, in both children and adults, especially during its active phase [20,66,67]. The primary mechanism for hypercoagulability in these patients is urinary loss of antithrombin III and free protein S [66,67]. These patients may also have thrombocytosis,

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increased platelet aggregation, increased levels of clotting factors, and blood hyperviscosity [66]. Patients with SLE may develop nephrotic syndrome with antithrombin III or free protein S deﬁciency [67]. Thus, SLE patients, who also often have aPLs, are at especially high risk of developing CVT. 10. Abnormal Blood Elements Patients with the myeloproliferative disorders polycythemia vera and essential thrombocythemia have abnormal platelet function and may present with CVT [68]. An elevated platelet count due to reactive thrombocytosis is not associated with increased thrombotic risk. Patients with the acquired hemolytic anemia paroxysmal nocturnal hemoglobinuria are prone to venous thrombosis, including CVT [69]. The mechanism of venous thrombosis in this condition is not clear. CVT may occur in patients with sickle-cell anemia or sickle-cell trait, presumably as a result of sickled erythrocytes in the microcirculation and resultant venous stasis [50,70]. Hypereosinophilia causes a hypercoagulable state, likely due to impairment of thrombomodulin with resultant failure to activate protein C, and has been associated with CVT [71,72]. Immune-mediated heparin-induced thrombocytopenia can cause arterial or venous thrombosis, including CVT [73]. 11. Other Hypercoagulable Conditions DIC of any etiology may result in CVT [74]. CVT may occur in healthy patients taking androgens for bodybuilding or in patients receiving androgen therapy for aplastic anemia— androgens appear to aﬀect platelet function and increase coagulation factors [75,76]. The chemotherapeutic agent L-asparaginase, used in children with acute lymphoblastic leukemia, is associated with thrombosis, likely due to acquired antithrombin III or protein S deﬁciency, and has been implicated as a cause of CVT [9,31,77–80]. Tamoxifen, the antiestrogen agent used in breast cancer patients, increases risk of venous thromboembolism, likely by causing decreases in antithrombin III and protein S, and has been associated with CVT [80,81]. Venous thromboembolism, including CVT, may occur due to paraneoplastic thrombophilia in some patients [82]. B. Low-Flow States Several investigators have implicated dehydration and iron-deﬁciency anemia as causes of CVT, particularly among neonates and young children who are prone to viral infections, sepsis, and diarrhea [9,31,39,50,83–86]. Mild diabetic ketoacidosis accompanied both dehydration and iron-deﬁciency anemia in one young boy with deep CVT [86]. The presumed prothrombotic mechanism for these conditions is a low-ﬂow state. Both low cardiac output due to left-heart failure and increased venous pressures from right-heart failure can cause a chronic low-ﬂow state in the cerebral veins and sinuses with resultant CVT; in one study, 9 of 19 neonates with CVT had either congenital heart disease or pulmonary hypertension [9]. Although reports have suggested that cerebral arterial occlusion may lead to a local low-ﬂow state with resultant CVT, causality is diﬃcult to determine since these patients likely have underlying hypercoagulable states with increased risk for both arterial and venous thrombosis [11]. Although quite uncommon, CVT may occur due to hyperviscosity in patients with secondary polycythemia, including polycythemia induced by epoetin alfa therapy [87] Compression of a cerebral venous sinus by a solid tumor can cause local stasis and CVT [9,31,80].

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C. Vessel-Wall Abnormalities 1. Infectious Phlebitis In the preantibiotic era, superﬁcial CVT was most often associated with chronic otitis media or chronic mastoiditis, due to the proximity of the lateral sinus, the middle ear, and the mastoid process. The prognosis was poor. With the advent of antibiotics, this syndrome has greatly decreased in frequency, though ear and mastoid infections are still important causes of CVT in children and in persons of all ages who, for either cultural or socioeconomic reasons, do not have access to modern medical care [5,9,11,88]. In addition, patients with partially treated middle-ear and mastoid infections may have less fulminant courses, leading to diagnostic delays. Peritonsillar abscesses may lead to lateral sinus thrombosis, and frontal, sphenoidal, and ethmoidal sinusitis may result in superior sagittal sinus thrombosis [5,11]. Generalized infection may result in CVT by direct bacterial seeding of the sinus wall. Bacterial or fungal meningitis may result in cerebral thrombophlebitis, as occurred in a patient with acquired immunodeﬁciency syndrome and coccidioidomycosis meningitis [89]. Sphenoid sinusitis is the most common cause of cavernous sinus thrombosis, though ethmoid or maxillary sinusitis are also potential causes [23]. The infection may be bacterial or fungal, e.g., mucormycosis or aspergillosis, which most often occur in diabetic or immunosuppressed patients. Orbital or nasal furuncles, especially those that have been traumatized, may cause septic cavernous sinus thrombosis with Staphylococcus aureus as the typical pathogen. Dental and pharyngeal abscesses may also result in thrombosis of the cavernous sinus. Patients with septic cavernous sinus thrombosis usually have symptoms of a systemic infection such as high fevers, tachycardia, and tachypnea. Meningitis or cerebral abscess may develop as a result of local spread of infection. 2. Noninfectious Phlebitis Direct invasion of the sinus wall by malignant cells may occur in patients with acute leukemia or solid tumors [80]. Carcinomatous meningitis may cause a phlebitis and subsequent sinus thrombosis [80]. Cancer patients who receive intrathecal chemotherapy may develop CVT; whether the cancer itself or the chemotherapeutic agent caused the thrombophlebitis in these patients is not clear [80]. Patients with other chronic meningitides, such as sarcoid, may also develop cerebral thrombophlebitis. Behcßet’s disease is an inﬂammatory condition manifested by oral ulcers, genital lesions, recurrent uveitis, arthritis, aseptic meningitis, and a vasculopathy involving all sizes and types of vessels. These patients frequently develop thromboembolic complications, probably as a result of endothelial dysfunction and decreased ﬁbrinolytic activity [90]. Behcßet’s disease, also called silk route disease, is more common among patients from the Middle East and Asia. The percentage of patients with CVT due to Behcß et’s varies depending on study location and patient ethnicity. In a Saudi Arabian series and one French series, 16– 25% of CVT patients had Behcßet’s disease, while in several other European series no patients were noted to have Behcßet’s [4,5,8,12,45]. 3. Trauma Even mild head trauma may lead to CVT [11,31]. The history of trauma may not be obvious, and a careful history may be necessary to detect its occurrence. Presumably injury to the sinus wall results in thrombosis. Since minor head trauma is much more common than CVT, it is likely that patients who suﬀer CVT due to head trauma have an underlying, subclinical

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hypercoagulable state as an added risk factor. The same holds true for CVT that occurs after trauma to the neck [33]. Birth trauma is a potential cause of CVT in neonates. Thrombosis around a catheter or cardiac pacemaker wire in the jugular vein may extend in a retrograde fashion to involve the intracranial sinuses [80].

IV. DIAGNOSTIC EVALUATION A. Imaging Studies MRI and MRV have completely changed the approach to diagnosis, management, and counseling of patients with CVT. The need for catheter angiography to diagnose CVT in the past hindered its diagnosis—clinicians often were not willing to perform an invasive procedure to evaluate a patient with a symptom as nonspeciﬁc as headache. MRI both excludes other possible causes such as an intracranial mass and, when combined with MRV, identiﬁes CVT essentially 100% of the time. 1. Computed Tomography CT may oﬀer clues to the diagnosis, but most often does not identify CVT with certainty. CT demonstrates evidence of a thrombosed vessel in only one third of cases and is completely normal in another third [11]. CT cannot diﬀerentiate vasogenic edema and infarction and provides only axial views. If MRI is available, obtaining CT as a preliminary step is usually unnecessary. CT without contrast, however, is an appropriate choice for emergency investigation due to its ability to detect acute blood and rule out a mass lesion, its general availability in the community, and the swiftness with which it can be performed. CT in a patient with CVT may show vasogenic edema, bland infarction, hemorrhagic infarction, or intracerebral hemorrhage in a distribution atypical for arterial disease, e.g., paramedian uni- or bilateral (superior sagittal sinus thrombosis), temporal (lateral sinus thrombosis), or bithalamic (deep cerebral veins). Both cytotoxic and vasogenic edema appear dark (hypodense) on CT, and both may demonstrate gyral enhancement on contrast CT due to disruption of the blood–brain barrier. The only clue in diﬀerentiating the two types of edema on CT is that vasogenic edema tends to track in white-matter areas with a resultant ﬁnger-like appearance, while cytotoxic edema aﬀects white- and gray-matter areas equally (Fig. 6). Noncontrast CT may demonstrate subarachnoid blood in CVT patients, and in some patients contrast CT demonstrates enhancement of the falx and tentorium cerebelli due to engorgement of venous collateral pathways. Many patients with CVT have small ventricles, but patients with deep CVT may develop hydrocephalus due to bithalamic edema and compression of the third ventricle or Sylvian aqueduct. CVT-speciﬁc signs on CT are the ‘‘cord sign,’’ a thrombosed cortical vein seen as a hyperdense superﬁcial lesion on noncontrast scan, and the ‘‘delta’’ or ‘‘empty triangle’’ sign, the cross-section appearance of thrombus in a dural sinus seen on contrast-enhanced scan. 2. Magnetic Resonance Imaging MRI has multiplanar capability, can distinguish vasogenic and cytotoxic edema (Fig. 2), visualizes the sinovenous anatomy well (Figs. 3 and 4), and detects the chronological stages of thrombosis. Spin-echo (SE) MRI includes T1-weighted, T2-weighted, ﬂuid-attenuated inversion recovery (FLAIR), and diﬀusion-weighted images. Gradient-recalled echo (GRE) MRI forms the basis for MRA and MRV.

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Figure 6 Noncontrast cerebral CT scan of a 24-year-old woman who is 32 weeks pregnant with new-onset seizures and a past history of calf vein thrombosis. Note the bilateral paramedian hypodense areas (marked by arrows) with ﬁnger-like projections tracking in the deep white matter (left greater than right). This pattern is consistent with vasogenic edema from a superior sagittal sinus thrombosis.

SE MRI is more sensitive than CT in detecting the parenchymal changes of CVT, including subacute and chronic hemorrhage and vasogenic and cytotoxic edema [91]. As on CT, parenchymal lesions on MRI tend to be paramedian, temporal, or bithalamic, depending on which cerebral vein or sinus is thrombosed. Parenchymal hemorrhages diﬀer in appearance based on both MR modality and age of the lesion. In general, acute hemorrhage is gray (isointense) on T1 and dark (hypointense) on T2 and FLAIR (Fig. 2). Subacute hemorrhage is bright (hyperintense) and chronic hemorrhage is dark on all three modalities. Vasogenic and cytotoxic edema both appear dark (hypointense) on T1-weighted images and bright (hyperintense) on T2-weighted and FLAIR images (Fig. 2). Vasogenic edema tends to track in white-matter areas on T2 and FLAIR (Fig. 2) and enhances with contrast on T1 (Fig. 7). DWI can more clearly distinguish vasogenic and cytotoxic edema, especially when correlated with an apparent diﬀusion coeﬃcient (ADC) map. Vasogenic edema is mildly bright or not seen on DWI (Fig. 2) and has increased ADC values, appearing bright on the ADC map [19,92,93]. Cytotoxic edema is quite bright on DWI and has decreased ADC values, appearing dark on the ADC map [19,92,93]. The individual CVT patient may have any combination of vasogenic edema, cytotoxic edema, and hemorrhage [93]. The DWI ﬁndings have important clinical and prognostic implications, since areas of high ADC (vasogenic edema) eventually return to normal on subsequent imaging, while areas of low ADC (cytotoxic edema) often undergo infarction [92]. In CVT patients, however, unlike in patients with arterial ischemic stroke, cytotoxic edema may be reversible, possibly due to persistent collateral pathways allowing perfusion at lower ﬂow rates [93]. Thus, DWI results assist in prognosis but should not deter the clinician from aggressive therapy if otherwise indicated, especially in the acute phase of illness. SE MRI detects changes in ﬂow and the chronological stages of venous thrombosis. On SE MRI, a vessel with normal ﬂow is dark (hypointense), the so-called ‘‘ﬂow-void

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Figure 7 Coronal T1-weighted MR images of the patient described in Figure 6. (A) Noncontrast image shows isointense subacute thrombus in the superior sagittal sinus (white arrow) and a left paramedian area of decreased signal intensity consistent with edema (black arrow). (B) Gadoliniumenhanced image shows the ‘‘delta’’ or ‘‘empty triangle’’ sign (white arrow) formed by white contrast surrounding darker thrombus in the triangular superior sagittal sinus. There is also left paramedian enhancement (white area marked by black arrow), consistent with blood-brain-barrier disruption in the area of vasogenic edema.

phenomenon.’’ A vessel with diminished ﬂow appears brighter (‘‘ﬂow-related enhancement’’). Acutely (ﬁrst 5 days), a thrombosed vessel appears gray (isointense) on T1-weighted images (Figs. 7A, 8) but remains dark on T2-weighted images due to the presence of intracellular deoxyhemoglobin; subacutely (days 5–15), the thrombus is white (hyperintense) ﬁrst on T1- and then on T2-weighted images due to the conversion of deoxyhemoglobin to extracellular methemoglobin [91]. In recanalized vessels, the hypointense appearance of normal ﬂow void returns to the vessels. Thus, low ﬂow and subacute

Figure 8 Midsagittal T1-weighted noncontrast MR image of patient described in Figure 6. Note the subacute thrombus in the superior sagittal sinus (arrow) corresponding to the ﬁndings on the coronal views seen in Figure 7. Normal ﬂow within the venous sinus would have been black. A = anterior, P = posterior.

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thrombus both appear white on SE MRI and may be confused for one another. One possible way to resolve the issue is to obtain gadolinium-enhanced T1-weighted MRI—as on CT, the presence of a ‘‘delta’’ or ‘‘empty triangle’’ sign conﬁrms the diagnosis of venous thrombosis (Fig. 7B). One may also detect a thrombosed cortical vein on SE MRI, similar to the cord sign of CT. 3. Magnetic Resonance Angiography Coronal two-dimensional time-of-ﬂight (2D TOF) MRA is the most frequently used technique to depict the cerebral sinovenous system, though recent studies suggest that CT venography or contrast-enhanced MRV may be as good or better [91,94]. Coronal 2D TOF MRA is a relatively quick technique that consistently visualizes the deep cerebral veins and cavernous sinus as well as the superﬁcial sinuses. Unlike SE MRI, normal ﬂow is white (hyperintense) and lack of ﬂow is dark (hypointense) on GRE MRI and, thus, MRA/MRV (Fig. 5). In order to detect ﬂow, the MRA plane of data acquisition must be perpendicular to the direction of ﬂow. As mentioned in Sec. I, acquisition in a coronal plane is optimal for MRV since most cerebral venous sinuses ﬂow in the axial plane. If a vein, however, happens to ﬂow in the direction of the MRV acquisition, it may be absent due to ‘‘in-plane ﬂow artifact.’’ Certain veins, such as the vein of Galen, often ﬂow in the coronal plane and falsely appear to have diminished ﬂow on coronal-acquisition MRV. It is important to keep in mind the plane of acquisition when interpreting MRA/MRV. Proper interpretation requires comparison of MRV with the diﬀerent views aﬀorded by MRI. MRA/MRV also has diﬃculty diﬀerentiating subacute thrombus from normal ﬂow since both methemoglobin and normal ﬂow are bright on GRE images. Comparison to noncontrast SE MRI is essential. 4. Cerebral Angiography With the advent of MRI and MRV, catheter cerebral angiography is no longer necessary in most patients with CVT. It is now the procedure of choice when MRI is not available. Options include conventional angiography and digital subtraction angiography with intravenous (IV) injection of contrast. Patients with CVT often have a delayed venous phase due to intracranial hypertension. Absence of sinovenous structures may be accompanied by dilated venous collaterals and dilated cortical veins that often have a corkscrew appearance. There also may be reversal of normal venous ﬂow. Unlike SE MRI, angiography does not visualize the clot itself, and thus cannot diﬀerentiate obstruction and thrombosis. B. Hypercoagulable Profile Recognizing the clinical features of CVT and making the diagnosis with MRI and MRV are only the ﬁrst steps. CVT occurs for a reason, and thrombosis is usually a multifactorial process. Even patients with identiﬁable thrombotic risk factors such as oral contraceptives, the puerperium, or ulcerative colitis often have an underlying hypercoagulable state. The detection of such a condition is likely to aﬀect decisions regarding long-term anticoagulation. Table 3 is a recommended hypercoagulable proﬁle for patients with CVT. C. Lumbar Puncture Lumbar puncture should be reserved for patients suspected of having meningitis. It is not necessary in the vast majority of patients with CVT and should be deferred if the patient has signiﬁcant mass eﬀect on CT or MRI. Nonspeciﬁc ﬁndings in CVT patients

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Table 3 Hypercoagulable Proﬁle in Patients with Cerebral Vein Thrombosis Protein C Protein S (free and total) Antithrombin III Fibrinogen Factor VIII Lupus anticoagulant (LA) Anticardiolipin antibodies (aCL) Anti-beta-2-glycoprotein 1 antibodies (ah2GP1) Activated protein C resistance (APCR) If APCR positive: factor V Leiden mutation Prothrombin II G20210A mutation Lipoprotein (a) Homocysteine Sickle cell prep (African heritage) If above hypercoagulable proﬁle is negative and no other cause of thrombosis found, test for 1) antiphospholipid antibodies other than LA, aCL, and ah2GP1 and 2) plasminogen activator inhibitor-1.

include elevated opening pressure (>200 mmHg), protein, white blood cells, red blood cells, and xanthochromia. D. Visual Field Testing If allowed to persist, papilledema can lead to blindness. Initial signs that the patient’s vision is at risk are enlarging of the blind spot and constriction of visual ﬁelds. All patients with CVT should undergo a formal visual-ﬁeld-testing procedure such as computerized perimetry with comparison of serial examinations.

V. MANAGEMENT The multiple etiologies and the variable clinical presentation dictate an individualized approach to the management of patients with CVT, but certain principles pertain to all patients. Care for a patient with CVT includes management of (1) the predisposing condition or conditions responsible for thrombosis, (2) seizures, (3) ﬂuids, (4) intracranial hypertension, and (5) thrombosis. Although controversies persist, there is increasing evidence that most, if not all, CVT patients should receive anticoagulation therapy. A. Predisposing Conditions Patients who develop CVT while taking oral contraceptives, androgen therapy, L-asparaginase, or epoetin alfa should discontinue these drugs. Patients with sepsis or infectious phlebitis should receive antibiotics and, when appropriate, undergo a surgical procedure to remove the source of infection such as mastoidectomy, sphenoidectomy, or abscess drainage. Treatment of thyrotoxicosis is important since this condition is associated with elevated factor VIII. Patients with hyperhomocysteinemia should receive folic acid and, if necessary,

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vitamin B6 or vitamin B12 to lower serum homocysteine levels. Therapy for inﬂammatory bowel disease includes sulfasalazine, mesalamine, and steroids. Nephrotic syndrome patients may respond to steroids, but these patients and patients with antithrombin III deﬁciency for other reasons may require fresh frozen plasma or IV antithrombin III therapy as acute antithrombotic therapy. Patients with Behcß et’s disease may respond to immunosuppressive therapy. Patients with sickle-cell disease should receive hydroxyurea and transfusions to maintain hemoglobin S concentrations V30%. Patients with immunemediated heparin-induced thrombocytopenia should immediately discontinue heparin and receive either IV lepirudin or IV danaparoid, followed by warfarin therapy. B. Seizures Seizures occur in approximately half of CVT patients, nearly always at onset of symptoms. Since antiepileptic drugs often have cognitive side eﬀects and many interact with warfarin or other medications taken by a patient with CVT, prophylactic administration of antiepileptic drugs in patients without seizures is not indicated. Aggressive treatment of patients who do have seizures, however, is important, because seizures increase cerebral blood ﬂow and intracranial pressure. The vast majority of seizures in CVT patients likely begin as partial seizures, even in patients who present only with generalized seizures. It is best to use a medication that is eﬀective for partial seizures and does not aﬀect warfarin, such as lamotrigine, topiramate, or levetiracetam. In emergency situations such as generalized status epilepticus, the patient may require a loading dose of IV fosphenytoin followed by daily phenytoin, but eventual conversion to one of the other agents is preferable if the patient is to receive warfarin. In a prospective study of 55 CVT patients treated with anticoagulation, 28 (51%) presented with seizures and only 7 had recurrent seizures at a median follow-up of 36 months [8]. In another prospective study of 33 CVT patients treated with anticoagulation, 15 (45%) presented with seizures, but none had recurrent seizures at one-year follow-up; the median duration of antiepileptic treatment in this study was 6 months (range 1–8 months) [95]. Thus, CVT patients generally do not require indeﬁnite antiseizure therapy. A conservative approach is to taper oﬀ antiepileptic medication after 3–6 months in a patient who has no recurrent seizures and an electroencephalogram without epileptiform activity. C. Fluids Fluid management of CVT patients is important and complex. Dehydration and hypotension can exacerbate cerebral thrombosis, yet overhydration and hypertension can exacerbate increased intracranial pressure. Euvolemia with IV normal saline is optimal for most CVT patients, though optimal ﬂuid management may vary depending on the patient’s situation, e.g., a patient with sickle-cell anemia and no hemorrhage on CT requires more vigorous hydration than a patient with congestive heart failure and an intracerebral bleed. In general, it is best to avoid hypotonic and glucose-containing solutions. Hypotonic solutions exacerbate vasogenic cerebral edema, and glucose worsens lactic acidosis in ischemic brain. D. Intracranial Hypertension The goal of intracranial hypertension management is the prevention or treatment of cerebral herniation and the prevention of visual loss secondary to papilledema. While the optimal

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method for decreasing intracranial pressure in patients with CVT is to promote resolution of the thrombus (e.g., via anticoagulation), some patients require supplemental medical or mechanical therapy. Keeping the patient’s head straight and elevated at approximately 30 degrees aids venous drainage and lessens intracranial pressure. Mannitol and steroids are indicated only if herniation is imminent. Mannitol dehydrates the patient, theoretically worsening thrombosis, and steroids may inhibit ﬁbrinolysis, cause hyperglycemia, and cause gastric irritation and hemorrhage with resultant iron-deﬁciency anemia. Acetazolamide therapy may be helpful in some patients with CVT-induced intracranial hypertension. Mechanical methods to decrease intracranial pressure are important adjuncts to medical therapy when vision is threatened. Optic nerve sheath fenestration is the preferred procedure in CVT patients with persistent papilledema. This procedure is eﬀective in patients with idiopathic intracranial hypertension (pseudotumor cerebri) and in those with intracranial hypertension due to CVT. Often a unilateral procedure is suﬃcient to salvage visual function [96]. Repeat lumbar punctures and lumboperitoneal shunt are other options for mechanically lowering intracranial pressure. Although investigators report performing decompressive craniectomy successfully in patients with CVT, it remains an option of last resort for patients with impending herniation [97].

E. Thrombosis 1. Anticoagulation Although anticoagulation is the accepted treatment of choice in patients with systemic venous thrombosis, the frequent occurrence of hemorrhagic infarction or intracerebral hemorrhage in patients with CVT has resulted in a bias against anticoagulant therapy in these patients. Thrombotic venous occlusion, however, is the cause of intracranial hemorrhage in these patients. Anticoagulation allows dissolution of the clot, permits forward ﬂow, and paradoxically leads to improvement in patients with intracerebral hemorrhage or hemorrhagic infarction due to CVT [8,11,15,45,98–101]. In fact, the risk of intracranial hemorrhage appears to be greater in CVT patients who do not receive anticoagulation [98,100]. Many investigators emphasize the need for thrombolytic or interventional treatments for CVT patients, but most often this ‘‘need’’ for aggressive therapy is a consequence of inadequate anticoagulation. It is the experience of this author and several others that, regardless of how dire the initial presentation, the vast majority of patients with CVT improve with full-dose anticoagulation, often in dramatic fashion [11]. Another diﬃculty some investigators have with using anticoagulant therapy in CVT patients is the paucity of evidence based on prospective, double-blind trials. The lack of evidence is due to the relative infrequency of the condition, leading to small numbers of patients in clinical trials, and the emotional barriers to patient randomization—some investigators feel it is unethical to withhold anticoagulation from CVT patients, while others have felt that intracranial hemorrhage is a contraindication to anticoagulation in CVT patients [95,102]. In 1991, Einhaupl and colleagues reported the ﬁrst prospective, blinded, placebocontrolled trial of anticoagulant therapy in patients with CVT [100]. They randomized 20 patients with angiographically proven, aseptic CVT to either placebo or adjusted-dose IV heparin with a relatively high target activated partial thromboplastin time (aPTT) of 80–100 seconds. The duration of treatment was at least 8 days. After 3 months, 8 of 10 heparin-

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treated patients had a complete recovery and 2 had a slight neurological deﬁcit; in contrast, only 1 of the 10 placebo-treated patients had a complete recovery, 6 had neurological deﬁcits, and 3 died. In the heparin group, three patients had an intracranial hemorrhage prior to therapy, but none developed a hemorrhage during therapy. In the placebo group, two patients had an intracranial hemorrhage prior to therapy; both of these patients had another intracranial hemorrhage during therapy and died. A third placebo-treated patient developed an intracranial hemorrhage during therapy. The authors did not quantify the bleeds. The study is often criticized for the small number of patients. The investigators, however, discontinued the study prematurely. Based on the overwhelming diﬀerence in the outcomes of the ﬁrst 20 patients, they felt it was unethical to continue. De Bruijn and colleagues performed a prospective, randomized, placebo-controlled trial of anticoagulant therapy in CVT patients using the low molecular weight heparin nadroparin for 3 weeks followed by oral anticoagulants with a target international normalized ratio (INR) of 2.5–3.5 [101]. Thirty patients received treatment, and 29 received placebo. In two patients—one in the nadroparin group and one in the placebo group—the treating physician stopped the trial medication and treated with IV unfractionated heparin instead. At 12 weeks, poor outcomes occurred in 4 of 30 (13%) nadroparin patients (including 2 deaths) and 6 of 29 (21%) placebo patients (including 4 deaths). The authors also report that at 12 weeks, 27 (90%) of the nadroparin patients and 23 (79%) of the placebo patients had no limitations in activities of daily living. These diﬀerences did not reach statistical signiﬁcance, though the numbers are small. The evidence from retrospective and nonrandomized prospective studies also suggests a beneﬁt for anticoagulation in patients with CVT. In 1966, Krayenbuhl reported treating 17 patients with anticoagulants with only one death; in contrast, 14 of 20 patients given no treatment died [103]. He found no evidence that cerebral hemorrhage occurs more often in patients treated with anticoagulants. Bousser and colleagues gave heparin followed by oral anticoagulants to 23 patients with CVT; no patient died, 19 recovered completely, and one patient greatly improved on heparin despite having a hemorrhagic infarction on CT [5]. In a complement to their prospective study, Einhaupl and colleagues reported the results of a retrospective study of 40 patients with CVT and intracranial hemorrhage [100]. Only 4 of 27 patients treated with full-dose heparin died (15% mortality) compared to 9 of 13 patients not treated with heparin (69% mortality). Complete recovery occurred in 14 (52%) of the patients who received heparin and in only 3 (23%) of those who did not receive heparin. In nearly all other retrospective or nonrandomized prospective series, over 80% of patients who receive anticoagulation have good outcomes; this is true for patients with superior sinus, lateral sinus, or deep cerebral vein thrombosis and is true for both adult and pediatric patients [8,14–16,39,45,95,102,104,105]. On the other hand, the outcomes of patients who do not receive anticoagulation are generally poor [16,102,105,106]. The optimal duration of anticoagulation for most patients with CVT appears to be approximately 4 months. Baumgartner and colleagues treated 33 CVT patients with warfarin for at least 4 months and followed the patients for 12 months [95]. They obtained MRIs and MRVs at the 4- and 12-month intervals. At the 4-month follow-up, most of the veins and sinuses had recanalized. At 12-month follow-up, no patient had suﬀered recurrent CVT, deep-vein calf thrombosis, or pulmonary embolism, and none of the veins and sinuses showed evidence of recanalization beyond what had occurred at 4 months, unrelated to the duration of oral anticoagulation. The optimal duration of anticoagulation for each individual, however, is likely to vary, depending on the predisposing cause of thrombophilia. Some patients with hypercoagulable states may require anticoagulation indeﬁnitely.

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2. Thrombolysis Evidence for the use of IV and local (direct) thrombolytic therapy in CVT patients exists in the form of case reports and small series. There are no data from randomized trials. Investigators universally report that most patients with CVT beneﬁt from thrombolytic therapy. Experience to date with urokinase includes IV urokinase in patients with nonseptic CVT (including cavernous sinus thrombosis) and local urokinase infusions in patients with CVT due to arteriovenous ﬁstulae, in patients with dural sinus thrombosis and hemorrhagic infarctions or intracranial hemorrhage, in a patient with deep CVT, and in a patient who underwent concurrent craniectomy for impending herniation [17,107–110]. Experience with tissue plasminogen activator (t-PA) includes IV t-PA in a young child with otitis media and lateral sinus thrombosis and local t-PA infusions in patients with both superﬁcial and deep CVT [32,112,113]. In the vast majority of these cases, the investigators administered anticoagulant therapy during or after the thrombolytic therapy but did not attempt to treat with IV heparin prior to thrombolytic therapy. Thus, it is unclear if these patients would have improved with anticoagulation alone and it is unclear if or when thrombolysis is indicated as a ﬁrst choice over anticoagulation. 3. Rheolytic Thrombectomy There are case reports of successful thrombectomy within the cerebral venous sinuses using a rheolytic catheter device [114–117]. In some of the cases thrombectomy was the ﬁrst therapy, and in others it was performed only after IV heparin was unsuccessful. Most patients undergo general anesthesia and receive local urokinase infusion and treatment with a double-lumen rheolytic catheter system in which one catheter uses high-velocity saline jets to break up the clot while another catheter collects the resultant debris. One patient received rheolytic therapy without urokinase with good result [116]. Rheolytic thrombectomy appears to be a viable option in patients who do not respond to anticoagulation, but the experience to date with this device is limited.

VI. CONCLUSION Although CVT is relatively uncommon, it is not rare among certain subsets of patients. One should consider CVT in the diﬀerential diagnosis of a patient with any of the following: suspected intracranial hypertension, persistent headache, depressed consciousness, seizures, or focal deﬁcits (e.g., aphasia, hemiparesis, hemianopsia), especially if the patient has a condition known to be associated with venous thrombosis such as the puerperium, inﬂammatory bowel disease, or a hypercoagulable state. Cavernous sinus thrombosis is a special case in which ocular symptoms are the rule. In summary, the recommendations for management of patients with CVT are as follows: 1. 2. 3. 4. 5. 6.

Obtain MRI with DWI and MRV to make the deﬁnitive diagnosis. Identify and treat any predisposing condition. Obtain a hypercoagulable proﬁle (Table 3). Elevate the head 30 degrees and keep the head straight. Maintain euvolemia with IV normal saline. Treat seizures if they occur: If possible, use agents that do not interact with warfarin. Attempt to discontinue antiepileptic drugs after 3–6 months.

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7. Obtain formal visual ﬁeld testing and treat intracranial hypertension: Follow visual ﬁelds daily during acute period. Initially administer acetazolamide if papilledema persists despite anticoagulation. Perform optic nerve sheath fenestration if papilledema persists. Perform repeat lumbar punctures or lumboperitoneal shunt if optic nerve sheath fenestration is not possible. 8. Anticoagulate even if cerebral imaging shows hemorrhage: Urgently—use a venous thromboembolism protocol with either: Full-dose IV unfractionated heparin (e.g., aPTT 2–3 times baseline) or Full-dose low molecular weight heparin. Chronically—administer oral warfarin (INR 2.0–3.0) for 4 months or longer, depending on predisposing condition and results of hypercoagulable proﬁle. 9.

If patient does not respond to full-dose anticoagulation, either: Administer thrombolytic therapy (t-PA or urokinase) or Perform rheolytic thrombectomy.

10. For impending herniation only: Administer IV mannitol and IV steroids. If mannitol and steroids unsuccessful, perform decompressive craniectomy.

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27 Diagnosis and Management of Vascular Disease of the Spinal Cord Enrique C. Leira, Osamah J. Al-baker, and Saleem I. Abdulrauf Saint Louis University, St. Louis, Missouri, U.S.A.

I. SPINAL CORD INFARCTIONS A. Epidemiology Spinal cord strokes are less common than vascular events of the brain, but the exact incidence is unknown. The literature about spinal cord infarction is scattered throughout numerous small series and case reports. Spinal cord infarctions are estimated to account for only 1% of the admissions to a stroke unit [1]. The clinical presentation of spinal cord strokes can result in an admission to a general neurology ward. Therefore, data from stroke units may underestimate the true incidence of the disease. Little is known about the risk factors for spontaneous spinal cord infarctions. Given the multiplicity of mechanisms in spinal cord ischemia, the role of traditional risk factors for atherosclerosis is not known. On the other hand, iatrogenic spinal cord infarctions are more common. Certain surgical procedures, such as repair of a thoracoabdominal aneurysm, are associated with spinal cord infarction [2]. B. Vascular Anatomy The spinal cord is supplied by perforating arteries that originate from three major longitudinal vessels: the anterior spinal artery (ASA) and the two posterior spinal arteries (PSA). These three vessels are anastomotic channels that extend longitudinally throughout the length of the spinal cord and are interconnected by a vascular network [3,4]. The ASA (Fig. 1a), the most important of these three longitudinal vessels, supplies the anterior two thirds of the spinal cord. The ASA normally runs uninterrupted on the ventral surface of the cord. The ASA originates cranially at the level of the foramen magnum from branches of either the vertebral or the posterior inferior cerebellar arteries. In addition, the ASA receives blood supply from a variable number (6–10) of transverse radicular arteries. These radicular arteries originate from diﬀerent vessels, including the vertebral arteries, thyrocervical trunk, and aorta, and are unevenly distributed throughout the cord. For example, the radicular arteries are scarce in the middle and lower thoracic segments, making this cord segment more vulnerable to isch border zone segments. A major radicular artery arises in the lower thoracic and lumbar region is the arteria radicularis magna (artery of 637

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Figure 1 (a) Anterior spinal artery; (b) posterior spinal artery.

Adamkiewicz), which supplies up to one fourth of the spinal cord [3]. The artery of Adamkiewicz is particularly vulnerable to damage during aortic dissection or surgery [5]. Perforating sulcal branches from the ASA (Fig. 2) enter the anterior median ﬁssure of the cord and supply the anterior and lateral horns and anterior and lateral funiculi. The posterior third of the spinal cord is supplied by the two PSA (Fig. 1b), which are posterior longitudinal channels that also originate from the intracranial portion of the vertebral arteries. Unlike the ASA, the PSA are seen only as distinct paired vessels at their origin before they intermingle in an anastomotic pial plexus. The PSA system is also supplied by radiculomedullary vessels, which are more abundant than in the ASA system (10–23) [3].

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Figure 2 Penetrating vessels supplying the spinal cord.

Perforator branches from the PSA (Fig. 2) supply the posterior horns and the posterior funiculus. Venous drainage from the cord occurs via the anterior central and posterior central spinal veins, which form an extensive network encircling the spinal cord [3]. These intrathecal veins join a longitudinally anastomosing extrathecal venous plexus that drain into the vertebral bodies and through numerous radicular veins.

C. Pathophysiology The relative rarity of spinal cord strokes suggests that the spinal cord is more resistant to ischemia than the brain. Mechanisms that have been proposed to explain this apparent resistance include the presence of abundant collateral circulation and diﬀerence in tissue

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vulnerability to ischemia [5]. Experimentally, the spinal cord was shown to tolerate interruptions of blood ﬂow for as long as 30 minutes [5]. Animal studies suggest that tissue perfusion requirements in the spinal cord range from 10 to 20 mL/min/100 g [6], which is substantially lower than the 50 mL/min/100 g required by the brain. Like the brain, the spinal cord vasculature has the capacity to autoregulate blood ﬂow to maintain constant perfussion [7]. This resistance to ischemia is not homogeneous throughout the spinal cord. For example, the gray matter is more vulnerable to ischemia and requires three to ﬁve times more blood ﬂow than the white matter [8]. The susceptibility to ischemia also varies with the radicular segment: the relative hypovascularity at the T4 to T8 midthoracic region [4] results in vulnerability to ischemia with low perfusion states.

D. Spinal Cord Vascular Syndromes Table 1 provides a list of spinal cord vascular syndromes. 1. Anterior Spinal Artery Syndrome Pain is a common symptom with anterior spinal cord infarctions, and usually heralds the onset of neurological symptoms. The pain, which is attributed to proximal nerve root ischemia, can be either lancinating or dull. It may be girdle-like in distribution and can mimic pain from cardiac or abdominal origin [9]. The pain is typically followed by symptoms of an acute myelopathy involving the anterior two thirds of spinal cord. This includes a combination of limb weakness, loss of bowel and bladder control, and loss of pain and temperature/sensation below the level of the lesion with preservation of the position and vibration sensation. Because the gray matter is often selectively aﬀected, the clinical presentation can be one of isolated paralysis and atrophy without sensory involvement [10]. Occasionally only one of the sulcal arteries is involved, resulting in a partial BrownSequard syndrome that spares the posterior columns [4]. The occlusion of a spinal radicular artery produces symptoms that are clinically indistinguishable from the ASA syndrome [4]. Depending on the segment of the spinal cord involved, the ASA syndrome has distinct regional characteristics. For example, an ASA infarction of the cervical cord can result in a painful brachial diplegia, with proximal isolated weakness in both arms mimicking the ‘‘man-in-a-barrel syndrome’’ [11]. It can also result in symptoms of autonomic dysfunction such as orthostatic hypotension, sexual dysfunction, and impairment of vasomotor and sudomotor tone below the level of the lesion. If the C3-5 cord segments are involved, diaphragmatic impairment can occur. On the other hand, an ASA infarct at the conus medullaris will result in a cauda equina syndrome with sphincter dysfunction and sensory loss over the perineal and perianal areas, mimicking a tumor in that location [12].

Table 1 Clinical Ischemic Spinal Cord Syndromes Anterior spinal artery syndrome Central cord syndrome (clinically similar to ASA) Posterior spinal artery syndrome Lacunar infarctions Transient ischemic attacks Venous infarctions

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2. Central Cord Infarction Infarctions that selectively involve the central structures of the spinal cord have been described [13]. These lesions are clinically indistinguishable from the ASA syndrome. Because central cord infarctions are the result of ischemia in the border-zone between the ASA and the two PSA, they can occur with conditions that result in hypoperfusion in the aortic system. 3. Posterior Spinal Artery Syndrome PSA distribution strokes are less common than the ASA, probably due to the presence of extensive collateral circulation in the posterior cord [3]. The PSA syndrome aﬀects mainly the posterior columns, with unilateral loss of vibration and position sense below the lesion, pain, and paresthesias. 4. Venous Infarction of the Cord Like PSA, venous infarctions of the cord are rare. The clinical presentation is similar to that of arterial infarctions [14]. The location of venous infarctions is variable and can have a subacute presentation. Venous infarctions also tend to become hemorrhagic [3]. 5. Lacunar Infarctions of the Spinal Cord Lacunar infarctions of the anterior horns can present as a subacute progressive myelopathy known as ‘‘vascular myelopathy in old age.’’ The typical symptom is weakness of the lower motor neuron type that mimicks either motor neuron disease or polio [15]. 6. Transient Ischemic Attacks of the Cord Deﬁcits related to transient ischemia occur in the spinal cord [4,16]. In the cervical cord transient ischemia can result in a ‘‘drop attack.’’ Conversely, in the lumbar region it can present as transient ‘‘spinal claudication’’ typically induced by exertion or postural changes.

E. Etiology The literature regarding the etiology of spinal cord infarctions is full of numerous distinct case reports that underscore the heterogenicity of causes and mechanisms. In general, spinal cord infarctions are categorized as either iatrogenic or noniatrogenic. Iatrogenic strokes (Table 2) include events secondary to surgery, endovascular interventions, other invasive procedures, and drugs. Surgical procedures can produce spinal cord infarction by generalized hypoperfusion, trauma to the aorta or the radicular arteries (Fig. 3), neck hyperextension, or unusual positioning. Endovascular procedures in that region can result in untoward embolization of the spinal cord arteries. Spinal cord infarctions can also result from drugs that induce vasoconstriction or hypotension/hypoperfusion. Noniatrogenic etiologies of spinal cord infarction are listed in Table 3. Several arteriopathies cause cord ischemia, which are classiﬁed as atherosclerotic and nonatherosclerotic. Nonatherosclerotic arteriopathies are further classiﬁed as noninﬂammatory or inﬂammatory. Noninﬂammatory arteriopathies comprise connective tissue abnormalities that result in abnormal vessels. Inﬂammatory arteriopathies can be either infectious or noninfectious. Infectious etiologies causing cord infarction include bacteria (e.g., syphilis, a common etiology in the past), viruses (e.g., herpes zoster), fungi (e.g., cryptococcal), and parasites (e.g., schistomiasis). Among the noninfectious inﬂammatory arteriopathies are

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Table 2 Etiologies for Iatrogenic Spinal Cord Infarctions Surgery: Aortic surgery (coarctation [45], aneurysm repair [46], intraortic balloon pump [47]) Thoracic surgery (thoracoscoplasty [5], thoracolumbar sympathectomy [48], pneumonectomy [5]) Abdominal surgery (gastrectomy [4], esophagectomy [49], esophageal sclerotherapy [50], hepatic transplant [51], retroperitoneal tumor resection [52]) Cardiac surgery (coronary artery bypass grafting [29], transposition of the great vessels [53]) Orthopedic surgery (e.g., scoliosis surgery [5], cervical laminectomy [54]) Neurosurgery (resection of thoracic dumbbell neuroblastoma [55], pineal region tumor resection [56]) Endovascular procedures: Embolization (renal artery [57], dural ﬁstula [58], bronchial artery [59], spinal dural AVM [60]) Angiography (cerebral [61], coronary [62]) Other procedures: Epidural catheter placement [63] Nerve block [64] Intrathecal phenol [65] Epidural/spinal anesthesia [66] Drugs (neoarsphenamine [66], zolmitriptan [67], carmustine + cisplatin [68])

Figure 3 A 57-year-old man underwent emergency replacement of a dissecting aortic aneurysm between the renal and distal common iliac arteries. After the surgery the patient was noted to have ﬂaccid paraplegia with absent reﬂexes and a pin-prick sensory level below the navel. His vibration sense was intact at the knees and ankles. His spinal cord MRI demonstrates two areas of infarction in the watershed areas. (Case courtesy of Prof. F. A. Mithen, St. Louis, Missouri.)

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Table 3 Etiologies of Noniatrogenic Spinal Cord Infarctions Arteriopathies Atherosclerotic (aortic occlusion/thrombosis [69], renal transplant [70]) Noninﬂammatory (aortic dissection [1], aortic trauma [71], vertebral artery dissection [72], moya-moya disease [73], Marfan syndrome [74], CADASIL [75]) Inﬂammatory infectious (e.g., syphilis [76], tuberculosis [77], herpes zoster and HIV [78], schistomiasis [79], mucormycosis [80], coccidiomycosis [81], meningitis [82]) Inﬂammatory noninfectious (Takayasu disease [83], lupus [4], giant cell arteritis [84], panarteritis nodosa [3], postinfectious/vaccination [1], granulomatous angitis [85]) Extrinsic vascular compression (cervical spondylosis [86], diaphragmatic crus [87], disc protrusion [88], tumor [89]) Embolism (atheroma [90], nucleus pulposus embolism [91], decompression sickness [4], paradoxical embolization [92], atrial myxoma [1], endocarditis [93]) Generalized hypoperfusion (hypotension [94], cardiac tamponade [95]) Hematological (protein S deﬁciency [96], antiphospholipid syndrome [97], sickle cell anemia [98], 20210 allele mutation [99]) Illicit drugs (e.g., cocaine [100], heroin [101]) Cryptogenic [102]

systemic vasculitis and isolated angiitis of the nervous system. Extrinsic compression of the spinal arteries is another etiology for cord infarction. Embolic infarctions also occur in the spinal cord. Embolic infarctions result from the typical high-risk cardiac sources or paradoxical embolization. In addition, unusual noncardiac sources of embolism (e.g., nucleus pulposus embolism) can appear in the spinal cord. Spinal cord infarctions can also result from generalized hypotension or hypoperfusion (e.g., cardiac arrest). Hematological disorders such as hypercoagulable states or red blood cell abnormalities have also been associated with spinal cord infarctions. F. Diagnosis/Differential Diagnosis The diagnosis should be suspected in a patient that suddenly develops an acute nontraumatic myelopathy, particularly if it follows a procedure with known risk for spinal cord infarction. The presence of symptoms attributed to concomitant aortic lesions, such as the loss of distal pulses in the lower extremities, can be helpful for diagnosis [5]. The diﬀerential diagnosis (Table 4) includes other forms of acute myelopathy, acute polyneuropathies, and psychiatric disorders. Among the myelopathies, acute cord compression (e.g., metastatic

Table 4 Diﬀerential Diagnosis of Spinal Cord Infarction Acute myelopathies Neoplastic (e.g., spinal cord tumors, extrinsic compression) Degenerative (e.g., disc herniation) Demyelination (e.g., acute transverse myelitis, multiple sclerosis) Infection (e.g., epidural abcess) Trauma (e.g., epidural hematoma) Cerebral (e.g., cerebral/brainstem ischemia) Peripheral nerve (e.g., Guillain-Barre´ syndrome) Conversion (hysteria) or malingering

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tumor or cervical spondylosis) is a medical or surgical emergency that needs to be immediately ruled out. Other etiologies of acute myelopathies that can be mistaken as spinal cord strokes include demyelination (e.g., transverse myelitis) or infection (e.g., epidural abcess). Spinal cord strokes could be potentially mistaken for cerebral infarctions, but the absence of symptoms above the foramen magnum and the presence of acute body or limb pain are hallmark clinical features that support a myelopathic origin. Because the diﬀerential diagnosis cannot be based solely on clinical grounds, ancillary studies must conﬁrm the diagnosis. G. Investigations Table 5 lists the ancillary investigations that can be used to establish the diagnosis and diﬀerential diagnosis of a spinal cord infarction. Neuroimaging studies are usually needed. Magnetic resonance imaging (MRI) with gadolinium enhancement is the best way to visualize the ischemic lesion. Diﬀusion-weighted magnetic resonance imaging is able to show the ischemic lesion in the acute stages [17]. Because of the greater susceptibility to ischemia of the gray matter, magnetic resonance imaging can have the characteristic appearance of an ‘‘owleye’’ [18]. The response to gadolinium of spinal cord infarctions varies with the age of the lesion: nonenhancement in acute stages, enhancement from one to 4 weeks, and then progressive tendency to nonenhancement. This characteristic, sequential response helps establish the age of the lesion and rule out a nonischemic etiology (e.g., cord tumor). In addition, magnetic resonance imaging can detect indirect signs suggestive of spinal cord ischemia, such as vertebral body infarction [19]. Alternatives include computed tomography (CT) of the spinal cord and conventional myelography. Computerized tomography can be of particular value in detecting hematomas or vertebral fractures. Plain ﬁlms are useful for rapidly evaluating the skeletal structures and can show aortic calciﬁcations suggestive of aortic atherosclerotic disease. Spinal cord angiography is technically cumbersome to perform and has a limited role in the evaluation of spinal cord infarctions. However, it may be necessary to diagnose an underlying arteriovenous malformation. Blood tests are needed to diagnose speciﬁc etiologies of infarction such as connective tissue diseases, vasculitis, or infection. Similarly, a spinal ﬂuid examination detects evidence of demyelination, infection, or vasculitis. H. Management The management of spinal cord infarction is directed at providing supportive care, preventing and treating medical and neurological complications, as well as investigating for speciﬁc treatable etiologies. Supportive care should be the same used for any other form of acute myelopathy. Potential complications include respiratory and airway failure, pressure sores, deep venous thrombosis, pulmonary embolism, urinary retention, urinary infections, constipation, and episodic dysautonomia. Table 5 Tests Commonly Ordered in the Evaluation of Acute Vascular Myelopathies Magnetic resonance imaging Computed tomography imaging Myelogram Spinal angiogram Plain spine ﬁlms Spinal ﬂuid examination Blood tests (e.g., cell blood count, coagulation studies, sedimentation rate, syphilis, HIV)

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At present there is no speciﬁc eﬀective therapy available to treat spinal cord infarctions. The rarity and heterogenicity of this disease are serious impediments for prospective clinical trials. The use of anticoagulation, high-dose steroids [20], cord revascularization [21], opiate antagonists [22], combined magnesium and hypothermia [23], sympathectomy [24], and hyperbaric oxygen [25] has been advocated, but their role is uncertain. I. Prevention Given the rarity and hetereogenicity of the disease, data regarding primary or secondary prevention for noniatrogenic infarctions are limited. The management of modiﬁable risk factors for atherosclerosis might reduce the risk of spinal cord strokes secondary to this form of arteriopathy. Similarly, anticoagulants might prevent embolic infarctions in patients with a high-risk cardiac source. Conversely, the prevention of iatrogenic spinal cord infarctions is a subject of special interest. Since a large proportion of spinal cord infarcts are related to surgery for aortic abdominal aneurysm, several techniques have been investigated to prevent spinal cord ischemia [26,27]. This includes distal perfusion methods, hypothermia, monitoring spinal cord somatosensory and motor-evoked potentials, pharmacological agents, intercostal artery reimplantation, endovascular stents, and ischemic preconditioning. One of the most utilized is cerebrospinal ﬂuid (CSF) drainage, which decreases CSF pressure and theoretically increases spinal cord blood ﬂow by increasing spinal cord perfusion pressure [28]. In order to avoid disruption of emboli from aortic plaques, hypertensive crisis should be avoided intraoperatively [29]. J. Prognosis Like cerebral infarctions, spinal cord strokes usually display the maximum deﬁcit in the acute setting, with a subsequent tendency toward improvement. Complete recovery is rare, and some degree of disability is expected in at least half of the patients [30]. In many patients with spinal cord strokes, central neuropathic pain is a common longterm disabling symptom [31]. A specialized spinal cord care unit is the ideal facility for the rehabilitation and treatment of the associated complications in those patients with severe, residual myelopathies.

II. VASCULAR MALFORMATIONS OF THE SPINAL CORD A. Epidemiology Spinal cord arteriovenous malformations (AVM) are relatively rare, accounting for 3–12% of the spinal cord masses [32]. Dural arteriovenous ﬁstulas tend to occur in elderly men and are by far the most common type. On the other hand, intramedullary AVM are more rare and tend to occur in younger patients [33]. Spinal AVM are located most commonly in the lower thoracic and lumbosacral spinal cord. B. Classification of Spinal AVM The classiﬁcation of spinal AVM is complex. Because surgical indications and techniques vary considerably between the diﬀerent lesion types, proper recognition and categorization of spinal AVM is important for management. Currently there are two types of classiﬁcations for spinal AVM (Table 6). In one classiﬁcation [34], three main categories for spinal AVM

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Table 6 Two Common Classiﬁcations for Spinal Arteriovenous Malformations with Correlation Dural AVFs Glomus AVM Juvenile AVM Perimedullary AVM Cavernous angiomas

Type Type Type Type

I II III IV

Source: Refs. 34–36b.

are recognized: dural arteriovenous ﬁstulas (AVF), intradural vascular malformations (juvenile, glomus, and perimedullary), and cavernous angiomas. Another older form of classiﬁcation [35], which has been recently revised [36a], classiﬁes the AVM into four categories: types I–IV. This is the most widely accepted system. Type I AVM are also known as spinal dural AVF, ‘‘single-coiled vessel malformation,’’ and ‘‘angioma racemosum venosum.’’ This is the most common type of spinal AVM. It is found mainly at the lower thoracic and lumbosacral cord segments. It usually consists of a single arterial feeder that penetrates the dura at the level of the root sleeve, where a small cluster of vessels forms a ﬁstula. The venous outﬂow from the dural ﬁstula drains intradurally, engorging a venous plexus along the dorsal surface of the spinal cord. These veins will eventually suﬀer a process of arterialization manifested by venous hypertension. Type II AVM are the second most common variety of spinal malformations and involve the spinal cord parenchyma. They are also known as ‘‘glomus type’’ or ‘‘angioma racemosum arteriosum.’’ Because these vascular lesions are under high-pressure and highﬂow conditions, during angiography they show rapid opaciﬁcation and early drainage. Type II AVM are usually located at the cervical cord and are fed by multiple branches from the anterior spinal artery. Those located at the cervicomedullary junction are often in the dorsal aspect and are fed by branches of the vertebral and posterior inferior cerebellar arteries, which makes them more amenable to surgical resection. Type III or ‘‘juvenile’’ AVM are less common than type I or type II AVM. They are more common in young adults and usually consist of large and complex malformations with multiple arterial feeders involving several spinal cord segments, often with extraspinal and paraspinal extensions. Type IV AVM are direct intradural ﬁstulas between the spinal cord arteries (typically the ASA) and an enlarged venous outﬂow tract. These ﬁstulas are usually perimedullary and can result in cord hemorrhage, cord compression from the dilated varicosities, vascular ‘‘steal’’ phenomenon, or venous hypertension. Cavernous angiomas are congenital lesions made of thin-walled capillaries. Cavernous angiomas are arranged in a sinusoidal pattern devoid of interposed neuron and glia. Unlike AVM, cavernous angiomas do not have an arterio-venous shunt. They are typically located in the cord parenchyma. They have been associated with previous trauma, pregnancy, and radiation to the spine [37]. C. Clinical Syndromes 1. Type I These patients are usually older men. Back or neurogenic intermittent claudication is the usual clinical presentation. Symptoms usually are that of a slowly progressive myelopathy,

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which includes gradually worsening weakness and sphincter disturbances. These symptoms typically increase with straining, standing, or walking. Sensory deﬁcits and sexual dysfunction are less common. Because the typical location is in the lower thoracic and lumbar level segment, paraparesis occurs more commonly than quadreparesis. The original description of ‘‘necrotic myelitis’’ by Foix and Alajouanine was based on a case series of patients who had ﬁndings of venous thrombosis on autopsy. Occasionally, due to severe venous congestion and thrombosis or arachnoiditis, these patients can present with sudden ﬂaccid leg weakness [38]. Venous hypertension can cause remote focal symptoms at a distance from the site of an AVF, which can lead to an erroneous localization of the lesion. The rate of neurological progression is variable. The majority of patients develop a major neurological disability within 5 years of the onset of symptoms. In the case series reported by Aminoﬀ and Logue, 91% had restricted mobility after 3 years [39]. Some cases have shown spontaneous resolution of symptoms, possibly due to the occurrence of a venous thrombosis that closed the ﬁstula. These lesions are usually cured by microsurgical or endovascular techniques, but is important to follow up with angiography to monitor success of these procedures. 2. Type II This type of AVM has a higher tendency to present as a hemorrhage, either subarachnoid or parenchymal, and consequently the symptoms tend to be acute. These patients present with severe neck pain or headache, meningeal irritation, opistotonus and coma, mimicking intracranial subarachnoid hemorrhage. A combination of clinical signs of a myelopathy and radiculopathy may be seen. Spinal bruits, although not frequent, are suggestive of this form of malformation. This type of malformation has a less predictable course. It most commonly presents with acute severe symptoms that persist in more than half of the patients. A less common scenario is a gradual progression of neurological dysfunction. 3. Type III Both acute and progressive symptoms have been described with these malformations. Symptoms can be precipitated by posture, activity, and pregnancy. Spinal bruits are frequently found in these malformations. Although the exact natural course is not known, most patients in this category have a poor prognosis. 4. Type IV These malformations typically present as a progressive myelopathy with gradual onset of leg weakness, back pain, and sphincter dysfunction. This is secondary to chronic venous hypertension and ‘‘steal phenomenon.’’ Subarachnoid hemorrhage with a sudden presentation is rarely seen. This malformation typically has a slow insidious course. However, some patients show spontaneous improvement. 5. Cavernous Angiomas Most patients remain asymptomatic. These lesions are commonly found as an incidental ﬁnding in MRI. Those patients who become symptomatic usually have a sudden presentation secondary to hemorrhage. Repeated hemorrhages can also result in a stepwise progressive myelopathy [40]. Spinal angiomas rarely cause symptoms secondary to mass eﬀect. The overall neurological prognosis is perceived to be better than for the intramedullary malformations.

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D. Diagnosis Magnetic resonance imaging is the preferred screening method [41]. It is noninvasive, readily available, and a sensitive tool to diagnose intrinsic cord lesions as well as the angiographically occult cavernous angiomas. Radiological features of AVF include cord enlargement, abnormal cord signal, dilated blood vessels on the surface of the cord, enhancement of the perimedullary veins, and patchy cord enhancement. The role of magnetic resonance angiography in the diagnosis of spinal vascular malformations is not yet established, but several reports showed its value in enhancing the diagnostic yield of conventional MRI [42]. Selective spinal angiography is the deﬁnitive test for diagnosis of spinal malformations. The angiogram is usually considered after an MRI, CT, or myelogram show suspicious vascular lesions. Digital subtraction angiography and superselective injection techniques minimize the total dose of dye injected. The spinal venous network extends for several segments, and therefore the angiogram should be as thorough as possible. If the preliminary angiogram is negative and an AVM is suspected based on remote evidence, a retrograde femoral injection and intracranial injection should be sought in order to complete the study. E. Management The treatment plan in patients with spinal vascular malformations involves a multidisciplinary team formed by a vascular neurosurgeon, interventional neuroradiologist, and a vascular neurologist. The goal is to individualize the best treatment plan for each patient. The treatment options include expectant follow-up, endovascular therapy [43], microsurgical treatment, or combination of the above. The decision is based on the patient’s clinical factors (age, previous hemorrhage, associated medical condition) and the type and location of the lesion. In general type I lesions are the simplest to manage and can be treated by endovascular techniques (embolization) or microsurgical vascular occlusion of the ﬁstula [44]. Types II–III AVM are the more complex to treat. If an intervention is decided, the usual protocol involves a combination of preoperative embolization followed by microsurgical resection. The management of cavernous angiomas of the spinal cord depends on the age, associated medical conditions, lesion location and size, and history of previous hemorrhage. The most common approach is the use of microsurgery. At present, endovascular embolization or gamma knife radiosurgery do not have a deﬁned role in the management of these lesions.

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28 Cerebral Vasculitis Jose´ Biller and Rafael G. Grau Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.

I. DIAGNOSIS AND MANAGEMENT OF CEREBRAL VASCULITIS The term vasculitis encompasses a heterogeneous group of disorders where inﬂammation and destruction of the vessel wall is the primary event. Classiﬁcation, based on vessel wall involved, has produced a clinically ‘‘workable’’ classiﬁcation of the idiopathic vasculitides (Table 1), although much overlapping is seen in the clinical setting. Secondary vasculitides are associated with many infectious and multisystem noninfectious inﬂammatory diseases. Both idiopathic and secondary forms of vasculitis can cause cerebral vasculitis (Table 2). Patients with cerebral vasculitis can present with diverse complaints including, headaches, personality changes, psychiatric disturbances, intracranial hemorrhage, ischemic stroke, or seizures. Multisystem vasculitis can be complicated by a variety of metabolic, hematological, and cardiac disorders that, in turn, cause neurological dysfunction. As a result, caution should be exercised when attributing neurological symptoms to cerebral vasculitis in a patient with multisystem vasculitis [1–10]. Cerebral vasculitis is a consideration in children and young adults with ischemic stroke; patients with recurrent strokes; patients with ischemic stroke accompanied by encephalopathic changes; and patients with stroke accompanied by fever, multifocal neurological events, unexplained skin lesions, scleritis, keratitis, uveitis, retinal vasculitis, or glomerulopathy. Patients with cerebral vasculitis may also have concurrent myelopathy, peripheral neuropathy, or multisystem signs. The goal of this chapter is to provide a roadmap to the diagnosis and management of cerebral vasculitis rather than an extensive review of the neurological manifestations of the vasculitides.

II. PATHOPHYSIOLOGY Vascular injury is the central pathology in the vasculitides, and the mechanisms of injury are diverse. Vasculitis is characterized by blood vessel inﬂammation and necrosis. The etiology of vasculitis in most patients is unknown, and the pathophysiology is incompletely understood. Four basic types of immunopathogenetic mechanisms have been accepted: (1) anaphylactic type, (2) cytotoxic/cell activating type, (3) immune complex type, and (4) cell-mediated type [11]. Injury can also occur by other pathways including direct cytokine-mediated, direct neutrophil involvement, genetically mediated, direct 653

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Table 1 Idiopathic Vasculitides Large vessel predominance Takayasu’s arteritis Temporal (cranial) arteritis Medium vessel predominance Polyarteritis nodosa Kawasaki disease Small vessel predominance Wegener’s granulomatosis Allergic angiitis and granulomatosis (Churg-Strauss) Hypersensitivity vasculitis Henoch-Scho¨nlein purpura Cryoglobulinemic vasculitis Microscopic polyangiitis Miscellaneous conditions Primary CNS vasculitis (isolated CNS angiitis) Behcßet’s disease Cogan’s syndrome Vasculitis associated with radiation Thromboangiitis obliterans (Buerger’s disease) Lymphomatoid granulomatosis

infectious, or environmental/chemical injury. More than one mechanism is likely to be involved in a particular vasculitis [12,13].

III. DIAGNOSIS The diagnosis of cerebral vasculitis is often inferential and is based on clinical presentation, presence of multisystem organ involvement, and abnormal serological tests [1–10]. However, atrial myxoma, septicemia, infective endocarditis, lymphoma, neoplastic angioendotheliosis, cholesterol embolization from large aneurysms, or intracranial atherosclerosis can cause a similar picture, and they should be considered in the diﬀerential diagnosis. Brain and/or meningeal biopsy are usually required for the deﬁnitive diagnosis of angiitis of the central nervous system (CNS) (histologically deﬁned angiitis of the CNS). The angiographic features of cerebral vasculitis are nonspeciﬁc and may be seen with migrainous vasoconstriction or vasospasm following aneurysmal subarachnoid hemorrhage, brain tumors, intracerebral hematomas, pyogenic meningitides, intracranial atherosclerosis, head trauma, vascular anomalies associated with neurocutaneous syndromes, moyamoya, sickle cell disease, neoplastic angioendotheliosis, oral contraceptive use, hypertension associated with pheochromocytoma, postpartum eclampsia, postcoital headaches, surgical manipulation of intracranial arteries, and reversible segmental cerebral vasoconstriction (Call syndrome). Once the diagnosis of vasculitis is established, sequential arteriograms may be useful in monitoring response to treatment in selected circumstances [1–3,14]. Magnetic resonance imaging (MRI) and cranial computed tomography (CT) help delineate the anatomical extent of CNS involvement, but there are no CT or

Cerebral Vasculitis Table 2 Cerebral Vasculitis Infectious vasculitis Bacterial Fungal Parasitic Spirochetal (syphilis, Lyme disease) Viral Rickettsial Mycobacterial Necrotizing vasculitides Wegener’s granulomatosis Classic polyarteritis nodosa Microscopic polyangiitis Allergic angiitis and granulomatosis (Churg-Strauss) Necrotizing systemic vasculitis-overlap syndrome Lymphomatoid granulomatosis Vasculitis associated with collagen vascular diseases Systemic lupus erythematosus Rheumatoid arthritis Scleroderma Sjo¨gren’s syndrome Vasculitis associated with other systemic diseases Behc¸et’ s disease Ulcerative colitis Sarcoidosis Relapsing polychondritis Kohlmeier-Degos disease Giant cell arteritides Takayasu’s arteritis Temporal (cranial) arteritis Hypersensitivity vasculitides Henoch-Scho¨nlein purpura Drug-induced vasculitides Chemical vasculitides Essential mixed cryoglobulinemia Miscellaneous Vasculitis associated with neoplasia Vasculitis associated with radiation Cogan’s syndrome Dermatomyositis-polymyositis X-linked lymphoproliferative syndrome Thromboangiitis obliterans Kawasaki disease Primary central nervous system (CNS) vasculitis

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MRI changes pathognomonic of cerebral vasculitis [15]. Cerebrospinal ﬂuid (CSF) can be abnormal or demonstrate nonspeciﬁc changes of increased protein content, normal glucose levels, and a discrete lymphocytic pleocytosis indicating inﬂammatory CNS activity. The combination of a normal MRI and a normal CSF is most reliable in excluding CNS vasculitis [16]. Serological ﬁndings including acute phase reactants can support the presence of a systemic inﬂammatory state, but are often nonspeciﬁc and may be absent on occasions. Electroencephalography (EEG) may be abnormal, demonstrate a focal or diﬀuse slowwave abnormality, or reveal epileptiform activity. Also, there can be a generalized reduction of cerebral blood ﬂow, measured by the xenon 133 inhalation method [17]. Suggested laboratory evaluations of patients with suspected noninfectious vasculitides are listed in Tables 3–6. Of particular diagnostic importance are the antineutrophil cytoplasmic antibodies (ANCA), which are most helpful in the diagnosis of the primary or idiopathic vasculitides such as Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, and less commonly in cases of polyarteritis nodosa. Positive titers by immunoﬂuorescent technique must be conﬁrmed by ELISA techniques demonstrating the presence of antibodies to the cytoplasmic enzymes, antimyeloperoxidase (antiMPO) or antiproteinase 3 (anti-PR3) [18].

IV. CLASSIFICATION: INFECTIOUS VASCULITIS Infectious vasculitides aﬀecting the cerebral vasculature cause ischemic or hemorrhagic cerebral complications and are predominantly bacterial or viral in nature [19]. Almost all species of bacteria or fungi can cause infective endocarditis. Neurological complications are common with infective endocarditis; strokes account for about half of the neurological manifestations. The pathophysiological mechanisms include septic embolization, aneurysm formation, and arteritis. Embolic lesions may be found in the brain, eye, kidney, spleen, liver, and coronary arteries [20]. Strokes may follow a variety of bacterial, fungal, parasitic, or viral cerebral vasculitides. The World Health Organization (WHO) estimates that the annual incidence of syphilis is approximately 12 million cases. Syphilis is a chronic infection caused by the spirochete Treponema pallidum. Intracranial vasculitis and stroke can result from meningovascular syphilis. Meningovascular syphilis occurs most frequently between 4 and 7 years after infection. Heubner’s arteritis occurs in meningovascular syphilis. Syphilitic meningovasculitis involves inﬂammation by lymphocytes and plasma cells of large and mediumsized arteries. There is associated subintimal proliferation leading to lumen occlusion and vessel thrombosis. The middle cerebral artery territory is preferentially involved. Prodromal manifestations are common before stroke. Seizures, hemiparesis, or aphasia may develop slowly over the course of days. Less commonly, focal ischemia aﬀects the basilar artery territory. Spinal cord infarction may result from meningomyelitis. CSF ﬁndings may show a modest lymphomononuclear pleocytosis, elevated protein content, and a positive CSF Venereal Disease Research Laboratory (VDRL). Concurrent human immunodeﬁciency virus (HIV) infection can lead to rapid progression of early syphilis to neurosyphilis. Luetic aneurysms of the ascending aorta can extend to involve the origin of the great vessels and can lead to stroke. Other neurological manifestations in patients with secondary syphilis include headaches, nausea, vomiting, photophobia, meningismus, mental status changes, cranial nerve abnormalities including sensorineural deafness, hydrocephalus, spinal pachymeningitis,

Cerebral Vasculitis Table 3 Evaluation of a Patient with Suspected Noninfectious Cerebral Vasculitis: Biochemical Evaluation Complete blood count with diﬀerential and platelet count Prothrombin time and partial thromboplastin time Serum creatinine and blood urea nitrogen levels Serum venereal disease research laboratory (VDRL) levels Plasma glucose levels Serum calcium Erythrocyte sedimentation rate (ESR) C-reactive protein (more sensitive, useful if ESR normal) Interleukin-6 (more experience needed) Liver function tests Serum bilirubin Aspartate aminotransferase (AST) Glutamyl transpeptidase (GTT) Alanine aminotransferase (SGPT) Lactic dehydrogenase (LDH) Alkaline phosphatase Creatine kinase (CK) Serum immunoelectrophoresis Urinalysis with microscopic evaluation Cerebrospinal ﬂuid analysis

Table 4 Evaluation of a Patient with Suspected Noninfectious Cerebral Vasculitis: Speciﬁc Laboratory Testing Antinuclear antibodies (ANA) Extractable nuclear antigens (Sm, nRNP) Antibody to double-stranded DNA (only if ANA positive) Rheumatoid factor Anticardiolipin antibodies IgG, IgM C3, C4, CH50 Neutrophil cytoplasmic antibody (cANCA) Neutrophil cytoplasmic antibody (pANCA) Hepatitis B surface antigen (HbsAg) Hepatitis C virus serology Scl 70 antibody (anti-isomerase antibody) Anticentromere antibodies Anti-Ro (SSA) cytoplasmic antibodies Anti-La (SSB) antibodies Serum angiotensin-converting enzyme Cryoglobulins Coombs’ test Shirmer’s test Skin test for anergy Pulmonary function tests to include spirometry, lung volumes, and diﬀusing capacity

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Table 5 Evaluation of a Patient with Suspected Noninfectious Cerebral Vasculitis: Imaging Evaluation Chest roentgenogram Paranasal sinus x-rays Gallium 67 scanning Computed tomography of the brain Magnetic resonance imaging of the brain Magnetic resonance angiography Cerebral angiography Arch arteriogram Visceral angiographya (renal, hepatic, mesenteric circulation) a If patient is symptomatic (e.g., abdominal pain, renal or hepatic dysfunction), and if PAN, necrotizing systemic vasculitis, overlap syndrome, or Takayasu’s arteritis is suspected.

and meningomyelitis. Treatment of neurosyphilis is with aqueous crystalline penicillin at a dose of 18–24 million units per day for 10–14 days. Alternative treatments include a single intramuscular dose of 2.4 million units of procaine penicillin plus oral probenecid, or intravenous or intramuscular ceftriaxone at a dose of 2 g daily for 10–14 days. Patients with concurrent HIV infection and meningovascular syphilis may require prolonged antibiotic treatment [21,22]. Worldwide, an estimated 1.6 billion people are infected with Mycobacterium tuberculosis. In the United States, half of all cases of tuberculosis occur among foreign-born persons. Neurotuberculosis aﬀects predominantly the basilar meninges. Predisposing conditions include alcoholism, substance abuse, corticosteroid use, and HIV infection. Approximately 8 million people are co-infected with HIV and tuberculosis. Strokes can

Table 6 Evaluation of a Patient with Suspected Noninfectious Cerebral Vasculitis: Possible Histological (Biopsy) Evaluation Sitesa Skin Nasal mucosa Lymph node Minor salivary glands Bone marrow Bronchial Lung Kidney Prostate Rectum Liver Muscle Nerve Temporal artery Brain/meningeal a

Multiple biopsies at multiple sites may be necessary.

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result from tuberculous endarteritis. Cerebral or subarachnoid hemorrhage are rare [23]. The exudative basilar inﬂammation entraps the cranial nerves at the base of the brain, most frequently the third, fourth, and sixth cranial nerves. The basilar arteriolitis most commonly involves penetrating branches of the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery (medial and lateral lenticulostriate, anterior choroidal, thalamoperforators, and thalamogeniculate arteries). There is usually a modest lymphocytic and mononuclear pleocytosis. The CSF protein is usually elevated, and the glucose level is depressed. In the early stages, a predominantly CSF neutrophilic response may be noted. Smears of CSF demonstrate Mycobacterium tuberculosis in 10–20% of cases. Repeated CSF examinations increase the yield considerably. First-line antimycobacterial drugs include isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. Drug-resistance patterns must be taken into account. The role of corticosteroids in the treatment of tuberculous meningitis is conﬂicting [24,25]. Bacterial meningitis is associated with vascular involvement by the inﬂammation of the subarachnoid space extending into the Virchow-Robin spaces along the vasculature. Complications of acute purulent meningitis include intracranial arteritis and thrombophlebitis of the major sinuses and cortical veins. Intracranial arterial stenoses have been associated with a complicated clinical course. Fungal infections such as candidiasis, rhinocerebral mucormycosis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, nocardiosis, and actinomycosis can cause cerebral vasculitis and strokes. Fungal arteritis may result in mycotic aneurysms, pseudoaneurysms, thrombus formation, and cerebral infarction. Rhinocerebral mucormycosis may cause cavernous sinus and internal carotid artery thrombosis (Fig. 1). Intracranial aspergillosis may cause subarachnoid hemorrhage attributable to ruptured mycotic aneurysms or to septic arteritis without aneurysm formation. Aspergillus valvular infections may be associated with multiple embolic events. Disseminated candidiasis may cause mycotic aneurysms, thrombotic brain infarction, hemorrhagic brain necrosis, subarachnoid hemorrhage, and cerebral vasculitis. Vasculitis complicating coccidioidal meningitis is becoming increasingly recognized; early encroachment of the blood vessels may result in vessel thrombosis. Cryptococcosis seldom involves the intracranial vessels [26–32]. Strokes have been described in patients with cat-scratch disease (Bartonella henselae), Mycoplasma pneumoniae infection, coxsackie 9 virus, parvovirus or B19 virus, California encephalitis virus, mumps paramyxovirus, hepatitis C virus, enteroviruses, cytomegalovirus, a variety of viral hemorrhagic fevers, infections with cytomegalovirus, varicella-zoster virus (VZV), and HIV [33–48]. VZV causes chickenpox (varicella) and shingles (herpes zoster). Cerebellar ataxia is the most common manifestation of CNS infection. VZV is associated with large or small vessel vasculopathy and may also cause a virus-induced necrotizing arteritis similar to granulomatous angiitis. CNS large-vessel vasculitis developing 4–6 weeks after herpes zoster ophthalmicus is the most common VZV-associated vasculitis. Cerebral angiography often demonstrates unilateral, segmental narrowing of the proximal segments of the middle, anterior, or less commonly the posterior cerebral or internal carotid artery. CSF may show a discrete lymphocytic pleocytosis. Intravenous acyclovir is the treatment of choice for complicated VZV infections. Other management options include valacyclovir, famcyclovir, or ganciclovir. Varicella usually occurs before the age of 10 years and may cause numerous complications, most commonly due to bacterial superinfection caused by excessive scratching. Hemorrhagic varicella and encephalitis are rare. Uncommonly, a postvaricella angiopathy aﬀecting small and large vessels may develop. Pathological

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Figure 1 Methenamine silver stain demonstrates numerous hyphae invading a vessel with subsequent thrombosis.

studies have demonstrated changes consistent with vasculitis with lymphocytic inﬁltration of the vessel walls [36–43]. Cerebral infarction is a complication of the acquired immunodeﬁciency syndrome (AIDS) and may result from vasculitis, meningovascular syphilis, VZV vasculitis, opportunistic infections, infective endocarditis, fusiform aneurysmal dilatation of major cerebral arteries, nonbacterial thrombotic endocarditis, antiphospholipid antibodies or other hypercoagulable states, hyperlipidemia due to protease inhibitors, and other factors such as HIV-related malignancy, cancer chemotherapy, or thrombotic thrombocytopenic purpura. HIV-infected children also have an increased incidence of cerebrovascular disease associated with severe immune suppression [44–48]. Hepatitis C–associated vasculitis can occur in patients with or without mixed cryoglobulinemia. Other infectious agents known to produce cerebral infarcts include the larval or metacestode stage (cysticercus) of the pork tapeworm Taenia solium. Cysticercosis is the most common parasitic infection to aﬀect the CNS. Cerebrovascular involvement in neurocysticercosis is usually caused by chronic meningitis, arteritis, or endarteritis of small cerebral vessels [49]. The frequency of cerebral arteritis is higher in cases of subarachnoid cysticercosis [50]. Rickettsiaceae are transmitted to vertebrate hosts by arthropods. Although a rare cause of stroke, rickettsial infections can cause a widespread febrile vasculitis of small

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venules and arterioles that can involve the cerebral vasculature leading to microinfarcts. Treatment of choice is with doxycycline [51]. Approximately two billion people are at risk of malaria in endemic tropical and subtropical areas. The pathophysiology of cerebral malaria is controversial. Tissue infarction is not a major feature of cerebral malaria. Malaria-associated cerebral vasculitis can cause small, punctate, brain microhemorrhages. Lyme disease is a tickborne disease caused by the spirochete Borrelia burgdorferi. Lyme carditis can cause heart block and other cardiac arrhythmias, but Lyme neuroborreliosis is an unusual cause of cerebral vasculitis or strokes. One of three patients with Borrelia burgdorferi infection associated with intracranial aneurysms was found to have perivascular and vasculitic lymphocytic inﬂammation on brain biopsy [52–54]. Typhoid fever (Salmonella typhi) may result in endocarditis and delirium, but strokes are rare. Large artery cerebrovascular occlusions have been found in association with meningoencephalitis caused by free-living amebae. Sparganosis is infection with the migratory larvae of cestodes of the genus Spirometra; rare cases of sparganosis-induced cerebral vasculitis have been reported [55]. Rarely, cerebral vasculitis may follow acute poststreptococcal glomerulonephritis [56]. The carotid sheath is within the posterior compartment of the lateral parapharyngeal space. Unilateral or bilateral carotid occlusion can complicate necrotizing fasciitis of the lateral parapharyngeal space. A purulent thrombophlebitis of the jugular vein (Lemierre syndrome) may develop. Compromise of cranial nerves IX–XII may follow. Atypical cases of Lemierre’s syndrome have been reported in association with carotid artery thrombosis [57]. Orbital cellulitis is the most common serious complication of sinusitis. Other complications of sinusitis arise from spread of the infection to the CNS. Rarely, a sphenoid sinusitis has been associated with basilar artery vasculitis [58]. Seroepidemiological studies suggest an association between elevated antibodies against Chlamydia pneumoniae and an increased risk of having a cardiac event. Chlamydia pneumoniae accelerates the process of atherosclerosis in animal studies; treatment with azithromycin has been shown to reduce the degree of atherosclerotic lesions in a rabbit model [59,60].

V. NECROTIZING VASCULITIDES A. Wegener’s Granulomatosis Wegener’s granulomatosis is characterized by necrotizing granulomas of the upper and lower respiratory tract, glomerulonephritis, and multisystem small vessel vasculitis. The focal necrotizing vasculitis (focal and segmental) involves both small arteries, arterioles, and venules and is often adjacent to a granuloma [61–66]. The most commonly aﬀected organs are the nose, paranasal sinuses, and lungs (Fig. 2). Neurological manifestations include cerebral and subarachnoid hemorrhage, cerebral arterial and venous thrombosis, cranial and peripheral neuropathies (primarily mononeuritis multiplex), diabetes insipidus, retinal vascular and optic nerve lesions, ocular myositis, orbital pseudotumor, and myopathy [66,67]. Antineutrophil cytoplasmic antibodies with diﬀuse staining of the cytoplasm (cANCA) are present in 90% of active cases. Lower cANCA values are seen in inactive and localized forms. Untreated, Wegener’s granulomatosis runs a rapidly fatal course with a mean survival of only few months. Prompt and appropriate treatment may be lifesaving. Successful management requires the combination of prednisone and cyclophosphamide.

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Figure 2 Wegener’s granulomatosis. Computed axial tomography (CT) scan reveals opaciﬁcation of both maxillary sinuses (arrow), destruction of the nasal septum (arrowhead), and soft tissue attenuation within the nasal cavity.

Cerebral vasculitis associated with Wegener’s granulomatosis is treated with high-dose glucocorticoids and cyclophosphamide [67]. The risk of bladder cancer can be minimized by the use of cyclophosphamide pulse therapy and concurrent Mesna (MesnexR) injection to minimize bladder toxicity. Cyclophosphamide is followed by generous hydration to avoid hemorrhagic cystitis. In addition to regular urinalysis to monitor for hematuria, white blood cell (WBC) counts should be drawn to follow for bone marrow suppression. Gonadal suppression, bladder ﬁbrosis, alopecia, gastrointestinal intolerance, and secondary malignancies are additional complications of cyclophosphamide therapy. Patients intolerant of cyclophosphamide can be treated with azathioprine or low-dose methotrexate [69–74]. The usefulness of intravenous immunoglobulin (IV Ig) in Wegener’s granulomatosis and other ANCA-associated vasculitides remains inconclusive.

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B. Polyarteritis Nodosa Classic polyarteritis (polyarteritis) nodosa (PAN) is an uncommon, focal, segmental, necrotizing panarteritis of medium-sized vessels. PAN can aﬀect any organ but characteristically spares the lung and spleen. Men and women of all ages are equally aﬀected. Onset is often between 40 and 60 years of age. Clinical manifestations are protean. Constitutional symptoms of fever, malaise, and weight loss are usually seen along with manifestations of multisystem involvement, such as skin rash, arthralgias, asymmetric polyarthritis, orchitis, and mononeuritis multiplex. Visceral involvement of kidney or gut may present coincidentally or appear later. Heart manifestations are due to vasculitis of the coronary arteries. The eye may be aﬀected with a retinal vasculitis. The cerebral vessels are rarely involved. Strokes in PAN are more often hemorrhagic than ischemic. Ischemic spinal cord involvement has also been described [75–79] (Fig. 3). Diagnosis is based on strong clinical suspicion. Laboratory tests that may be helpful include serology for hepatitis B, C, and HIV. Angiography of the superior mesenteric and renal arteries may show aneurysmal dilatation and areas of focal stenosis. Deﬁnitive diagnosis requires biopsy of aﬀected tissues, most commonly, nerve and muscle, usually the sural or superﬁcial peroneal nerves.

Figure 3 Patient with polyarteritis nodosa: (a) axial unenhanced cranial computed tomography shows a left parietal hemorrhagic infarction with surrounding edema; (b) cyanotic discoloration of digits secondary to ischemia; (c) left lateral malleolar ulceration in a patient with a foot drop secondary to a peroneal neuropathy.

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Figure 3 Continued.

Treatment is based on corticosteroids with concurrent use of daily oral or pulse cyclophosphamide or other corticosteroid-sparing agent. If an associated viral disorder is found, treatment of the underlying condition may be beneﬁcial. The risk of bladder cancer can be minimized by the use of cyclophosphamide pulse therapy and concurrent Mesna (Mesnex) to minimize bladder toxicity [80,81].

C. Microscopic Polyangiitis The 1993 Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis adopted the name of microscopic polyangiitis as a separate entity from PAN. Microscopic polyangiitis is a multisystem small-vessel necrotizing vasculitis, aﬀecting especially arterioles, capillaries, and venules. Microscopic polyangiitis is associated with a rapidly progressive focal segmental necrotizing glomerulonephritis. Other clinical manifestations include fever, weight loss, pulmonary hemorrhages, asymptomatic microscopic hematuria, and proteinuria. Mononeuritis multiplex is less commonly found than in cases of PAN [82]. CNS involvement is very rare and may present as a stroke. Approximately 75% of patients have a positive ANCA with a perinuclear immunoﬂuorescent distribution (pANCA) being the most common pattern. Treatment is primarily with corticosteroids

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Figure 3 Continued.

and occasionally with cytotoxic agents. Current treatment recommendations for induction include the administration of cyclophosphamide combined with oral prednisone. Plasmapheresis may be useful in selective patients with dialysis-dependent renal failure [83]. The usefulness of intravenous immunoglobulin (IV Ig) remains controversial.

D. Allergic Angiitis and Granulomatosis Allergic angiitis and granulomatosis (Churg-Strauss vasculitis) describe the association of asthma or allergic rhinitis, blood eosinophilia, vasculitis, and extravascular granulomas. It is characterized by necrotizing vasculitis involving small arterioles and venules and small necrotizing granulomas. Unlike PAN, it is more common among women. Clinical features include a history of asthma or atopy, bronchitis or pneumonias, systemic symptoms of fever and weight loss, subcutaneous nodules, and peripheral neuropathy mononeuritis multiplex. Cranial nerve palsies, optic neuropathy, and optic disc vasculitis are less common. Phrenic nerve palsies, thought to be secondary to a nerve vasculitis, have been rarely described [84]. CNS involvement is rare. Meningeal and intraventricular hemorrhages secondary to choroid plexus necrotizing vasculitis have been reported [85]. ANCA can be seen in up to 70% of patients and are of the perinuclear immunoﬂuorescent pattern

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(pANCA). Treatment is with glucocorticoids and cyclophosphamide. Azathioprine can be used for steroid-resistant cases or for steroid-sparing purposes [86]. Cyclosporine has been administered in few cases.

E. Lymphomatoid Granulomatosis Lymphomatoid granulomatosis is an angiocentric, angiodestructive inﬁltrative disease aﬀecting predominantly the respiratory tract, skin, and CNS and is characterized by inﬁltrates of atypical lymphocytoid and plasmacytoid cells. Treatment with high-dose prednisone and cyclophosphamide, as described for Wegener’s granulomatosis, has induced remissions in patients who have not undergone malignant transformation [87,88].

VI. VASCULITIS ASSOCIATED WITH COLLAGEN VASCULAR DISEASE Although vasculitis associated with many collagen vascular diseases has been described rarely, only a few diseases have CNS involvement frequently enough to warrant detailed elaboration [89].

A. Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is associated with accelerated atherogenesis, hypercoagulability, endothelial dysfunction, cardiac embolic sources, and an increased risk of arterial hypertension in patients with associated renal involvement, all contributing to the neurological manifestations seen in this disease [90]. Vasculitis as a manifestation of SLE is not rare and most commonly aﬀects the skin [91]. However, true immune complex– mediated CNS vasculitis is surprisingly uncommon in SLE patients who develop CNS signs. One postmortem series involving examination of 50 patients with SLE found no instances of CNS vasculitis. The development of focal seizures in the absence of other causes (i.e., posttraumatic) and with negative angiograms, CT, and MRI, may result from local vasculopathy, vascular irritation, and leakage caused by circulating immune complexes. Strokes in SLE may occur from thrombotic arterial occlusions associated with antiphospholipid antibodies (APLs) or from embolism associated with verrucous endocarditis (Libman-Sacks endocarditis). Transverse myelopathy has also been associated with the presence of APLs, and may result from either thrombosis or vasculitis [92]. CNS disease may also be secondary to aseptic meningitis, underlying infection, metabolic derangements, or the presence of antineuronal antibodies. Therapy is based on operative mechanisms. True vasculitis is treated with high-dose glucocorticoids. The use of intravenous methylprednisolone, cyclophosphamide, azathioprine, or IV Ig is anecdotal, and response has been evaluated only in an uncontrolled way [93–102]. Thrombotic manifestations related to APLs are treated with chronic anticoagulation and antimalarials (Plaquenil).

B. Rheumatoid Arthritis Cerebrovascular manifestations of rheumatoid arthritis (RA) are uncommon. CNS vasculitis associated with RA is extremely rare; it was reported to occur in less than

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0.1% of admissions to a neurological unit serving 2.5 million people [103,104]. A panarteritis aﬀecting small and medium-sized vessels usually accompanies long-standing, erosive, nodular rheumatoid factor–positive patients, and it typically presents as a mild distal sensory neuropathy or a severe mononeuritis multiplex. Rarely, it may account for cerebral ischemia, manifested by focal lesions, diﬀuse cerebritis, intracerebral or subarachnoid hemorrhage, or seizures. High-dose corticosteroids are frequently ineﬀective when used alone in controlling active RA, and cyclophosphamide, either by mouth or intravenously, is frequently required [105–109]. Patients on higher doses of prednisone should be on bone-protective regimens. C. Scleroderma Neurological involvement with scleroderma is uncommon, and, when present, it is related to concurrent arterial hypertension and uremia. Some patients with scleroderma have cerebral arteritis [110–112]. Treatment is symptomatic. There is little information concerning the use of corticosteroids, but this form of therapy has been advocated for some patients. Calcium channel blockers are commonly used as ﬁrst-line therapy for the management of Raynaud’ s phenomenon. D. Sjo¨gren’s Syndrome Sjo¨gren’s syndrome is characterized by dryness of the eyes (xerophthalmia) and mouth (xerostomia); this is also known as the sicca syndrome. Sjo¨gren’s syndrome may be primary, or it may be secondary when associated with other well-deﬁned autoimmune disorders such as RA, scleroderma, SLE, or polymyositis. Up to 25% of patients with primary Sjo¨gren’s syndrome have CNS involvement. Few patients with Sjo¨gren’s syndrome have shown histological evidence of vasculitis of small to medium-sized vessels causing encephalopathy or thrombotic strokes. Glucocorticoid therapy has been used in the treatment of neurological complications with some success [113–120]. Cyclophosphamide, methotrexate, and cyclosporin A have also been used in selective instances.

VII. VASCULITIS ASSOCIATED WITH OTHER SYSTEMIC DISEASES Behcßet’s disease is prevalent in Middle Eastern and Mediterranean populations. Behcßet’s disease is a chronic, relapsing, multisystem small-vessel vasculitis characterized by relapsing oral and genital ulcerations, iritis, uveitis, synovitis, polyarthritis, erythema nodosum and cutaneous vasculitis. Arterial and venous involvement is common. Migratory superﬁcial venous thrombophlebitis often antedates deep venous involvement. Patients may develop systemic and pulmonary large vessel aneurysms. Neurological involvement (neuro-Behc¸et’s) is common but is rarely the initial manifestation of the disease. CNS disease may be secondary to aseptic meningitis, meningoencephalitis, brainstem syndromes, multifocal CNS white matter involvement, and cerebral venous thrombosis [121]. Features of CNS vasculitis have been reported [122]. Corticosteroids are often used but may be ineﬀective in some instances. Immunosuppressive therapy with cyclophosphamide, azathioprine, or chlorambucil may be required [123–125]. Cyclosporine is better avoided [126]. Cerebral venous thrombosis often responds well to a combination of anticoagulant and corticosteroid therapy [127].

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A small portion of patients with ulcerative colitis may suﬀer strokes associated with an underlying hypercoagulable state. Cerebral vasculitis is uncommon. Treatment may require immunosuppressive therapy [128–130]. Sarcoidosis is a systemic disease characterized by noncaseating granulomatous reaction of unknown origin. It most frequently involves the lymph nodes and lungs, but any organ can be involved. Neurological involvement in the form of vasculitis is rare and can aﬀect both large and small vessels, mimicking Takayasu arteritis, polyarteritis nodosa, or hypersensitivity vasculitis [131]. The vasculitic form of sarcoidosis primarily aﬀects the eyes, meninges, and cerebral arteries and veins. Current treatment involves the use of corticosteroids [132,133]. Cerebral arteritis has been described in relapsing polychondritis, a rare disorder of cartilage characterized by auricular, nasal, and laryngotracheal chondritis, producing a saddle nose and ﬂoppy ear deformities. Vasculitis may aﬀect small, medium, and large vessels. Cardiovascular involvement is present in up to half of the patients. Aortic regurgitation is a frequent complication. Neurological involvement occurs in 3% of patients and includes meningoencephalitis, seizure, strokes, subarachnoid hemorrhage, dementia, cerebellar and cranial nerve involvement. Corticosteroids may be eﬀective [134,135]. Kohlmeier-Degos or malignant atrophic papulosis is an unusual vaso-occlusive disease of unknown etiology. Necrotizing arteritic skin lesions often antedate the neurological manifestations. Cerebrovascular complications include ischemic and hemorrhagic strokes. Corticosteroids appear to be contraindicated [136–138].

VIII. GIANT CELL ARTERITIDES A. Takayasu’s Arteritis Takayasu’s arteritis (TA) is a chronic panarteritis localized to the aorta and its proximal branches (aortic arch or its branches, the ascending thoracic aorta, the abdominal aorta, or the entire aorta. TA, also) and is known as the‘‘pulseless disease.’’ It is more common in women than in men and is more frequent in Far Eastern countries and in Mexico. Eighty to ninety percent of cases occur in women, most between the ages of 10 and 30 years. Pathologically, all three arterial layers are aﬀected, with presence of granulomatous changes and giant cells in the media and adventitia. TA has been associated with certain human leukocyte antigen (HLA) genes such as HLA-B52, B-39, and MICA [139]. TA has two distinctive clinical phases: a prepulseless (inﬂammatory or systemic phase), and a pulseless phase. Systemic symptoms of TA include fatigue, weight loss, lowgrade fever, arthralgias, thoracic back pain, and new onset hypertension. Amaurosis fugax, TIAs, and strokes are relatively common. Other ischemic-related symptoms include vertigo when looking upwards, syncope, convulsions, dementia, headaches, claudication in one arm or leg, ischemia of the extremities, ischemic optic neuropathy, and decreased visual acuity. Widespread bruits, a weak or absent radial pulse, and diﬀerences in blood pressure between both arms are helpful diagnostic clues. Intermittent claudication of the jaw muscles and atrophy of the facial musculature may be evident. Diagnosis is often conﬁrmed by aortic angiography or three-dimensional CT. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) are valuable noninvasive diagnostic tools, and both are useful for the follow-up of these patients. Laboratory abnormalities may include normochromic or hypochromic anemia, leukocytosis, increased erythrocyte

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sedimentation rate (ESR), elevated C-reactive protein (CRP), and hypergammaglobulinemia [140,144]. Management includes high-dose glucocorticoids with subsequent tapering. Antiplatelet therapy is often employed to prevent thrombus formation. Cytotoxic drugs have not oﬀered improved outcome. Surgical reconstructive methods or percutaneous transluminal angioplasty are often needed for the chronic arterial lesions of TA. B. Temporal Arteritis Temporal arteritis, also known as giant cell arteritis, cranial arteritis, and Horton’s disease, is a systemic granulomatous inﬂammation of large and medium-sized arteries of unknown etiology and is seen in the elderly . The disease is more common among whites of Scandinavian descent, and is rare among African Americans and native Americans. Women are aﬀected twice as frequently as men. Temporal arteritis aﬀects preferentially the superﬁcial temporal, ophthalmic, posterior ciliary artery, and vertebral arteries. Aortic involvement is a late complication that occurs in 10% of patients. Pathological ﬁndings show destruction of the internal elastica lamina and a mononuclear granulomatous inﬂammatory inﬁltrate accompanied by giant cells in approximately half of the biopsies [146–162]. Temporal arteritis is an important cause of preventable visual loss in older patients. Visual loss is most often secondary to reduced blood ﬂow to the posterior ciliary arteries, causing infarction of the optic nerve head (anterior ischemic optic neuropathy) or, less frequently, secondary to infarction of the retina due to central retinal artery occlusion. Narrowing or occlusion of the carotid and vertebral arteries may cause TIAs or strokes. Infarction of the occipital cortex can cause cortical blindness. Vascular dementia is a rare occurrence [161]. Myocardial infarction, aortic dissections, and aortic regurgitation are also potential life-threatening complications. Temporal arteritis is often associated with jaw claudication and polymyalgia rheumatica, a myalgic syndrome involving the neck, shoulders and pelvic areas, and accompanied by low-grade fever, anorexia, weight loss, anemia, and elevated ESR values. The CRP is often elevated. The CRP and interleukin-6 levels appear to be more sensitive biological markers for the diagnosis of temporal arteritis than the ESR. Half of the patients have some degree of normocytic, normochromic anemia. The WBC count may be elevated. The a2-globulin fraction, a2-glycoprotein, and von Willebrand’s factor values are elevated. The albumin level is decreased; the serum gamma globulin and complement may be normal or slightly increased. There can be evidence of liver dysfunction [146–162]. Patients with suspected temporal arteritis should have a long (2.5–4.0 cm in length) temporal artery biopsy on the symptomatic side. The biopsy specimen should have serial sections through its length. Because the arteritis is segmental and skip areas may be found, the temporal artery biopsy may not demonstrate evidence of inﬂammation. Sampling the contralateral temporal artery is useful if the ﬁrst biopsy is negative, as temporal arteritis may be unilateral. Even with this diligence, up to 10% of patients with temporal arteritis may have negative temporal artery biopsies and management should be based on a strong clinical suspicion alone. Treatment consists of high-dose long-term corticosteroids. In patients with visual loss in one eye and impending visual loss in the contralateral eye, a high dose of pulse intravenous methylprednisolone, 1000 mg every 12 hours, has been suggested, although it has not been shown to be superior in preventing visual loss than the oral route. Although temporal arteritis is a self-limited disease, the course may be prolonged, and maintenance doses of

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corticosteroids may be required for 2–3 years. Corticosteroids should be initiated in any patient with a presentation compatible with temporal arteritis. Biopsies obtained up to 2 weeks after treatment onset have demonstrated characteristic diagnostic changes. Treatment is begun with 40–60 mg of prednisone on a daily basis. This dosage is maintained for 2– 3 weeks. Subsequently, gradual tapering is accomplished by careful titration of the dose of corticosteroids, according to the patient’s clinical response and serial measurements of ESRs and CRPs. Treatment is continued for at least 6–8 months in most instances, although longer courses of treatment are not uncommon. Recurrence of symptoms and elevation of acute-phase reactants, but not the latter alone, requires an increased dose of corticosteroids. Alternate-day corticosteroid administration is ineﬀective. Methotrexate has been used in an attempt to lower the corticosteroid requirements, but this treatment modality remains controversial. Bone mass preservation can be accomplished by the daily use of calcium with concurrent use of a biphosphonate.

IX. HYPERSENSITIVITY VASCULITIDES These vasculitides comprise a heterogeneous group of disorders characterized by inﬂammation of small blood vessels, particularly the postcapillary venules. The clinical picture is dominated by a variable clinical course and, primarily, cutaneous manifestations (e.g., palpable purpura, persistent urticaria). Henoch-Scho¨nlein purpura (HSP), the most common type of vasculitis in children, is a hypersensitivity vasculitis characterized by palpable purpura, arthritis, neuropathy, colicky abdominal pain, ileoileal intussusceptions, gastrointestinal hemorrhage, and renal disease. Neurological involvement is very rare. Some studies suggest a widespread arteritis and arteriolitis. Cases of cerebral infarction, subdural hematoma, and intracranial hemorrhage have been described. Management consists of treatment of precipitating infections, removal of any oﬀending food or drug, and administration of corticosteroids for seriously ill patients [163–165]. Drug abuse can cause vasculitis, but the mechanisms are unclear. Drug-induced vasculitides have been reported with the use of heroin, pentazocine (Talwin) and pyribenzamine (Ts and blues), lysergic acid diethylamide (LSD), methylphenidate, amphetamines, phenylpropanolamine, ephedrine, and cocaine [166–182]. Hemorrhagic strokes are often related to either underlying aneurysms or arteriovenous malformations or are attributed to acute arterial hypertension, enhanced plasminogen activator activity, or vasculitis. Multiple pathogenetic mechanisms, beyond vasculitis, may account for ischemic strokes associated with drug abuse. These include septic embolism, embolization of foreign material, cerebral vasoconstriction, enhanced platelet aggregation, and cardiac abnormalities (e.g., arrhythmias, cardiomyopathy, myocardial infarction, intracavitary thrombi). Procaine penicillin, sulfonamides and other antimicrobials, aspirin and other nonsteroidal anti-inﬂammatories, anticonvulsants, allopurinol, gold compounds, interferons, and vaccines are uncommon causes of medication-related vasculitides. Treatment consists of removal of the oﬀending substance. If symptoms progress despite abstinence and evidence of persistent vasculitis is present, therapy with corticosteroids may be considered. Hypersensitivity vasculitis may be observed with essential mixed cryoglobulinemia. The cryoglobulins in patients with this disorder contain polyclonal IgG and monoclonal IgM with rheumatoid factor activity. Treatment is with corticosteroids and cytotoxic agents. Plasmapheresis is also used.

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X. MISCELLANEOUS VASCULITIDES Vasculitis occasionally precedes, accompanies, or follows neoplasia, especially lymphoproliferative and myeloproliferative disorders. Treatment consists of management of the underlying malignancy [183,184]. Brain irradiation may rarely result in cerebral vasculitis associated with circulating immune complexes. Treatment is uncertain [185]. Cogan’s syndrome, a rare condition of young adults, is characterized by nonsyphilitic interstitial keratitis and vestibuloauditory dysfunction. Cogan’s syndrome is an uncommon cause of stroke. Large and medium-size vessel vasculitis has been reported. Other ocular manifestations include conjunctivitis, episcleritis, uveitis, retinal vasculitis, and orbital pseudotumor. Systemic manifestations include myalgias, arthralgias, arthritis, and cardiovascular manifestations. Patients with Cogan’s syndrome may develop aortitis with or without aortic regurgitation. Steroid therapy may be beneﬁcial [186]. There are isolated case reports of stroke caused by vasculitis in a case of dermatomyositis associated with agammaglobulinemia and in another patient with polymyositis despite the use of steroids [187,188]. A fatal necrotizing cerebral vasculitis resembling polyarteritis nodosa has been described in a patient with X-linked lymphoproliferative syndrome. The mechanism for this vasculitis is unclear [189]. Thromboangiitis obliterans (Buerger disease) is characterized by distal arterial occlusive disease of the limbs, with or without recurrent superﬁcial thrombophlebitis, occurring preponderantly in adult men smokers in the fourth or ﬁfth decade of life. Immunological studies implicate a hypersensitivity reaction directed against arterial antigens as a cause of thromboangiitis obliterans. The existence of cerebral thromboangiitis obliterans has been controversial [190]. Rarely, Kawasaki disease or syndrome may be associated with stroke. This is a vasculitic syndrome of infants and young children, characterized by high fever, lymphadenitis, mucosal and cutaneous inﬂammation, vasculitis of the coronary arteries, and widespread aneurysmal formation. The use of corticosteroids is controversial [191,192]. IV Ig along with aspirin is eﬀective treatment.

XI. PRIMARY CENTRAL NERVOUS SYSTEM VASCULITIS Primary CNS vasculitis (granulomatous angiitis of the CNS) is a rare, noninfectious, granulomatous, necrotizing angiopathy of unknown cause. Primary CNS vasculitis is characterized by predominant or exclusive involvement of the CNS. Usual symptoms include headaches and mental status changes. Symptoms of predominant small-vessel involvement may present as a mass lesion or as a multifocal encephalopathy. Small-vessel strokes may occur over weeks to many months. The ESR is usually normal or minimally elevated. Other acute phase reactants are characteristically normal. CSF abnormalities include increased opening pressure, increased protein values, normal glucose level, and a discrete lymphocytic pleocytosis rarely exceeding 250 cells/mm3. Contrast-enhanced MRI studies are abnormal in over 90% of cases. Arteriography may show segmental arterial narrowing, vascular occlusions, peripheral aneurysms, vascular shifts, and avascular areas or may be entirely unremarkable. Brain leptomeningeal biopsy is the gold standard of diagnosis. However, because of its focal nature, a negative biopsy result does not preclude the diagnosis of isolated CNS angiitis.Early recognition and management is essential because of its progressive and often fatal course if untreated. Therapy consists of long-

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term treatment with high-dose corticosteroids, with the addition of cyclophosphamide in progressive or steroid-resistant cases [193–199].

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29 Neurological Complications of Cardiac Procedures Osvaldo Camilo Duke University, Durham, North Carolina, U.S.A.

Larry B. Goldstein VA Medical Center, Durham, North Carolina, U.S.A.

I. INTRODUCTION A variety of procedures have come into common use for the treatment of speciﬁc cardiac conditions. Although neurological complications are relatively infrequent, they can be devastating. These complications include acute encephalopathy, longer-term cognitive impairment, stroke, peripheral neuropathies, and movement disorders. This review focuses on ﬁve of the procedures: coronary revascularization, cardiac valve replacement, percutaneous coronary interventions [diagnostic cardiac catheterization and percutaneous transluminal coronary angioplasty; (PTCA)], intra-aortic balloon counterpulsation (IABP), and the use of ventricular assist devices (VAD). Complications of cardiac procedures in children are also brieﬂy discussed.

II. CORONARY REVASCULARIZATION It is estimated that more than 800,000 patients worldwide undergo myocardial revascularization procedures annually [1]. Up to 6.1% of these procedures are associated with adverse neurological complications [1]. A multicenter study at 24 U.S. centers calculated the health care expenditures resulting from such neurological complication to be $2 to $4 billion annually [1]. The steady increase in the average age of the patients undergoing surgery will likely further raise this clinical and economic burden. A. Acute Encephalopathy 1. Background and Incidence Encephalopathy, presenting with confusion, hallucinations, agitation, and sometimes seizures, is perhaps one of the most frequent reasons for neurological consultation in 681

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the acute period following cardiac surgery. The mechanisms underlying postoperative encephalopathy are diverse and not entirely clear. Possible etiologies include toxicmetabolic causes, adverse eﬀects of medications including anesthetics, procedure-related microembolization, cerebral hypoperfusion, hypoxia, and cerebral edema [2–4]. Diﬀusionand perfusion-weighted magnetic resonance imaging (MRI) has revealed that a signiﬁcant proportion of encephalopatic patients with no focal abnormalities on neurological examination have small radiographic lesions consistent with ischemia [4]. Surprisingly, only few studies quantify the risk of encephalopathy after heart surgery. Depending on the study design and the age and comorbidities of the patients studied, the incidence of postoperative encephalopathy ranges from 3% to 47% [5]. For example, in one prospective cohort study, 23 of 71 (32%) patients experienced delirium [6]. The incidence of encephalopathy was 6.9% in a prospective evaluation of 2701 patients (average age of 64 years) who underwent coronary artery bypass grafting (CABG) surgery [7]. 2. Risk Factors Several speciﬁc patient characteristics are associated with an increased risk of post-CABG encephalopathy (Table 1). These include patient age, prior history of stroke, hypertension, diabetes mellitus, hypoalbuminemia, and time on the bypass pump [5–7]. A retrospective study of 296 patients found an overall incidence of delirium of 13.5% in patients less than 60 years old and 20% in patients over age 60 [8]. An additional hour on cardiopulmonary bypass is associated with almost a doubling of the risk of postoperative encephalopathy [7]. 3. Prognosis Post-CABG encephalopathy is associated with overall poorer outcomes [7]. Those with encephalopathy can have signiﬁcant increases in length of stay and a mortality rate 5 times higher as compared with patients without encephalopathy or stroke. 4. Prevention and Treatment The treatment of encephalopathy depends on the identiﬁcation of its underlying cause. The impact of preoperative identiﬁcation of risk factors on the incidence of postoperative encephalopathy needs to be addressed in future studies.

Table 1 Predictors of Acute Encephalopathy After Cardiac Surgery in Diﬀerent Studies Study [Ref.] Rolfson et al. [6]

van Der Mast et al. [8] Mckann et al. [7]

Age > 65

Prior stroke

CPB time

Hypoalbuminemia

NA

OR 8.10 (1.2, 54.3) p < 0.03 NA

OR 1.02 (1.00, 1.04) p < 0.005 NA

NA

OR 2.15 (1.34, 3.44) p < 0.002

NA

OR 5.2 (2.1, 13.3) p < 0.001 OR 2.84 (1.93, 4.18) p < 0.001

OR 3.5 (1.6–7.6) p < 0.002 NA

OR, odds ratio (95% conﬁdence interval); CBP, cardiopulmonary bypass; NA, not analyzed.

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B. Stroke 1. Background and Incidence The reported incidence of stroke after CABG varies depending on the patient population undergoing the operation (Table 2). Rates based on data collected from single institutions range from 1 to 5.2% in most published studies [9–14]. Data from a multicenter regional database from the Bureau of Health Care Research Information Services encompassing all 31 institutions that performed cardiac surgery within a deﬁned region in the State of New York found a stroke incidence of 1.4% among a study population of 19,234 patients undergoing CABG [14]. Few studies investigate the incidence of late stroke after bypass surgery. One population-based long-term follow-up study found that stroke occurred ﬁve times more frequently during the ﬁrst year after revascularization than in age- and sexmatched controls [15]. Neuroimaging studies consisting mainly of conventional MRI and computed tomography (CT) have been utilized in the assessment of neurological deﬁcits after CABG, with some also revealing asymptomatic brain lesions resembling small cerebral infarcts [16,17]. Multiple infarcts can occur in 65% of patients [18]. In patients who sustain an intraoperative stroke, the cerebellar hemispheres are frequently aﬀected, with the cerebellum acquiring a ‘‘salt-and-pepper’’ appearance [18]. Hemispheric borderzone infarcts suggesting hypoperfusion are often seen. However, multiple microemboli reaching these regions may result in a similar radiographic appearance [18]. A retrospective review of 6682 consecutive coronary bypass surgery patients found that the middle cerebral (48%) and the posterior cerebral arteries (10%) were the most frequently involved, also consistent with an embolic etiology [9]. Diﬀusion-weighted MRI (DW-MRI) may be particularly useful in the detection of small cerebral infarcts as compared with conventional brain CT or MRI [4,7,19]. Although studies are limited by small sample size, they demonstrate that focal brain abnormalities occur frequently after CABG in patients with and without clinically identiﬁed stroke [19]. However, this ﬁnding is not consistent [4]. Stroke can be recognized soon after a patient awakens from anesthesia or may occur over the ensuing days, suggesting diﬀering potential mechanisms. A study of 2977 patients having cardiac surgery found that the majority of events (65%) occurred after an uneventful initial neurological recovery from the operation [20]. Disease of the ascending aorta (atheromatous or calciﬁcation) has been incriminated as the most likely source of embolization caused by surgical manipulation due to cannulation-decannulation, crossclamp application/removal, and construction of proximal anastomoses [1,9,13,14]. Cerebral hypoperfusion during the operation may also cause stroke. The risk of perioperative stroke is reduced if mean arterial pressure is maintained above 80 mmHg

Table 2 Incidence of Stroke After CABG Surgery Study [Ref.] Ranjit et al. [14] Calaﬁore et al. [11] Borger et al. [9] Almassi et al. [10] Hogue et al. [20] Ascioni et al. [35] Kaarisalo et al. [15]

Incidence/No. of patients in study

Type of study

1.4%/19,234 1.0%/4,823 1.5%/6,662 3.4%/4,941 1.6%/2,972 1.1%/4,077 7.2%/2,160

Retrospective Retrospective Retrospective Prospective observational Prospective observational Retrospective Prospective observational

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during the procedure [21]. New-onset postoperative atrial ﬁbrillation, with a peak incidence in the ﬁrst 4 postoperative days, occurs in 30% of patients undergoing CABG and is associated with a two- to threefold increase in the risk of postoperative stroke [22,23]. However, not all studies ﬁnd this association [11]. 2. Risk Factors Age and the presence of aortic atheromatous disease have been consistently cited as the most robust risk factors for stroke after cardiac surgery (Table 3). Diﬀerent age groups appear to have diﬀerent vulnerabilities to cerebrovascular events. A multicenter, prospective observational study reported an incidence of stroke of 1.6% in patients under 60 years of age that increased to 5.25% in those over age 70 [10]. Intraoperative transcranial Doppler (TCD) ultrasonography and/or tranesophageal echocardiography (TEE) are commonly used for the detection of emboli during coronary artery bypass surgery [24,25]. Although increased microembolic signals (MES) detected by TCD correlates with postoperative stroke, only a small number of patients with MES develop post-operative neurological deﬁcits [10]. Whether or not these microemboli impair cerebral autoregulation has not been established [26,27]. The bulk of embolization occurs

Table 3 Independent Predictors of Postoperative Stroke Study [Ref.]

Factors

Almassi et al. [10]

Advancing age

Roach et al. [1]

Mobile aortic plaque and aortic atheromatosis

Hogue et al. [20] Redmond et al. [33]

Prior stroke

Ascione et al. [35] D’ Agostino et al. [32]

Extracranial carotid disease(>50%)

Ascione et al. [35]

Unstable angina

Ascione et al. [35]

Peripheral vascular disease

Ranjit et al. [14] Ranjit et al. [14]

CPB time

Roach et al. [1]

Hypertension

Roach et al. [1]

Low output syndrome

Ascione et al. [35]

Salvage operations

OR, 95% CI OR 1.36 per decade 95% CI 1.13, 1.64 p < 0.001 OR 4.52 95% CI 2.52,8.09 p < 0.05 OR 1.4 95%C1 1.0– 2.0 p = 0.047 OR and 95% CI not reported p < 0.05 OR 2.26 95% CI 0.88, 5.83 p < 0.09 OR 2.69 95% CI not reported p < 0.00043 OR 2.69 95% CI 1.49, 4.86 p < 0.001 OR 3.89 95% CI 1.88, 8.06 p < 0.001 OR 1.50 95% CI 1.09, 2.34 p = 0.0157 OR 1.27 per 60 min. 95% CI not reported p = 0.0004 OR 2.31 95% CI 1.20, 4.47 p < 0.05 OR 1.92 95%CI 0.93,3.97 p > 0.05 OR 16.1 95% CI 5.47,47.5 p < 0.001

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after aortic cross-clamp and partial clamp release [24,25]. The importance of the type of aortic plaque was emphasized in one study that found a 25% stroke incidence in patients with a mobile aortic arch plaque as compared with 2% in those with a sessile plaque [28]. Large, protruding, mobile aortic atheromas close to the oriﬁces of the innominate, carotid, and subclavian arteries are particularly prone to cause strokes [29]. A prior history of stroke is also a major, independent predictor of perioperative stroke [1,10,30–32]. For example, a prospective analysis of 71 patients with prior stroke found a reappearance of previous deﬁcits in 26.8%, worsening of old deﬁcits in 8.5%, and a higher incidence of new strokes (8.5% vs. 1.4%; p < 0.05) as compared to a similar group of patients without a stroke history [33]. This increased risk likely reﬂects a more diseased cerebral vasculature with impaired autoregulation and/or inadequate collateral circulation [34]. Other identiﬁed predictive factors include extracranial carotid disease, unstable angina, peripheral vascular disease, preoperative use of an intra-aortic balloon pump, diabetes, cardiopulmonary bypass time, hypertension, a preoperative creatinine greater than 150 mg/dL, low output syndrome, and salvage operations [9,11,35]. In patients undergoing CABG surgery, the incidence of carotid stenosis greater than 75% documented by duplex ultrasound ranges from 4.7 to 8.7% [36,37]. However, the role of extracranial carotid disease in the pathogenesis of perioperative stroke in patients undergoing isolated myocardial revascularization procedures remains uncertain. It is among the strongest risk factors for perioperative stroke in some studies [1,38,39]. For example, one study found that more than 70% of the patients with hemispheric stroke had 50% or greater stenosis of the ipsilateral extracranial internal carotid artery [39]. Another study found a perioperative risk of <2% in patients with carotid stenosis <50% [32]. The risk increased to 10% with stenosis 50–80% and 11–19% with stenosis >80% [32]. Data from the Multicenter Preoperative Stroke Risk Index study was used to develop a so-called stroke index for rapid assessment of cerebrovascular risk following CABG surgery [40]. Bivariate analysis were ﬁrst used to determine associations between preoperative variables and neurological events such as stroke and transient ischemic attack (TIA). Signiﬁcant bivariate predictors were identiﬁed and then logically grouped. For each cluster, a score was calculated based on the principal components. With this model, age, history of symptomatic neurological disease, prior heart surgery, prior vascular surgery, diabetes, and history of pulmonary disease were established as the strongest predictors of major perioperative cerebrovascular events. However, this model must be validated in further studies. 3. Prevention and Treatment The optimal surgical management of patients requiring coronary revascularization who also have asymptomatic disease in the extracranial carotid circulation remains controversial. Options include performing only CABG, staging carotid endarterectomy (CEA) and CABG, with CEA performed either before or after the cardiac procedure, or performing both CEA and CABG during the same operation [41]. The complication rates reported for the various approaches vary [42–44]. Retrospective surveys have found alarmingly high complication rates associated with combined operations [45]. However, direct comparative data are limited. An early prospective randomized study of 129 patients with unstable coronary disease and asymptomatic unilateral carotid stenosis (z70%) found a higher incidence of stroke in those having staged operations (14%) as compared with those having combined procedures (2.4%; p < 0.045) [46]. A meta-analysis of 16 studies compared 844 patients having combined CEA and CABG with 920 patients

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having staged operations [47]. There was a higher risk of the composite endpoint of stroke or death for those having combined operations [relative risk (RR) 1.49; 95% CI 1.03, 2.15; p = 0.034]. The crude event rates for stroke were 6% for the combined procedure as compared to 3.2% for staged procedures. However, none of the studies included in the meta-analysis were completely randomized trials, and reporting bias is likely. Another meta-analysis did not ﬁnd a signiﬁcant diﬀerence in stroke rates in those having combined versus staged CABG/CEAprocedures [48]. This controversy will not be resolved until a large, prospective randomized study is completed. There is ample evidence to suggest that several neuroprotective strategies may be beneﬁcial in diminishing the likelihood of postoperative stroke in CABG surgery patients. The routine use of epiaortic ultrasonography, the most accurate method of evaluating atherosclerosis of the ascending aorta, may play an important role in decreasing the risk of embolization by providing the surgeon with information about underlying disease during the operation [49]. Several other methods of decreasing the risk of embolization have been investigated including the use of intra-aortic ﬁlters [50]. Another approach is the use of alternative aortic cannulation techniques [51]. A prospective randomized trial found cannulation of the distal aortic arch resulted in a 50% reduction in cerebral emboli during CABG surgery [49]. The use of oﬀ-pump cardiac surgery has also received a great deal of attention, with several studies reporting a reduction in the incidence of cerebral microemboli and stroke as compared to patients who had on-pump CABG [11,52–56]. As indicated above, the risk of perioperative stroke is reduced if mean arterial pressure can be maintained above 80 mmHg during the procedure [21]. The treatment of stroke in the postoperative cardiac surgery patient is problematic and mainly based on anecdotal experience. Cardiopulmonary bypass is associated with a decrease in the levels of several coagulation factors and dysfunctional platelets, and an increase in ﬁbrinolytic activity [57]. Postoperatively, tPA levels fall, there is an increase in plasminogen activator inhibitor levels, and a relative hypercoagulable state [57]. Major surgery within 2 weeks is a standard exclusion criterion for intravenous thrombolysis [58]. However, intra-arterial thrombolysis has been used in small groups of selected patients who sustained a stroke after cardiac surgery. One group reported on 13 patients having acute ischemic stroke within 12 days of a cardiac operation who were treated with intra-arterial thrombolysis within 6 hours of the onset of stroke symptoms [59]. In this series, arterial occlusions were detected in branches of the middle cerebral artery in 9 patients, the terminal carotid artery in 2, the proximal internal carotid artery in 1, and the basilar artery in 1 patient. There was no neurological improvement in 8 patients, improvement in 5 patients, and hemorrhagic complications in 3 patients. The largest and only multicenter analysis of the safety of intra-arterial thrombolysis (with either tPA or urokinase) in the postoperative period included 36 patients [60]. Half had undergone openheart surgery. The overall risk of minor bleeding was 25% and 2 of the 18 post-CABG surgery patients sustained symptomatic intracranial hemorrhage and fatal pericardial tamponade, respectively. These high complication rates argue for caution with this approach, the safety and eﬃcacy of which must be conﬁrmed in future trials [61–63]. Pharmacological approaches to reducing perioperative stroke risk have also been studied. A meta-analysis indicates that high-dose aprotinin, a bovine serine protease inhibitor, may reduce the incidence of perioperative stroke [64]. An observational database analysis of 2575 consecutive patients who underwent CABG surgery at one hospital found that those who received a h-adrenergic receptor antagonistic had a substantial reduction in the incidence of postoperative neurological complications, including stroke [65]. These promising results need to be validated by further studies.

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4. Prognosis Stroke can be a devastating complication of CABG surgery and is associated with increased perioperative mortality and reduced long-term survival [9–11]. A large multicenter, prospective observational study found those patients whose surgery was complicated by stroke had longer stays in the intensive care unit (median 5.9 vs. 2.7 days), longer overall hospital stays (30 vs. 8 days), and a sixfold increase in hospital mortality (21.2% with stroke vs. 3.81% with no stroke; p < 0.001) [10]. Another study reported a mortality rate of 27.6% in patients who had CABG complicated by stroke versus 2.6% in the nonstroke patients [12]. C. Neuropsychological Impairment 1. Background and Incidence Cognitive changes after cardiac surgery can be subtle and often diﬃcult to recognize clinically. Despite more than 20 years of comprehensive research, neuropsychological deﬁcits remain an important cause of postoperative morbidity [66]. The reported incidence of cognitive decline varies widely (Table 4). This variability is partly explained by methodological features of the studies: a variety of deﬁnitions of cognitive decline are used, a large number of neuropsychological tests exist to assess the various cognitive domains, and there is no agreed on timing of the assessments [67]. For example, depending on the deﬁnition used, one study found that the incidence of cognitive impairments ranged from 1.1 to 34% at 6 weeks and from 3.4 to 19.4% at 6 months postoperatively [68]. In addition, most investigations have ignored the ‘‘practice eﬀect’’ that can lead to improved performance with repeated testing [69]. In an attempt to solve these problems, a consensus meeting in 1994 established several guidelines for the assessment of neuropsychological deﬁcits after cardiopulmonary bypass [70]. The primary recommendations were that an accurate baseline neuropsychological assessment needs to be obtained prior to operation, that a control group should be incorporated when indicated, that concurrent evaluation of the patient mood should be performed, that care b used in the selection of appropriate tests because of time constraints and physical limitations, and that the selection of such tests should take into consideration several factors including the cognitive domain of the test, its sensitivity and reliability, the time required for completion, the degree to which learning may aﬀect responses, and the physical eﬀort required to conduct the test. They also recommend that the test should be repeated at least once 3 months postoperatively, taking into consideration that improvement in performance can occur on repeat testing. The incidence of cognitive impairments at the time of hospital discharge has been reported to be as high as 80–90% [71]. However, a systematic review of six highly

Table 4 Incidence of Neuropsychological Impairment After Cardiac Procedures Study [Ref.] Diegler et al. [71] van Dijk et al. [72] Newman et al. [73] Mulges et al. [74] Newman et al. [73]

Time of evaluation Discharge 2 months 6 months 5 Years 5 Years

Incidence (%) 80–90 22.5 24 13 42

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comparable studies found an incidence of cognitive decline of 22.5% at 2 months after CABG [72]. A prospective study to determine the eﬀect of perioperative cognitive deterioration on longer-term cognitive function evaluated patients longitudinally over 5 years after cardiac surgery [73]. In this study, 53% of patients had evidence of cognitive decline at discharge, with rates of 24% at 6 months and 42% at 5 years. The investigators postulated that early cognitive impairment is a harbinger of later cognitive decline. In contrast, a cohort study of 52 patients who underwent CABG 5 years earlier found that the majority of patients had cognitive improvement with only a 13% incidence of mild cognitive decline [74]. Although the investigators attributed these encouraging results to rigorous control of vascular risk factors (including hypertension, diabetes, and hypercholesterolemia) after the cardiac surgery, the study was quite small and had a high proportion of drop-outs. Cognitive dysfunction after CABG surgery can be due to patient or procedurerelated factors. Patient-related factors include the age of the patient and underlying agerelated cognitive dysfunction, with a consequent tendency to develop cognitive impairment after any type of major surgery [75]. Procedure-related factors include the use of cardiopulmonary bypass and the microemboli that can be detected during the operation. A neuropathological study showed small arteriolar and capillary dilations throughout the brain after cardiopulmonary bypass surgery and suggested that these were due to microscopic emboli [76]. Cardiopulmonary bypass is also known to induce a proinﬂammatory state characterized by the release of cytokines in response to activation of the ﬁbrinolitic and complement cascades [77]. This can have several potential adverse consequences including changes in vascular resistance in various vascular beds and the development of microemboli [78]. The few available neuroimaging studies that included conventional and DW-MRI report varying results with regard to the presence of new ischemic lesions and their correlation with cognitive impairment [17,79]. A small study using magnetic resonance spectrospcopy found an association between a reduction in the focal brain N-acetylaspartate (NAA)/creatine ratio and poorer neurocognitive function, suggesting an ischemic etiology [79]. This observation needs to be further explored in a larger study. 2. Risk Factors Age appears to be one of the strongest risk factors for cognitive impairments after cardiac surgery [1,80,81]. Other important predictors include lower preoperative cognitive performance, proximal aortic atheromas, previous stroke, cardiac dysrhythmia such as atrial ﬁbrillation, intracardiac thrombus, and peripheral vascular disease [82]. Carriers of the APOEe4 allele may also be at increased risk. These individuals were found to have a decline in four of nine measures of cognitive function at discharge from hospital and 6 weeks after surgery [83]. Several studies have documented a positive relationship between neuropsychological impairment and the number of cerebral microembolic signals detected by TCD, particularly during clamping and unclamping of the aorta [24,84,85]. Another risk factor may be clinical management during the postoperative rewarming period. Analysis of one series of 255 patients found the cerebral arterio-venous oxygen diﬀerence on rewarming was signiﬁcantly associated with overall cognitive decline [86]. 3. Prevention and Treatment Diverse strategies aimed at reducing the incidence of cognitive impairment after CABG surgery have been employed. The eﬀect of maintenance of higher cerebral perfusion pressures during the procedure was investigated in a prospective study of 248 patients

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undergoing CABG who were allocated randomly to either lower (50–60 mmHg) or higher (80–100 mmHg) perfusion pressures [21]. The diﬀerence in perfusion pressures was not associated with a diﬀerence in cognitive outcomes after 6 months. The use of oﬀ-pump CABG surgery has also been studied. Two small randomized controlled trials, each involving less than 100 patients, have provided conﬂicting results [71,87]. The largest randomized controlled trial conducted to date comparing oﬀ-pump and on-pump cardiac surgery included 248 patients and found no signiﬁcant diﬀerence in cognitive decline between the groups after 1 year (30.8% in the oﬀ-pump group vs. 33.6% in the on-pump group; RR 0.88; 95% CI 0.52–1.49; p = 0.69) [88]. 4. Prognosis Although several authors postulate that, in the vast majority of patients, the neurocognitive deﬁcit following CABG does not impair functional capabilities, a small proportion of patients become intellectually disabled based on measures of memory, attention, visuospatial ability and motor speed, eventually becoming unable to return to employment [1].

D. Spinal Cord Injury Spinal cord injury is an uncommon but devastating complication of CABG surgery. Its true incidence is unknown. Most of the reported cases have occurred in patients with an intra-aortic balloon pump, but the association is not universal [89–91]. Spinal cord injury is generally caused by anterior spinal artery distribution infarction, resulting in paraplegia with a loss of pin-prick and temperature sensation below the level of injury, but a relative preservation of proprioception. The precise mechanism producing this complication has not been elucidated, although hypotension resulting in watershed spinal cord infarction and microembolization from atherosclerotic plaque or cholesterol emboli have been postulated [90,91].

E. Brachial Plexopathy 1. Background and Incidence Neuropathies after surgery were the second most common claim in the American Society of Anesthesiology Committee on Professional Liability’s Closed Claims Project, a standardized collection of case summaries of adverse anesthesia-related outcomes [92]. Several peripheral nerves can be aﬀected (Table 5). The long thoracic nerve, due to its long and superﬁcial course, is vulnerable to damage at various levels. There have been a few case reports of injury to this nerve during CABG [93]. Injury manifests as a ‘‘winged scapula’’ because of innervation of the serratus anterior muscle, which abducts and elevates the arm. The brachial plexus is particularly susceptible to injury during CABG. The majority of symptomatic brachial plexus neuropathies involve the lower roots (C8–T1) [94]. The incidence ranges from 1.5 to 24%. Signs on examination can be misinterpreted as representing an ulnar neuropathy. The severity of the damage varies considerably [94], but pain is generally not reported as a clinical issue [95]. 2. Risk Factors Sternal retraction and internal mammary artery (IMA) dissection are the main factors associated with brachial plexus injury [96,97]. A prospective study of 1000 cardiac surgery patients found a 1% frequency of neuropathies in patients without IMA as compared to a

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Table 5 Incidence of Peripheral Nerve Injuries After CABG Surgery Study Sherma et al. [96] Barbut et al. [106] Shaw et al. [107] Shafei et al. [108] Mountney et al. [113] Vasquez-Jimenez et al. [114] De Vita et al. [119] Chroni et al. [126] Tolis et al. [127] Werner et al. [129] Efthimiou et al. [130]

Injury

Incidence (%)

Brachial plexopathy Horner’s syndrome

1.5–24 1.3–7.6

Recurrent nerve palsy Saphenous nerve injury Peroneal nerve palsy Unilateral phrenic nerve palsy

1.5 10 0.19 2–31

Bilateral phrenic nerve palsy

3–4

10.6% rate in those having IMA dissections [97]. Studies attempting to correlate arm positioning with brachial plexus neuropathy have been inconsistent [96]. Other factors such as the duration of cardiopulmonary bypass, aortic cross-clamp times, total anesthesia times, hematocrit during bypass, or type of oxygenator have not been associated with the frequency of brachial plexopathy after CABG [98,99]. In addition, recent studies have not found an association between central venous catheter placement and brachial plexus damage [96]. Several studies have employed intraoperative somatosensory-evoked potential (SSEP) monitoring to evaluate the impact of various surgical techniques on brachial plexus function. One prospective study found that the use of sternal retractors was associated with signiﬁcant SSEP changes in 70% (21 of 30) patients, but none had evidence of a postoperative brachial plexus injury [99]. Another monitored 60 patients having IMA harvesting to evaluate the eﬀects of diﬀerent types of IMA dissection retractors on brachial plexus function during the procedure [100]. Despite diﬀerences in the eﬀects of the studied retractors on intraoperative SSEPs, there was no associated diﬀerence in the frequency of postoperative brachial plexus neuropathy. Similar results were found in an earlier study [101]. A prospective study evaluated the eﬀects of arm position on brachial plexus SSEPs during asymmetrical sternal retraction for IMA harvest in 80 patients [102]. Although diﬀerences in the eﬀects of arm position on SSEPs were detected, there was no association with the development of plexopathy. Finally, there is no clear relationship between transient as compared with persistent SSEP changes and symptomatic postoperative brachial plexus neuropathy [103]. 3. Prevention and Treatment The optimal placement of the retractor to prevent brachial plexus injury is uncertain [96]. A prospective study of 335 cardiac surgery patients undergoing median sternotomy found a 4.8% lower frequency of brachial plexus injury associated with placing the sternal retractor in the caudal vs. the rostral position [104]. Based on the studies previously discussed, it appears that intraoperative SSEPs are of limited value in identifying patients at increased risk for the development of postoperative brachial plexopathy. Unfortunately, the true value of electrophysiological monitoring may be underestimated, as the majority of studies have generally lacked adequate statistical power [96]. Factors that may reduce the frequency of brachial plexus neuropathy include a precise midline sternectomy to

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avoid subsequent asymmetrical sternal traction and perhaps more caudal placement of the sternal retractor [97]. 4. Prognosis Electrophysiological studies can detect changes in nerve function during the postoperative period, but these changes do not reliably predict postoperative neuropathic symptoms [96]. The rate and degree of recovery from postoperative brachial plexopathy vary widely. Some patients begin to improve within a few weeks and are fully recovered by 2 months. However, others have a more prolonged recovery (up to one year), and residual symptoms may persist in some [105]. A prospective study of 1000 patients found that 8 of the 27 (29.6%) who developed brachial plexopathy were still symptomatic at 3 months [97]. In general, the prognosis for complete recovery is excellent [98,99]. F. Horner’s Syndrome 1. Background and Incidence The cervical sympathetic chain lies medial to the inferior trunk of the brachial plexus as it crosses over the ﬁrst rib, making it vulnerable to injury in much the same way as the brachial plexus [96]. Horner’s syndrome, characterized by miosis, ptosis, and anhydrosis, is a common but relatively benign complication of CABG surgery [106]. One study found evidence of Horner’s syndrome in 4 of a series of 312 (1.3%) CABG patients [107]. In each case, it was unilateral and associated with injury to the inferior trunk of the ipsilateral brachial plexus. Another series in CABG patients found a somewhat higher incidence (19 of 248; 7.6%). In this study, Horner’s syndrome occurred more frequently in isolation (5.2%) than in conjunction with a brachial plexopathy (2.8%) [106]. 2. Prevention and Treatment Speciﬁc strategies to prevent Horner’s syndrome after CABG have not been studied. The issues would be similar to those discussed for brachial plexopathy. Treatment is not available and the condition is generally benign. 3. Prognosis Horner’s syndrome after CABG persisted in some patients for at least 6 months postoperatively [106]. G. Recurrent Laryngeal Nerve Injury Recurrent laryngeal nerve palsy following CABG surgery is a less well-recognized entity, and its cause remains unclear. In one series, it occurred in 5 of 270 patients who underwent open heart surgery [108]. H. Saphenous Nerve Injury 1. Background and Incidence Despite increasing use of the IMA as a graft conduit, the long saphenous vein continues to be widely used for CABG surgery. The saphenous nerve, a branch of the femoral nerve, becomes superﬁcial in the lower leg, descending with the long saphenous vein toward the

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medial malleolus. Injury to the nerve, particularly the infrapatellar branch, can occur during saphenous vein harvest [109]. Its incidence is reported to be 10% at 18 months after surgery [110]. It usually presents with hyperesthesia and anesthesia along the medial side of the calf and foot and extends to the great toe [111]. 2. Prevention and Treatment Endoscopic saphenous vein harvest permits removal of the vein with minimal handling. This technique may result in less local inﬂammation and hematoma formation [96]. One study prospectively randomized 60 CABG patients to either open or endoscopic long saphenous vein harvest [112]. Local pain was lower in the endoscopic group, but larger studies are needed to determine whether the incidence of neuropathic symptoms is reduced. There is no speciﬁc treatment for patients having a saphenous nerve injury. 3. Prognosis Nearly 90% of patients examined after long saphenous vein harvest have some degree of anesthesia at 3 days with 72% having residual numbness after 20 months [113]. I. Peroneal Nerve Injury 1. Background and Incidence The incidence of peroneal nerve injury after cardiac surgery in unknown. There were no reports of injury to this nerve related to cardiac surgery in the Closed Claims Study of 4183 patients having CABG [92]. A study conducted by German neurologists found that only 39 out of 20,718 patients (0.19%) had evidence of a common peroneal nerve injury [114]. 2. Risk Factors The risk of peroneal nerve injury appears to increase with the duration of the operative procedure, the number of comorbidities, and in those with subnormal body weight [114]. The nerve is most frequently injured at the level of the ﬁbular head because of its superﬁcial location [115]. 3. Prognosis Based on the limited available data, the prognosis of patients with peroneal nerve injury is mostly favorable [114]. J. Phrenic Nerve Injury 1. Background and Incidence Phrenic nerve dysfunction and resulting diaphragmatic paralysis can occur unilaterally or bilaterally after either CABG or valve replacement surgery. The diagnosis of mild unilateral phrenic neuropathy is most likely underreported given the paucity of symptoms as well as limited detection by nerve conduction studies [96]. It is suspected in a postoperative patient with elevation of one hemidiaphragm. This can occur in 30–70% of patients after cardiac surgery and is best detected with ultrasonography and ﬂuoroscopy [96]. There were only 2 cases of bilateral phrenic nerve injury among 360 elective CABG surgery patients in one series [116].

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The nerve can be injured in several diﬀerent ways. One mechanism is through the topical cooling used to obtain myocardial asystole [117]. This has been referred to as ‘‘phrenic nerve frostbite’’ [118] and can result in a demyelination injury [119–121]. In ones series, 79% of 56 patients who received topical icy slush sustained unilateral diaphragm paralysis, with diminished phrenic nerve conduction times in 88% [116]. The nerve is also vulnerable to direct surgical damage from retraction, cauterization, or other interruption of its blood supply related to internal mammary artery dissection [122,123]. For example, an animal model demonstrated that ligation of the pericardiophrenic artery, a small branch of the internal mammary artery (IMA), caused ischemic phrenic nerve injury [123]. Clinically, the relationship is less clear because the left IMA is used more frequently and the left phrenic nerve is more susceptible to cold injury [96]. The combination of topical cooling with ice slush and the use of the IMA may be particularly hazardous [120]. However, a prospective study of 63 patients undergoing CABG found no association between left IMA dissection and phrenic neuropathy, which occurred in 10.3% of patients [124]. The reported incidence of phrenic nerve injury varies with the techniques used for diagnosis [125]. For example, the rate of detection with the use of electrophysiological studies is somewhat less than with the exclusive use of chest x-rays or sonograms. In one prospective observational study, 78 of 92 (85%) patients had abnormalities on a 48-hour chest x-ray. When this group was assessed with sonography, the incidence decreased to 54%. Based on nerve conduction studies, the incidence fell to 26% [119]. The amplitude and area of the diaphragmatic response on electrophysiological testing are more sensitive than latency in detecting abnormalities [126]. Using electrophysiological techniques, the incidence of phrenic nerve injury following cardiac surgery ranges from 2 to 31% [119,126,127] with bilateral injuries occurring in 3–4% of patients [128,129]. 2. Risk Factors The risk of phrenic nerve injury has been most strongly associated with cooling. There is no relationship between this type of injury and patient age, diabetes mellitus, left ventricular ejection fraction, or bypass time [119,124,130]. 3. Prevention and Treatment Warm blood cardioplegia may substantially diminish the incidence of phrenic nerve injury [127,135]. Ice slush appears to be more detrimental than cold saline solution [124,130,131]. Acute treatment strategies include early tracheostomy and plication of the diaphragm. Although diaphragmatic pacing has also been advocated, some investigators argue that the degree of demyelination and axonal degeneration leading to phrenic nerve injury would preclude the eﬀective use of this technique [132]. 4. Prognosis Symptoms range from mild, with nocturnal orthopnea and moderate exertional dyspnea [124], to severe, resulting in prolonged mechanical ventilation and hospitalization [116,122,125,133,134]. However, at least one study found no diﬀerence in the duration of mechanical ventilation, ICU stay, or postoperative complications in patients with phrenic neuropathy as compared to those with normal phrenic nerve function [124]. In another series, 24 of 42 (57%) consecutive patients who underwent cardiac cooling developed phrenic nerve injury manifested by an elevated hemi-diaphragm that persisted

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for 1 year [119]. Most of the patients with post-CABG phrenic nerve injury fully recover within 3–6 months [119]. However, a retrospective case-control study found evidence of permanent phrenic nerve neuropathy in 13 of 49 (26%) patients [136]. These patients had more readmissions for respiratory complications and a signiﬁcantly reduced quality of life compared with the control group.

III. CARDIAC VALVE REPLACEMENT A. Background and Incidence More than 200,000 open-chamber cardiac procedures, including approximately 100,000 CABG/valve surgery combined operations, are performed annually around the world [137]. Stroke and cognitive impairment are the most frequent complications. Patients undergoing valve replacement surgery are relatively more prone to embolization than those having isolated CABG surgery [138]. This population of patients frequently harbor intracardiac thrombus or valvular vegetations, and air bubbles may remain trapped within the heart after the chambers are closed, factors that may account for the increase risk of embolization [137]. Those having combined procedures may be at particular risk. A multicenter prospective observational study of 4941 patients undergoing isolated CABG, valve replacement surgery, or combined procedures found an overall 3.4% incidence of stroke, with an 11.54% rate in those having the combined operations [10]. Among the single procedures, mitral valve replacement carried the highest stroke risk (3.2%). Another analysis focused on 4734 octogenarians having either CABG or combined CABG/valve surgery at 22 centers in the National Cardiovascular Network [139]. The rate of postoperative stroke after CABG combined with mitral valve replacement was 8.8% as compared to 4.9% following CABG combined with aortic valve replacement and 3.9% after CABG performed alone. The Multicenter Study of Perioperative Ischemia (McSPI) group has reported adverse neurological outcomes in 43 of 273 (16%) patients undergoing combined intracardiac (i.e., mitral or aortic valve procedures) and coronary artery procedures [137]. Patients who had valve surgery also develop a higher frequency of cognitive impairment compared to CABG procedures alone [81,140]. B. Risk Factors Comparative TCD studies evaluating the occurrence of microemboli during valve replacement or CABG surgery have noted that patients undergoing valve surgery have a higher number of embolic events measured in the middle cerebral artery [141,142]. Serum biomarkers of neuronal injury have not been clearly associated with the risk of postoperative cognitive impairments. Although a signiﬁcantly greater elevation in S-100 and neuron-speciﬁc enolase (NSE) was found after intracardiac operations than CABG, there was no correlation between the levels of these markers and cognitive impairment [140,143]. C. Prevention and Treatment Mechanical and bioprosthetic heart valves confer diﬀering long-term risks of cerebral and systemic embolization, with a higher risk of stroke in patients with implanted mechanical valves [144]. Despite high levels of anticoagulation (INR 3.0–4.5), the stroke rate with mechanical heart valves is approximately 2–4% annually [144]. Some studies have suggested an additional decrease in the stroke rate after mechanical heart valve replace-

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ment when an antiplatelet agent is added to warfarin. However, a meta-analysis indicated that the risk of hemorrhage outweighed the reduction in ischemic events [145]. Although routine long-term anticoagulation is not indicated in patients with porcine bioprostheses, there may be an initial higher risk period for embolization [146]. As a result, some have advocated anticoagulation during the ﬁrst 2–3 months after porcine valve implantation [146]. D. Prognosis Prognosis for recovery from stroke or cognitive impairments is similar to that described for CABG procedures.

IV. PERCUTANEOUS TRANSLUMINAL CORONARY INTERVENTIONS (CARDIAC CATHETERIZATION AND PTCA) A. Background and Incidence There has been a marked expansion in both the indications for percutaneous coronary interventions and the array of devices that may be employed for treatment. Relatively older and sicker patients are now being evaluated and treated with these modalities [147– 150]. Stroke is one of the most serious neurological complications of these procedures, accounting for a signiﬁcant portion of the morbidity and mortality associated with the intervention [147,151]. In one study, 121 of 12,000 patients who underwent PTCA died after the procedure, with 4% of the deaths being related to stroke [152]. Another study reviewed all cases of acute neurological complications developing during or within 36 hours of diagnostic catheterization or angioplasty [153]. Of 6465 patients who underwent diagnostic left heart catheterization and balloon angioplasty or vavuloplasty, 27 (0.4%) sustained an acute neurological complication. Other studies have reported stroke rates varying from 0.05 to 0.38% [150,151,154]. The clinical manifestations of stroke following percutaneous coronary interventions depend on the particular vascular territory involved, which varies among studies. Some have reported posterior circulation involvement in up to 87% of catheterization-related neurological events [155,156], whereas another found deﬁcits localizable to the anterior circulation in 64% of the cases and involvement of the posterior circulation in only 36% [153]. Another study investigated patients within 24 hours after percutaneous intervention and employed brain CT during the hyperacute phase [151]. There was a peri-procedural stroke in 43 of 9662 (0.38%) consecutive patients, with 48.8% being hemorrhagic. Of those with ischemic stroke, 47.6% were in middle cerebral and 23.8% in posterior cerebral artery territories. The high incidence of hemorrhages may be related to the use of anticoagulants and other drugs during the procedure. Both hemodynamic and embolic mechanisms have been postulated for the development of ischemic neurological complications during catheter-based coronary interventions [157]. Dislodging atheromatous plaque or thrombus by catheter movement may generate emboli. As with cardiac surgery, TCD has been used for the assessment of potential embolization during percutaneous coronary procedures and has consistently showed that asymptomatic MES commonly occurs during left heart catheterization and PTCA. Microembolic signals (MES) are detected mainly during left ventriculography and contrast media injection into the coronary arteries or with movement of the PTCA guide wire or catheter [158–161]. Other studies have attempted to determine whether there is a

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relationship between the frequency of microembolism detected by TCD and the degree of aortic arch atheroma assessed by TEE [159,160,162]. These studies were limited by small sample sizes and the lack of severe aortic disease (>4 mm) in the cohort of patients studied. Further studies are needed to establish whether there is an association between microemboli detected during heart catheterization/PTCA and cognitive impairment. B. Risk Factors A variety of factors may increase the risk of stroke after percutaneous cardiac procedures, but results are conﬂicting [147,151]. A retrospective study reported an incidence of stroke of 0.3% and identiﬁed previous bypass surgery as a predisposing factor [147]. The Bypass Angioplasty Revascularization Investigation reported that patients with peripheral vascular disease were at signiﬁcantly higher risk for major neurological complications, including stroke after either PTCA or CABG [163]. Another retrospective study found female gender, left ventricular hypertrophy, reduced cardiac ejection fraction, and the presence of two or more coronary arteries with >50% narrowing were independent predictors of a neurological complication [153]. A second multivariate analysis found that emergency use of an intra-aortic balloon pump (IABP) was the strongest predictor for stroke [odds ratio (OR) 9.6; 95% CI 3.9, 23.9; p < 0.001] followed by prophylactic use of an IABP (OR 5.1; 95% CI 1.8–14.0; p < 0.002) and age >80 years (OR 3.2; 95% CI 3.6–7.0; p < 0.001), but no independent eﬀect of a history of prior stroke [151]. Consistent with this ﬁnding, data from the multicenter National Cardiovascular Network were used to analyze procedural outcomes in octogenarians undergoing percutaneous coronary interventions (PCI) in the era of intracoronary stenting [150]. There was a fourfold increase in complications, including death (3.8% vs. 1.1%; p < 0.0001) and a more than doubling in the risk of stroke (0.58% vs. 0.23%; p < 0.0001) in octogenarians undergoing PCI as compared to younger patients (<80 years). However, the absolute complication rate was low. Although the octogenarians in this study had more comorbidities and more extensive coronary disease, relatively low-risk patients were included, and the authors underscored that the results were limited to selected octogenarians undergoing the procedure in high-volume centers with experienced operators. Catheterization technique may also aﬀect the risk of embolization. In one study, 43 patients referred for diagnostic left heart catheterization had TCDs of the left middle cerebral artery during the procedure to determine if the incidence and frequency of cerebral MES were inﬂuenced by guidewire techniques and catheter types [164]. MES were detected in 86% of the patients when a protruding guidewire was used to advance the coronary catheters over the aortic arch as compared with 29% when the catheters were advanced without a guidewire, suggesting that the risk of embolization is greater with straight tip guidewires. This will need to be further explored in outcomes-driven studies as the correlation between MES and clinical events is weak. Drugs used during the procedures, including antiplatelet agents, thrombolytics, and anticoagulants, may increase the risk of brain hemorrhages. The use of clopidogrel in addition to aspirin has become standard therapy for patients after stenting due to a rapid onset of action and pronounced antithrombotic eﬀect [165]. A combination of warfarin and aspirin is sometimes started before coronary angioplasty. The Balloon Angioplasty and Anticoagulation Study found a reduction in the early and late composite endpoint of death, myocardial infarction, and stroke at 30 days (3.4% in patients treated with aspirin plus warfarin compared with 6.4% in patients treated with aspirin alone), (RR 0.53; 95%

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CI 1.26, 9.11) [166]. At 1 year, the rates were 14.3% and 20.3%, respectively (RR 0.71; 95% CI 0.54, 0.93). There was a slightly higher risk of bleeding complication during hospitalization with the combined regimen as compared to aspirin alone (3.2% vs. 1.0%; RR 3.39; 95% CI 1.26, 9.11; p = 0.062). A post hoc analysis of these data was carried out in patients in whom aspirin and warfarin were initiated 1 week before intervention, with the target INR of 2.1–4.8 during the angioplasty and follow-up [167]. There were no ischemic events during or after PTCA, with 3 of 530 patients having ‘‘late’’ (deﬁned as 14– 365 days after the procedure) hemorrhagic strokes. The glycoprotein IIb/IIIa antagonists are being used more frequently with these procedures [154]. The eﬀect of abciximab was investigated in a combined analysis of 8555 patients undergoing PCI with and without stent deployment in four large randomized, double-blind, placebo-controlled trials [168]. There were 33 strokes reported in 31 patients. There was not a signiﬁcant diﬀerence in stroke rates between patients who received abciximab (0.40%) and those who received placebo (0.29%; p = 0.46). The rates of ischemic stroke were 0.17% and 0.20% and the rates of hemorrhagic strokes were 0.15% and 0.10% for patients receiving abciximab or placebo, respectively. There are also considerable data available for eptiﬁbatide and tiroﬁtan. The incidence of intracranial hemorrhage associated with eptiﬁbatide and tiroﬁtan treatment was 0.15 in patients undergoing PCI in the IMPACT-11 and RESTORE trials, a rate that was comparable to treatment with placebo [169,170]. In PURSUIT, a trial including more than 10,000 patients with acute coronary syndromes, there was no diﬀerence in stroke rates between patients who received placebo (0.8%, with hemorrhagic stroke rate <0.1%) and those who received eptiﬁbatide (0.6%, with hemorrhagic stroke rate <0.1%) [171]. C. Prevention and Treatment An understanding of the procedural and nonprocedural factors increasing the risk of both nonhemorrhagic and hemorrhagic stroke after percutaneous procedures should help to reduce their incidence. Management of stroke after these procedures is generally similar to those that are not procedurally related. Thrombolytic therapy has been used, but controlled data are lacking [172,173]. D. Prognosis Prognosis largely depends on the severity of the stroke. Patients with stroke as a complication of a percutaneous cardiac procedure have a prolonged hospital stay as well as a higher in hospital and 1-year cumulative mortality [151].

V. INTRA-AORTIC BALLOON COUNTERPULSATION A. Background and Incidence IABP is used to support patients with low cardiac output by volume displacement, augmenting the coronary blood ﬂow and increasing diastolic perfusion pressure [174]. Potential indications include ongoing unstable angina, acute myocardial infarction associated with PTCA, perioperative low cardiac output syndrome, cardiogenic shock after myocardial infarction, congestive heart failure, and as a bridge to cardiac surgery, including heart transplantation [175]. Although the transfemoral route is most commonly used, the device can also be inserted via the transthoracic arch, the subclavian or the

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axillary artery. A large prospective cohort study of 1119 patients found an overall complication rate of 15% with the use of the femoral artery insertion [176]. Only 1 of the 166 complications in the previously cited prospective cohort study was related to a cerebrovascular event [176]. Another study found similar results with stroke accounting for only 2 of 36 complications among 303 patients who underwent transfemoral IABP insertion [177]. In contrast, an international, multicenter, prospective, randomized trial carried out to determine the role of prophylactic IABP after PTCA in patients with acute myocardial infarction found that its use was associated with an increased stroke incidence (2.4% vs. 0%; p = 0.03) [178]. However, the association may have been confounded by other factors. B. Risk Factors Retrospective data regarding the insertion of the IABP device suggest a higher risk of cerebrovascular complications with the transthoracic as compared to other routes of insertion. A review of 646 patients reported only 24 patients (3.7%) treated with the device inserted through the ascending aorta, and only 3 of these patients sustained a cerebrovascular accident [179]. Early mortality was 58.3% in patients having transthoracic placement in comparison to 46.1% in patients with transfemoral insertion of the device ( p > 0.2). C. Other Complications There were no neurological complications reported in one retrospective review of 4756 patients receiving IABP support [181], in another recent review [182], or in the worldwide Benchmark Counterpulsation Outcomes Registry [183]. However, neurological complications are likely underreported. Of the reported complications of IABP insertion, limb ischemia is one of the most common, reported in 8–42% of cases [174]. The wide range reﬂects diﬀerent patient populations, sample sizes, and study designs. Peripheral vascular disease has been implicated as the most important factor predisposing to vascular complications [180,186,187]. Injuries to the peripheral nervous system as a result of direct damage to the nerve during IABP insertion or secondary ischemic involvement in the setting of limb ischemia have occasionally been reported after transfemoral insertion of the IABP device. For example, a retrospective review of a 15-year experience with the use of IABP found that 5 out of 66 patients had a late development of foot droop attributed to an ischemic neuropathy [180]. Of 367 IABP insertions, another group reported 2 cases of femoral nerve palsy [184]. Paresthesias over the anterior thigh in the distribution of the lateral femoral cutaneous nerve that persisted after surgical IABP removal and were unrelated to limb ischemia were noted in 1% of 100 consecutive patients in another series [185].

VI. VENTRICULAR ASSIST DEVICES A. Background and Incidence Implantable left ventricular assist devices have been used in patients with end-stage heart failure as a bridge to cardiac transplantation [188]. They have also been used in patients with advanced congestive heart failure. REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure), a prospective trial, found a

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clinically signiﬁcant survival beneﬁt and improvement in the quality of life after 1–2 years with a VAD in patients with advanced heart failure who were not candidates for heart transplantation [188]. Stroke is the most serious complication of VADs. Modern VADs have surfaces designed to reduce the risk of thromboembolism, but the risk is not completely eliminated [189]. In addition there can be systemic abnormalities of coagulation and ﬁbrinolysis after implantation of VADs that can aﬀect the risk of postoperative bleeding and later thromboembolism [190–192]. The incidence of cerebral thromboembolism with VADs varies from 0 to 30%, depending on the type of device and other factors [193]. A neuropathological study of patients with VADs found evidence of cerebral infarctions in 70% and cerebral hemorrhages in 42% of the 33 patients examined [194]. A retrospective series of 23 patients reported that 9 had neurological complications after placement of a VAD [195]. These included 4 strokes (17%), 3 seizures, and 2 cases of delirium. Another retrospective study reported 17 cases of cerebral embolism in 36 patients (47%) who underwent VAD implantation [196]. The rate per patient-year of neurological events in the device group of the REMATCH trial (0.39 in the device group vs. 0.09 in the medical therapy group) (RR 9.47; 95% CI 1.31, 14.50) was 4.35 times higher than the rate in the medical therapy group. However, 76% of patients in the device group were free of neurological events without routine anticoagulation. B. Risk Factors TCD demonstrates MES in patients with VADs. As in other settings, the correlation between MES and clinical events is not strong. The reported frequency varies according to the type of device and timing of study. A study of 8 patients found MES in 28% of the tests, but none of the patients developed cerebral thromboembolism [197]. Another reported a 26% incidence of MES in 14 patients with only 1 developing a thromboembolic stroke [198]. A study with a diﬀerent VAD found an incidence of MES of 18%, but no association between MES and stroke [193]. In contrast to these studies, another reported an 84% frequency of MES (143 of 170 monitorings), with signiﬁcantly higher MES counts on the days with clinically manifest embolic events as compared with event-free days (18.5 vs. 4, respectively; p < 0.001). Signiﬁcant diﬀerences in the incidence and counts of MES as well as in the incidence of clinically manifest embolic events were noted among the six patients ( p < 0.01) [199]. Given these varying results, it does not appear that MES as demonstrated by TCD provides a useful tool for identifying patients at greater risk for VAD-associated embolism.

VII. CARDIAC PROCEDURES IN CHILDREN A. Background and Incidence Cardiac procedures in children are subject to many of the same complications as in adults, although the frequency and etiologies may diﬀer. In addition, a choreoathetoid syndrome may rarely occur in children after cardiac surgery for congenital malformations. A study of 668 infants who underwent open heart surgery with extracorporeal circulation (ECC) between 8 and 34 months of age found an incidence of coreoathetoid syndrome of 1.2% [200]. Another study reported an incidence 1.05% in 758 children having cardiac surgery with ECC and hypothermia [201].

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Both a mild and a severe form of the syndrome can occur, with onset generally within the ﬁrst week after surgery [200–203]. The mild form is usually transient and develops mainly in children who undergo cardiac surgery as infants. The severe form more commonly occurs children in whom the procedure is done after infancy [203]. B. Risk Factors The pathogenesis of the syndrome is presently unknown. Limited neuropathological data suggest nonspeciﬁc hypoxic-ischemic injury as well as neuronal loss and nerve ﬁber degeneration aﬀecting the external globus pallidus [202,204,205]. C. Prevention and Treatment Short-term symptomatic treatment of the severely aﬀected patients with dopamine antagonists such as haloperidol has been advocated [200]. D. Prognosis In conjunction with the hyperkinetic movement disorder, a variety of manifestations may ensue during the acute and long-term course of this syndrome. These include oculomotor apraxia, supranuclear opthalmoplegia, oromotor dysfunction, hypotonia, epilepsy, and cognitive and behavioral disturbances [200–203,206,207].

VIII. CONCLUSION A variety of neurological complications can occur after cardiac procedures. The incidence varies widely with the type of procedure and study methodology. Preventive measures need to be tailored appropriately. Despite the frequency with which these procedures are performed and the generally low complication rates, much work needs to be done to further reﬁne the interventions.

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30 Hematological Abnormalities in Stroke Bruce M. Coull The University of Arizona College of Medicine, Tucson, Arizona, U.S.A.

Scott Olson The University of California, San Diego, California, U.S.A.

It has been estimated that only about 4% of all ischemic strokes are directly caused by an underlying, well-deﬁned hematological abnormality [1], but this represents but a fraction of the important pathological interactions between blood and blood vessels that result in both hemorrhagic and thrombotic stroke. Hematological aspects of neurology are evolving to include disorders of hemostatis and thrombosis, also encompassing neurological symptoms produced as a result of malignancy or by compromise of the immune system. The diseases and conditions aﬀecting hemostasis and thrombosis with respect to stroke can be divided into abnormalities that produce bleeding and those that cause thrombosis, although this distinction is not always clear-cut. It is also useful to evaluate abnormalities in plasma factors separately from the cellular or organelle elements of blood, such as platelets that are associated with a risk of stroke. These hemorheological considerations are particularly important with respect to the cerebral microcirculation or during episodes of cerebral hypoperfusion or ischemia when there is coexisting impaired collateral circulation or severe large vessel stenosis. The following discussion focuses on the common bleeding, thrombotic and hemorheological conditions that contribute to an increased risk of stroke. Within this framework, certain speciﬁc hematological disorders and syndromes are described in some detail.

I. BLEEDING DISORDERS Clotting abnormalities account for approximately 8% of all intracerebral hemorrhages (ICH) [2] and may be either inherited (primary) or acquired (secondary). In either instance, the bleeding tendency involves alterations in coagulation factors and cofactors or platelets, or both. Most individuals with a bleeding diathesis present with systemic bleeding, but intracranial hemorrhages, including subdural or epidural hematomas, subarachnoid hemorrhage (SAH), and ICH, often following insigniﬁcant trauma, can be the initial event [3,4]. Extreme prolongation of the prothrombin time from warfarin therapy is the most common cause of iatrogenic ICH [5], but ICH an also occur with deﬁciencies or 713

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abnormalities from other causes that aﬀect the function of coagulation factors VII, VIII, IX, XIII, von Willebrand’s factor, or ﬁbrinogen. ICH may also occur with thrombolytic therapy and use of other anticoagulants. Hemophilia (factor VIII) and von Willebrand’s disease (von Willebrand’s factor) are the most common inherited disorders of coagulation, but these are uncommon causes of central nervous system (CNS) bleeding. Acquired immune inhibitors, typically IgG antibodies that interfere with factor VIII function, may eﬀectively worsen an underlying factor deﬁciency [2]. Disorders that aﬀect platelet concentration including severe thrombocytopenia and idiopathic thrombocytopenia purpura (ITP) can also cause ICH. Essential thrombocythemia and uremia, in contrast, impair platelet function despite normal platelet levels and thereby cause hemorrhages. ICH has also been reported in patients with red blood cell (RBC) disorders including aplastic anemia and sickle cell disease [6]. Disseminated intravascular coagulation (DIC) and hematological malignancies may aﬀect either blood plasma or cellular components of blood [2]. A. Hemophilia Hemophilia is an X-linked coagulation disorder that causes low concentrations of clotting factors VIII (hemophilia A) and IX (hemophilia B). A family history of hemophilia is lacking in roughly one third of cases, suggesting the possibility of spontaneous mutations, and sporadic cases can occur in some individuals with autoimmune diseases or cancer as an acquired hemophilia. Hemophilia A is more common than hemophilia B and has a prevalence of roughly 1:10,000 persons [7]. Depending upon the concentrations of factors VIII or IX, hemophilia is considered clinically as severe, moderate, or mild. In severe cases, plasma levels of factors VIII or IX are usually no more than 1% of normal, whereas in mildly aﬀected persons, factor concentrations may range up to 25% of normal (i.e., 0.25 U/mL). Approximately 10–15% of men with hemophilia eventually develop factor VIII inhibitor antibodies, commonly IgG, that when present in high titers may produce spontaneous ICH [2,8,9]. Although factor VIII inhibitors most often occur in persons with severe hemophilia, they sometimes occur in normal subjects [10] but are not associated with ICH [11]. An acquired factor IX deﬁciency has been reported in nephrotic syndrome [12]. Diagnosis is based on conﬁrming low factor VIII and IX levels measured in blood. Intracranial bleeding in hemophilia often follows major surgical procedure or severe head injury, but for unknown reasons bleeding is sometimes delayed several days following the trauma [3]. The incidence of intracranial hemorrhage is probably less than 8%, but when ICH happens, the consequences are dire [2,13]. Mortality ranges from 20% to 50%, and severe neurological deﬁcits remain in up to 50% of survivors [3,4,14]. Besides ICH, other neurological complications include spinal cord compression from focal hematomas and peripheral nerve entrapment from compartment syndromes that often involve femoral (iliopsoas bleeding) and median nerves. Although ICH is the leading cause of death in hemophilia, until the recent advent of recombinant therapy, human immunodeﬁciency virus (HIV) infection and hepatitis C associated with hepatic failure were major comorbidities. Spontaneous ICH in hemophiliacs with acquired immunodeﬁciency syndrome (AIDS) has been described [15,16]. B. Von Willebrand’s Disease Von Willebrand’s disease (vWD) is a relatively common bleeding disorder caused by defects in the von Willebrand factor (vWF) gene [17]. The prevalence in the general

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population is estimated at 1%, but a large majority of these patients do not have signiﬁcant bleeding episodes. Type I vWD is an autosomal dominant disorder characterized by low serum vWF level as a result of decreased release of vWF from endothelial cells, and it accounts for 70–80% of all cases of vWD [17,18]. Type II vWD involves dysfunctional vWF and has several subtypes, while type III is a rare autosomal recessive disorder with complete absence of vWF [17]. High-molecular weight multimers of vWF are necessary for stabilizing coagulation factor VIII in plasma and for the adhesion of platelets to subendothelial surfaces following injuries. In general, plasma concentrations of vWF and factor VIII coagulant activity may be low, and subjects are at risk of intracranial or other bleeding following injury [19–21]. When considering the diagnosis of hemophilia or vWD, a careful history should be obtained on whether the patient or family members have experienced excessive bleeding after surgical trauma or dental extractions. Laboratory studies should include assays for vWF and a cutaneous bleeding time to exclude von Willebrand’s disease. C. Thrombocytopenia When the platelet count is severely reduced (<20,000 mm3), the profound thrombocytopenia may result in intracerebral hemorrhage [22,23]. Decreased platelet production causing thrombocytopenia often happens because of bone marrow suppression by drugs or toxins, acquired bone marrow failure in certain hematological cancers such as leukemia, and rarely, because of inherited disorders of platelet production. A decreased platelet life span leading to thrombocytopenia is often caused by a consumption coagulopathy, such as disseminated intravascular coagulation (DIC) or antibody-mediated shortening of platelet survival, as observed in thrombotic thrombocytopenic purpura (TTP), or immune mediated thrombocytopenic purpura (ITP). Acute ITP is typically a disease of childhood that closely follows a viral infection in about two-thirds of cases, whereas chronic ITP is more often seen in adults [24,25]. Central nervous system (CNS) hemorrhage is more likely to occur in the chronic form of ITP [26], but this complication occurs in less than 5% of cases [2]. Fewer than 2% of children with immune-mediated ITP experience ICH, but because of impaired platelet function, serious intracerebral hemorrhages can occur even when the platelet count is higher than 50,000/mm3. When clinically necessary, lumbar puncture or invasive angiography usually can be performed safely as long as the platelet count is above 20,000/mm3 and no other coagulopathy is present. D. Intracerebral Hemorrhage Associated with Anticoagulant and Thrombolytic Therapy Bleeding is a frequent and untoward complication of both anticoagulant and thrombolytic therapies. ICH constitutes 40% of all strokes and 70% of all serious hemorrhagic complications in patients on oral anticoagulant therapy (OAC) [27]. The absolute risk of ICH with chronic warfarin treatment ranges from 0.3% to 1% per year. The bleeding risk is proportional to the degree of anticoagulation, and the addition of aspirin to an anticoagulation regimen approximately doubles the risk of hemorrhage. Other anticoagulants include heparin and low-molecular weight heparins (LMWH), glycoprotein IIb/IIIa (GP IIb/IIIa) antagonists, and direct thrombin inhibitors. The risk of ICH with use of these agents is increased, but the exact degree of risk in nonstroke patients is unclear for several reasons. First, trials do not typically report ICH as a separate entity; instead, it is reported as part of a group of ‘‘major events,’’ which includes other

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catastrophic hemorrhages. Second, most of the information comes from the cardiology literature and involves situations in which many patients are receiving more than one agent that can aﬀect clotting. Data on the use of GP IIb/IIIa antagonist abciximab for treatment of acute ischemic stroke suggest an increased risk of symptomatic ICH of approximately 3% [28]. There are also reports of ICH associated with neuroendovascular and percutaneous coronary interventional procedures while using heparin and GP IIb/IIIa antagonists in combination [29,30]. Direct thrombin inhibitors, such as hirudin, have been shown to increase the ICH rate in a dose-dependent manner, particularly when used as an adjunct to thrombolytics [31,32]. Based on the cardiology literature, there is probably little risk of major cerebral bleeding in patients who have not had a recent stroke and who are treated with dose-adjusted unfractionated heparin or LMWH alone [31,33]. However, there does seem to be a dose-dependent increase when used in conjunction with thrombolytics for acute myocardial infarction (MI). In the setting of acute ischemic stroke, subcutaneous, intravenous, and LWMH are all associated with an increased risk of ICH compared to placebo [34]. The risk of ICH with thrombolytic therapy is diﬀerent for acute MI than for acute ischemic stroke. Thrombolytic therapy for MI probably decreases the overall incidence of stroke but causes a small increase in the likelihood of hemorrhagic stroke, whereas ﬁbrinolytic treatment of brain infarction results in a 6% incidence of parenchymal hemorrhage [35]. In several trials of patients with acute MI, both streptokinase and recombinant tissue plasminogen activator (rt-PA) were associated with a small risk of symptomatic ICH (0.3–1%) [36–38]. By one month, ICH that accompanied thrombolytic therapy for MI caused death in one-half to two-thirds of cases. E. Disseminated Intravascular Coagulation DIC is characterized by activation and consumption of the plasma clotting factors and platelets. Excess thrombin generation in DIC causes ﬁbrin deposition within blood vessels and the heart and causes thrombosis of both arteries and veins. Bleeding is usually due to (1) depletion of the intrinsic coagulation factors, (2) thrombocytopenia, or (3) inhibition of ﬁbrin-split products on blood coagulation. The causes of DIC include systemic infections, septic shock, cancer, heat stroke, transfusion reactions, and abruptis placentae. Acute brain injury, especially when massive, such as may occur with head injury, SAH, brain tumors, or major neurosurgical procedures, sometimes triggers DIC [39]. In the absence of a systemic malignancy, CNS bleeding with acute DIC is uncommon. Rather, bleeding typically occurs from the gastrointestinal tract, into the skin, from venipuncture sites, or from the urinary tract [40]. In contrast, fully 15% of patients with cancer-related DIC develop CNS ischemic events [41–44]. These events are frequently associated with microangiopathy. Acute and chronic forms of DIC have diﬀering clinical characteristics. Acute DIC usually presents with bleeding and, if uncorrected, may lead to shock and hypoperfusion of various organs, often causing acute renal failure. Thromboembolic complications are less frequent than a bleeding tendency. With acute DIC, bleeding may involve any organ system, and petechiae are often present. With chronic DIC, prominent features of the underlying systemic disorder often obscure the presence of DIC. When chronic, DIC is less fulminant and petechiae are less conspicuous, although recurrent epistasis can provide a diagnostic clue. Thromboembolic events are both the rule and often may be the presenting complaint. Characteristic features of chronic DIC include progressive impairment of renal function, confusion, transient ischemic attacks (TIAs), and recurrent ischemic strokes.

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Strokes may be caused by large- and small-vessel occlusive events or by cardioembolism from nonbacterial endocarditis [45]. Lymphomas and mucin-secreting adenocarcinomas, in which chronic DIC and marantic endocarditis coexist, often present in this fashion [46– 48]. Pathological studies show ﬁbrin thrombi in small vessels and both large and small brain infarctions with necrosis [49]. Petechial hemorrhages in brain, focal demyelination, and subarachnoid hemorrhage also have been observed. Laboratory studies show (1) thrombocytopenia, (2) prolonged prothrombin, partial thromboplastin, and thrombin times, (3) decreased ﬁbrinogen, and (4) markedly elevated ﬁbrin degradation products. Abnormal RBC morphology with small fragmented cells, termed schistocytes or burr cells, is seen on the peripheral smear.

II. THROMBOTIC COMPLICATIONS Activation of blood coagulation with thrombosis is an essential event in virtually all ischemic strokes. The thrombotic process in this circumstance typically results from the sudden and pathological activation of the clotting cascade that often follows endothelial activation or plaque rupture within an atherosclerotic precerebral or cerebral artery. In some individuals, whether inherited or acquired, intrinsic abnormalities in hemostasis are associated with an increased risk of stroke. Recent advances in biochemical and molecular biology techniques have identiﬁed numerous putative genetic polymorphisms and other novel molecules that could be either associative markers of risk or intrinsic risk factors for ischemic stroke. These genes and related molecular markers include many that involve hemostasis such as clotting factors and associated regulatory proteins as well as substances that can aﬀect endothelial cell and platelet function. The true signiﬁcance of many of these potential risk factors is unknown. A. Pathogenesis of Thrombosis The processes that ultimately culminate in pathological thromboses causing stroke are complex and dynamic and frequently involve perverted endothelial cell function, inﬂammatory pathways, and activation of coagulation factors and sometimes dysfunction of antithrombotic plasma proteins. Three regulatory plasma proteins, protein C, protein S, and antithrombin (AT), in concert with normal vascular endothelial cells provide an important barrier to thrombosis and serve to focus and limit the thrombotic process once activated. A key glycoprotein, thrombomodulin, expressed on the endothelial cell surface, is required for the activation of protein C, a vitamin K–dependent plasma factor. When linked to protein S, another vitamin K–dependent plasma factor, the activated protein C– protein S complex rapidly destroys activated factors V and VIII. Heparan, a glycosaminoglycan, is widely distributed on the normal endothelial surface. Heparan binds to and enhances the anticoagulant function of AT. Once bound to heparan, AT rapidly inactivates thrombin as well as activated factor Xa and other prothrombotic serine proteases. In addition to providing a surface for the eﬀective functioning of antithrombotic enzymes, the normal vascular endothelium inhibits platelet adhesion and aggregation. The vascular endothelium also contributes to vascular tone by release of substances such as prostacyclin (PGI2) and endothelial nitric oxide synthase (eNOS)–derived nitric oxide (NO) that can promote vasodilation and further inhibit platelet activation. Under appropriate circumstances, blood vessels also markedly enhance local ﬁbrinolysis by the synthesis and release of tissue plasminogen activator (t-PA). Injury to the vascular

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endothelium not only causes a loss of antithrombotic functions, but can also actually promote thrombosis partially via activation of inﬂammatory pathways. Mediators of inﬂammation such as interleukin-1 (IL-1), tumor necrosis factor (TNF), or immune complexes may induce endothelial cells to downregulate thrombomodulin, expose binding sites for clotting factors, and express tissue factor (TF) [50,51]. Systemic markers of inﬂammation, including elevated plasma ﬁbrinogen and Creactive protein (CRP), are implicated as biomarkers of an increased risk of stroke. It is also possible that these and other constituents of the inﬂammatory process are actually risk factors for stroke [52]. Our understanding of exactly how or why inﬂammation promotes thrombophilia is incomplete, but one possible relationship is via TF expression within vascular tissues [53]. When TF is expressed on the surface of injured endothelial cells, in subendothelial vascular tissues, or on activated monocytes, the conversion of factor VII to VIIa is greatly ampliﬁed, thereby initiating and sustaining the downstream coagulation pathway. Activated monocytes interact directly with platelets and promote the assembly of the prothrombinase complex on their membrane surfaces. A dramatic example of these events is the expression of TF within the atheromas of diseased carotid and coronary arteries, where TF expression surrounds the lipid-rich core [54]. Important relationships between lipid abnormalities, integrity of the vascular endothelium, and inﬂammation are linked to thrombosis. For example, oxidized low-density lipoprotein (LDL) deposits in athrosclerotic plaques promote expression of subendothelial TF whereas increased serum levels of CRP promotes TF expression on the membranes of circulating monocytes. B. Antithrombin, Protein C, and Protein S: Hereditary and Acquired Deficiencies AT, protein C, and protein S are important regulatory proteins that prevent excessive or inappropriate thrombus formation. Deﬁciencies of these factors can be identiﬁed by laboratory assays showing either low concentrations or low functional activity (e.g., 50% or less) [55,56]. Both activity- and concentration-based tests may be required, since some antigenic assays do not detect genetic mutations producing dysfunctional molecules. Since protein S exists either free or protein bound, both forms should be measured [7]. Hereditary AT deﬁciency occurs in roughly 1:2000–1:5000 persons and is probably less common than hereditary protein C or protein S deﬁciency. About 20% of patients with venous thrombosis or a strong family history of thromboemboli will be found to have a deﬁciency of one of these natural anticoagulant proteins [57]. The prevalence of stroke is low among persons with hereditary deﬁciencies of these proteins and depends in part upon age and the population studied. Data from various studies provide a range from 0 to 21% [58–61]. In young individuals and especially peripartum women whose anticoagulant proteins are reduced or dysfunctional, TIAs, amaurosis fugax, and occlusive arterial strokes have all been reported, but a cerebral venous thrombosis appears to be the most common cerebral thrombotic event [62–69]. Acquired deﬁciencies of AT and proteins C and S also produce a prothrombotic state and contribute to brain infarction [70]. These acquired deﬁciencies, outlined in Table 1, include disseminated intravascular coagulation, nephrotic syndrome, postoperative state, pregnancy, and use of oral contraceptives [71,72]. Overall, these deﬁciencies probably account for a minority of strokes (1–4%), except in certain populations, such as young patients, or when accompanied by other risk factors for stroke such as oral contraceptive use [73]. This point is exempliﬁed by prospective studies in the general population that have failed to show a signiﬁcant association with

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Table 1 Acquired Deﬁciencies of AT, Protein C, and Protein S Consumption coagulopathy DIC (shock, sepsis) Post Surgery Preeclampsia Liver dysfunction Acute hepatic failure Cirrhosis Renal disease Nephrotic syndrome HUS Malignancies Leukemia (APL) Malnutrition or gastrointestinal loss Vascular reconstruction (diabetes, age) Inﬂammatory bowel disease Drugs Estrogens-progestins Heparin Therapy L-Asparaginase Vasculitis Infection/neutropenia Hemodialysis Plasmapharesis HUS, hemolytic uremic syndromes; APL, acute promyelocytic leukemia.

ischemic stroke [73–76]. As a result, routine testing is not indicated for adult stroke patients, but may be considered in young stroke patients or patients with cerebral venous thrombosis [77]. C. Dysfibrinogenemia Elevated plasma levels of ﬁbrinogen are a weak biomarker of increased risk for stroke, whereas molecular structural changes in the ﬁbrinogen molecule that deﬁne dysﬁbrinogenemia have been associated with both thrombotic and mild bleeding tendencies. Most of these defects in ﬁbrinogen molecule reﬂect genetic single point mutations. Fibrinogen is a large macromolecule composed of three pairs of nonidentical polypeptides, the genes for which are located on the long arm of chromosome 4 [78]. The complex molecular biology of ﬁbrinogen aﬀords ample opportunity for genetic abnormalities in the ﬁbrinogen molecule. Fortunately, approximately 55% of ﬁbrinogen polymorphisms are clinically silent, and of the remaining percentage, 25% are associated with bleeding and 20% with thrombotic events, including stroke [79]. Disorders such as hepatic failure, ﬁbrinolytic drug administration or treatment with L-asparaginase or valproate, snakebite, and DIC are among the acquired forms of hypoﬁbrinogenemia [78,80]. When the thrombinadsorbing capacity of ﬁbrinogen is reduced or binding to platelets by ﬁbrinogen is increased, both venous and arterial thrombotic episodes, including stroke, may occur [81]. To form a stable ﬁbrin clot, ﬁbrinogen cleavage must interact eﬀectively with factor

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XIII. Some polymorphisms in ﬁbrinogen allow the formation of ﬁbrin clots that are markedly resistant to ﬁbrinolysis [82,83]. Certain factor XIII abnormalities are associated with bleeding because of impaired ﬁbrin cross-linking in clot stabilization. Although elevated plasma levels are an indicator of increased risk of stroke, a single ﬁbrinogen measurement is diﬃcult to interpret clinically and therefore routine determinations are not recommended. The thrombin time is a sensitive but not speciﬁc measure of ﬁbrinogen function, whereas the reptilase time is a less sensitive measure but is unaﬀected by heparin. Other than determinations of plasma concentration, routine testing for dysﬁbrinogenemia in individuals with stroke is not currently recommended [79]. D. Homocystinuria and Homocysteinemia Based upon a large volume of clinical evidence, elevated plasma homocysteine is an independent risk factor for ischemic stroke and related thrombotic occlusive events. In homocystinuria, the 20-fold or more increases in plasma homocysteine, homocystine, and cysteine-homocysteine-mixed disulﬁde produce premature atherosclerosis that is sometimes associated with brain infarction from carotid or other large intracranial arterial occlusions [84,85]. Homocysteinuria usually results from one of several inborn errors of metabolism that impair cystathionine h-synthase (CBS) or the related enzyme systems aﬀecting methionine metabolism. As autosomal recessive traits, homozygous persons often experience premature atherosclerosis and thromboembolic complications, including stroke, by age 30. Individuals with homocystinuria are sometimes phenotypically distinct with characteristic occular, vascular, skeletal, and nervous system abnormalities. These include a marfanoid habitus with arm spans greater than body height, setting-sun lenticular dislocations, cognitive impairments, malar ﬂush, and livedo reticularis, but such clinical signs are not consistent features of the syndrome [84,86]. About 0.3–1.5% of the general population may be heterozygous for CBS deﬁciency, and the estimated incidence of homocystinuria is approximately 1:332,000 live births [84,87]. In obligate heterozygotes, CBS activity is reduced by 50%. The impact of elevated plasma homocysteine levels on stroke risk is less clear, but it appears to impart a slightly increased risk [88]. Recently, a large meta-analysis found a small but signiﬁcant reduced risk of ischemic stroke (OR 0.81, 95% CI 0.69–0.95) with lower plasma homocysteine levels when compared to individuals in the highest fraction [89]. Several previous retrospective studies and meta-analyses have also shown elevated homocysteine levels to be associated with an increased risk of ischemic stroke [87,90–93], but prospective studies are less supportive [94]. The strongest association may be with carotid atherosclerosis and related large artery, noncardioembolic stroke [95]. The exact role of elevated homocysteine in the pathogenesis of stroke is currently unknown, but both experimental animal and tissue culture experiments suggest that homocysteine, a highly reactive species, causes direct vascular endothelial injury. Elevated homocysteine is associated with other important risk factors for stroke, including increasing age, male gender, tobacco smoking, renal impairment, atherogenic diet, and especially with nutritional deﬁciencies and decreased intake of folic acid and vitamin B12. A common ‘‘thermolabile’’ polymorphism in the methylene tetrahydrofolate reductase gene is associated with elevated levels of homocysteine in individuals with low dietary folate, but a relationship between this mutation and risk of vascular events including stroke in adults is not established. Although controversial, in the absence of elevated plasma homocysteine and related compounds, heterozygosity for CBS deﬁciency per se does not impart an increased risk for

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premature atherosclerosis [96]. In contrast, several others report that heterozygosity for CBS deﬁciency does increase risk for premature atherosclerosis and stroke [87,97]. This interpretation remains open to question. E. Hematological Polymorphisms Polymorphisms that are present in both clotting and platelet-related proteins are being reported in increasing numbers. These observations provide a better understanding of stroke mechanisms, elucidate ‘‘novel’’ risk factors for stroke, and eventually can lead to improved prevention and treatment of stroke. The importance of a genetic polymorphism depends upon its prevalence in a given population and the relative risk imparted by the variant allele in either the hetero- or homozygous state. Unfortunately, so far, many studies that have identiﬁed putative polymorphisms that impart an increased risk of stroke have not been substantiated when investigated in larger, more genetically diverse populations. Such is the case of the factor V Leiden mutation, which produces resistance to inhibition of factor V by activated protein C. Factor V Leiden, caused by a single mutation in the factor V gene, is a relatively common genetic mutation, accounting for about 95% of all activated protein C resistance (APCR) [98], and has a prevalence of about 7% in ischemic stroke patients [99]. However, the prevalence among controls is similar [99]. Although this point mutation may be contributory to stroke in young individuals [100], the importance of the mutation as a risk factor for stroke in the general population has not been substantiated [73,101,102]. Another relatively common polymorphism that may impart an increased risk of ischemic stroke is the prothrombin 20210 A variant (G 20210 A). This mutation is found in about 5% of ischemic stroke patients. While several studies have failed to ﬁnd a link [73,103], a meta-analysis has suggested a slightly increased odds ratio (1.4) for ischemic stroke when the mutation is present (95% CI 1.03–1.9) [99]. In some patients with cerebrovascular disease, diminished ﬁbrinolysis has been reported and has been linked to an increased likelihood of thrombosis. Several studies have found evidence of reduced endogenous ﬁbrinolytic activity for up to 4 weeks after acute stroke [104,105]. These results are supported by reports that show both increased ﬁbrinopeptide A levels after stroke and a direct correlation between ﬁbrinopeptide A levels and stroke-related mortality [106,107]. Most often, decreased ﬁbrinolytic activity is a result of increased levels of plasminogen activator inhibitor (PAI-1); for example, a group of young men have been shown to have increased PAI-1 levels following myocardial infarction [105]. Studies of PAI-1 levels in acute stroke and genetic polymorphisms, though, have had mixed results, with the majority of studies failing to ﬁnd a link [102,108,109]. Tissue plasminogen activator, usually existing in a complex with PAI-1, is increased in both ischemic and hemorrhagic stroke patients when compared with controls [102,110– 112]. However, a genetic basis to account for this observation has not been clearly established [102]. There are nine classes of platelet membrane glycoprotein receptors that mediate various platelet functions such as surface interactions and binding of ﬁbrinogen and von Willebrand factor. A large number of polymorphisms in these glycoprotein receptors have been identiﬁed, and some appear to be over represented in individuals with stroke [113]. Genetic polymorphisms in glycoproteins Ia, Ib, IIb, and IIIa have all been associated with increased stroke risk, but again the results are inconsistent, suggesting that certain populations (e.g., young persons) may be more susceptible [113]. Finally, genetic polymorphisms of 5,10-methylene-tetrahydrofolate reductase, endothelial cell nitric oxide

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synthase, and angiotensin-converting enzyme have been evaluated and found not to be strongly associated with an increased risk of ischemic stroke [102]. Genetic mutation, besides increasing the risk of stroke, can also be protective against stroke. An example is the Val34Leu mutation in the factor XIII gene, which seems to actually impart protection against ischemic stroke. In one small case-control study, the Val34Leu allele was associated with an odds ratio for ischemic stroke of 0.58 (95% CI 0.44–0.75) [114]. It is possible that the Val34Leu mutation causes the ﬁbrin clot to be more susceptible to thrombolysis with t-PA. Studies of larger populations are needed to conﬁrm this observation. Overall, there is a lack of reproducible evidence of links between these genetic variations and risk for ischemic stroke. The reason for this currently unknown, but the coincidence of the G 20210 A variant with other potentially thrombogenic polymorphisms including the factor V Leiden mutation and polymorphisms in the platelet GP IIb/IIIa receptor has been described [115,116]. This suggests that combinations of two or more polymorphisms that favor thrombosis are one important way in which such mutations confer a risk of stroke [117]. Furthermore, it is possible that thrombophilic mutations can interact with convnetional vascular risk factors to amplify the risk of stroke. Nonetheless, routine testing for these genetic polymorphisms in most typical adult individuals who experience an ischemic stroke is not recommended. Such testing may be considered in younger patients, patients with paradoxical emboli, or patients with cerebral venous sinus thromboses [77].

F. Thrombotic Thrombocytopenia Purpura Despite the presence of thrombocytopenia, thrombotic thrombocytopenia purpura (TTP) is more often associated with thrombotic events than hemorrhagic complications. TTP is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and a variety of neurological symptoms, renal failure, and fever. Young adults are most often aﬀected with a peak incidence in the third decade of life and a female-to-male ratio of 2:1 [118]. Almost all patients have neurological symptoms including parasthesias, confusion, seizures, delerium, and focal neurological deﬁcits [119]. Neurological manifestations often ﬂuctuate and are probably the result of microthrombus formation within the brain capillaries [120]. With eﬀective treatment, neurological signs usually resolve witin 48 hours, but deﬁcits may persist [121]. TTP is usually an idiopathic, acute, monophasic illness, but chronic relapsing and familial forms are described [120]. TTP is related to the hemolytic uremic syndrome (HUS) in children, but the neurological abnormalities are much more prominent in TTP. Nevertheless, brain infarction has been reported to occur in HUS. The vascular pathology of TTP demonstrates ﬁbrinoid microthrombi in small brain vessels. At the molecular level, an ineﬀective or deﬁcient metalloprotease involved in processing von Willebrand factor has recently been implicated [122–125] with resultant ‘‘unusually large von Willebrand multimers’’ [118] detected in the peripheral blood. Antibodies to the vWF metalloprotease have been found in patients with acquired TTP [123,124]. In contrast, protease activity in a small series of patients with HUS was found to be normal, suggesting that TTP and HUS have a diﬀerent pathogenesis [124]. Other abnormalities observed in TTP include decreased PGI2 production, inhibition of ﬁbrinolysis at the site of thrombus formation, circulating platelet activating factors, and oxidative injury to the vascular endothelium during acute TTP. The link between all of these abnormalities is unclear [120].

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The many secondary causes of TTP include pregnancy, systemic diseases, cancers, use of medications including ticlopidine and clopidogrel [126,127], chemotherapies, and infections (e.g., verotoxin producing Escherichia coli, Shigella dysenteriae, Salmonella typhi, Campylobacter jejuni, Yersiani, Pneumococcus, Streptococcus, Legionella, Mycoplasma, human immunodeﬁciency virus (HIV), Epstein-Barr virus (EBV), Herpes Simplex virus (HSV), inﬂuenza, coxsackievirus B) [120]. Postinfectious TTP is the most common secondary form, occurring in up to 40% of cases [120]. Systemic diseases including systemic lupus erythematosus (SLE) and gastric cancer may also cause TTP. The relationship of TTP to acute or chronic DIC remains controversial; however, in contrast with DIC, ﬁbrinogen levels are usually elevated, rather than depressed in TTP, and most patients with TTP do not have markedly elevated ﬁbrin-degradation products. Diagnosis of TTP is primarily based on clinical features, but only about 40% of patients manifest the entire pentad of symptoms (i.e., paresthesias, confusion, seizures, delirium, focal neurological symptoms) [118]. Abnormal laboratory values demonstrate thrombocytopenia, anemia with or without schistocytes on peripheral smear, elevated lactate dehydrogenase (LDH) and unconjugated hyperbilirubinemia from red blood cell destruction. Coagulation tests and d-dimers are typically not aﬀected. Newer tests of metalloprotease activity have been developed but are not yet commercially available [118]. Treatment involves plasma exchange, antiplatelet, and immunosuppressive agents. Of these, plasma exchange is the only therapy shown to be consistently eﬀective. With aggressive treatment, survival has improved to 80–90% [128,129]. G. Fibrinolytic Defects PAI-1, the most common cause of diminished ﬁbrinolytic activity, is discussed above. A second cause of decreased ﬁbrinolysis is elevated lipoprotein(a) [Lp(a)]. Lp(a) has substantial structural homology with plasminogen, the precursor to the ﬁbrinolytic enzyme plasmin, and has been shown to inhibit ﬁbrinolysis in vitro. It stimulates the release of PAI-1 from endothelial cells and eﬀectively competes with plasminogen for binding either to ﬁbrin or to the surface of vascular endothelial cells [130,131]. Elevated Lp(a) levels have been found to be associated with ischemic stroke and large vessel atherosclerosis in some, but not all, patient population [132–140]. H. Platelet Disorders A variety of conditions in which platelet concentration or function is deranged are associated with stroke, but so far ‘‘novel’’ intrinsic platelet-related risk factors for stroke have not been identiﬁed. Most abnormalities of platelet function contribute to bleeding, but some are linked to thrombotic events [141]. Elevated numbers of circulating platelets (thrombocytosis), especially in relationship to myeloproliferative disorders, including essential thrombocythemia and polycythemia vera (P. Vera), increase the risk for stroke. Thrombotic events, including stroke, occur in up to 20% of aﬀected individuals with essential thrombocythemia. Age over 70 years, tobacco smoking, and untreated P. Vera further increase the risk of thrombotic events. In P. Vera, both hemorheological eﬀects on blood viscosity and thrombocytosis contribute to the thrombotic risk. Whether or not a signiﬁcant proportion of individuals with ischemic stroke have platelet ‘‘hyperactivity’’ remains controversial, as does the notion of aspirin resistance to platelet inhibition [142,143]. Another platelet disorder that supposedly contributes to thromboses and thereby could represent a ‘‘novel’’ risk factor for stroke is the ‘‘sticky

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platelet syndrome.’’ This syndrome is diagnosed by the hyperactive aggregation response of platelets to epinephrine and ADP in ex vivo testing, but such tests are artifact prone and not universally available, and the concept of ‘‘sticky platelets’’ has not gained widespread clinical acceptance. I. Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that often results in both thrombocytopenia and thrombotic events, including stroke. About 0.3–3% of patients who receive unfractionated heparin for more than 5 days develop HIT [144– 146], and of these, about 5–10% have neurological involvement, including arterial and venous thromboses. Vascular occlusive events may arise even while the platelet count is still in the normal range [147]. Unlike many coagulopathies, arterial occlusions are more common than venous events [147]. HIT should be suspected when an arterial thrombosis occurs in patients with vascular disease receiving heparin or in the postsurgical settings; such as following carotid endarterectomy [148,149]. Venous occlusions are more common when additional hypercoagulable risk factors (e.g., pregnancy) are present [147,150]. There are two reports of patients developing transient confusional episodes following high-dose heparin administration in the absence of other evidence of thrombosis [147,151]. It is hypothesized in these cases that symptoms were caused by diﬀuse platelet activation and clumping. In most cases of HIT, moderate to severe thrombocytopenia develops 5–15 days after initiating heparin therapy [152]. In one case, the thrombocytopenia, coagulopathy, and antiplatelet antibodies persisted for several months after the heparin was discontinued [153]. Although platelet counts may fall as low as 20,000 mm3 HIT, hemorrhagic complications are relatively uncommon. Antibodies directed against a complex of heparin and platelet factor 4 (PF4) appear to be the cause of HIT [154,155]. These antibodies have been shown to activate platelets and produce thrombosis (white clot syndrome) and thrombocytopenia [156,157]. It is recommended that the diagnosis of HIT be considered in any patient with an ischemic stroke or cerebral venous sinus thrombosis who presents within 30 days of heparin exposure with a platelet count less than 50% of baseline [77]. HIT occurs less frequently with the administration of low-molecular weight heparins (LMWH) [147], but in vitro cross-reactivity with antibodies directed against unfractionated heparin is high [152]. Direct thrombin inhibitors are not associated with HIT and are eﬀective in treating thromboses due to HIT [158–161]. J. Antiphospholipid Antibodies Antiphospholipid antibodies (aPL), including the lupus anticoagulant (LA) and anticardiolipin antibodies (aCL), are associated with arterial and venous thromboses in virtually every organ in the body, and particularly with stroke and TIA [162]. aPL include a repertoire of distinct polyclonal antibodies directed against various phospholipids including cardiolipin, phosphotidyl choline, and phosphotidyl serine, among others. Thus, aCL and LA are clearly distinct from one another and can be separated using polyacrylamide gel– phospholipid aﬃnity chromatography [163,164]. At least two populations of aPL exist: one associated with infections that is not pathogenic [165] and another that recognizes only phospholipids complexed to certain phospholipid-binding proteins, such as h2glycoprotein I (h2-GPI), prothombin, annexin V, protein C, protein S, and kininogens,

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which are bound to activated cellular membranes such as injured endothelial cells, monocytes, and platelets [162,166–169]. Patients with autoimmune diseases including SLE and Sjo¨gren’s syndrome typically have the cofactor-dependent aPL [162] that confers increased risk of thrombotic events [170]. Diﬀerences in immunoglobulin isotype (i.e., IgG, IgM, and IgA), titer, and speciﬁcity [e.g., aCL, antiphosphatidylethanolamine (PE), or antiphosphatidylserine (PS)], are also implicated as altering the risk of thrombotic events such as stroke [171–180]. The LA is deﬁned by the prolongation of phospholipid-dependent coagulation tests, such as the activated partial thromboplastin time (APTT), when speciﬁc coagulation factor deﬁciencies are not present. Other methods for identifying aPLs employ anticardiolipin, h2-GPI, prothrombin, or other antigens such as phosphotidyl serine in an enzyme-linked immunosurbent assay (ELISA) [162,181,182]. 1. Epidemiology Studies assessing the prevalence of aCL and aPL in stroke patients report widely variable results. Overall, aPL are found in about 10–30% of unselected stroke patients [171,183– 192] 4–46% of young stroke patients [193,194], and 2–12% of controls. Persons with LA have about a 30% lifetime chance of experiencing a thromboembolic event [195]. In individuals with SLE, the frequency of elevated aPL is 40%, and characteristically the LA and aCL frequently coexist [196]. The antibodies are also often detected in patients with other rheumatic diseases such as Sjo¨gren’s syndrome, Becßhet’s syndrome, mixed connective tissue disease, rheumatoid arthritis, and autoimmune TTP [196–200]. The association of aPL with thrombosis in patients without a deﬁnitive diagnosis of an autoimmune disorder is termed the primary antiphospholipid antibody syndrome [201]. Patients with aPL usually experience venous thrombosis, but cerebral ischemia is the most common arterial complication [193,202–208]. Of the many studies that have examined the relationship between aPL and stroke, approximately half report a signiﬁcant association [99]. In particular, the Antiphospholipid Antibodies in Stroke Study (APASS) found that about 10% of patients with ﬁrst-ever stroke had aCL compared with only 4% of controls (OR 2.3) [171]. However, in a follow-up study the presence of aCL did not predict additional thromboembolic events when the patients were followed for a median of 24 months [209]. Using meta-analyses, Bushnell and Goldstein calculated an OR for ischemic stroke as 5.8 for patients less than 50 years of age and 2.5 for all ages when aCL were present and 2.9 for all ages when LA was present [99]. There was no signiﬁcance of LA in patients less than 50 years of age. Conﬂicting results have also been found regarding whether the presence of aPL increases morbidity and mortality in patients with ischemic stroke and aPL [210,211]. There are several potential explanations for the disparate result, including the lack of standardization of the ELISA test substrates and cut-oﬀ values between laboratories [212,213]. Another problem is that aPL levels ﬂuctuate over time, so positive results must be conﬁrmed by repeat testing with at least a 6-week interval between determinations [99]. Finally, there is a suggestion that immunoglobulin isotype (e.g., IgG, IgA) and speciﬁcity of the phospholipid epitope (e.g., aCL, PE, PS) also aﬀect stroke risk [175]. 2. Clinical Aspects Stroke and TIA with a wide variety of presentations are associated with aPL [193,204– 207,214]. Thromboses may involve large and small arteries and veins both in the anterior and posterior circulations. Amaurosis fugax, retinal vein or artery occlusion, ischemic

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retinopathy, ophthalmoplegia from a cranial neuropathy, and migrainelike positive or negative visual phenomena, with or without headache, are all reported [214–217]. Deep lacunar infarctions, isolated punctate white matter lesions detected by magnetic resonance imaging (MRI) scanning, and large brain infarctions are seen, but most ischemic strokes are small and involve cortex and adjacent white matter. A few pathological reports have demonstrated nonspeciﬁc microvascular platelet–ﬁbrin deposits, suggesting possible thrombosis in situ or microembolic mechanisms [218]. It is likely that cardiac lesions, including mitral valve degeneration and nonbacterial thrombotic endocarditis, are responsible for many of these lesions [219,220]. Sneddon’s syndrome and vascular dementia are particularly characteristic of aPLrelated stroke, but atypical migraine, encephalopathy, chorea, epilepsy, and myelopathy have also been reported [193,221]. Sneddon’s syndrome, with stroke and livedo reticularis, in the absence of systemic disease is a syndrome that characterizes stroke associated with aPL [221–225]. Besides livedo reticularis, patients with Sneddon’s syndrome often have Raynaud’s phenomenon and demonstrate acrocyanosis, with ﬁndings of focal epidermal ulceration, but without evidence of vasculitis [221]. aPL are often present in high titers in persons with Sneddon’s syndrome who develop dementia [223] or become severely disabled [225]. With or without Sneddon’s syndrome, recurrent stroke and vascular dementia are an untoward consequence in individuals with aPL [206,224]. These patients are usually younger than the general stroke population with multi-infarction dementia, but, except for a direct relation to high aPL levels, no other speciﬁc markers have been found to identify those patients who are likely to experience recurrent ischemic events and progressive intellectual decline. Several cases have documented progressive cognitive deterioration in the absence of a history of strokelike episodes and despite antithrombotic therapy [226]. This course is reminiscent of the insights of both Sneddon and Rebollo et al., who emphasized that stroke with Sneddon’s syndrome often left little physical or neurological deﬁcit, but the patients gradually became demented [222,227]. Several other syndromes that may or may not have an ischemic basis are described with aPL, including migrainelike headaches, seizures, chorea, myelopathy and GuillainBarre´ syndrome. Most migraineurs do not have aPL or aPL-related features, but many patients with aPL describe prominent migrainelike headaches with visual symptoms [193,204,228]. Individuals with typical migraine do not require aPL testing, but people who have SLE or other connective tissue disorders and have thrombocytopenia and migrainelike headache should be considered for further evaluation. Seizures, both focal and generalized, are sometimes encountered in patients with aPL who do not have a prior history of stroke [193,229]. Certain syndromes, such as aPL-related dementia, also have a propensity for seizures or epilepsy. Generalized seizures and status epilepticus are cardinal features of a rare but catastrophic aPL syndrome of acute ischemic encephalopathy, which includes altered mental status, diﬀuse systematic involvement of pulmonary and cardiac functions, and dermatological manifestation [204,230]. Myelopathy, termed lupoid sclerosis in patients with SLE, has been associated with aPL and may have a clinical presentation indistinguishable from the myelopathic form of multiple sclerosis [217,231,232]. 3. Eﬀects of Antiphospholipid Antibodies on the Coagulation System The pathological features of microvascular occlusion by platelet-ﬁbrin plugs observed in patients with aPL are indicative of abnormalities in vascular endothelial cell function that

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contribute to thromboses. Some aPL can bind to endothelial cells in vitro [233–235], but in vivo binding seems unlikely since negatively charged phospholipids are found on the inner rather than the outer surface of the cell membrane. Separate antiendothelial antibodies have also been found in some patients with aPL, but the clinical signiﬁcance of this observation is unknown [210,235,236]. Complement activation has been observed in some stroke patients with aPL [237], but evidence that this causes subsequent endothelial cell injury is lacking [235]. The mechanism by which aPL induces thromboses remains murky, and many potential mechanisms are postulated, but so far no single mechanism has yet been proven. Speciﬁc endothelial cell functions, such as production of PGI2 or AT III, placental anticoagulant protein (PAP) binding, activation of proteins C or S, complement activation, ﬁbrinolysis, or platelet activation remain as possible targets for aPL [210,238–243]. 4. Diagnosis of the Antiphospholipid Antibody Syndrome A diagnosis of the primary aPL syndrome is established by application of both clinical and laboratory ﬁndings. Prominent systemic manifestations include livedo reticularis, cardiac valve lesions, pulmonary hypertension, adrenal insuﬃciency, and a history of spontaneous abortion in women. Routine testing for aPL is not recommended for the general stroke population but should be considered in young patients with ischemic stroke or in stroke patients with autoimmune disease [77]. Laboratory criteria for the diagnosis of LA are characterized by abnormalities in two of three phospholipid-dependent coagulation tests including the aPTT, dilute prothrombin time, dilute Russell viper venom test (dRVVT) and failure to correct the abnormality with mixing studies containing pooled plasma, correction of the abnormality with addition of excess phospholipids, and no other coagulopathies present [162,244]. aPL and aCL can also be detected using ELISA techniques with a variety of substrates. Concurrent use of anticoagulants will aﬀect coagulation tests, but not ELISAs. Individuals with positive titers of aPL should be retested after at least 8 weeks to conﬁrm persistence of the antibody elevation and not an acute phase reaction. 5. Treatment Since high-quality clinical studies are lacking, it remains uncertain whether any speciﬁc treatment beneﬁts patients with aPL [245]. Some individuals with aPL remain entirely asymptomatic despite having high aPL levels, whereas others experience recurring stroke and become severely demented or disabled. Thrombotic events are more probable when aCL levels are high and consist of IgG rather than IgM, when aCL and the LA coexist, or when SLE or other connective tissue disease is present. Patients with aPL should receive treatment for coexisting risk factors, such as hypertension or cigarette smoking, since these may contribute to an increased risk of thromboses. Large prospective randomized trials outlining treatment of individuals with aPL are currently not available. Case-control studies suggest that individuals with minimal symptoms or a single mild nondisabling event can be given aspirin or other antiaggregate treatment. Patients who experience serious or recurrent events, or who have livedo reticularis, high levels particularly of the IgG, aCL, or multiple antibody types, including both LA and aCL, should be considered for oral anticoagulant therapy. Warfarin treatment may be particularly useful in subjects with cardiac vascular lesions or other evidence for cardiac emboli.

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Lupus anticoagulant can sometimes be suppressed with high doses of prednisone, but aCL are often not responsive. In patients who experience recurrent cerebral ischemic events despite warfarin therapy, immunosuppressive therapy might be considered, although there is no evidence that these therapies prevent vascular occlusion. For a few patients who experienced acute encephalopathy, seizures, or disseminated coagulation, plasmapheresis and immunosuppression therapy has been of apparent beneﬁt [204,230].

III. SICKLE CELL DISEASE AND OTHER RED CELL DISORDERS Stroke, including silent cerebral infarction as a complication of sickle cell disease (SCD) anemia, causes cognitive impairments, developmental delay, and sometimes severe disability in the aﬀected individual [246]. The single point mutation in the hemoglobin hchain responsible for sickle cell anemia (SSA) causes substitution of valine for glutamic acid in the h-globin chain, thereby markedly lowering the solubility of deoxyhemoglobin S. This mutation promotes hemoglobin polymerization when erythrocytes are exposed to microenvironmental acidosis or hypoxemia [247–249]. The polymerization produces a rigid red blood cell with the characteristic sickle shape. Sickle cell disease can also result from inheritance of one sickle cell gene mutation and one other h-globulin chain, such as sickle cell hemoglobin C disease or sickle-thalassemia disease. In general, other SCDs do not carry the same increased risk of stroke as sickle cell anemia [246]. The prevalence of sickle trait (HBSA) in African Americans is estimated to be 8.5%, with hemoglobin HbSS approximately 0.03–0.16%, and the variant HBSC 0.21% of the population. Stroke occurs in roughly 10% of children with HbSS, but estimates vary between 8% and 17% [248,250,251], and the true incidence including silent cerebral infarctions is probably even higher. The lifetime risk of a clinical stroke is estimated to be 25–30% [251,252]. The hallmark of SCD is a progressive systemic vasculopathy with occlusive events involving brain and other organs such as kidney, skin, and bone [253–255]. Although never a benign condition, for unknown reasons only about 30% of aﬀected individuals with SSA develop SCD as children and young adults [250], whereas others have a less fulminant course, with some individuals reaching early or middle adulthood before manifesting symptoms. SCDs are associated with both ischemic and hemorrhagic strokes. For ischemic strokes, there is a bimodal distribution, with the ﬁrst and most prominent peak occurring from age 2 to 5 years and the second peak from 35 to 45 years [256]. MRI studies have shown that silent strokes aﬀect one in 10 children with SCD before age 12, thereby causing cognitive and related developmental impairments [246]. While brain hemorrhages can occur in children, ICH is most common in the third decade of life. Other neurological complications of SCD include seizures, probably as a result of stroke and myelopathy. Among the risk factors for ischemic stroke in patients with SCD [256] are increased middle cerebral artery blood velocities as determined by transcranial Doppler (TCD), prior ischemic stroke or TIA, chronic low hemoglobin concentrations, recent acute chest syndrome, increased number of acute chest syndromes in the preceding 2 years, silent infarction, hypertension, and cardiomegaly [246,257]. Risk factors for hemorrhagic stroke include prior ischemic stroke, low hemoglobin concentration, and elevated leukocyte count [256]. While sickle crises are associated with strokes, most strokes do not occur during a crisis, but seem to occur de novo. Hypoxemia itself, and particularly drops in mean nocturnal oxygen saturation, are predictive of ischemic stroke [258]. Markers of large vessel disease, such as arterial stenosis greater than 75% and increased mean blood velocity in the middle cerebral artery (z200 cm/s) on TCD increase the risk of cerebral

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infarction. TCD is particularly useful in primary stroke prevention for identifying children at high risk of stroke [258–260], and it is currently recommended that all children with TCD velocity z200 cm/s receive chronic blood transfusions in order to maintain the HbSS concentration at less than 30%. This treatment dramatically decreases the relative risk of stroke by 90% [260]. When stroke occurs, there is no particular predilection for the type of infarction and no region of the brain is spared. Cortical, deep subcortical, brain stem, spinal cord, central retinal artery occlusions, retinal hemorrhages, and dural sinus thrombosis are all reported in the literature. Pavlakis and colleagues have emphasized the association of watershed infarctions, particularly in territories of the middle cerebral artery [261], with the combination of occlusive arteriopathy and perfusion failure. Although strongly associated with vasculopathy, brain infarctions, sometimes occur in subjects who have little demonstrable arteriopathy. The mechanism for ICH is thought to be similar to ischemic strokes, with the underlying arteropathy causing the eventual weakening of the aﬀected blood vessel leading to rupture [246]. Increased cerebral blood ﬂow, only partially explained by underlying anemia, and increased cerebral blood volume may also have a relation to ICH [262]. Despite the fact that the rheological properties of the sickled RBC predict a propensity for microvascular and venous occlusion, the major cerebral vascular defect in SCD is segmental narrowing of the distal internal carotid artery along with portions of the circle of Willis and proximal major brain arteries. This large-vessel arteriopathy is characterized by intimal proliferation and an increase in ﬁbroblasts and smooth muscle cells within the arterial wall. The progressive nature of this occlusive arteriopathy is sometimes evidenced by the development of the moyamoya syndrome [263]. RBCs containing HbSS can adhere to vascular endothelium, resulting in endothelial damage and thrombosis [246]. It is likely that inﬂammation plays a signiﬁcant role, as cell adhesion molecules activate monocytes and polymorphonuclear cells at the site of endothelial injury [264]. Systemic markers of inﬂammation such as CRP are often elevated during a crisis [246,265]. Finally, decreased endothelial NO production and diminished vasomotor response to endothelial NO may also contribute to the overall hypoperfusion and stroke [246]. Besides injury to large cerebral arteries, plugging of the microcirculation and venous thromboses are also well-documented ischemic complications of SCD [266].

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systemic lupus: association with anticardiolipin antibodies. Clin Exp Rheumatol 1984; 2:47– 51. Asherson RA, Mercey D, Phillips G, Sheehan N, Gharavi AE, Harris EN, Hughes GR. Recurrent stroke and multi-infarct dementia in systemic lupus erythematosus: association with antiphospholipid antibodies. Ann Rheumat Dis 1987; 46:605–611. Levine SR, Welch KM. The spectrum of neurologic disease associated with antiphospholipid antibodies. Lupus anticoagulants and anticardiolipin antibodies. Arch Neurol 1987; 44:876– 883. Hart RG, Miller VT, Coull BM, Bril V. Cerebral infarction associated with lupus anticoagulants—preliminary report. Stroke 1984; 15:114–118. Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. The Antiphospholipid Antibodies and Stroke Study Group (APASS). Neurology 1997; 48:91–94. Feldmann E, Levine SR. Cerebrovascular disease with antiphospholipid antibodies: immune mechanisms, signiﬁcance, and therapeutic options. Ann Neurol 1995; 37(suppl 1):S114–S130. Tanne D, D’Olhaberriague L, Trivedi AM, Salowich-Palm L, Schultz LR, Levine SR. Anticardiolipin antibodies and mortality in patients with ischemic stroke: a prospective follow-up study. Neuroepidemiology 2002; 21:93–99. Favaloro EJ, Silvestrini R, Mohammed A. Clinical utility of anticardiolipin antibody assays: high inter-laboratory variation and limited consensus by participants of external quality assurance programs signals a cautious approach. Pathology 1999; 31:142–147. Alving B. Update on recognition and management of patients with acquired or inherited hypercoagulability. Compr Ther 1998; 24:302–309. Levine SR, Deegan MJ, Futrell N, Welch KM. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology 1990; 40:1181–1189. D’Alton JG, Preston DN, Bormanis J, Green MS, Kraag GR. Multiple transient ischemic attacks, lupus anticoagulant and verrucous endocarditis. Stroke 1985; 16:512–514. Elias M, Eldor A. Thromboembolism in patients with the ’lupus’-type circulating anticoagulant. Arch Intern Med 1984; 144:510–515. Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985; 19:265–275. Hughson MD, McCarty GA, Brumback RA. Spectrum of vascular pathology aﬀecting patients with the antiphospholipid syndrome. Hum Pathol 1995; 26:716–724. Anderson D, Bell D, Lodge R, Grant E. Recurrent cerebral ischemia and mitral valve vegetation in a patient with antiphospholipid antibodies. J Rheumatol 1987; 14:839–841. Asherson RA, Hughes GR. The expanding spectrum of Libman Sacks endocarditis: the role of antiphospholipid antibodies. Clin Exp Rheumatol 1989; 7:225–228. Levine SR, Langer SL, Albers JW, Welch KM. Sneddon’s syndrome: an antiphospholipid antibody syndrome? Neurology 1988; 38:798–800. Sneddon IB. Cerebrovascular lesions and livedo reticularis. Br J Dermatol 1965; 77:180–185. Bruyn RP, van der Veen JP, Donker AJ, Valk J, Wolters EC. Sneddon’s syndrome. Case report and literature review. J Neurol Sci 1987; 79:243–253. Coull BM, Bourdette DN, Goodnight SH Jr, Briley DP, Hart R. Multiple cerebral infarctions and dementia associated with anticardiolipin antibodies. Stroke 1987; 18:1107–1112. Kalashnikova LA, Nasonov EL, Kushekbaeva AE, Gracheva LA. Anticardiolipin antibodies in Sneddon’s syndrome. Neurology 1990; 40:464–467. Chapman JA-K. Prevalence and clinical features of dementia associated with the antiphospholipid syndrome and circulating anticoagulatns. J Neurol Sci 2002; 203–204(C): 81–84. Rebollo M, Val JF, Garijo F, Quintana F, Berciano J. Livedo reticularis and cerebrovascular lesions (Sneddon’s syndrome). Clinical, radiological and pathological features in eight cases. Brain 1983; 106:965–979. Brandt KD, Lessell S, Cohen AS. Cerebral disorders of vision in systemic lupus erythematosus. Ann Intern Med 1975; 83:163–169.

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229. Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13:486–489. 230. Ingram SB, Goodnight SH Jr, Bennett RM. An unusual syndrome of a devastating noninﬂammatory vasculopathy associated with anticardiolipin antibodies: report of two cases. Arthritis Rheuma 1987; 30:1167–1172. 231. Fulford KW, Catterall RD, Delhanty JJ, Doniach D, Kremer M. A collagen disorder of the nervous system presenting as multiple sclerosis. Brain 1972; 95:373–386. 232. Tellez-Zenteno JF, Remes-Troche JM, Negrete-Pulido RO, Davila-Maldonado L. Longitudinal myelitis associated with systemic lupus erythematosus: clinical features and magnetic resonance imaging of six cases. Lupus 2001; 10:851–856. 233. Hasselaar P, Derksen RH, Blokzijl L, de Groot PG. Crossreactivity of antibodies directed against cardiolipin, DNA, endothelial cells and blood platelets. Thromb Haemostasis 1990; 63:169–173. 234. Walker TS, Triplett DA, Javed N, Musgrave K. Evaluation of lupus anticoagulants: antiphospholipid antibodies, endothelium associated immunoglobulin, endothelial prostacyclin secretion, and antigenic protein S levels. Thromb Res 1988; 51:267–281. 235. Hess DC, Sheppard JC, Adams RJ. Increased immunoglobulin binding to cerebral endothelium in patients with antiphospholipid antibodies. Stroke 1993; 24:994–999. 236. D’Cruz DP, Houssiau FA, Ramirez G, Baguley E, McCutcheon J, Vianna J, Haga HJ, Swana GT, Khamashta MA, Taylor JC. Antibodies to endothelial cells in systemic lupus erythematosus: a potential marker for nephritis and vasculitis. Clin Exp Immunol 1991; 85:254–261. 237. Davis WD, Brey RL. Antiphospholipid antibodies and complement activation in patients with cerebral ischemia. Clin Exp Rheumatol 1992; 10:455–460. 238. Cariou R, Tobelem G, Soria C, Caen J. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314:1193–1194. 239. Cariou R, Tobelem G, Bellucci S, Soria J, Soria C, Maclouf J, Caen J. Eﬀect of lupus anticoagulant on antithrombogenic properties of endothelial cells—inhibition of thrombomodulin-dependent protein C activation. Thromb Haemostasis 1988; 60:54–58. 240. Carreras LO, Vermylen JG. ‘‘Lupus’’ anticoagulant and thrombosis—possible role of inhibition of prostacyclin formation. Thromb Haemostasis 1982; 48:38–40. 241. Moreb J, Kitchens CS. Acquired functional protein S deﬁciency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: report of two cases. Am J Med 1989; 87:207–210. 242. Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ. Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro. J Clin Pathol 1993; 46:908–911. 243. Cosgriﬀ TM, Martin BA. Low functional and high antigenic antithrombin III level in a patient with the lupus anticoagulant and recurrent thrombosis. Arthritis & Rheum 1981; 24:94–96. 244. Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientiﬁc and Standardisation Committee of the ISTH. Thromb Haemostasis 1995; 74:1185–1190. 245. Jacobs BSL. Antiphospholipid antibody syndrome. Cur Treat Options Neurol 2000; 2:449– 458. 246. Prengler M, Pavlakis SG, Prohovnik I, Adams RJ. Sickle cell disease: the neurological complications. Ann Neurol 2002; 51:543–552. 247. Green MA, Noguchi CT, Keidan AJ, Marwah SS, Stuart J. Polymerization of sickle cell hemoglobin at arterial oxygen saturation impairs erythrocyte deformability. J Clin Invest 1988; 81:1669–1674. 248. Grotta JC, Manner C, Pettigrew LC, Yatsu FM. Red blood cell disorders and stroke. Stroke 1986; 17:811–817.

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249. Keidan AJ, Sowter MC, Johnson CS, Noguchi CT, Girling AJ, Stevens SM, Stewart J. Eﬀect of polymerization tendency on haematological, rheological and clinical parameters in sickle cell anaemia. Br J Haematol 1989; 71:551–557. 250. Powars D, Chan LS, Schroeder WA. The variable expression of sickle cell disease is genetically determined. Semin Hematol 1990; 27:360–376. 251. Ohene-Frempong K. Stroke in sickle cell disease: demographic, clinical, and therapeutic considerations. Semin Hematol 1991; 28:213–219. 252. Styles LA, Hoppe C, Klitz W, Vichinsky E, Lubin B, Trachtenberg E. Evidence for HLArelated susceptibility for stroke in children with sickle cell disease. Blood 2000; 95:3562–3567. 253. Merkel KH, Ginsberg PL, Parker JC Jr, Post MJ. Cerebrovascular disease in sickle cell anemia: a clinical, pathological and radiological correlation. Stroke 1978; 9:45–52. 254. Rothman SM, Fulling KH, Nelson JS. Sickle cell anemia and central nervous system infarction: a neuropathological study. Ann Neurol 1986; 20:684–690. 255. Wood DH. Cerebrovascular complications of sickle cell anemia. Stroke 1978; 9:73–75. 256. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288–294. 257. Miller ST, Macklin EA, Pegelow CH, Kinney TR, Sleeper LA, Bello JA, DeWitt LD, Gallagher DM, Guarini L, Moser FG, Ohene-Frempong K, Sanchez N, Vachinsky EP, Wang WC, Whethers DL, Younkin DP, Zimmerman RA, DeBaun MR. The Cooperative Study of Sickle Cell Disease. Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. J Pediatr 2001; 139:385– 390. 258. Kirkham FJ, Hewes DK, Prengler M, Wade A, Lane R, Evans JP. Nocturnal hypoxaemia and central-nervous-system events in sickle-cell disease. Lancet 2001; 357:1656–1659. 259. Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, Figueroa R, Litaker M, Thompson W, Hess D. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 1992; 326:605–610. 260. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a ﬁrst stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5–11. 261. Pavlakis SG, Bello J, Prohovnik I, Sutton M, Ince C, Mohr JP, Piomelli S, Hilal S, DeVivo DC. Brain infarction in sickle cell anemia: magnetic resonance imaging correlates. Ann Neurol 1988; 23:125–130. 262. Prohovnik I, Pavlakis SG, Piomelli S, Bello J, Mohr JP, Hilal S, DeVivo DC. Cerebral hyperemia, stroke, and transfusion in sickle cell disease. Neurology 1989; 39:344–348. 263. Stockman JA, Nigro MA, Mishkin MM, Oski FA. Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med 1972; 287:846–849. 264. Sultana C, Shen Y, Rattan V, Johnson C, Kalra VK. Interaction of sickle erythrocytes with endothelial cells in the presence of endothelial cell conditioned medium induces oxidant stress leading to transendothelial migration of monocytes. Blood 1998; 92:3924–3935. 265. Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood 2000; 96:2451–2459. 266. Portnoy BA, Herion JC. Neurological manifestations in sickle-cell disease, with a review of the literature and emphasis on the prevalence of hemiplegia. Ann Intern Med 1972; 76:643–652.

31 Genetic Causes of Stroke James F. Meschia Mayo Clinic, Jacksonville, Florida, U.S.A. Mayo Medical School, Rochester, Minnesota, U.S.A.

I. INTRODUCTION Studies of twins and other family structures have generally shown a tendency for stroke to cluster within families. Deﬁning the molecular basis for the inherited risk of so-called common stroke is a work in progress. Although the genetics of common stroke are reviewed, this chapter focuses mainly on known mendelian and mitochondrial disorders that cause ischemic stroke, hemorrhagic stroke, and cerebrovascular malformations. Some genetic disorders, such as sickle cell anemia and Fabry disease, have proven therapies, whereas others have no eﬀective treatment. However, it remains essential for physicians to diagnose even presently untreatable familial disorders. Early diagnosis of such genetic disorders spares patients from needless and potentially dangerous diagnostic tests and ineﬀective therapies. A precise diagnosis of a genetic disorder also permits rational family counseling.

II. IMPORTANCE OF A DETAILED FAMILY HISTORY When a patient with a mendelian or mitochondrial disorder presents with stroke, the diagnosis may be delayed because the family history has not been adequately taken or the clinical stroke phenotypes are not clearly recognized. When a patient presents to an emergency department with an acute stroke, medical attention is focused on reperfusion therapies. When the patient is subsequently admitted to the hospital ward, medical attention shifts to preventing recurrent strokes and nonneurological complications of stroke. Unfortunately, competing clinical priorities can lead to cursory family history taking. Obtaining an accurate family history is even more challenging when patients are rendered less reliable as historians because of neurological deﬁcits caused by the stroke. The most thorough way to record a proper family history is with the aid of a pedigree diagram (or family tree). Pedigree diagrams unambiguously show the genetic relatedness of family members who are aﬀected or unaﬀected by a given disease or condition. At ﬁrst, pedigree diagrams may look like arcane hieroglyphs. However, the proper use of basic pedigree symbols is easily grasped, and the symbols are standardized by international convention [1] (Fig. 1). 743

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Figure 1 Sample pedigree diagram showing a living male proband (arrow). The proband’s father died with the disease (solid square with slash). The proband’s mother is alive and does not have her son’s disease (open circle). The proband had one sister who died but did not share her brother’s disease (open circle with slash), and the proband has one living sister who shares his disease (solid circle).

A family history can be taken for virtually every patient (an exception would be an adopted, childless patient). There is value in drawing a pedigree diagram even if no one else in the family suﬀers from the same condition as the proband. For example, it is less likely that a patient has an autosomal dominant condition if six of six full siblings are unaﬀected than if two of only two siblings are unaﬀected. A pedigree diagram allows physicians to infer mode of inheritance. The basic modes of inheritance are autosomal dominant, autosomal recessive, X-linked, and mitochondrial. Autosomal dominant conditions can be passed from either the father or the mother to the next generation. When one parent is aﬀected by an autosomal dominant condition, members of a given sibship have a 50% chance of being aﬀected. Autosomal dominant disorders show a vertical transmission pattern of inheritance on pedigree diagrams. When both parents are carriers of an autosomal recessive mutation, members of a given sibship have a 25% chance of being aﬀected and a 50% chance of being a carrier of the mutation. Autosomal recessive disorders show a horizontal transmission pattern of inheritance on pedigree diagrams. X-linked disorders do not show father-to-son transmission. Also, with rare exceptions, only women transmit mitochondrial DNA mutations to subsequent generations. These rules are only approximations of inheritance patterns seen in clinical practice. For several reasons, including nonpaternity, competing mortality, variable penetrance of disease, and missing data on estranged or unknown family members, the pattern of inheritance in any given pedigree may not ﬁt neatly into one of the classical inheritance patterns. For some patients, a pedigree diagram is more helpful for excluding some modes of inheritance than for proving the actual mode of inheritance.

III. FABRY DISEASE Fabry disease is an X-linked storage disorder caused by mutations in the a-galactosidase A gene (Table 1). With an incidence of one case per 117,000 live births, Fabry disease is the second most prevalent metabolic storage disorder after Gaucher’s disease. Numerous causative mutations have been found in the a-galactosidase A gene. Patients with Fabry disease cannot metabolize globotriaosylceramide (Gb3) normally. The result is progressive lysosomal accumulation of Gb3 in vascular endothelial cells and smooth muscle cells.

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Table 1 Fabry Disease Mode of inheritance X-linked Neurological features Painful small-ﬁber peripheral neuropathy (often the presenting symptom) Small-vessel ischemic strokes Nonneurological features Reddish-purple angiokeratomas Progressive renal insuﬃciency with proteinuria Cardiomyopathy Myocardial infarction Tortuous retinal vessels Whorl keratopathy seen on slit-lamp examination

Deposits can be found in brain, myocardium, dorsal root ganglia, and the autonomic nervous system. Patients with Fabry disease who present with stroke often have symptoms unrelated to stroke. Fabry disease can cause a glove-stocking pattern of burning pain due to small-ﬁber peripheral neuropathy. Because small nerve ﬁbers are selectively involved, patients often have a grossly normal neurological examination and normal results on electromyography and nerve conduction studies. Most patients have proteinuria and progressive renal failure manifesting in the third through ﬁfth decades of life. The clinical diagnosis of Fabry disease is based on the presence of skin angiokeratomas, renal disease, and painful neuropathy. Ophthalmological examination, including a slit-lamp examination, is helpful in identifying hemizygous males and female carriers. Carriers of the mutation can have a distinctive but asymptomatic corneal dystrophy known as whorl keratopathy. However, in diﬀerential diagnosis, it must be kept in mind that prolonged amiodarone exposure can produce a phenocopy of the corneal dystrophy of Fabry disease. Electron microscopy can reveal suggestive deposits on skin biopsy samples. The diagnosis of Fabry disease is conﬁrmed by a blood test assessing a-galactosidase A activity. Stroke in patients with Fabry disease typically occurs by the third or fourth decade of life. The most common type of initial stroke is small-vessel ischemic stroke [2]. Stroke involvement does not appear to favor either the anterior or the posterior circulation. Both small- and large-artery ischemic strokes can occur by the ﬁfth decade of life. Hemorrhagic stroke has been described in patients with vertebrobasilar dilatation [3]. Most strokes appear to be related to in situ thrombosis of a small-caliber blood vessel rendered abnormal by Gb3 deposits. However, other potentially relevant factors likely to cause stroke may coexist in the same patient, particularly in patients over the age of 40 years. Many patients are hypertensive, and some have cardiac abnormalities, including myocardial infarction, valvulopathies, and arrhythmias. Replacement therapy with a-galactosidase A has been shown to reduce neuropathic pain and improve creatinine clearance in a randomized, double-blind, placebo-controlled study of 26 hemizygous men [4]. Enzyme-replacement therapy also causes signiﬁcant reductions in resting regional cerebral blood ﬂow [5]. The clinical signiﬁcance of this ﬁnding is unknown. Although thrombosis is common in Fabry disease, no antithrombotic treatment has been shown to be safe and eﬀective [6]. Long-term studies of the safety and eﬃcacy of enzyme replacement therapy have not yet been done. Gene therapy is now being tested [7].

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IV. MELAS Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited syndrome caused by mutations in mitochondrial DNA [8]. Hirano and Pavlakis [9] proposed the following clinical diagnostic criteria: stroke before age 40 years, encephalopathy characterized by seizures or dementia, and blood lactic acidosis or ragged red ﬁbers in skeletal muscle biopsy specimens (Table 2). The mitochondrial mutations that result in MELAS cause defects in the respiratory chain enzymes, particularly complex I. Substitution of an adenine for guanine at nucleotide position 3243 (A3243G) in the gene encoding tRNALeu(UUR) accounts for 80% of the cases of MELAS. Spontaneous A3243G mutations are rarely reported [10]. The phenotypic expression of the A3243G mutation is variable. Although MELAS is the most common phenotype for mitochondrial A3243G, the mutation can present as chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, or diabetes mellitus, with or without deafness [11]. Other gene defects that can cause MELAS include a mutation at position 3260 [12] and the C3256T mutation in the tRNALeu(UUR) gene [13], as well as large-scale mitochondrial DNA deletions [11]. There have been promising open-label pharmacological trials [14], but to date there is no clearly established treatment for MELAS. In patients with recurring seizures, anticonvulsants other than valproate should be used, because valproate can cause a severe paradoxical reaction in which patients develop repeated convulsions [15].

V. CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a stroke syndrome caused by mutations in Notch 3 [16], a gene encoding the large Notch 3 transmembrane receptor. The function of the human Notch 3 receptor is not precisely known. Studies in animals suggest that the Notch 3 gene plays an important role in development of the central nervous system [17]. The Notch 3 mutations

Table 2 Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Mode of inheritance Maternal Clinical features Onset of stroke before age 40 years Focal or generalized seizures Migraine headaches Vomiting Dementia Blood lactic acidosis Radiographic features Brain MR imaging typically shows lesions involving occipital lobes Lesions are not limited to speciﬁc vascular territories such as the posterior cerebral artery Pathological features Ragged red ﬁbers on muscle biopsy MR, magnetic resonance.

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that cause CADASIL are highly stereotyped missense mutations within epidermal growth factor (EGF)–like repeats in the extracellular domain of Notch 3. Mutations lead to loss or gain of a cysteine residue and an odd number of cysteine residues within a given EGF domain [18]. Joutel and colleagues [19] have found that Notch 3 expression is restricted to smooth muscle cells and that the Notch 3 receptor normally undergoes proteolysis, thereby generating a 210 kDa extracellular fragment and a 97 kDa intracellular fragment. Patients with CADASIL have prominent accumulation of the Notch 3 ectodomain (i.e., the 210 kDa fragment) within the cerebrovasculature. This appears to be due to impaired clearance of the receptor from the surface of vascular smooth muscle cells and pericytes rather than from increased production of receptors. Most cases are inherited in an autosomal dominant fashion, but a de novo symptomatic mutation Arg182Cys has been reported [20]. Stroke, dementia, psychiatric illness, and migraines are common features of CADASIL (Table 3). In a study of 102 patients from 29 families, 71% of patients presented with recurrent transient ischemic attacks or ischemic stroke (mean age at onset, 46.1 years) [21]. Cognitive deﬁcits were present in 48% of patients. More than 80% of the patients with dementia also had gait disorder, urinary incontinence, or both. A total of 39% of patients had a history of migraine, and 87% of these had migraine with aura. The level of disability from the disease varied considerably, both within and among pedigrees. However, less than half of patients older than 60 years could walk without assistance. Magnetic resonance (MR) imaging of the brain plays a crucial role in raising a suspicion of CADASIL in the diagnostic process. Notable abnormalities in the white matter can be observed on MR imaging well before patients present with stroke or transient ischemic attack. Therefore, MR imaging is a useful screening test for presymptomatic carriers. A DNA test is commercially available for the most common Notch 3 mutations. However, this test currently has a false-negative rate of at least 20%, because it screens only mutational hot spots located in exons 3, 4, 11, and 18. Scanning all 23 exons that encode all 34 EGF-like repeat sequences is considered the most accurate test for CADASIL, but this is time-consuming and costly. It is also possible to secure a pathological diagnosis of CADASIL. Vascular osmophilic granules can be seen on electron microscopy in several tissues, including skin, muscle, and peripheral nerves [22]. Even asymptomatic patients with minimal abnormalities on MR imaging can have characteristic granular electron-dense deposits in or near the outer side of

Table 3 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) Mode of inheritance Autosomal dominant Clinical features Ischemic strokes Migraine with aura Mood disorders Subcortical dementia (apragmatism and apathy) Radiographic features Brain MR imaging always abnormal after age 35 years Punctate hypointensities on T1-weighted MR images Hyperintensities on T2-weighted MR images correspond to T1 lesions Cortex and cerebellum rarely involved MR, magnetic resonance.

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the thickened basal lamina of vessels in the dermis [23]. Although skin biopsy is a convenient test and electron microscopic ﬁndings can be characteristic of the disease, false-negative skin biopsies have been reported [24]. Some investigators suggest that a leptomeningeal biopsy or a second skin biopsy should be considered if clinical suspicion for CADASIL is high and the ﬁrst skin biopsy is negative [24]. Recently, an immunostaining technique has been developed that uses murine monoclonal antibody 1E4 raised against EGF-like repeats 17–21. Skin biopsy immunostaining has a high sensitivity (96%) and speciﬁcity (100%) for diagnosing CADASIL [25]. There is no proven treatment for CADASIL. Platelet antiaggregate medications such as aspirin are often used in the hope of preventing thrombotic occlusion of thick-walled narrow cerebral blood vessels. However, the beneﬁts of platelet antiaggregates have not been established in patients with CADASIL. It has recently been observed that microbleeds can be seen on brain MR imaging in just under one third of symptomatic carriers of CADASIL mutations, suggesting that antithrombotic therapies might place patients at risk for intracranial hemorrhage. One study suggested an association between stroke and hyperhomocysteinemia in patients with CADASIL [26]. It remains to be established whether lowering homocysteine with vitamin supplementation reduces the risk of stroke in these patients.

VI. SICKLE CELL DISEASE Sickle cell disease is an autosomal recessive disorder in which valine is substituted for glutamic acid at position number 6 of the h-polypeptide chain of hemoglobin. The disorder is most prevalent in patients of African or African American descent. The mutation causes polymerization or aggregation of abnormal hemoglobin within red blood cells. Patients commonly have compensated hemolytic anemia, mild jaundice, and vaso-occlusive crises that cause excruciating pain in the back, chest, and extremities. Many patients experience their ﬁrst stroke before entering elementary school. The Cooperative Study of Sickle Cell Disease, a multicenter study of about 4000 patients followed for up to 10 years from 1978 to 1988, found the ﬁrst incidence peak for stroke to be between ages 2 and 5 years [27]. The cumulative risk for ﬁrst-ever stroke was 11% by age 20 years and 24% by age 45 years. In children, ischemic stroke was more common than hemorrhagic stroke, but the reverse was true for ﬁrst-ever strokes occurring in patients older than 20 years. Previous transient ischemic attack, high systolic blood pressure, low hemoglobin levels, and frequent or recent acute chest syndromes were all risk factors for ischemic stroke. Low hemoglobin levels and increased white blood cell count were also identiﬁed as being risk factors for hemorrhagic stroke. The STOP trial showed that chronic transfusion therapy dramatically reduces the risk of ﬁrst-ever stroke in high-risk patients. In the STOP trial, about 2000 children between the ages of 2 and 16 years underwent screening with transcranial Doppler ultrasonography [28]. About 9% of the patients screened had time-averaged maximal mean velocities of >200 cm/s in either the middle cerebral artery or the internal carotid artery on the right or left side. Patients were randomly assigned to receive either episodic blood transfusions in accordance with standard care or chronic transfusion therapy intended to reduce hemoglobin S (HbS) to <30% of the total hemoglobin. The trial was halted ahead of the planned recruitment goal when 11 strokes were observed in the group that received standard care compared with only one stroke observed in the group that received systematic chronic transfusion therapy [29].

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Despite dramatic success in the STOP trial, chronic transfusion therapy has not been adopted universally because of the rigors of therapy. Children have to be transfused about once a month to achieve the target HbS levels. Chronic transfusion therapy also puts patients at risk for iron overload. Complexities of the therapy generally require that patients receive treatment under the care of an experienced pediatric hematologist. The eﬃcacy of chronic transfusion therapy for secondary prevention of stroke has not been as rigorously studied as its eﬃcacy for primary prevention. It might be anticipated that chronic transfusion therapy would be at least as eﬀective for secondary prevention as it is for primary prevention. The STOP trial showed that transfusion therapy lowered the risk of new silent infarcts and stroke in the 37% of patients who had clinically silent cerebral infarcts on baseline brain MR imaging [30]. Brain MR imaging can be used in combination with transcranial Doppler to stratify stroke risk. In addition to transfusion therapy, other therapies have been tried or considered for the neurological complications of sickle cell anemia. These include stem cell transplantation; hydroxyurea, which increases production of fetal hemoglobin; arginine diet supplementation, which increases nitric oxide production and may improve blood ﬂow; integrin receptor inhibitors; and encephaloduroarteriosynangiosis for moyamoya syndrome [31]. At present only chronic transfusion therapy has proven eﬃcacy.

VII. HOMOCYSTINURIA Homocystinuria is an autosomal recessive disease characterized by marked increase of homocystine in plasma and urine. The clinical phenotype includes mental retardation, thromboembolism, premature atherosclerosis, ectopia lentis, osteoporosis, and skeletal abnormalities. Homocystinuria is most commonly caused by homozygous defects in the gene encoding the enzyme cystathionine h-synthase. About 50% of patients have experienced a thromboembolic event by the age of 30 years. Homocystinuria can also be the result of a severe deﬁciency of methylenetetrahydrofolate reductase (MTHFR). Ideally, all newborns should be screened for homocystinuria. Pyridoxine-responsive patients are treated with pyridoxine (25–500 mg/day), folic acid (1–5 mg/day), and vitamin B12 (250 Ag to 2 mg/day). Pyridoxine-unresponsive patients are treated with a diet low in methionine and supplemented by cysteine, folate, and vitamin B12. Betaine, a methyl donor, is sometimes used as adjunctive therapy. Given the complexities of diet therapy, these patients are best managed with the assistance of a clinical geneticist. It is uncertain what the best antithrombotic therapy is, but antiplatelet therapy should be considered for every patient with homocystinuria and a history of ischemic stroke.

VIII. GENETIC RISK FACTORS FOR CEREBRAL VEIN THROMBOSIS From a genetic perspective, cerebral vein thrombosis has more in common with deep vein thrombosis than with ischemic stroke. Factor V Leiden is the most common inherited risk factor for deep vein thrombosis. The Leiden mutation is a single base substitution (G1691A) in the factor V gene that leads to the sequence change of Arg506Gln. The mutation destroys a cleavage site for the inactivating enzyme known as activated protein C. The factor V Leiden mutation is also a risk factor for cerebral vein thrombosis [32]. Martinelli and colleagues [33] found that the odds ratio for cerebral vein thrombosis for the factor V G1691A mutation was 7.8. Another mutation, the G20210A mutation in the 3V-untranslated

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region of the prothrombin gene, is also a risk factor for cerebral vein thrombosis. Martinelli and colleagues [33] found the odds ratio for having cerebral vein thrombosis to be 10.2 for patients who carried the prothrombin G20210A mutation. Use of oral contraceptives appears to compound the risk of cerebral vein thrombosis in patients with hereditary prothrombotic disorders. There was a striking interaction between the use of oral contraceptives and the risk conferred by having the prothrombin G20210A mutation, with an odds ratio of nearly 150 for cerebral vein thrombosis relative to risk in women who did not use oral contraceptives and who lacked the mutation [33]. In another study, the risk of cerebral vein thrombosis was 30-fold greater in women who used oral contraceptives and had a hereditary prothrombotic disorder, such as factor V Leiden or protein C, protein S, or antithrombin deﬁciency, than in women who had neither risk factor [34]. Every patient who presents with cerebral vein thrombosis should be asked whether they have a history of deep vein thrombosis or pulmonary embolism. Women of childbearing potential who present with cerebral vein thrombosis should be oﬀered testing for factor V G1691A and prothrombin G20210A. Those found to be carriers of either mutation should be advised to seek alternatives to oral contraception. Genetic counseling of family members should also be considered.

IX. CEREBRAL AMYLOID ANGIOPATHIES Cerebral amyloid angiopathies (CAAs) are deﬁned by the presence of amyloid deposits in cerebral blood vessels. Amyloid consists of proteinaceous ﬁbrils that form h-pleated sheets. Morphologically, amyloid deposits stain red with Congo red dye under routine light microscopy and apple green with Congo red dye under polarized light microscopy. The amyloid deposits are ﬂuorescent when stained with thioﬂavine S or T. Familial CAAs are classiﬁed according to the abnormally aggregated proteins (Table 4). A. HCHWA-D Hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D) is an autosomal dominant condition caused by a mutation in the gene that encodes amyloid precursor protein (APP). Speciﬁcally, it is due to a single amino acid substitution (glutamine for glutamic acid) at amino acid position number 22, which corresponds to a point mutation at base pair position 693 of the APP gene. As a rule, mutations within the APP coding region cause hemorrhagic strokes, and mutations outside the coding region are chieﬂy characterized by dementia. About two thirds of patients with HCHWA-D experience fatal intracerebral hemorrhage, and the remaining one third present with vascular dementia.

Table 4 Familial Cerebral Amyloid Angiopathies Associated with Intracranial Hemorrhage Disease HCHWA-D HCHWA-I Familial amyloid polyneuropathy

Gene defect(s)

Inheritance

Glu22Gln mutation in the APP gene Glu68Leu in the cystatin C gene Gly53Glu, Val30Met, and Phe64Ser point mutations in the transthyretin gene

Autosomal dominant Autosomal dominant Autosomal dominant

APP, amyloid precursor protein; HCHWA-D, hereditary cerebral hemorrhage with amyloidosis of the Dutch type; HCHWA-I, hereditary cerebral hemorrhage with amyloidosis of the Icelandic type (cystatin C–related).

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B. Cystatin C–Related Familial Cerebral Amyloid Angiopathy Cystatin C–related familial CAA is also known as hereditary cerebral hemorrhage with amyloidosis of the Icelandic type (HCHWA-I). It is an autosomal dominant disorder caused by a point mutation in codon 68 of the cystatin C gene located on chromosome 20p11.2 [35]. The mutation causes an amino acid change from leucine to glutamine. The amino acid substitution modiﬁes the structure of cystatin C by destabilizing a-helical structures and exposing the tryptophan residue to a more polar environment, yielding a more unfolded molecule [36]. This more open structure makes the variant cystatin C (C68Q) more amyloidogenic. About 17% of strokes in Iceland in patients under age 35 are due to HCHWA-I [37]. A majority of patients with HCHWA-I experience their ﬁrst stroke before age 30 years, and most patients die before the age of 50 years.

C. Familial Amyloid Polyneuropathy Several mutations in the transthyretin gene located on chromosome 18 typically cause familial amyloid polyneuropathy, which predominantly aﬀects small-ﬁber sensory nerves and autonomic nerves. The Phe64Ser mutation of the transthyretin gene causes oculoleptomeningeal amyloidosis and cerebral hemorrhage [38,39]. A case of fatal cerebral hemorrhage was described in a patient with a Val30Met mutation [40]. On autopsy, the patient had massive intracerebral hemorrhages involving frontal and occipital lobes and the pons. Two French siblings had recurrent subarachnoid hemorrhage due to the Gly53Glu transthyretin mutation [41].

X. CEREBROVASCULAR MALFORMATIONS A. Cerebral Cavernous Malformations Cerebral cavernous malformations (CCMs) have a prevalence of 0.1–0.5% in the general population [42]. They can be single or multiple and can cause hemorrhagic stroke. The lesions can also cause focal neurological deﬁcits without obvious hemorrhage and can act as an ictal focus [43]. Cavernous malformations can be sporadic or dominantly inherited. Three CCM loci have been mapped: CCM1 on 7q21-q22, CCM2 on 7p13-p15, and CCM3 at 3q25.2-q27 [44]. The genetic defects for CCM2 and CCM3 have yet to be discovered. However, the genetic defect for CCM1 is known. CCM1 is due to various mutations in the gene Krit1, which encodes for the Krev Interaction Trapped 1 (Krit1) protein. Krit1 has at least 16 exons that encode a 736-amino-acid protein. Krit1 mutations causing CCM1 include frame shifts, nonsense mutations, missense mutations, and invariant splice junction mutations. Frame shifts account for 50% of the observed mutations. The function of Krit1 is not known. Some investigators suspect that it is a tumor suppressor gene like the neuroﬁbromatosis 2 and retinoblastoma genes, because mutations are evenly distributed in the gene and are not limited to structural domains.

B. Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disease characterized by the classic triad of epistaxis,

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mucocutaneous telangiectasia, and a positive family history. Patients can have vascular malformations involving the lung, liver, gastrointestinal tract, or brain. Single or multiple arteriovenous malformations are the most common cerebrovascular malformation. At least two genetically distinct types of HHT have been characterized. HHT type 1 is caused by mutations in the endoglin gene located on chromosome 9q [45]. HHT type 2 is caused by mutations in the activin receptor–like kinase 1 (ALK1) gene located on chromosome 12q [46]. In both types of HHT, the mutations seem to cause disease through haploinsuﬃciency. Both endoglin and ALK1 are cell surface receptors involved in the transforming growth factor-h (TGF-h) signaling pathway. Mutations in the genes for endoglin and ALK1 lead to reduced levels of wild-type receptor concentrations on the surface of vascular endothelium [47]. The optimal management of arteriovenous malformations associated with HHT is not known. In one series of 321 consecutive patients, only seven patients (2.1%) presented with intracranial hemorrhage, and the hemorrhages were typically self-limiting [48]. In the same series, cerebral infarction and transient ischemic attacks were noted in nearly 30% of individuals. These events were attributed to paradoxical embolism by way of syndromic pulmonary arteriovenous malformations. Patients with HHT and cerebrovascular ischemic events should be evaluated for the possibility of ablation of pulmonary arteriovenous malformations.

C. Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous. At least two loci have been identiﬁed: PKD1 on chromosome 16p and PKD2 on chromosome 4q [49]. About 4–12% of patients with ADPKD have intracranial aneurysms compared to about 1% of the general population. ADPKD is not only a risk factor for intracranial aneurysms, but it is also a risk factor for ruptured aneurysms. Belz and colleagues [50] found that 5.5% of family members with ADPKD had deﬁnite, possible, or probable ruptured intracranial aneurysm compared to 0% of the other family members who did not have ADPKD. Monte Carlo statistical analysis showed that ruptured intracranial aneurysms tended to cluster within some of the ADPKD families, which might be due to the nature of the underlying ADPKD mutation speciﬁc to aﬀected pedigrees or to the eﬀects of as yet unidentiﬁed modiﬁer genes. The optimum protocol for screening for and treating unruptured aneurysms has yet to be deﬁned for patients with ADPKD. Magnetic resonance angiography and computed tomographic angiography can safely and eﬀectively identify aneurysms of 5 mm or greater. Serial angiography can identify the development of new aneurysms. A longitudinal MR angiography study of Japanese patients with APDKD identiﬁed new intracranial aneurysms in 2 of 15 patients over the course of 18–72 months of follow-up [51]. A practical recommendation is to screen for unruptured intracranial aneurysms in ADPKD patients who are older than 30 years and who have a ﬁrst-degree relative with a history of ruptured or unruptured aneurysms, with follow-up screening angiography every 5–10 years [52].

D. Moyamoya Disease Moyamoya disease is a speciﬁc cerebrovascular occlusive disease characterized by stenosis or occlusion of the terminal portions of the internal carotid arteries bilaterally, along with an abnormal vascular network near the arterial occlusion. Both familial and sporadic forms

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have been described. There is a considerably increased prevalence of the disorder in the Japanese population. The disease can aﬀect individuals of all ages, but the highest incidence peak occurs in children younger than 10 years. The disease is not associated with atherosclerosis. The abnormal arteries show ﬁbrocellular thickening of the intima with proliferated smooth muscle cells and prominently tortuous, often duplicated internal elastic lamina [53]. A recent microsatellite linkage analysis of 24 families containing 56 aﬀected patients revealed linkage with a marker on chromosome 17q25; however, the gene responsible for familial moyamoya disease remains to be identiﬁed [54]. Moyamoya syndrome shows the same cerebral angiographic characteristics as moyamoya disease, but is due to a known systemic disease process. Neuroﬁbromatosis, tuberosclerosis, and sickle cell anemia have all been associated with moyamoya syndrome. In a recent study of 43 patients with homozygous sickle cell anemia and one patient with sickle trait who had suﬀered strokes while under the age of 18 years, the presence of moyamoya syndrome as detected by cerebral angiography more than doubled the risk of recurrent cerebrovascular events (stroke or ischemic attack) [55]. This increased risk occurred despite chronic transfusion therapy. At present, it is unknown whether ﬁrst-degree relatives of patients with moyamoya disease should be screened for moyamoya. At least one small single-center study in Japan has suggested that MR angiography in asymptomatic relatives may have a high yield in identifying new cases. However, given the lack of a proven treatment for preventing stroke, routine screening of ﬁrst-degree relatives cannot be recommended [56].

XI. HEREDITARY ENDOTHELIOPATHY, RETINOPATHY, NEPHROPATHY, AND STROKE The syndrome of hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS) is a rare autosomal dominant disorder. The gene defect is not known, but HERNS has recently been linked to a locus on 3p21 [57]. In a family spanning three generations with 11 aﬀected members, visual impairment and renal dysfunction were the usual initial manifestations [58]. Ophthalmological ﬁndings include macular edema with capillary dropout and perifoveal microangiopathic telangiectasia. Hematuria and proteinuria are common. Neurological symptoms are similar to CADASIL and include migraine-like headaches, strokes, and psychiatric symptoms. Brain imaging shows contrastenhancing subcortical lesions.

XII. RISK FACTOR POLYMORPHISMS A. Polymorphisms in Thrombosis Genes Thrombosis has a central role in the pathophysiology of ischemic stroke. It is not surprising, therefore, that considerable eﬀort has been expended to examine genes that play a role in thrombosis—for example, those for ﬁbrinogen and platelet receptors—in order to identify polymorphisms that may predispose to ischemic stroke. Fibrinogen is a 340,000 Da glycoprotein consisting of three polypeptide chains: a, h, and g. The genes that encode these polypeptides reside in a cluster on chromosome 4q. Three European studies have investigated three diﬀerent polymorphisms within the h-ﬁbrinogen gene.

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Kessler et al. [59] studied the G455A polymorphism in 227 cases and 225 controls recruited from a single center in Greifswald, Germany. They did not ﬁnd an overall association of the polymorphism with stroke. However, heterozygosity for the A allele was more common in patients with large-vessel ischemic stroke ( p = 0.045). Schmidt et al. [60] studied the C148T polymorphism in a population-based crosssectional study of residents of Graz, Austria, aged 45–75 years. The focus of the study was carotid atherosclerosis and not ischemic stroke. Normal neurological status was a prerequisite for enrollment. Carotid atherosclerosis was seen in 53.6% of patients with the C/C genotype, 54.1% of those with the C/T genotype, and 88% of those with the T/T genotype ( p = 0.003). Abnormal results on carotid ultrasonography were signiﬁcantly more common in the T/T genotype group [odds ratio (OR), 6.29; 95% conﬁdence interval (CI), 1.91–20.71]. It remains to be seen whether the C148T polymorphism in the h-ﬁbrinogen gene is a risk factor for large-vessel ischemic stroke. That the risk of ischemic stroke is not simply related to degree of carotid atherosclerosis can be inferred from randomized clinical trials of carotid endarterectomy demonstrating a substantially greater risk of stroke in patients with highgrade symptomatic cervical carotid stenosis than in patients with high-grade asymptomatic stenosis [61,62]. Carter et al. [63] studied the G448A polymorphism of the h-ﬁbrinogen gene in 305 patients with stroke recruited from four hospitals in Leeds, England. They detected no diﬀerence in genotype distribution overall or relative to subtype of stroke as deﬁned by the Oxfordshire classiﬁcation system [64]. However, only 25% of the female patients were heterozygous at the h-ﬁbrinogen 448 site compared with 44% of the female control subjects ( p = 0.008). The investigators speculated that functional diﬀerences in the ﬁbrinogen molecule may play a more important role in determining stroke risk for women. Several platelet receptor polymorphisms, including the platelet glycoproteins (GP) Ia/IIa, Iba, and IIb-IIIa, have also been evaluated in relation to ischemic stroke (Table 5). GP Ia/IIa is involved in collagen-induced platelet aggregation. It does not bind collagen monomers, but it does bind collagen ﬁbrils and immobilized collagen. Carlsson et al. [65] studied the GP Ia (a2) C807T genotype distribution in 227 ischemic stroke patients compared with hospitalized patients without cerebrovascular disease and with healthy blood donors. Patients with transient ischemic attacks were included. No overall association between the polymorphism and stroke was seen. However, in patients 50 years of age or younger (n = 45), there was an overrepresentation of the C807T polymorphism compared with age-matched controls (OR, 3.02; 95% CI, 1.20–7.61). No such overrepresentation was detected in patients older than 50 years. GP Iba is a 143,000 Da transmembranous platelet glycoprotein that forms noncovalent complexes with GP Ibh, GP IX, and GP V to form the GP Ib-IX-V receptor, which is involved in shear stressinduced platelet activation by binding to von Willebrand factor

Table 5 Platelet Glycoprotein Receptors with Polymorphisms Possibly Associated with Ischemic Stroke Platelet GP

Alternate name

Function

Preferred ligand

Ia-IIa Iba (Ib-IX-V) IIb-IIIa

Integrin a2h1 (None) Integrin aIIbh3

Adhesion Adhesion Adhesion

Collagen vWF Fibrinogen

GP, glycoprotein; vWF, von Willebrand factor.

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(vWF). This receptor may be particularly relevant in large-vessel atherosclerotic ischemic stroke because high shear stresses like those seen in atherosclerotic carotid arteries increase ligand-receptor aﬃnity. The receptor may also have a role in so-called aspirin failure, in which patients suﬀer stroke despite taking daily aspirin for stroke prophylaxis. Cyclooxygenase inhibition by aspirin has little eﬀect on initial aggregation in response to shear forces. Gonzalez-Conejero et al. [66] conducted case-control studies of two GP Iba polymorphisms. The ﬁrst was a polymorphism termed ‘‘VNTR’’ because it consists of a variable number of tandem repeats of 39 base pairs, with each repeat leading to a 13-amino-acid addition that pushes a vWF-binding domain further away from the platelet membrane surface. The second was human platelet antigen-2 (HPA-2), which codes for either a thr (HPA-2a) or a met (HPA-2b) at position 145. The HPA-2 site resides next to the vWFbinding and high-aﬃnity thrombin-binding sites. The study enrolled 104 patients with cerebrovascular disease, of whom 31 had transient ischemic attacks. There was an association between the C/B genotype of the VNTR polymorphism and cerebrovascular disease (OR, 2.83; 95% CI, 1.16–7.07; p = 0.0114). There was also an association between the b allele of the HPA-2 polymorphism and cerebrovascular disease. Of the 104 patients with cerebrovascular disease, 22.11% carried at least one b allele, compared with 10.58% of controls (OR, 2.40; 95% CI, 1.04–5.63; p = 0.0244). Neither polymorphism showed signiﬁcant diﬀerences related to age, sex, or type of cerebrovascular disease. One intriguing ﬁnding of the Gonzalez-Conejero et al. study [66] was that both polymorphisms studied also correlated with coronary artery disease, but neither polymorphism correlated with deep vein thrombosis. This is the converse of what Ridker and others [67] found for factor V Leiden. Taken together, the studies suggest that polymorphisms predisposing to arterial thrombosis may diﬀer from those predisposing to deep vein thrombosis. GP IIb/IIIa is a transmembranous heterodimer with several ligands, including ﬁbrinogen, ﬁbrin, ﬁbronectin, and vWF. Many receptors are involved in platelet adhesion, and many agonists stimulate platelet aggregation, but platelet aggregation requires GP IIb/IIIa. When platelets aggregate, GP IIb/IIIa binds to ﬁbrinogen and vWF. Binding to vWF gains importance under conditions of high shear stress. A European study of 505 patients with cerebral infarction conﬁrmed by computed tomography showed no association between the P1A2 polymorphism of the GP IIb/IIIa gene and stroke overall [68]. However, a subgroup analysis showed signiﬁcant genotype distribution diﬀerences in nonsmokers. The risk of stroke was greater in nonsmokers heterozygous for the P1A2 allele than in those homozygous for P1A2 (OR, 2.37; 95% CI, 1.19–4.74; p = 0.01). Information on young stroke patients was limited (n = 37), but in a logistic regression model that included status regarding P1A genotype, smoking, hypertension, and diabetes, the OR for stroke in those possessing the A2 allele was 1.68 (95% CI, 1.00–2.82; p = 0.05). This study highlights the need for further studies of the interaction between genes and environmental factors, in this case smoking, in attempts to elucidate inherited stroke risk.

B. Apolipoprotein E The apolipoprotein E gene (APOE) has been studied extensively with regard to its relationship to cerebrovascular diseases. Most studies have focused on the relationship between APOE alleles and intracerebral hemorrhage. Speciﬁc APOE genotypes correlate with risk of Alzheimer’s disease. Because Alzheimer’s disease is associated with an amyloid

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deposition in sporadic cases of cerebral amyloid angiopathies, it has been assumed that there would be an association between APOE alleles and intracerebral hemorrhage. However, not all sporadic cases of cerebral amyloid angiopathy are neuropathologically homogeneous, and APOE alleles may be more of a risk factor for certain neuropathological types of CAA. For example, in a neuropathological study of 41 cases of CAA, Thal and colleagues [69] described two distinct types. In Type 1 CAA, cortical capillaries showed evidence of involvement with amyloid-h protein deposition. Type 2 CAA did not show deposition in cortical capillaries. This study demonstrated that the APOE q4 allele (apoE4) was four times more frequent in type 1 CAA than in type 2 CAA. Such studies suggest that apoE4 is predominantly a risk factor for vessel-speciﬁc amyloid deposition. Many investigators have found an association between the apoE2 and apoE4 alleles and incidence of recurrence of lobar intracerebral hemorrhage. In a hospital-based regional study comparing 188 cases of intracerebral hemorrhage (67 lobar, 121 nonlobar) with population-based controls, Woo and colleagues [70] found that apoE2 and apoE4 alleles were signiﬁcant independent risk factors for lobar intracerebral hemorrhage. The attributable risk of E2-E4 alleles for lobar intracerebral hemorrhage was 29%. O’Donnell and colleagues [71] conducted a prospective longitudinal study of 71 patients with lobar intracerebral hemorrhage. A total of 19 cases had recurrent intracerebral hemorrhage. Carriers of apoE4 or apoE2 had a risk ratio of 3.8 relative to patients who had the E3/E3 genotype. It should be noted that not all studies demonstrate a clear relationship between APOE genotype and intracerebral hemorrhage [72]. The diﬀerence may relate to whether investigators clearly distinguished between lobar and nonlobar intracerebral hemorrhage. There has been a suggestion that APOE genotype also correlates with ischemic stroke risk. In a meta-analysis of nine case-control studies of apoE4 and ischemic stroke, McCarron and colleagues [73] demonstrated a relative overrepresentation of apoE4. Aﬀected patients had an apoE4 allele frequency of 0.14 versus a control frequency of 0.09 (OR, 1.68). However, the same systematic overview found no protective eﬀect for the apoE2 allele. The way in which APOE alleles might relate to ischemic stroke is less clear than the potential relationship between APOE genotype and intracerebral hemorrhage. Slooter and colleagues [74] performed a cross-sectional study on 5401 subjects to investigate the relationship between APOE genotype and carotid atherosclerosis. The investigators did not ﬁnd an increase in frequency of carotid atherosclerosis among members of the group who had the E4/E4 genotype. Romas and colleagues [75] were not able to demonstrate a relationship between APOE genotype and plasma lipoproteins in a population-based study of elderly inhabitants of New York City. If, in fact, APOE genotype correlates with ischemic stroke risk, it does not appear to operate through traditional atherosclerotic risk factors. Studies diﬀer on the question of whether APOE genotype aﬀects poststroke survival. Weir and colleagues [76] studied 529 patients with ischemic stroke and found an association between apoE4 dose (i.e., presence of zero, one, or two alleles) and the risk of death. The association was found with or without adjustment for baseline stroke severity (according to the National Institutes of Health Stroke Scale). Catto and colleagues [72] did not ﬁnd an association between APOE genotype and survival in a study of 592 cases of acute ischemic stroke. In a retrospective subgroup analysis of the National Institute of Neurological Disorders and Stroke tissue plasminogen activator (t-PA) stroke trial [77], the eﬃcacy of intravenous t-PA appeared to be enhanced in patients with acute ischemic stroke who were positive for the apoE2 allele. There was no detectable relationship between apoE4 status and clinical outcome.

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39. Uitti RJ, Donat JR, Rozdilsky B, Schneider RJ, Koeppen AH. Familial oculoleptomeningeal amyloidosis: report of a new family with unusual features. Arch Neurol 1988; 45:1118–1122. 40. Sakashita N, Ando Y, Jinnouchi K, Yoshimatsu M, Terazaki H, Obayashi K, Takeya M. Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhage. Pathol Int 2001; 51:476–480. 41. Ellie E, Camou F, Vital A, Rummens C, Grateau G, Delpech M, Valleix S. Recurrent subarachnoid hemorrhage associated with a new transthyretin variant (Gly53Glu). Neurology 2001; 57:135–137. 42. Rigamonti D, Hadley MN, Drayer BP, Johnson PC, Hoenig-Rigamonti K, Knight JT, Spetzler RF. Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 1988; 319:343–347. 43. Labauge P, Laberge S, Brunereau L, Levy C, Tournier-Lasserve E. Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Soc¸iete´ Franc¸aise de Neurochirurgie. Lancet 1998; 352:1892–1897. 44. Verlaan DJ, Davenport WJ, Stefan H, Sure U, Siegel AM, Rouleau GA. Cerebral cavernous malformations: mutations in Krit1. Neurology 2002; 58:853–857. 45. McAllister KA, Lennon F, Bowles-Biesecker B, McKinnon WC, Helmbold EA, Markel DS, Jackson CE, Guttmacher AE, Pericak-Vance MA, Marchuk DA. Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype. J Med Genet 1994; 31:927–932. 46. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE, Attisano L, Kucherlapati R, Porteous ME, Marchuk DA. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13:189–195. 47. Amin-Hanjani S. The genetics of cerebrovascular malformations. Sem Cerebrovasc Dis Stroke 2002; 2:73–81. 48. Maher CO, Piepgras DG, Brown RD Jr, Friedman JA, Pollock BE. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke 2001; 32:877–882. 49. McConnell RS, Rubinsztein DC, Fannin TF, McKinstry CS, Kelly B, Bailey IC, Hughes AE. Autosomal dominant polycystic kidney disease unlinked to the PKD1 and PKD2 loci presenting as familial cerebral aneurysm (lett). J Med Genet 2001; 38:238–240. 50. Belz MM, Hughes RL, Kaehny WD, Johnson AM, Fick-Brosnahan GM, Earnest MP, Gabow PA. Familial clustering of ruptured intracranial aneurysms in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2001; 38:770–776. 51. Nakajima F, Shibahara N, Arai M, Gohji K, Ueda H, Katsuoka Y. Intracranial aneurysms and autosomal dominant polycystic kidney disease: followup study by magnetic resonance angiography. J Urol 2000; 164:311–313. 52. Mariani L, Bianchetti MG, Schroth G, Seiler RW. Cerebral aneurysms in patients with autosomal dominant polycystic kidney disease—to screen, to clip, to coil? Nephrol Dial Transplant 1999; 14:2319–2322. 53. Fukui M, Kono S, Sueishi K, Ikezaki K. Moyamoya disease. Neuropathology 2000; 20(suppl):S61–S64. 54. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, Inoue T, Ikezaki K, Matsushima T, Fukui M. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000; 31:930–935. 55. Dobson SR, Holden KR, Nietert PJ, Cure JK, Laver JH, Disco D, Abboud MR. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002; 99:3144–3150. 56. Houkin K, Tanaka N, Takahashi A, Kamiyama H, Abe H, Kajii N. Familial occurrence of moyamoya disease: magnetic resonance angiography as a screening test for high-risk subjects. Child Nerv Syst 1994; 10:421–425. 57. Ophoﬀ RA, DeYoung J, Service SK, Joosse M, Caﬀo NA, Sandkuijl LA, Terwindt GM, Haan J, van den Maagdenberg AM, Jen J, Baloh RW, Barilla-LaBarca ML, Saccone NL, Atkinson

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32 The Relationship Between Stroke and Migraine Mark Gorman Yale University School of Medicine, New Haven, CT, U.S.A.

Steven R. Levine and Paul Hart The Mount Sinai School of Medicine, New York, New York, U.S.A.

Nabih M. Ramadan Rosalino Franklin University of Medicine and Science, Chicago, IL, U.S.A.

I. INTRODUCTION Despite tremendous advances in the neurosciences of migraine and stroke, the relationship between these two conditions remains to be fully elucidated. For example, the exact pathophysiological basis for cerebral infarction during the course of a true migraine attack is still an enigma to be unraveled. Occasional clues are provided to us. We will review the evidence to suggest that such strokes may indeed occur, given the limits of our current knowledge, although this exact scenario is quite rare, overdiagnosed, of uncertain mechanism(s), and generally carries an excellent prognosis. The terms migrainous stroke or migraine stroke have been used to label strokes in patients with migraine and no other explainable cause, even if the stroke began without a typical migraine aura. However, given the prevalence of both disorders (stroke in young people over age 25 = 5–8/1000 and migraine f6% in men and 15–17% in women), coincidental occurrence is to be expected. The relationship between migraine and stroke has fascinated clinicians for over 100 years. The ﬁrst report of such a possible association was by Charcot [1,2], who observed that the transient neurological deﬁcits of migraine could remain permanently. The International Headache Society (IHS) classiﬁcation is an operant deﬁnition designed for further study, research, and treatment protocols. Limited to a single consensus perspective on this clinical dilemma, it provides an opportunity to more rigorously and narrowly deﬁne and organize the condition. Headache is a common symptom of both transient ischemic attack (TIA) and stroke. Distinguishing between migraine with transient neurological dysfunction (aura) and TIA or stroke with headache is, at times, clinically challenging, especially if the aura symptoms are atypical. Generally diﬀerences are clear. A migrainous aura tends to have positive phenomena (scintillations, fortiﬁcation spectra, paresthesias, etc.) arising solely from or 763

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preceding negative phenomena (scotoma or hemianopia), while TIAs are generally associated with a loss of function. The aura of migraine does not respect vascular borders. It generally progresses at a steady pace (f2–3 mm/min) and then resolves at a similar pace, the entire episode lasting approximately 20–30 minutes. This is in contradistinction to the pace and progression of stroke, which typically has an acute onset of maximal severity, respecting vascular boundaries, with a stable deﬁcit that sometimes resolves. Strokes infrequently occur in close temporal connection to migraine headaches, and the etiology is rarely secure. These occurrences are often referred to as migrainous stroke. Interestingly, migraine headaches appear to decrease signiﬁcantly both in frequency and severity following migrainous stroke [3]. Although the focal neurological symptoms associated with migraine are most commonly visual, within the vascular territory of the posterior cerebral artery, ischemic strokes attributed to the migrainous process most commonly have been reported to occur within the territory of the middle cerebral artery [4].

II. ASSOCIATION BETWEEN STROKE AND MIGRAINE Why should an association between migraine and stroke be suspected? During the course of migraine with aura (MA), patients experience transient focal neurological deﬁcits that may mimic transient ischemic attacks: monocular or homonymous hemianopic visual loss, diplopia, somatosensory disturbances, memory loss (transient global amnesia), aphasia, and focal weakness that virtually always resolves completely. There are rare patients, however, whose focal neurological deﬁcits persist following a typical migraine attack, and these deﬁcits may become permanent. It is this unusual patient, in the absence of other stroke risk factors, that supports the association of migraine leading to stroke. However, patients reported in the literature with stroke attributed to migraine often have had one or more other possible confounding factors, such as cigarette smoking, hypertension, hyperlipidemia, atherosclerotic cerebrovascular disease, arterial dissection, oral contraceptive use, antiphospholipid antibodies (aPL), or cardiac disease [5]. Also, some patients have their ﬁrst migraine-like headache at the time of their ischemic stroke and were labeled migraine stroke [6]. Data from the clinical observations of patients in the throes of a migraine attack associated with focal neurological deﬁcits, with or without alterations in level of consciousness, combined with speciﬁc abnormalities on cerebral blood ﬂow, computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), conventional cerebral angiography, and platelet function studies, taken together implicate the migrainous process as being responsible for stroke. However, it is uncertain whether the migrainous process primarily and directly causes ischemic or infarcted brain or if the stroke in the setting of migraine is secondary to arterial or hematological dysfunction triggered by a cascade of events from, or as an abnormal response to, the migraine. A. Migraine with Aura The aura of migraine has been considered a focal neurological deﬁcit of presumed ischemic origin. Detailed studies of regional cerebral blood ﬂow (rCBF) during the migraine ictus have documented signiﬁcantly reduced areas of rCBF into the oligemic range, suggesting that the migrainous process can be associated with rCBF low enough to cause ischemic

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focal neurological deﬁcits [7,8]. Most authorities now believe that this vascular response comes after a primarily neuronal aberration. O’Brien [9] ﬁrst demonstrated global oligemia that persisted beyond the brief period of the migraine aura’s focal symptoms. Oleson et al. [7] reported rCBF changes in some, but not all, patients with MA that were consistent with focal hyperemia, then subsequent spreading oligemia, and impaired activation of rCBF. Levels of oligemia were subsequently shown to be low enough to produce ischemic symptoms [8]. The headache of the migraine attack is generally ipsilateral to the rCBF decrease [7]. Some argue that only patients with MA can truly have a migraine stroke [10]. There is evidence from conscious rats [11] that there is a period of up to 3 hours of reduced CBF following spreading cortical depression (SCD) of Leao. The spreading cortical depression ﬁrst appeared in the parietal and frontal cortex and spread to involve the occipital cortex. A 35% ﬂow reduction occurred 4 minutes after the onset of SCD and persisted for at least 1 hour, returning to control CBF 200 minutes after the onset of SCD. (This is apparently the opposite of the direction of rCBF changes in MA.) The underlying vascular tone is a factor in determining the microcirculatory response to SCD. If spreading cortical depression is truly involved in the human migrainous process, as some have speculated [12–14], then the basis for a persistent focal neurological deﬁcit resulting from prolonged brain ischemia may be a direct consequence of the neuronal depolarization and spreading depression. B. Asymmetries of Cerebral Blood Flow and Altered Cerebral Blood Flow Regulation There is evidence that rCBF patterns between migraine attacks diﬀer between migraineurs and nonmigraineurs [10]. Migraineurs have more frequent rCBF asymmetries, suggesting altered CBF regulation and perhaps more labile interictal CBF control. Interictal rCBF has also been compared between late-onset migraine equivalents [15] and patients with vertebrobasilar TIAs, with the two groups diﬀering in the degree of rCBF asymmetries. In spontaneous MA or attacks triggered by angiography, rCBF was reduced in cortical regions not necessarily within the territory of a single cerebral artery [10,16]. The rCBF reduction can last up to 3 hours after symptom onset [17]. CBF abnormalities have been well documented in migraine by a variety of methods [rCBF by radionuclide inhalation, single-photon emission computed tomography (SPECT), and positron emission tomography (PET)] [18]. Despite methodological limitations and occasional contradictory conclusions, certain generalities appear well validated and widely agreed upon. CBF abnormalities generally begin focally, spreading slowly (about 2–3 mm/min) outward without regard to vascular territories and even to the other hemisphere (in some cases bilateral at onset) [19]. Some cases of a transient initial hyperemia have been noted, but almost all studies reveal a spreading hypoperfusion (including following the initial hyperemia in those few cases) lasting hours, at times apparently reaching ischemic levels. The areas involved and the degree of hypoperfusion appears to correlate well with the symptoms of aura, although the hypoperfusion may precede the aura and last longer than the neurological symptoms. This is followed by slow transition to regional hyperperfusion, which then subsequently normalizes. These changes are most clearly demonstrated in MA and are less prominent (or absent) in migraine without aura (MWOA). The pain of the headache correlates to some degree with location of the CBF abnormality, but its temporal relationship is variable, with headache generally beginning in the hypoperfusion phase and subsequent hyperperfusion lasting well beyond

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resolution of the pain. There is also evidence for abnormal circulatory regulation in migraineurs interictally, which may play a role in their propensity towards stroke in addition to the hypoperfusion noted in the course of an attack of migraine with aura. C. Migraine and Platelet Activity It is still unclear whether migraine contributes to changes in platelet function, if platelets play a role in triggering migraine, or if migraine and platelet activity are independent [20]. D. Migraine and Coagulation Alterations of the hemostatic system have been investigated in migraine. While some evidence for abnormalities of the coagulation cascade have been documented in migraine (see below), a strong and consistent relationship remains to be established [21]. Prothrombotic genetic risk factors do not seem to play an important role [22]. Recent data suggest that von Willebrand factor (vWF), an endothelial cell procoagulant, is elevated in migraineurs (primarily women) with a history of stroke compared to controls. Also, vWF antigen and activity levels were higher in migraineurs without stroke [23]. Prior work had suggested that elevated levels of vWF may be an acute phase reactant during a migraine attack. These data suggest that the elevated interictal levels are sustained. As some data suggest, the elevated vWF may be an independent risk factor for stroke. These data further support a coagulation-based link in migraine-stroke. Elevated prothombin factor 1.2 (F1.2), a cleavage product of prothrombin and a sensitive and speciﬁc marker of ongoing thrombin generation, was found to be elevated in 50% of MAs compared to no MWOA without aura or controls [24]. Despite anecdotal data suggesting a link between antiphospholipid antibodies and migraine, the largest prospective study to date [25] failed to conﬁrm this relationship in subjects fulﬁlling IHS criteria for migraine. However, among those with transient focal neurological events, those who were anticardiolipin antibody (aCL) positive were more likely to have evidence of an appropriate lesion on CT or MRI (blinded review) compared to those without aCL. In a retrospective review of patients attending a single headache clinic, those with livedo reticularis were more likely to have a history of migraine compared to those without the skin disorder [26]. E. Migraine and Cerebral Embolism An association between patent foramen ovale (PFO) and transient global amnesia (TGA) has been noted [26a]. The authors reported that twice as many patients with MA (48%; 54/ 113) as controls (20%) were found to have a PFO by transcranial Doppler with intravenous injection of agitated saline. More recently, it was reported that closure of PFO or anticoagulation therapy reduced the incidence of migraine with aura attacks and stroke [26b,26c]. F. Matrix Metalloproteinases Matrix metalloproteinases may be released during cortical spreading depression (Moskowitz M. presentation at the 2003 American Headache Society Meeting), which could damage the basal lamina, increase the blood-brain barrier permeability, and predispose the migraine brain to recurrent neuroinﬂammation and possibly stroke [26d].

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G. Migraine-Vasospasm Evidence of cerebral arterial vasospasm occurring during a migraine episode has come primarily from arteriographic studies that have shown focal, multifocal, or diﬀuse segmental narrowing of the intracranial or extracranial vessels, long, smooth narrowing of the extracranial common and/or internal carotid artery, or ‘‘beading’’ [27]. Some, if not all, of the angiographic demonstration of migrainous vasospasm may be induced by the catheter procedure or by the contrast agent [10]. It is generally believed that angiography may precipitate migraine, migrainous stroke, and cerebral arterial vasospasm, although others did not ﬁnd an increased risk of angiography-related stroke among migraineurs compared with those not suﬀering from migraine [28]. In a 60-year-old patient with a history of MA, headaches provoked by swimming in cold water, MRA (6 days after onset and after use of ergotamine) revealed multiple branch narrowing and follow-up MRA was normal at day 71 [29]. H. Migraine and Dissection On the basis of a small case-control study, D’Anglejan-Chatillon et al. [30] suggested that patients with nontraumatic cerebral arterial dissection more commonly (20/50; 40%) had a history of migraine (independent of type, with 20% of migraineurs having an aura) and current oral contraceptive use than matched controls (24/100; 24%), the implication being that migraine may be a risk factor for dissection. However, the stroke occurred during a typical migraine attack in only three patients. If migraine is a risk factor for dissection and, therefore, for stroke, repeated episodes of migraine-induced vasoconstriction and vasodilatation may weaken the intimal-elastic lamina portion of the vessel and predispose to ‘‘spontaneous’’ dissection, This certainly does not explain all of the angiographic ﬁndings described in migrainous strokes, but it may help shed light on some. We have seen three patients with dissection in the context of a migraine-like headache attack (resulting in lasting focal neurological deﬁcits in one) [31]. I. Malignant Migraine with Coma One end of the spectrum of migraine may be an autosomal dominant form of cerebral edema associated with cerebrospinal ﬂuid pleocytosis and cerebellar ataxia [32,33]. J. Mitochondrial Encephalomyopathies with Stroke-Like Episodes Episodic headaches with vomiting are characteristic of several of the mitochondrial encephalomyopathies (MELAS) and are most often accompanied by other features Strokelike episodes involving hemiparesis, hemianopia, or cortical blindness occur, and focal lesions may be seen on CT [34,35]. However, these regions of focal encephalomalacia generally are not within a vascular distribution. It has been speculated that migraine may be a forme fruste of this family of mitochondrial disorders, and the more severe cases could possibly progress to migraine stroke. A defect in mitochondrial DNA has been proposed as the basis for migraine. It will be diﬃcult to ascertain whether patients with migraine stroke have cerebral angiopathy on the basis of a mitochondropathy. Many patients with severe migraine complain of weakness, but they do not have clinically evident myopathy as a rule. Against migraine stroke being a forme fruste of MELAS is the

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vascular distribution of most migraine strokes and the general lack of recurrent migraine strokes in the same individual. SPECT studies in patients with cerebral manifestations of MELAS are not typical of cerebral infarction from an occluded cerebral vessel. K. CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is a rare inherited disease characterized by subcortical infarction and migraine (generally with aura), as well as cognitive and emotional disturbances found in middle age. Little is known about its underlying progressive medium-sized vessel and arteriolar vasculopathy, although lesions indistinguishable from those of primary central nervous system angiitis have been reported [36] and the MRI picture typically has multiple subcortical infarctions and leukoencephalopathy. L. Familial Hemiplegic Migraine A rare subtype of MA characterized by long-lasting hemiplegic auras, familial hemiplegic migraine (FHM), is transmitted as an autosomal dominant trait linked to various mutations on both chromosomes 1 and 19 [37]. The gene product regulates a speciﬁc neuronal calcium channel (CACNA1A). How this calcium channel is involved in causing the migraine or other symptoms is unclear, but vascular changes consistent with basal vessel vasoconstriction and impaired perfusion as well as meningeal enhancement (felt to implicate inﬂammation) have been documented [38,39]. FHM has not been speciﬁcally linked to stroke. M. Migraine Aura Without Headache Migraine aura without headache (MAWH) is deﬁned as fulﬁlling the standard IHS criteria for migraine, not including headache. It was previously known as ‘‘migrainous accompaniments’’ [40], ‘‘acephalgic migraine’’ [41], and migraine equivalents. Despite a superﬁcial similarity, this entity seems to be clearly distinguishable from TIA. MAWH is typically characterized by a history of similar events; most of the symptomatology is positive (fortiﬁcation spectra, ﬂashing lights, etc.), mainly localizing to the posterior circulation. MAWH has a better prognosis than TIAs when patient groups are age- and gender-matched [42]. The duration of the attacks may be helpful as the large majority of TIAs last less than 10 minutes and MAWH tends to last 15–30 minutes. The presence of headache does not help diﬀerentiate the two entities. The syndrome of MAWH was ﬁrst coherently characterized by C. Miller Fisher [40]. Generally, the episodes begin after the age of 40 in patients without a personal history of migraine [40,41]. Family history of migraine occurs in only a quarter [41]. There may be an accompanying headache in approximately half, but these are generally milder and do not have typical migrainous features. Fisher felt that one could distinguish between migrainous accompaniments and TIA by the presence of visual symptoms [40,43]. Scintillating scotoma is a common and predominant symptom, and the ‘‘build-up’’ or ‘‘march’’ phenomena (now both attributed to spreading depression), both of which are characteristic of MA and may be more easily recognized as the aura without the headache, describe a characteristic progression either of symptoms in the visual ﬁeld, slowly changing over minutes, or the gradual change from one symptom, e.g., paresthesias to dysphasia.

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MAWH typically has a benign course, and recurrent events generally recede without sequelae within a few months [40,41]. Despite this general rule, the literature contains many reports of permanent deﬁcits occurring with an attack of migraine accompaniments [44,45]. N. Migraine and Intracerebral Hemorrhage Cole and Aube [46] postulate a relationship between migraine and intracerebral hemorrhage, speculating that vasospasm with necrosis of the cerebral vessel wall, with subsequent reperfusion rupturing the ischemic vessels, is the basis of the hemorrhage. Proof of true migraine-induced cerebral hemorrhage is lacking. Most cases probably represent symptomatic migraine or migraine mimics (such as occult cerebral vascular malformation).

III. MIGRAINE STROKE RESEARCH Neurological dysfunction caused by ischemic brain parenchyma within the middle cerebral artery territory has been the most common stroke syndrome attributed to migraine [47]. We are unaware of any report of migraine stroke in the territory of the anterior cerebral artery. Several large series [48,49] and reviews [47,50] have characterized the demographic, clinical, and radiological features of migraine stroke. The diagnosis of migraine stroke is reasonable only in patients who have had a typical history of recurring migrainous aura and when the stroke follows a typical attack that fails to reverse itself in the absence of another explanation for the event [51,52]. It is rare that migraine stroke is the heralding event of the migraine syndrome [27]. Caplan [27] concluded from a review of the literature on migraine stroke that posterior circulation ischemia is common in migraine and not always benign, aﬀects a wide age range, that the temporal pattern of ischemia varies widely, diﬀerent anatomical regions within the posterior circulation can be aﬀected, and the basilar and posterior cerebral artery can be occluded on angiography in migraine. Severe vertebral artery and basilar artery vasoconstriction does occur in migraine. Olesen et al [53] suggested that ischemiainduced migraine attacks (symptomatic migraine) may be more common than migraineinduced ischemia. A. Optic Nerve–Retinal Infarction Associated with Migraine Migraine stroke involving the anterior visual pathway is extremely rare, and, when reported, only a small fraction of these patients have been completely evaluated for other causes. The spectrum of migraine stroke in the anterior visual system includes central and branch retinal arterial occlusion, ischemic optic neuropathy, and central retinal vein occlusion. SCD can readily be produced in the animal retina. B. Computed Tomography Findings Migrainous cerebral infarction does not appear on CT to be diﬀerent in any important respect from infarcts from other causes, other than perhaps a relative lack of lacunar strokes attributed to migraine. We are unaware of any formal studies on this. Transient

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focal, low attenuation CT abnormalities have been reported in migraine as well, probably reﬂecting focal cerebral edema, reversible ischemia, or both.

C. Magnetic Resonance Imaging Findings MRI examination in some patients with migraine demonstrated small punctate or patchy white matter lesions, presumably ischemic, in up to 40% of those studied [33,54,66,67]. There may be a direct relationship between the number of migraine attacks and the number of MRI lesions seen. Lesions may be larger than 3 mm. They are predominately subclinical.

D. Angiographic Findings Cerebral angiography in migraine-related stroke has generally been normal, perhaps because of the delay from symptom onset to investigation. More rapid study may lead to a higher yield of angiographic abnormalities. When arterial occlusion has been demonstrated on cerebral angiography in stroke caused by migraine [4], the posterior cerebral artery is the most commonly occluded artery. Angiographic ﬁndings associated with migraine stroke include a pial arterial occlusion, diﬀuse spasm, intraluminal clot in the posterior cerebral artery either in the presence of normal-appearing artery or associated with more proximal focal dilatation and stenosis of the artery, extracranial carotid artery occlusion beyond the bulb, carotid stenosis-spasm, decreased ﬁlling of the major intracranial arteries, and even common carotid artery spasm with diﬀuse narrowing. Occasional reports have documented bilateral cerebral arterial abnormalities in migraine-associated cerebrovascular disease and some documented revascularization of a previously occluded posterior cerebral artery of integral carotid artery on follow-up cerebral angiography. Larger series of migraine stroke [6,48,49] have found normal angiograms in 19/22 [49], 7/12 (abnormalities consisting primarily of ‘‘spasm’’; 1 had posterior cerebral artery beading) [48], and 7/12 [6]. When angiography has been performed during a migraine attack or when angiography induced an attack, severe vasospasm can be seen [55]. In two patients with ophthalmoplegic migraine, internal carotid artery (ICA) siphon vasoconstriction was seen [56]. One critical issue is whether the vasospasm seen on angiography is a result of the migrainous process or the angiographic process itself (iatrogenic). MRA should help settle this important issue, as transcranial Doppler (TCD) could still show high CBF velocities in the absence of large-vessel vasoconstriction if the resistance vessels are altered. Spasm has been noted in all major arteries supplying the brain, brain stem, and cerebellum in association with migraine stroke [27]. There appears to be a propensity for the basilar artery and internal carotid artery tree. The diﬀerential diagnoses of ‘‘vasospasm’’ on angiography that should be considered before labeling a stroke migrainous are outlined in Table 1.

E. Autopsy Findings Only one case of fatal migraine stroke [57] has been reported to our knowledge. Unfortunately, the cerebral arteries were not reported to have been studied.

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Table 1 Diagnoses to Be Ruled Out in the Putative Setting of Migraine Stroke and Angiographic Evidence of ‘‘Vasospasm’’ Subarachnoid hemorrhage Cocaine (either alkaloidal or hydrochloride), amphetamines, LSD Medications: ergots, tryptans, oral contraceptives, phenylpropanolamine, selective serotonin reuptake inhibitors Alcohol or nicotine Central nervous system infection/pachymeningitis Toxemia of pregnancy, eclampsia/preeclampsia Cerebral arterial dissection Fibromuscular dysplasia Hypertensive encephalopathy Cerebral embolism Cerebral trauma Syndrome of reversible segmental cerebral vasoconstriction Connective tissue diseases: systemic lupus erythematosus, scleroderma Radiation arteropathy Malignant endotheliomatosis

F. Epidemiology: Does Having Migraine Put One at Higher Risk for Stroke? Both case-controlled studies and a large-scale epidemiological study reveal a signiﬁcant relationship between migraine and ischemic stroke [58–62] (Table 2). This relationship was stronger in MA (classic) than in MWOA (common) [58,60,62]. It is also higher for women under the age of 45. Most studies have a number of limitations. The majority of studies have been hospital-based. As migraine-stroke may only aﬀect vision, these patients may not be hospitalized. The combined studies suggest that the estimate for the incidence of ﬁrst-stroke in migraineurs is on the order of 15 per 100,000 women-years. Generally, the odds ratio of having an ischemic stroke for a migraineur varied between 1.5 and 2— perhaps higher in younger migraineurs (OR 3.3) [62a]—but there was no increased risk of hemorrhagic forms of stroke. Active migraine (as opposed to a history of migraine) has been found to be a much more prevalent risk factor in younger ischemic stroke patients (present in 14.9–29.3%) [59,60,63]. Also, migraine for more than 12 years duration and frequent attacks seems to increase the risk for ischemic stroke [63a]. Even a family history of migraine carries a greater risk of stroke (ischemic or hemorrhagic) [62]. A combination of two large epidemiological studies did not ﬁnd an increased risk of coronary heart disease in self-reported migraineurs [64], raising questions as to the role of atherosclerosis in strokes of migraineurs. The combination of a personal history of migraine headaches with smoking, oral contraceptive use, or hypertension increases the risk of stroke [60]. In one study the combination multiplies this risk (a combination of these four yields a 34-fold greater risk than a similarly aged female without these risk factors, for women aged 20–44) [62]. Another study documented a similar eﬀect of migraine on stroke risk, but found that it was only signiﬁcant in the absence of other risk factors (hypertension, diabetes mellitus, and smoking) [58], and in combination with other vascular risk factors it actually conferred a lower risk of stroke when compared to migraine alone in men aged 40–84 years [59]. A similar (nonsigniﬁcant) trend of the relative risk being most prominent in those patients without other stroke risk factors was found in other trials [59,60]. These ﬁndings seem to indicate that migraine is a more prominent risk factor in the young [65],

Year

2003

2002

1999

1998

1996

Author [Ref.]

Schwaag [62a]

Donaghy [63a]

Chang [62]

Mitchell [68]

Carolei [60]

Population-based >48 y CC HB(7) 47%F 15–44 y (mean 35.6) 1st TIA or stroke (IS) Excl: headache in TIA patient

CC as for Donaghy, 2002

CC HB(8) 100%F 20–44 y (mean 36.1) 1st-ever IS Excl: TIA, death within 24 hrs, menopause

CC HB(2) 47%F <46 y (mean35.1) 1st-ever TIA or IS Excl: D, HS, CVT, LS, MI

Study type

308 (27.6%) 591 (11.8%)

3654 (17%)

291 (25.4%) 736 (13%)

86 214

160 (23.1) 160 (12.5)

No. of patients + controls (%migraine)

Table 2 Studies on the Association Between Migraine and Stroke Quoting Odds Ratios

4.61 8.37 10.4 1.78 1.62 2.25 3.54 3.81 3.0 1.1 0.86 1.84 2.2 NS 1.7

1.9 1.2

F M

3.26 1.43 2.68 1.49 1.0 2.5

<35 35–46 F M MA+ MA Total group

Mig > 12 y Initial MA+ >12 attacks per year All stroke all patients All stroke MA+ All stroke MA IS all patients IS MA+ IS MA HS all patients HS MA+ HS MA >49 M >49 F Total group

2.11

OR

Total group

Total group + subgroups

1.1–3.1 NS

1.1–2.8

1.27–16.8 2.33–30.1 2.18–49.4 1.14–2.77 0.98–2.67 1.1– 4.63 1.3–9.61 1.3–11.5 0.7–13.5 0.63–1.94 0.44–1.67 0.77–4.39

1.33–7.98 0.63–3.22 1.25–5.75 0.54–4.11 0.28–3.53 1.3–6.3

1.16–3.82

95% CI

772 Gorman et al.

1995

1995

1993

1993

Lidegaard [70]

Buring [59]

Tzourio [71]

Marini [72]

CC HB ?%F 15–44 y TIA or IS within 8 weeks of admission 1 hospital + 1 population control

CC HB(5) 100%F 18–44 y 1st IS CC Register-based 100% F 15–44 y IS or TIA Patients entered into therapeutic trial 100% male 40–84 y Self-reported diagnosis of migraine 60-month F/U CC HB(2) 35.4% F 18–80 mean (56 y) IS Excl: TIA CVT

308

212

22071 (6.7%)

497 (13.7%) 1370 (4.1%)

72 (60%) 173(30%)

14.8

1.1 1.6 4.3 0.7 1.3 0.8

M F F<45 M<45 MA+ MA

MA+

1.3

RR 1.84 RR 2.0

2.8

Total group

Total stroke Ischemic stroke

Migraine > 1 month

3.7 5.2 1.5 3.5 6.2 3.0

0.5–2.2 0.7–3.5 1.2–16.3 p = 0.33 0.5–3.8 0.4–1.5

0.8–2.3

1.06–3.02 1.1–3.64

p < 0.001

1.5–9 1.4–20 0.9–2.5 1.8–6.4 2.1–18.0 1.5–5.8

Abbreviations: OR, odds ratio; CI, conﬁdence interval; n, number of patients and controls; CC, case control; HB, hospital-based; F, female; M, male; y, years; TIA, transient ischemic attack; IS, ischemic stroke; HS, hemorrhagic stroke; CVT, cerebral venous thrombosis; D, dissection; Excl, exclusion criteria; MA+, migraine with aura; MA, migraine without aura; RR, relative risk ratio; NS, not statistically signiﬁcant; F/U, follow-up.

1995

Tzourio [69]

Female <35 MA+ MA Total group MA+ MA

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Gorman et al.

Table 3 Classiﬁcation of Migraine Stroke I. Stroke and migraine coexisting II. Stroke with clinical features of migraine A. Established (symptomatic migraine) B. New onset (migraine mimic) III. Migraine-induced stroke (migraine stroke) A. Without known stroke risk factors present B. With known stroke risk factors present IV. Uncertain/complex/multiple factors

perhaps being overshadowed by stronger risk factors in older patients, and that perhaps its interaction with other stroke risk factors is stronger in women. The IHS has published criteria required to classify and diagnose migraine stroke (Tables 3 and 4). As there are no absolute criteria for the diagnosis of migraine and no speciﬁc or sensitive laboratory markers for the condition, the diagnosis remains a clinical judgment aided by published criteria; therefore, opinions may diﬀer concerning whether or not migraine is present in an individual. G. Migraine Following Stroke It has been our experience, as well as that of others, that true migraine appears to occur less intensely and less frequently following migraine-associated or migraine-‘‘induced’’ stroke. It is almost as if the process of cerebral arterial occlusion and subsequent infarction during the course of a migraine attack raises the threshold for subsequent migraine attacks or has eliminated or attenuated the vascular pain mechanisms. The neuronal and vascular structures that may be responsible for the initiating events of a migraine may be damaged or destroyed by the stroke.

IV. CONCLUSIONS AND SUMMARY Epidemiological evidence points to an association of migraine and stroke, with migraine being a risk factor for stroke. The direct pathophysiology of ischemic stroke and migraine headache appear divergent—ischemic stroke being directly related to vascular occlusion and migraine being a primary neurological event with secondary vascular changes. Strokes occur more frequently in migraineurs (coexisting stroke and migraine), migraine occurs in the setting of ischemic stroke (stroke with clinical features of migraine), and, rarely, strokes are a result of a migraine headache (migraine-induced stroke). The migraine aura has secondary vascular changes of hypoperfusion, which at times approaches ischemic levels. While the vast majority of migraineurs experience this without

Table 4 Criteria for Migraine Stroke 1. The neurological deﬁcit must exactly replicate the migrainous symptoms of previous attacks, only if it is not transient. 2. The stroke must occur during the course of a typical migraine attack. 3. All other causes of stroke must be excluded. Other known stroke risk factors may be present and interacting.

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Table 5 Criteria for Diagnosis of Late-Life Migraine Accompaniments 1. Scintillations or other visual display in the spell. Next most common symptoms (in order): paresthesias, aphasia, dysarthria, and paralysis. 2. Build-up of scintillations. 3. ‘‘March’’ of paresthesias. 4. Progression from one accompaniment to another, often without delay. 5. Occurrence of two or more identical spells. 6. Headache in the spell (50%). 7. Episodes last 15–25 minutes. 8. Characteristic mid-life ‘‘ﬂurry’’ of migrainous accompaniments. 9. A generally benign course. 10. Normal angiography. 11. Exclusion of other causes of stroke.

harm, a few have infarction that appears directly related to the migraine itself. The pathophysiology of rare migraine syndromes may shed some light on these infrequent occurrences, but is unlikely to explain the majority of migraine-stroke cases. It seems clear that many potential mechanisms could account for a migraine-stroke in any one individual and that several of these may interact at a particular moment to result in infarction [51]. To compound the issue, migraine, through anorexia, nausea, vomiting, and worsening of the headache with movement, can lead to dehydration, possibly contributing to a transient hypercoagulable state. A multifactorial mechanistic approach has been invoked to explain some cases of migraine stroke. When the correct concatenation of events occurs, ischemic infarction may result. The classiﬁcation of migraine and migraine stroke by the IHS may prove helpful both in guiding clinicians through a standardized diagnostic schema and in providing researchers with speciﬁc criteria for more homogeneous patient subgrouping for natural history, investigations into mechanisms, and response to treatment. Diﬀerentiating latelife migraine accompaniments from ischemic events is also important (Table 5). Why migraine-stroke ensues only rarely during episodes of a very common problem is still an enigma, but is possibly related to individual diﬀerences in coagulation status, cerebral hemodynamic reactivity, mitochondrial genetic material, the presence of other potential risk factors for stroke, and the interaction of each during a migraine attack. A putative scenario is: Migraine ! oligemia ! ischemia=cerebral edema ! platelet activation=increased aggregability ! vasospasm ! intraluminal arterial clot in cerebral pial artery ! infarction The process may stop at any point in an individual before stroke or, rarely, proceed all the way to stroke.

ACKNOWLEDGMENTS This work was supported, in part, by Public Health Service Grants (NIH) PO1 NS 23392, K24 NS43992, RO1 NS30896, and CDC U50/CCU520272. We thank Jerry Chao for help with literature reviews.

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33 Overview of Stroke in Children and Young Adults Michael Reardon Driscoll Children’s Hospital, Corpus Christi, Texas, U.S.A.

Katherine D. Mathews University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

I. ARTERIAL ISCHEMIC STROKE Medical professionals and laypersons alike tend to think of stroke as a disease of the elderly. When a young adult between the ages of 18 and 45 develops a sudden focal neurological deﬁcit, we immediately consider the possibility of a stroke. When a young child presents with a generalized tonic-clonic seizure, depressed level of conciousness, and dehydration, it may be only the most astute clinician who notices hemiparesis and recognizes that, while Todd’s paralysis and encephalitis are more common, this is also a typical presentation of childhood stroke. Arterial ischemic stroke occurs in 1–2 per 100,000 children under 18 years of age [1]. Among young adults it aﬄicts 14–62 per 100,000 per year [2]. Studies of predominantly Caucasian, middle class, North American populations consistently reproduce these numbers, but the rates of stroke are higher for some ethnic groups and geographic regions. In speciﬁc clinical populations, such as those with cyanotic congenital heart disease, sickle cell disease, and some inborn errors of metabolism, the risk of stroke is known to be higher, and hence the diagnosis is less confusing. In adolescents and young adults, stroke causes sudden focal deﬁcits that conform to a vascular territory, just as in older adults. Children, on the other hand, may have a more complex presentation that is diﬃcult to diagnose. Most children with acute ischemic stroke develop sudden hemiparesis or hemiplegia. However, half of these have focal or generalized tonic-clonic seizures, either before or in the ﬁrst few hours after the onset of hemiparesis. Up to half have fever, only some of whom have evidence of infection. Meningitis or encephalitis may be found, but many have an upper respiratory or other systemic infection. Headaches frequently proceed or accompany the focal ﬁndings. A small percentage of children develop movement disorders, such as hemidystonia or hemichorea, either in addition to or instead of hemiparesis. In most children, transient ischemic attacks (TIA) have not occurred before the stroke. Presentation is even more variable in neonates, where prenatal ischemic infarcts may present as seizures or go unrecognized; focal neurological deﬁcits are rarely found, even after 779

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a computed tomography (CT) scan has revealed a lesion. As the child develops purposeful movement between 4 and 6 months, an early pathological hand preference, or frank hemiparesis, emerges. A. Pathophysiology and Anatomy of Stroke in Children and Young Adults There are multiple potential mechanisms for stroke in children and young adults. The most common are not the atherothrombotic events that occur in adults with diabetes and hyperlipidemia, or the small vessel lacunar thrombotic strokes that occur in hypertensive adults who smoke. The most common site of vascular occlusion in childhood stroke is the distal internal carotid artery (ICA) or proximal middle cerebral artery (MCA). This can result from either a local vascular disease or an embolus. Occlusion of the proximal MCA produces one of two patterns of infarct: involvement of both the deep structures and the cortex, or infarction of only the basal ganglia and internal capsule, sparing the cortex. This is thought to be due, at least in part, to more eﬀective collateral circulation in children, compared to adults who have stroke. There is not at present an optimal system to classify stroke by mechanism in children or young adults. The standard classiﬁcation system according to the trial of ORG10172 in acute stroke therapy (TOAST) criteria has been applied to children and young adults [2]. The categories considered include (1) large vessel atherothrombotic (AT), (2) cardioembolic (CE), (3) small vessel disease (SV), (4) other determined cause, or (5) unknown. Using this system, approximately 85% of children fall into categories 4 and 5. The remaining cases are cardioembolic. The other determined causes consisted largely of sickle cell disease and moyamoya, with a few vasculitidies, dissections, other vasculopathies, other prothrombotic states, infections, and metabolic diseases. The young adult group, like the children, had few lacunar infarcts (3%), but did have AT infarcts (16%), and fewer unknowns (23%). The percentages of cardioembolic strokes and other determined causes were similar. B. Risk Factors As suggested above, the list of potential causes or risk factors for stroke in children and young adults is extensive. These can be grouped broadly into cardiac diseases, vasculopathies, prothrombotic conditions, and metabolic strokes, mostly caused by mitochondrial respiratory chain disorders. In some children and young adults, more than one risk factor is identiﬁed. In all of these categories, some disorders are apparent long before the occurrence of stroke and some remain occult until the stroke is investigated. In addition to these medical risk factors that cannot be modiﬁed, epidemiological studies demonstrate environmental and lifestyle factors that increase the risk of ischemic stroke, particularly in older adolescents and young adults. Among these factors are obesity and diabetes and cigarette smoking [3]. There is a clear association between certain recreational drugs and strokes (discussed below). Epidemiological studies indicate that recent heavy alcohol ingestion increases the risk of stroke, at least in some populations [4–6]. On the other hand, limited alcohol intake appears to be protective against ischemic stroke [7].

II. CARDIAC DISORDERS Cardiac disease is identiﬁed as a predisposing factor in 15–20% of children and young adults with ischemic stroke [2,8,9]. Patients under 15 years of age most commonly have a congenital heart defect, while cardiac causes in those over 15 years include patent foraman ovale (PFO),

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atrial septal defects, noninfectious valvular disease, endocarditis, left atrial or ventricular thrombus, cardiomyopathy, and atrial ﬁbrillation. Children with cyanotic congenital heart disease are at risk for embolic strokes, either spontaneous or related to catheterization and surgical procedures. Modern surgical procedures that allow earlier anatomical correction and improved intraoperative care of children with congenital heart disease have minimized these risks. Children with congenital heart disease are also at risk for diﬀuse ischemic changes (not in a speciﬁc vascular territory) related to relative hypoxemia and anemia [10]. In patients without congenital structural heart disease, careful evaluation of the heart constitutes an important component of the search for a cause for stroke. If the routine echocardiogram is normal, a contrast study and transesophageal echocardiogram might demonstrate subtle abnormalities. Management options for atrial septal defects or patent foramen ovale (PFO) include medical treatment (antiaggregation or anticoagulation), surgical PFO closure, or catheter closure [11].

III. VASCULAR DISORDERS Thirty-ﬁve to ﬁfty percent of children with arterial ischemic stroke are found to have a vasculopathy [12], making this the single most common cause of childhood stroke. The most important types are infectious or parainfectious vasculopathy, arterial dissection, and moyamoya syndrome. Migraine is associated with increased risk of stroke, presumably due to vasculopathy and sometimes due to dissection. With increasing age, other disorders become more important, including drug abuse, typical large vessel atherothrombotic stroke, and, to a lesser extent, small vessel lacunar strokes associated with hypertension, diabetes, and smoking as risk factors. A. Vasculopathy Associated with Infection A monophasic, transient cerebral arteriopathy is frequently associated with stroke in children [4,13]. This association has been recognized since the earliest studies of childhood hemiplegia [14]. Childhood cerebral infarction associated with infection can occur during the acute infection or, more commonly, as a postinfectious event. Peri-infectious vasculitis typically involves the proximal middle cerebral artery, with embolism to or occlusion of the perforating branches. Thus, the strokes in this setting most frequently aﬀect the basal ganglia and internal capsule. Perhaps because of the general health of the vascular system in childhood and abundance of collateral vessels, large MCA distribution strokes are the exception. The angiographic ﬁndings are nonspeciﬁc and generally consist of irregularity (‘‘bead on a string’’) of proximal large vessels. The ﬁndings are indistinguishable from chronic or systemic forms of vasculitis, such as Polyarteritis Nodosa, that are less common in children. In many cases, serial angiography shows resolution of the arterial irregularity [15,16], consistent with the view that peri-infectious stroke in childhood is monophasic and selflimited. (As discussed below, stroke associated with varicella may be an exception to this rule.) Infection-associated stroke has been reported with common respiratory viruses, Mycoplasma pneumoniae, coxsackie B4 and A9, and parvovirus B19. Most of these associations are isolated case reports. Viral vasculitis has been best studied in association with varicella zoster virus (VZV), where a threefold increase in VZV infection within the preceeding year has been found in children with stroke, compared with age-matched

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controls [17]. Most varicella-associated strokes occur within the ﬁrst 6 months after infection. An epidemiological study and review of the literature suggests that nearly half of these children have stroke recurrence [18]. VZV antigen-positive giant cells have been found in the walls of cerebral vessels in children with stroke [19], although in other cases no active viral invasion can be demonstrated [20]. Perhaps through a related mechanism, in adults VZV causes internal carotid vasculitis after herpes ophthalmicus, a latent VZV infection in the distribution of the opthalmic division of the trigeminal nerve. An association between HIV infection and stroke in children has been recognized in recent years. This association is seen independent of opportunistic infection or drug exposure and includes both ischemic and hemorrhagic strokes. In addition to strokes presenting with typical focal neurological deﬁcits, radiographic screening and autopsy studies of HIV-infected children have identiﬁed areas of infarction that were not recognized clinically [21,22]. Ischemic stroke in the setting of acute meningitis and encephalitis is well described [23,24] and usually does not create a diagnostic challenge. With meningitis there is vascular inﬂammation either in the parenchyma or at the base of the brain. Infarction occurs in the setting of typical bacterial agents, as well as atypical agents, such as tuberculosis, syphilis, Lyme disease, mycoplasma, and Cryptococcus. B. Noninfectious Vasculitis Many rheumatological diseases aﬀect young adults and children, but noninfectious vasculitis associated with rheumatological disease is an uncommon cause of cerebral infarction. When present, vasculitis is more likely to present with seizures or acute encephalopathy than focal deﬁcit. Some rheumatological diseases—systemic lupus erythematosis (SLE) most notably [25]—are associated with a hypercoagulable state that predisposes to stroke. Table 1 lists autoimmune conditions that have been associated with stroke in children or young adults. Systemic lupus erythematous is the second most common rheumatological disease in children, with 3.5% of cases presenting before age 10 and 8% before age 20. Eighty percent of patients are female. Cerebrovascular disease occurs in 3% of childhood cases, and the

Table 1 Vasculitic Diseases Associated with Stroke Systemic lupus erythematosus Mixed connective tissue disease PAN Kawasaki’s disease Henoch-Scho¨nlein purpura Takayasu’s arteritis Inﬂammatory bowel disease Scleroderma Sjo¨gren’s syndrome Cogan’s syndrome Behcßet’s syndrome Kohlmeier-Degos syndrome Wegener’s granulomatosis Churg-Strauss disease Isolated central nervous system angiitis

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incidence increases with age. Strokes have been attributed to a hypercoagulable state due to antiphospholipid antibodies and cardioembolic disease, in addition to central nervous system (CNS) vasculitis. Takayasu’s arteritis is a chronic, large vessel vasculitis of unknown cause that is more common in Asian, Indian Native American, and Latin American populations than in Europeans. The prepulseless stage can begin in childhood, but the disease is often not recognized until young adulthood, with pulselessness and end-organ ischemia. Children commonly have constitutional symptoms and abdominal aorta involvement, but up to 8% of children have been found to have hemiplegia [26]. Polyarteritis nodosa is a rare necrotizing vasculitis of small- and medium-sized vessels that can aﬀect older children and adolescents. It can present with fever, headache, progressive encephalopathy, and strokes in combination with renal and gastrointestinal vasculitis. The cause is unknown, but it has been associated with prior infection with respiratory viruses, Streptococcus, hepatitis B, Epstein–Barr virus (EBV), cytomegalovirus (CMV), tuberculosis (TB), and parvovirus B19. Inﬂammatory bowel disease has been associated with CNS vasculitis and hypercoagulable state, resulting in arterial stroke or venous sinus thrombosis in about 3% of childhood cases [27]. Isolated angiitis of the CNS is rare in childhood, but 10 biopsy-proven cases have been reported [28]. Five of these had progressive, multifocal neurological dysfunction, negative angiogram ﬁndings, biopsy-proven small vessel, nongranulomatous angiitis, and had clinical resolution with steroids and cyclophosphamide. The other ﬁve presented with large artery stroke, large artery involvement on angiogram, and biopsy-proven granulomatous angiitis and had poor response to treatment, with death in all cases. C. Arterial Dissection Cervicocephalic artery dissections account for up to 25% of strokes in patients under 45 years of age. It may be an underrecognized cause of stroke in childhood, as dissection accounted for 20% of consecutive childhood strokes in one series [29]. Dissection can be caused by penetrating or blunt trauma to the neck or marked rotation or ﬂexion/extension of the head and neck, such as trauma, contact sports [30], or chiropractic manipulation. Dissection does not, however, require a history of trauma [31–33]. It has been associated with such seemingly trivial mechanical events as coughing or sneezing, painting a ceiling, taking a drink, or undergoing anesthesia. In some of these cases, there may be a predisposition to vascular disease such as vasculitis, hyperhomocysteinemia [34], or migraine [35]. Dissections commonly present with focal neurological dysfunction associated with head and/or neck pain. Carotid dissections can cause monocular visual loss, Horner’s syndrome, and hypoglossal and other cranial nerve dysfunction. Dissections may also cause pulsitile tinnitus or subjective bruit. Dissection can usually be diagnosed noninvasively with MRI and MRA of the head and neck [36,37]. If the MRA results are uncertain, transfemoral angiography is indicated. Typical ﬁndings are a tapered occlusion or stenosis, pseudoaneurysm, a ‘‘string sign’’ or ‘‘pearl sign,’’ a double lumen, or an intimal ﬂap. D. Moyamoya Disease and Moyamoya Syndrome Moyamoya (‘‘puﬀ of smoke’’) refers to a clinical syndrome characterized by progressive noninﬂammatory occlusion of the distal ICA and proximal cerebral arteries, accompanied by a telangectatic network of collaterals in the deep hemispheres. The moyamoya phenomenon can be primary (moyamoya disease) or secondary to a variety of underlying diseases

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(see Table 2). About 10% of primary cases are familial, and moyamoya disease may be a genetic disorder that is most common in Japanese and other Asian populations, but it occurs in all ethnic groups. Genetic studies have identiﬁed linkage to chromosomal locations 3p24.2–p26 [38] and 17q25 [39]. The underlying pathophysiology for moyamoya syndrome remains unknown. It is appropriate to seek an underlying disease in all patients who present with moyamoya syndrome. As shown in Table 2, a wide range of disorders has been associated with moyamoya syndrome. Neuroﬁbromatosis, sickle cell disease, and trisomy 21 are among the more common predisposing conditions.

Table 2 Conditions Found in Association with Moyamoya Syndrome Infections Propionibacterium acnes HIV EBV Atypical TB Leptospirosis Meningovascular syphilis Inﬂammatory/Autoimmune SLE CREST syndrome Nonarteritic vasculopathy Atherosclerosis Fibromuscular dysplasia (FMD)/renovascular hypertension Alport’s syndrome Radiation vasculopathy Genetic/Congenital Down syndrome Noonan’s syndrome Cardio-facial-cutaneous syndrome Neuroﬁbromatosis Shimke’s immuno-osseous dyplasia Sphenopharyngeal meningoencephalocele Hematological/Prothrombotic Sickle cell disease Thalassemia Protein C and protein S deﬁciency Factor V leiden (FVL) Antiphospholipid antibodies Hereditary spherocytosis Paroxysmal nocturnal hemoglobinura (PNH) Plasminogen deﬁciency Hemophilia A Hyperhomocysteinemia

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The natural history of moyamoya syndrome diﬀers between Asian and Caucasian populations, perhaps due to diﬀerences between the disease and the syndrome. In Asian series, children tend to present with ischemic stroke, while hemorrhagic stroke becomes more prevalent in adulthood. Progression is usually relentless, and outcomes are almost always bad. Case series in the United States show predominance of ischemic stroke in both child and adult cohorts. Stroke recurrence is lower, ranging from 10% to 15% per year with medical and/or surgical treatment [40,41]. Management is generally surgical, using one of several diﬀerent procedures for connecting intracranial and extracranial circulations [42,43]. E. Fibromuscular Dysplasia Fibromuscular dysplasia (FMD) is a noninﬂammatory vasculopathy that most commonly aﬀects young women. Presenting symptoms can include TIA and stroke, head and neck pain, Horner’s syndrome, subarachnoid hemorrhage, arterial dissection, or hypertension from renal artery stenosis. Pathologically, there is segmental, nonatherosclerotic and nonarteritic hyperplasia and stenosis of medium- and small-sized arteries. The vasculopathy is not limited to the cervicocephalic circulation, but may aﬀect systemic vascular territories. Etiology is unknown. It is usually diagnosed by angiography, which shows a ‘‘string of beads’’ appearance in 80% and tubular stenosis in others. F. Drug-Related Vasculopathy Drugs most commonly associated with cerebral vascular disease are the sympathomimetics such as cocaine [44], amphetamine, and methamphetamine [45]. Rarely, over-the-counter sympathomimetics have been associated with ischemic infarction, while there is a strong association with cerebral hemorrhage. Any IV drug use creates a risk of embolic stroke and infective endocarditis. Heroin has been associated with vasculopathy and can also cause stroke through infective endocarditis, hypersensitivity reaction, and foreign body embolus. G. Premature Atherosclerotic Disease Though very rare in children, early atherothrombotic disease proves to be a signiﬁcant risk factor for young adults in several series. Atherosclerosis is a complex disease with multiple interacting environmental and genetic causes. Some single gene defects cause early hyperlipidemia that is transmitted in a mendelian fashion and can cause atherothrombotic strokes even in young children. Examples include autosomal dominant familial hyperlipidemia, a disorder of the low-density apo B/E receptor, familial hypertrigliceridemia, and types III and IV hyperlipoproteinemia. Atherosclerotic lesions in children with such disorders tend to involve the intracranial vessels rather than the carotid bifurcation and are thought to be mediated by lipoprotein-mediated endothelial damage. Fabry’s disease is an X-linked deﬁciency in the lysosomal enzyme, a-galactosidase A, leading to accumulation of glycosphingolipids in vascular smooth muscle, cardiac muscle, kidney, cornea, and peripheral nerves. The phenotype consists of cutaneous angiokeratoma, corneal opacities, renal failure, painful neuropathy, and predisposition to strokes. Strokes can be caused by small or large vessel occlusion or as a consequence of heart failure. Unlike many childhood stroke syndromes, this tends to cause both carotid and vertebrobasilar infarcts [46,47]. Tangier disease is a rare autosomal recessive disease causing low HDL and accelerated atherosclerosis, in addition to hyperplastic, orange tonsils, hepatospleno-

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megally, and peripheral neuropathy. Some conditions producing progeria may be associated with early atherosclerosis, including de Lange’s, Deckel, Bloom, and Cockayne’s syndromes. H. Homocyst(e)inemia Homocyst(e)inemia refers to a group of genetic disorders that share an elevated level of homocysteine, homocystine, and related metabolites. These disorders have been associated with vascular disease and stroke in both adults and children [48]. The most easily recognized of this group of disorders is homocystinuria, an autosomal recessive disease most commonly caused by deﬁciency of cystathione h-synthase (CBS). The phenotype includes tall stature, mental retardation, ectopic lentis, seizures, mental retardation, and skeletal abnormalities. Patients with mild CBS mutations and those heterozygous for CBS mutations also have increased risk for ischemic stroke, although they do not manifest the dysmorphic phenotype and can only be diagnosed with laboratory testing [49]. The same applies to people with elevations in homocyst(e)ine from methylenetetrahydrofolate reductase (MTHFR) deﬁciency, transcobalamin II deﬁciency, methylcobalamin deﬁciency, and other disorders of vitamin B12, B6, and folate. Laboratory testing for this group of disorders is complex, as no single test will identify all patients with these disorders. Studies to consider include MTHFR mutation testing, fasting serum homocysteine level, and homocysteine level after methionine load. I. Migraine There is a poorly deﬁned relationship between migraine and stroke. Migraine prevalence is increased in young adults who have had a stroke [50]. Women migraineurs in particular are at increased risk of stroke, and the association is stronger for those taking oral contraceptives [51,52]. Stroke can occur either during a migraine attack or independently. Migrainous stroke, as deﬁned by the International Headache Society (IHS), occurs during a migraine with aura and cannot be explained by any other cause. Stroke has also been documented during migraine without aura. These strokes present with hemianopia more often than hemiparesis; accordingly, infarcts are more often found in the PCA territory than the anterior circulation. Onset is often gradual over an hour, rather than abrupt. Preceding TIAs are rare. The pathogenesis of stroke in migraineurs is unknown, but is hypothesized to be due to vasospasm or other vasculopathy. Patent foramen ovale and arterial dissection have also been associated with migrainous infarction. The relationship between migraine and stroke is less clear in the pediatric population, as many of the studies do not address this age group. On the other hand, numerous case reports document childhood stroke in the context of migraine. Pediatric cases often do not meet the strict IHS criteria for migrainous infarct, largely due to lack of prior aura or the presence of other potential causes [53]. J. Cerebral Autosomal Dominant Arteriopathy with Subcortical Strokes and Leukoencephalopathy Patients with cerebral autosomal dominant arteriopathy with subcortical strokes and leukoencephalopathy (CADASIL) constitute a subgroup of patients with migraine and ischemic stroke. This disorder typically presents with migraine headaches in childhood or

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young adulthood or TIAs and strokes in young and mid-adulthood. Recurrent strokes often lead to dementia and premature death [54]. MRI shows widespread white matter disease, and MRI changes may preceed the neurological symptoms [55]. The disorder is recognized clinically by the family history and distinctive MRI ﬁndings. CADASIL is caused by mutations in the NOTCH 3 gene [56] resulting in ultrastructural abnormalities of vascular smooth muscle [57]. Electron microscopy of blood vessels in skin or muscle biopsy shows characteristic electron-dense granules that can be diagnostic [58]. Conﬁrmatory or diagnostic testing through NOTCH 3 mutation analysis is commercially available. There is no speciﬁc treatment, but genetic counseling is a key element of management in this disorder.

IV. HEMATOLOGICAL DISORDERS AND ISCHEMIC STROKE Hematological disorders that predispose to stroke are both primary, such as sickle cell disease, and secondary, such as the hypercoagulable state induced by chemotherapeutic agents. As demonstrated by these examples they may involve the coagulation pathway or other components of the hematological system. A. Prothrombotic Conditions Many advances have been made in the identiﬁcation of inherited or acquired disorders of the coagulation system, and some progress has been made in studying the relationship of various defects to arterial and venous stroke. Most prothrombotic disorders have been robustly linked to venous thrombosis, including sinus thrombosis (discussed later in this chapter), while only a few, such as antiphospholipid antibodies and hyperhomocysteinemia, have been clearly associated with arterial stroke. While still a somewhat controversial issue, several series indicate an important association between prothrombotic states and arterial stroke and argue for conducting laboratory investigations in cases of idiopathic stroke, particularly in patients under age 45 years. Complicating the review of published studies is the fact that there have not been standardized normal values, and levels of some factors, such as protein C and protein S, are decreased in the setting of an acute stroke, so can only be interpreted if they are rechecked much later [59]. In children under 18 years, prothrombotic factors are identiﬁed in at least 25% of strokes, with multiple factors found in some. Table 3 summarizes clinical tests of coagulation abnormalities that should be considered in unexplained stroke. B. Sickle Cell Disease Sickle cell disease (SCD) represents a group of inherited hemoglobinopathies, the most severe of which is the homozygous inheritence of HbS. SCD leads to erythrocyte sickling at reduced oxygen tension, causing episodic pain, hypoxemia, and end-organ ischemia. It occurs most frequenty in descendants of equatorial Africa, and, to a lesser extent, those of northern and southern Africa, the Mediterranean, and India. Patients are susceptable to a wide range of neurological complications, including stroke, headaches, seizures, cognitive impairment, and acute encephalopathy [60]. Sickle cell disease is among the most common causes of stroke in childhood. Serial MRI studies demonstrate that the clinically symptomatic strokes (aﬀecting approximately 10% of children with SCD) represent only a subset of infarctions [61]. Radiographically

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Table 3 Disorders Associated with Thrombosis Primary disorders of coagulation proteins Inherited: Factor V Leiden mutation Prothrombin G20210A mutation Lipoprotein (a) Plasminogen activator inhibitor-1 mutation Inherited or acquired: Protein C deﬁciency Protein S deﬁciency Antithrombin-III deﬁciency Heparin cofactor-II deﬁciency Dysﬁbrinogenemia Hypoplasminogenemia Abnormal plasminogen Other conditions causing prothrombotic states Hyperhomocysteinemia Antiphospholipid antibodies (e.g., anticardiolipin antibody, lupus anticoagulant) Malignancy DIC Hyperviscosity syndromes; Polycythemia Leukocytosis (>100,000) Thrombocytosis Thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Sickle cell anemia Paroxysmal nocturnal hemoglobinura L-Asparaginase therapy Pregnancy/postpartum Oral contraceptive pills Nephrotic syndrome Liver disease Surgery Trauma Acute inﬂammation Human immunodeﬁciency virus Varicella zoster virus

apparent strokes without a corresponding clinical ictus (silent strokes) result in progressive neurobehavioral deterioration. Among those with SCD, stroke risk is not evenly distributed. There is familial aggregation of propensity to stroke in SCD [62]. Those with clinically silent infarcts [63] and patients with increased ﬂow velocity on transcranial doppler (>200 cm/s) are at risk of future strokes [64]. There is also an increased risk of stroke in the setting of intercurrent illness and anemia [65]. Developing moyamoya syndrome signiﬁcantly increases the recurrence of strokes and predicts neuropsychological decline, even with chronic transfusion to keep HbS <30% [66].

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A cascade of factors is involved in the pathophysiology underlying stroke in the patient with SCD, beginning with sickled erythrocytes adhering to and damaging the endothelium. This leads to intimal hyperplasia, antiphospholipid antibody production, deﬁciency of protein C and S, and inﬂammatory reactions that further damage and occlude vessels. Preventative treatment consists primarily of transfusion (or exchange transfusion) to keep the HbS <30% [67]. Hydroxyurea stimulates production of fetal hemoglobin. When used in SC patients who have had a stroke, there is anecdotal evidence that it may decrease the recurrence rate [68] even in patients with the moyamoya syndrome [69], although there are not yet conﬁrmatory controlled studies. C. Hematological Malignancy Although hemorrhage is much more common in patients with leukemia, ischemic stroke does occur more frequently than in the normal population. It is usually associated with DIC or septic thrombus and can occur with leukocytosis over 100,000. L-Asparaginase, used for acute lymphoblastic leukemia (ALL) induction chemotherapy, causes abnormalities in anticoagulant proteins. It may lead to arterial stroke, although it more often causes venous thrombosis, including that of cerebral sinuses. D. Myeloproliferative Disease Polycythemia rubra vera is a rare primary panhyperplasia that causes hyperviscosity and arterial occlusion. Risk of arterial stroke is very high and remains at 4–5% per year even with phlebotomy treatment. Stroke risk is higher in this primary condition than in secondary polycythemia [70].

V. MITOCHONDRIAL DISORDERS Diseases of electron transport chain function are referred to collectively as mitochondrial diseases. This group of disorders leads to an array of systemic and neurological signs and symptoms and can be diﬃcult to exclude from a diﬀerential diagnosis. Several clinical syndromes have been identiﬁed, although there is extensive overlap in manifestations. The mitochondrial syndrome most frequently associated with stroke in young people is mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Patients with MELAS may have seizures, progressive hearing loss, short stature, visual disturbance, migraine symptoms with recurrent headaches and episodic vomiting, muscle weakness, and neuropathy [71]. The strokelike episodes can be transient, but often ultimately result in ﬁxed deﬁcits such as hemiparesis. Symptoms almost always begin before age 40 years, and most begin much earlier. There may be a family history of similar symptoms, showing a mitochondrial pattern of inheritance. Laboratory testing includes signiﬁcantly elevated serum lactate in more than 90% of patients. CT and MRI are usually abnormal and may show focal areas of abnormal signal or density suggesting infarction, but not following a vascular distribution. Cerebral atrophy and basal ganglia calciﬁcation have also been seen. Ragged red ﬁbers are often found on muscle biopsy, and about half of patients have decreased staining for cytochrome c oxidase activity in muscle [72]. A point mutation in a mitochondrial tRNA gene is found in about 80% of MELAS cases [73]. Mutation analysis is commercially available and can be initiated

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in blood, but analysis of additional tissues may be required. Genetic counseling is complex due to the variability of mutant load between individuals and between tissues [74].

VI. EVALUATION OF CHILDREN AND YOUNG ADULTS WITH SUSPECTED STROKE When stroke is suspected in a young person, attempts should be made to rapidly determine whether a stroke has occurred, address acute medical issues such as seizures and dehydration, and begin to narrow the list of possible causes, keeping in mind the major categories of cardiac disease, vasculopathy, pro-thrombotic states, and metabolic disease. Review of medical history will identify underlying diseases predisposing to stroke. Recent infections or head and neck trauma should be sought speciﬁcally. Family history is an important part of the evaluation and should include questions about relatives with heart attacks or stroke before age 45 years. Physical ﬁndings that may give clues as to the reason for stroke in a young person include fever, abnormal blood pressure or heart rate, dysmorphic features, pallor or cyanosis, arrhythmia, heart murmur, congestive heart failure, stigmata of peripheral emboli, bruits, arachnodactyly, joint laxity, neurocutaneous stigmata (e.g., cafe´ au lait spots), rash, petechiae, ecchymosis, or purpura. Due to the diﬃculty in diagnosing stroke in children, many experts advocate the early use of MRI, with diﬀusion weighted imaging, to identify acute ischemia and rule out disorders that mimic stroke. An advantage of MRI is that MRA can be added immediately to evaluate for large vessel cerebrovascular abnormalities. CT with CT angiogram is an alternative, which can potentially be obtained more rapidly, without sedation [75]. When a young person has an ischemic stroke of uncertain cause, extensive laboratory evaluation is usually indicated. A list of tests to consider is shown in Table 4. Recall that the protein C, protein S, antithrombin III, and ﬁbrinogen levels are not valid during the acute period and should be deferred for several months.

VII. NATURAL HISTORY AND MANAGEMENT OF STROKE IN CHILDHOOD AND YOUNG ADULTHOOD It has long been clear that the functional outcome after stroke in childhood diﬀers from the outcome after a similar injury to the mature brain. There are few prospective longitudinal studies describing outcomes after childhood and young adult stroke. Motor deﬁcits, including hemiparesis and dystonia, are common after early stroke [76]. Epilepsy is an uncommon sequelae of young adult ischemic stroke, found in approximately 5% of patients in the ﬁrst 3 years after stroke [77], but more common in childhood stroke. About 30% of children developed recurrent seizures after ischemic stroke [78], and recurrent seizures predict a poorer cognitive outcome [79]. In both populations, involvement of the cortex is associated with increased risk of seizures. Identiﬁcation of more than one risk factor for stroke may predict a worse functional outcome in children [80]. The recovery of language after cerebral injury in childhood is usually functionally quite good. Left hemisphere infarction before the age of 5 years results in near normal language, although neuropsychological testing demonstrates subtle abnormalities [81,82]. Recent investigations evaluate executive systems and social and emotional functioning after childhood and young adult stroke. Longer follow-up has revealed behavioral and

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Table 4 Laboratory Tests to Consider in Young Patients with Stroke Laboratory test Cardiac Chest x-ray Echocardiogram ECG Transesophageal echo Contrast echocardiogram Vascular disease MRA, CTA Conventional angiography ANA ESR Drug screen Fasting lipid proﬁle a-Galactosidase A MTHFR mutation testing Fasting homocysteine level Homocysteine level after methionine load Skin biopsy, ultrastructure of vessels NOTCH 3 mutation analysis Hematological disease CBC, peripheral smear Hemoglobin electrophoresis PTT, PT/INR Lupus anticoagulant Anticardiolipin antibodies, IgG and IgM Protein C Protein S Antithrombin III Antiphospholipid antibodies Activated protein C resistance (or factor V Leiden) Prothrombin gene rearrangement Metabolic disease Serum or CSF lactate Muscle biopsy MELAS-related mutation analysis

Notes

Consider in older patients For occult right-to-left shunt

Drugs of abuse Fabry disease, males only

CADASIL CADASIL

Sickle cell disease, thalassemia

Do Do Do Do

test test test test

2–3 2–3 2–3 2–3

months months months months

after after after after

stroke stroke stroke stroke

Ragged red ﬁbers, mutation analysis Should be tested on muscle if blood negative

cognitive diﬃculties that were not appreciated in younger children [83]. Compared to a control group with primary congenital orthopedic deformity, children with stroke have signiﬁcantly higher frequency of behavior problems, including attention deﬁcit/hyperactivity disorder (ADHD), anxiety disorders, mood disorders, and personality change [84]. Analysis of lesion localization in this cohort revealed that ADHD symptoms were speciﬁcally associated with putamenal lesions, which is the most common site of infarct in children [85]. In young adults with stroke, occupational and marital discord are occasionally seen after stroke, even in the absence of overt sensorimotor deﬁcits [86].

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The management of stroke in the young is complicated by the often delayed recognition as well as diverse range of etiologies. Proper management relies upon knowledge of the underlying risk factors and suspected stroke mechanism, and this is often diﬃcult to ascertain quickly. Also, complicating treatment are speciﬁc clinical circumstances and conditions present in young people who have strokes, which may preclude the use of certain therapies that are used in adults. Appropriate treatment of dissection, one of the most common causes of stroke in young people, has been controversial. Treatment with thrombolytics, anticoagulation, or antithrombotic therapy has been considered, but data on use of these agents are so far largely anecdotal. Caution must be exercised before initiating therapy that could result in extension of the intramural hematoma or intracranial hemorrhage [87–89]. Another area of uncertainty in treatment concerns the use of thrombolytics in children. Case reports describe good outcomes with r-tPa in adolescents with embolic stroke [90–92]. Some data are available with the use of thrombolytics for systemic arterial occlusions in children. In one series of 65 children treated for systemic arterial occlusions with 0.55 mg/kg/h of r-tPa, 65% had successful clot resolution. Two children had intracranial hemorrhage [93]. Until results of prospective studies are available to guide treatment decisions, the use of thrombolytics in childhood stroke remains a matter of clinical judgment. The goals of treatment, the natural history of the disease, and the potential risks must be considered in each case. In current practice, antiplatelet therapy is recommended for most children with postnatal cerebral infarction when a speciﬁcally treatable cause of stroke is not identiﬁed. Rehabilitation therapy (speech, physical, occupational, and educational intervention) is critical. Early identiﬁcation of cognitive, attention, and social disorders may allow for improved functional outcomes.

VIII. SINOVENOUS THROMBOSIS Thrombosis of the venous sinuses occurs in 0.67/100,000 children per year. Term neonates account for about half of childhood cases. Of nonneonates, most sinovenous thrombosis (SVT) occurs before 3 months of age, but older children, adolescents, and young adults also develop this serious disorder. A. Neonates Neonatal SVT is associated with maternal or perinatal complications such as gestational diabetes, maternal infection, fetal distress, birth hypoxia, congenital heart defects, or sepsis in about 85% of cases [94]. About 20% of neonates are found to have a prothrombotic state, either genetic or acquired (see Table 3). Most neonates with SVT have seizures and decreased responsiveness, though the clinical signs can be subtle. Few have focal neurological ﬁndings. About 35% have hemorrhagic infarction, and fewer have bland infarctions. Over a third have neurological sequelae, including hydrocephalus, hemiparesis, developmental delay, and vision and speech impairment. Only 5% have recurrent thrombotic events. B. Children and Young Adults Older infants and children are still vulnerable to many of the acute and congenital illnesses that predispose neonates to SVT, including congenital heart disease, polycythemia, menin-

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gitis, sepsis, DIC, and dehydration. As children age, chronic diseases that predispose to thrombosis become more common, including connective tissue diseases, cancer and its treatment, and hematological disorders. Usually emerging in the preschool years, head and neck infections, such as otitis, sinusitis, and mastoiditis, can precipitate SVT. Inherited and acquired coagulation disorders (see Table 3) are found in up to 40% of children with SVT [95–98]. Almost all children and young adults with SVT have at least one of these risk factors. In older adolescents and young adults, contraceptive hormones and pregnancy become signiﬁcant risk factors for SVT. As children age, the presentation of SVT becomes more like that of adults. This includes any combination of headache, vomiting, decreased level of conciousness, focal neurological signs, and papilledema. About half of children with SVT will have seizures. One-third of children with SVT have been found to have infarcts, about half of which are hemorrhagic. C. Diagnosis Head CT will reveal hemorrhagic infarcts and may show a hyperdensity in the superior sagital sinus [99], but is usually not suﬃcient for diagnosis. CT venogram has demonstrated high sensitivity and speciﬁcity for sinus thrombosis [100]. Both T1 and T2 MRI will reveal sinus hyperdensity in many cases, while magnetic resonance venogram (MRV) or computed tomography venogram (CTV) is often necessary, especially within the ﬁrst few days. In addition to these tests, patients should be evaluated selectively for underlying conditions. D. Management and Outcome Currently, children diagnosed with SVT are treated with aspirin, unfractionated heparin, low-molecular weight heparin, or warfarin. Prospective studies comparing anticoagulation to placebo and those demonstrating the safety and eﬃcacy of intravascular thrombolytics have been performed in adults [101–103] but have not been replicated in the pediatric population. Surgery may be necessary for mastoiditis, and VP shunt may be required for hydrocephalus. About 40% of children have focal neurological sequelae at long-term follow-up, and 10% have epilepsy. Seizures at presentation and brain infarction predict a worse prognosis. About 20% of children have been found to have recurrent thrombotic events.

IX. HEMORRHAGIC STROKE IN CHILDREN AND YOUNG ADULTS Outside of the newborn period, spontaneous cerebral hemorrhage is rare in children and young adults, and even less common than ischemic stroke. Overall, patients with cerebral hemorrhage have higher morbidity and mortality than do patients with ischemic stroke [104]. A. Aneurysm and Subarachnoid Hemorrhage Cerebral aneurysms most commonly present as subarachnoid hemorrhage (SAH). Population-based incidence of SAH is roughly 0.1/100,000 for children under 14 years, gradually increasing to 7.4/100,000 in young adults 35–44 years old in a largely northern European population [105,106]. Several studies indicate that these values are approximately doubled in

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the urban African American population [107,108]. Environmental, preventable risk factors may play a role in determining which aneurysms rupture (thus are identiﬁed). The clinical presentation of cerebral hemorrhage is no diﬀerent in children and young adults than in an older population, with sudden onset of severe atypical headache being the consistent feature. This presentation in a young adult is generally evaluated with a CT scan and, if that is negative, a cerebrospinal ﬂuid (CSF) examination to ensure the absence of blood or xanthrochromia. In children, all other causes for severe headache are so much more common than subarachnoid hemorrhage (SAH) that CSF exams are very rarely indicated for headache alone. B. Risk Factors for Aneurysm and SAH Unlike aneurysms in late adulthood, childhood aneurysms are generally not related to underlying systemic disease and are very rare. Young adults with ruptured cerebral aneurysms are more likely to have an underlying predisposition, either genetic or environmental. The Hemorrhagic Stroke Project identiﬁed current cigarette smoking, recent cocaine use, hypertension, low body mass index (BMI), and family history of hemorrhagic stroke as risk factors with odds ratios of >2.5 [109]. 1. Infection and Aneurysm Septic aneurysms can be seen in young patients and may be associated with immune insuﬃciency or underlying valvular cardiac disease. There is also an association between HIV infection and the development of cerebral aneurysm. Aneurysms were found on neuroimaging in 1.5% of patients who acquired HIV during childhood (either vertical transmission or childhood acquisition). Most of these were asymptomatic at the time of imaging [110]. 2. Vein of Galen Aneurysm The aneurysm that most commonly presents in infancy is the giant vein of Galen aneurysm. This malformation very rarely presents with hemorrhage or cerebral vascular events (6% of 34 infants presented with spontaneous hemorrhage [111]). The most common indication for evaluation is congestive heart failure. 3. Genetic Factors There is distinct familial clustering of cerebral aneurysms. Prospecitive MRA in ﬁrst-degree relatives of SAH patients found aneurysms in 4%. Younger age and multiple aneurysms in the probands were risk factors for their ﬁrst-degree relatives [112]. Some of this clustering results from known genetic syndromes associated with an increased risk of cerebral aneurysm in childhood and young adulthood. Autosomal dominant (and rarely, autosomal recessive) polycystic kidney disease (ADPKD) is a rare cause of all aneurysms (0.5% in one series), but the aﬀected population tends to be younger than average (mean age of hemorrhage, 41 vs. 53 years overall) [113]. ADPKD is usually caused by mutations in the genes for the proteins polycystin 1 and 2. Immunostaining demonstrates that both polycystins are found in the vascular smooth muscle of adult elastic arteries, and show a disrupted pattern in pathological arterial specimens from intracranial aneurysms, although these disruptions were not limited to the ADPKD patient specimens [114,115]. The ADPKD patients at highest risk for

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aneurysms are those with a family history of intracranial hemorrhage or aneurysm, and screening should be considered in this group [116]. It is probable that a subset of ADPKD mutations predispose to vascular fragility and cerebral hemorrhage. Aneurysm may be the primary manifestation of the arterial form of Ehlers-Danlos syndrome (Ehlers-Danlos type IV). In one retrospective review, 19 of 202 (9%) patients with genetically or biochemically proven Ehlers-Danlos type IV had symptomatic cerebral vascular disease. Carotid-cavernous ﬁstulas were the most common ﬁnding, with cerebral hemorrhage being next most common. The cerebrovascular complications tend to aﬀect older adolescents and young adults [117]. 4. Management The management of cerebral aneurysms is discussed in detail elsewhere in this volume. The primary options for obliteration of cerebral aneurysms are microsurgical clipping or endovascular coils. A large international randomized trial compared these two approaches in patients over the age of 18 years with recent hemorrhage, where either approach was deemed technically feasible and appropriate by the treating physicians. The randomization was stopped early because of a clear reduction in risk of severe disability or death in the group treated with endovascular coil placement [118]. The authors take care to point out that some aneurysms are technically better approached neurosurgically, and these patients were not included in the randomized trial. Clinical judgment and experience remain critical for treatment decisions [119]. Published information on the treatment of aneurysms in children under the age of 18 remains largely anecdotal. Both microsurgical and endovascular approaches have been used successfully in children. C. Arteriovenous Malformations Arteriovenous malformations (AVMs) are less common than aneurysms. A recent average annual AVM detection rate is 1.34 per 100,000 person-years [120]. Long-term follow-up demonstrates that AVMs have a high propensity to bleed, estimated at 1–2% per year, and rebleed (2–4%/year). Death or signiﬁcant neurological deﬁcit often follows hemorrhage [121]. Cerebral hemorrhage due to ruptured AVM tends to be a disease of young adulthood. The mean age at ﬁrst hemorrhage is around 35 years, and less than 5% of AVMs bleed before age 10 years [122]. Ruptured AVMs lead to parenchymal hemorrhage, which may aﬀect any part of the brain, usually resulting in rapid alteration of consciousness and focal deﬁcit. The diagnosis is generally clear with CT scan. 1. Hereditary Hemorrhagic Telangectasia A rare inherited cause of cerebral vascular malformation is hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease. This autosomal dominant disorder of vascular development generally presents with mucocutaneous telangiectasia, recurrent epistaxis, and GI bleeding. Approximately 20% will develop pulmonary arteriovenous ﬁstulas and a risk of embolic cerebral infarction and brain abscess. A small subset of HHT patients develop vascular malformations that predispose to cerebral hemorrhage. The most common vascular malformations in this population are cerebral telangectasias or cavernous angiomas, followed by AVMs [123,124]. An interesting study focusing on HHT individuals under the age of 46 years found that AVMS in this population have an annual rate of

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hemorrhage similar to that of patients without HHT (i.e., 1–2% per year). Thus, males under age 45 with HHT were 20 more likely to have cerebral hemorrhage than males in the general population. The authors suggest that it may be appropriate to screen at-risk young adults and consider presymptomatic treatment [125]. 2. Treatment Treatment of AVMs may include surgery, radiosurgery [126], less commonly endovascular thrombosis, or a combination of these modalities in more complex lesions [127]. One series of radiosurgical treatment in the pediatric population demonstrates a signiﬁcant correlation between radiation dose and likelihood of obliteration, without a concomitant increase in complications, at least in the short term (z36 months follow-up) [128]. D. Cavernous Angioma Cavernous angiomas consist of collections of thin-walled vascular channels that are under low pressure. These malformations generally have lower rates of hemorrhage than do AVMs or aneurysms and are unlikely to lead to hemorrhage in childhood. In addition to hemorrhage, common presentations include seizures, headaches, and focal neurological signs. They are often asymptomatic. An autosomal dominant disorder characterized by multiple cerebral cavernous malformations (CCM) is caused by mutations in a proposed tumor suppressor gene, KRIT1 (Krev interaction trapped-1), on chromosome 7q21–q22. Mutations in KRIT1 have been identiﬁed in at least 47% of familial and sporadic cases [129]. There is a common KRIT1 mutation found in U.S. Hispanics, and patients without a family history of CCM are more likely to have a mutation identiﬁed if they are Hispanic [130]. The natural history of asymptomatic angiomas is best described for inherited CCM, where family members have serial MRIs. The hemorrhage rate in this group is approximately 1.1–2.5% per lesion per year [131,132]. Serial MRI studies have also demonstrated that the vascular lesions are not static over time. They show changes in size and signal characteristics and an increase in number [133]. Because of the dynamic nature of the lesions, decisions about treatment are diﬃcult. Management of symptomatic cranial cavernous angiomas has included surgery and radiosurgical (gamma knife) ablation. There is a high complication rate following radiosurgery for these lesions, and it is not clear the beneﬁts outweigh the risks for most patients [134,135]. E. Bleeding Diathesis Cerebral hemorrhage has long been associated with anticoagulant medications and systemic diseases associated with bleeding diathesis. These are unlikely to be diagnostic challenges. A recent Cochrane database review estimated that long-term anticoagulant therapy for noncardioembolic ischemic stroke or transient ischemic attack was responsible for about 11 additional fatal intracranial hemorrhages for every 1000 patients [136]. Risk of death in patients on oral anticoagulants is lowest with an INR of 2.2 and rises steadily when INR is >2.5. A subset of these deaths are related to cerebral hemorrhage [137]. Use of anticoagulation in children is likely to be even more hazardous because of increased chance of minor head trauma. In children with known inherited coagulopathy, such as the various forms of hemophilia, intracranial hemorrhage is one of the leading causes of mortality. The rate of intracranial hemorrhage has approximately doubled in recent years, an increase attributable

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to the rise in HIV infection from contaminated factor concentrate used to treat the hemophilia. In one series the incidence of intracranial hemorrhage was 0.0054 case/year. Forty percent of these were infected with HIV, and the hemorrhage was fatal in 18% [138]. Treatment consists largely of factor replacement. There may be subtle disorders of coagulation that predispose to hemorrhage under certain circumstances. As more factors are analyzed, the multifactorial nature of many spontaneous hemorrhages becomes clear. Coagulation factor XIII is involved in the hemostasis and vascular repair [139]. Certain polymorphisms in factor XIII were found to be associated with an increased risk of hemorrhage in white women <45 years old. The combination of speciﬁc factor XIII polymorphisms with a polymorphism in plasminogen activator inhibitor-1 resulted in a 20-fold increased risk of cerebral hemorrhage in young women [140]. Other systemic diseases associated with an increased chance of cerebral hemorrhage include thrombotic thrombocytopenic purpura, Henoch-Scho¨nlein purpura, disseminated intravascular coagulation, and malignancy. F. Moyamoya Moyamoya disease and syndrome were discussed previously under ischemic stroke, as that is the most common presentation. In a U.S.-based series, 17% of moyamoya patients presented with cerebral hemorrhage compared to 74% presenting with ischemic stroke or TIA [141]. A predilection for intraventricular hemorrhage has been identiﬁed in moyamoya patients. G. Menke’s Syndrome Menke’s syndrome is a rare X-linked recessive disorder of copper absorption that produces dysfunction in copper-dependent mitochondrial respiratory chain enzymes. It leads to tortuosity, elongation, and occlusion of cerebral and systemic arteries. The vascular disease can manifest as subdural hematoma [142], parenchymal hemorrhage, or stroke [143]. H. Drug-Related Disorders Sympathomimetic drugs are associated with cerebral hemorrhage as well as infarction. Speciﬁc drugs that have been associated with hemorrhage include phenylpropanolamine, amphetamine, cocaine, and the designer drug Ecstasy. The association between cerebral vascular events and phenylpropanolamine was compelling enough that since 2000, FDA has worked with drug companies to remove it from all cold and weight-reduction medications. There are several potential pathophysiological bases for cerebral hemorrhage associated with drug exposure, including vasculitis, and hypertension or rapid changes in blood pressure. In some cases, the drug exposure appears to be the precipitating factor that causes preexisting vascular malformations (aneurysms or AVMs) to rupture [144].

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34 Diagnosis and Management of Cerebrovascular Disorders in Pregnancy Kathleen B. Digre, Michael W. Varner, Elaine Skalabrin, and Michael A. Belfort The University of Utah, Logan, Utah, U.S.A.

When cerebrovascular disease aﬀects any young adult, it is tragic. However, when the young adult is also pregnant or immediately postpartum, the tragedy aﬀects an entire family unit. The incidence of stroke during pregnancy in developed countries is 4.3–11.0/ 100,000 deliveries [1]. Cerebrovascular disease is ranked as the ﬁfth most common cause of maternal mortality [2]. This means that while stroke in pregnancy is rare, fatality due to cerebrovascular disease is not. Although the majority of such women will survive, substantial persistent functional loss is common. Pregnancy complicated by stroke poses many problems for the clinician. One must not only consider the many causes of stroke in the young, but also the conditions causing stroke that are peculiar to pregnancy such as cardiomyopathy of pregnancy, eclampsia, amniotic ﬂuid embolism, and choriocarcinoma. In addition, the normal physiological changes can predispose a woman to stroke during pregnancy and the puerperium. In the care of the pregnant or parturient woman with an acute neurological event, we must not have an arrest in our thinking that all events are related to one thing—for example, preeclampsia or eclampsia [3], since a speciﬁc diagnosis may be delayed. Treatment of these conditions is also problematic because one must consider the eﬀect on the unborn fetus. In a review of stroke associated with pregnancy, Jaigobin and Silver found that the most common stroke type was arterial infarct (f33%) followed in order by venous thrombosis, subarachnoid hemorrhage, and intracerebral hemorrhage [2]. Others have found that arterial occlusions are the cause of stroke in 60–80% of pregnant women [4]. Most arterial strokes occurred in the third trimester, while venous thrombosis was seen primarily postpartum.

I. INCIDENCE AND PREVALENCE OF CEREBROVASCULAR DISEASE IN PREGNANCY The incidence of stroke in young women is estimated to be about 10.7/100,000 Caucasian women [5], and almost twice that in black women [6]. Although pregnancy in the past has been thought to increase the stroke rate from 3–13 times the expected values [7], and still 805

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does in poorer countries, a recent large study found that although the risks of infarction, hemorrhage, and thrombosis are increased after delivery, pregnancy itself does not appreciably increase the risk [8]. Three large population-based studies from Maryland, Denmark, and Paris have born this out [8–10]. The Maryland study reports an adjusted relative risk of 2.4 (95% CI 1.6–3.6) for stroke, either ischemic or hemorrhagic, in association with pregnancy and the puerperium, being higher for hemorrhagic than ischemic and higher in the puerperium than during pregnancy. Ros et al. [11] concluded that the risk of some type of circulatory disease (stroke, venous thrombosis) is mainly seen within a few days of delivery. What is also clear is that the incidence of stroke during pregnancy, and in young adults in general, is higher in some developing countries. For example, India’s stroke rate has been estimated at 1 per 481 (208/100,000) pregnancies [70]. Libya has an incidence of 40/100,000 in young men and women, although speciﬁc incidence ﬁgures are not available for pregnant women [12]. Whatever the rate, there are obstetric risk factors for development of stroke in women. Ros et al. documented that preeclampsia, multiple birth, cesarean delivery, and major infection were all important risk factors for pulmonary embolism and stroke [13]. In addition, parity may also increase the risk of stroke [14].

II. PHYSIOLOGICAL CHANGES IN PREGNANCY AND VASCULAR DISORDERS Numerous physiological changes occur during pregnancy that predispose women to cerebrovascular disease (see Table 1). Pregnancy is known to be associated with dramatic cardiovascular changes. Increases in stroke volume and heart rate are seen as early as the ﬁrst trimester [15]. While blood volume and cardiac output increase by 30–50% in a normal singleton pregnancy [16], vascular resistance (represented by the ratio of cardiac output to mean arterial pressure) declines. In fact, decreased systemic vascular resistance is one of the earliest changes in the pregnant woman’s vasculature. This adaptation ensures optimum perfusion of the developing fetoplacental unit. These changes essentially resolve by 2 weeks postpartum. The combination of increased cardiac output and decreased systemic vascular resistance results in characteristic blood pressure changes. Mid-trimester systolic blood pressure decreases by 5–10 mmHg in uncomplicated pregnancy, while diastolic pressures are lowest (by 10–15 mmHg) at mid-pregnancy. Both measurements return to normal nonpregnant levels at term. The blood vessels themselves undergo changes that can predispose to vascular accidents. The arterial media thickens and there is fragmentation of reticular ﬁbers plus mild hyperplasia of smooth muscle cells [17]. Pregnancy is also a mildly hypercoagulable state. Many clotting factors, including plasminogen and ﬁbrinogen, increase during pregnancy, but ﬁbrinolytic activity decreases. The thrombotic tendency worsens in the puerperium when there is a further increase in ﬁbrinogen and platelet aggregation and a further decrease in ﬁbrinolysis. Coupled with the reestablishment of a normal blood volume from a brisk diuresis beginning within 24 hours postpartum [18], the puerperium is the time of greatest risk of venous thromboembolic disease [19,20]. These risks are most pronounced in the ﬁrst 2 weeks after delivery and diminish rapidly thereafter.

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Table 1 Representative Physiological Changes in Pregnancy Parameter Arterial blood pressure Heart rate Blood volume Red cell mass Cardiac output Coagulation factors

Arterial media Cerebral blood ﬂow Intracranial pressure and cerebrospinal ﬂuida Pituitary size Brain

Changes Decreases during mid-trimester, returns to normal by term Increases by 10–15 bpm 30–50% increase by term in a singleton pregnancy; 50–70% increase in twin pregnancy Increases 20–30% with singleton pregnancy; new result is a decrease in hematocrit (‘‘physiological dilution’’) 30–50% increase by term in singleton pregnancy; further increase during labor Increase: plasminogen, ﬁbrinogen, factor VII, VIII, IX, X No change: thrombin, factor V, anti-thrombin II, platelet adhesion Decrease: ﬁbrinolytic activity Thickening and fragmentation of reticular ﬁbers, mild hyperplasia of smooth muscle cells Modest increase in normal pregnancy; further increase in labor Normal in pregnancy, labor, and with contractions; Valsalva maneuver in labor shows pressures may be >700 Increases in size during pregnancy 0.08 mm/week;b return to normal 1 week post-partum whether breast-feeding or not Size of brain decreases by MR volume analysis while ventricles increase slightly in size; size then increases postpartum; unknown signiﬁcancec

a

From Ref. 200. From Ref. 201. c From Ref. 202. Source: Ref. 199. b

The decade of the 1990s saw substantial interest in the risks of heritable thrombophilias during pregnancy. In retrospective and cross-sectional studies, factor V Leiden, prothrombin 20210, and methylene tetrahydrofolate reductase mutations have all been associated with pregnancy complications, including thromboembolic disease, pre-eclampsia, and fetal growth restriction [21,22]. However, more recent prospectively collected series [23,24] suggest the thromboembolic risks during pregnancy and the puerperium may be lower than originally thought. These recent studies support the recommendation against population screening and prophylaxis. While normal pregnancy for years was said not to aﬀect cerebral blood ﬂow [25], transcranial Doppler techniques have changed the way we perceived cerebral blood ﬂow in pregnancy. Careful longitudinal measurements of normal pregnant women have shown that normal pregnancy results in a 24% decrease in middle cerebral artery systolic velocity and 17% decrease in the mean velocity. The diastolic velocity in the middle cerebral artery changes little during normal pregnancy. Cerebral resistance decreases by about 19% (as represented by measurements from the middle cerebral artery resistance index). Cerebral perfusion pressure increases signiﬁcantly (52%) between 12 and 40 weeks of pregnancy [26]. This situation indicates that arterial distensability increases during pregnancy while peripheral arterial resistance decreases. The increase in cerebral perfusion pressure coupled with a reduction in cerebrovascular resistance causes an increase in cerebral blood ﬂow. The magnitude of this change is diﬃcult to estimate given our current technology.

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Cerebral perfusion and cerebral blood velocity also increase during labor. Uterine contractions transfuse 250–300 cc of blood from the uterine into the central venous reservoir, which translates into an increase in the central venous pressure by 5–6 mm [27]. The Valsalva maneuver performed during the second stage of labor is also associated with wide ﬂuctuations in blood pressure and intracranial pressure. McCausland found that one third of women experience intracranial pressures of >500 mm cerebrospinal ﬂuid (CSF) in the second stage of labor (with Valsalva maneuver) [28,29].

III. EVALUATION OF PREGNANT WOMEN IN A VASCULAR EVENT The ﬁrst goal of treatment is to establish the correct diagnosis. When a pregnant woman presents with an acute neurological event, prompt and accurate diagnosis is crucial. Consider all of the causes of stroke in the young as well as pregnancy-speciﬁc causes. In general, the evaluation of any pregnant woman with a cerebrovascular event should proceed as if in the nonpregnant state (Table 2). Furthermore, Witlin et al. have shown that suspected eclampsia delayed the diagnosis of stroke in a signiﬁcant number of acute

Table 2 Evaluating Neurological Conditions in Pregnancy Test MRI (with diﬀusion and perfusion) MRI with gadolinium (FDA risk category C) MRA CT CT with contrast SPECT Angiography Ultrasound Carotid/vertebral TCD Echocardiogram TEE & TTE Lumbar puncture EEG Visual ﬁelds Dilated eye examination Fluorescein angiogramb Indocyanine green angiogramc

Risk to mother

Risk to fetus

Contraindications

None

None known

None

None known

Metal, cardiac pacemaker, otological implant Same as above

None None None None Minimal

None known Minimala Minimala minimal (<0.5rad) Minimala

As above None Contrast agent allergy None Contrast agent allergy

None None None

None None None

None None None

None

None

None None None

None None None with punctal occlusion None (FDA C) None (FDA C)

Incipient herniation or mass lesion None None Incipient glaucoma

None None

TEE, transesophageal echocardiogram; TTE, transthoracic echocardiogram. a Abdominal shielding. b From Refs. 203, 204. c From Ref. 205.

Minimal allergies Minimal allergies

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neurological events complicating pregnancy [30]. Computed tomography (CT) scanning, with and without contrast, has been used for years. In the emergency room, CT is usually the ﬁrst procedure to determine whether an acute hemorrhage has occurred. The American College of Obstetrics and Gynecology (ACOG) has suggested that less than 5 rad of ionizing radiation directed at the uterus has not been associated with fetal defects [31]. CT scans are usually less than 2 rad [32], with only a small fraction of this amount being deﬂected to the level of the uterus. Magnetic resonance (MR) imaging is now the major imaging tool for most acute vascular disease. Diﬀusion imaging has been helpful in identifying early ischemic disease. Importantly, diﬀusion imaging can distinguish between cerebral ischemia and confounding severe preeclampsia, since diﬀusion imaging is generally normal in the latter [33]. Magnetic resonance angiography (MRA) and venography (MRV) are very helpful in determining whether there is acute occlusion of a major vessel or vein. There are no known adverse eﬀects of MR on fetus or pregnancy. ACOG has indicated that it knows of no obvious harm from MR, but recommends imaging after the ﬁrst trimester whenever possible. Carotid angiography can safely be performed if a diagnosis has not been established. This can be safely done with abdominal shielding [31]. Digital techniques minimize the dye load and the amount of iodine exposure. Maternal hydration is important in order to avoid fetal dehydration. There is also concern about the iodine load after 25 weeks [31]. Figure 1 illustrates MR features of an acute stroke in a pregnant woman. Since strokes in young adults are most commonly cardioembolic in etiology, transesophageal echocardiography is the preferred imaging technique for the identiﬁcation of predisposing cardiac defects, including valvular disease, patent foramen ovale, and intracardiac clots. The importance of a thorough evaluation of neurological events in pregnancy cannot be overemphasized. A typical evaluation of a pregnant woman with an acute ischemic event is shown in Table 3. First, we will consider causes of stroke in the young, which can also occur outside of pregnancy, and consider speciﬁcally the eﬀect of pregnancy on these causes. See Table 4 for causes of stroke in pregnancy. For timing of when the stroke occurs in pregnancy, see Table 5.

IV. ARTERIAL OCCLUSIVE CEREBROVASCULAR DISORDERS (STROKE) IN PREGNANCY Arterial occlusive cerebrovascular disorders have multiple etiologies, including cardiac anomalies with associated embolic disease, atherosclerosis, and acute arterial dissection. The hallmark of these events is the development of an acute neurological deﬁcit in a vascular territory. These disorders require prompt diagnosis and appropriate treatment. Lanska and Kryscio [34] found that the risk of stroke was strongly correlated with pregnancy-related hypertension, so evaluation for risk factors that could lead to stroke should also be considered. Fortunately, Lamy et al. [35] found that women who have had a stroke in pregnancy or the puerperium who have no known etiology for stroke have a low risk of recurrent stroke in subsequent pregnancies; therefore, subsequent pregnancies in a woman who has had a stroke during pregnancy need not be contraindicated. The use of oral contraceptives is probably prohibited since the relative risk of stroke involved is 3.5 and if the patient has migraine the odds ratio (OR) increases to 13.9 [36].

Figure 1 A woman presented with abdominal pain, vaginal bleeding, and acute hemi-body numbness and ataxia. She was found to be 8 weeks pregnant and in the process of having a miscarriage. MR showed an acute stroke of the superior cerebellum. (a) Flair image shows the acute stroke. (b) Diﬀusion nicely delineates the extent of the stroke. (c) The ADC map shows low intensity (dark) indicating an ischemic event.

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Table 3 Evaluation of Acute Stroke in Pregnancy Imaging MR with diﬀusion for acute stroke CT without contrast for any acute event to rule out hemorrhage Blood Complete blood count Homocysteine level Protein C, S, Leiden factor V Prothrombin 20210 Antithrombin III Anticardiolipin antibody PT/PTT: lupus anticoagulant testing Fibrinogen Urine Toxicology screen for cocaine, other metabolites Echocardiogram

A. Cardiac Abnormalities Cardiac causes of stroke remain the most common cause of arterial ischemic infarction in pregnancy. This is probably related to the changes in the hemodynamic system during pregnancy. Congenital heart defects such as mitral valve prolapse and other valvular disease, atrial septal defect, intracardiac clot, and patent foramen ovale are the most common sources of embolism, followed by peripartum cardiomyopathy and infectious endocarditis. In one study 13% of women with heart disease complicating pregnancy were at risk for complications including stroke, pulmonary edema, arrhythmia, and cardiac death [37]. Patients with artiﬁcial heart valves may have a higher risk. Cardiac emboli may occur at any time during or after pregnancy. Common presentations are during the second and third trimesters and during the ﬁrst week after delivery [30]. Atrial ﬁbrillation, which can develop during pregnancy, has a risk of stroke between 2 and 10% [38]. Atrial ﬁbrillation associated with heart failure and rheumatic heart disease in the past was reported to increase both fetal and maternal mortality [39]. Recent studies show much lower maternal mortality rates [40]. Atrial ﬁbrillation is more likely to occur in pregnant women with heart failure due to rheumatic heart disease and/or cardiomyopathy. Anticoagulation with heparin and possible cardioversion are suggested treatments. There are certain congenital heart defects that are felt to contraindicate pregnancy. These include Marfan’s syndrome with a dilated aortic root, pulmonary vascular obstructive disease, dilated aortic root, severe aortic stenosis, and severe ventricular dysfunction [41]. Mitral valve prolapse (MVP), the most common valvular abnormality found in women of reproductive age, is found in 5–21% of women [42]. While the risk of stroke in pregnancy due to MVP is low, MVP does raise the risk for bacterial endocarditis, and antibiotic prophylaxis following delivery is indicated. Atrial septal defects (ASD) are generally associated with good pregnancy outcomes [43]. However, ASD may be responsible for paradoxical emboli and a potential cause of stroke.

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Table 4 Causes of Stroke in Pregnancy I. Arterial occlusive disease A. Thrombotic causes 1. Atherosclerosis 2. Fibromuscular dysplasia 3. Arterial dissection B. Embolic causes 1. Cardiac a. Peripartum cardiomyopathy b. Mitral valve prolaspe c. Rheumatic heart disease d. Endocarditis (bacterial and nonbacterial) e. Paradoxical embolism 2. Amniotic ﬂuid or air embolism II. Venous occlusive disease A. Hypercoaguable state B. Infections III. Drug-induced stroke A. Illicit drugs: cocaine B. Sympathomimetics and others: ergotamine, bromocriptine, isometheptene, phenylpropanolamine IV. Hypotensive disorders A. Watershed infarctions B. Pituitary necrosis (Sheehan’s pituitary necrosis) V. Hematological disorders A. Lupus anticoagulant; Sneddon’s syndrome B. Thrombotic thrombocytopenic purpura C. Sickle cell disease D. Thrombophilias: factor V Leiden, prothrombin 20210 mutation, protein C deﬁciency, antithrombin III, protein S deﬁciency, homocysteinemia, MTHFR deﬁciency VI. Arteritis A. Systemic lupus erythematosus B. Infectious arteritis (syphilis, tuberculosis, meningococcal) C. Cerebral angiitis D. Takayasu’s arteritis E. Postpartum cerebral angiopathy VII. Intracerebral hemorrhage A. Eclampsia and hypertensive disorders B. Venous thrombosis C. Choriocarcinoma or other metastatic malignancy D. Arteriovenous malformation E. Vasculitis F. Moyamoya disease VIII. Subarachnoid hemorrhage A. Aneurysm (saccular, mycotic) B. Arteriovenous malformation (cerebral, spinal cord); angioma C. Eclampsia D. Vasculitis E. Choriocarcinoma F. Venous thrombosis G. Uncommon causes: dural puncture; idiopathic

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Table 4 Continued IX. Pregnancy-speciﬁc vascular disease: eclampsia and preeclampsia; postpartum cerebral angiopathy X. Other A. Carotid cavernous ﬁstula B. Dural vascular malformation

Patent foramen ovale (PFO) occurs in about 5–30% of the general population, but is present in about 50% of young patients with cerebral infarctions. A patent foramen ovale occurs when the pressure in the right atrium is higher than in the left atrium, for example, during Valsalva maneuver—including straining at stool, during sexual intercourse, and during the second stage of labor. Since venous thromboses in the legs and pelvis are more common during pregnancy, and especially in the puerperium, the presence of a PFO maybe important [44]. A search for thrombophilias should also ensue since PFOassociated strokes occur more frequently in such women. Since PFO is such a common variant, some have suggested that one must rule out all other causes of stroke before invoking a PFO etiology [45]. The transesophageal echocardiogram along with a ‘‘bubble study’’—injection of a small amount of agitated saline into a cubital vein—allows for the optimal view of the atrial septum and enables the sonographer to visualize a shunt of bubbles traveling from the right atria to the left. In addition, transcranial Doppler can be utilized over the MCA to listen for these bubbles with and without Valsalva maneuver. Atrial septal aneurysms associated with PFO make a paradoxical embolism more likely [46]. Successful percutaneous closure of a PFO can be performed under echocardiographic guidance during pregnancy [47]. With improvement in cardiac surgical techniques, increasing numbers of women of reproductive age have undergone valvular replacement procedures. The risk of embolism during pregnancy in women who have mechanical mitral valves have been reported to be as high as 35% [48], which is higher than in the nonpregnant state (1.24–5.4%) [49]. Anticoagulation is recommended as prophylactic in these cases. Although some advocate using warfarin after the ﬁrst trimester using unfractionated heparin or therapeutic doses of low molecular weight heparin in the ﬁrst and third trimesters [50], most U.S. practitioners would use heparin through the duration of pregnancy, with conversion to warfarin after delivery. Warfarin therapy is not a contraindication to nursing. A search for cardiomyopathy should be considered in any woman who presents with a stroke and symptoms of cardiac failure. Cardiomyopathy is caused by loss of the cardiac myocytes from either inﬂammation or ﬁbrosis. Potential causes of cardiomyopathy include drugs, toxins, ischemia, infections, and pregnancy. Peripartum cardiomyopathy

Table 5 Timing of Stroke in Pregnancy and Parturition

Ischemic stroke Cerebral venous thrombosis Subarachnoid hemorrhage Arteriovenous malformation Severe pre-eclampsia

First trimester

Second trimester

Third trimester

Postpartum

X X X X 0

X X X X X

X X XXX X XXX

XX XXXX X X XX

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occurs in 1 in 3,000–15,000 pregnancies and is deﬁned by the onset of cardiomyopathy of otherwise unknown etiology during the last half of pregnancy or at least within 6 months of delivery, with reduced left ventricular function of less than 40% as measured by echocardiography [51]. Older women (>35 years) and black women are at increased risk. Although almost 50% of women who develop peripartum cardiomyopathy will have a complete clinical resolution, for those whose myopathy persists, there is a high mortality rate. Bernstein and Magriples [52] compared peripartum cardiomyopathy with dilated cardiomyopathy diagnosed before pregnancy. They found that women with stable cardiac disease before pregnancy did well, whereas those who had the initial onset of cardiomyopathy during pregnancy and the puerperium had increased mortality and were more likely to go on to cardiac transplant. These women should be heparinized if ischemic events or thrombi develop. Women who survive peripartum cardiomyopathy should be counseled that subsequent pregnancies could be associated with further decrease in left ventricular function, which can lead to deterioration and death [51]. Rheumatic fever may become symptomatic during pregnancy. Some advocate continuous antibiotic treatment during pregnancy to avoid reactivation of the disease [4]. Infectious endocarditis complicating pregnancy is rare. The most common organisms reported to cause endocarditis during obstetric and gynecological procedures include Streptococcus viridans, Staphylococcus aureus, and enterococci. All women with cardiac conditions such as MVP, rheumatic valve, or prosthetic valves should receive prophylactic antibiotics (penicillin G, gentamycin, or both) before delivery. Air embolism has been reported with increased frequency in pregnancy [53], especially with underlying congenital heart defects. Air embolism occurs when air enters the venous circulation. This has been reported with cunnilingus, where air insuﬄates the vagina, enters a venous sinus, and proceeds through the right atrium into the arterial circulation through a patent ductus arteriosus or foramen ovale. Symptoms include a sudden loss of consciousness, seizure, or focal neurological deﬁcit after sexual activity. In such a situation, the patient should be placed in the left lateral Trendelenburg position (minimizing further arterialization of air emboli) and given 100% oxygen. Hyperbaric oxygen treatment can also decompress the bubble size. Steroids may be required if there is cerebral edema, and giving aspirin will decrease platelet aggregation. B. Premature Atherosclerosis While atherosclerosis is a common cause of stroke in the elderly, it is an uncommon etiology for stroke during pregnancy [24]. Stroke of atherosclerotic origin in pregnancy is more likely in women who are older (>30 years), smokers, diabetic, hypertensive, and/or hyperlipidemic [54]. In addition, hyperhomocysteinemia may lead to premature atherosclerosis. Carotid and vertebral artery dissections can occur during or following childbirth. Jaigobin and Silver found that carotid dissection accounted for about 8% of arterial infarctions during pregnancy. Such patients usually present with headache or neck pain. Horner’s syndrome frequently accompanies a carotid dissection. Vertebral artery dissections initially produce neck and occipital pain, and then signs of brainstem or cerebral ischemia [55]. Patients with ﬁbromuscular dysplasia are particularly predisposed to dissections [56]. Ischemic events are sometimes delayed after the dissection has occurred. Since strenuous exercise and neck manipulation have been associated with carotid dissection, the rigors of labor and delivery have also been implicated [57]. Diagnosis is made with MR (best seen with axial T1-weighted fat saturation sequences at the skull base) and MRA, and treatment usually consists of anticoagulation.

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Moyamoya syndrome is a condition of progressive occlusion of the internal carotid arteries intracranially. The name comes from Japanese clinicians who likened the angiogram seen in the condition to a ‘‘puﬀ of smoke.’’ The diagnostic criteria for moyamoya disease include cerebral angiographic evidence of bilateral stenosis or occlusion of the large intracranial arteries with compensatory vascular networks [58]. Moyamoya is almost 50 times more common in women than in men [59] and is sometimes seen in pregnancy. The condition can present with seizure [60], lacunar strokes, and most commonly with intracerebral hemorrhages [61,62]. Because hypertension may complicate the condition, anyone with moyamoya syndrome should have frequent blood pressure examinations during pregnancy. Treatment even in the nonpregnant state is palliative. Medical treatments like vasodilators, anticoagulants, ﬁbrinolytics, antiﬁbrinolytics, and anticonvulsants have been tried unsuccessfully. Surgical treatments also have variable success [58]. The outcome is not always benign, and complications can abound [63]. Takayasu’s disease was also initially described in Japanese girls and women and remains more common in Asians than in North Americans. Criteria for diagnosis of Takayasu arteritis include systemic features (fever, musculoskeletal), elevated erythrocyte sedimentation rate, features of vascular ischemia (e.g., claudication, absent pulse, bruit, unequal blood pressures), and characteristic angiographic ﬁndings [64]. The disease involves progressive narrowing of the aorta and its branches; hence, it is often called ‘‘pulseless diseases.’’ While the disease most commonly causes limb and organ ischemia from the gradual stenosis, stroke has also been reported. The most common neurological symptoms include dizziness and lightheadedness from vertebral artery stenosis. If there are transient ischemic attacks or strokes, concomitant carotid or vertebral artery stenosis is present. Certainly asymptomatic carotid and vertebral artery stenosis can also be present. Since it is a disease of generally young women, it can be present during pregnancy [64]. These patients often initially become symptomatic in pregnancy because of the increased blood volume and the narrowing of the blood vessels. Treatment outside of pregnancy includes gluocorticoids with or without a cytotoxic agent like methotrexate. Surgical treatments such as by-pass procedures, arterial reconstruction, and angioplasty have been reported as well. Since remissions can occur, pregnancy is generally recommended during a remission [64]. Symptomatic gravid women can be treated safely with steroids. Careful attention to signs of hypertension, aortic insuﬃciency, and congestive heart failure is important [65].

V. VENOUS OCCLUSIVE CEREBROVASCULAR DISEASE IN PREGNANCY Cerebral venous thrombosis (CVT) was once thought to be the most common cause of stroke in pregnancy and the puerperium. According to Lanska, the risk of intracranial venous thrombosis is 11.4/100,000 deliveries. He found that increasing maternal age had the strongest association [34]. In epidemiological studies from around the world, the rate of intracranial venous thrombosis complicating the peripartum was anywhere from 1/100,000 in U.S. series to 195/100,000 in India. In India, CVT in pregnancy causes almost 15–20% of the total number of strokes in the young and at least one fourth of the total number of maternal deaths [66]. It is frequently associated with infection, hypercoaguable states, and hyperviscosity syndromes (sickle cell disease, dehydration). See Table 6 for causes of CVT in pregnancy. The most frequent symptom of venous thrombosis is severe headache. Seizures will occur in 80%, while coma or paresis occurs in half [30]. (See Table 7 for diﬀerentiating causes of seizures in pregnancy.) Sometimes the symptoms are vague, like headache, so it is

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Table 6 Causes of Venous Thrombosis in Pregnancy Leiden factor V with protein C resistance Protein C deﬁciency Protein S deﬁciency [209] Antithrombin III deﬁciency Anticardiolipin antibodies Prothrombin (20210A) gene mutation Homocysteinemia Paraproteinemia Thrombocythemia Systemic lupus erythematosus Cryoﬁbrinogenemia Paroxysmal nocturnal hemoglobinuria Behcßet’s disease Familial Mediterranean fever Oral contraceptive use Pregnancy Androgen therapy for anemia Infection—especially middle ear infections in children Dehydration Chronic mastoiditis Sarcoidosis Trauma-accidental Iatrogenic (e.g., catheter-induced subclavian vein thrombosis)

Table 7 Diﬀerentiating Causes of Seizures in Pregnancy Cerebral venous thrombosis Timing

Postpartum

Other associations

Infection

Imaging

MRI/MRV: poor ﬂow in sinuses

Cerebrospinal ﬂuid

Bloody; increased pressure

Eclampsia Antepartum (2/3) or postpartum (1/3) Proteinuria, hypertension, elevated liver function tests MRI typical curvilinear abnormalities at the gray-white junction in the parietal occipital lobes Increased pressure possible; otherwise normal

Idiopathic seizures Any trimester

Normal or mesial temporal sclerosis; look for other causes of seizure, e.g., tumor Normal

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important that healthcare professionals consider this diagnosis whenever they see a pregnant or postpartum woman with new complaints like headache, particularly if the headache and neurological deﬁcits are migratory or intermittent. Focal signs of papilledema, especially in dural venous thrombosis, and focal neurological signs may be present. There are three primary types of cerebral venous thrombosis reported in pregnancy: cortical vein thrombosis, dural venous thrombosis, and internal cerebral vein thrombosis. (See Table 8 for distinguishing characteristics.) The diﬀerential diagnosis usually includes eclampsia, brain tumor, meningitis, and idiopathic intracranial hypertension. The most important tool in diagnosing venous thrombosis is the MR scan. While CT can show hemorrhage and possible infarctions, MR reveals all of this, plus subtle edema. Phase-contrast MR venography will outline dural sinuses in detail. Furthermore, MR will assist in the diagnosis since eclampsia can have a similar clinical presentation (headache and seizure) but very diﬀerent imaging ﬁndings [67]. Figures 2–4 which demonstrate the diﬀerent kinds of venous thrombosis in pregnancy. One study compared 67 patients with venous thrombosis in pregnancy with 46 cases unrelated to obstetrical causes. The authors found that patients with obstetrically related thrombosis were younger and had a more acute onset. Anemia was more frequent. Although the severity of illness was similar in both groups, the obstetrical group had a better outcome and mortality was also less (9% obstetrical group vs. 33% other causes) [68].

Table 8 Diﬀerentiating Cerebral Venous Thrombosis

Presenting features

Radiographic features

Associations

Outcome

a

From Ref. 208. Source: Refs. 206, 207.

Cortical vein thombosisa

Dural sinus thrombosis

Internal cerebral vein thrombosis

Seizure—usually focal onset with generalization; headache; focal neurological dysfunction May see focal brain edema with a hemorrhage near the cortical surface; doesn’t follow arterial territory; MRV may be normal Similar to dural vein thrombosis; oral contraceptives

Papilledema from increased intracranial pressure; headache; seizure

Stupor and coma with spasticity, posturing, vertical gaze abnormalities

MRV will show absent ﬂow of the sagittal (most common) and/ or lateral sinus

MR will show changes in the thalamus bilaterally; may see absent ﬂow in the straight sinus and internal cerebral vein on MRV

Infection, coagulopathies, mastoiditis; oral contraceptive use Good if recognized early; watch for blindness from papilledema

Sepsis, dehydration, sickle cell disease, ulcerative colitis, oral contraceptives Generally poor; often goes unrecognized

Generally good

Figure 2 A 22-year-old presented with a generalized seizure 4 weeks postpartum; she was discovered to have a transverse venous sinus occlusion with involvement of a cortical vein. (a) Gradient recall echo shows small hemorrhage within the left temporal lesion. (b) Flair MR showing focal brain edema with a hemorrhage near the cortical surface. (c) MRV showing occlusion of the left transverse venous sinus.

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Figure 3 Dural venous thrombosis: 28-year-old woman at 8 weeks gestation with sagittal and straight sinus thrombosis. (a) Axial T2-weighted MR shows that where a ﬂow void should arise, there is a mixed signal within the sagittal sinus. (b) Sagittal view of MR (gradient recall echo image) shows large occlusion of the straight sinus along with occlusion of the sagittal sinus.

Treatment of venous sinus thrombosis starts with correction of predisposing factors such as infections, controlling seizures with anticonvulsants, improving hydration, and anticoagulation. Local thrombolysis utilizing a ﬂuoroscopically guided transvenous catheter to deliver ﬁbrinolytic agents may be indicated for progressive clinical deterioration despite aggressive medical management. Occasionally antiedema agents such as dexamethasone may be required. Mannitol may be used postpartum for incipient herniation, but should be avoided during pregnancy because of fetal compromise as a result of osmotic hypovolemia. Anticoagulation for cerebral venous thrombosis is the mainstay of treatment even if cerebral hemorrhage is present. A large Indian study showed that although 10 of 42 postpartum women receiving heparin died of CVT, only one death caused by heparinrelated hemorrhagic complication occurred, whereas 21 of 47 women not treated with hep-

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Figure 4 (a) Typical MR T1 and ﬂair images of internal cerebral vein thrombosis showing hypodensity on T1 images of bilateral thalami and bright signal on ﬂair of both thalami. This woman is a 26-year-old woman on birth control pills presenting with altered mental status. (b) The sagittal image shows bright signal in the straight sinus and into the internal cerebral vein (arrow).

arin died [69,70]. A French study showed that none of the 23 patients treated with heparin for CVT died, whereas 4 of 15 women not treated with heparin died [71]. Anticoagulation should be continued for 4–6 weeks postpartum. In subsequent pregnancies, prophylactic anticoagulation with heparin should at least be considered post-partum and usually during pregnancy as well. Endovascular treatment of dural sinus thrombosis has been proposed for diﬃcult cases, especially those that do not respond to anticoagulation and have progressive neurological symptoms despite adequate anticoagulation with heparin. The use of thrombolysis and thrombectomy in pregnancy has been reported [72]. Complications of CVT include blindness from papilledema (see Fig. 5). Therefore, women with CVT should have visual acuity and visual ﬁeld studies. If a woman’s vision deteriorates despite treatment of the underlying CVT and medical treatment of acetazol-

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Figure 5 Disc swelling in a postpartum woman with a sagittal sinus thrombosis.

amide, an optic nerve sheath decompression can be performed under local anesthesia and need not be withheld from the patient because she is pregnant [73]. A. Drug-Induced Stroke in Pregnancy A postpartum cerebral angiopathy has been associated with the use of ergot alkaloids such as ergonovine, which is commonly used to control postpartum bleeding. Besides the wellknown association with ergotamines, bromocriptine, sympathomimetic amines (many diet pills, Neosynephrine, isometheptene [74]), phenylpropanolamine, and illicit drugs such as amphetamine and cocaine have all been associated with cerebral angiopathy (Table 9). The presentation is usually one of headache and possibly seizure. It is often confused with eclampsia. Even the imaging characteristics can be similar to that seen in eclampsia with bilateral occipital/parietal increased signal intensity. Angiography will show multiple areas of segmental vasospasm. B. Illicit Drug Use Cocaine abuse remains a major public health problem. It has been associated with ischemic cerebral infarction, subarachnoid hemorrhage, intracerebral hemorrhage, and/or intraventricular hemorrhage. Seven percent of all cocaine users are pregnant [75]. In a multicentered urine toxicology screening study, cocaine metabolites were detected in 11% (0.427%) of pregnant women [76]. Cocaine crosses the placenta and is associated with

Table 9 Drugs Related to Stroke in Pregnancy Bromocriptine and ergotamines Sympathomimetic amines (e.g., neosynephrine; isometheptene; phenylpropanolamine; ephedrine, pseudoephedrine) Amphetamine Cocaine Phencyclidine

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preterm birth and fetal growth restriction birth weight infants. Cocaine has been associated with intracerebral hemorrhage [77] and both maternal and neonatal cerebral infarctions [78]. Cocaine ingestion can also mimic severe preeclampsia and eclampsia and should be in the diﬀerential diagnosis of that condition [79]. There has also been a signiﬁcant rise in the use of methamphetamines among young adults. Acute and chronic ingestion is associated with cerebral infarction, hemorrhage, and postpartum angiopathy [80]. Urine toxicology screen should be performed on all young adults with stroke. Certainly the index of suspicion should be high for all women with any stroke-like event in pregnancy, irrespective of socioeconomic status. C. Hypotensive Disorders in Pregnancy Watershed infarction causes bihemispheric coma, preserved brainstem function, but bilateral often asymmetrical motor ﬁndings. MR imaging shows characteristic defects between the middle cerebral artery territory and the posterior cerebral artery. Causes of watershed infarctions include cardiac arrest, sudden cardiovascular collapse from amniotic ﬂuid emboli and hypovolemic shock. Certainly, excessive blood loss at delivery with inadequate resuscitation can result in watershed infarction with long-term sequelae and even vegetative state. D. Pituitary Necrosis Because of its increased blood supply and size in late pregnancy, the pituitary gland is more susceptible to peripartum infarction, most commonly in association with major placental abruptions complicated by ﬁbrin microemboli (consumptive coagulopathy). Pituitary necrosis can occur within in the ﬁrst few hours of delivery or can be a delayed reaction [81]. In the acute form, or Sheehan’s syndrome, the patient may present with persistent hypotension, tachycardia, failure of lactation, fatigue, nausea, and hypoglycemia. Diﬀerentiating ischemic necrosis from lymphocytic hypophysitis is important [81]. While the exact mechanism is unknown, the necrosis is secondary to pituitary ischemia and is often preceded by obstetrical hemorrhage and/or retained placental products. Pituitary autoantibodies may also play a role in the development of the more delayed form of pituitary insuﬃciency [82]. Immediate treatment consists of hydrocortisone and dextrose. Acute pituitary hemorrhage with associated apoplexy has been reported with the use of clomiphene for infertility [83]. E. Hematological Disorders Leading to Stroke Sickle cell disease is one of the most common hemoglobinopathies in African Americans. Maternal mortality has been reported to be increased to 1–14%. Patients with the disease and trait are at increased risk for stroke, venous thrombosis, and subarachnoid hemorrhage. Patients also have an increased risk of cardiac dysfunction [84]. Adequate prenatal care is important to minimize the frequency and intensity of sickle crisis and associated vascular complications. Neurological deﬁcits, renal failure, fever, thrombocytopenia, and hemolytic anemia characterize Thrombotic thrombocytopenic purpura (TTP). One of the most common accompaniments to TTP is neurological symptomatology, including transient ischemic attacks, cortical infarction, lacunar stroke, and diﬀuse encephalopathy. The encephalopathy may be associated with headache, seizures, and visual loss. TTP then becomes

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important to diﬀerentiate from severe preeclampsia. It can even have a reversible posterior leukoencephalopathy syndrome in the parietal-occipital regions that can mimic the MR changes seen in severe preeclampsia and eclampsia. Treatment is directed toward plasma exchange [85]. One of the most common thrombophilic coagulopathies to cause arterial stroke and venous thrombosis during pregnancy and the puerperium are the antiphospholipid antibodies—lupus anticoagulant and anticardiolipin antibodies. Antiphospholipid syndrome is characterized by the presence of an antiphospholipid antibody, with a history of arterial, venous thrombosis. Transient ischemic attacks, especially amaurosis fugax, arterial occlusion, cerebral venous thrombosis, thrombocytopenia, chorea, and even migrainous phenomenon, typify the presence of these antibodies and represent the most common neurological manifestation of these antibodies. Venous thrombosis, including lower extremity, retinal vein, sagittal sinus, and mesenteric thrombosis, is more common than arterial thrombosis [86]. Antiphospholipid antibodies are also associated with placental infarction, resulting in recurrent spontaneous abortions and second trimester fetal demise, preeclampsia, fetal growth restriction, and/or fetal demise, all obstetrical hallmarks of the antiphospholipid syndrome. Sometimes splinter hemorrhages in the ﬁngernails can signal the presence of antiphospholipid antibodies [87] (see Fig. 6). Studies correlating the presence of antiphospholipid antibodies and preeclampsia have yielded conﬂicting results. A study of 317 women with a history of preeclampsia found that 20% had recurrence. Testing positive for antiphospholipid antibodies was not predictive of recurrent preeclampsia. Antiphosphatidylserine antibody was associated with severe preeclampsia. Positive results for IgG anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. However, the positive predictive value of all these associations was modest [88]. Complications associated with antiphospholipid antibodies can be minimized using prophylaxis with low-dose aspirin (60–80 mg/day) and heparin [5000 U unfractionated heparin SQ bid or low molecular weight heparin (LMWH) in prophylactic doses]. One protocol reported with successful pregnancy outcome is LMWH, 40–80 mg of enoxaparin each day (titrated to the level of antifactor Xa activity), and 80 mg of aspirin. In this study the authors reported that successful pregnancy and delivery is possible [89]. Other treatments have included

Figure 6 Antiphospholipid antibodies frequently present with splinter hemorrhages such as these. (See Ref. 87.)

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prednisone and intravenous gamma globulin. Long-term anticoagulation after pregnancy in anyone who has suﬀered a stroke is usually recommended [86]. Thrombocytosis or essential thrombocythemia is a myeloproliferative disorder that can be seen in young women and therefore will be seen in pregnancy. It usually causes thrombosis localized to the placenta but can be systemic as well. Neurological manifestations include transient ischemic attacks, migraine, stroke, and ischemia of the microcirculation of the extremities (erythromelagia) [86]. The most common consequence of this disorder usually involves the placenta, resulting in recurrent abortions, fetal demise, and intrauterine growth retardation (IUGR). In the non-pregnant state, treatment with aspirin and platelet-lowering medications such as hydroxyruea, anagrelide, and interferon-alpha (IFN-a) reduce thrombotic tendency. In pregnancy, aspirin is generally the treatment of choice. Thrombotic episodes can occur despite the falling platelet levels, which occur with volume expansion up to 34 weeks [86]. Even though aspirin is associated with bleeding complications, the risk of thrombosis exceeds the risk of bleeding in most cases [86]. In the postpartum state, attention to the platelet count is essential, since platelets tend to rise— aspirin and platelet reduction therapy should then be administered. Sticky platelet syndrome is a rare autosomal dominant platelet problem that can be associated with venous and arterial thrombosis. Neurovascular problems include retinal thrombosis, stroke, transient ischemic attacks as well as unexplained acute myocardial infarction and peripheral arterial/venous thrombosis. The diagnosis is made when platelets display hyperaggregability in platelet-rich plasma with adenosine diphosphate with and without combinations of epinephrine [90]. The disorder has been reported in pregnancy [90]. Sometimes concomitant congenital clotting factors may also be abnormal [91]. Treatment is aspirin. Hereditary conditions of the coagulation pathway, such as the presence of factor V Leiden or prothrombin 20210A, and less frequently deﬁciencies of antithrombin III, protein C, and protein S, are associated with venous thrombosis. A family history of venous events should alert one to the presence of these factors. The results of proteins C and S drawn during pregnancy should be interpreted with caution, as the levels gradually decrease throughout pregnancy. Deﬁnitive diagnosis of protein C or protein S deﬁciency should be delayed until at least 6 weeks postpartum [92]. F. Arteritis Systemic lupus erythematosus (SLE) is an autoimmune condition that primarily involves women of reproductive age. The angiopathy associated with SLE aﬀects primarily small vessels, resulting in various clinical manifestations such as encephalopathy, seizures, and multifocal cerebral infarctions. Steroids are the mainstay therapy and should be continued through pregnancy and the puerperium.

VI. TREATMENT OF STROKE IN PREGNANCY While speciﬁc treatments for certain conditions in pregnancy, mentioned above, are appropriate, a general approach to treatment of stroke including venous thrombosis is necessary. Just as in the nonpregnant young adult, risk factors such as diabetes, preexisting hypertension, hypercholesterolemia, and cigarette smoking should be identiﬁed and treated. Medications used in the treatment of stroke are shown in Table 10. While no

FDA pregnancy category

C

B

Thrombolytic

Category D:

B

C

B B B (PDR) C (Briggs)

C: during ﬁrst and second trimester D: during third trimester at full dosage (325 mg)

Agent used in acute stroke

Standard anticoagulant therapy Anticoagulant—used in DVT Standard anticoagulant therapy for mechanical heart valves

Stroke prevention; treatment after stroke; low dose prevention of eclampsia; prevention of recurrent fetal loss in APLA syndrome Stroke prevention Stroke prevention Stroke prevention

Indication

No—due to high molecular weight Yes;

No

Yes Yes

Yes

Crosses the placenta

Case report evidence

Intra-arterial treatment may be safer

Known to cause birth defects 6–12 weeks: fetal intraventricular hemorrhage, microcephaly, cataracts, blindness

Watch for thrombocytopenia; osteopenia Osteopenia may occur

Use only when indicated Use only when indicated

If possible, avoid in the last 3 months due to bleeding

Special considerations

United States Food & Drug Administration. Classiﬁcation of Drugs in Pregnancy, 1975. The current FDA classiﬁcation schema uses the following classiﬁcation of drugs: A = Safe, controlled studies fail to show a risk to fetus in the ﬁrst trimester. B = Animal studies have not shown a risk, but there are no controlled studies in pregnant women. C = Studies in animals may show risk or there are no controlled studies in women and animals. Therefore, these drugs should be used when the beneﬁt outweighs potential risk. D = There is risk shown in human fetuses, but the beneﬁts may warrant the use in a pregnant woman for a life-threatening condition. X = Studies in animals or humans have shown deﬁnite risk, and the risk outweighs any possible beneﬁt. a From Ref. 211. Source: Ref. 210.

Thrombolysis Tissue plasminogen activator t-PA (Alteplase)a Urokinase

Low molecular weight heparin (Enoxaparin) Warfarin

Clopidrogel (Plavix) Ticlopidine Dipyramidole Anticoagulant Heparin—unfractionated

Antiplatelet Aspirin

Drug

Table 10 Drugs Used in Treatment of Cerebrovascular Disorders

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medication is actually safe during pregnancy, many medications can be used to prevent or treat stroke, with proper counseling for pregnant women. Aspirin has been used in pregnancy for stroke prevention. Although listed in FDA pregnancy category C, we have many years of experience using this drug. Low-dose aspirin has been used extensively for preeclampsia prevention. Low dose (60–80 mg) has not been associated with adverse fetal eﬀects [93]. This is because salicylate is completely metabolized by the liver on a ﬁrst-pass basis, whereas prolonged (>48 h) higher-dose (325 mg) aspirin use is not recommended in pregnancy because it has been associated with prolonged pregnancy, dysfunctional labor, postpartum hemorrhage, and/or fetal compromise (premature constriction of the ductus arteriosus, intracerebral hemorrhage, decreased renal blood ﬂow with resultant oligohydramnios). Low-dose aspirin is routinely used during pregnancy in women who have antiphospholipid antibodies. While it has been touted as a preventative for preeclampsia [93], recent larger studies have not shown similar eﬃcacy [94,95]. The use of heparin and warfarin in pregnancy remains somewhat controversial. Heparin is the preferred drug, since it does not cross the placenta but is not risk-free. Heparin is favored over warfarin mainly due to a well-described warfarin embryopathy. Monitoring women on heparin in pregnancy is also problematic since pregnancy can change pharmacokinetics [96]. In general, heparin may be stopped at the onset of labor (though for high-risk situations it need not be) and 4–6 hours before spinal epidural anesthesia. Complications of heparin include bleeding, thrombocytopenia, and osteoporosis. The complication rate from both heparin and LMWH is about 2% and does not diﬀer from the nonpregnant state [102]. Low molecular weight heparin may oﬀer advantages over heparin; it does not cross the placenta, but it is easier to administer and also has the advantage of sparing calcium. DeBruijn et al., studying LMWH for cerebral sinus thrombosis, found that it was eﬀective and safe even in concurrent cerebral hemorrhage [97]. Not much experience with LMWH exists, and while it is clear that it is eﬃcacious for deep venous thrombosis, there are fewer studies showing its eﬃcacy in ischemic cerebral disease [98,99]. Complications from LMWH include bleeding and thrombocytopenia. Warfarin causes an embryopathy in 8–30% of fetuses exposed during menstrual weeks 6 through 12 [100]. The syndrome includes microcephalus, mental retardation, bone stippling, and mid-facial hypoplasia. Warfarin administration has also been associated for years (despite evidence from studies that did not control for the underlying condition for which the drug was administered) with mental retardation, optic atrophy, microcephalus, and cerebral agenesis during any time of pregnancy [101]. A study of 72 pregnancies undergoing anticoagulation with warfarin for heart valve defects during the second and third trimester showed relatively few fetal defects [100]. Guidelines for anticoagulation in pregnancy for stroke and venous thrombosis suggest that women who require long-term anticoagulation and who plan pregnancy can use heparin given subcutaneously every 12 hours to prolong the PTT 1.5 times normal OR, use warfarin and do a pregnancy test each week until pregnant, and then switch to heparin after a positive pregnancy test. Women with mechanical prosthetic valves should be treated with subcutaneous heparin every 12 hours during the entire pregnancy or continue until week 13, using warfarin until the middle of the third trimester, and then switch back to heparin [102]. Most obstetricians in the United States favor heparin or LMWH throughout pregnancy. The use during pregnancy of ﬁbrinolytics such as tissue plasminogen activator (t-PA) has been considered contraindicated because of unknown risks to mother and fetus. There is, however, limited safety information in the literature of pregnant patients receiving

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ﬁbrinolytic therapy for indications including myocardial infarction, vein thrombosis, thrombosed mitral and tricuspid valve, and pulmonary embolism [103,104]. In these cases all patients recovered, and one pregnancy had to be interrupted because of bleeding. Dapprich and Boessenecker reported a single case of a 31-year-old woman with left MCA stroke who was successfully treated at 12 weeks gestation with complete neurological recovery and normal delivery of healthy child at 40 weeks [105]. While there are no formal recommendations of ﬁbrinolytic use during pregnancy, it is reasonable to weigh the ﬁbrinolytic potential beneﬁt of preventing permanent disability with the risk of bleeding complications and possible fetal eﬀects on a case-by-case basis [106]. More experience is clearly needed before further recommendations can be made.

VII. NONTRAUMATIC BRAIN HEMORRHAGE Intracerebral hemorrhages during pregnancy are fortunately not common, since they are associated with a deﬁnite increase in maternal mortality. While the most common cause of intracerebral hemorrhage is aneurysmal rupture and arteriovenous malformation, other causes, such as preeclampsia, vasculitis, cavernous angioma, thrombocytopenia, anticoagulation therapy, and disseminated intravascular coagulation, should be considered [2]. Rarely, subarachnoid hemorrhage has been reported after spinal anesthesia for delivery [107]. Full evaluation including angiography may be required. On occasion, no cause of hemorrhage can be determined despite extensive evaluation [108]. See Table 11 for diﬀerentiating hemorrhage in pregnancy. A. Aneurysm Symptomatic intracranial aneurysms complicate pregnancy in about 1 in 1,100–25,000 pregnancies [109,110]; this incidence is higher than the risk of aneurysmal rupture in the nonpregnant woman. The risk increases with each trimester and with increasing age of the mother. Between 5 and 12% of maternal deaths are attributed to subarachnoid hemorrhage due to aneurysm; this makes nontraumatic subarachnoid hemorrhage the third most common cause of nonobstetric death. Pregnancy increases the risk of aneurysmal rupture by a factor of 5 when compared to age-matched nonpregnant women [109]. Although aneurysms may rupture during any trimester, historical data would suggest that rupture is more frequent in the third trimester [109]. Dias and Sekhar’s review suggests that rupture occurs equally in all three trimesters [111]. In both animal and human research, hyperplasia of the intima and reorganization of the media are seen during pregnancy [112]. Whether this aﬀects growth or development of an aneurysm or causes fragility of the aneurysm is unknown. The symptoms of subarachnoid hemorrhage in pregnancy are similar to those in non-pregnant individuals. They include sudden onset of the worst headache of one’s life, nausea, vomiting, meningismus, and even coma [113]. CT imaging characteristically demonstrates an acute spontaneous hemorrhage. If there is any question, lumbar puncture can safely and quickly demonstrate hemorrhage. Once the diagnosis is made, three-vessel angiography is important to demonstrate the aneurysm and prepare for surgical correction. Abdominal shielding precautions should be employed during pregnancy (Fig. 7). Treatment is generally neurosurgical or a combination of endovascular/neurosurgical treatment of the aneurysms. Since 60–70% of pregnant patients treated conserva-

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Table 11 Diﬀerentiating Causes of Subarachnoid Hemorrhage Characteristic

Aneurysm

Age of onset

25–37; increases with age Severe Mulitparous Absent +/ 3rd 1/3 to 2/3 Prominent 15–30% 30–50% 30% 20% Blood Less than 2 weeks Good if mother treated Treated: 11% mortality; Untreated: 63% mortality 27% mortality

Headache Parity Epigastric pain Nausea/vomiting Trimester Loss of consciousness Nuchal rigidity Seizure Hypertension Proteinuria Focal weakness Cerebrospinal ﬂuid Recurrent hemorrhage Subsequent pregnancies Prognosis—mother

Prognosis—fetus

AVM

Eclampsia

15–20

Any age

May be severe Primiparous Absent +/ 3rd + May be present Present 14% 14% Frequent Blood May occur Good

60% frontal; often dull Any Present + 3rd or postpartum May be present Rare 100% All All Rare May be clear No May recur especially if predisposing causes Good if delivered

Untreated: 32% mortality

Variable depends on fetal age at diagnosis

Source: Ref. 126 and Digre KB, Varner MW. Diagnosis and Management of Cerebrovascular disorders in pregnancy. In: Adams HP, ed. Handbook of Cerebrovascular Disease. New York: Marcel Dekker, 1993: 255–286.

tively with bedrest died from rebleeding within 3–8 weeks versus only 8–10% of pregnant patients treated with surgery, immediate surgical intervention is recommended [111]. In most cases surgery should be performed within 24 hours of the initial bleed. If the patient is in active labor, has fetal distress, or has preeclampsia or eclampsia in addition to the aneurysm, one should consider delivering ﬁrst and then follow with neurosurgical intervention. Endovascular treatment of acutely ruptured aneurysms is gaining favor in pregnancy [114,115]. If the aneurysm is to be surgically treated during pregnancy, general anesthesia can and should be administered. Positioning the mother during surgery in the lateral decubitus position should be considered, since the supine position may cause inferior vena cava compression leading to maternal hypotension and fetal compromise [111]. Hypothermia has been used in pregnancy without known ill eﬀects. Hypotension has been used when necessary during surgery, but many feel that it is contraindicated because of a potential decrease in uteroplacental blood ﬂow [111]. Corticosteroid therapy can be safely given when not otherwise clinically contraindicated. Mannitol is generally contraindicated because of the change in fetal plasma osmolality and subsequent dehydration [109]. Once the aneurysm has been repaired, pregnancy may proceed with normal delivery. However, when there is no correction of the aneurysm or only partial treatment of the aneurysm, cesarean delivery should be considered.

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Figure 7 (a) CT without contrast in a pregnant woman with a sudden onset of severe headache during pregnancy. The CT shows diﬀuse blood in the Sylvian ﬁssure. (b) The angiogram easily revealed an aneurysm.

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Complications of aneurysmal rupture include vasospasm. How often vasospasm occurs during pregnancy after rupture is unknown. Early surgical intervention with removal of clots may prevent vasospasm, a complication that typically occurs in the non-pregnant patient 3–7 days after hemorrhage. With proper intravascular monitoring, vasospasm can be treated with colloids and volume expansion to improve blood ﬂow in pregnancy. Nimodipine has been used in pregnancy without signiﬁcant adverse side eﬀects [111]. Maternal outcome is generally excellent with grade 1–3 hemorrhages. Grade 4 hemorrhages carry a 45–75% mortality [109]. Fetal outcome is normal in 95% of cases when the mother has had surgical correction of the aneurysm, whereas fetal survival dropped to 27% when the mother had no surgical correction [111]. Subsequent pregnancies after successful clipping of an aneurysm have been uneventful [111]. Asymptomatic aneurysms discovered incidentally in pregnancy should be treated if they are larger than 10 mm [116]. If surgery is not undertaken, the aneurysm should be treated follow the delivery. Aneurysms associated with infections (mycotic aneurysms) have rarely been reported in pregnancy. The source is usually from cardiac vegetations, and the most common organism is Staphylococcus aureus. Concomitant substance abuse (especially intravenous drug abuse) is a risk factor. Since these aneurysms are often multiple, conservative therapy with antibiotics is warranted. Management of the delivery should follow recommendations for unruptured aneurysms [117]. B. Arteriovenous Malformation Since aneurysms are 5–10 times more frequent than arteriovenous malformations (AVMs), there are fewer established guidelines for management of intracranial AVMs in pregnancy. Hemorrhage occurs in almost 40% of patients with AVMs by the age of 40 years, and 72% of those destined to bleed will have done so by that time [118]. While some believe that the rate of hemorrhage from AVM in pregnancy shows a fourfold increased hemorrhage rate [118], a retrospective study of 451 women with AVM and 438 live births and 102 abortions showed no increased rate of hemorrhage above what would be expected during an equivalent time period, and the author concluded that pregnancy was not a risk factor for hemorrhage in women with no previous hemorrhage [119]. More recent reviews have found pregnancy not to be a risk for hemorrhage [120]. The risk in pregnancy for a ﬁrst bleed was 3.5% with unruptured AVMs and 5.8% for those that had previously bled [119]. Evaluation of any woman with a hemorrhage related to an AVM should be the same as for women in the nonpregnant state. A CT scan and three-vessel angiogram may be performed, and coincident aneurysm is found 6–10% of the time [121]. Cavernous malformations (cavernous angioma, cavernoma) are a collection of vascular spaces without smooth muscle in the vascular wall and without brain tissue intervening within the hamartomatous malformation. These cavernomas have become understood only since the advent of brain scanning, especially MR. They are usually silent until they bleed and may present with seizures (the usual case) [122] or hemorrhage. There is deﬁnitely an inherited component. The course of illness does not appear to be diﬀerent in pregnancy than in the nonpregnant state [123]. A dural venous ﬁstula in pregnancy has been successfully treated in the third trimester with embolization [124]. Carotid-cavernous ﬁstulas in pregnancy can also be safely treated with endovascular techniques [125].

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VIII. PREGNANCY-SPECIFIC CEREBROVASCULAR DISEASE Cardiovascular collapse from amniotic ﬂuid embolism is fortunately rare. The cause of death is usually not stroke, but cor pulmonale and hemorrhage caused by disseminated intravascular coagulation [126]. If there is a stroke related with amniotic ﬂuid embolism, it is usually a watershed type. Risk factors for amniotic ﬂuid embolism are advanced maternal age, increasing parity, postdate pregnancy, and tumultuous labor [127]. Finding fetal cells in the buﬀy coat of blood makes the diagnosis. Treatment requires immediate recognition, oxygen by positive pressure, treatment of vasospasm, shock, and pulmonary edema [128]. By far the most common pregnancy-speciﬁc vascular disorder is eclampsia and severe pre-eclampsia. Preeclampsia (also known as toxemia) is a syndrome characterized by the initial onset of proteinuria (>300 mg/24 h) and hypertension (>140/90 mmHg) in late pregnancy (see Table 12) [129]. Although edema has historically been considered in additional diagnostic criteria, it has proven to be suﬃciently common and nonspeciﬁc in late pregnancy that it has been discarded from current diagnostic criteria. Hypertension still characterizes the disorder. Preeclampsia is characterized by a systemic loss of endothelial integrity and can thus cause complications in every organ system. It is associated with pulmonary edema, oliguria, serum chemistry (liver function) abnormalities and hepatic hemorrhages, thrombocytopenia, disseminated intravascular coagulopathy, and numerous neurological signs and symptoms that distinguish severe preeclampsia from nonsevere preeclampsia (Table 12). Preeclamptic women who develop these complications require delivery. The hallmark distinction of eclampsia is the occurrence of seizures in preeclamptic women in whom no other cause can be identiﬁed. (See Table 13 for a diﬀerential diagnosis of severe preeclampsia.) The incidence of severe preeclampsia or eclampsia (SPE/E) complicating pregnancy is 1/2000 (50/100,000) deliveries in the United States, Europe, and the developed world, while the incidence in developing countries ranges from 1 in 100 (1000/100,000) to about 1 in 1700 (58.8/100,000) [130]. The risk is higher in ﬁrst pregnancies, multiple gestations, women with underlying microvascular disease, and women with family histories of preeclampsia. SPE/E still is a major cause of maternal/fetal morbidity and mortality [131].

Table 12 Criteria for Severe Preeclampsia I. II. III. IV. V. VI. VII. VIII. IX. X. XI.

Blood pressure > 160 mmHG systolic or > 110 mmHG diastolic Proteinuria > 5 g/24 h (normal <300 mg/24 h) Elevated serum creatinine Grand mal seizures (eclampsia) Pulmonary edema Oliguria < 500 mL/24 h Microangiopathic hemolysis Thrombocytopenia Hepatocellular dysfunction (elevated alanine aminotransferase, aspartase aminotransferase) Intrauterine growth retardation or oligohydramnios Symptoms suggesting signiﬁcant end-organ involvement: headache, visual disturbances, or epigastric or right-upper quadrant pain

Source: American College of Obstetricians and Gynecologists. Hypertension in Pregnancy. ACOG Technical Bulletin 219. Washington, DC: ACOG, 1996.

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Table 13 Diﬀerential Diagnosis of Severe Preeclampsia/Eclampsia Venous thrombosis: especially cortical vein thrombosis Drug abuse: cocaine, amphetamines, sympathomimetics Seizure disorder: epilepsy Intracranial hemorrhage Thrombotic thrombocytopenia purpura Hypertension: chronic, renal disease, primary aldosteronism, Cushing’s syndrome, pheochromocytoma, coarctation of the aorta, glomerulonephritis, and other renal disease Vasculitis Behavioral disturbances Acute fatty metamorphosis of pregnancy Long-chain 3 hydroxyacyl coenzyme A dehydrogenase (LCHAD) deﬁciency Systemic lupus erythematosus Budd-Chiari syndrome Source: Varner MW. The diﬀerential diagnosis of pre-eclampsia and eclampsia. In: Belfort MA, Thornton M, Saade GR, eds. Hypertension in Pregnancy. New York: Marcel Dekker Inc., 2002:57–83.

It usually occurs after 20 weeks of gestation. Those with previous eclampsia are at risk for development of the disorder in subsequent pregnancies. While hypertension characterizes the disorder, the absolute increase in hypertension may be relative. In young healthy women during the third trimester, blood pressure typically is low. Therefore, even a modest increase in blood pressure to 140/70 may suggest early preeclampsia. The eﬀect of hypertension is thought to be a breakdown of autoregulation with the resulting hyperperfusion and vasogenic edema. When this occurs in the brain, seizures, neurological abnormalities, and coma may result. The neurological clinical presentations of SPE/E vary. The neurological manifestations include seizures, headache, visual changes (including scotoma), confusion or obtundation, and possible stroke. Generalized tonic-clonic and focal motor seizures have all been reported. The etiology of eclamptic seizure remains incompletely understood, but it is thought to occur due to hypoperfusion of the cortex especially in watershed (temporal parietal occipital) regions caused by loss of autoregulation of the blood supply in response to hypertension. Visual disturbances are legion in SPE/E. They can be the result of changes on the visual axis anywhere from the cornea to the cerebral cortex. Changes in the retina include retinal artery vasospasm, papilledema, central retinal artery occlusion, and choroidal infarction. These can lead to serous retinal detachment (see Fig. 8) and hemorrhages, all of which may cause unilateral or bilateral visual loss [132]. Furthermore, the visual cortex is frequently aﬀected by subcortical edema leading to cortical blindness [133,134], complex cortical symptoms such as Balint’s syndrome [135], and Anton’s syndrome (cortical blindness with agnosia of the visual deﬁcit) [136]. The preferential disturbance to the parietal-occipital region is thought to be due to the fact that the anterior circulation is better innervated than the posterior circulation [133] (see Fig. 9). In the past we relied exclusively on the clinical presentation of SPE/E to make the diagnosis. While the clinical presentation remains most important, imaging in the last 10 years has played an increasingly important role in the diagnosis of neurological consequences of SPE/E. At ﬁrst CT greatly helped our understanding, showing hypodensities consistent with cerebral edema in the parietal and occipital areas. Later, MR further improved our ability to make the diagnosis (Fig. 10). One of the ﬁrst studies to report

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Figure 8 Serous retinal detachments can occur in severe preeclampsia. Viewing with the ophthalmoscope, it may appear as almost a plastic wrap bubble, which frequently, as in this case, surrounds the disc.

these ﬁndings demonstrated typical gyriform T2 signal at the gray-white junction in the parietal-occipital region [137]. After more experience we have shown that MR ﬁndings reﬂect what we know about the pathology of this disorder [138]. While the characteristic lesions are usually at the parietal occipital cortical areas, T2 signals are frequently also seen in the basal ganglia, and even the cerebellum [139]. MR easily identiﬁes the cerebral edema that complicates SPE/E. Schwartz et al. [140] compared patients diagnosed with SPE/E who had MR cerebral edema and those who did not. They found that patients who were more likely to develop brain edema on MR had more frequent abnormal red blood cell morphology and also increased levels of lactic dehydrogenase (LDH). Blood pressure did not predict the development of brain edema in SPE/E [140]. The typical ﬁndings on MR have been categorized as ‘‘posterior leukoencephalopathy syndrome’’ [141]. While very typical of SPE/E, other conditions have been reported to cause a similar ﬁnding, including cyclosporin neurotoxicity, acute intermittent porphyria, hemiplegic migraine, thrombotic thrombocytopenic purpura, prolonged seizures, and MELAS syndrome [142]. Diﬀusion-weighted imaging (DWI), a recent improvement in technology, diﬀerentiates between infarction and edema only. This technique importantly provides the very earliest indications that cerebral ischemic damage has occurred. DWI shows decreased water diﬀusion from cytotoxic edema. Interestingly, the diﬀusion imaging that has been done in eclampsia frequently shows no diﬀusion-weighted abnormality, indicating that most of what is seen on MR represents vasogenic edema and can be associated with a good prognosis [143–146], but diﬀusion imaging may also be abnormal, suggesting that in some cases infarction can accompany the edema [147]. Diﬀusion-weighted imaging is excellent at diﬀerentiating infarction from edema, especially when the diﬀerential diagnosis could be cortical vein thrombosis (see Fig. 11). A composite of MR ﬁndings in severe preeclampsia, eclampsia is shown in Fig. 12a. These ﬁndings correlate well with what we know of the pathological changes in the disease (Fig. 12b).

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Figure 9 (a) MR in a woman who had a seizure followed by acute cortical blindness almost 48 hours after delivery. The MR reveals T2 signals predominantly in the occipital lobes. (b) The MRA shows narrowing presumably reﬂecting vasospasm of the posterior cerebral arteries. All symptoms resolved within 24 hours. Follow-up MR was normal.

Magnetic resonance angiography uses MR techniques to view intracranial blood vessels. These scans show frequent reversible vasospasm of the arteries of the circle of Willis [148] (Fig. 9). Single photon emission computed tomography (SPECT) showed hypoperfusion abnormalities in the watershed areas (where the posterior, middle, and cerebral arteries meet) in 63 women studied. Furthermore, at least 89% of the women had other perfusion abnormalities as well. Five to 7 days later SPECT showed complete recovery [149].

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Figure 10 MR ﬁndings in eclampsia. This woman seized after delivery. There are multiple T2 signals, especially in the parietal occipital areas and basal ganglia.

Due to its invasive nature, angiography is rarely used in SPE/E. When it has been performed, reversible cerebral segmental arterial narrowing of large and medium vessels seems to be present [150,151]. One use of angiography may be in refractory cases of eclampsia that do not respond to magnesium therapy. Ringer et al. [152] reported a case of a woman who developed postpartum eclampsia with angiographically documented severe vasospasm of both carotid arteries as well as the vertebrobasilar systems. Angioplasty brought improvement of her symptoms along with steady treatment with magnesium [152]. Electroencephalography (EEG) has been reported to be abnormal in eclampsia with both focal and diﬀuse slowing as well as focal and generalized epileptiform activity [153]. The etiology of seizures in eclampsia remains unclear. Cerebral vasospasm, hypertensive encephalopathy, and reversible posterior leukoencephalopathy, as well as excitation of brain receptors, have all been implicated [154–157]. Cerebral vasospasm is one of the more commonly ascribed etiologies of eclamptic seizures and has been consistently described in eclampsia with a number of modalities, including angiography, computed tomography, and transcranial Doppler ultrasound [158–162]. A factor in support of this ﬁnding is that blood ﬂow velocity in the middle cerebral artery is signiﬁcantly higher in eclamptic women than in preeclamptic women [163]. The middle cerebral artery is known to be an important supplier of the cerebrum from which the seizure activity originates. One of the diﬃculties in interpreting this information is that most women studied have been examined after the event and subsequent to treatment with various drugs. Many of the agents used have potent vascular eﬀects and may have caused cerebral vasodilatation. However, the persistence of severe vasospasm, even after such drug therapy, does suggest that the vasospasm was worse prior to therapy and that vasospasm is an important contributor to some eclamptic convulsions. Of note is a case report by Hashimoto et al. [164], who showed that middle cerebral artery velocity only

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Figure 11 Preeclampsia: (a) ADC map shows hyperintensity conﬁrming the presence of vasogenic edema. (b) Diﬀusion demonstrates symmetrical bilateral occipital-temporal-parietal ‘‘T2 shine through,’’ not cytotoxic edema. This can often be read as a positive diﬀusion-weighted image, but since the ADC map shows hyperintensity, we know that this is vasogenic edema, and not cytotoxic (infarction).

increased after the eclamptic seizures resolved. They suggest that cerebral arterial vasospasm may be a consequence of eclampsia rather than the cause and that the real etiology of the condition may lie in the arterioles and not the arteries. Until longitudinal studies on women who subsequently develop eclampsia are available, this theory will remain speculative. More recently data have become available from a large randomized controlled trial suggesting that cerebral vasospasm may not be the prime etiology of

Figure 12 (a) A composite drawing of actual MR ﬁndings in severe preeclampsia and eclampsia. (b) MR ﬁndings correlate dramatically with what is known about the pathological ﬁndings of eclampsia. This drawing summarizes what is known about the pathological ﬁndings from Sheehan and Lynch [212]. (From Ref. 138 with permission.)

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eclampsia in ‘‘uncomplicated’’ cases where recovery is rapid and residual CNS damage is absent [165]. In this study women with severe preeclampsia were randomized to magnesium sulfate versus nimodipine (a speciﬁc cerebral vasodilator) as prophylaxis against eclampsia. The hypothesis was that if cerebral vasospasm is the cause of eclampsia, then a speciﬁc cerebral vasodilator will prevent seizures more eﬀectively than magnesium sulfate, which does not have selective cerebral vasodilator eﬀects. Surprisingly, signiﬁcantly more women treated with nimodipine seized as opposed to magnesium sulfate. These data support the notion that cerebral vasospasm is not present prior to eclampsia in most cases and that any vasoconstriction that may be present in the middle cerebral artery is actually protective rather than pathological. This obviously does not exclude vasospasm as a cause of eclampsia in rare cases where vessel wall damage has occurred, but one would expect more prolonged and profound seizure activity and a greater extent of residual CNS damage in such cases. The authors concluded that interfering with protective vasoconstriction in preeclamptic women increases their risk for eclampsia. This implies that overperfusion, rather than ischemia, is the more likely cause of eclampsia. The most common condition resulting in cerebral over perfusion is hypertensive encephalopathy. Hypertensive encephalopathy has long been suggested by internists and neurologists as the cause of eclamptic seizures [155,166–168], but this etiology has traditionally not been well accepted by the obstetric community. The typical ﬁndings in hypertensive encephalopathy include ﬁbrinoid necrosis, ﬁbrin thrombi, microinfarcts and microglial nodules, petechial hemorrhages, lacunar infarcts, and microhemorrhages [169], and these have been shown to be present in some eclamptic women [155]. In addition, it has been shown that experimental hypertensive encephalopathy causes a ‘‘beaded’’ or ‘‘sausage string’’ appearance in the cerebral microvasculature, which represents areas of forced arteriolar dilatation separated by segments of normally reactive vessel [170]. This type of vascular architecture is typical of the segmental dilatation and spasm seen in the retinal and cerebral arteries of eclamptic women [151]. It has been known for some time that cerebral edema (as diagnosed with MR scanning) is an integral part of eclampsia. Sophisticated MRI and MRA techniques now allow diﬀerentiation between vasogenic (indicative of transient and reversible cerebral damage) and cytotoxic edema (representing underlying more severe, irreversible gliosis). While it is felt that some women with severe preeclampsia have cerebral vasoconstriction leading to underperfusion and ischemia, it is becoming increasingly apparent that most eclamptics who recover without residual signs have experienced hypertensive encephalopathy and cerebral overperfusion with transient focal vasogenic edema rather than cerebral ischemia [171,172]. Belfort et al. [173] have recently introduced the notion of ‘‘cerebral barotrauma’’ in eclampsia, which explains how elevated cerebral perfusion pressure (rather than overperfusion in terms of blood ﬂow itself) can cause transient vasogenic edema without necessarily progressing to ﬁbrinoid necrosis, infarction, and permanent damage. In this hypothesis the middle cerebral artery (MCA) undergoes protective vasoconstriction when maternal cerebral perfusion pressure increases. In preeclamptic women with signiﬁcant elevation of cerebral perfusion pressure (CPP), one explanation of the progression of events is that initial protective vasoconstriction in the resistance vessels will limit overperfusion of the brain in the tissue distal to the MCA. As the CPP increases or remains persistently elevated, the MCA (and its smaller branches) is damaged by the barotrauma. As each smaller MCA branch becomes involved, the increased pressure is propagated further and further into the peripheral brain tissue and into smaller diameter vessels less capable of protecting

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themselves from the increased pressure. Ultimately autoregulation is overwhelmed and distal overperfusion occurs, which leads to hypertensive encephalopathy [174]. Once this happens, vasogenic edema supervenes. At this time there may be persistent hypertensive encephalopathy, rupture of small vessels and intracranial hemorrhage, or severe conducting vessel trauma that causes pathological vasospasm and regional or global cerebral ischemia. In this model, initial overperfusion may result in either hypertensive encephalophy or ischemia. This hypothesis is diﬀerent from the traditional thinking which has relied on absolute cerebral blood ﬂow (either high or low) as the primary cause of the pathology in eclampsia. The barotrauma hypothesis allows for signiﬁcant pathology in the region and distribution of the middle cerebral artery (on the basis of arterial barotrauma and damage) within the constraint of maintained normal brain blood ﬂow. This is in concert with MRI/MRA data that show normal brain blood ﬂow in eclamptic women [175]. HELLP syndrome is a subset of severe preeclampsia characterized by hemolysis, elevated liver enzymes, and low platelets. HELLP syndrome often presents as epigastric pain, nausea, and vomiting and may present with only modest increases in blood pressure and urine protein excretion. It is also relatively more common in multiparous women. As a result it is often initially misdiagnosed as a concurrent gastrointestinal disorder such as cholelithiasis. Delay in diagnosis and proper treatment is thus common. Many believe that HELLP is a subset or a severe form of preeclampsia, while others think HELLP is a separate disorder [176]. Mortality from SPE/E complicated by HELLP syndrome has been estimated to be about 1% [177]. Isler et al. [178] analyzed 54 maternal deaths in HELLP syndrome patients. The most common cause of death in these cases was stroke or intracranial hemorrhage (26%) followed by cardiopulmonary arrest (15%), respiratory failure (adult respiratory distress syndrome) (13%), hepatic hemorrhage (8%), hypoxic ischemic encephalopathy (8%), and DIC (6%). Recognition of this disorder is important since prompt treatment with dexamethasone therapy and delivery can reduce maternal mortality and morbidity [179]. Obstetricians usually begin management of SPE/E and HELLP syndrome. Delivery is the ﬁrst goal of treatment, since delivery often brings about remission of the abnormalities. The other universally recommended treatment is seizure prophylaxis with magnesium sulfate. While magnesium versus antiepileptic drugs or antihypertensives was debated for many years, since the outcome of the Eclampsia Trial Collaborative Treatment Group study was reported [180], further consideration of alternative seizure prophylaxis regimens has ceased. This study randomized 1687 patients into two arms: magnesium sulfate versus diazepam and magnesium sulfate versus phenytoin. Recurrent seizures were lower in the magnesium group than with diazepman (52%) and phenytoin (67%). Furthermore, the magnesium sulfate group had a lower mortality rate, and the babies were less likely to be admitted to intensive care than the babies whose mothers received either diazepam or phenytoin [180]. Lucas et al. [181] compared 1089 women assigned to phenytoin to 1049 women who received magnesium sulfate. There were 10 seizures in the phenytoin group versus none in the women who received magnesium. Since these two studies, magnesium sulfate has become the treatment of choice in SPE/E. Magnesium sulfate is generally continued for approximately 24 hours postpartum. Although delivery is the ultimate curative procedure, it is important to consider that one third of eclamptic convulsions occur in the immediate puerperium, usually within the ﬁrst 24 hours. Hypertension frequently responds to magnesium; however, if hypertension continues, some recommend using oral nifedipine [182], IV labetolol, or IV nitroprusside [183].

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The prognosis of eclampsia is generally good if cerebral hemorrhage has not complicated the course. About one ﬁfth deaths related to eclampsia are from intracerebral hemorrhage [184]. Other causes of death include pulmonary edema, hepatic rupture, and hemorrhage from preeclampsia-associated abruptions. Patients who have had preeclampsia or eclampsia are at risk in future pregnancies for the condition. Although the eﬃcacy of preventative treatment with low-dose aspirin and supplementary calcium was demonstrated in initial reports [185], larger, prospective controlled trials have not found these treatments to produce statistically signiﬁcant reductions [186]. There is current interest in the protective eﬀects of antioxidants (vitamin C and E) [183], but their eﬃcacy in large-scale studies has yet to be conﬁrmed. The other risk that women with preeclampsia and preterm delivery may face is a seemingly increased risk of death from cardiovascular causes [187]. Rarely, eclamptic convulsions can occur beyond the ﬁrst several days postpartum. This is referred to as delayed postpartum eclampsia, or ‘‘delayed peripartum vasculopathy’’ [188], or sometimes ‘‘postpartum angiopathy.’’ The usual deﬁnition of pregnancyassociated eclampsia is within 48 hours of delivery [188]. Late-onset or late postpartum eclampsia is usually considered more than 48 hours after delivery [189]. It has been reported up to 23 days after delivery [190]. Presentations may vary, and there may even be no previous preeclampsia (up to 44% had no preceding preeclampsia) [191] until the patient announces the diagnosis by having a seizure. Work-up is extremely important, since venous thrombosis presents in a similar way. The etiology of these cases remains unclear. Complications of eclampsia are also important. Cunningham and Twicker [192] reviewed 10 cases with severe cerebral edema and symptoms of coma, seizures, and blindness at Parkland Hospital. Three cases showed edema severe enough that transtentorial herniation occurred, with one dying of uncal herniation and the other two recovering. Treatment with mannitol and dexamethasone seemed to improve the two who survived [192]. Permanent blindness has also been reported as a rare complication of eclampsia [193]. The blindness can be from both choroidal/retinal ischemia [194] and ischemia to the lateral geniculate nuclei as well as the occipital lobes [193]. It is important to recall that there are other causes of the angiopathy besides eclampsia. The use of ergots or their derivatives (e.g., bromocriptine) has been associated with cerebral angiopathy. Furthermore, migraine has also been associated with this picture. The important aspect to recognize is that these ﬁndings are spontaneously reversible usually within a few weeks, and few sequelae follow. Some have proposed postpartum angiopathy as a variant of benign vasculitis or reversible angiopathy (Call’s syndrome) [150,195]. Reversible peripartum cerebral angiopathy is a poorly understood condition occurring at the end of pregnancy and within the ﬁrst month of the puerperium [38]. It may be related to a postpartum cerebral angiopathy and changes associated with eclampsia, which may not be reversible but can also be associated with intracranial hemorrhage [196]. The typical story is a woman presenting shortly after a normal pregnancy with headache, seizure, and focal neurological deﬁcits. While concomitant sympathomimetic drugs and labile hypertension often suggest an alternative diagnosis, the angiogram is typical for stenosis of multiple intracranial vessels and possible vasospasm or vasculitis [196]. The cause of this entity is not known. Women most frequently have rapid resolution without much treatment, but hemorrhage and even death have been reported [197]. Cerebrospinal ﬂuid may show elevated protein and pleocytosis, or it may be normal [196]. Treatment has consisted of a short course of high-dose steroids, although frequently cases will resolve spontaneously as well [196]. This condition is very diﬃcult to distinguish from severe

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preeclampsia, and only the lack of other associated features (hypertension, proteinuria, elevated liver functions tests) may help to distinguish them. Another of intracranial hemorrhage is metastatic choriocarcinoma. In this very rare malignant tumor of the placenta, metastases to the brain may occur, and because of the fragile nature of the blood vessels, hemorrhage into the brain may be a presenting symptom. The major diﬀerential diagnosis is metastatic tumors, especially melanoma, which also go to the brain and cause hemorrhage [198]. The diagnosis can be made postpartum by demonstration of persistently elevated serum h-HCG levels. Imaging plays an ever-increasing role in the correct diagnosis of this condition. Most often the cancer develops after a molar pregnancy, but it has occurred after full-term delivery and abortions. The majority of cases are responsive to chemotherapy.

ACKNOWLEDGMENT This study was supported in part by a grant to the Moran Eye Center, University of Utah, from the Research to Prevent Blindness, New York, New York.

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Index

Abciximab (see Glycoprotein IIb/IIIa receptor blockers) Acalculia, 249 Activated protein C resistance, 615, 721 Activated factor X, 307 Activated partial thromboplastin time (aPTT), 307 Acquired immune deﬁciency syndrome (AIDS) (see HIV) Acute stroke care, 163–176 diﬀerential diagnosis, 164 factors favoring early care, 168 public education—stroke, 165–166 reaction, 167–169 recognition, 164–166 response, 169–170 reveal, 170 treatment, 170 Adenosine transport inhibitor (see Propentoxylline) Adhesion molecule/neural inﬂammation blockade/leucocyte adhesion inhibitors, 418 Air embolism, 814 Alcohol, 31, 219, 514 Alexia, 249, 252 Allergic angiitis and granulomatosis (see Churg-Strauss angiitis) Alteplase (see Thrombolytic therapy) Amnesia following stroke, 243–245 Amaurosis fugax, 22, 306

Aminocaproic acid (see Subarachnoid hemorrhage) AMPA antagonists (see Glutamate antagonists) Amniotic ﬂuid embolism, 831 Amphetamines, 489 Amyloid angiopathy, 490, 756 Ancrod, 366–367, 401 Aneurysms (see Saccular aneurysms, Dissection, Dolichoectactic) Angiography, 594 Angioplasty and stenting, 13, 356 See also Balloon and Stent-Assisted Percutaneous Angioplasty Angiotensin converting enzyme (ACE) inhibitors, 28, 137 Angiotensin receptor blockers, 28 Anosognosia, 254 Anterior cerebral artery (ACA), 44–47 anatomy and vascular territory, 44 clinical features, 46 etiology and frequency, 44 Anterior choroidal artery (AchA), 48–49 anatomy and vascular territory, 48 clinical features, 48 etiology and frequency, 48 Anterior inferior cerebellar artery (AICA), 66 Anterior spinal artery, 638 Anterior spinal artery syndrome, 640 Anticoagulants (see Warfarin, Heparin, Low molecular weight heparins) 851

852 Anticoagulant and antiplatelet treatment for acute stroke, 383–403 intracerebral hemorrhage, 489 subarachnoid hemorrhage, 527 Antiﬁbrinolytic drugs (see Subarachnoid hemorrhage) Antihypertensive medications (see Hypertension) Antineutrophil cytoplasmic antibodies (ANCA), 656, 661, 664, 665 Antioxidants (see Free-radical scavengers) Antiphospholipid antibodies, 12, 119, 617, 666, 724–728, 764, 823 clinical aspects, 725–726 diagnosis, 727 eﬀects on coagulation system, 729–727 epidemiology, 725 treatment, 727–728 Antiplatelet agents (see Aspirin, Clopidogrel, Dipyridamole, Glycoprotein IIb/IIIa receptor blockers, or Ticlopidine) Antithrombin (antithrombin III), 11, 613, 717, 718 Antithrombotic therapies for prevention of ischemic stroke, 305–334 Antithrombotic treatment of acute ischemic stroke, 383–384 risk of intracranial hemorrhage, 384 Anton syndrome, 253 Anxiety disorders (see Neuropsychiatric disorders) Aortic disease, 214, 318 anticoagulants, 318 atherothrombotic syndrome (trash toes, cholesterol emboli), 149 plaques, 148–150 Apathy (see Neuropsychiatric disorders) Aphasia following stroke, 245–248 Apolipoprotein E, 755–756 Apoptosis inhibitors, 419 Apraxia, 248–249 Aprosody, 254 Arterial dissection (see Dissection) Arteriography, 104, 114–115, 770 Arteriovenous ﬁstula (see Arteriovenous malformations) Arteriovenous malformations, 114–115, 490, 492, 524, 583–596, 795–796 association with aneurysms, 565, 579, 591 cavernous angioma, 796 cerebral cavernous malformations, 751 classiﬁcation of lesions, 583–588 clinical presentations, 588–592

Index [Arteriovenous malformations] endovascular treatment, 586 epidemiology, 587 evaluation, 592–595 features, 588–592 headaches, 591 hemorrhage, 589–590 hereditary hemorrhagic telangiectasia, 751–752 mass lesions and cerebral steal, 592 natural history and clinical presentations, 588 pregnancy, 830 radiotherapy, 596 seizures, 591 surgical treatment, 595 treatment, 595–596 L-Asparaginase, 719, 789 Aspirin, 29, 31, 136, 142, 143, 147, 188, 293, 306, 319–324, 332–333, 356, 826 acute ischemic stroke, 324, 384, 393–400, 402 angioplasty and stenting, 440 asymptomatic carotid artery disease, 293 eﬃcacy, 322–324 myocardial infarction, 142 pharmacology, 319–321 safety, 321–322 side eﬀects, 320 Aspirin and dipyridamole, 31, 325, 333 Asymptomatic carotid artery disease, evaluation and treatment, 283–297 carotid bruit, 284, 306 epidemiology, 284–288 evaluation, 290–292 intimal-medial thickness, 283, 286–288 risk for stroke, 288–289 stenosis, 285–286 treatment, 292–296, 352, 353, 435 Atherosclerosis, 9, 351 epidemiology, 133 pathophysiology, 134 Atrial ﬁbrillation, 29, 139, 205, 306 aspirin, 323 anticoagulants, 140, 315–316, 390 cardioversion, 141, 316 non-valvular atrial ﬁbrillation, 139–141 Atrial ﬂutter, 141 Atrial myxoma (see Cardiac tumors) Atrial septal aneurysm (ASA), 146, 317 Atrial septal defects, 811 Autosomal dominant polycystic kidney disease (ADPKD), 514, 565, 577, 752, 794 Azathioprine, 662, 667

Index Balint syndrome, 252–253 Balloon- and Stent-Assisted Percutaneous Transluminal Angioplasty of Cerebrovascular Occlusive Disease for Prevention of Stroke, 433–472 advantages, 438–439 background, 435–438 complications, 447–451 disadvantages, 439 review of clinical outcomes, 459–479 techniques, 439–447 extracranial angioplasty and stenting, 441–444 intracranial revascularization, 444–446 Basilar artery, 43, 61 occlusion, 183 thrombosis, 389 Behcßet syndrome, 620, 655, 667 Biomarkers for stroke, 11–12 Bleeding diathesis, 796–797 Blood pressure (see Hypertension) Borderzone infarction, 67, 68 clinical features, 67 etiology and frequency, 67 Brain and/or meningeal biopsy, 654 Brain attack coalition (BAC), 172 Brain edema, 184–185, 421 Brain imaging in stroke, 81–98, 103 Brain stem infarctions, 61 blood supply and vascular territories, 61 medullary infarctions, 62–63 midbrain infarctions, 65 pontine infarctions, 63–65 Bronchogenic carcinoma, 492 Buerger disease (see thromboangiitis obliterans), 654 C-reactive protein (CRP), 12, 134, 215, 289 Calcium channel blockers, 410–413, 537–538 Call syndrome, 654 Capillary telangiectasia (see Arteriovenous malformation) Cardiac catheterization, 695–697 Cardiac procedures in children, 699–700 Cardiac tumors, 148, 526 Cardiac ultrafast CT of the heart, 139 Cardiac valve replacement, 694–695 Cardioembolic stroke, 137–150 clinical diagnosis, 137 evaluation for detection of cardiac sources of embolism, 150 high-risk lesions, 138

853 [Cardioembolic stroke] low or uncertain risk lesions, 138 treatment with anticoagulants, 387 Cardiomyopathies, 144 Carotid angioplasty and stenting, 14, 296 asymptomatic carotid stenosis, 296 Carotid artery atherosclerotic disease, 351–355, 435 Carotid artery injuries, 359 Carotid bruit (see Asymptomatic carotid) Carotid duplex (see Carotid ultrasound) Carotid endarterectomy, 13, 29, 30, 135, 203, 293–296, 351, 435–438, 462–467 asymptomatic carotid stenosis, 293–296, 351–353 Carotid stenosis (see Internal carotid artery) Carotid transient ischemic attack, 22 Carotid ultrasound (carotid duplex), 94, 95, 104–107 advantages and disadvantages, 83 asymptomatic carotid artery disease, 290, 291 plaque characteristics, 290 transient ischemic attack, 24, 30 Catastrophic reaction (see Neuropsychiatric disorders) Catheter angiography (see Arteriography) Cavernous angioma (see Arteriovenous malformation) Cavernous malformation (see Arteriovenous malformation) Central cord syndrome, 641 Centrum ovale infarctions, 55, 56 Cerebellar infarction, 65–67, 184 blood supply and vascular territories, 65 clinical features, 66 etiology and frequency, 66 surgical treatment of malignant, 421 Cerebral amyloid angiopathy (see Amyloid angiopathy) Cerebral blood ﬂow, 764, 765, 808 Cerebral autosomal dominant arteriopathy with subcortical ischemic leukoencephalopathy (CADASIL), 120, 746–748, 768, 786–787 Cerebral edema (see Brain edema) Cerebral infarction with transient symptoms (CITS), 32 Cerebral sinovenous anatomy, 606–608 Cerebral vasculitis (see Vasculitis, cerebral) Cerebral venous thrombosis (see Venous thrombosis, cerebral) Cerebrospinal ﬂuid (CSF) examination, 103, 120, 517–518, 624–625, 656 Chain of recovery, 164

854 Chickenpox (see Varicella-zoster virus) Chlamydia pneumoniae, 10 Cholesterol (also see Hypercholesterolemia), 11 HDL cholesterol, 11, 210 LDL cholesterol, 11, 210 Choriocarcinoma, 492, 841 Churg-Strauss angiitis, 654, 655, 665 Cincinnati Prehospital Stroke Scale (CPSS), 167 Citicoline, 418 Classiﬁcation of cerebrovascular disease, 2, 3 Claudication, 306 Clopidogrel, 31, 136, 306, 328–330, 333, 717 angioplasty and stenting, 440 eﬃcacy, 329 pharmacology, 328–329 safety, 329 Coarctation of the aorta, 656 Cocaine, 489, 524, 526 Cogan syndrome, 654, 655, 671 Cognitive impairments after stroke, 243–257 acalculia, 249 alexia, 243–245 amnesia, 241–243 aphasia, 245–248 apraxia, 248–249 executive functions, 255–256 Gerstmann syndrome, 249 right hemisphere disorders, 253–255 treatment, 256–257 visual disorders, 250–252 Color processing disorders following stroke, 251–252 Complications of acute ischemic stroke and treatment, 186–196 cardiac complications, 190 neurological complications, 184–189 psychiatric complications, 189–190 systemic complications, 190–195 Computed tomographic angiography, 94, 111, 116, 520 advantages and disadvantages, 83 Computed tomography of the brain, 24, 103 advantages and disadvantages, 83 arteriovenous malformations, 593 early signs of stroke, 86 hemorrhage, 87, 496 hemorrhagic transformation, 88 ischemia, 81–85 migraine, 769 subarachnoid hemorrhage, 516–517 transient ischemic attack, 24 venous thrombosis, 621 Confusion after stroke, 187

Index Congenital heart disease, 781 Constipation, 194 Cooling (see Hypothermia) Coronary artery disease, 9, 134–136, 283 algorithm for detection, 135 coronary artery angioplasty and stenting, 135, 695–697 coronary artery bypass grafting (CABG), 135, 288, 681–700 acute encephalopathy, 682 brachial plexopathy, 689–691 Horner’s syndrome, 691 neuropsychological impairment, 687–689 peroneal nerve injury, 692 phrenic nerve injury, 692–694 recurrent laryngeal nerve injury, 691 saphenous nerve injury, 691–692 spinal cord injury, 689 stroke, 683–687 evaluation, 291 identiﬁcation, 134 identiﬁcation in patients with stroke, 135, 136 treatment, 136 Coronary revascularization (see Coronary artery bypass grafting) Cortical blindness, 253 Corticosteroids, 499, 618 Crohn’s disease, 618 Cryoglobulinemia, 655 Cryptococcus, 782 Cyanotic heart disease, 781 Cyclophosphamide, 662, 664, 665, 667, 672 Cysticercosis, 660 Decompressive surgery, 185 Decubitus ulcers (see Pressure sores) Deep vein thrombosis (see Venous thrombosis) Dehydration, 619 Delays in early stroke care, 167 Depression after stroke (see Neuropsychiatric disorders after stroke) Dermatomyositis-polymyositis, 655 Diabetes mellitus, 9, 25, 208–211 diagnosis, 208–211 ketoacidosis, 619 testing, 207 treatment, 208 Digital subtraction angiography, 95, 115 advantages and disadvantages, 83 Dipyridamole (also see aspirin and dipyridamole), 31, 143, 306, 325–326 dipyridamole myocardial perfusion scintigraphy, 135

Index [Dipyridamole] dipyridamole echocardiography, 135 eﬃcacy, 325 pharmacology, 325 safety, 325 Dissection, 115, 783, 814 carotid or vertebral artery dissection, 357–359, 389 subarachnoid hemorrhage, 523 Disseminated intravascular coagulation (DIC), 715, 716–717 Doppler (see also carotid ultrasound and transcranial Doppler): B-mode imaging, 105 color-ﬂow imaging, 106 echo-contrast Doppler, 108 plaques, 106 power Doppler imaging, 106 Drug abuse, 670, 785, 797, 821–822 Dural arteriovenous malformation, 524 Dysphagia, 194 Dysﬁbrinogenemia, 719–720 Dysfunctional coagulation factors, 615–619 Echocardiography (see Transthoracic and transesophageal echocardiography) Eclampsia and pre-eclampsia, 831–841 Ehlers-Danlos syndrome, 514, 656 Electrocardiogram (ECG/EKG), 30, 113, 117, 139, 188 exercise electrocardiogram (treadmill), 133 Emergency department, 375 Emergency medical services (EMS), 166, 375 Epidemiology of stroke, 3–12 Epilepsy, 188, 626 Estrogens (see also exogenous ovarian hormones), 10, 11 Evaluation of patients with stroke, 101–116 Exogenous ovarian hormones, 217–218 Extracranial—intracranial arterial bypass, 434 Fabry’s disease, 744–745, 785–786 Face, Arm, Speech Test (FAST), 167 Factor V, 717 Factor V Leiden, 12, 616, 721, 722, 749, 750, 824 Factor VIII, 617, 714, 717 Factor IX, 717 Factor X, 617 Factor XIII, 719, 720, 722 Familial amyloid polyneuropathy, 751 Familial hemiplegic migraine, 768 Fecal incontinence, 194 Fever, 192

855 Fibrinogen, 215, 616, 719, 754, 755 Fibrinogen depleting agents (see Ancrod) Fibrinolytic defects, 723 Fibromuscular dysplasia, 359, 565, 785, 814 Flunarizine (see Calcium channel blockers) Free radical scavengers, 417 GABA agonists, 415–416 Gastrointestinal hemorrhage, 195 Genetic causes of stroke, 743–756 apolipoprotein E, 755–756 autosomal dominant polycystic kidney disease, 752 cerebral amyloid angiopathies, 750–751 cerebral cavernous malformations, 751 CADASIL, 746–748 cerebrovascular malformations, 751–753 detailed family history, 743–744 Fabry’s disease, 744–745 HERNS, 753 hereditary hemorrhagic telangiectasia, 751–752 homocystinuria, 749 MELAS, 746 Moyamoya disease, 752–753 risk factors for cerebral vein thrombosis, 749–750 risk factors for polymorphisms, 753–756 sickle cell disease, 748–749 Gerstmann syndrome, 249 Giant cell arteritis, 654, 655, 669 Glasgow Coma Scale, 74, 75, 528 Glioblastoma, 492 Glucose intolerance, 211 Glutamate antagonists, 413–415 Glycine site antagonists (see Glutamate antagonists) Glycoprotein IIb/IIIa receptor blockers, 306, 330, 401, 440, 715–716 Glycoprotein polymorphisms, 721, 754, 755 Gradient-echo MRI (see Magnetic resonance imaging) Growth factors, 418 Guidelines, 30, 171 Health People Program, 1 Heart failure, 142 Hematological abnormalities in stroke, 713–729 antiphospholipid antibodies, 724–728 antithrombin, protein C and protein S, 718–719 bleeding disorders, 713–717

856 [Hematological abnormalities in stroke] disseminated intravascular coagulation, 716–717 dysﬁbrinogenemia, 719 ﬁbrinolytic defects, 723 hematological polymorphisms, 721–722 hemophilia, 714 hemorrhage associated with anticoagulants or thrombolytics, 715–716 heparin-induced thrombocytopenia, 724 homocystinuria and homocysteinemia, 720 platelet disorders, 723 sickle cell disease, 728–729 thrombotic complications, 717–728 thrombotic thrombocytopenia purpura, 722–723 thrombocytopenia, 715 Von Willebrand disease, 714–715 Hematological polymorphisms, 721–722 Hemimedullary infarction, 63 Hemolysis, elevated liver enzymes, and low platelets (HELPP), 839 Hemolytic-uremic syndrome (see Thrombotic thrombocytopenia purpura) Hemorrhagic transformation of infarction, 187–188 Hemophilia, 714 Henoch-Scho¨nlein purpura, 654, 655, 670 Heparan, 717 Heparin, 29, 187, 188, 192, 307–309, 384, 402, 823, 826 bleeding complications, 385, 392, 715–716 deep vein thrombosis and pulmonary embolism, 387, 390 dose and route of administration, 391 eﬀect on mortality, 387 eﬃcacy in prevention of stroke, 308 pharmacology, 307 recurrent ischemic stroke, 385 safety, 307–308 thrombocytopenia, 392, 724 treatment of acute ischemic stroke, 384–393 venous thrombosis, 627–628, 819–820 Heparin-induced thrombocytopenia, 724 Heparins, low molecular weight (LMW) (see also Heparin), 192, 307, 384, 385 Heparinoid (danaparoid) (see Heparin), 306, 384 Hepatitis serology, 645 Hereditary hemorrhagic telangiectasia (see Rendu-Osler-Weber syndrome) Hereditary cerebral hemorrhage with amyloidosis—Dutch, 750

Index Hereditary cerebral hemorrhage with amyloidosis—Icelandic, 751 Hereditary endotheliopathy, retinopathy, nephropathy and stroke, 753 Herniation (see Brain edema) Hiccups, 188 Holter monitoring, 139 Homocysteine (see Hyperhomocysteinemia) Homocystinuria (see Hyperhomocysteinemia) Hormone replacement therapy (see Exogenous ovarian hormones) Hospital discharges—stroke, 6 Human immunodeﬁciency virus (HIV), 656, 658, 660, 782 Hydrocephalus, 76, 529 treatment, 529 Hypercholesterolemia (hyperlipidemia), 12, 212–214, 785 treatment, 14, 31 Hypercoagulable state of pregnancy, 806, 807 Hyperdense middle cerebral artery sign (dense artery sign), 84, 103 Hyperglycemia after stroke, 191 Hyperhomocysteinemia, 12, 216, 617, 720, 749, 786 Hypersensitivity vasculitis, 654 Hypertension (arterial), 8, 9, 206–208 following stroke, 190, 191 hemorrhage, 489 pregnancy, 806 risk factor for stroke, 206 subarachnoid hemorrhage, 536–537, 539 treatment, 12–13, 205, 206, 293 Hypertensive encephalopathy, 838 Hypertonic saline, 184 Hyperventilation, 499 Hypotension, 190, 191, 822 Hypothermia, 184, 185, 192, 420 Ibuprofen, 330 Identiﬁcation of carotid artery disease, 134 Identiﬁcation of coronary artery disease, 134 Immune thrombocytopenic purpura (ITP), 715 In-hospital time-related treatment goals, 169 Incidence of stroke—subtypes, 7 cerebral infarction, 8 intracerebral hemorrhage, 8 subarachnoid hemorrhage, 8 Increased intracranial pressure, 185, 421 hyperventilation, 421 medical therapy, 421 surgical therapy, 421 venous thrombosis, 608, 609, 622

Index Indium 111-label platelet scintigraphy, 139 Infection vasculopathy, 781 Infective endocarditis, 145, 814 septic aneurysm, 524, 526, 794 Infectious vasculitis, 655 Infections after stroke, 192 Inﬂammation and infections and risk of stroke, 214, 215 inﬂammatory markers, 215 Inﬂammatory bowel disease, 618, 783 Insulin resistance, 211 Interactions between cardiovascular and cerebrovascular disease, 133–150 Internal carotid artery (also see Carotid endarterectomy and carotid angioplasty and stenting, Asymptomatic carotid artery disease): algorithm for identiﬁcation of disease, 136 stenosis, 14, 25 treatment, 136 International Classiﬁcation of Diseases (ICD–10), 2 International normalized ratio, 309–311 Intimal-medial thickness (see asymptomatic carotid artery disease) Intra-aortic balloon counterpulsation, 697–698 Intracerebral hemorrhage, 73–77, 489–505, 528, 769 bleeding disorders, 713–717 blood pressure management, 498–499 clinical presentation, 493–496 causes, 74, 484–493 evaluation, 103, 115, 116, 484 ﬂuid management, 500 incidence, 489, 528 indications for surgery, 502 initial management, 497–498 management of intracranial pressure, 499–500 medical management, 496–501 minimally invasive clot aspiration, 503 mortality, 74–76 prevention of seizures, 500 prevention of intracerebral hemorrhage, 504–505 recovery, 76 recurrence, 77 surgical management, 76, 501–504 temperature management, 500 volume of hematoma, 76 Intraventricular hemorrhage, 74, 75 Ischemic cascade, 409–410

857 Ischemic stroke, 305 Ischemic stroke mimics, 164 Ischemic stroke syndromes, 43–68 Isolated central nervous system vasculitis (see Primary central nervous system vasculitis) Kawasaki disease, 654, 671 Kearns-Sayre syndrome, 746 Kohlmeier-Degos disease, 655, 668 Lacunar infarction, 52 Lacunar syndromes, 53 Lateral medullary infarction, 62 Left atrial appendage occlusion, 138 Left ventricular thrombus (see Myocardial infarction) Leukemia, 789 Libman-Sacks endocarditis, 666 Lipids (see Hypercholesterolemia) Lipoprotein (a), 11, 612, 723 Locked in syndrome, 183 Los Angeles Prehospital Stroke Scale (LAPSS), 168 Low molecular weight (LMW) heparin (see Heparin, low molecular weight) Lumbar puncture (see Cerebrospinal ﬂuid examination) Lupus anticoagulant, 612, 724 Lyme disease, 655, 661, 782 Lymphomatoid granulomatosis, 655, 666 Magnetic resonance angiography (MRA), 94, 104, 110–111, 115, 496, 521, 621 advantages and disadvantages, 83 Magnetic resonance imaging (MRI), 103, 583 advantages and disadvantages, 83, 111 age of hematomas, 89 apparent diﬀusion coeﬃcient (ADC) map, 622 arteriovenous malformations, 593 cardiac imaging, 86, 137 diﬀusion weighted MRI, 622 ﬂow void phenomenon, 623 gradient-echo MRI, 90 hemorrhage, 87–91, 484 ischemia, 85–87 migraine, 770 perfusion and diﬀusion MRI, 83 transient ischemic attack, 24 venous thrombosis, 593, 607–609 Malnutrition, 195

858 Management of modiﬁable risk factors for stroke or accelerated atherosclerosis, 205–220 Mania after stroke (see Neuropsychiatric disorders) Mannitol, 185, 499 Marfan syndrome, 514, 565, 811 Matrix metalloproteinases, 766 Medial medullary infarction, 63 Medullary infarction, 62–63 Melanoma, 492 Meningitis and stroke, 782 Menke syndrome, 797 Metabolic syndrome, 211 Methotrexate, 662 Methylenetetrahydrofolate reductase (MTHFR), 749 Midbrain infarction, 65 Microscopic polyangiitis, 654, 655, 664 Middle cerebral artery (MCA), 49–56 anatomy and vascular territories, 49 anterior pial middle cerebral artery infarction, 52, 53 centrum ovale infarctions, 55, 56 clinical features, 51 complete (deep plus superﬁcial) infarction, 50, 51 deep middle cerebral artery infarction, 52 posterior pial middle cerebral artery infarction, 52, 54 striatocapsular infarction, 55 superﬁcial (pial) infarction, 50, 52 surgical treatment of malignant infarction, 421 Migraine, 23, 763–775, 786 association with stroke, 764 asymmetries of cerebral blood ﬂow, 765–766 CADASIL, 768 cerebral embolism, 766 classiﬁcation, 774 coagulation, 766 criteria for migraine stroke, 774 dissection, 767 epidemiology, 771–774 familial hemiplegic migraine, 768 intracerebral hemorrhage, 769 malignant migraine with coma, 767 matrix metalloproteinases, 766 MELAS, 767–768 migraine equivalents, 768, 775 migraine with aura, 764–765 platelet activity, 766 retinal infarction, 769 vasospasm, 767

Index Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), 112, 746, 767–768, 148 Mitral annulus calciﬁcation, 146 Mitral stenosis, 315, 317 Mitral valve prolapse (MVP), 148, 811 Monogangliosides, 415 Mood disorders (see Neuropsychiatric disorders following stroke) Mortality from stroke, 4, 5, 74, 183 Moyamoya disease, 752, 753, 783–785 Moyamoya syndrome, 565, 783–785, 797, 815 MTHFR gene mutation (see hyperhomocysteinemia) Myocardial infarction, 134, 141, 306, 315, 316 National Institutes of Health (NIH) Stroke Scale, 4, 75, 167 Necrotizing systemic vasculitis—overlap syndrome, 655 Neonatal sinovenous thrombosis, 774 Neoplasms of the neck with arterial involvement, 360 Neoplastic angioendotheliosis, 654 Nephrotic syndrome, 618, 718 Neuroﬁbromatosis, 514 Neurological complications of cardiac procedures, 681–700 cardiac procedures in children, 699–700 cardiac valve replacement, 694–695 coronary revascularization, 681–694 intra-aortic balloon counterpulsation, 697–698 percutaneous coronary interventions, 695–697 ventricular assist devices, 698–699 Neurological worsening (see Progressive neurological deﬁcit) Neuroprotective agents and other therapies for acute stroke, 409–424 Neuropsychiatric disorders following stroke, 262–278 anxiety disorder, 271–273 apathy, 275 catastrophic reaction, 275–276 depression, 187, 261–271 mania, 274–275 pathological crying or laughing, 276–278 poststroke psychosis, 278 Nicardipine (see Calcium channel blockers) Nimodipine (see Calcium channel blockers) Nitric oxide, 717, 729 Nitric oxide inhibitors (see Free-radical scavengers)

Index NMDA antagonists (see Glutamate antagonists) Non-bacterial thrombotic endocarditis, 315 Obesity, 31, 211 Osmotherapy (see Mannitol) Opioid antagonists, 418 Oral anticoagulants (see Warfarin) Oral contraceptives, 10, 618, 718, 764, 809 Organization of stroke services in the hospital and community, 163–176 Paradoxical embolism, 9 Patent foramen ovale, 9, 146–147, 315, 766, 780, 781, 813 anticoagulation, 317 closure of PFO, 145 Pentoxifylline, 330 Perfusion CT, 83, 92 Perfusion MRI, 83, 92 Perfusion status, 91 Periarteritis nodosa (see Polyarteritis nodosa) Perimesencephalic subarachnoid hemorrhage, 532–533 Peripartum cardiomyopathy, 811, 813–814 Peripartum cerebral angiopathy, 840 Peritonsillar abscess, 620 Phenylpropanolamine, 489 Phosphatidylcholine precursor (see Citicoline) Physical exercise (activity), 31, 216 Pituitary apoplexy (pituitary necrosis), 524, 526, 822 Pituitary tumors, 565 Plasma exchange, 723 Plasminogen activator inhibitor, 721, 723 Plasminogen deﬁciency, 616 Platelet disorders, 723–724 Pneumonia, 192, 193 Polyarteritis nodosa, 654, 655, 663–664, 783 Polycystic kidney disease (See autosomal dominant polycystic kidney disease) Polycythemia, 723, 789 Pontine infarction, 63 Posterior inferior cerebellar artery (PICA), 66 Posterior cerebral artery (PCA), 56–61, 67 anatomy and vascular territories, 56 cortical posterior cerebral infarctions, 57, 58 thalamic infarctions, 60–61 Posterior communicating artery (PcommA), 57 Posterior spinal artery, 638 Posterior spinal artery syndrome, 641 Positron emission tomography (PET), 84, 93 Potassium channel opener, 416

859 Prednisone, 661, 669, 670, 672 Pregnancy and stroke, 618, 805–841 aneurysm, 827 arterial occlusive diseases, 809–815 arteriovenous malformation, 830 arteritis, 824 cardiac abnormalities, 811–814 drug-induced stroke, 821 eclampsia and pre-eclampsia, 831–841 evaluation, 808–809 hematological disorders, 822–824 hemorrhage, 827–830 hypotensive disorders, 822 incidence and prevalence, 805–806 physiological changes, 806–808 pituitary necrosis, 822 premature atherosclerosis, 814–815 treatment, 824–827 venous occlusive disease, 815–824 Pressure sores, 192 Prevalence of stroke, 6 Prevention strategies for stroke, 12, 333 Primary central nervous system vasculitis, 654, 671–672, 783 Progressive neurological deﬁcit, 182, 388 Proptentofylline, 419 Prosopagnosia, 250–251 Prostacyclin, 717 Prosthetic cardiac valves (mechanical or bioprosthetic), 143, 314, 315 Protein C, 11, 612–613, 717, 718, 824 Protein S, 11, 612–613, 717, 718, 824 Prothrombin G20210A mutation, 616, 721, 722, 749, 750, 824 Prourokinase (recombinant urokinase— prolong) (see Thrombolysis) Pseudoephedrine, 489 Pseudoxanthoma elasticum, 565 Psychosis (see Neuropsychiatric disorders) Puerperium, 618 Pulmonary embolism, 192, 387, 501 Purple toe syndrome, 311 Recombinant tissue plasminogen activator (rt-PA) (see Thrombolysis) Recurrent stroke, 188, 382 Rehabilitation after stroke, 231–239 assessment, 233, 234 basic concepts, 231–236 deﬁnition, 233 evidence regarding eﬀectiveness, 237 neuropsychological deﬁcits, 237 pain, 237 principles and goal planning, 234

860 [Rehabilitation after stroke] rehabilitation of motor deﬁcits, 236 therapy of some common conditions, 236 Relapsing polychondritis, 668 Renal cell carcinoma, 492 Rendu-Osler-Weber syndrome, 585, 586, 751–752, 795–796 Respiratory insuﬃciency (failure), 193 Retinal infarction, 769 Reversible ischemic neurological deﬁcit (RIND), 32 Rheumatoid arthritis, 625, 666–667 Risk factors (see Stroke risk factors) Ruptured aneurysms (see Saccular aneurysms) Saccular aneurysms (see also Subarachnoid hemorrhage), 793 anesthesia, 554 endovascular treatment, 535–536, 551–553, 574–576 genetic factors, 794–795 growth and rupture of aneurysms, 566–568 management of patients with unruptured intracranial aneurysms, 565–578 natural history of unruptured aneurysms, 568–573 operative clipping, 533, 573–574 operative techniques, 555–559 pathogenesis, 566 pregnancy, 827–830 surgical management of ruptured aneurysms, 551–561 timing of surgical treatment, 553–554 Sarcoidosis, 655, 668 Scleroderma, 655, 667 Seizures (see Epilepsy) Serotonin agonists, 416 Sickle cell disease, 9, 12, 527, 618, 728–729, 748–749, 787–789, 822 Single photon emission computed tomography (SPECT), 84, 93, 112, 116 Sjo¨gren’s syndrome, 655, 667 Smoking, 9, 218–219 smoking cessation, 31 Sneddon syndrome, 726 Sodium channel blocking drugs, 413 Spectacular shrinking deﬁcit, 102 Spetzler-Martin classiﬁcation, 588 Sphenoid sinusitis, 670 Spinal cord, diagnosis and management of vascular disease, 637–648 arteriovenous malformations, 526, 645–648 classiﬁcation, 645–646 clinical syndrome, 646–647

Index [Spinal cord, diagnosis and management of vascular disease] diagnosis, 648 epidemiology, 645 management, 648 infarctions, 637–645 causes, 641–643 diﬀerential diagnosis, 643 evaluation, 644 epidemiology, 637 management, 644 pathophysiology, 639–640 prevention, 645 prognosis, 645 vascular anatomy, 637–639 vascular syndromes, 640–641 venous infarction, 641 Statins (HMG–coA reductase inhibitors), 13, 28, 137, 292 Steroids (see Corticosteroids) Sticky platelet syndrome, 824 Streptokinase (see Thrombolysis) Striatocapsular infarction, 55 Stroke center, 173, 374–377 Stroke-in-evolution (see Progressing stroke) Stroke in children and young adults, 779–797 aneurysm and subarachnoid hemorrhage, 793–794 arterial dissection, 783 arterial ischemic stroke, 779–780 arteriovenous malformations, 795–796 bleeding diathesis, 796–797 CADASIL, 786–787 cardiac disorders, 780–781 cavernous angiomas, 796 drug-related vasculopathy, 785 evaluation, 790 ﬁbromuscular dysplasia, 785 hematological disorders, 787–789 hematological malignancy, 789 hemorrhagic stroke, 793–797 homocysteinemia, 786 Menke syndrome, 797 migraine, 786 mitochondrial disorders, 789 Moyamoya disease and moyamoya syndrome, 783–785, 797 myeloproliferative disease, 789 natural history and management, 790–792 noninfectious vasculitis, 782 pathophysiology and anatomy in children and young adults, 780 premature atherosclerotic disease, 785 prothrombotic conditions, 787

Index [Stroke in children and young adults] risk factors, 794–795 sickle cell disease, 787–789 sinovenous thrombosis, 792 vascular disorders, 781 vasculopathy associated with infection, 781 Stroke risk factors, 8–11, 164 Stroke team, 375, 376 Stroke units, 174–176 components, 174 guidelines, 174 Stroke warning signs, 166 Subarachnoid hemorrhage, 73, 513–540, 713, 793 antiﬁbrinolytic drugs, 532 blood pressure management, 536 calcium channel blockers, 537 causes, 519–527 clinical features, 515–516 endovascular treatment, 535–536, 539 evaluation, 103, 117, 516–522 ﬂuid balance and electrolytes, 537 incidence, 513 operative clipping of the aneurysm, 533–535 outcomes, 514 prevention of rebleeding, 531–536 prevention of secondary cerebral ischemia, 536–539 rebleeding, 528 risk factors, 514 treatment of delayed cerebral ischemia, 539 Subdural hematoma, 529 Sulﬁnpyrazone, 330 Superior cerebellar artery (SCA), 66 Surgical management options to prevent ischemic stroke, 351–360 Syphilis, 655, 656, 658, 782 Systemic lupus erythematosus (SLE), 656, 666, 726, 782, 824 Takayasu disease, 654, 668–689, 782, 815 Tamoxifen, 619 Temporal arteritis (see Giant cell arteritis) Tenectoplase (see Thrombolysis) Thalamic infarctions, 58–61 clinical features, 60 etiology and frequency, 59 inferomedial infarction, 60 paramedian infarction, 60 polar infarction, 60 posterior choroidal infarction, 60 Thrombin inhibitors (direct), 306, 309, 386 Thromboangiitis obliterans, 654, 671 Thrombocythemia (see Thrombocytosis)

861 Thrombocytopenia, 308, 392, 715 Thrombocytosis, 602, 723, 824 Thrombolysis, 173, 363–378, 826–827 ancrod, 366–367 alteplase (rt-PA), 365–366 combined with neuroprotection, 419 intra-arterial therapy, 366, 367 hemorrhagic transformation, 185, 373, 716 prourokinase, 367 reteplase, 368 risks and beneﬁts, 370–373 selection criteria, 373 streptokinase, 368 systems to rapidly deliver thrombolysis, 373–374 tenectoplase, 369 urokinase, 369–370 venous thrombolysis, 629 Thrombosis, pathogenesis, 717–718 Thrombotic thrombocytopenia purpura, 327, 715, 722–723, 822 Ticlopidine, 306, 326–328, 333, 401, 723 eﬃcacy, 328 pharmacology, 326 safety, 326 Tissue plasminogen activator (rtPA/tPA/ alteplase), 170, 717 Tobacco (see Smoking) Trauma, 524, 620 Tranexamic acid (see Subarachnoid hemorrhage) Transcranial Doppler ultrasonography (TCD), 95, 104, 108, 109, 114, 116, 289, 290, 807 applications, 95 arteriovenous malformations, 593 asymptomatic carotid stenosis, 289–290 high-intensity transient (microembolic) signals, 109 paradoxical embolism, 112 sickle cell disease, 728–729 Transesophageal echocardiography (TEE), 112, 138 Transient global amnesia, 23 Transient ischemic attack (TIA), 21–34, 205, 306 carotid (anterior) TIA, 23 deﬁnition, 31 diagnosis, 23 diﬀerential diagnosis, 23 evaluation, 24 guidelines, 30 high-risk TIA, 25, 26 management, 28 natural history and prognosis, 25 vertebrobasilar TIA, 23

862 Transthoracic echocardiography (TTE), 112, 138 Tuberculosis, 658–659 Tumor necrosis factor, 718 Ulcerative colitis, 618, 637 Ultrasound (see carotid ultrasound) Unruptured saccular aneurysms (see saccular aneurysms) Urinary incontinence, 193 Urinary tract infection, 192, 194 Valvular heart disease, 143 Valvular strands, 148 Varicella zoster virus vasculitis, 659, 781–782 Vasculitis, cerebral, 653–672, 805 associated with collagen vascular disease, 666–667 associated with radiation therapy, 654 associated with other systemic diseases, 667–668 diagnosis and management, 653–655 giant cell arteritides, 668–670 hypersensitivity vasculitides, 670 idiopathic, 654 infectious, 656–661 miscellaneous vasculitides, 671 necrotizing vasculitides, 661–666 pathophysiology, 653 primary central nervous system vasculitis, 671–672 Vasospasm, 767 Vein of Galen aneurysm, 794 Venous malformation (see arteriovenous malformation) Venous thrombosis, 192, 387, 390, 792, 815–821 intracranial (cerebral), 390, 391, 492 cavernous sinus, 608 cavernous sinus thrombosis, 610–611 clinical presentation, 608–611 deep vein thrombosis, 610 deep venous system, 607 diagnosis and management, 605–630 evaluation, 117–118, 621–625 hypercoagulable states, 611–619, 624 infectious phlebitis, 620 low-ﬂow states, 619 management, 625–629 non-infectious phlebitis, 620 predisposing conditions, 611–621 pregnancy, 815–820

Index [Venous thrombosis] sinovenous anatomy, 606–608 superﬁcial sinus thrombosis, 610 superﬁcial veins and sinuses, 606–607 vessel wall abnormalities, 620–621 Ventricular assist devices, 698–699 Vertebral artery, 61 Vertebral artery atherosclerosis, 355–357 Visual agnosia, 250–251 Visual loss following stroke, 250–253 visual ﬁeld testing, 610 visual perceptual and spatial functions, 255 Vitamin K, 309, 310, 314 Von Willebrand disease, 714–715, 754, 755, 766 Von Willebrand factor (see Von Willebrand disease) Von Willebrand factor metalloprotease, 722 Warfarin, 29, 306, 309–319, 355 atrial ﬁbrillation, 138, 315 combination with antiplatelet agents, 331 conditions that increase or decrease eﬀects, 311 desired levels of anticoagulation, 310 cardiomyopathies, 144 eﬃcacy, 315–319 embryopathy, 826 food interactions, 311 intracerebral hemorrhage, 715–716 medication interactions, 312 myocardial infarction, 139, 316 pharmacology, 309 predictors of high risk of bleeding complications, 314 prevention of cardioembolic stroke, 333 prosthetic heart valves, 143 safety, 311–315 valvular heart disease, 143 venous thrombosis, 628 Watershed infarction (see Borderzone infarction) Wegener granulomatosis (disease), 654, 655, 661–662 White clot syndrome (see heparin-induced thrombocytopenia) Women’s Health Initiative, 11 World Federation of Neurological Surgeons Scale, 528 Wyburn-Mason Syndrome, 585 Xenon computed tomography (CT), 84, 91, 92

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