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

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.)

6

Torner

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.

Epidemiology and Risk Factors for Stroke

7

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.)

8

Torner

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.’’

Epidemiology and Risk Factors for Stroke

9

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

10

Torner

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

Epidemiology and Risk Factors for Stroke

11

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,

12

Torner

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

Epidemiology and Risk Factors for Stroke

13

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-

14

Torner

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

Epidemiology and Risk Factors for Stroke

15

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.

REFERENCES 1. Broderick J, Brott T, Kothari R, Miller R, Khoury J, Pancioli A, Gebel J, Mills D, Minneci L, Shukla R. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke 1998; 29(2):415–421. 2. Health People 2000 Final Review, http://www.cdc.gov/nchs/products/pubs/pubd/hp2k/review/ highlightshp2000.htm. 3. Aho K, Harmsen P, Hatano S, et al. Cerebrovascular disease in the communit: results of a WHO collaborative study. Bull WHO 1980; 58:113. 4. World Health Organization. Recommendations on stroke prevention, diagnosis and therapy. Report of the WHO task force on stroke and other cerebrovascular disorders. Stroke 1989; 20:1407–1431. 5. Anderson RN, Minino AM, Hoyert DL, Rosenberg HM. Comparability of cause of death between ICD-9 and ICD-10: preliminary estimates. Natl Vital Statistics Reports 2001; 49(2):1– 32. 6. Anonymous. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990; 21(4):637–676. 7. Davis PH, Hachinski V. Epidemiology of Cerebrovascular Disease. In: Neuroepidemiology: A Tribute to Bruce Schoenberg, Anderson DW, Schoenberg DG, eds. CRC Press, 1991:34.

16

Torner

8. Broderick JP, Phillips SJ, Whisnant JP, O’Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline of stroke? Stroke 1989; 20:577–582. 9. Keir SL, Wardlaw JM, Warlow CP. Stroke epidemiology studies have underestimated the frequency of intracerebral hemorrhage. A systematic review of imaging in epidemiological studies. J Neurol 2002; 249(9):1226–1231. 10. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtypes of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 1993; 23:35. 11. Brott T, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864–870. 12. Goldstein LB, et al. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660–662. 13. Rosamond WD, Folsom AR, Chambless LE, Wang CH, McGovern PG, Howard G, Copper LS, Shahar E. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 1999; 30(4):736–743. 14. 2003 Heart and Stroke Statistical Update, American Heart Association, 2003. 15. National Vital Statistics Reports. Vol. 50, No. 15. National Center for Health Statistics, September 16, 2002. 16. Fullerton HJ, Chetkovich DM, Wu YW, Smith WS, Johnston SC. Deaths from stroke in US children, 1979 to 1998. Neurology 2002; 59(1):34–39. 17. Lanska DJ. Geographic distribution of stroke mortality in the United States, 1939–1941 to 1979–1981. Neurology 1993; 43:1839. 18. Sarti C, Rastenyte D, Cepaitis Z, Tuomilchto J. International trends in mortality from stroke, 1968 to 1994. Stroke 2000; 31(7):1588–1601. 19. Gillum RF. New considerations in analyzing stroke and heart disease mortality trends: the Yar 2000 Age Standard and International Statistical Classification of Diseases and Related Health Problems, 10th Revision. Stroke 2002; 33(6):1717–1722. 20. Fang J, Alderman MH. Trend of stroke hospitalization, United States, 1988–1997. Stroke 2001; 32(10):2221–2226. 21. Kozak LJ, Hall MJ, Owings MF. National Hospital Discharge Survey: 2000 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat 2002; 13(153). 22. Taylor TN, Davis PH, Torner JC, et al. Lifetime cost of stroke in the United States. Stroke 1996; 27:1459. 23. Leibson CL, Hu T, Brown RD, et al. Utilization of acute care services in the year before and after first stroke: a population-based study. Neurology 1996; 46:861. 24. Holloway RG, Witter DM, Lawton KB, et al. Inpatient costs of specific cerebrovascular events at five academic medical centers. Neurology 1996; 46:854. 25. Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996; 27(3):373–380. 26. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30(12):2513– 2516. 27. Sacco RL, Hauser WA, Mohr JP. Hospitalized stroke incidence in blacks and Hispanics in northern Manhattan. Stroke 1991; 22:1491–1496. 28. Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman DE, Shea S, Paik MC, Hauser WA. Stroke incidence among white, black, and Hispanic residents of an urban community: the Northern Manhattan Stroke Study. Am J Epidemiol 1998; 147(3):259–268. 29. Woo D, Gebel J, Miller R, Kothari R, Brott T, Khoury J, Salisbury S, Shukla R, Pancioli A, Jauch E, Broderick J. Incidence rates of first-ever ischemic stroke subtypes among blacks: a population-based study. Stroke 1999; 30(12):2517–2522. 30. Sudlow CL, Warlow CP. Comparing stroke incidence worldwide: what makes studies comparable? Stroke 1996; 27(3):550–558. 31. WHO MONICA Project: Stroke trends in the WHO MONICA Project. Stroke 1997; 28:500– 506.

Epidemiology and Risk Factors for Stroke

17

32. Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 1997; 28(3):491–499. 33. Krishner HS. Medical prevention of stroke. South Med J 2003; 96(4):354–358. 34. Gardner P, Hudson BL. Advance report of final mortality statistics, 1993. Monthly Vital Statistics Report 1996; 44(7 suppl):1–83. 35. Morrison AC, Fornage M, Liao D, Boerwinkle E. Parental history of stroke predicts subclinical but not clinical stroke: the Atherosclerosis Risk in Communities Study. Stroke 2000; 31(9):2098– 2102. 36. He J, Whelton PK. Elevated systolic blood pressure and risk of cardiovascular and renal disease: overview of evidence from observational epidemiologic studies and randomized controlled trials. Am Heart J 1999; 138(3 pt 2):211–219. 37. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med 1993; 153(5):598–615. 38. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335(8692):765–774. 39. SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265:3255–3264. 40. Sinton R, Beevers G. Meta-analysis of the relation between cigarette smoking and stroke. BMJ 1989; 25(298):784–794. 41. Wolf PA, D’Agostino RB, Kannel WB, Bonita R, Belanger AJ. Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 1988; 259(7):1025–1029. 42. Barrett-Connor E, Khaw KT. Diabetes mellitus: an independent risk factor for stroke? Am J Epidemiol 1988; 128(1):116–123. 43. Anonymous. Beneficial effect of carotid endarterectomy in symptomatic patients with highgrade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325(7):445–453. 44. Tsang TS, Petty GW, Barnes ME, et al. The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades. J Am Coll Cardiol 2003; 42(1):93–100. 45. Gilon D, Buonanno FS, Joffe MM, Leavitt M, Marshall JE, Kistler JP, Levine RA. Lack of evidence of an association between mitral-valve prolapse and stroke in young patients. N Engl J Med 1999; 341(1):8–13. 46. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foreman ovale in patients with stroke. N Engl J Med 1988; 318:1148. 47. Bogousslavsky J, Devuyst G, Nendaz M, Yamamoto H, Sarasin F. Prevention of stroke recurrence with presumed paradoxical embolism. J Neurol 1997; 244(2):71–75. 48. Styles LA, Hoppe C, Klitz W, Vichinsky E, Lubin B, Trachtenberg E. Evidence for HLA-related susceptibility for stroke in children with sickle cell disease. Blood 2000; 95(11):3562–3567. 49. Hoppe C, Klitz W, Noble J, Vigil L, Vichinsky E, Styles L. Distinct HLA associations by stroke subtype in children with sickle cell anemia. Blood 2003; 101(7):2865–2869. 50. Adams RJ. Lessons from the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study. J Child Neurol 2000; 15(5):344–349. 51. Gorelick PB, Mazzone T. Plasma lipids and stroke. J Cardiovasc Risk 1999; 6(4):217–221. 52. Shahar E, Chambless LE, Rosamond WD, Boland LL, Ballantyne CM, McGovern PG, Sharrett AR. Plasma lipid profile and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 2003; 34(3):623–631. 53. Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, Rimm E, Colditz GA. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 2001; 161(13):1581–1586.

18

Torner

54. Rexrode KM, Hennekens CH, Willett WC, Colditz GA, Stampfer MJ, Rich-Edwards JW, Speizer FE, Manson JE. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA 1997; 277(19):1539–1545. 55. Kurl S, Laukkanen JA, Rauramaa R, Lakk TA, Sivenius J, Salonen JT. Cardiorespiratory fitness and the risk for stroke in men. Arch Intern Med 2003; 163(14):1682–1688. 56. LaBiche R, Koziol D, Quinn TC, Gaydos C, Azhar S, Ketron G, Sood S, DeGraba TJ. Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque. Stroke 2001; 32(4):855–860. 57. Elkind MS, Lin IF, Grayston JT, Sacco RL. Chlamydia pneumoniae and the risk of first ischemic stroke: The Northern Manhattan Stroke Study. Stroke 2000; 31(7):1521–1525. 58. Cook PJ, Honeybourne D, Lip GY, Beevers DG, Wise R, Davies P. Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke 1998; 29(2):404–410. 59. Heuschmann PU, Neureiter D, Gesslein M, Craiovan B, Maass M, Faller G, Beck G, Neundoerfer B, Kolominsky-Rabas PL. Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: results from a populationbased case-control study. Stroke 2001; 32(10):2253–2258. 60. Wimmer MLJ, Sandman-Strupp R, Saikku, Haberl RL. Association of chlamydial infection with cerebrovascular disease. Stroke 1996; 27:2007. 61. Elkind MS, Jackson LA, Wang S-P, et al. Elevated Chlamydia pneumoniae IgA titers are a risk factor for ischemic stroke. Cerebrovasc Dis 1998; 8(suppl 4):4. 62. Siritho S, Thrift AG, McNeil JJ, You RX, Davis SM, Donnan GA. Melbourne Risk Factor Study (MERFS) Group. Risk of ischemic stroke among users of the oral contraceptive pill: The Melbourne Risk Factor Study (MERFS) Group. Stroke 2003; 34(7):1575–1580. 63. Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996; 335(1):8–15. 64. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ. WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003; 289(20):2673–2684. 65. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345(17):1243–1249. 66. Dahl T, Kontny F, Slagsvold CE, Christophersen B, Abildgaard U, Odegaard OR, Morkrid L, Dale J. Lipoprotein(a), other lipoproteins and hemostatic profiles in patients with ischemic stroke: the relation to cardiogenic embolism. Cerebrovasc Dis 2000; 10(2):110–117. 67. Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L, Whelton PK. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke 2002; 33(5):1183–1188. 68. Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32(8):1793– 1799. 69. Moster ML. Coagulopathies and arterial stroke. J Neuro-Ophthalmol 2003; 23(1):63–71. 70. Tuhrim S, Rand JH, Wu X, Horowitz DR, Weinberger J, Goldman ME, Godbold JH. Antiphosphatidyl serine antibodies are independently associated with ischemic stroke. Neurology 1999; 53(7):1523–1527. 71. Brey RL, Stallworth CL, McGlasson DL, Wozniak MA, Wityk RJ, Stern BJ, Sloan MA, Sherwin R, Price TR, Macko RF, Johnson CJ, Earley CJ, Buchholz DW, Hebel JR, Kittner SJ. Antiphospholipid antibodies and stroke in young women. Stroke 2002; 33(10):2396–2401. 72. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979. 73. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular events in women. N Engl J Med 2000; 342:836– 843.

Epidemiology and Risk Factors for Stroke

19

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.

20

Torner

93. Hobson RW 2nd, Brott T, Ferguson R, Roubin G, Moore W, Kuntz R, Howard G, Ferguson J. CREST: carotid revascularization endarterectomy versus stent trial. Cardiovasc Surg 1997; 5(5):457–458. 94. National Institute of Neurological Disorders and Stroke, rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333(24):1581–1587. 95. Cummins RO, et al. Improving survival from sudden cardiac arrest. The ‘‘Chain of Survival’’ concept. Circulation 1991; 83:1832–1847. 96. Rothwell PM. Incidence, risk factors and prognosis of stroke and TIA: the need for high-quality, large-scale epidemiological studies and meta-analyses. Cerebrovasc Dis 2003; 16(suppl 3):2–10. 97. Wattigney WW, Croft JB, Mensah GA, et al. Establishing data elements for the Paul Coverdell National Acute Stroke Registry. Part 1: proceedings of an expert panel. Stroke 2003; 34:151– 156.

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

22

Johnston and Ruff

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.

Diagnosis and Prognosis of Transient Ischemic Attacks

23

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

24

Johnston and Ruff

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

Diagnosis and Prognosis of Transient Ischemic Attacks

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

26

Johnston and Ruff

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

27

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.

28

Johnston and Ruff

[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

Diagnosis and Prognosis of Transient Ischemic Attacks

29

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

30

Johnston and Ruff

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

32

Johnston and Ruff

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

34

Johnston and Ruff

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.

REFERENCES 1. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergencydepartment diagnosis of transient ischemic attack. JAMA 2000; 284:2901–2906. 2. Dennis MS, Bamford JM, Sandercock PA, Warlow CP. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke 1989; 20(3):333–339. 3. Brainin M, McShane LM, Steiner M, Dachenhausen A, Seiser A. Silent brain infarcts and transient ischemic attacks. A three-year study of first-ever ischemic stroke patients: the Klosterneuburg Stroke Data Bank. Stroke 1995; 26(8):1348–1352. 4. Shelton JE, Gaines KJ. Patients’ attitudes towards TIA. Va Med Q 1995; 122(1):24–28. 5. Johnston SC, Fayad PB, Gorelick PB, Hanley DF, Van Husen D, Weiskopf T. Prevalence and knowledge of transient ischemic attack among US adults. Neurology 2003; 60:1429–1434. 6. Goldstein LB, Bian J, Samsa GP, Bonito AJ, Lux LJ, Matchar DB. New transient ischemic attack and stroke: outpatient management by primary care physicians. Arch Intern Med 2000; 160(19):2941–2946. 7. Brown RD Jr, Petty GW, O’Fallon WM, Wiebers DO, Whisnant JP. Incidence of transient ischemic attack in Rochester, Minnesota, 1985–1989. Stroke 1998; 29(10):2109–2113. 8. National Stroke Association. 2002, http://www.stroke.org/brain_stat.cfm. 9. Matchar DB. The value of stroke prevention and treatment. Neurology 1998; 51(3 suppl 3):S31–35. 10. Mushinski M. Variations in average charges for strokes and TIAs: United States, 1995. Stat Bull Metrop Insur Co 1997; 78(4):9–18. 11. Gubitz G, Phillips S, Dwyer V. What is the cost of admitting patients with transient ischaemic attacks to hospital? Cerebrovasc Dis 1999; 9(4):210–214. 12. Reed SD, Blough DK, Meyer K, Jarvik JG. Impatient costs, length of stay, and mortality for cerebrovascular events in community hospitals. Neurology 2001; 57(2):305–314. 13. Phillips SJ, Whisnant JP, O’Fallon WM, Frye RL. Prevalence of cardiovascular disease and diabetes mellitus in residents of Rochester, Minnesota. Mayo Clin Proc 1990; 65(3):344–359. 14. Gibbs RG, Newson R, Lawrenson R, Greenhalgh RM, Davies AH. Diagnosis and initial management of stroke and transient ischemic attack across UK health regions from 1992 to 1996: experience of a national primary care database. Stroke 2001; 32(5):1085–1090. 15. Toole JF, Lefkowitz DS, Chambless LE, Wijnberg L, Paton CC, Heiss G. Self-reported transient ischemic attack and stroke symptoms: methods and baseline prevalence. The ARIC Study, 1987–1989. Am J Epidemiol 1996; 144(9):849–856. 16. Williams LS, Bruno A, Rouch D, Marriott DJ. Stroke patients’ knowledge of stroke. Influence on time to presentation. Stroke 1997; 28(5):912–915. 17. Rodriguez RM, Passanante M, Phelps MA, Dresden G, Kriza K, Carrasco M, Franklin J. Delayed emergency department presentation in critically ill patients. Crit Care Med 2001; 29(12):2318–2321. 18. Sempere AP, Duarte J, Cabezas C, Claveria LE. Incidence of transient ischemic attacks and minor ischemic strokes in Segovia, Spain. Stroke 1996; 27(4):667–671. 19. Lauria G, Gentile M, Fassetta G, Casetta I, Agnoli F, Andreotta G, Barp C, Caneve G, Cavallaro A, Cielo R, Mongillo D, Mosca M, Olivieri P. Incidence of transient ischemic attacks in the Belluno Province, Italy. First-year results of a community-based study. Acta Neurol Scand 1996; 93(4):291–296.

Diagnosis and Prognosis of Transient Ischemic Attacks

35

20. Matias-Guiu J, Oltra A, Falip R, Martin R, Galiano L. Occurrence of transient ischemic attacks in Alcoi: descriptive epidemiology. Neuroepidemiology 1994; 13(1–2):34–39. 21. Fratiglioni L, Arfaioli C, Nencini P, Ginanneschi A, Iaquinta L, Marchi M, Inzitari D. Transient ischemic attacks in the community: occurrence and clinical characteristics. A population survey in the area of Florence, Italy. Neuroepidemiology 1989; 8(2):87–96. 22. Ostfeld AM, Shekelle RB, Klawans HL. Transient ischemic attacks and risk of stroke in an elderly poor population. Stroke 1973; 4(6):980–986. 23. Karp HR, Heyman A, Heyden S, Bartel AG, Tyroler HA, Hames CG. Transient cerebral ischemia. Prevalence and prognosis in a biracial rural community. JAMA 1973; 225(2):125– 128. 24. Chambless LE, Shahar E, Sharrett AR, Heiss G, Wijnberg L, Paton CC, Sorlie P, Toole JF. Association of transient ischemic attack/stroke symptoms assessed by standardized questionnaire and algorithm with cerebrovascular risk factors and carotid artery wall thickness. The ARIC Study, 1987–1989. Am J Epidemiol 1996; 144(9):857–866. 25. Wilkinson WE, Heyman A, Burch JG, Ostfeld A, Labarthe DR, Leviton A, O’Fallon WM, Whisnant J. Use of a self-administered questionnaire for detection of transient cerebral ischemic attacks: I Survey of elderly persons living in retirement facilities. Ann Neurol 1979; 6(1):40–46. 26. Mittelmark MB, Psaty BM, Rautaharju PM, Fried LP, Borhani NO, Tracy RP, Gardin JM, O’Leary DH. Prevalence of cardiovascular diseases among older adults. The Cardiovascular Health Study. Am J Epidemiol 1993; 137(3):311–317. 27. Urakami K, Igo M, Takahashi K. An epidemiologic study of cerebrovacular disease in western Japan: with special reference to transient ischemic attacks. Stroke 1987; 18(2):396–401. 28. Whisnant JP, Matsumoto N, Elveback LR. Transient cerebral ischemic attacks in a community. Rochester, Minnesota, 1955 through 1969. Mayo Clin Proc 1973; 48(3):194–198. 29. Lai SM, Alter M, Friday G, Sobel E, Gil-Peralta A, McCoy RL, Levitt LP, Isack T. Transient ischemic attacks: their frequency in the Lehigh Valley. Neuroepidemiology 1990; 9(3):124–130. 30. Broderick J, Brott T, Kothari R, Miller R, Khoury J, Pancioli A, Gebel J, Mills D, Minneci L, Shukla R. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke 1998; 29(2):415–421. 31. Feinberg WM, Albers GW, Barnett HJ, Biller J, Caplan LR, Carter LP, Hart RG, Hobson RW 2nd, Kronmal RA, Moore WS, Robertson JT, Adams HP, Mayberg M. Guidelines for the management of transient ischemic attacks. From the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks of the Stroke Council of the American Heart Association. Circulation 1994; 89(6):2950–2965. 32. Martin PJ, Young G, Enevoldson TP, Humphrey PR. Overdiagnosis of TIA and minor stroke: experience at a regional neurovascular clinic. QJM 1997; 90(12):759–763. 33. Ferro JM, Falcao I, Rodrigues G, Canhao P, Melo TP, Oliveira V, Pinto AN, Crespo M, Salgado AV. Diagnosis of transient ischemic attack by the nonneurologist. A validation study. Stroke 1996; 27(12):2225–2229. 34. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke: outcomes, patient mix, and practice variation for neurologists and generalists in a community. Neurology 1998; 50(6):1669–1678. 35. Koudstaal PJ, Gerritsma JG, van Gijn J. Clinical disagreement on the diagnosis of transient ischemic attack: is the patient or the doctor to blame? Stroke 1989; 20(2):300–301. 36. Kraaijeveld CL, van Gijn J, Schouten HJ, Staal A. Interobserver agreement for the diagnosis of transient ischemic attacks. Stroke 1984; 15(4):723–725. 37. Tomasello F, Mariani F, Fieschi C, Argentino C, Bono G, De Zanche L, Inzitari D, Martini A, Perrone P, Sangiovanni G. Assessment of inter-observer differences in the Italian multicenter study on reversible cerebral ischemia. Stroke 1982; 13(1):32–35. 38. Calanchini PR, Swanson PD, Gotshall RA, Haerer AF, Poskanzer DC, Price TR, Conneally PM, Dyken ML, Futty DE. Cooperative study of hospital frequency and character of transient ischemic attacks. IV. The reliability of diagnosis. JAMA 1977; 238(19):2029–2033.

36

Johnston and Ruff

39. Koudstaal PJ, van Gijn J, Staal A, Duivenvoorden HJ, Gerritsma JG, Kraaijeveld CL. Diagnosis of transient ischemic attacks: improvement of interobserver agreement by a checklist in ordinary language. Stroke 1986; 17(4):723–728. 40. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990; 21(4):637–676. 41. Fisher CM. Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci 1980; 7(1):9–17. 42. Lee H, Lerner A. Transient inhibitory seizures mimicking crescendo TIAs. Neurology 1990; 40(1):165–166. 43. Libman RB, Wirkowski E, Alvir J, Rao TH. Conditions that mimic stroke in the emergency department. Implications for acute stroke trials. Arch Neurol 1995; 52(11):1119–1122. 44. Koudstaal PJ. Clinical diagnosis and prognosis of transient ischemic attacks. In: Adams HP Jr, ed. Handbook of Cerebrovascular Diseases. New York: Marcel Dekker, Inc, 1993:35–50. 45. Bots ML, van der Wilk EC, Koudstaal PJ, Hofman A, Grobbee DE. Transient neurological attacks in the general population. Prevalence, risk factors, and clinical relevance. Stroke 1997; 28(4):768–773. 46. Mishriki YY. Subdural hematoma mimicking a transient ischemic attack due to antihypertensive medication. South Med J 1999; 92(9):905–906. 47. Wijman CA, Wolf PA, Kase CS, Kelly-Hayes M, Beiser AS. Migrainous visual accompaniments are not rare in late life: the Framingham Study. Stroke 1998; 29(8):1539–1543. 48. Burger SK, Saul RF, Selhorst JB, Thurston SE. Transient monocular blindness caused by vasospasm. N Engl J Med 1991; 325(12):870–873. 49. Johnston SC, Sidney S, Bernstein AL, Gress DR. A comparison of risk factors for recurrent TIA and stroke in patients with TIA. Neurology 2003; 60:280–285. 50. Culebras A, Kase CS, Masdeu JC, Fox AJ, Bryan RN, Grossman CB, Lee DH, Adams HP, Thies W. Practice guidelines for the use of imaging in transient ischemic attacks and acute stroke. A report of the Stroke Council. American Heart Association. Stroke 1997; 28(7):1480– 1497. 51. Gotshall RA, Price TR, Haerer AF, Swanson PD, Calanchini PR, Conneally PM, Dyken ML, Futty DE, Poskanzer DC. Cooperative study of hospital frequency and character of transient ischemic attacks. JAMA 1978; 239(19):2001–2003. 52. Barnett HJ, Gunton RW, Eliasziw M, Fleming L, Sharpe B, Gates P, Meldrum H. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA 2000; 283(11):1429–1436. 53. Johnson SE, Skre H. Transient cerebral ischemic attacks in the young and middle aged. A population study. Stroke 1986; 17(4):662–666. 54. Wolf PA, Clagett GP, Easton JD, Goldstein LB, Gorelick PB, Kelly-Hayes M, Sacco RL, Whisnant JP. Preventing ischemic stroke in patients with prior stroke and transient ischemic attack: a statement for healthcare professionals from the stroke council of the American Heart Association. Stroke 1999; 30(9):1991–1994. 55. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. AHA Scientific Statement. Supplement to the guidelines for the management of transient ischemic attacks: A statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks. Stroke Council, American Heart Association. Stroke 1999; 30(11):2502–2511. 56. Elkins JS, Sidney S, Gress DR, Go AS, Bernstein AL, Johnston SC. Electrocardiographic findings predict short-term cardiac morbidity after transient ischemic attack. Arch Neurol 2002; 59(9):1437–1441. 57. Pop GA, Koudstaal PJ, Meeder HJ, Algra A, van Latum JC, van Gijn J. Predictive value of clinical history and electrocardiogram in patients with transient ischemic attack or minor ischemic stroke for subsequent cardiac and cerebral ischemic events. The Dutch TIA Trial Study Group. Arch Neurol 1994; 51(4):333–341. 58. Hankey GJ, Warlow CP. Cost-effective investigation of patients with suspected transient ischaemic attacks [editorial]. J Neurol Neurosurg Psychiatry 1992; 55(3):171–176.

Diagnosis and Prognosis of Transient Ischemic Attacks

37

59. Da´valos A, Matı´ as-Guiu J, Torrent O, Vilaseca J, Codina A. Computed tomography in reversible ischaemic attacks: clinical and prognostic correlations in a prospective study. J Neurol 1988; 235(3):155–158. 60. Evans GW, Howard G, Murros KE, Rose LA, Toole JF. Cerebral infarction verified by cranial computed tomography and prognosis for survival following transient ischemic attack. Stroke 1991; 22(4):431–436. 61. Awad I, Modic M, Little JR, Furlan AJ, Weinstein M. Focal parenchymal lesions in transient ischemic attacks: correlation of computed tomography and magnetic resonance imaging. Stroke 1986; 17(3):399–403. 62. Kimura K, Minematsu K, Wada K, Yonemura K, Yasaka M, Yamaguchi T. Lesions visualized by contrast-enhanced magnetic resonance imaging in transient ischemic attacks. J Neurol Sci 2000; 173(2):103–108. 63. Kidwell CS, Alger JR, Di Salle F, Starkman S, Villablanca P, Bentson J, Saver JL. Diffusion MRI in patients with transient ischemic attacks. Stroke 1999; 30(6):1174–1180. 64. Johnston CM, Sidney S, Gress DR, Johnston SC. The prognostic value of head computerized tomography in TIA evaluation. Neurology 2001; 56:A159–A160. 65. Ziegler DK, Hassanein RS. Prognosis in patients with transient ischemic attacks. Stroke 1973; 4(4):666–673. 66. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998; 339(20):1415–1425. 67. Friedman GD, Wilson WS, Mosier JM, Colandrea MA, Nichaman MZ. Transient ischemic attacks in a community. JAMA 1969; 210(8):1428–1434. 68. Ad Hoc Committee on Cerebrovascular Disease. A classification and outline of cerebrovascular diseases. Neurology 1958; 8:395–434. 69. Kernan WN, Horwitz RI, Brass LM, Viscoli CM, Taylor KJ. A prognostic system for transient ischemia or minor stroke. Ann Intern Med 1991; 114(7):552–557. 70. Hankey GJ, Slattery JM, Warlow CP. The prognosis of hospital-referred transient ischaemic attacks. J Neurol Neurosurg Psychiatry 1991; 54(9):793–802. 71. Muuronen A, Kaste M. Outcome of 314 patients with transient ischemic attacks. Stroke 1982; 13(1):24–31. 72. Sorensen PS, Marquardsen J, Pedersen H, Heltberg A, Munck O. Long-term prognosis and quality of life after reversible cerebral ischemic attacks. Acta Neurol Scand 1989; 79(3):204– 213. 73. Calandre L, Bermejo F, Balseiro J. Long-term outcome of TIAs, RINDs and infarctions with minimum residuum. A prospective study in Madrid. Acta Neurol Scand 1990; 82(2):104– 108. 74. Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299(2):53–59. 75. Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325(18):1261–1266. 76. EAFT Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke. Lancet 1993; 342(8882):1255–1262. 77. UK-TIA Study Group. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54:1044–1054. 78. Heyman A, Burch JG, Rosati R, Haynes C, Utley C. Use of a computerized information system in the management of patients with transient cerebral ischemia. Neurology 1979; 29(2):214–221. 79. Hankey GJ, Slattery JM, Warlow CP. Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events? J Neurol Neurosurg Psychiatry 1992; 55(8): 640–652.

38

Johnston and Ruff

80. Dennis M, Bamford J, Sandercock P, Warlow C. Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project. Stroke 1990; 21(6):848–853. 81. Whisnant JP, Wiebers DO. Clinical epidemiology of transient cerebral ischemic attacks (TIA) in the anterior and posterior circulation. In: Sundt TM, ed. Occlusive Cerebrovascular Disease. Philadelphia: WB Saunders, 1987:60–65. 82. Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996; 27(3):373– 380. 83. Kennedy J, Hill MD, Eliasziw M, Buchan AM, Barnett HJ. Short-term prognosis following acute cerebral ischemia. Stroke 2002; 33(1):382. 84. Streifler JY, Eliasziw M, Benavente OR, Harbison JW, Hachinski VC, Barnett HJ, Simard D. The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial. Arch Neurol 1995; 52(3):246–249. 85. Benavente O, Eliasziw M, Streifler JY, Fox AJ, Barnett HJ, Meldrum H. Prognosis after transient monocular blindness associated with carotid-artery stenosis. N Engl J Med 2001; 345(15):1084–1090. 86. Hurwitz BJ, Heyman A, Wilkinson WE, Haynes CS, Utley CM. Comparison of amaurosis fugax and transient cerebral ischemia: a prospective clinical and arteriographic study. Ann Neurol 1985; 18(6):698–704. 87. Cartlidge NE, Whisnant JP, Elveback LR. Carotid and vertebral-basilar transient cerebral ischemic attacks. A community study, Rochester, Minnesota. Mayo Clin Proc 1977; 52(2): 117–120. 88. Wilterdink JL, Easton JD. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol 1992; 49(8):857–863. 89. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Survival and recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 1975 through 1989. Neurology 1998; 50(1):208–216. 90. Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Long-term risk of recurrent stroke after a first-ever stroke. The Oxfordshire Community Stroke Project. Stroke 1994; 25(2):333–337. 91. Sacco RL, Shi T, Zamanillo MC, Kargman DE. Predictors of mortality and recurrence after hospitalized cerebral infarction in an urban community: the Northern Manhattan Stroke Study. Neurology 1994; 44(4):626–634. 92. Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, StewartWynne EG. Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998; 29(12):2491–2500. 93. Moroney JT, Bagiella E, Paik MC, Sacco RL, Desmond DW. Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke 1998; 29(10):2118– 2124. 94. Lai SM, Alter M, Friday G, Sobel E. A multifactorial analysis of risk factors for recurrence of ischemic stroke. Stroke 1994; 25(5):958–962. 95. Sacco RL, Foulkes MA, Mohr JP, Wolf PA, Hier DB, Price TR. Determinants of early recurrence of cerebral infarction. The Stroke Data Bank. Stroke 1989; 20(8):983–989. 96. Hier DB, Foulkes MA, Swiontoniowski M, Sacco RL, Gorelick PB, Mohr JP, Price TR, Wolf PA. Stroke recurrence within 2 years after ischemic infarction. Stroke 1991; 22(2):155– 161. 97. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349(9065):1569–1581. 98. CAST Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349(9066):1641–1649. 99. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)

Diagnosis and Prognosis of Transient Ischemic Attacks

100.

101.

102. 103. 104. 105.

106. 107.

108. 109. 110.

111. 112. 113.

114. 115. 116.

117. 118. 119.

39

Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998; 279(16):1265–1272. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333(24):1588–1593. Bath PM, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D, Marttila R, Olsson J, O’Neill D, Orgogozo J, Ringelstein B, van der Sande J, Turpie AG. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet 2001; 358(9283):702– 710. Wiebers DO, Whisnant JP, O’Fallon WM. Reversible ischemic neurologic deficit (RIND) in a community: Rochester, Minnesota, 1955–1974. Neurology 1982; 32(5):459–465. Humphrey PR, Marshall J. Transient ischemic attacks and strokes with recovery prognosis and investigation. Stroke 1981; 12(6):765–769. Heyman A, Wilkinson WE, Hurwitz BJ, Haynes CS, Utley CM, Rosati RA, Burch JG, Gore TB. Risk of ischemic heart disease in patients with TIA. Neurology 1984; 34(5):626–630. Koudstaal PJ, Algra A, Pop GA, Kappelle LJ, van Latum JC, van Gijn J. Risk of cardiac events in atypical transient ischaemic attack or minor stroke. The Dutch TIA Study Group. Lancet 1992; 340(8820):630–633. Kimura K, Minematsu K, Yasaka M, Wada K, Yamaguchi T. The duration of symptoms in transient ischemic attack. Neurology 1999; 52(5):976–980. Brott TG, Clark WM, Fagan SC, Grotta JC, Hopkins LN, Jauch EC, Latchaw RE, Starkman S. Stroke—The First Hours. Guidelines for Acute Treatment. Englewood, CO: National Stroke Association, 2000. Johnston SC, Smith WS. Practice variability in management of transient ischemic attacks. Euro Neurol 1999; 42:105–108. Henneman PL, Lewis RJ. Is admission medically justified for all patients with acute stroke or transient ischemic attack? Ann Emerg Med 1995; 25(4):458–463. Lanska DJ. Review criteria for hospital utilization for patients with cerebrovascular disease. Task Force on Hospital Utilization for Stroke of the American Academy of Neurology. Neurology 1994; 44(8):1531–1532. Barnett HJ, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995; 332(4):238–248. Sacco RL. Clinical practice. Extracranial carotid stenosis. N Engl J Med 2001; 345(15):1113– 1118. Biller J, Feinberg WM, Castaldo JE, Whittemore AD, Harbaugh RE, Dempsey RJ, Caplan LR, Kresowik TF, Matchar DB, Toole JF, Easton JD, Adams HP Jr, Brass LM, Hobson RW II, Brott TG, Sternau L. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a Special Writing Group of the Stroke Council. American Heart Association. Circulation 1998; 97(5):501–509. Mead GE, O’Neill PA, McCollum CN. Is there a role for carotid surgery in acute stroke? Eur J Vasc Endovasc Surg 1997; 13(2):112–121. Gubitz G, Counsell C, Sandercock P, Signorini D. Anticoagulants for acute ischaemic stroke (Cochrane Review). The Cochrane Library, 2002; (1). Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials. Stroke 2000; 31(7):1770– 1778. Fisher CM. Transient ischemic attacks. N Engl J Med 2002; 347(21):1642–1643. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999; 281(19):1830–1835. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet 2000; 355(9211):1205–1210.

40

Johnston and Ruff

120. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 2001; 32(10):2333–2337. 121. Matchar DB, McCrory DC, Barnett HJ, Feussner JR. Medical treatment for stroke prevention [published erratum appears in Ann Intern Med 1994 Sep 15; 121(6):470]. Ann Intern Med 1994; 121(1):41–53. 122. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308(6921):81–106. 123. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31(6):1240–1249. 124. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348(9038):1329–1339. 125. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143(1–2):1–13. 126. A classification and outline of cerebrovascular diseases II. Stroke 1975; 6(5):564–616. 127. Koudstaal PJ, van Gijn J, Frenken CW, Hijdra A, Lodder J, Vermeulen M, Bulens C, Franke CL. TIA, RIND, minor stroke: a continuum, or different subgroups? Dutch TIA Study Group. J Neurol Neurosurg Psychiatry 1992; 55(2):95–97. 128. Koudstaal PJ, van Gijn J, Lodder J, Frenken WG, Vermeulen M, Franke CL, Hijdra A, Bulens C. Transient ischemic attacks with and without a relevant infarct on computed tomographic scans cannot be distinguished clinically. Dutch Transient Ischemic Attack Study Group. Arch Neurol 1991; 48(9):916–920. 129. Bogousslavsky J, Regli F. Cerebral infarct in apparent transient ischemic attack. Neurology 1985; 35(10):1501–1503. 130. Calandre L, Gomara S, Bermejo F, Millan JM, del Pozo G. Clinical-CT correlations in TIA, RIND, and strokes with minimum residuum. Stroke 1984; 15(4):663–666. 131. Engelter ST, Provenzale JM, Petrella JR, Alberts MJ. Diffusion MR imaging and transient ischemic attacks. Stroke 1999; 30(12):2762–2763. 132. Waxman SG, Toole JF. Temporal profile resembling TIA in the setting of cerebral infarction. Stroke 1983; 14(3):433–437. 133. Toole JF. The Willis lecture: transient ischemic attacks, scientific method, and new realities. Stroke 1991; 22(1):99–104. 134. Norris JW, Zhu CZ. Silent stroke and carotid stenosis. Stroke 1992; 23(4):483–485. 135. Eliasziw M, Streifler JY, Spence JD, Fox AJ, Hachinski VC, Barnett HJ. Prognosis for patients following a transient ischemic attack with and without a cerebral infarction on brain CT. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group. Neurology 1995; 45(3 Pt 1):428–431. 136. Caplan LR. Are terms such as completed stroke or RIND of continued usefulness? Stroke 1983; 14(3):431–433. 137. Dennis M, Bamford J, Sandercock P, Molyneux A, Warlow C. Computed tomography in patients with transient ischaemic attacks: when is a transient ischaemic attack not a transient ischaemic attack but a stroke? J Neurol 1990; 237(4):257–261. 138. Levy DE. How transient are transient ischemic attacks? Neurology 1988; 38(5):674–677. 139. Dennis MS, Bamford JM, Sandercock PA, Warlow CP. A comparison of risk factors and prognosis for transient ischemic attacks and minor ischemic strokes. The Oxfordshire Community Stroke Project. Stroke 1989; 20(11):1494–1499. 140. Gent M, Hirsh J. Definition of high risk/high response population for stroke in patients with transient ischemic attacks. Thromb Haemost 1979; 41(1):43–57. 141. Gueyffier F, Boissel JP, Boutitie F, Pocock S, Coope J, Cutler J, Ekbom T, Fagard R,

Diagnosis and Prognosis of Transient Ischemic Attacks

142.

143.

144. 145. 146.

147.

148.

149.

41

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

44

de Freitas and Bogousslavsky

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.)

Ischemic Stroke Syndromes

45

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

46

de Freitas and Bogousslavsky

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.

Ischemic Stroke Syndromes

47

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.

48

de Freitas and Bogousslavsky

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).

Ischemic Stroke Syndromes

49

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.

50

de Freitas and Bogousslavsky

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

Ischemic Stroke Syndromes

51

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.

52

de Freitas and Bogousslavsky

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

Ischemic Stroke Syndromes

53

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

54

de Freitas and Bogousslavsky

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.

Ischemic Stroke Syndromes

55

(‘‘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).

56

de Freitas and Bogousslavsky

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

Ischemic Stroke Syndromes

57

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

58

de Freitas and Bogousslavsky

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.

Ischemic Stroke Syndromes

59

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.

60

de Freitas and Bogousslavsky

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).

Ischemic Stroke Syndromes

61

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

62

de Freitas and Bogousslavsky

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).

Ischemic Stroke Syndromes

63

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.

64

de Freitas and Bogousslavsky

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.

Ischemic Stroke Syndromes

65

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.)

66

de Freitas and Bogousslavsky

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.

Ischemic Stroke Syndromes

67

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.

68

de Freitas and Bogousslavsky

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.

REFERENCES 1. Marino R Jr. The anterior cerebral artery: I. Anatomo-radiological study of its cortical territories. Surg Neurol 1976; 5:81–87. 2. Kazui S, Sawada T, Naritomi H, Kuriyama Y, Yamaguchi T. Angiographic evaluation of brain infarction limited to the anterior cerebral artery territory. Stroke 1993; 24:549–553. 3. Gags G, Fox AJ, Barnett HJM, Vinuela F. Occurrence of occlusion of the anterior cerebral artery. Stroke 1983; 14:952–959. 4. Bogousslavsky J, Regli F. Anterior cerebral artery territory infarction in the Lausanne Stroke Registry: clinical and etiologic patterns. Arch Neurol 1990; 47:144–150. 5. Caplan LR, Scmahmann JD, Kase CS, et al. Caudate infarcts. Arch Neurol 1990; 47:133–143. 6. Critchley M. The anterior cerebral artery, and its syndromes. Brain 1930; 53:120–165. 7. Alexander MP, Schmitt AS. The aphasia syndrome of stroke in the left anterior cerebral artery territory. Arch Neurol 1980; 37:97–100. 8. Geschwind N, Kaplan E. A human cerebral disconnection syndrome: a preliminary report. Neurology 1962; 12:675–685. 9. Bogousslavsky J, Hommel M. Ischemic stroke syndromes: clinical features, anatomy, vascular

Ischemic Stroke Syndromes

10.

11. 12. 13.

14. 15. 16.

17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

29. 30. 31. 32. 33. 34. 35.

69

territories. In: Adams HP Jr, ed. Handbook of Cerebrovascular Diseases. New York: Marcel Dekker, 1993:51–94. Hupperts RMM, Lodder J, Heuts-van Raak EPM, Kessels F. Infarcts in the anterior choroidal artery territory: anatomical distribution, clinical syndromes, presumed pathogenesis and early outcome. Brain 1994; 117:825–834. Ghika J, Bogousslavsky J, Regli F. Infarcts in the territory of the deep perforators from the carotid system. Neurology 1989; 39:507–512. Levy R, Duyckaerts C, Hauw JJ. Massive infarcts involving the territory of the anterior choroidal artery and cardioembolism. Stroke 1995; 26:609–613. Foix CH, Chavany JA, Hillemand P, Schiff Wertheimer S. Oblite´ration de l’arte`re choroidienne ante´rieure. Ramolissement de son territoire cerebral, he´miple´gie, he´mianesthe´sie, he´mianopsie. Bull Soc d’Ophthalmol (Paris) 1925; 27:221–223. Decroix JP, Graveleau Ph, Masson M, Cambier J. Infarction in the territory of the anterior choroidal artery. Brain 1986; 109:1071–1085. Helgason C, Caplan LR, Goodwin J, Hedges T III. Anterior choroidal artery-territory infarction: report of cases and review. Arch Neurol 1986; 43:681–686. Bogousslavsky J, Regli F, Delaloye B, Delaloye-Bischoff A, Uske A, Despland PA. He´miataxie et de´ficit sensitif ipsilate´ral. Infarctus du territoire de l’arte`re choroidienne ante´rieure. Diachisis ce´re´belleux croise´. Rev Neurol (Paris) 1986; 142:671–676. Gibo H, Carver CC, Rhoton AL Jr, Lenkey C, Mitchell RJ. Microsurgical anatomy of the middle cerebral artery. J Neurosurg 1981; 54:151–169. Blackwood W, Hallpike JF, Kocen RS, Mair WGP. Atheromatous disease of the carotid arterial system and embolism from the heart: a morbid anatomic study. Brain 1969; 92:897–910. Lhermitte F, Gautier JC, Derouesne´ C. Nature of occlusions of the middle cerebral artery. Neurology 1970; 20:82–88. Caplan LR, Helgason C, Hier DB, et al. Occlusive disease of the middle cerebral artery. Neurology 1985; 35:972–982. Bogousslavsky J, Van Melle G, Regli F. Middle cerebral artery pial territory: a study of the Lausanne Stroke Registry. Ann Neurol 1989; 25:555–560. Heinsius T, Bogousslavsky J, Van Melle G. Large infarcts in the middle cerebral artery territory: etiology and outcome. Neurology 1998; 50:341–350. Bamford J, Sandercock P, Dennis M, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337:1521–1526. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Krummer R. Malignant middle cerebral artery territory infarction. Arch Neurol 1996; 53:309–315. Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after right hemisphere stroke. Neurology 1983; 33:337–344. Foix C, Levy M. Les ramolissements sylviens. Rev Neurol (Paris) 1927; 2:1–51. Derouesne´ C. L’artere cerebral moyenne et ses syndromes. Rev Me´d 1973; 42:2833–2848. Neau JP, Bogousslavsky J. Middle cerebral artery syndromes. In: Ginsberg MD, Bogousslavsky J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management. MA: Blackwell Science, 1998:997–1027. Caplan LR, Kelly M, Kase CS, et al. Infarcts of the inferior division of the right middle cerebral artery: mirror image of Wernicke’s aphasia. Neurology 1986; 36:1015–1020. Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982; 32:871–876. Fisher CM. Lacunar infarcts: a review. Cerebrovasc Dis 1991; 1:311–320. Bogousslavsky J, Regli F. Capsular genu syndrome. Neurology 1990; 40:1499–1502. Tatemichi TK, Desmond DW, Prohovnik I, et al. Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome? Neurology 1992; 42:1966–1979. Bamford J, Sandercock P, Jones L, Warlow C. The natural history of lacunar infarction: the Oxfordshire Community Stroke Project. Stroke 1987; 18:545–551. Donnan GA, Bladin PF, Berkovic SF, Longley WA, Saling MM. The stroke syndrome of striatocapsular infarction. Brain 1991; 114:51–70.

70

de Freitas and Bogousslavsky

36. Boiten J, Lodder J. Large striatocapsular infarcts: clinical presentation and pathogenesis in comparison with lacunar and cortical infarcts. Acta Neurol Scand 1992; 86:298–303. 37. Bogousslavsky J, Regli F. Centrum ovale infarcts: subcortical infarction in the superficial territory of the middle cerebral artery. Neurology 1992; 43:1992–1998. 38. Leys D, Mounier-Vehier F, Rondepierre P, Leclerc X, Godefroy O, Marchau M Jr, Scheltens P, Pruvo JP. Small infarcts in the centrum ovale: study of predisposing factors. Cerebrovasc Dis 1994; 4:83–87. 39. Krayenbuhl H, Yasargil GM. Cerebral Angiography. Stuttgart: Thieme Verlag, 1982. 40. Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR. Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and review of the literature. Cerebrovasc Dis 2000; 10:170–182. 41. Caplan LR. Posterior circulation disease: clinical findings, diagnosis and management. Cambridge, MA: Blackwell Science, 1996. 42. Castaigne P, Lhermitte F, Gautier JC, et al. Arterial occlusions in the vertebro-basilar system. A study of 44 patients with post-mortem data. Brain 1973; 96:133–154. 43. Pessin MS, Kwan ES, De Witt LD, Hedges TR, Gale D, Caplan LR. Posterior cerebral artery stenosis. Ann Neurol 1987; 21:85–89. 44. Milandre L, Brosset C, Botti G, Khalil R. E´tude de 82 infarctus du territoire des arte`res ce´re´brales poste´rieures. Rev Neurol (Paris) 1994; 150:133–141. 45. Von Cramon DY, Hebel N, Schuri U. Verbal memory and learning in unilateral posterior cerebral infarction. A report on 30 cases. Brain 1988; 111:1061–1077. 46. Devinsky O, Bear D, Volpe BT. Confusional states following posterior cerebral artery infarction. Arch Neurol 1988; 45:160–163. 47. Bogousslavsky J, Van Melle G, Regli F. The Lausanne Stroke Registry: analysis of 1000 consecutive patients with first stroke. Stroke 1988; 19:1083–1092. 48. Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 1988; 38:837–848. 49. Deje´rine J, Roussy G. Le syndrome thalamique. Rev Neurol (Paris) 1906; 14:521521. 50. de Freitas GR, Bogousslavsky J. Thalamic infarcts. In: Donnan GA, Norrving B, Bamford J, Bogousslavsky J, eds. Subcortical Stroke. 2d ed.. Oxford: Oxford University Press, 2002:255– 285. 51. Bogousslavsky J, Miklossy J, Deruaz JP, Regli F, Assal G. Unilateral left paramedian infarction of thalamus and midbrain: a clinico-pathological study. J Neurol Neurosurg Psychiat 1986; 49:686–694. 52. Bogousslavsky J, Regli F, Assal G. The syndrome of tubero-thalamic artery territory infarction. Stroke 1986; 17:434–441. 53. Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of the human brain: brainstem and cerebellum. Neurology 1996; 47:1125–1135. 54. Norrving Bo, Cronqvist S. Lateral medullary infarction: prognosis in an unselected series. Neurology 1991; 41:244–248. 55. Vuilleumier P, Bogousslavsky J, Regli F. Infarction of the lower brainstem: clinical, aetiological and MRI-topographical correlations. Brain 1995; 118:1013–1025. 56. Currier RD, Giles CL, DeJong RN. Some comments on Wallenberg’s lateral medullary syndrome. Neurology 1961; 12:778–791. 57. Kim JS, Kim HG, Chung CS. Medial medullary syndrome: report of 18 new patients and review of the literature. Stroke 1995; 26:1548–1552. 58. de Freitas GR, Moll J, Araujo AQ. The Babinski-Nageotte syndrome. Neurology 2001; 56:1604. 59. Bassetti C, Bogousslavsky J, Barth A, Regli F. Isolated infarcts of the pons. Neurology 1996; 46:165–175. 60. Kim JS, Lee JH, Im JH, Lee MC. Syndromes of pontine base infarction: a clinical-radiological correlation study. Stroke 1995; 26:950–955. 61. Bogousslavsky J, Maeder P, Regli F, Meuli R. Pure midbrain infarction: clinical syndromes, MRI, and etiologic patterns. Neurology 1994; 44:2032–2040.

Ischemic Stroke Syndromes

71

62. Barth A, Bogousslavsky J, Regli F. The clinical and topographic spectrum of cerebellar infarcts: a clinical-magnetic resonance imaging correlation study. Ann Neurol 1993; 33:451– 456. 63. Amarenco P, Hauw JJ. Cerebellar infarction in the territory of the anterior and inferior cerebellar artery: a clinicopathological study of 20 cases. Brain 1990; 113:139–155. 64. Amarenco P, Rosengart A, DeWitt LD, Pessin MS, Caplan LR. Anterior inferior cerebellar artery territory infarcts: mechanisms and clinical features. Arch Neurol 1993; 50:154–161. 65. Amarenco P, Hauw JJ. Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathological study of 33 cases. Neurology 1990; 40:1383–1390. 66. Amarenco P. Spectrum of cerebellar infarctions. Neurology 1991; 41:973–979. 67. Bogousslavsky J, Regli F. Unilateral watershed cerebral infarction. Neurology 1986; 36:373– 377. 68. Bogousslavsky J, Regli F. Borderzone infarctions distal to internal carotid artery occlusion: prognostic implications. Ann Neurol 1986; 20:346–350. 69. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55:1475–1482.

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

74

Chang

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

Intracerebral Hemorrhage

75

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

76

Chang

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

Intracerebral Hemorrhage

77

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].

78

Chang

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.

REFERENCES 1. Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993; 78(2):188–191. 2. Sacco RL, SA. Epidemiology of intracerebral hemorrhage. In: Feldmann E, ed. Intracerebral Hemorrhage. Armonk, NY: Futura Publishing Co, 1994:3–23. 3. Broderick JP. Stroke Trends in Rochester, Minnesota, during 1945 to 1984. Ann Epidemiol 1993; 3(5):476–479. 4. Immonen-Raiha P, Mahonen M, Tuomilehto J, et al. Trends in the case fatality of stroke in Finland during 1983 to 1992. Stroke 1997; 28(12):2493–2499. 5. Broderick JP, Adams HP, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999; 30:905–915. 6. Qureshi AI, Safdar K, Patel M, Janssen RS, Frankel MR. Stroke in young black patients. Risk factors, subtypes, and prognosis. Stroke 1995; 26:1995–1998. 7. Qureshi AI, Safdar K, Well J, Barch C, Bliwise DL, Colohan AR, Mackay B, Frankel MR. Predictors of early deterioration and mortality in black Americans with spontaneous intracerebral hemorrhages. Stroke 1995 Oct; 26:1764–1767. 8. Jakovljevic D, Sarti C, Sivenius J, et al. Socioeconomic differences in the incidence, mortality, and prognosis of intracerebral hemorrhage in Finnish Adult Population. The FINMONICA Stroke Register. Neuroepidemiology 2001; 20:85–90. 9. Hung TP, Chen ST. Cerebral hemorrhage in Taiwan. J Formos Med Assoc 1993; 92(suppl 4):S161–S168. 10. Hsiang JN, Zhu XL, Wong LK, Kay R, Poon WS. Putaminal and thalamic hemorrhage in ethnic Chinese living in Hongkong. Surg Neurol 1996; 46(5):441–445. 11. el Chami B, Milan C, Giroud M, Sautreaux JL, Faivre J. Intracerebral hemorrhage survival: French register data. Neurol Res 2000; 22:791–796. 12. Szczudlik A, Turaj W, Slowik A, Strojny J. Hyperthermia is not an independent predictor of greater mortality in patients with primary intracerebral hemorrhage. Med Sci Monit 2002; 8(10):CR702–CR770. 13. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med 1999; 27(3):617–621. 14. Mase G, Zorzon M, Biasutti E, Tasca G, Vitrani B, Cazzato G. Immediate prognosis of primary intracerebral hemorrhage using an easy model for the prediction of survival. Acta Neurol Scand 1995; 91:305–309. 15. Karnik R, Valentin A, Ammerer HP, Hochfelner A, Donath P, Slany J. Outcome in patients with intracerebral hemorrhage: predictors of survival. Wien Klin Wochenschr 2000; 112(4):169– 173. 16. Phan TG, Koh M, Vierkant RA, Wijdicks EF. Hydrocephalus is a determinant of early mortality in putaminal hemorrhage. Stroke 2000; 31:2157–2162.

Intracerebral Hemorrhage

79

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.

80

Chang

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

82

Kidwell et al.

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

Brain Imaging in Stroke

83

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

84

Kidwell et al.

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.

Brain Imaging in Stroke

85

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

86

Kidwell et al.

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).

Brain Imaging in Stroke

87

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.

88

Kidwell et al.

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).

Brain Imaging in Stroke

89

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

90

Kidwell et al.

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.

Brain Imaging in Stroke

91

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

92

Kidwell et al.

V6 cm3/100 g
1/min
1 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.

Brain Imaging in Stroke

93

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].

94

Kidwell et al.

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].

Brain Imaging in Stroke

95

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

96

Kidwell et al.

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).

Brain Imaging in Stroke

97

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

98

Kidwell et al.

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.

REFERENCES 1. Moulin T, Cattin F, Crepin-Leblond T, Tatu L, Chavot D, Piotin M, et al. Early CT signs in acute middle cerebral artery infarction: predictive value for subsequent infarct locations and outcome. Neurology 1996; 47(2):366–375. 2. von Kummer R, Nolte PN, Schnittger H, Thron A, Ringelstein EB. Detectability of cerebral hemisphere ischaemic infarcts by CT within 6 h of stroke. Neuroradiology 1996; 38(1):31–33. 3. NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA for ischemic stroke. Stroke 1997; 28:2109–2118. 4. Patel SC, Levine SR, Tilley BC, Grotta JC, Lu M, Frankel M, et al. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA 2001; 286(22):2830– 2838. 5. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274(13):1017–1025. 6. Schriger DL, Kalafut M, Starkman S, Krueger M, Saver JL. Cranial computed tomography interpretation in acute stroke: physician accuracy in determining eligibility for thrombolytic therapy. JAMA 1998; 279(16):1293–1297. 7. Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355(9216):1670–1674. 8. Adams HP Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003; 34(4):1056–1083. 9. Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab 1998; 18(6):583–609. 10. Mohr JP, Biller J, Hilal SK, Yuh WT, Tatemichi TK, Hedges S, et al. Magnetic resonance versus computed tomographic imaging in acute stroke. Stroke 1995; 26(5):807–812. 11. Schlaug G, Siewert B, Benfield A, Edelman RR, Warach S. Time course of the apparent diffusion coefficient (ADC) abnormality in human stroke. Neurology 1997; 49(1):113–119. 12. Kidwell CS, Alger JR, Di Salle F, Starkman S, Villablanca P, Bentson J, et al. Diffusion MRI in patients with transient ischemic attacks. Stroke 1999; 30(6):1174–1180. 13. Ay H, Oliveira-Filho J, Buonanno FS, Schaefer PW, Furie KL, Chang YC, et al. ‘Footprints’ of transient ischemic attacks: a diffusion-weighted MRI study. Cerebrovasc Dis 2002; 14(3–4):177– 186. 14. Engelter ST, Provenzale JM, Petrella JR, Alberts MJ. Diffusion MR imaging and transient ischemic attacks [letter; comment]. Stroke 1999; 30(12):2762–2763. 15. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28(1):1–5. 16. Kidwell CS, Chalela JA, Saver JL, Davis S, Starkman S, Warach S. Hemorrhage early MRI

Brain Imaging in Stroke

17.

18.

19.

20.

21.

22. 23. 24. 25.

26. 27. 28.

29.

30. 31.

32.

33.

34.

35.

99

evaluation (HEME) study: preliminary results of a multicenter trial of neuroimaging in patients with acute stroke symptoms within 6 hours of onset [abstr]. Stroke 2003; 34:239. Schellinger PD, Fiebach JB, Gass A, Roether J, Siebler M, Villringer A, et al. Accuracy of stroke MRI in hyperacute intracerebral hemorrhage <6 hours: a prospective standardized blinded multicenter study. Stroke 2003; 34:239. Kidwell CS, Saver JL, Villablanca JP, Duckwiler G, Fredieu A, Gough K, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis: an emerging application. Stroke 2002; 33(1):95–98. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. Am J Neuroradiol 1999; 20(4):637–642. Heiss WD, Huber M, Fink GR, Herholz K, Pietrzyk U, Wagner R, et al. Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab 1992; 12:193–203. Touho H, Karasawa J. Evaluation of time-dependent thresholds of cerebral blood flow and transit time during the acute stage of cerebral embolism: a retrospective study. Surg Neurol 1996; 46(2):135–146. Kaufmann AM, Firlik AD, Fukui MB, Wechsler LR, Jungries CA, Yonas H. Ischemic core and penumbra in human stroke. Stroke 1999; 30(1):93–99. Firlik AD, Rubin G, Yonas H, Wechsler LR. Relation between cerebral blood flow and neurologic deficit resolution in acute ischemic stroke. Neurology 1998; 51(1):177–182. Klotz E, Konig M. Perfusion measurements of the brain: using dynamic CT for the quantitative assessment of cerebral ischemia in acute stroke. Eur J Radiol 1999; 30(3):170–184. Wintermark M, Reichhart M, Thiran JP, Maeder P, Chalaron M, Schnyder P, et al. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol 2002; 51(4):417–432. Alsop DC, Detre JA. Multisection cerebral blood flow MR imaging with continuous arterial spin labeling. Radiology 1998; 208(2):410–416. Detre JA, Alsop DC, Vives LR, Maccotta L, Teener JW, Raps EC. Noninvasive MRI evaluation of cerebral blood flow in cerebrovascular disease. Neurology 1998; 50(3):633–641. Tong DC, Yenari MA, Albers GW, M OB, Marks MP, Moseley ME. Correlation of perfusionand diffusion-weighted MRI with NIHSS score in acute (<6.5 hour) ischemic stroke. Neurology 1998; 50(4):864–870. Baron JC, Bousser MG, Rey A, Guillard A, Comar D, Castaigne P. Reversal of focal ‘‘miseryperfusion syndrome’’ by extra-intracranial arterial bypass in hemodynamic cerebral ischemia. A case study with 15O positron emission tomography. Stroke 1981; 12(4):454–459. Furlan M, Marchal G, Viader F, Derlon JM, Baron JC. Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra. Ann Neurol 1996; 40(2):216–226. Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader F, et al. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis [see comments]. Stroke 1996; 27(4):599–606. Heiss WD, Grond M, Thiel A, von Stockhausen HM, Rudolf J, Ghaemi M, et al. Tissue at risk of infarction rescued by early reperfusion: a positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute stroke. J Cereb Blood Flow Metab 1998; 18(12):1298–1307. Read SJ, Hirano T, Abbott DF, Sachinidis JI, Tochon-Danguy HJ, Chan JG, et al. Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole. Neurology 1998; 51(6):1617–1621. Heiss WD, Grond M, Thiel A, Ghaemi M, Sobesky J, Rudolf J, et al. Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 1998; 29(2):454– 461. Grubb RL Jr, Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, et al. Importance

100

36.

37.

38.

39.

40. 41.

42. 43. 44.

45.

46.

47.

48.

49.

50.

Kidwell et al. of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998; 280(12):1055–1060. Ueda T, Sakaki S, Yuh WT, Nochide I, Ohta S. Outcome in acute stroke with successful intraarterial thrombolysis and predictive value of initial single-photon emission-computed tomography. J Cereb Blood Flow Metab 1999; 19(1):99–108. Berrouschot J, Barthel H, von Kummer R, Knapp WH, Hesse S, Schneider D. 99m technetiumethyl-cysteinate-dimer single-photon emission CT can predict fatal ischemic brain edema. Stroke 1998; 29(12):2556–2562. Berrouschot J, Barthel H, Hesse S, Koster J, Knapp WH, Schneider D. Differentiation between transient ischemic attack and ischemic stroke within the first six hours after onset of symptoms by using 99mTc-ECD-SPECT. J Cereb Blood Flow Metab 1998; 18(8):921–929. Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, Ferguson G, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415–1425. Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. N Engl J Med 2000; 343(10):710– 722. Wildermuth S, Knauth M, Brandt T, Winter R, Sartor K, Hacke W. Role of CT angiography in patient selection for thrombolytic therapy in acute hemispheric stroke. Stroke 1998; 29(5):935– 938. Shrier DA, Tanaka H, Numaguchi Y, Konno S, Patel U, Shibata D. CT angiography in the evaluation of acute stroke. AJNR 1997; 18(6):1011–1020. Qureshi AI, Isa A, Cinnamon J, Fountain J, Ottenlips JR, Braimah J, et al. Magnetic resonance angiography in patients with brain infarction. J Neuroimag 1998; 8:65–70. Scarabino T, Carriero A, Giannatempo GM, Marano R, De Matthaeis P, Bonomo L, et al. Contrast-enhanced MR angiography (CE MRA) in the study of the carotid stenosis: comparison with digital subtraction angiography (DSA). J Neuroradiol 1999; 26(2):87–91. Rasanen HT, Manninen HI, Vanninen RL, Vainio P, Berg M, Saari T. Mild carotid artery atherosclerosis: assessment by 3-dimensional time-of-flight magnetic resonance angiography, with reference to intravascular ultrasound imaging and contrast angiography. Stroke 1999; 30(4):827–833. Jackson MR, Chang AS, Robles HA, Gillespie DL, Olsen SB, Kaiser WJ, et al. Determination of 60% or greater carotid stenosis: a prospective comparison of magnetic resonance angiography and duplex ultrasound with conventional angiography. Vasc Surg 1998; 12:236–243. Nederkoorn PJ, van der Graaf Y, Hunink MG. Duplex ultrasound and magnetic resonance angiography compared with digital subtraction angiography in carotid artery stenosis: a systematic review. Stroke May 2003; 34(5):1324–1332. Goertler M, Kross R, Baeumer M, Jost S, Grote R, Weber S, et al. Diagnostic impact and prognostic relevance of early contrast-enhanced transcranial color-coded duplex sonography in acute stroke. Stroke 1998; 29(5):955–962. Saver JL, Feldmann E. The basic transcranial Doppler examination: technique and anatomy. In: Babikian VL, Wechsler L, eds. Transcranial Doppler Sonography: Clinical and Research Applications. Philadelphia: B.C. Decker, 1992:11–28. Kidwell CS, Saver JL, Mattiello J, Starkman S, Vinuela F, Duckwiler G, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol 2000; 47(4):462–469.

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

102

Hodics and Caplan

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

Evaluation of Stroke Patients

103

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

104

Hodics and Caplan

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

Evaluation of Stroke Patients

105

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

106

Hodics and Caplan

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

Evaluation of Stroke Patients

107

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

108

Hodics and Caplan

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].

Evaluation of Stroke Patients

109

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].

110

Hodics and Caplan

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].

Evaluation of Stroke Patients

111

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

112

Hodics and Caplan

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].

Evaluation of Stroke Patients

113

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

114

Hodics and Caplan

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

Evaluation of Stroke Patients

115

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

116

Hodics and Caplan

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].

Evaluation of Stroke Patients

117

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

118

Hodics and Caplan

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,

Evaluation of Stroke Patients

119

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-

120

Hodics and Caplan

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.

Evaluation of Stroke Patients

121

6. Arboix A, et al. Cardioembolic infarction in the Sagrat Cor-Alianza Hospital of Barcelona Stroke Registry. Acta Neurol Scand 1997; 96(6):407–412. 7. Adams HP Jr, et al. CT and clinical correlations in recent aneurysmal subarachnoid hemorrhage: a preliminary report of the Cooperative Aneurysm Study. Neurology 1983; 33(8):981–988. 8. Sames TA, et al. Sensitivity of new-generation computed tomography in subarachnoid hemorrhage. Acad Emerg Med 1996; 3(1):16–20. 9. Kase CS, Mohr JP, Caplan LR. Intracerebral hemorrhage. In: Barnett HJM, et al., ed. Stroke. Edinburgh: Churchill Livingstone, 1998:649–700. 10. Kjellin KG, Soderstrom CE. Cerebral haemorrhages with atypical clinical patterns. A study of cerebral haematomas using CSF spectrophotometry and computerized transverse axial tomography (‘‘EMI scanning’’). J Neurol Sci 1975; 25(2):211–226. 11. Culebras A, et al. Practice guidelines for the use of imaging in transient ischemic attacks and acute stroke. A report of the Stroke Council. American Heart Association. Stroke 1997; 28(7):1480–1497. 12. Ernst R, et al. Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke. Stroke 2000; 31(11):2552–2557. 13. Keris V, et al. Combined intraarterial/intravenous thrombolysis for acute ischemic stroke. AJNR Am J Neuroradiol 2001; 22(2):352–358. 14. Lewandowski CA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999; 30(12):2598–2605. 15. del Zoppo GJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 1998; 29(1):4–11. 16. Furlan A, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. Jama 1999; 282(21):2003–2011. 17. Chalela JA, et al. Safety of intra-arterial thrombolysis in the postoperative period. Stroke 2001; 32(6):1365–1369. 18. Qureshi AI. New grading system for angiographic evaluation of arterial occlusions and recanalization response to intra-arterial thrombolysis in acute ischemic stroke. Neurosurgery 2002; 50(6):1405–1415. 19. Yock DH Jr. CT demonstration of cerebral emboli. J Comput Assist Tomogr 1981; 5(2):190–196. 20. Gacs G, et al. CT visualization of intracranial arterial thromboembolism. Stroke 1983; 14(5):756–762. 21. Flacke S, et al. Middle cerebral artery (MCA) susceptibility sign at susceptibility-based perfusion MR imaging: clinical importance and comparison with hyperdense MCA sign at CT. Radiology 2000; 215(2):476–482. 22. Chalela JA, et al. The hypointense MCA sign. Neurology 2002; 58(10):1470. 23. Young GR, et al. Observer variation in the interpretation of intra-arterial angiograms and the risk of inappropriate decisions about carotid endarterectomy. J Neurol Neurosurg Psychiatry 1996; 60(2):152–157. 24. Eliasziw M, et al. Carotid artery stenosis: external validity of the North American Symptomatic Carotid Endarterectomy Trial measurement method. Radiology 1997; 204(1): 229–233. 25. Yucel EK, et al. AHA scientific statement. Magnetic resonance angiography: update on applications for extracranial arteries. Circulation 1999; 100(22):2284–2301. 26. Liberopoulos K, et al. Comparative study of magnetic resonance angiography, digital subtraction angiography, duplex ultrasound examination with surgical and histological findings of atherosclerotic carotid bifurcation disease. Int Angiol 1996; 15(2):131–137. 27. Caplan LR, et al. Transcranial Doppler ultrasound: present status. Neurology 1990; 40(4):696–700.

122

Hodics and Caplan

28. Tegeler CH, Ratanakorn D. Ultrasound in cerebrovascular disease. In: Greenberg JO, ed. Neuroimaging. New York: McGraw-Hill, 1999:645–666. 29. Rubin JM, et al. Power Doppler US: a potentially useful alternative to mean frequency-based color Doppler US. Radiology 1994; 190(3):853–856. 30. Steinke W, et al. Power Doppler imaging of carotid artery stenosis. Comparison with color Doppler flow imaging and angiography. Stroke 1997; 28(10):1981–1987. 31. Griewing B, et al. Cerebrovascular disease assessed by color-flow and power Doppler ultrasonography. Comparison with digital subtraction angiography in internal carotid artery stenosis. Stroke 1996; 27(1):95–100. 32. Furst G, et al. Reliability and validity of noninvasive imaging of internal carotid artery pseudo-occlusion. Stroke 1999; 30(7):1444–1449. 33. Clinical alert: benefit of carotid endarterectomy for patients with high-grade stenosis of the internal carotid artery. National Institute of Neurological Disorders and Stroke Stroke and Trauma Division. North American Symptomatic Carotid Endarterectomy Trial (NASCET) investigators. Stroke 1991; 22(6):816–817. 34. Mayberg MR, et al. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group. Jama 1991; 266(23):3289–3294. 35. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. European Carotid Surgery Trialists’ Collaborative Group. Lancet 1991; 337(8752):1235–1243. 36. Hobson RW II, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med 1993; 328(4):221–227. 37. Clinical advisory: carotid endarterectomy for patients with asymptomatic internal carotid artery stenosis. Stroke 1994; 25(12):2523–2524. 38. Results of a randomized controlled trial of carotid endarterectomy for asymptomatic carotid stenosis. Mayo Asymptomatic Carotid Endarterectomy Study Group. Mayo Clin Proc 1992; 67(6):513–518. 39. Steinke W, Kloetzsch C, Hennerici M. Carotid artery disease assessed by color Doppler flow imaging: correlation with standard Doppler sonography and angiography. AJNR Am J Neuroradiol 1990; 11(2):259–266. 40. Berman SS, et al. Distinguishing carotid artery pseudo-occlusion with color-flow Doppler. Stroke 1995; 26(3):434–438. 41. Steinke W, et al. Symptomatic and asymptomatic high-grade carotid stenoses in Doppler color-flow imaging. Neurology 1992; 42(1):131–138. 42. Liapis CD, Kakisis JD, Kostakis AG. Carotid stenosis: factors affecting symptomatology. Stroke 2001; 32(12):2782–2786. 43. Gronholdt ML, et al. Ultrasonic echolucent carotid plaques predict future strokes. Circulation 2001; 104(1):68–73. 44. Gronholdt ML, et al. Lipid-rich carotid artery plaques appear echolucent on ultrasound Bmode images and may be associated with intraplaque haemorrhage. Eur J Vasc Endovasc Surg 1997; 14(6):439–445. 45. Gomez CR. Carotid plaque morphology and risk for stroke. Stroke 1990; 21(1):148–151. 46. Sterpetti AV, et al. Ultrasonographic features of carotid plaque and the risk of subsequent neurologic deficits. Surgery 1988; 104(4):652–660. 47. O’Farrell CM, FitzGerald DE. Prognostic value of carotid ultrasound lesion morphology in retinal ischaemia: result of a long term follow up. Br J Ophthalmol 1993; 77(12):781–784. 48. Tong DC, Albers GW. Transcranial Doppler-detected microemboli in patients with acute stroke. Stroke 1995; 26(9):1588–1592. 49. Forteza AM, et al. Effect of time and cerebrovascular symptoms of the prevalence of microembolic signals in patients with cervical carotid stenosis. Stroke 1996; 27(4):687–690. 50. Censori B, et al. Doppler microembolic signals predict ischemic recurrences in symptomatic carotid stenosis. Acta Neurol Scand 2000; 101(5):327–331.

Evaluation of Stroke Patients

123

51. Valton L, et al. Microembolic signals and risk of early recurrence in patients with stroke or transient ischemic attack. Stroke 1998; 29(10):2125–2128. 52. Hennerici M, Steinke W, Rautenberg W. High-resistance Doppler flow pattern in extracranial carotid dissection. Arch Neurol 1989; 46(6):670–672. 53. Sturzenegger M. Ultrasound findings in spontaneous carotid artery dissection. The value of duplex sonography. Arch Neurol 1991; 48(10):1057–1063. 54. Logason K, et al. Duplex scan findings in patients with spontaneous cervical artery dissections. Eur J Vasc Endovasc Surg 2002; 23(4):295–298. 55. Bartels E, Fuchs HH, Flugel KA. Duplex ultrasonography of vertebral arteries: examination, technique, normal values, and clinical applications. Angiology 1992; 43(3 Pt 1):169–180. 56. Bartels E, Flugel KA. Advantages of color Doppler imaging for the evaluation of vertebral arteries. J Neuroimaging 1993; 3(4):229–233. 57. Touboul PJ, et al. Duplex scanning in extracranial vertebral artery dissection. Stroke 1988; 19(1):116–121. 58. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982; 57(6):769–774. 59. Hennerici M, et al. Transcranial Doppler ultrasound for the assessment of intracranial arterial flow velocity—Part 1. Examination technique and normal values. Surg Neurol 1987; 27(5): 439–448. 60. Ringelstein EB, et al. Transcranial Doppler sonography: anatomical landmarks and normal velocity values. Ultrasound Med Biol 1990; 16(8):745–761. 61. Schlief R. Ultrasound contrast agents. Curr Opin Radiol 1991; 3(2):198–207. 62. Bogdahn U, et al. Contrast-enhanced transcranial color-coded real-time sonography. Results of a phase-two study. Stroke 1993; 24(5):676–684. 63. Ries F, et al. A transpulmonary contrast medium enhances the transcranial Doppler signal in humans. Stroke 1993; 24(12):1903–1909. 64. Koennecke HC, et al. Microemboli in patients with vertebrobasilar ischemia: association with vertebrobasilar and cardiac lesions. Stroke 1997; 28(3):593–596. 65. Babikian VL, et al. Transcranial Doppler ultrasonography: year 2000 update. J Neuroimaging 2000; 10(2):101–115. 66. Schwarze JJ, et al. Longitudinal monitoring of intracranial arterial stenoses with transcranial Doppler ultrasonography. J Neuroimaging 1994; 4(4):182–187. 67. Akopov S, Whitman GT. Hemodynamic studies in early ischemic stroke: serial transcranial Doppler and magnetic resonance angiography evaluation. Stroke 2002; 33(5):1274–1279. 68. Kaps M, et al. Intracranial haemodynamics in patients with spontaneous carotid dissection. Transcranial Doppler ultrasound follow-up studies. Eur Arch Psychiatry Neurol Sci 1990; 239(4):246–256. 69. Kaps M, Teschendorf U, Dorndorf W. Haemodynamic studies in early stroke. J Neurol 1992; 239(3):138–142. 70. Alexandrov AV, Bladin CF, Norris JW. Intracranial blood flow velocities in acute ischemic stroke. Stroke 1994; 25(7):1378–1383. 71. Wong KS, et al. Progression of middle cerebral artery occlusive disease and its relationship with further vascular events after stroke. Stroke 2002; 33(2):532–536. 72. Griewing B, Doherty C, Kessler C. Power Doppler ultrasound examination of the intracerebral and extracerebral vasculature. J Neuroimaging 1996; 6(1):32–35. 73. Postert T, et al. Comparison of transcranial power Doppler and contrast-enhanced colorcoded sonography in the identification of intracranial arteries. J Ultrasound Med 1998; 17(2): 91–96. 74. Zunker P, et al. Echo contrast-enhanced transcranial ultrasound: frequency of use, diagnostic benefit, and validity of results compared with MRA. Stroke 2002; 33(11):2600–2603. 75. Demchuk AM, et al. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke 2001; 32(1):89–93.

124

Hodics and Caplan

76. Alexandrov AV, et al. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation 2001; 103(24):2897–2902. 77. Burgin WS, et al. Transcranial doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke 2000; 31(5):1128–1132. 78. Lauer CG, et al. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992; 86(4):1257–1264. 79. Kimura M, et al. Evaluation of the thrombolytic effect of tissue-type plasminogen activator with ultrasonic irradiation: in vitro experiment involving assay of the fibrin degradation products from the clot. Biol Pharm Bull 1994; 17(1):126–130. 80. Akiyama M, et al. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery 1998; 43(4):828–833. 81. Alexandrov AV, et al. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial doppler monitoring. Stroke 2000; 31(3):610–614. 82. Suchkova V, et al. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998; 98(10):1030–1035. 83. Spengos K, et al. Acceleration of thrombolysis with ultrasound through the cranium in a flow model. Ultrasound Med Biol 2000; 26(5):889–895. 84. Molloy J, Markus HS. Multigated Doppler ultrasound in the detection of emboli in a flow model and embolic signals in patients. Stroke 1996; 27(9):1548–1552. 85. Brucher R, Russell D. Automatic online embolus detection and artifact rejection with the first multifrequency transcranial Doppler. Stroke 2002; 33(8):1969–1974. 86. Devuyst G, et al. The matching pursuit: a new method of characterizing microembolic signals? Ultrasound Med Biol 2000; 26(6):1051–1056. 87. Russell D, Brucher R. Online automatic discrimination between solid and gaseous cerebral microemboli with the first multifrequency transcranial Doppler. Stroke 2002; 33(8):1975–1980. 88. Markus HS, Brown MM. Differentiation between different pathological cerebral embolic materials using transcranial Doppler in an in vitro model. Stroke 1993; 24(1):1–5. 89. Spencer MP, et al. Detection of middle cerebral artery emboli during carotid endarterectomy using transcranial Doppler ultrasonography. Stroke 1990; 21(3):415–423. 90. Markus H. Transcranial Doppler detection of circulating cerebral emboli. A review. Stroke 1993; 24(8):1246–1250. 91. Sliwka U, et al. Occurrence of transcranial Doppler high-intensity transient signals in patients with potential cardiac sources of embolism. A prospective study. Stroke 1995; 26(11):2067– 2070. 92. Daffertshofer M, et al. High-intensity transient signals in patients with cerebral ischemia. Stroke 1996; 27(10):1844–1849. 93. Siebler M, et al. Cerebral microembolism in symptomatic and asymptomatic high-grade internal carotid artery stenosis. Neurology 1994; 44(4):615–618. 94. Babikian VL, et al. Cerebral microembolism and early recurrent cerebral or retinal ischemic events. Stroke 1997; 28(7):1314–1318. 95. Grosset DG, et al. Doppler emboli signals vary according to stroke subtype. Stroke 1994; 25(2):382–384. 96. Orlandi G, et al. Carotid plaque features on angiography and asymptomatic cerebral microembolism. Acta Neurol Scand 1997; 96(3):183–186. 97. Orlandi G, et al. Silent cerebral microembolism in asymptomatic and symptomatic carotid artery stenoses of low and high degree. Eur Neurol 1997; 38(1):39–43. 98. Koennecke HC, et al. Microemboli on transcranial Doppler in patients with spontaneous carotid artery dissection. J Neuroimaging 1997; 7(4):217–220. 99. Valton L, et al. Asymptomatic cerebral embolic signals in patients with carotid stenosis. Correlation with appearance of plaque ulceration on angiography. Stroke 1995; 26(5):813–815. 100. Siebler M, et al. Silent cerebral embolism caused by neurologically symptomatic high-grade

Evaluation of Stroke Patients

101. 102.

103. 104. 105. 106. 107. 108. 109. 110. 111.

112. 113. 114. 115. 116. 117.

118. 119. 120. 121. 122. 123. 124. 125.

125

carotid stenosis. Event rates before and after carotid endarterectomy. Brain 1993; 116(pt 5): 1005–1015. Georgiadis D, et al. Differentiation between gaseous and formed embolic materials in vivo. Application in prosthetic heart valve patients. Stroke 1994; 25(8):1559–1563. Levi CR, et al. Transcranial Doppler detected cerebral microembolism following carotid endarterectomy. High microembolic signal loads predict postoperative cerebral ischaemia. Brain 1997; 120(pt 4):621–629. Kaps M, et al. Clinically silent microemboli in patients with artificial prosthetic aortic valves are predominantly gaseous and not solid. Stroke 1997; 28(2):322–325. Siebler M, et al. Microembolism in carotid artery disease. Echocardiography 1996; 13(5):529–536. Stork JL, et al. Source of microembolic signals in patients with high-grade carotid stenosis. Stroke 2002; 33(8):2014–2018. van Zuilen EV, et al. Detection of cerebral microemboli by means of transcranial Doppler monitoring before and after carotid endarterectomy. Stroke 1995; 26(2):210–213. Sitzer M, et al. Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. Stroke 1995; 26(7):1231–1233. Sliwka U, et al. Prevalence and time course of microembolic signals in patients with acute stroke. A prospective study. Stroke 1997; 28(2):358–363. Baker AJ, et al. Cerebral microemboli during coronary artery bypass using different cardioplegia techniques. Ann Thorac Surg 1995; 59(5):1187–1191. Barbut D, Caplan LR. Brain complications of cardiac surgery. Curr Probl Cardiol 1997; 22(9):449–480. Braekken SK, et al. Cerebral microembolic signals during cardiopulmonary bypass surgery. Frequency, time of occurrence, and association with patient and surgical characteristics. Stroke 1997; 28(10):1988–1992. Pugsley W, et al. The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 1994; 25(7):1393–1399. Clark RE, et al. Microemboli during coronary artery bypass grafting. Genesis and effect on outcome. J Thorac Cardiovasc Surg 1995; 109(2):249–258. Kidwell CS, et al. Transcranial Doppler pulsatility indices as a measure of diffuse small-vessel disease. J Neuroimaging 2001; 11(3):229–235. Parker DL, Yuan C, Blatter DD. MR angiography by multiple thin slab 3D acquisition. Magn Reson Med 1991; 17(2):434–451. Handelsman H. Magnetic resonance angiography: vascular and flow imaging. Health Technol Assess (Rockv) 1994; 3:1–20. Huston J III, et al. Carotid artery: prospective blinded comparison of two-dimensional timeof-flight MR angiography with conventional angiography and duplex US. Radiology 1993; 186(2):339–344. Atlas SW. MR angiography in neurologic disease. Radiology 1994; 193(1):1–16. Runge VM, Kirsch JE, Lee C. Contrast-enhanced MR angiography. J Magn Reson Imaging 1993; 3(1):233–239. Krinsky G, Weinreb J. Gadolinium-enhanced three-dimensional MR angiography of the thoracoabdominal aorta. Semin Ultrasound CT MR 1996; 17(4):280–303. Carpenter JP, et al. Magnetic resonance angiography of the aortic arch. J Vasc Surg 1997; 25(1):145–151. Mittl RL Jr, et al. Blinded-reader comparison of magnetic resonance angiography and duplex ultrasonography for carotid artery bifurcation stenosis. Stroke 1994; 25(1):4–10. Johnston DC, Goldstein LB. Clinical carotid endarterectomy decision making: noninvasive vascular imaging versus angiography. Neurology 2001; 56(8):1009–1015. Nederkoorn PJ, et al. Preoperative diagnosis of carotid artery stenosis: accuracy of noninvasive testing. Stroke 2002; 33(8):2003–2008. Nederkoorn PJ, et al. Time-of-flight MR angiography of carotid artery stenosis: does a flow void represent severe stenosis? AJNR Am J Neuroradiol 2002; 23(10):1779–1784.

126

Hodics and Caplan

126. Blakeley DD, et al. Noninvasive carotid artery testing. A meta-analytic review. Ann Intern Med 1995; 122(5):360–367. 127. Kent KC, et al. Perioperative imaging strategies for carotid endarterectomy. An analysis of morbidity and cost-effectiveness in symptomatic patients. JAMA 1995; 274(11):888–893. 128. Bhadelia RA, et al. Efficacy of MR angiography in the detection and characterization of occlusive disease in the vertebrobasilar system. J Comput Assist Tomogr 2001; 25(3):458– 465. 129. Dillon EH, et al. CT angiography: application to the evaluation of carotid artery stenosis. Radiology 1993; 189(1):211–219. 130. Cumming MJ, Morrow IM. Carotid artery stenosis: a prospective comparison of CT angiography and conventional angiography. AJR Am J Roentgenol 1994; 163(3):517–523. 131. Marks MP, et al. Diagnosis of carotid artery disease: preliminary experience with maximumintensity-projection spiral CT angiography. AJR Am J Roentgenol 1993; 160(6):1267–1271. 132. Leclerc X, et al. Computed tomographic angiography for the evaluation of carotid artery stenosis. Stroke 1995; 26(9):1577–1581. 133. Leclerc X, et al. Internal carotid arterial stenosis: CT angiography with volume rendering. Radiology 1999; 210(3):673–682. 134. Alberico RA, et al. Evaluation of the circle of Willis with three-dimensional CT angiography in patients with suspected intracranial aneurysms. AJNR Am J Neuroradiol 1995; 16(8):1571– 1580. 135. Wong KS, et al. Variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis. Stroke 1996; 27(6):1084–1087. 136. Alberico RA, et al. Helical CT angiography: dynamic cerebrovascular imaging in children. AJNR Am J Neuroradiol 1999; 20(2):328–334. 137. Prokop M. Multislice CT angiography. Eur J Radiol 2000; 36(2):86–96. 138. Caplan LR. Question-driven technology assessment: SPECT as an example. Neurology 1991; 41(2 pt 1):187–191. 139. Alberts MJ, Faulstich ME, Gray L. Stroke with negative brain magnetic resonance imaging. Stroke 1992; 23(5):663–667. 140. Ueda T, et al. Evaluation of risk of hemorrhagic transformation in local intra-arterial thrombolysis in acute ischemic stroke by initial SPECT. Stroke 1994; 25(2):298–303. 141. Vorstrup S, Brun B, Lassen NA. Evaluation of the cerebral vasodilatory capacity by the acetazolamide test before EC-IC bypass surgery in patients with occlusion of the internal carotid artery. Stroke 1986; 17(6):1291–1298. 142. Yonas H, et al. Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg 1993; 79(4):483–489. 143. Kuroda S, et al. Acetazolamide test in detecting reduced cerebral perfusion reserve and predicting long-term prognosis in patients with internal carotid artery occlusion. Neurosurgery 1993; 32(6):912–919. 144. Schmiedek P, et al. Improvement of cerebrovascular reserve capacity by EC-IC arterial bypass surgery in patients with ICA occlusion and hemodynamic cerebral ischemia. J Neurosurg 1994; 81(2):236–244. 145. Hasegawa Y, et al. Sequential change of hemodynamic reserve in patients with major cerebral artery occlusion or severe stenosis. Neuroradiology 1992; 34(1):15–21. 146. Hirano T, et al. Acetazolamide reactivity on 123I-IMP single photon emission computed tomography in patients with major cerebral artery occlusive disease: correlation with positron emission tomography parameters. J Cereb Blood Flow Metab 1994; 14(5):763–770. 147. Webster MW, et al. Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease. J Vasc Surg 1995; 21(2):338–345. 148. Vernieri F, et al. Outcome of carotid artery occlusion is predicted by cerebrovascular reactivity. Stroke 1999; 30(3):593–598. 149. Yokota C, et al. Effect of acetazolamide reactivity on [corrected] long-term outcome in patients with major cerebral artery occlusive diseases. Stroke 1998; 29(3):640–644.

Evaluation of Stroke Patients

127

150. Yonas H, et al. Qualitative versus quantitative assessment of cerebrovascular reserves. Neurosurgery 1998; 42(5):1005–1012. 151. Kuroda S, et al. Long-term prognosis of medically treated patients with internal carotid or middle cerebral artery occlusion: can acetazolamide test predict it? Stroke 2001; 32(9):2110– 2116. 152. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55(11):1475–1482. 153. Emmi L, et al. MRI and SPECT investigations of the CNS in SLE patients. Clin Exp Rheumatol 1993; 11(1):13–20. 154. Tokumaru S, et al. Technetium-99m-ECD SPECT in antiphospholipid antibody syndrome: a drastic improvement in brain perfusion by antiplatelet therapy. Eur Radiol 2001; 11(12):2611– 2615. 155. Satoh M, et al. N-Isopropyl-p-[123I]iodoamphetamine SPECT in MELAS syndrome: comparison with CT and MR imaging. J Comput Assist Tomogr 1991; 15(1):77–82. 156. Ogasawara K, et al. Combination of early and delayed SPET imaging using technetium-99m ethyl cysteinate dimer immediately after local intra-arterial thrombolysis. Eur J Nucl Med 2001; 28(4):498–505. 157. Sugawara Y, et al. Hyperactivity of 99mTc-HMPAO within 6 hours in patients with acute ischemic stroke. J Nucl Med 2001; 42(9):1297–1302. 158. Pearson AC, et al. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17(1):66–72. 159. Sansoy V, et al. Low yield of transthoracic echocardiography for cardiac source of embolism. Am J Cardiol 1995; 75(2):166–169. 160. Cheitlin MD, et al. ACC/AHA Guidelines for the Clinical Application of Echocardiography. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Clinical Application of Echocardiography). Developed in colloboration with the American Society of Echocardiography. Circulation 1997; 95(6):1686– 1744. 161. Leung DY, et al. Selection of patients for transesophageal echocardiography after stroke and systemic embolic events. Role of transthoracic echocardiography. Stroke 1995; 26(10):1820– 1824. 162. Orihashi K, et al. Aortic arch branches are no longer a blind zone for transesophageal echocardiography: a new eye for aortic surgeons. J Thorac Cardiovasc Surg 2000; 120(3):466–472. 163. Homma S, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105(22):2625–2631. 164. Prystowsky EN, et al. Management of patients with atrial fibrillation. A statement for healthcare professionals. From the Subcommittee on Electrocardiography and Electrophysiology. American Heart Association. Circulation 1996; 93(6):1262–1277. 165. Ogilvy CS, et al. AHA Scientific Statement: Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council. American Stroke Association. Stroke 2001; 32(6):1458–1471. 166. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg 1986; 65(4):476–483. 167. Forster DM, Steiner L, Hakanson S. Arteriovenous malformations of the brain. A long-term clinical study. J Neurosurg 1972; 37(5):562–570. 168. Drake CG. Arteriovenous malformations of the brain. The options for management. N Engl J Med 1983; 309(5):308–310. 169. Hartmann A, et al. Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 1998; 29(5):931–934. 170. Ondra SL, et al. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 1990; 73(3):387–391.

128

Hodics and Caplan

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.

Evaluation of Stroke Patients

129

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.

130

Hodics and Caplan

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.

Evaluation of Stroke Patients

131

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

134

Di Pasquale et al.

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].

Interactions Between Cardiovascular and Cerebrovascular Disease

135

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].

136

Di Pasquale et al.

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.

Interactions Between Cardiovascular and Cerebrovascular Disease

137

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.

138

Di Pasquale et al.

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

Interactions Between Cardiovascular and Cerebrovascular Disease

139

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.

140

Di Pasquale et al.

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

Interactions Between Cardiovascular and Cerebrovascular Disease

141

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

142

Di Pasquale et al.

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.

Interactions Between Cardiovascular and Cerebrovascular Disease

143

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,

144

Di Pasquale et al.

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

Interactions Between Cardiovascular and Cerebrovascular Disease

145

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

146

Di Pasquale et al.

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-

Interactions Between Cardiovascular and Cerebrovascular Disease

147

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)

148

Di Pasquale et al.

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

Interactions Between Cardiovascular and Cerebrovascular Disease

149

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

150

Di Pasquale et al.

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.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

Furlan AJ. The Heart and Stroke. Heidelberg: Springer -Verlag, 1987. Kulbertus HE, Franck G. Neurocardiology. Mount Kisco, NY: Futura, 1988. Di Pasquale G, Pinelli G. Heart-Brain Interactions. Heidelberg: Springer -Verlag, 1992. Wilterdink JL, Furie KL, Easton JD. Cardiac evaluation of stroke patients. Neurology 1998; 51(suppl):S23–S26. Di Pasquale G, Pozzati A. Heart disease and stroke. In: Fieschi C, Fisher M, eds. Prevention of Ischemic Stroke. London: Martin Dunitz Ltd, 1999:27–50. Rothwell PM, Villagra R, Gibson R, et al. Evidence of a chronic systemic cause of instability of atherosclerotic plaques. Lancet 2000; 335:19–24. Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000; 343:915–922. Libby P, Ridker PM, Maseri A. Inflammation and atheroscleroris. Circulation 2002; 105:1135– 1143. Blann AD, Ridker PM, Lip GYH. Inflammation, cell adhesion molecules, and stroke: tools in pathophysiology and epidemiology? Stroke 2002; 33:2141–2143.

Interactions Between Cardiovascular and Cerebrovascular Disease

151

10. Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome. Circulation 2002; 106:804–808. 11. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–979. 12. Rost NS, Wolf PA, Kase CS, et al. Plasma concentrations of C-reactive protein and risk of ischemic stroke and transient ischemic attack. Stroke 2001; 32:2575–2579. 13. Marchioli F, Barzi F, et al. Assessment of absolute risk of death after myocardial infarction by use of multiple risk-factor assessment equations: GISSI-Prevenzione mortality risk chart. Eur Heart J 2001; 22:2085–2103. 14. Jones AF, Walker J, Jewkes C, et al. Comparative accuracy of cardiovascular risk prediction methods in primary care patients. Heart 2001; 85:37–43. 15. Pozzati A, Uguccioni M, DiPasquale G. Advantages and limitations of the cardiovascular risk chart. Monaldi Arch Chest Dis 2002; 58:129–131. 16. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997; 96:1432–1437. 17. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study 1987–1993. Am J Epidemiol 1997; 146:483–494. 18. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid artery intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998; 128:262–269. 19. O’Leary DH, Polak JF, Kronmal RA, et al., for the Cardiovascular Health Study Collaborative Research Group. Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340:2–14. 20. Iglesias del Sol A, Moons KGM, Hollander M, et al. Is carotid intima-media thickness useful in cardiovascular disease risk assessment? The Rotterdam Study. Stroke 2001; 32:1532– 1536. 21. Schmermund A, Erbel R, Silber S. Age and gender distribution of coronary artery calcium measured by four-slice computed tomography in 2030 persons with no symptoms of coronary artery disease. Am J Cardiol 2002; 90:168–173. 22. Wahys R, Zelinger A, Raggi P, et al. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol 2002; 39:225–230. 23. Lee TC, O’Malley PG, Feuerstein I, et al. The prevalence and severity of coronary artery calcification on coronary artery computed tomography in black and white subjects. J Am Coll Cardiol 2003; 41:39–44. 24. Hiatt WR. Medical treatment of perpheral arterial disease and claudication. N Engl J Med 2001; 344:1608–1621. 25. Guillot F. Atherothrombosis as a marker for disseminated atherosclerosis and a predictor of further ischemic events. A review. Eur Heart J Suppl 1999; 1:A 14–26. 26. Criqui MH, Denenberg JO. The generalized nature of atherosclerosis: how peripheral arteries disease may predict adverse events from coronary artery disease. Vasc Med 1998; 3:241–245. 27. Heyden S, Heiss G, Heyman A, et al. Cardiovascular mortality in transient ischemic attacks. Stroke 1980; 11:252–255. 28. Kannel WB, Wolf PA, Verter J. Manifestations of coronary artery disease predisposing to stroke. The Framingham Study. JAMA 1983; 250:2942–2946. 29. Toole JF, Juson CPP, Janeway R. Transient ischemic attacks. A prospective study of 225 patients. Neurology 1978; 28:746–748. 30. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med 1986; 315:860–865. 31. Stuart Lee K, Courtland Davis H. Stroke, myocardial infarction and survival during long-term follow-up after carotid endarterectomy. Surg Neurol 1989; 31:113–119. 32. Hertzer RN, Young JR, Beven EG, et al. Coronary angiography in 506 patients with extracranial cerebrovascular disease. Arch Intern Med 1985; 145:849–852.

152

Di Pasquale et al.

33. Chimowitz MI, Weiss DG, Cohen SL, et al. Cardiac prognosis of patients with carotid stenosis and no history of coronary artery disease. Stroke 1994; 25:759–765. 34. Di Pasquale G, Andreoli A, Pinelli G, et al. Cerebral ischemia and asymptomatic coronary artery disease: a prospective study of 83 patients. Stroke 1986; 1:1098–2002. 35. Urbinati S, Di Pasquale G, Andreoli A, et al. Frequency and prognostic significance of silent coronary artery disease in patients with cerebral ischemia undergoing carotid endarterectomy. Am J Cardiol 1992; 69:1166–1170. 36. Urbinati S, Di Pasquale G, Andreoli A, et al. Preoperative noninvasive coronary risk stratification in patients candidates to carotid endarterectomy. Stroke 1994; 25:2022–2027. 37. Di Pasquale G, Andreoli A, Carini GC, et al. Noninvasive screening for silent ischemic heart disease in patients with cerebral ischemia unable to excercise. Cerebrovasc Dis 1991; 1:31–37. 38. Stratmann HG, Kennedy HL. Evaluation of coronary artery disease in the patients unable to exercise: alternatives to exercise stress testing. Am Heart J 1989; 117:1344–1364. 39. Lette J, Carini GC, Tatum JL, et al. Safety of dipyridamole testing in patients with cerebrovascular disease. Am J Cardiol 1995; 75:535–537. 40. Mangano DT, London MJ, Tubau JF, et al., for the Study of Perioperative Ischemia Research group. Dipyridamole thallium 201 scintigraphy as a preoperative screening test. A reexamination of its predictive potential. Circulation 1991; 84:493–502. 41. Baron JF, Mundler O, Bertrand M, et al. Dipyridamole thallium scintigraphy and gated radionuclide angiography to assess cardiac risk before abdominal aortic surgery. N Engl J Med 1994; 330:663–669. 42. Sicari R, Lusa AM, Salustri A, et al. on behalf of the EPIC study-subproject risk stratification before major vascular surgery. The value of dipyridamole echocardiography in risk stratification before vascular surgery: a multicenter study. Eur Heart J 1995; 16:842–847. 43. Davila Roman VG, Waggoner AD, Sicard GA, Geltman EM, Schechtman KB, Perez JE. Dobutamine stress echocardiography predicts surgical outcome in patients with an aortic aneurysm and peripheral vascular disease. J Am Coll Cardiol 1993; 21:957–963. 44. Poldermans D, Fioretti PM, Forster T, et al. Dobutamine stress echocardiography for assessment of perioperative cardiac risk in patients undergoing major vascular surgery. Circulation 1993; 87:1506–1512. 45. Love BB, Grover McKay M, Biller J, et al. Coronary artery disease and cardiac events in patients with asymptomatic and symptomatic cerebrovascular disease. Stroke 1992; 23:939– 945. 46. Kallikazaros I, Tsioufis C, Sideris S, et al. Carotid artery disease as a marker for the presence of severe coronary artery disease in patients evaluated for chest pain. Sroke 1999; 30:1002– 1007. 47. Adams HP, Kassel NK, Mazuz H. The patient with transient ischemic attacks: is this the time for a new therapeutic approach? Stroke 1984; 15:371–375. 48. Eagle KA, Rihal CS, Foster ED, et al., for the CASS Investigators. Long-term survival in patients with coronary artery disease: importance of peripheral vascular disease. J Am Coll Cardiol 1994; 23:1091–1095. 49. Wilt TJ, Davis BR, Meyers DG, et al. Prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with coronary heart disease and cholesterol levels less than 240 mg/dl: baseline results from the CARE study. Angiology 1996; 47:533–541. 50. Sutton-Tyrell K, Rihal C, Sellers MA, et al., for the BARI Investigators. Long-term prognostic value of cerebral and lower extremity atheroscleroris in patients undergoing coronary revascularizations in the BARI. Am J Cardiol 1998; 81:375–381. 51. Richer-Riess H, Jonas M, Tanne D, et al. Prognostic significance of cerebrovascular disease in 11,526 chronic coronary artery disease patients. Am J Cardiol 1998; 82:1532–1535. 52. Cotter G, Cannon CP, McCabe CH, et al. Prior peripheral arterial disease and cerebrovascular disease are independent predictors of adverse outcome in patients with acute coronary syndromes: are we doing enough? Results from the OPUS-TIMI 16 study. Am Heart J 2003; 145:622–627.

Interactions Between Cardiovascular and Cerebrovascular Disease

153

53. Urbinati S, Salpietro V, Labanti G, et al. Prevalence and prognostic significance of active carotid plaques in patients with acute coronary syndromes. Eur Heart J 1998; 19:298A. 54. Mooe T, Olofsson BO, Stegmayr B, Eriksson P. Ischemic stroke. Impact of a recent myocardial infarction. Stroke 1999; 30:997–1001. 55. Bodenheimer MM, Sauer D, Shareef B, et al. Relation between myocardial infarct location and stroke. J Am Coll Cardiol 1994; 24:61–66. 56. Modrego-Pardo PJ, Labrador Fuster T, Torres Nuez J, et al. Silent brain infarctions in patients with coronary artery disease. A Spanish population survey. J Neurol 1998; 245:93–97. 57. Tanne D, Shotan A, Glodbourt U, et al. Severity of angina pectoris and risk of ischemic stroke. Stroke 2002; 33:245–250. 58. Lichtman JH, Krumholz HM, Wang Y, et al. Risk and predictors of stroke after myocardial infarction among the elderly. Circulation 2002; 105:1082–1087. 59. Mukherjiee D, Lingam P, Chetcuti S, et al. Missed opportunities to treat atherosclerosis in patients undergoing peripheral vascular interventions. Circulation 2002; 106:1909–1912. 60. Ades PA. Cardiac rehabilitation and secondary prevention of coronary artery disease. N Engl J Med 2001; 345:892–902. 61. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71–86. 62. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996; 348:1329–1339. 63. Rosenson RS, Tahgney CC. Antiatherothrombotic properties of statins. JAMA 1998; 279: 1643–1650. 64. MRC/BHF Heart Protection Study of cholestreol lowering with simvastatin in 20,536 high risk individuals: a randomised planned controlled trial. Lancet 2002; 360:7–22. 65. De Caterina R, Manes C. Inflammation in early atherogenesis: impact of ACE inhibition. Eur Heart J Suppl 2003; 5:15A–24A. 66. Marinelli G, Turinetto B, Cazzato M, Pierangeli A. Surgical strategy in patients with associated carotid and coronary artery lesions: staged or combined operations? In: Di Pasquale G, Pinelli G, eds. Heart-Brain Interactions. Berlin: Springer-Verlag, 1992:221–224. 67. Graor RA, Hertzer NR. Management of coexistent carotid and coronary artery disease. Stroke 1988; 19:1441–1444. 68. Salasidis GC, Latter DA, Steinmetz OK, Balir JF, Graham AM. Carotid artery duplex scanning in preoperative assessment for coronary artery revascularization: the association between peripheral vascular disease, carotid artery stenosis and stroke. J Vasc Surg 1995; 21:154–162. 69. Duda AM, Letwin LB, Sutter FP, Golmand SM. Does routine use of aortic ultrasonography decrease the stroke rate in coronary artery bypass surgery? J Vasc Surg 1995; 21:98–109. 70. Cerebral Embolism Task Force. Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol 1989; 46:727–743. 71. Hart RG. Cardiogenic embolism to the brain. Lancet 1992; 339:589–594. 72. Daniel WG, Angerman C, Engherding R, et al. Transesophageal echocardiography in patients with cerebral ischemic events and arterial embolism. A European multicenter study. Circulation 1989; 80:473. 73. De Rook FA, Comess KA, Albers GW, Popp RL. Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med 1992; 117:922–932. 74. Kronzon I, Tunick PA. Transesophageal echocardiography as a tool in the evaluation of patients with embolic disorders. Progr Cardiovasc Dis 1993; 36:39–60. 75. O’Brien PJ, Thiemann DR, McNamara RL, et al. Usefulness of transesophageal echocardiography in predicting mortality and morbidity in stroke patients without clinically known cardiac sources of embolus. Am J Cardiol 1998; 81:1144–1151. 76. Sacco RL, Ellenberg JH, Tatemichi TK, Price TR, Wolf PA. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989; 25:382–390. 77. Hart RG, Miller TV. Cerebral infarction in young adults: a practical approach. Stroke 1983; 14:110–114.

154

Di Pasquale et al.

78. Adams HP, Butler MJ, Biller J, Toffol GJ. Non hemorrhagic cerebral infarction in young adults. Arch Neurol 1986; 43:793–796. 79. Biller J, Johnson MR, Adams HP, et al. Echocardiographic evaluation of young adults with non hemorrhagic cerebral infarction. Stroke 1986; 17:608–612. 80. Bogousslavsky J, Regli F. Ischemic stroke in adults younger than 30 years of age. Cause and prognosis. Arch Neurol 1987; 44:479–482. 81. Alvarez J, Matias-Guju J, Sumalla J, et al. Ischemic stroke in young adults. I Analysis of the etiological subgroups. Acta Neurol Scand 1989; 80:28–34. 82. Urbinati S, Di Pasquale G, Andreoli, et al. Role and indication of two-dimensional echocardiography in young adults with cerebral ischemia: a prospective study in 125 patients. Cerebrovasc Dis 1992; 2:14–21. 83. Labovitz AJ. The increasing role of transthoracic echocardiography in unexplained cerebral ischemia. Echocardiography 1993; 10:363–365. 84. Greenland P, Knopman DS, Mikell FL, Asinger RV, Anderson DC, Good DC. Echocardiography in diagnostic assessment of stroke. Ann Intern Med 1981; 95:51–53. 85. Lovett JL, Sandok BA, Giuliani ER, Nasser FN. Two-dimensional echocardiography in patients with focal cerebral ischemia. Ann Intern Med 1981; 95:1–4. 86. Bogousslavsky J, Van Melle G, Regli F. The Lausanne stroke registry: analysis of 1000 consecutive patients with first stroke. Stroke 1988; 19:1089–1092. 87. Millikan C, Futrell N. The fallacy of the lacune hypothesis. Stroke 1990; 21:1251–1257. 88. Lodder J, Bamford JM, Sadnercock PA, Jones LN, Warlow CP. Are hypertension or cardiac embolism likely causes of lacunar infarction. Stroke 1990; 21:375–381. 89. Khanderia BK, Oh J. Transesophageal echocardiography: state of the art and future directions. Am J Cardiol 1992; 69(H):61–75. 90. Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial fibrillation: a population-based study over three decades. N Engl J Med 1987; 317:669–674. 91. European Atrial Fibrillation Trial (EAFT) Study Group. Secondary prevention in nonrheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255– 1262. 92. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154:1449–1457. 93. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989; 1:175–179. 94. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of lowdose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 325:1505–1511. 95. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C, for the CAFA Study Coinvestigators. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349–355. 96. The Stroke Prevention in Atrial Fibrillation Investigators. The Stroke Prevention in Atrial Fibrillation trial: final results. Circulation 1991; 84:527–539. 97. Ezekowitz MD, Bridgers SL, James KE, et al., for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992; 327:1406–1412. 98. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: I Clinical features of patients at risk. Ann Intern Med 1992; 116:1–5. 99. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: II Echocardiographic features of patients at risk. Ann Intern Med 1992; 116: 6–12. 100. Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119:8–21S.

Interactions Between Cardiovascular and Cerebrovascular Disease

155

101. Di Pasquale G, Urbinati S, Pinelli G. New echocardiographic markers of embolic risk in atrial fibrillation. Cerebrovasc Dis 1995; 5:315–322. 102. Manning WJ, Douglas PS. Transesophageal echocardiography and atrial fibrillation: added value or expensive toy? Ann Intern Med 1998; 128:685–687. 103. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. J Am Coll Cardiol 1998; 31:1622–1626. 104. Sievert H, Lesh MD, Trepels T, et al. Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation: early clinical experience. Circulation 2002; 105:1887–1889. 105. Sievert H, et al. Occlusion of LAA to prevent stroke in AF is safe, feasible. Heartwire, News. April 2, 2003 www.theherat.org. 106. Wyse DG, Waldo AL, Di Marco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825–1833. 107. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation for the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. N Engl J Med 2002; 347:1834– 1840. 108. Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995; 25:1354– 1361. 109. Klein AL, Grimm RA, Black IW, et al., for the ACUTE Investigators. Cardioversion guided by transesophageal echocardiography: the ACUTE pilot study: a randomized, controlled trial. Ann Intern Med 1997; 126:200–209. 110. The Investigators of FASTER Study. Fibrillazione Atriale Studio Transesofageo EmilianoRomagnolo, Italy: Transesophageal echocardiografic correlates of prior thromboembolism in non-valvular atrial fibrillation: a multicenter study. Eur Heart J 1996; 17(suppl):442A. 111. Omran H, Jung W, Rabahieh R, et al. Left atrial appendage function in patients with atrial flutter. Heart 1997; 78(3):250–254. 112. Grimm RA, Stewart WJ, Arheart K, Thomas JD, Klein AL. Left atrial appendage ‘‘stunning’’ after electrical cardioversion of atrial flutter: an attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events. J Am Coll Cardiol 1997; 29:582–589. 113. Jordaens L, Missault L, Germonpre´ E, et al. Delayed restoration of atrial function after conversion of atrial flutter by pacing or electrical cardioversion. Am J Cardiol 1993; 71:63–67. 114. Sparks PB, Jayaprakash S, Vohra JK, et al. Left atrial ‘‘stunning’’ following radiofrequency catheter ablation of chronic atrial flutter. J Am Coll Cardiol 1998; 32:468–475. 115. Sgalambro A, Corrado G, Gentile F, et al. Thromboembolic risk in atrial flutter: preliminary results of the Italian multicenter FLASIEC study. Circulation 1998; 98(suppl):I–703. 116. Irani WN, Willett DL, Grayburn PA, Brickner E, Afridi I. Prevalence of atrial thrombi and spontaneous echo contrast in atrial flutter: a prospective study using transesophageal echocardiography. Circulation 1995; 92(suppl I):537–538. 117. Black IW, Hopkins AP, Lee LCL, Walsh WF. Evaluation of transesophageal echocardiography before cardioversion of atrial fibrillation and flutter in nonanticoagulated patients. Am Heart J 1993; 126:375–381. 118. Bikkina M, Alpert MA, Mulekar M, Shakoor A, Massey CV, Covin FA. Prevalence of intraatrial thrombus in patients with atrial flutter. Am J Cardiol 1995; 76:186–189. 119. Mehta B, Baruch L. Thromboembolism following cardioversion of ‘‘common’’ atrial flutter. Risk factors and limitations of transesophageal echocardiography. Chest 1996; 110(4):1001– 1003. 120. Wood KA, Eisenberg SJ, Kalman JM, et al. Risk of thromboembolism in chronic atrial flutter. Am J Cardiol 1997; 79:1043–1047.

156

Di Pasquale et al.

121. Lanzarotti CJ, Olshansky B. Thromboembolism in chronic atrial flutter: is the risk underestimated. J Am Coll Cardiol 1997; 30:1506–1511. 122. Seidl K, Hauer B, Schwick N, Zellner D, Zahn R, Senges J. Risk of thromboembolic events in patients with atrial flutter. Am J Cardiol 1998; 82:580–583. 123. Keating EC, Gross SA, Schlamowitz RA, et al. Mural thrombi in myocardial infarctions: prospective evaluation of two-dimensional echocardiography. Am J Med 1983; 74:989–995. 124. Weinreich DJ, Burke JF, Pauletto FJ. Left ventricular mural thrombi complicating acute myocardial infarction: long-term follow-up with serial echocardiography. Ann Intern Med 1984; 100:789–794. 125. Ezekowitz MD, Kellerman DJ, Smith EO, et al. Detection of active left ventricular thrombosis during acute myocardial infarction using indium-III platelet scintigraphy. Chest 1984; 86:35–39. 126. Johannessen KA, Nordrehaug JE, von der Lippe G. Left ventricular thrombosis and cerebrovascular accident in acute myocardial infarction. Br Heart J 1984; 51:553–556. 127. Cairns JA, Theroux P, Lewis HD Jr, Ezekowitz M, Meade TW, Sutton GC. Antithrombotic agents in coronary artery disease. Chest 1998; 114(suppl):611S–633S. 128. Van Dantzig JM, Delemarre BJ, Bot H, Visser CA. Left ventricular thrombus in acute myocardial infarction (review article). Eur Heart J 1996; 17:1640–1645. 129. Spirito P, Bellotti P, Chiarella F, Domenicucci S, Sementa A, Vecchio C. Prognostic significance and natural history of left ventricular thrombi in patients with acute anterior myocardial infarction: a two-dimensional echocardiographic study. Circulation 1985; 72:774–780. 130. Vaitkus PT, Barnathau ES. Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: a meta-analysis. J Am Coll Cardiol 1993; 22:1004– 1009. 131. Loh E, Sutton MSJ, Wun C-C. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997; 336:251–257. 132. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: 1. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994; 308:81–106. 133. Report of the Sixty Plus Reinfarction Study Research Group. A double-blind trial to assess long-term anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1980; 2:989–994. 134. ASPECT Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994; 343:499–503. 135. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323:147–152. 136. Azar AJ, Cannegieter SC, Deckers JW, et al. Optimal intensity of oral anticoagulant therapy after myocardial infarction. J Am Coll Cardiol 1986; 27:1349–1355. 137. Breddin D, Loew D, Lechner K, et al. The German-Austrian Aspirin Trial: a comparison of acetylsalicylic acid, placebo and phenprocoumon in secondary prevention of myocardial infarction. Circulation 1980; 62(suppl 5):63–72. 138. The EPSIM Research Group. A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction. N Engl J Med 1982; 307:701–708. 139. Coumadin Aspirin Reinfarction Study (CARS). Randomized double-blind trial of fixed lowdose warfarin with aspirin after myocardial infarction. Lancet 1997; 350:389–396. 140. Fiore LD, Ezekowitz MD, Brophy MT, et al. Department of Veterans Affairs Cooperative Studies Program Clinical trial comparing combined warfarin and aspririn with aspirin alone in survivors of acute myocardial infarction: preliminary results of the CHAMP study. Circulation 2002; 105:557–563. 141. Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a metaanalysis. JAMA 1999; 282:2058–2067. 142. Van Es RF, Jonker JJ, Verheught FW, et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT 2 study): a randomized controlled trial. Lancet 2002; 360:109–113. 143. Brouwer MA, van der Bergh PJPC, Aengevaeren WRM, et al. Aspirin plus coumarin versus

Interactions Between Cardiovascular and Cerebrovascular Disease

144. 145.

146. 147. 148. 149.

150. 151.

152.

153.

154. 155. 156. 157.

158. 159. 160. 161. 162. 163. 164.

157

aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotis in the Prevention of Reocclusion In COronary Thrombolisis (APRICOT 2) trial. Circulation 2002; 106:659–665. Hurle M, Abdelnoor M, Smith P, et al. Warfarin, aspirin or both after myocardial infarction. N Engl J Med 2002; 347:969–974. Lapeyre AC III, Steele PM, Kazmier FV, Chesebro JH, Vliestra RE, Fuster V. Systemic embolization in chronic left ventricular aneurysm: incidence and the role of anticoagulation. J Am Coll Cardiol 1985; 6:534–538. Vongpatanasin W, Hillis LD, Lange R. Prosthetic heart valves (review article). N Engl J Med 1996; 335:407–416. Cannegieter SC, Rosendaal FR, Brie¨t E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89:635–641. Bloomfield P, Wheatley DJ, Prescott RJ, et al. Twelve-year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. N Engl J Med 1991; 324:573–579. Hammermeister KE, Sethi GK, Henderson WG, Oprian C, Kim T, Rahintoola S, for the Veterans Affairs Cooperative Study on Valvular Heart Disease. A comparison of outcomes in men 11 years after heart-valve replacement with a mechanical valve or bioprosthesis. N Engl J Med 1993; 328:1289–1296. Stein PD, Alpert JS, Copeland J, Dalen JE, Godman S, Turpie AGG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114:602S–610S. Cannegieter SC, Rosendaal FR, Wintzen AR, Van der Meer FJM, Vandenbroucke JP, Brie¨t E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333:11–17. Chesebro JH, Fuster V, Elveback LR, et al. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983; 51:1537–1541. Pouleur H, Boyse M. Effects of dipyridamole in combination with anticoagulant therapy on survival and thromboembolic events in patients with prosthetic heart valves. A meta-analysis of the randomised trials. J Thorac Cardiovasc Surg 1995; 110:463–472. Altman R, Boullon F, Rouvier J. Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thorac Cardiovasc Surg 1976; 72:127–129. Dale J, Myhre E, et al. Prevention of arterial thromboembolism with acetylsalicylic acid: a controlled clinical study in patients with aortic ball valves. Am Heart J 1977; 94:101–111. Turpie AGG, Gent M, Laupacis A, et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993; 329:524–529. Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari MA. Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves. J Thorac Cardiovasc Surg 1997; 113:910–916. Turpie AGG, Gustensen J, Hirsh J. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988; 1:1242–1245. Heras M, Chesebro JH, Fuster V, et al. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol 1995; 25:1111–1119. Salem DN, Levine HJ, Pauker SG, Eckman MH, Daudelin DH. Antithrombotic therapy in valvular heart disease. Chest 1998; 114(suppl):590S–601S. Petty GW, Khanderia BK, Whisnant JP, et al. Predictors of cerebrovascular events and death among patients with valvular heart study. Stroke 2000; 31:2628–2635. Chesebro JH, Adams PC, Fuster V. Antithrombotic therapy in patients with valvular heart disease and prosthetic heart valves. J Am Coll Cardiol 1986; 8:41–56. Brockmeier LB, Adolph RJ, Gustin BW, et al. Calcium emboli to the retinal artery in calcific aortic stenosis. Am Heart J 1981; 101:32–37. Rancurel G, Marelle L, Vincent D, et al. Spontaneous calcific cerebral embolus from a calcific aortic stenosis in a middle cerebral artery infarct. Stroke 1989; 20:691–693.

158

Di Pasquale et al.

165. Davidson CJ, Skelton TN, Kisslo KB, et al. The risk of systemic embolization associated with percutaneous balloon valvuloplasty in adults. Ann Intern Med 1988; 108:557–560. 166. Di Pasquale G, Ribani MA, Andreoli A, Zampa GA, Pinelli G. Cardioembolic stroke in primary oxalosis with cardiac involvement. Stroke 1989; 20:1403–1406. 167. Boon A, Lodder J, Cheriex E, Kessels F. Risk of stroke in a cohort of 815 patients with calcification of the aortic valve with or without stenosis. Stroke 1996; 27:847–851. 168. Gottdiener JS, Gay JA, Van Voorhees L, Di Bianco R, Flercher RD. Frequency and embolic potential of left ventricular thrombus in dilated cardiomyopathy: assessment by 2-dimensional echocardiography. Am J Cardiol 1983; 52:1281–1285. 169. Ciaccheri M, Castelli Q, Cecchi F, et al. Lack of correlation betwenn intracavitary thrombosis detected by cross-sectional echocardiography and systemic emboli in patients with dilated cardiomyopathy. Br Heart J 1989; 62:26–29. 170. Yokota Y, Kawanishi H, Hayakawa M, Kumaki T, Takarada A, Nakanishi O, Fukusaki H. Cardiac thrombus in dilated cardiomyopathy. Relationship between left ventricular pathophysiology and left ventricular thrombus. Jpn Heart J 1989; 30:1–11. 171. Falk RH, Foster E, Coats MH. Ventricular thrombi and thromboembolism in dilated cardiomyopathy: a prospective follow-up study. Am Heart J 1992; 123:136–142. 172. Fuster V, Gersh BJ, Giuliani Er, Tajik AJ, Brandenburg RO, Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47:525–531. 173. Halperin JL. Thrombosis in the left ventricle in patients with dilated cardiomyopathy. G Ital Cardiol 1994; 24:281–289. 174. Kyrle P, Korninger C, Gossinger H, et al. Prevention of arterial and pulmonary embolism by oral anticoagulants in patients with dilated cardiomyopathy. Thromb Haemost 1985; 54:521– 523. 175. Keogh AM, Freund J, Baron DW, Hickie JB. Timing of cardiac transplantation in idiopathic dilated cardiomyopathy. Am J Cardiol 1988; 61:418–422. 176. Ciaccheri M, Castelli G, Nannini M, Santoro G, Troiani V, Dolara A. Oral anticoagulant therapy in dilated cardiomyopathy. Results of treatment with warfarin in groups of patients at risk of embolic complications. G Ital Cardiol 1995; 25:689–694. 177. Koniaris LS, Goldhaber SZ. Anticoagulation in dilated cardiomyopathy. J Am Coll Cardiol 1998; 31:745–748. 178. Di Pasquale G, Andreoli A, Lusa AM, et al. Cerebral embolic risk in hypertrophic cardiomyopathy. In: Baroldi G, Camerini F, Goodwin JF, eds. Advances in Cardiomyopathies. Berlin: Springer-Verlag, 1990:90–96. 179. Furlan AJ, Craciun AR, Raju NR, Hart N. Cerebrovascular complications associated with idiopathic hypertrophic subaortic stenosis. Stroke 1984; 15:282–284. 180. Kogure S, Yanamoto Y, Tomono S, Hasegawa A, Suzuki T, Murata K. High risk of systemic embolism in hypertrophic cardiomyopathy. Jpn Heart J 1986; 27:475–480. 181. Baker DW, Wright RF. Management of heart failure: anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. J Am Med Assoc 1994; 272:1614–1618. 182. Sharma NV, Gandhi RS, Philbin EF, et al. Which patients with left ventricular dysfunction require chronic anticoagulation? A prospective analysis. J Am Coll Cardiol 1998; 91:33A. 183. Stratton JR, Nemanich JN, Johannessen KA, et al. Fate of left ventricular thrombi in patients with remote myocardial infarction on idiopathic cardiomyopathy. Circulation 1988; 78:1388– 1393. 184. Alkhadra S, Salem DN, Rand WM, et al. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol 1998; 31:749–753. 185. Urbinati S, Bosi E, Gorini M, et al. Oral anticoagulation therapy in congestive heart failure. Analysis on 6428 patients of the Italian Network–Congestive Heart Failure (IN-CHF). Eur Heart J 1998; 19:298A. 186. Di Pasquale G, Passarelli P, Ribani MA, Borgatti ML, Urbinati S, Pinelli G. Prophylaxis of thromboembolic events in congestive heart failure. Arch Gerontol Geriatr 1996; 23:329–336. 187. Salgado AV, Furlan AJ, Keys TF, et al. Neurologic complications of endocarditis: a 12-year experience. Neurology 1989; 39:173–178.

Interactions Between Cardiovascular and Cerebrovascular Disease

159

188. Hart RG, Foster JW, Luther MF, Kanter MC. Stroke in infective endocarditis. Stroke 1990; 21:695–700. 189. Paschalis C, Pugsley W, John R, Harrison MJG. Rate of cerebral embolic events in relation to antibiotic and anticoagulant therapy in patients with bacterial endocarditis. Eur Neurol 1991; 30:87–89. 190. Horng RG, Yip PK, Chen WJ, Chen RC. Cerebrovascular complications of infective endocarditis. J Stroke Cerebrovasc Dis 1993; 3:222–227. 191. Delahaye JP, Poncet P, Malquarti V, et al. Cerebrovascular accidents in infective endocarditis: role of anticoagulation. Eur Heart J 1990; 11:1074–1078. 192. Villacosta I, Graupner C, San Roman JA, et al. Risk of embolization after institution of antibiotic therapy for infective endocarditis. J Am Coll Cardiol 2002; 39:1489–1495. 193. Flachskampf FA, Decoodt P, Fraser AG, et al. Recommendations for performing transesophageal echocardiography. Eur J Echocardiography 2001; 2:8–21. 194. Gallet B, Malergue MC, Adams C, et al. Atrial septal aneurysm: a potential cause of systemic embolism. An echocardiographic study. Br Heart 1985; 53:292–297. 195. Di Pasquale G, Andreoli A, Grazi P, Dominici P, Pinelli G. Cardioembolic stroke from atrial septal aneurysm. Stroke 1988; 19:640–643. 196. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneurysm and stroke: a transesophageal ecocardiographic study. J Am Coll Cardiol 1991; 18:1223–1229. 197. Zagalboita-Reys M, Herrera C, Gandhi DK, et al. A possible mechanism for neurologic ischemic events in patients with atrial septal aneurysm. Am J Cardiol 1990; 66:761–764. 198. Agmon Y, Khanderia BK, Meissner I, et al. Frequency of atrial septal aneurysms in patients with cerebral ischemic events. Circulation 1999; 99:1942–1944. 199. Mugge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients: a multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995; 91:2785–2792. 200. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiari’s network: normal anatomic variant or risk factor for arterial embolic events. J Am Coll Cardiol 1995; 26:203–210. 201. Burger AJ, Sherman HB, Cjharlamb MJ, et al. Low incidence of embolic strokes with atrial septal aneurysm: a prospestive long-term study. Am Heart J 2000; 139:149–152. 202. Schneider B, Hanrath P, Vogel P, et al. Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebral events. J Am Coll Cardiol 1990; 16:1000–1009. 203. Albers WG, Comess KA, Albers GW, Popp RL. Transesophageal echocardiography findings in stroke subtypes. Stroke 1994; 25:23–38. 204. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993; 24:1865–1873. 205. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent formane ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740–1746. 206. Lechat PH, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148–1152. 207. Webster MWI, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2:11–12. 208. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992; 117:461–465. 209. Louie EK, Konstadt SN, Rao TL, Scanlon PJ. Transesophageal echocardiographic diagnosis of right to left shunting across the foramen ovale in adults without prior stroke. J Am Coll Cardiol 1993; 21:1231–1237. 210. Hausmann D, Mugge A, Becht I, Daniel WG. Diagnosis of patent foramen ovale by transesophageal echocardiography and association with cerebral and peripheral embolic events. Am J Cardiol 1992; 70:1668–1672. 211. Schminke U, Ries S, Daffertshafer M, et al. Patent foramen ovale: a potential source of cerebral embolism? Cerebrovasc Dis 1995; 5:133–138.

160

Di Pasquale et al.

212. Ranoux D, Cohen A, Cabanes L, et al. Patent foramen ovale: is stroke due to paradoxical embolism? Stroke 1993; 24:31–34. 213. De Belder MA, Tourikis L, Leech G, Camm AJ. Risk of patent foramen ovale for thromboembolic events in all age groups. Am J Cardiol 1996; 69:1316–1320. 214. De Castro S, Cartoni D, Fiorelli M, et al. Morphologic and functional characteristics of patient foramen ovale and their embolic implications. Stroke 2001; 31:2407–2413. 215. Steiner MM, Di Tullio MR, Rundek T, et al. Patent foramen ovale size and embolic brain imaging findings among patients ischemic stroke. Stroke 1998; 29:944–948. 216. Arquizan C, Coste J, Touboul PJ, et al. Is patent forman ovale a family trait? A transcranial Doppler sonographic study. Stroke 2001; 32:1563–1566. 217. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent forman ovale. The PFO-ASA study. Stroke 2002; 33:706– 711. 218. Nendaz MR, Sarasin FP, Junod AF, Bogousslavsky J. Preventing stroke recurrence in patients with patent foramen ovale: antithrombotic therapy, foramen closure, or therapeutic abstension? A decision analytic perspective. Am Heart J 1998; 135:532–541. 219. Biller J, Johnson MR, Adams HP, et al. Further observations on cerebral or retinal ischemia with right-left intracardiac shunts. Arch Neurol 1987; 44:740–743. 220. Hanna JP, Sun JP, Furlan AJ, et al. Patent foramen ovale and brain infarct. Stroke 1994; 25: 782–786. 221. Bogousslavski J, Garazi S, Jeanrenaud X, Aebischer N, Van Melle G. Stroke recurrence in patients with patent foramen ovale: the Lausanne study. Neurology 1996; 46:1301–1305. 222. Homma S, Sacco RL, Di Tullio, Sciacca RR, Mohr JP, for the PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale. Patent foramen ovale in cryptogenic stroke study. Circulation 2002; 105:2625–2631. 223. Ende DJ, Chopra PS, Rao PS. Transcatheter closure of atrial septal defect or patent foramen ovale with the buttoned device for prevention of recurrence of paradoxic embolism. Am J Cardiol 1996; 78:233–236. 224. Bridges ND, Hellenbrand W, Latson L, Filiano J, Newburger JW, Lock JE. Trancatheter closure of patent foramen ovale after presumed paradoxycal embolization. Circulation 1992; 86:1902–1908. 225. Homma S, Di Tullio MR, Sacco RL, Sciacca RR, Smith C, Mohr JP. Surgical closure of patent foramen ovale in cryptogenic stroke patients. Stroke 1997; 28:2376–2381. 226. Ruchat P, Bogousslavsky J, Hurni M, Fischer AP, Jeanrenaud X, Von Segesser LK. Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study. Eur J Cardiothorac Surg 1997; 11:824–827. 227. Cujec B, Mainra R, Johnson DH. Prevention of recurrent cerebral ischemic events in patients with patent foramen ovale and cryptogenic strokes or transient ischemic attacks. Can J Cardiol 1999; 15:57–64. 228. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolicm. Circulation 2000; 101:893–898. 229. Hart RG, Easton DJ. Mitral valve prolapse and cerebral infarction. Stroke 1982; 13:429–430. 230. Nishimura RA, McGoon MD, Shub C, Miller FA, Ilstrup DM, Taijk AJ. Echocardiographically documented mitral valve prolapse. Long-term follow-up of 237 patients. N Engl J Med 1985; 313:1305–1309. 231. Devereux RB, Hawkins I, Kramer-Fox R, et al. Complications of mitral valve prolapse. Am J Med 1986; 81:751–758. 232. Marks AR, Choong CY, Sanfilippo AJ, Ferry M, Weyman AE. Identification of high-risk and low-risk subgroups of patients with mitral valve prolapse. N Engl J Med 1989; 313:1305– 1309. 233. Gilon D, Buonanno FS, Joffe MM, et al. Lack of evidence of an association between mitral valve prolapse and stroke in young patients. N Engl J Med 1999; 341:8–13.

Interactions Between Cardiovascular and Cerebrovascular Disease

161

234. Sharf RE, Hennerici M, Blutschke V, Lueck J, Kladetzky RG. Cerebral ischemia in young adults: is it associated with mitral valve prolapse and abnormal platelet activity in vivo? Stroke 1982; 13:454–458. 235. Fisher M, Weiner BH, Ockene IS, Forsberg A, Duffy CP, Levine PH. Platelet activation and mitral valve prolapse. Neurology 1983; 33:384–386. 236. The Antiphospholipid Antibodies in Stroke Study Group. Clinical and laboratory findings in patients with antiphospholipid antibodies in cerebral ischemia. Stroke 1990; 21:1268–1273. 237. de Bono DP, Warlow CP. Mitral annulus calcification and cerebral or retinal ischemia. Lancet 1979; 2:383–385. 238. Nair CK, Thomson W, Ryschon K, et al. Long-term follow-up of patients with echocardiographically detected mitral annular calcium and comparison with age- and sex-matched control subjects. Am J Cardiol 1989; 63:465–470. 239. Aronow WS, Koenigsberg M, Kronzon I, Gutstein H. Association of mitral annular calcium with new thromboembolic stroke and cardiac events at 39-month follow-up in elderly patients. Am J Cardiol 1990; 65:1511–1512. 240. Aronow WS, Schoenfeld MR, Gutstein H. Frequency of thromboembolic stroke in persons z 60 years of age with extracranial carotid arterial disease and/or mitral annular calcium. Am J Cardiol 1992; 70:123–124. 241. Benjamin EJ, Plehn JF, D’Agostino RB, et al. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J Med 1992; 327:374–379. 242. Freedberg RS, Goodkin GM, Perez JL, Tunick PA, Kronzon L. Valve strands are strongly associated with systemic embolization: a transesophageal echocardiographic study. J Am Coll Cardiol 1995; 26:1709–1712. 243. Orsinelli DA, Pearson AC. Detection of prosthetic valve strands by transesophageal echocardiography: clinical significance in patients with suspected cardiac source of embolism. J Am Coll Cardiol 1995; 26:1713–1718. 244. Tice FD, Slivka AP, Walls ET, Orsinelli DA, Pearson AC. Mitral valve strands in patients with focal cerebral ischemia. Stroke 1996; 27:1183–1186. 245. Roberts JK, Omarali I, Di Tullio MR, Sciacca RR, Sacco RL, Homma S. Valvular strands and cerebral ischemia: effects of demographics and strand characteristics. Stroke 1997; 28:2185– 2188. 246. Reynen K. Cardiac myxoma. N Engl J Med 1995; 333:1610–1616. 247. Knepper LE, Biller J, Adams HP, Bruno A. Neurologic manifestations of myxoma. Stroke 1988; 19:1435–1440. 248. Tunick PA, Kronzon I. Protruding atherosclerotic plaque in the aortic arch of patients with systemic embolization: a new finding seen by transesophageal echocardiography. Am Heart J 1990; 120:658–660. 249. Katz E, Tunick PA, Rusinek H, et al. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: a review of our experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992; 20:70–77. 250. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474–1479. 251. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221–225. 252. Davila-Roman VG, Barzilai B, Wareing TH, et al. Atherosclerosis of the ascending aorta: prevalence and role as an independent predictor of cerebrovascular events in cardiac patients. Stroke 1994; 25:2010–2016. 253. Tunick PA, Kronzon I. Atheromas of the thoracic aorta: clinical and therapeutic update. J Am Coll Cardiol 2000; 35:545–554. 254. Demopoulos LA, Tunick PA, Bernstein NE, et al. Protruding atheromas of the aortic arch and neurologic events in patients with carotid artery disease. Am Heart J 1995; 129:40–44. 255. Fazio GP, Redberg RF, Winslow T, et al. Transesophageal echocardiography detected atherosclerotic aortic plaque is a marker of artery disease. J Am Coll Cardiol 1993; 21:144–150.

162

Di Pasquale et al.

256. Blackshear JL, Pearche LA, Hart RG, et al., for the SPAF Investigators Committee on Echocardiography. Aortic plaque in atrial fibrillation: prevalence, predictors and thromboembolic implications. Stroke 1999; 30:834–840. 257. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216–1221. 258. Stone DA, Hawke MW, LaMonte M, et al. Ulcerated atherosclerotic plaques in the thoracic aorta are associated with cryptogenic stroke: a multiplane transesophageal echocardiographic study. Am Heart J 1995; 130:105–108. 259. Cohen A, Tzourio C, Bertrand B, et al. on behalf of the FAPS Investigators. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. Circulation 1997; 96:3841–3847. 260. Montgomery DH, Ververis JJ, McGorisk G, et al. Natural history of severe atheromatous disease of the thoracic aorta: a transesophageal echocardiographic study. J Am Coll Cardiol 1996; 27:95–101. 261. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1000 cases. J Am Coll Cardiol 1998; 32:1861–1865. 262. Katz ES, Tunick PA, Rusinek H, et al. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: a review of our experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992; 20:70–77. 263. Stern A, Tunick PA, Culliford AT, et al. Protruding aortic arch atheromas: risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 1999; 138:746–752. 264. Coy KM, Maurer G, Goodman D, Siegel RJ. Transesophageal echocardiographic detection of aortic atheromatosis may provide clues to occult renal dysfunction in the elderly. Am Heart J 1992; 123:1646–1648. 265. Davila-Roman VG, Kouchoukos NT, Schechtman KB, Barzilai B. Atherosclerosis of the ascending aorta is a predictor of renal dysfunction after cardiac operations. J Thorac Cardioavsc Surg 1997; 117:111–116. 266. Bruns FJ, Segel DP, Adler S. Case report, control of cholesterol embolization by discontinuation of anticoagulant therapy. Am J Med Sci 1978; 1:105–108. 267. Hilton TC, Menke D, Blackshear JL. Variable effect of anticoagulation in the treatment of severe protruding atherosclerotic aortic debris. Am Heart J 1994; 127:1645–1647. 268. Hyman BT, Landas SK, Ashman RF, Schelper RL, Robinson RA. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987; 82:1233–1237. 269. Dressler FA, William RC, Castello R, Labovitz AJ, et al. Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke. JACC 1998; 31:134–138. 270. Ferrari E, Vidal R, Chevallier T, Baudouy M. Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants. J Am Coll Cardiol 1999; 33:1317–1322. 271. Tunick PA, Nayar AC, Goodkin GM, for the NYU Atheroma Group. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002; 90:1320–1325.

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

164

Kennedy et al.

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)

Organizing Stroke Services

165

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,

166

Kennedy et al.

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

Organizing Stroke Services

167

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

168

Kennedy et al.

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

Organizing Stroke Services

169

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

170

Kennedy et al.

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

Organizing Stroke Services

171

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.

172

Kennedy et al.

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

Organizing Stroke Services

173

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

174

Kennedy et al.

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,

Organizing Stroke Services

175

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

176

Kennedy et al.

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.

REFERENCES 1. The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischaemic stroke. N Engl J Med 1995; 333:1581–1587.

Organizing Stroke Services

177

2. Marler JR, Tilley BC, Lu M, Brott TG, Lyden PD, Grotta JC, Broderick JP, Levice SR, Frankel MP, Horowitz SH, Haley EC, Lewandowski CA, Kwiatkowski TP. Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000; 55:1649–1655. 3. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F, for the PROACT Investigators. Intra-arterial prourokinase for acute ischemic stroke. JAMA 1999; 282:2003–2011. 4. Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischemic stroke (Cochrane Review on CD-ROM). Oxford, England: Cochrane Library, Update Software, 2002. 5. National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997; 28: 2109–2118. 6. Buchan AM, Barber PA, Newcommon N, Karbalai H, Demchuk AM, Hoyte K, Klein GM, Feasby TE. Effectiveness of t-PA in acute ischemic stroke: outcome relates to appropriateness. Neurology 2000; 54:679–684. 7. Katzan IL, Furlan AJ, Lloyd LE, Frank JL, Harper DL, Hinchley JA, Jeffery JP, Qu A, Sila CA. Use of tissue plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000; 283:1151–1158. 8. Horrowitz SH. Thrombolytic therapy in acute stroke. Arch Neurol 1998; 55:155–157. 9. Kennedy J, Buchan AM, Barnett HJM. Thrombolysis must be considered after stroke (lett). BMJ 2001; 323:937. 10. Fieschi C, Argentino C, Lenzi GL, Fantuzzi L, Sacchetti ML, Pace A, Rasura M, Bastianello S, Bozzoa L, Zanette E. Therapeutic window for pharmacological treatment in acute focal cerebral ischemia. Ann NY Acad Sci 1988; 522:662–666. 11. Ringelstein FB, Biniek R, Weiller C, Amneling B, Nolte PN, Thron A. Type and extent of hemispheric infarctions and clinical outcomes in early and delayed middle cerebral artery recanalization. Neurology 1992; 42:289–298. 12. Siesjo BK. Pathophysiology and treatment of focal cerebral ischaemia, I: pathophysiology. J Neurosurg 1992; 77:169–184. 13. Pepe PE, Zachariah BS, Sayre MR, et al. Ensuring the chain of recovery for stroke in your community. Acad Emerg Med 1998; 5:352–358. 14. Hill MD, Barber PA, Demchuk AM, Sevick RJ, Newcommon NJ, Green T, Buchan AM. Building a ‘‘brain attack’’ team to administer thrombolytic therapy for acute ischemic stroke. CMAJ 2000; 162:1589–1593. 15. Pancioli AM, Broderick J, Kothari R, Brott T, Tuchfarber A, Miller R, Khoury J, Jauch E. Public perception of stroke warning signs and knowledge of potential risk factors. JAMA 1998; 279:1288–1292. 16. Kothari R, Sauerbeck L, Jauch E, Broderick J, Brott T, Khoury J, Liu T. Patients’ awareness of stroke signs, symptoms, and risk factors. Stroke 1997; 28:1871–1875. 17. Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R, et al. Urgent therapy for stroke, I: pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992; 23:632–640. 18. Haley EC Jr, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, Massey S, Reed R, et al. Urgent therapy for stroke, II: pilot study of tissue plasminogen activator administered 91– 180 minutes from onset. Stroke 1992; 23:641–645. 19. Williams LS, Bruno A, Rouch D, Marriott MAS. Stroke patients’ knowledge of stroke. Stroke 1997; 28:912–915. 20. Alberts MJ, Perry A, Dawson DV, Bertels C. Effects of public and professional education on reducing the delay in presentation and referral of stroke patients. Stroke 1992; 23:352–356. 21. Kereiakes DJ, Weaver WD, Anderson JL, Feldman T, Gibler B, Aufderheide T, Williams DO, Martin LH, Anderson LC, Martin JS, et al. Time delays in the diagnosis and treatment of acute myocardial infarction: a tale of eight cities. Report from the Pre-hospital Study Group and the Cincinnati Heart Project. Am Heart J 1990; 120:773–780.

178

Kennedy et al.

22. Goff DC, Nichaman MZ, Ramsey DJ, Meyer PS, Labarthe DR. A population-based assessment of the use and effectiveness of thrombolytic therapy: the Corpus Christi Heart Project. Ann Epidemiol 1995; 5:171–178. 23. Luepker RV, Raczynski JM, Osganian S, Goldberg RJ, Finnegan JR Jr, Hedges JR, Goff DC Jr, Eisenberg MS, Zapka JG, Feldman HA, Labarthe DR, McGovern PG, Cornell CE, Proschan MA, Simons-Morton DG. Effect of a community intervention on patient delay and emergency medical service use in acute coronary heart disease: The Rapid Early Action for Coronary Treatment (REACT) Trial. JAMA 2000; 284:60–67. 24. Raczynski JM, Finnegan JR Jr, Zapka JG, Meischke H, Meshack A, Stone EJ, Bracht N, Sellers DE, Daya M, Robbins M, McAlister A, Simons-Morton D. REACT theory-based intervention to reduce treatment-seeking delay for acute myocardial infarction. Rapid Early Action for Coronary Treatment. Am J Prev Med 1999; 16:325–334. 25. Harper GD, Haigh RA, Potter JF, Castleden CM. Factors delaying hospital admission after stroke in Leicestershire. Stroke 1992; 23:835–838. 26. Feldmann E, Gordon N, Brooks JM, Brass LM, Fayad PB, Sawaya KL, Nazareno F, Levine SR. Factors associated with early presentation of acute stroke. Stroke 1993; 24:1805–1810. 27. Fogelholm R, Murros K, Rissanen A, Ilmavirta M. Factors delaying hospital admission after acute stroke. Stroke 1996; 27:398–400. 28. Barsan WG, Brott TG, Broderick JP, Haley EC, Levy DE, Marler JR. Time of hospital presentation in patients with acute stroke. Arch Intern Med 1993; 153:2558–2561. 29. Wester P, Radberg J, Lundgren B, Peltonen M. Factors associated with delayed admission to hospital and in-hospital delays in acute stroke and TIA: a prospective, multicenter study. SeekMedical-Attention-in-Time Study Group. Stroke 1999; 30:40–48. 30. Kothari R, Jauch E, Broderick J, Brott T, Sauerbeck L, Khoury J, Liu T. Acute stroke: delays to presentation and emergency department evaluation. Ann Emerg Med 1999; 33:3–8. 31. Lacy CR, Suh DC, Bueno M, Kostis JB. Delay in presentation and evaluation for acute stroke: Stroke Time Registry for Outcomes Knowledge and Epidemiology (S.T.R.O.K.E.). Stroke 2001; 32:63–69. 32. Schroeder EB, Rosamond WD, Morris DL, Evenson KR, Hinn AR. Determinants of use of emergency medical services in a population with stroke symptoms: the Second Delay in Accessing Stroke Healthcare (DASH II) Study. Stroke 2000; 31:2591–2596. 33. Goldstein LB, Edwards MG, Wood DP. Delay between stroke onset and emergency department evaluation. Neuroepidemiology 2001; 20:196–200. 34. Menon SC, Pandey DK, Morgenstern LB. Critical factors determining access to acute stroke care. Neurology 1998; 51:427–432. 35. Harraf F, Sharma AK, Brown MM, Lees KR, Vass RI, Kalra L. A multicentre observational study of presentation and early assessment of acute stroke. BMJ 2002; 325:17–21. 36. Barsan WG, Brott TG, Broderick JP, Haley EC Jr, Levy DE, Marler JR. Urgent therapy for acute stroke. Effects of a stroke trial on untreated patients. Stroke 1994; 25:2132–2137. 37. Evenson KR, Rosamond WD, Morris DL. Prehospital and in-hospital delays in acute stroke care. Neuroepidemiology 2001; 20:65–76. 38. Porteus GH, Corry MD, Smith WS. Emergency medical services dispatcher identification of stroke and transient ischemic attack. Prehosp Emerg Care 1999; 3:211–216. 39. Evensen KR, Schroeder EB, Legare TB, Brice JH, Rosamund WD, Morris DL. A comparison of emergency medical services times for stroke and myocardial infarction. Prehosp Emerg Care 2001; 5:335–339. 40. Kothari RU, Pancioli A, Liu T, Brott T, Broderick J. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373–378. 41. Brott T, Adams HP, Olinger CP. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864–870. 42. Harbison J, Hossain O, Jenkinson D, Davis J, Louw SJ, Ford GA. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians and ambulance staff using the Face Arm Speech Test. Stroke 2003; 34:71–76.

Organizing Stroke Services

179

43. Kidwell CS, Starkman S, Eckstein M, Weems K, Saver JL. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71–76. 44. Scott PA, Temovsky CJ, Lawrence K, Gudaitis E, Lowell MJ. Analysis of Canadian population with potential geographic access to intravenous thrombolysis for acute ischemic stroke. Stroke 1998; 29:2304–2310. 45. Chalela JA, Kasner SE, Jauch EC, Pancioli AM. Safety of air medical transportation after tissue plasminogen activator administration in acute ischemic stroke. Stroke 1999; 30:2366– 2368. 46. Levine SR, Gorman M. ‘‘Telestroke’’: the application of telemedicine for stroke. Stroke 1999; 30:464–469. 47. Riopelle RJ, Howse DC, Bolton C, Elson S, Groll DL, Holtom D, Brunet DG, Jackson AC, Melanson M, Weaver DF. Regional access to acute ischemic stroke intervention. Stroke 2001; 32:652–655. 48. Alberts MJ, Hademenos G, Latchaw RE, Jagoda A, Marler JR, Mayberg MR, Starke RD, Todd HW, Viste KM, Girgus M, Shepherd T, Emr M, Shwayder P, Walker MD, for the Brain Attack Coalition. Recommendations for the Establishment of Primary Stroke Centers. JAMA 2000; 283:3102–3109. 49. National Institute of Neurological Disorders and Stroke: Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke, Washington, DC, 1997. 50. Lin CS, Tsai J, Woo P, Chang H. Prehospital delay and emergency department management of ischemic stroke patients in Taiwan, ROC. Prehosp Emerg Care 1999; 3:194–200. 51. Kothari R, Barsan W, Brott T, Broderick J, Ashbrook S. Frequency and accuracy of prehospital diagnosis of acute stroke. Stroke 1995; 26:937–941. 52. Goldstein LB, Hey LA, Laney R. North Carolina stroke prevention and treatment facilities survey. TPA therapy for acute stroke. Stroke 1998; 29:2069–2072. 53. Ruland S, Gorelick PB, Schneck M, Kim D, Moore CG, Leurgans S. Acute stroke in Illinois: a statewide assessment of diagnostic and treatment capabilities. Stroke 2002; 33:1334–1340. 54. Tilley BC, Lyden PD, Brott TG, Lu M, Levine SR, Welch KMA, for the NINDS Stroke Study Group. Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. Arch Neurol 1997; 54:1466– 1474. 55. Deming WE. The New Economics for Industry, Education, Government. Cambridge, MA: Massachusetts Institute of Technology, Center for Advanced Engineering Study, 1993. 56. Berwick DM, Godfrey AB, Roaessner J. Curing Health Care: New Strategies for Quality Improvement: a Report on the National Demonstration Project on Quality Improvement in Health Care. San Francisco: Jossey-Bass, 1990. 57. Grotta JC, Burgin WS, El-Mitwalli A, Long M, Campbell M, Morgenstern LB, Malkoff M, Alexandrov AV. Intravenous Tissue-Type Plasminogen Activator for Ischemic Stroke. Arch Neurol 2001; 58:2009–2013. 58. Kennedy J, Newcommon NJ, Cole-Haskayne A, Barber PA, Hill MD, Demchuk AM, Buchan AM. Organised Stroke Care Increases the Number and the Speed with Which Patients with Acute Ischemic Stroke Are Thrombolysed. Stroke 2002; 33:354. 59. Chapman KM, Woolfenden AR, Graeb D, Johnston DCC, Beckman J, Schulzer M, Teal PA. Intravenous tissue plasminogen activator for acute ischemic stroke. Stroke 2000; 31:2920–2924. 60. 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; 32:1074–1078. 61. 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; 29:1544–1549. 62. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke. JAMA 2000; 283:1145–1150.

180

Kennedy et al.

63. Wang DZ, Rose JA, Honings DS, Garwacki DJ, Milbrandt JC, for the OSF Stroke Team. Treating acute stroke patients with intravenous tPA. Stroke 2000; 31:77–81. 64. Mullins RJ, Mann NC. Population-based research assessing the effectiveness of trauma systems. J Trauma 1999; 47(3 suppl):S59–66. 65. Mann NC, Mullins RJ, MacKenzie EJ, Jurkovich GJ, Mock CN. Systematic review of published evidence regarding trauma system effectiveness. J Trauma 1999; 47(3 suppl):S25–33. 66. Holloway RG, Vickrey BG, Benesch C, Hinchey JA, Bieber J. Development of performance measures for acute ischemic stroke. Stroke 2001; 32:2058–2074. 67. Wattigney WA, Croft JB, Mensah GA, Alberts MJ, Shephard TJ, Gorelick PB, Nilasena DS, Hess DC, Walker MD, Hanley DF Jr, Shwayder P, Girgus M, Neff LJ, Williams JE, LaBarthe DR, Collins JL. Establishing data elements for the Paul Coverdell National Acute Stroke Registry: Part 1: proceedings of an expert panel. Stroke 2003; 34:151–156. 68. Stegmayr B, Asplund K, Danielsson BP, Hulter-Asberg K, Norrving B, Peltonen M, Terent A, Thorngren M, Wester PO. Stroke unit care saves lives. The Swedish national quality assessment registry of stroke care is the first of its kind in the world. Lakartidningen 1999; 96:2719–2724, 2726. 69. Rudd AG, Irwin P, Rutledge Z, Lowe D, Wade DT, Pearson M. Regional variations in stroke care in England, Wales and Northern Ireland: results from the National Sentinel Audit of Stroke. Royal College of Physicians Intercollegiate Stroke Working Party. Clin Rehabil 2001; 15:562–572. 70. Langhorne P. Organization of acute stroke care. Br Med Bull 2000; 56(no 2):436–443. 71. Shah E, Harwood R. Acute Management: Admission to Hospital in Stroke: Epidemiology, Evidence and Clinical Practice. 2d ed. Oxford: Oxford University Press, 1999. 72. Kalra L, Evans A, Perez I, Knapp M, Donaldson N, Swift CG. Alternative strategies for stroke care: a prospective randomised controlled trial. Lancet 2000; 356:894–899. 73. Rudd AG, Wolfe CDA, Tilling K, Beech R. Randomised controlled trial to evaluate early discharge scheme for patients with stroke. BMJ 1997; 315:1039–1044. 74. Stroke Unit Trialists Collaboration. Organized inpatient (stroke unit) care for stroke (Cochrane Review). In: The Cochrane Library, Issue 3, 2002. Oxford Update Software. 75. Husbands SL, Lincoln NB, Drummond AER, Gladman JRF, Berman P. Five year follow up of a randomised controlled trial of a stroke rehabilitation unit [abstr]. Clin Rehabili 1999; 13:530– 531. 76. Indredavik B, Bakke F, Slordahl SA, Rokseth R, Haheim LL. Stroke unit treatment: 10 year follow up. Stroke 1999; 30:1524–1527. 77. Kalra L. The influence of stroke unit rehabilitation on functional recovery from stroke. Stroke 1994; 25:821–825. 78. Ronning OM, Guldvog B. Stroke unit versus general medical wards, II: neurological deficits and activities of daily living. A quasi randomised controlled trial. Stroke 1998; 29:586–590. 79. Indredavik B, Bakke F, Slordahl SA, Rokseth R, Haheim LL. Stroke units treatment improves long terms quality of life: a randomised controlled trial. Stroke 1999; 30:1524–1527. 80. Wood-Dauphinee S, Shapiro S, Bass E, Fletcher C, Georges P, Hensby V, Mendelsohn B. A randomised trial of team care following stroke. Stroke 1984; 15:864–872. 81. Stevens RS, Ambler NR, Warren MD. A randomised controlled trial of a stroke rehabilitation ward. Age Ageing 1984; 13:65–75. 82. Kalra L, Dale P, Crome P. Improving stroke rehabilitation: a controlled study. Stroke 1993; 24:1462–1467. 83. National Clinical Guidelines for Stroke prepared by the Intercollegiate Working Party for Stroke. London: Royal College of Physicians. March 2000. 84. Wells PS, Lensing AW, Hirsh J. Graded compression stockings in the prevention of postoperative venous thromboembolism: a meta analysis. Arch Intern Med 1994; 154:67–72. 85. Gubitz G, Sandercock P, Counsell C. Antiplatelet therapy for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 3, 2002:Update Software. 86. Koudstaal, P. Anticoagulants for preventing stroke in patients with nonrheumatic atrial fi-

Organizing Stroke Services

87.

88.

89. 90. 91.

92. 93.

94.

95.

96.

97.

98.

181

brillation and a history of stroke or transient ischaemic attacks. (Cochrane Review) In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering on 20536 high risk individuals: a randomised placebo controlled trial. Lancet 2002; 360:7–22. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415–1425. Kwan J, Sandercock P. In hospital care pathways for stroke (Cochrane Review). In: Cochrane Library, Issue 3 2002. Oxford:Update Software. Wade DT. Stroke. In: Stevens A, Rafferty J, eds. Health Care Needs Assessment. Vol 1. Oxford: Radcliffe Medical Press, 1994:111–225. Langhorne P, Dennis M, Kalra L, Shepperd S, Wolfe CDA. Services for helping acute stroke patients avoid hospital admission (Cochrane Review). In: The Cochrane Library, Issue 2, 2002. Oxford: Update Software. Wade DT, Langton-Hewer R, Skilbeck CE, Bainton D, Burns-Cox C. Controlled trial of a home care service for acute stroke patients. Lancet 1985; 1(8424):323–326. Shepperd S, Harwood D, Gray A, Vessey M, Morgan P. Randomised controlled trial comparing hospital at home with inpatient hospital care. II: Cost minimisation analysis. BMJ 1998; 316:1791–1796. Early Supported Discharge Trialists. Services for reducing duration of hospital care for acute stroke patients (Cochrane Review). In: Cochrane Library, Issue 3, 2002. Oxford:Update Software. Rubenach S, Anderson C, Russell M, Spencer C, Winsor A. Early supported discharge and rehabilitation trial (ESPIRIT) in stroke: preliminary results. Cerebrovasc Dis 1998; 8(suppl 4): 82. Beech R, Rudd AG, Tilling K, Wolfe CDA. Economic consequences of early supported discharge to community based rehabilitation for stroke in an inner London teaching hospital. Stroke 1999; 30:729–735. Widen Holmqvist L, von Koch L, Kostulas V, Holm M, Widsell G, Tegler H, Johansson K, Almazan J, de Pedro-Cuesta J. A randomised controlled trial of rehabilitation at home after stroke in south west Stockholm. Stroke 1998; 29:591–597. Smith DS, Goldenberg E, Ashburn A, Kinsella G, Sheikh K, Brennan PJ, Meade TW, Zutshi DW, Perry JD, Reeback JS. Remedial therapy after stroke : a randomised controlled trial. Br Med J (Clin Res Ed) 1981; 282(6263):517–520.

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

184

Hofmeijer et al.

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

Complications of Acute Ischemic Stroke

185

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

186

Hofmeijer et al.

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.

Complications of Acute Ischemic Stroke

187

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

188

Hofmeijer et al.

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

Complications of Acute Ischemic Stroke

189

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

190

Hofmeijer et al.

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

Complications of Acute Ischemic Stroke

191

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

192

Hofmeijer et al.

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].

Complications of Acute Ischemic Stroke

193

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-

194

Hofmeijer et al.

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

Complications of Acute Ischemic Stroke

195

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.

196

Hofmeijer et al.

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.

REFERENCES 1. Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Stroke incidence, prevalence, and survival: secular trends in Rochester, Minnesota, through 1989. Stroke 1996; 27:373–380. 2. Silver FL, Norris JW, Lewis AJ, Hachinski VC. Early mortality following stroke: a prospective review. Stroke 1984; 15:492–496. 3. Gladman JR, Harwood DM, Barer DH. Predicting the outcome of acute stroke: prospective evaluation of five multivariate models and comparison with simple methods. J Neurol Neurosurg Psychiatry 1992; 55:347–351. 4. Chambers BR, Norris JW, Shurvell BL, Hachinski VC. Prognosis of acute stroke. Neurology 1987; 37:221–225. 5. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Survival and recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 1975 through 1989. Neurology 1998; 50:208–216. 6. Henon H, Godefroy O, Leys D, Mounier-Vehier F, Lucas C, Rondepierre P, Duhamel A, Pruvo JP. Early predictors of death and disability after acute cerebral ischemic event. Stroke 1995; 26:392–398. 7. Viitanen M, Winblad B, Asplund K. Autopsy-verified causes of death after stroke. Acta Med Scand 1987; 222:401–408. 8. Biller J, Adams- HP Jr, Bruno A, Love BB, Marsh EE. Mortality in acute cerebral infarction in young adults—a ten-year experience. Angiology 1991; 42:224–230. 9. Toni D, Fiorelli M, Gentile M, Bastianello S, Sacchetti ML, Argentino C, Pozzilli C, Fieschi C. Progressing neurological deficit secondary to acute ischemic stroke. A study on predictability, pathogenesis, and prognosis. Arch Neurol 1995; 52:670–675. 10. Britton M, Roden A. Progression of stroke after arrival at hospital. Stroke 1985; 16:629–632. 11. Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Effect of blood pressure and diabetes on stroke in progression. Lancet 1994; 344:156–159. 12. Davalos A, Cendra E, Teruel J, Martinez M, Genis D. Deteriorating ischemic stroke: risk factors and prognosis. Neurology 1990; 40:1865–1869. 13. Jones HJ, Millikan CH. Temporal profile (clinical course) of acute carotid system cerebral infarction. Stroke 1976; 7:64–71. 14. Reith J, Jorgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL, Olsen TS. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996; 347:422–425. 15. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’

Complications of Acute Ischemic Stroke

16. 17. 18. 19. 20. 21.

22. 23.

24. 25. 26. 27. 28.

29.

30.

31.

32.

33.

34.

35.

197

middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 1996; 53:309–315. Heinsius T, Bogousslavsky J, Van Melle G. Large infarcts in the middle cerebral artery territory. Etiology and outcome patterns. Neurology 1998; 50:341–350. Wijdicks EF, Diringer MN. Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. Mayo Clin Proc 1998; 73:829–836. Ropper AH, Shafran B. Brain edema after stroke. Clinical syndrome and intracranial pressure. Arch Neurol 1984; 41:26–29. Frank JI. Large hemispheric infarction, deterioration, and intracranial pressure. Neurology 1995; 45:1286–1290. Hofmeijer J, van der Worp HB, and Kappelle LJ. Treatment of space-occupying cerebral infarction. Crit Care Med. Adams- HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA. 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; 25:1901–1914. Schwab S, Spranger M, Schwarz S, Hacke W. Barbiturate coma in severe hemispheric stroke: useful or obsolete? Neurology 1997; 48:1608–1613. Muizelaar JP, Marmarou A, Ward JD, Kontos HA, Choi SC, Becker DP, Gruemer H, Young HF. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 1991; 75:731–739. Schell RM, Applegate RL, Cole DJ. Salt, starch, and water on the brain. J Neurosurg Anesthesiol 1996; 8:178–182. Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I: the significance of intracranial pressure monitoring. J Neurosurg 1979; 50:20–25. Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg 1992; 77:584–589. Schwab S, Aschoff A, Spranger M, Albert F, Hacke W. The value of intracranial pressure monitoring in acute hemispheric stroke. Neurology 1996; 47:393–398. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998; 29:2461– 2466. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke 2001; 32:2033–2035. Steiner T, Friede T, Aschoff A, Schellinger PD, Schwab S, Hacke W. Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke 2001; 32:2833–2835. Rieke K, Schwab S, Krieger D, von Kummer R, Aschoff A, Schuchardt V, Hacke W. Decompressive surgery in space-occupying hemispheric infarction: results of an open, prospective trial. Crit Care Med 1995; 23:1576–1587. Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O, Hacke W. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke 1998; 29:1888– 1893. Frank JI, Krieger D, Chyatte D, Cancian S. Hemicraniectomy and durotomy upon deterioration from massive hemispheric infarction. A proposed multicenter, prospective, randomized study. Stroke 1999; 30:243. Hofmeijer J, van der Worp HB, Amelink GJ, Algra A, Kappelle LJ. Decompressive surgery in space-occupying cerebral infarction. A randomized controlled trial. Cerebrovasc Dis 2001; 11:34. Kasner SE, Demchuk AM, Berrouschot J, Schmutzhard E, Harms L, Verro P, Chalela JA, Abbur R, McGrade H, Christou I, Krieger DW. Predictors of fatal brain edema in massive hemispheric ischemic stroke. Stroke 2001; 32:2117–2123.

198

Hofmeijer et al.

36. Krieger DW, Demchuk AM, Kasner SE, Jauss M, Hantson L. Early clinical and radiological predictors of fatal brain swelling in ischemic stroke. Stroke 1999; 30:287–292. 37. Oppenheim C, Samson Y, Manai R, Lalam T, Vandamme X, Crozier S, Srour A, Cornu P, Dormont D, Rancurel G, Marsault C. Prediction of malignant middle cerebral artery infarction by diffusion-weighted imaging. Stroke 2000; 31:2175–2181. 38. Ropper AH. Neurological intensive care. Ann Neurol 1992; 32:564–569. 39. Correia M, Silva M, Veloso M. Cooling therapy for acute stroke. Cochrane Database Syst Rev CD001247-2000. 40. Chaves CJ, Caplan LR, Chung CS, Tapia J, Amarenco P, Teal P, Wityk R, Estol C, Tettenborn B, Rosengart A, et al. Cerebellar infarcts in the New England Medical Center Posterior Circulation Stroke Registry. Neurology 1994; 44:1385–1390. 41. Kase CS, Norrving B, Levine SR, Babikian VL, Chodosh EH, Wolf PA, Welch KM. Cerebellar infarction. Clinical and anatomic observations in 66 cases. Stroke 1993; 24:76–83. 42. Mathew P, Teasdale G, Bannan A, Oluoch-Olunya D. Neurosurgical management of cerebellar haematoma and infarct. J Neurol Neurosurg Psychiatry 1995; 59:287–292. 43. Hart RG, Easton JD. Hemorrhagic infarcts. Stroke 1986; 17:586–589. 44. Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction—a prospective study. Stroke 1986; 17:179–185. 45. Hornig CR, Bauer T, Simon C, Trittmacher S, Dorndorf W. Hemorrhagic transformation in cardioembolic cerebral infarction. Stroke 1993; 24:465–468. 46. Mayer TE, Schulte-Altedorneburg G, Droste DW, Bruckmann H. Serial CT and MRI of ischaemic cerebral infarcts: frequency and clinical impact of haemorrhagic transformation. Neuroradiology 2000; 42:233–239. 47. Toni D, Fiorelli M, Bastianello S, Sacchetti ML, Sette G, Argentino C, Montinaro E, Bozzao L. Hemorrhagic transformation of brain infarct: predictability in the first 5 hours from stroke onset and influence on clinical outcome. Neurology 1996; 46:341–345. 48. Jaillard A, Cornu C, Durieux A, Moulin T, Boutitie F, Lees KR, Hommel M. Hemorrhagic transformation in acute ischemic stroke. The MAST-E study. MAST-E Group. Stroke 1999; 30:1326–1332. 49. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274:1017–1025. 50. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial—Europe Study Group. N Engl J Med 1996; 335:145–150. 51. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial—Italy (MAST-I) Group. Lancet 1995; 346:1509–1514. 52. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581–1587. 53. Stalnikowicz R, Fich A, Troudart T. Amitriptyline for intractable hiccups. N Engl J Med 1986; 315:64–65. 54. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349:1569–1581. 55. Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a supplement to the 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 1996; 27:1711–1718. 56. Sacco RL, Foulkes MA, Mohr JP, Wolf PA, Hier DB, Price TR. Determinants of early recurrence of cerebral infarction. The Stroke Data Bank. Stroke 1989; 20:983–989. 57. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol 1986; 43:71–84.

Complications of Acute Ischemic Stroke

199

58. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997; 349:1641–1649. 59. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet 2000; 355:1205– 1210. 60. Lancman ME, Golimstok A, Norscini J, Granillo R. Risk factors for developing seizures after a stroke. Epilepsia 1993; 34:141–143. 61. Giroud M, Gras P, Fayolle H, Andre N, Soichot P, Dumas R. Early seizures after acute stroke: a study of 1,640 cases. Epilepsia 1994; 35:959–964. 62. Kilpatrick CJ, Davis SM, Tress BM, Rossiter SC, Hopper JL, Vandendriesen ML. Epileptic seizures in acute stroke. Arch Neurol 1990; 47:157–160. 63. So EL, Annegers JF, Hauser WA, O’Brien PC, Whisnant JP. Population-based study of seizure disorders after cerebral infarction. Neurology 1996; 46:350–355. 64. Gupta SR, Naheedy MH, Elias D, Rubino FA. Postinfarction seizures. A clinical study. Stroke 1988; 19:1477–1481. 65. Awada A, Omojola MF, Obeid T. Late epileptic seizures after cerebral infarction. Acta Neurol Scand 1999; 99:265–268. 66. Kraus JA, Berlit P. Cerebral embolism and epileptic seizures—the role of the embolic source. Acta Neurol Scand 1998; 97:154–159. 67. Kumar A, Dromerick AW. Intractable hiccups during stroke rehabilitation. Arch Phys Med Rehabil 1998; 79:697–699. 68. Friedgood CE, Ripstein CB. Chlorpromazine in the treatment of intractable hiccups. JAMA 1955; 157:309–310. 69. McFarling DA, Susac JO. Carbamazepine for hiccoughs. JAMA 1974; 230:962. 70. Ives TJ, Fleming MF, Weart CW, Bloch D. Treatment of intractable hiccups with intramuscular haloperidol. Am J Psychiatry 1985; 142:1368–1369. 71. Lance JW, Bassil GT. Familial intractable hiccup relieved by baclofen. Lancet 1989; 2:276–277. 72. Burke AM, White AB, and Brill, N. Baclofen for intractable hiccups. N Engl J Med 319:1354– 1988. 73. 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; 14:736–741. 74. Starkstein SE, Robinson RG. Affective disorders and cerebral vascular disease. Br J Psychiatry 1989; 154:170–182. 75. Paolucci S, Antonucci G, Pratesi L, Traballesi M, Grasso MG, Lubich S. Poststroke depression and its role in rehabilitation of inpatients. Arch Phys Med Rehabil 1999; 80:985–990. 76. MacHale SM, O’Rourke SJ, Wardlaw JM, Dennis MS. Depression and its relation to lesion location after stroke. J Neurol Neurosurg Psychiatry 1998; 64:371–374. 77. Kim JS, Choi-Kwon S. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000; 54:1805–1810. 78. Sandberg O, Franklin KA, Bucht G, Gustafson Y. Sleep apnea, delirium, depressed mood, cognition, and ADL ability after stroke. J Am Geriatr Soc 2001; 49:391–397. 79. Robinson RG, Starr LB, Price TR. A two year longitudinal study of mood disorders following stroke. Prevalence and duration at six months follow-up. Br J Psychiatry 1984; 144:256–262. 80. Andersen G, Vestergaard K, Lauritzen L. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 1994; 25:1099–1104. 81. Gesztelyi R, Fekete I, Kellermann M, Csiba L, Bereczki D. Screening for depressive symptoms among post-stroke outpatients in eastern Hungary. J Geriatr Psychiatry Neurol 1999; 12:194– 199. 82. Fassbender K, Schmidt R, Mossner R, Daffertshofer M, Hennerici M. Pattern of activation of the hypothalamic-pituitary-adrenal axis in acute stroke. Relation to acute confusional state, extent of brain damage, and clinical outcome. Stroke 1994; 25:1105–1108.

200

Hofmeijer et al.

83. Rokey R, Rolak LA, Harati Y, Kutka N, Verani MS. Coronary artery disease in patients with cerebrovascular disease: a prospective study. Ann Neurol 1984; 16:50–53. 84. Broderick JP, Phillips SJ, O’Fallon WM, Frye RL, Whisnant JP. Relationship of cardiac disease to stroke occurrence, recurrence, and mortality. Stroke 1992; 23:1250–1256. 85. McDermott MM, Lefevre F, Arron M, Martin GJ, Biller J. ST segment depression detected by continuous electrocardiography in patients with acute ischemic stroke or transient ischemic attack. Stroke 1994; 25:1820–1824. 86. Mikolich JR, Jacobs WC, Fletcher GF. Cardiac arrhythmias in patients with acute cerebrovascular accidents. JAMA 1981; 246:1314–1317. 87. Oppenheimer SM, Hachinski VC. The cardiac consequences of stroke. Neurol Clin 1992; 10:167–176. 88. Norris JW, Hachinski VC, Myers MG, Callow J, Wong T, Moore RW. Serum cardiac enzymes in stroke. Stroke 1979; 10:548–553. 89. Oppenheimer SM, Cechetto DF. Cardiac chronotropic organization of the rat insular cortex. Brain Res 1990; 533:66–72. 90. Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Insular cortex stimulation produces lethal cardiac arrhythmias: a mechanism of sudden death? Brain Res 1991; 550:115–121. 91. Hachinski VC, Oppenheimer SM, Wilson JX, Guiraudon C, Cechetto DF. Asymmetry of sympathetic consequences of experimental stroke. Arch Neurol 1992; 49:697–702. 92. Lane RD, Wallace JD, Petrosky PP, Schwartz GE, Gradman AH. Supraventricular tachycardia in patients with right hemisphere strokes. Stroke 1992; 23:362–366. 93. Kocan MJ. Cardiovascular effects of acute stroke. Prog Cardiovasc Nurs 1999; 14:61–67. 94. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002; 33:1315–1320. 95. Britton M, Carlsson A, de Faire U. Blood pressure course in patients with acute stroke and matched controls. Stroke 1986; 17:861–864. 96. Harper G, Castleden CM, Potter JF. Factors affecting changes in blood pressure after acute stroke. Stroke 1994; 25:1726–1729. 97. Lisk DR, Grotta JC, Lamki LM, Tran HD, Taylor JW, Molony DA, Barron BJ. Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Arch Neurol 1993; 50:855–862. 98. Christensen H, Meden P, Overgaard K, Boysen G. The course of blood pressure in acute stroke is related to the severity of the neurological deficits. Acta Neurol Scand 2002; 106:142–147. 99. Carlberg B, Asplund K, Hagg E. Factors influencing admission blood pressure levels in patients with acute stroke. Stroke 1991; 22:527–530. 100. Waltz AG. Effect of blood pressure on blood flow in ischemic and in nonischemic cerebral cortex. The phenomena of autoregulation and luxury perfusion. Neurology 1968; 18:613– 621. 101. Fieschi C, Agnoli A, Battistini N, Bozzao L, Prencipe M. Derangement of regional cerebral blood flow and of its regulatory mechanisms in acute cerebrovascular lesions. Neurology 1968; 18:1166–1179. 102. Dirnagl U, Pulsinelli W. Autoregulation of cerebral blood flow in experimental focal brain ischemia. J Cereb Blood Flow Metab 1990; 10:327–336. 103. Davis JN. An experimental study of hiccup. Brain 1970; 93:851–872. 104. Powers WJ. Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993; 43:461–467. 105. Interventions for deliberately altering blood pressure in acute stroke. Cochrane Database Syst Rev CD000039-2001. 106. Chamorro A, Vila N, Ascaso C, Elices E, Schonewille W, Blanc R. Blood pressure and functional recovery in acute ischemic stroke. Stroke 1998; 29:1850–1853. 107. Dyker AG, Grosset DG, Lees K. Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke 1997; 28:580–583. 108. Rordorf G, Cramer SC, Efird JT, Schwamm LH, Buonanno F, Koroshetz WJ. Pharmaco-

Complications of Acute Ischemic Stroke

109.

110. 111. 112. 113.

114.

115.

116. 117. 118. 119.

120.

121. 122.

123.

124. 125. 126. 127. 128. 129.

201

logical elevation of blood pressure in acute stroke. Clinical effects and safety. Stroke 1997; 28:2133–2138. Toni D, Sacchetti ML, Argentino C, Gentile M, Cavalletti C, Frontoni M, Fieschi C. Does hyperglycaemia play a role on the outcome of acute ischaemic stroke patients. J Neurol 1992; 239:382–386. van Kooten F, Hoogerbrugge N, Naarding P, Koudstaal PJ. Hyperglycemia in the acute phase of stroke is not caused by stress. Stroke 1993; 24:1129–1132. O’Neill PA, Davies I, Fullerton KJ, Bennett D. Stress hormone and blood glucose response following acute stroke in the elderly. Stroke 1991; 22:842–847. Tracey F, Stout RW. Hyperglycemia in the acute phase of stroke and stress response. Stroke 1994; 25:524–525. Adams HP Jr, Olinger CP, Marler JR, Biller J, Brott TG, Barsan WG, Banwart K. Comparison of admission serum glucose concentration with neurologic outcome in acute cerebral infarction. A study in patients given naloxone. Stroke 1988; 19:455–458. Els T, Klisch J, Orszagh M, Hetzel A, Schulte-Monting J, Schumacher M, Lucking CH. Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc Dis 2002; 13:89–94. Bruno A, Biller J, Adams HP Jr, Clarke WR, Woolson RF, Williams LS, Hansen MD. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology 1999; 52:280–284. Berger L, Hakim AM. The association of hyperglycemia with cerebral edema in stroke. Stroke 1986; 17:865–871. Candelise L, Landi G, Orazio EN, Boccardi E. Prognostic significance of hyperglycemia in acute stroke. Arch Neurol 1985; 42:661–663. Kagansky N, Levy S, Knobler H. The role of hyperglycemia in acute stroke. Arch Neurol 2001; 58:1209–1212. Sandercock PA, van den Belt AG, Lindley RI, Slattery J. Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. J Neurol Neurosurg Psychiatry 1993; 56:17–25. Landi G, D’Angelo A, Boccardi E, Candelise L, Mannucci PM, Morabito A, Orazio EN. Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability. Arch Neurol 1992; 49:279–283. Noel P, Gregoire F, Capon A, Lehert P. Atrial fibrillation as a risk factor for deep venous thrombosis and pulmonary emboli in stroke patients. Stroke 1991; 22:760–762. Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326:975–982. Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ 1994; 309:299–304. Davenport RJ, Dennis MS, Wellwood I, Warlow CP. Complications after acute stroke. Stroke 1996; 27:415–420. Bounds JV, Wiebers DO, Whisnant JP, Okazaki H. Mechanisms and timing of deaths from cerebral infarction. Stroke 1981; 12:474–477. Przelomski MM, Roth RM, Gleckman RA, Marcus EM. Fever in the wake of a stroke. Neurology 1986; 36:427–429. Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G, D’Alessandro R. Fever in acute stroke worsens prognosis. A prospective study. Stroke 1995; 26:2040–2043. Hindfelt B. The prognostic significance of subfebrility and fever in ischaemic cerebral infarction. Acta Neurol Scand 1976; 53:72–79. Boysen G, Christensen H. Stroke severity determines body temperature in acute stroke. Stroke 2001; 32:413–417.

202

Hofmeijer et al.

130. Fukuda H, Kitani M, Takahashi K. Body temperature correlates with functional outcome and the lesion size of cerebral infarction. Acta Neurol Scand 1999; 100:385–390. 131. Hajat C, Hajat S, Sharma P. Effects of poststroke pyrexia on stroke outcome : a meta-analysis of studies in patients. Stroke 2000; 31:410–414. 132. Castillo J, Davalos A, Marrugat J, Noya M. Timing for fever-related brain damage in acute ischemic stroke. Stroke 1998; 29:2455–2460. 133. Castillo J, Davalos A, Noya M. Aggravation of acute ischemic stroke by hyperthermia is related to an excitotoxic mechanism. Cerebrovasc Dis 1999; 9:22–27. 134. Busto R, Globus MY, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989; 20:904–910. 135. Wijdicks EF, Scott JP. Outcome in patients with acute basilar artery occlusion requiring mechanical ventilation. Stroke 1996; 27:1301–1303. 136. Burtin P, Bollaert PE, Feldmann L, Nace L, Lelarge P, Bauer P, Larcan A. Prognosis of stroke patients undergoing mechanical ventilation. Intensive Care Med 1994; 20:32–36. 137. el Ad B, Bornstein NM, Fuchs P, Korczyn AD. Mechanical ventilation in stroke patients—is it worthwhile? Neurology 1996; 47:657–659. 138. Borrie MJ, Campbell AJ, Caradoc-Davies TH, Spears GF. Urinary incontinence after stroke: a prospective study. Age Ageing 1986; 15:177–181. 139. Gelber DA, Good DC, Laven LJ, Verhulst SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24:378–382. 140. Patel M, Coshall C, Rudd AG, Wolfe CD. Natural history and effects on 2-year outcomes of urinary incontinence after stroke. Stroke 2001; 32:122–127. 141. Patel M, Coshall C, Lawrence E, Rudd AG, Wolfe CD. Recovery from poststroke urinary incontinence: associated factors and impact on outcome. J Am Geriatr Soc 2001; 49:1229–1233. 142. van Kuijk AA, van der Linde H, van Limbeek J. Urinary incontinence in stroke patients after admission to a postacute inpatient rehabilitation program. Arch Phys Med Rehabil 2001; 82:1407–1411. 143. Jacobson PL, Messenheimer JA, Farmer TW. Treatment of intractable hiccups with valproic acid. Neurology 1981; 31:1458–1460. 144. Honde C, Derks C, Tudor D. Local treatment of pressure sores in the elderly: amino acid copolymer membrane versus hydrocolloid dressing. J Am Geriatr Soc 1994; 42:1180–1183. 145. Smithard DG, O’Neill PA, Parks C, Morris J. Complications and outcome after acute stroke. Does dysphagia matter? Stroke 1996; 27:1200–1204. 146. Westergren A, Ohlsson O, Rahm, Hallberg I. Eating difficulties, complications and nursing interventions during a period of three months after a stroke. J Adv Nurs 2001; 35:416–426. 147. Barer DH. The natural history and functional consequences of dysphagia after hemispheric stroke. J Neurol Neurosurg Psychiatry 1989; 52:236–241. 148. Daniels SK, Foundas AL. Lesion localization in acute stroke patients with risk of aspiration. J Neuroimaging 1999; 9:91–98. 149. Hamdy S, Aziz Q, Rothwell JC, Crone R, Hughes D, Tallis RC, Thompson DG. Explaining oropharyngeal dysphagia after unilateral hemispheric stroke. Lancet 1997; 350:686–692. 150. Smithard DG, O’Neill PA, England RE, Park CL, Wyatt R, Martin DF, Morris J. The natural history of dysphagia following a stroke. Dysphagia 1997; 12:188–193. 151. Mann G, Hankey GJ, Cameron D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke 1999; 30:744–748. 152. Mann G, Hankey GJ. Initial clinical and demographic predictors of swallowing impairment following acute stroke. Dysphagia 2001; 16:208–215. 153. Westergren A, Hallberg IR, Ohlsson O. Nursing assessment of dysphagia among patients with stroke. Scand J Caring Sci 1999; 13:274–282. 154. Daniels SK, Ballo LA, Mahoney MC, Foundas AL. Clinical predictors of dysphagia and aspiration risk: outcome measures in acute stroke patients. Arch Phys Med Rehabil 2000; 81:1030–1033.

Complications of Acute Ischemic Stroke

203

155. Bath PM, Bath FJ, and Smithard DG. Interventions for dysphagia in acute stroke. Cochrane Database Syst Rev CD000323-2000. 156. Norton B, Homer-Ward M, Donnelly MT, Long RG, Holmes GK. A randomised prospective comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding after acute dysphagic stroke. BMJ 1996; 312:13–16. 157. James A, Kapur K, Hawthorne AB. Long-term outcome of percutaneous endoscopic gastrostomy feeding in patients with dysphagic stroke. Age Ageing 1998; 27:671–676. 158. Wilkinson TJ, Thomas K, MacGregor S, Tillard G, Wyles C, Sainsbury R. Tolerance of early diet textures as indicators of recovery from dysphagia after stroke. Dysphagia 2002; 17:227– 232. 159. DePippo KL, Holas MA, Reding MJ, Mandel FS, Lesser ML. Dysphagia therapy following stroke: a controlled trial. Neurology 1994; 44:1655–1660. 160. Perez I, Smithard DG, Davies H, Kalra L. Pharmacological treatment of dysphagia in stroke. Dysphagia 1998; 13:12–16. 161. Reddy NP, Simcox DL, Gupta V, Motta GE, Coppenger J, Das A, Buch O. Biofeedback therapy using accelerometry for treating dysphagic patients with poor laryngeal elevation: case studies. J Rehabil Res Dev 2000; 37:361–372. 162. Davalos A, Ricart W, Gonzalez-Huix F, Soler S, Marrugat J, Molins A, Suner R, Genis D. Effect of malnutrition after acute stroke on clinical outcome. Stroke 1996; 27:1028–1032. 163. Goulding R, Bakheit AM. Evaluation of the benefits of monitoring fluid thickness in the dietary management of dysphagic stroke patients. Clin Rehabil 2000; 14:119–124. 164. Wijdicks EF, Fulgham JR, Batts KP. Gastrointestinal bleeding in stroke. Stroke 1994; 25:2146–2148. 165. Davenport RJ, Dennis MS, Warlow CP. Gastrointestinal hemorrhage after acute stroke. Stroke 1996; 27:421–424. 166. Langhorne P, Williams BO, Gilchrist W, Howie K. Do stroke units save lives? Lancet 1993; 342:395–398.

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

206

Fayad

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

Modifiable Risk Factors for Stroke 207

208

Fayad

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

Modifiable Risk Factors for Stroke

209

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.

210

Fayad

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

Modifiable Risk Factors for Stroke

211

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].

212

Fayad

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.

Modifiable Risk Factors for Stroke

213

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

214

Fayad

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

Modifiable Risk Factors for Stroke

215

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.

216

Fayad

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

Modifiable Risk Factors for Stroke

217

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

218

Fayad

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

Modifiable Risk Factors for Stroke

219

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

220

Fayad

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.

REFERENCES 1. Gorelick PB. Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review. Stroke 2002; 33:862–875. 2. Vasan RS, Beiser A, Seshadri S, Larson MG, Kannel WB, D’Agostino RB, Levy D. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham heart study. JAMA 2002; 287:1003–1010. 3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903–1913. 4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560–2572. 5. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou V, Probstfield J, Wright JT Jr, Alderman MH, Weiss RJ, Piller L, Bettencourt J, Walsh SM. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich) 2002; 4:393– 404. 6. Black HR, Elliott WJ, Neaton JD, Grandits G, Grambsch P, Grimm RH Jr, Hansson L, Lacouciere Y, Muller J, Sleight P, Weber MA, White WB, Williams G, Wittes J, Zanchetti A, Fakouhi TD, Anders RJ. Baseline characteristics and early blood pressure control in the CONVINCE trial. Hypertension 2001; 37:12–18. 7. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2000; 356:1955–1964. 8. Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension 2000; 35:539–543. 9. Izzo JL Jr, Levy D, Black HR. Clinical Advisory Statement. Importance of systolic blood pressure in older Americans. Hypertension 2000; 35:1021–1024. 10. Staessen JA, Wang J. Blood-pressure lowering for the secondary prevention of stroke. Lancet 2001; 358:1026–1027. 11. Di Bari M, Pahor M, Franse LV, Shorr RI, Wan JY, Ferrucci L, Somes GW, Applegate WB. Dementia and disability outcomes in large hypertension trials: lessons learned from the systolic hypertension in the elderly program (SHEP) trial. Am J Epidemiol 2001; 153:72–78. 12. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H,

Modifiable Risk Factors for Stroke

13.

14.

15.

16. 17.

18.

19. 20. 21. 22.

23. 24. 25.

26.

27.

28.

29.

30.

221

Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:995–1003. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressurelowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033–1041. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, Davies R, Ostergren J, Probstfield J. Use of ramipril in preventing stroke: double blind randomised trial. BMJ 2002; 324:699–702. The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. The Trials of Hypertension Prevention, phase II. Arch Intern Med 1997; 157:657–667. He J, Whelton PK, Appel LJ, Charleston J, Klag MJ. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 2000; 35:544–549. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller 3rd ER, Simons-Morton DG, Karanja N, Lin PH. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001; 344:3–10. Vollmer WM, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, Conlin PR, Svetkey LP, Erlinger TP, Moore TJ, Karanja N. Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial. Ann Intern Med 2001; 135:1019–1028. Chobanian AV, Hill M. National Heart, Lung, and Blood Institute Workshop on Sodium and Blood Pressure. A critical review of current scientific evidence. Hypertension 2000; 35:858–863. Kelley GA, Kelley KS, Tran ZV. The effects of exercise on resting blood pressure in children and adolescents: a meta-analysis of randomized controlled trials. Prev Cardiol 2003; 6:8–16. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: a metaanalysis of randomized, controlled trials. Ann Intern Med 2002; 136:493–503. Xin X, He J, Frontini MG, Ogden LG, Motsamai OI, Whelton PK. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2001; 38:1112–1117. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 2003; 26(suppl 1):S33–S50. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA 2003; 290:1884–1890. Sacco RL, Boden-Albala B, Abel G, Lin IF, Elkind M, Hauser WA, Paik MC, Shea S. Raceethnic disparities in the impact of stroke risk factors: the northern Manhattan stroke study. Stroke 2001; 32:1725–1731. Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, Holman RR. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke 2002; 33:1776–1781. Gillett M, Davis WA, Jackson D, Bruce DG, Davis TM. Prospective evaluation of carotid bruit as a predictor of first stroke in type 2 diabetes: the Fremantle Diabetes Study. Stroke 2003; 34:2145–2151. Chamorro A, Sacco RL, Mohr JP, Foulkes MA, Kase CS, Tatemichi TK, Wolf PA, Price TR, Hier DB. Clinical-computed tomographic correlations of lacunar infarction in the Stroke Data Bank. Stroke 1991; 22:175–181. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, Glahn J, Brandt T, Hacke W, Diener HC. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32:2559–2566. Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003; 34:2050–2059.

222

Fayad

31. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513– 2516. 32. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421–1428. 33. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998; 339:1415–1425. 34. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853. 35. Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 1995; 75:894–903. 36. Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O’Leary DH, Genuth S. Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes mellitus. N Engl J Med 2003; 348:2294–2303. 37. UK Prospective Diabetes Study 6. Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990; 13:1–11. 38. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703–713. 39. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355:253–259. 40. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383–393. 41. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, Zinman B. Ramipril and the development of diabetes. JAMA 2001; 286:1882–1885. 42. Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif JC. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003; 107:1291–1296. 43. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103:357–362. 44. Hu FB, Stampfer MJ. Is type 2 diabetes mellitus a vascular condition? Arterioscler Thromb Vasc Biol 2003; 23:1715–1716. 45. Suk SH, Sacco RL, Boden-Albala B, Cheun JF, Pittman JG, Elkind MS, Paik MC. Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke 2003; 34:1586–1592. 46. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Horwitz RI. Insulin resistance and risk for stroke. Neurology 2002; 59:809–815. 47. Meigs JB. The metabolic syndrome. BMJ 2003; 327:61–62. 48. Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143–3421. 49. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15:539–553. 50. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003; 289:76–79. 51. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, McVeety JC,

Modifiable Risk Factors for Stroke

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64. 65.

66.

67.

68.

69.

223

Horwitz RI. Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke. Neurology 2003; 60:1447–1451. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356–359. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24:683–689. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002; 288:2709–2716. Pyorala M, Miettinen H, Laakso M, Pyorala K. Plasma insulin and all-cause, cardiovascular, and noncardiovascular mortality: the 22-year follow-up results of the Helsinki Policemen Study. Diabetes Care 2000; 23:1097–1102. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study. Diabetes Care 2003; 26:1251–1257. Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, Lipinska I, D’Agostino RB, Wilson PW. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 2000; 283:221–228. Meigs JB, Jacques PF, Selhub J, Singer DE, Nathan DM, Rifai N, D’Agostino RB Sr, Wilson PW. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care 2001; 24:1403–1410. Ford ES. The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey. Atherosclerosis 2003; 168:351–358. Black PH. The inflammatory response is an integral part of the stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 2003; 17:350–364. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, McVeety JC, Horwitz RI. Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. Stroke 2003; 34:1431–1436. Lorenzo C, Okoloise M, Williams K, Stern MP, Haffner SM. The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. Diabetes Care 2003; 26:3153– 3159. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497. Prospective studies collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995; 346:1647–1653. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and sixyear mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989; 320:904–910. Benfante R, Yano K, Hwang LJ, Curb JD, Kagan A, Ross W. Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic stroke in Hawaiian Japanese men. Implications of shared risk. Stroke 1994; 25:814–820. Koren-Morag N, Tanne D, Graff E, Goldbourt U. Low- and high-density lipoprotein cholesterol and ischemic cerebrovascular disease: the bezafibrate infarction prevention registry. Arch Intern Med 2002; 162:993–999. Sacco RL, Roberts JK, Boden-Albala B, Gu Q, Lin IF, Kargman DE, Berglund L, Hauser WA, Shea S, Paik MC. Race-ethnicity and determinants of carotid atherosclerosis in a multiethnic population. The Northern Manhattan Stroke Study. Stroke 1997; 28:929–935. Sacco RL, Benson RT, Kargman DE, Boden-Albala B, Tuck C, Lin IF, Cheng JF, Paik MC,

224

70. 71. 72. 73.

74.

75.

76.

77.

78.

79. 80.

81. 82.

83.

84.

85. 86.

87.

Fayad Shea S, Berglund L. High-density lipoprotein cholesterol and ischemic stroke in the elderly: the Northern Manhattan Stroke Study. JAMA 2001; 285:2729–2735. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989; 20:1460–1465. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 1998; 352:1801–1807. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–1389. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335:1001–1009. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339:1349–1357. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361:1149–1158. Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 2001; 103:2828–2833. Amarenco P, Bogousslavsky J, Callahan AS, Goldstein L, Hennerici M, Sillsen H, Welch MA, Zivin J. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis 2003; 16:389–395. Sadoshima S, Kurozumi T, Tanaka K, Ueda K, Takeshita M, Hirota Y, Omae T, Uzawa H, Katsuki S. Cerebral and aortic atherosclerosis in Hisayama, Japan. Atherosclerosis 1980; 36:117–126. Amarenco P, Duyckaerts C, Tzourio C, Henin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221–225. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul PJ, Bousser MG. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474–1479. The French Study of Aortic Plaques in Stroke Group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216–1221. Di Tullio MR, Sacco RL, Gersony D, Nayak H, Weslow RG, Kargman DE, Homma S. Aortic atheromas and acute ischemic stroke: a transesophageal echocardiographic study in an ethnically mixed population. Neurology 1996; 46:1560–1566. Stern A, Tunick PA, Culliford AT, Lachmann J, Baumann FG, Kanchuger MS, Marschall K, Shah A, Grossi E, Kronzon I. Protruding aortic arch atheromas: risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 1999; 138:746–752. Konecky N, Malinow MR, Tunick PA, Freedberg RS, Rosenzweig BP, Katz ES, Hess DL, Upson B, Leung B, Perez J, Kronzon I. Correlation between plasma homocysteine and aortic atherosclerosis. Am Heart J 1997; 133:534–540. Elkind MS, Sciacca R, Boden-Albala B, Homma S, Di Tullio MR. Leukocyte count is associated with aortic arch plaque thickness. Stroke 2002; 33:2587–2592. Sugioka K, Hozumi T, Sciacca RR, Miyake Y, Titova I, Gaspard G, Sacco RL, Homma S, Di Tullio MR. Impact of aortic stiffness on ischemic stroke in elderly patients. Stroke 2002; 33:2077–2081. Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P. Aortic

Modifiable Risk Factors for Stroke

88.

89. 90. 91.

92. 93.

94.

95.

96.

97. 98.

99. 100.

101.

102. 103. 104. 105.

225

stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003; 34:1203–1206. Tunick PA, Nayar AC, Goodkin GM, Mirchandani S, Francescone S, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM, Kronzon I. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002; 90:1320–1325. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115–126. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105:1135–1143. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499–511. Lindsberg PJ, Grau AJ. Inflammation and infections as risk factors for ischemic stroke. Stroke 2003; 34:2518–2532. Syrjanen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients. Br Med J (Clin Res Ed) 1988; 296:1156–1160. Macko RF, Ameriso SF, Barndt R, Clough W, Weiner JM, Fisher M. Precipitants of brain infarction. Roles of preceding infection/inflammation and recent psychological stress. Stroke 1996; 27:1999–2004. Grau AJ, Buggle F, Ziegler C, Schwarz W, Meuser J, Tasman AJ, Buhler A, Benesch C, Becher H, Hacke W. Association between acute cerebrovascular ischemia and chronic and recurrent infection. Stroke 1997; 28:1724–1729. Grau AJ, Buggle F, Becher H, Zimmermann E, Spiel M, Fent T, Maiwald M, Werle E, Zorn M, Hengel H, Hacke W. Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: clinical and biochemical studies. Neurology 1998; 50:196–203. Joshipura KJ, Hung HC, Rimm EB, Willett WC, Ascherio A. Periodontal disease, tooth loss, and incidence of ischemic stroke. Stroke 2003; 34:47–52. Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs DR Jr, Papapanou PN, Sacco RL. Relationship between periodontal disease, tooth loss, and carotid artery plaque: the Oral Infections and Vascular Disease Epidemiology Study (INVEST). Stroke 2003; 34:2120– 2125. Wimmer ML, Sandmann-Strupp R, Saikku P, Haberl RL. Association of chlamydial infection with cerebrovascular disease. Stroke 1996; 27:2207–2210. Heuschmann PU, Neureiter D, Gesslein M, Craiovan B, Maass M, Faller G, Beck G, Neundoerfer B, Kolominsky-Rabas PL. Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: results from a population-based case-control study. Stroke 2001; 32:2253–2258. Neureiter D, Heuschmann P, Stintzing S, Kolominsky-Rabas P, Barbera L, Jung A, Ocker M, Maass M, Faller G, Kirchner T. Detection of Chlamydia pneumoniae but not of Helicobacter pylori in symptomatic atherosclerotic carotids associated with enhanced serum antibodies, inflammation and apoptosis rate. Atherosclerosis 2003; 168:153–162. Kalayoglu MV, Libby P, Byrne GI. Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA 2002; 288:2724–2731. Higgins JP. Chlamydia pneumoniae and coronary artery disease: the antibiotic trials. Mayo Clin Proc 2003; 78:321–332. Brassard P, Bourgault C, Brophy J, Kezouh A, Suissa S. Antibiotics in primary prevention of stroke in the elderly. Stroke 2003; 34:e163–e166. Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol 1999; 19:1368– 1377.

226

Fayad

106. Tanne D, Benderly M, Goldbourt U, Boyko V, Brunner D, Graff E, Reicher-Reiss H, Shotan A, Mandelzweig L, Behar S. A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study. Am J Med 2001; 111:457–463. 107. Resch KL, Ernst E, Matrai A, Paulsen HF. Fibrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors. Ann Intern Med 1992; 117:371–375. 108. Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgarde F. Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 2002; 105:2632–2637. 109. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001; 32:917–924. 110. Arenillas JF, Alvarez-Sabin J, Molina CA, Chacon P, Montaner J, Rovira A, Ibarra B, Quintana M. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke 2003; 34:2463– 2468. 111. Cao JJ, Thach C, Manolio TA, Psaty BM, Kuller LH, Chaves PH, Polak JF, Sutton-Tyrrell K, Herrington DM, Price TR, Cushman M. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation 2003; 108:166–170. 112. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001; 32:2575–2579. 113. 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. 114. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557–1565. 115. Kiely DK, Wolf PA, Cupples LA, Beiser AS, Kannel WB. Physical activity and stroke risk: the Framingham Study. Am J Epidemiol 1994; 140:608–620. 116. Lindenstrom E, Boysen G, Nyboe J. Lifestyle factors and risk of cerebrovascular disease in women. The Copenhagen City Heart Study. Stroke 1993; 24:1468–1472. 117. Hu FB, Stampfer MJ, Colditz GA, Ascherio A, Rexrode KM, Willett WC, Manson JE. Physical activity and risk of stroke in women. JAMA 2000; 283:2961–2967. 118. Evenson KR, Rosamond WD, Cai J, Toole JF, Hutchinson RG, Shahar E, Folsom AR. Physical activity and ischemic stroke risk. The Atherosclerosis Risk in Communities study. Stroke 1999; 30:1333–1339. 119. Sacco RL, Gan R, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, Shea S, Paik MC. Leisure-time physical activity and ischemic stroke risk: the Northern Manhattan Stroke Study. Stroke 1998; 29:380–387. 120. Wannamethee G, Shaper AG. Physical activity and stroke in British middle aged men. BMJ 1992; 304:597–601. 121. Lee IM, Paffenbarger RS Jr. Physical activity and stroke incidence: the Harvard Alumni Health Study. Stroke 1998; 29:2049–2054. 122. Rodriguez CJ, Sacco RL, Sciacca RR, Boden-Albala B, Homma S, Di Tullio MR. Physical activity attenuates the effect of increased left ventricular mass on the risk of ischemic stroke: The Northern Manhattan Stroke Study. J Am Coll Cardiol 2002; 39:1482–1488. 123. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke 2003; 34:2475–2481. 124. Laaksonen DE, Lakka HM, Salonen JT, Niskanen LK, Rauramaa R, Lakka TA. Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome. Diabetes Care 2002; 25:1612–1618. 125. Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schrock H, Nickenig G,

Modifiable Risk Factors for Stroke

126.

127. 128.

129.

130.

131.

132.

133.

134.

135. 136.

137. 138. 139.

140. 141. 142. 143.

144. 145.

227

Kuschinsky W, Dirnagl U, Laufs U. Mechanisms of stroke protection by physical activity. Ann Neurol 2003; 54:582–590. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, Buchner D, Ettinger W, Heath GW, King AC, et al. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995; 273:402–407. Physical activity and cardiovascular health. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. JAMA 1996; 276:241–246. Malinow MR, Bostom AG, Krauss RM. Homocysteine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999; 99:178–182. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996; 93:7–9. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346:1395–1398. Bostom AG, Rosenberg IH, Silbershatz H, Jacques PF, Selhub J, D’Agostino RB, Wilson PW, Wolf PA. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med 1999; 131:352–355. Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Witteman JC, Koudstaal PJ, Grobbee DE. Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med 1999; 159:38–44. Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ. Total homocysteine concentration and the likelihood of nonfatal stroke: results from the Third National Health and Nutrition Examination Survey, 1988–1994. Stroke 1998; 29:2473–2477. Tanne D, Haim M, Goldbourt U, Boyko V, Doolman R, Adler Y, Brunner D, Behar S, Sela BA. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke 2003; 34:632–636. Boysen G, Brander T, Christensen H, Gideon R, Truelsen T. Homocysteine and risk of recurrent stroke. Stroke 2003; 34:1258–1261. Malinow MR, Nieto FJ, Szklo M, Chambless LE, Bond G. Carotid artery intimal–medial wall thickening and plasma homocysteine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation 1993; 87:1107–1113. The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288:2015–2022. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325:1202. Howard VJ, Sides EG, Newman GC, Cohen SN, Howard G, Malinow MR, Toole JF. Changes in plasma homocysteine in the acute phase after stroke. Stroke 2002; 33:473– 478. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C->4T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002; 288:2023–2031. Toole JF. Vitamin intervention for stroke prevention. J Neurol Sci 2002; 203–204:121–124. Bushnell CD, Goldstein LB. Homocysteine testing in patients with acute ischemic stroke. Neurology 2002; 59:1541–1546. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996; 348:498–505. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA 2000; 284:72–78. Kemmeren JM, Tanis BC, van den Bosch MA, Bollen EL, Helmerhorst FM, van der Graaf Y, Rosendaal FR, Algra A. Risk of Arterial Thrombosis in Relation to Oral Contraceptives

228

146.

147.

148. 149. 150.

151.

152.

153.

154.

155.

156.

157. 158.

159. 160. 161. 162. 163.

164.

Fayad (RATIO) study: oral contraceptives and the risk of ischemic stroke. Stroke 2002; 33:1202– 1208. Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338:1793–1797. Siritho S, Thrift AG, McNeil JJ, You RX, Davis SM, Donnan GA. Risk of ischemic stroke among users of the oral contraceptive pill: The Melbourne Risk Factor Study (MERFS) Group. Stroke 2003; 34:1575–1580. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340:1801–1811. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab 2000; 20:631–652. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med 1985; 313:1038–1043. Falkeborn M, Persson I, Terent A, Adami HO, Lithell H, Bergstrom R. Hormone replacement therapy and the risk of stroke. Follow-up of a population-based cohort in Sweden. Arch Intern Med 1993; 153:1201–1209. Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users. Results from a national cohort. Arch Intern Med 1993; 153:73–79. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335:453–461. Simon JA, Hsia J, Cauley JA, Richards C, Harris F, Fong J, Barrett-Connor E, Hulley SB. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen–Progestin Replacement Study (HERS). Circulation 2001; 103:638–642. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605–613. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49–57. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345:1243–1249. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003; 289:2673–2684. Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. JAMA 2002; 288:366–368. Bailar J. Hormone-replacement therapy and cardiovascular diseases. N Engl J Med 2003; 349:521–522. Herrington DM, Howard TD. From presumed benefit to potential harm—hormone therapy and heart disease. N Engl J Med 2003; 349:519–521. Kuller LH. Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women’s Health Initiative. Arterioscler Thromb Vasc Biol 2003; 23:11–16. Iribarren C, Tekawa IS, Sidney S, Friedman GD. Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men. N Engl J Med 1999; 340:1773–1780. Shaper AG, Wannamethee SG, Walker M. Pipe and cigar smoking and major cardiovascular

Modifiable Risk Factors for Stroke

165. 166.

167.

168.

169. 170. 171.

172. 173.

174.

175. 176. 177.

178.

179. 180. 181.

182.

183. 184. 185.

229

events, cancer incidence and all-cause mortality in middle-aged British men. Int J Epidemiol 2003; 32:802–808. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ 1989; 298:789–794. Kiechl S, Werner P, Egger G, Oberhollenzer F, Mayr M, Xu Q, Poewe W, Willeit J. Active and passive smoking, chronic infections, and the risk of carotid atherosclerosis: prospective results from the Bruneck Study. Stroke 2002; 33:2170–2176. Howard G, Wagenknecht LE, Burke GL, Diez-Roux A, Evans GW, McGovern P, Nieto FJ, Tell GS. Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA 1998; 279:119–124. Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232–236. Wolf PA, D’Agostino RB, Kannel WB, Bonita R, Belanger AJ. Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 1988; 259:1025–1029. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155–160. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996; 334:150–154. Bonita R, Duncan J, Truelsen T, Jackson RT, Beaglehole R. Passive smoking as well as active smoking increases the risk of acute stroke. Tob Control 1999; 8:156–160. Gorelick PB. Stroke prevention: windows of opportunity and failed expectations? A discussion of modifiable cardiovascular risk factors and a prevention proposal. Neuroepidemiology 1997; 16:163–173. Hansagi H, Romelsjo A, Gerhardsson de Verdier M, Andreasson S, Leifman A. Alcohol consumption and stroke mortality. 20-year follow-up of 15,077 men and women. Stroke 1995; 26:1768–1773. Wannamethee SG, Shaper AG. Patterns of alcohol intake and risk of stroke in middle-aged British men. Stroke 1996; 27:1033–1039. Leppala JM, Paunio M, Virtamo J, Fogelholm R, Albanes D, Taylor PR, Heinonen OP. Alcohol consumption and stroke incidence in male smokers. Circulation 1999; 100:1209–1214. Tanaka H, Ueda Y, Hayashi M, Date C, Baba T, Yamashita H, Shoji H, Tanaka Y, Owada K, Detels R. Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community. Stroke 1982; 13:62–73. Stampfer MJ, Colditz GA, Willett WC, Speizer FE, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 1988; 319:267–273. Klatsky AL, Armstrong MA, Friedman GD, Sidney S. Alcohol drinking and risk of hemorrhagic stroke. Neuroepidemiology 2002; 21:115–122. Palomaki H, Kaste M. Regular light-to-moderate intake of alcohol and the risk of ischemic stroke. Is there a beneficial effect? Stroke 1993; 24:1828–1832. Sacco RL, Elkind M, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, Shea S, Paik MC. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281:53–60. Berger K, Ajani UA, Kase CS, Gaziano JM, Buring JE, Glynn RJ, Hennekens CH. Light-tomoderate alcohol consumption and risk of stroke among U.S. male physicians. N Engl J Med 1999; 341:1557–1564. Hillbom M, Numminen H. Alcohol and stroke: pathophysiologic mechanisms. Neuroepidemiology 1998; 17:281–287. Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J. Alcohol consumption and risk of stroke: a meta-analysis. JAMA 2003; 289:579–588. Gorelick PB, Sacco RL, Smith DB, Alberts M, Mustone-Alexander L, Rader D, Ross JL,

230

186. 187.

188. 189.

190.

Fayad Raps E, Ozer MN, Brass LM, Malone ME, Goldberg S, Booss J, Hanley DF, Toole JF, Greengold NL, Rhew DC. Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA 1999; 281:1112–1120. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. Addendum to the supplement to the guidelines for the management of transient ischemic attacks. Stroke 2000; 31:1001. Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB, Hademenos G, Hill M, Howard G, Howard VJ, Jacobs B, Levine SR, Mosca L, Sacco RL, Sherman DG, Wolf PA, del Zoppo GJ. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 2001; 32:280–299. Redfern J, McKevitt C, Dundas R, Rudd AG, Wolfe CD. Behavioral risk factor prevalence and lifestyle change after stroke: a prospective study. Stroke 2000; 31:1877–1881. Mouradian MS, Majumdar SR, Senthilselvan A, Khan K, Shuaib A. How well are hypertension, hyperlipidemia, diabetes, and smoking managed after a stroke or transient ischemic attack? Stroke 2002; 33:1656–1659. Ruland S, Raman R, Chaturvedi S, Leurgans S, Gorelick PB. Awareness, treatment, and control of vascular risk factors in African Americans with stroke. Neurology 2003; 60:64–68.

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

232

Kischka and Wade

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).

Rehabilitation After Stroke

233

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

234

Kischka and Wade

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.

Rehabilitation After Stroke

235

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

236

Kischka and Wade

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

Rehabilitation After Stroke

237

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

238

Kischka and Wade

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

Rehabilitation After Stroke

239

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.

REFERENCES 1. Gresham GE, Alexander D, Bishop DS, Giuliani C, Goldberg G, Holland A, Kelly-Hayes M, Linn RT, Roth EJ, Stason WB, Trombly CA. American Heart Association Prevention Conference. Rehabilitation. Stroke 1997; 28:1522–1526. Website: http://stroke.ahajournals.org/ cgi/content/full/28/7/1522. 2. Intercollegiate Working Party for Stroke. National Clinical Guidelines for Stroke, London: Royal College of Physicians, 2000. 3. Committee on Stroke Units of the Deutsche Gesellschaft fu¨r Neurologie (eds). Guidelines for the implementation of stroke units. Nervenarzt 2000; 72:317–319. 4. Wood P. International Classification of Impairments, Disabilities and Handicaps: A Manual of Classification Relating to the Consequences of Disease. Geneva: World Health Organization, 1980. 5. Badley EM. An introduction to the concepts and classifications of the International Classification of Impairments, Disabilities and Handicaps. Disabil Rehabil 1993; 15:161–178. 6. ICIDH-2: International Classification of Functioning and Disability. Beta-2 draft. Geneva: World Health Organisation, 1999. 7. Wade DT, De Jong BA. Recent advances in rehabilitation. Br Med J 2000; 320:1385–1388. 8. Wade DT. Measurement in Neurological Rehabilitation. Oxford: Oxford University Press, 1992. 9. Brott T, Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1992; 23:864–870. 10. Demeurisse G, Demol O, Robaye E. Motor evaluation in vascular hemiplegia. Eur Neurol 1980; 19:382–389. 11. Collin FM. Wade DT Assessing motor impairment after stroke: a pilot reliability study. J Neurol Neurosurg Psychiatry 1990; 53:576–579. 12. Halligan PW, Marshall JC, Wade DT. Visuospatial neglect: underlying factors and test sensitivity. Lancet 1989; 2:908–910.

240

Kischka and Wade

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.

Rehabilitation After Stroke

241

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

244

Jones and Tranel

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

Cognitive Impairments After Stroke

245

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

246

Jones and Tranel

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.

Cognitive Impairments After Stroke

247

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

248

Jones and Tranel

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

Cognitive Impairments After Stroke

249

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.

250

Jones and Tranel

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

Cognitive Impairments After Stroke

251

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

252

Jones and Tranel

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).

Cognitive Impairments After Stroke

253

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

254

Jones and Tranel

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

Cognitive Impairments After Stroke

255

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

256

Jones and Tranel

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

Cognitive Impairments After Stroke

257

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.

258

Jones and Tranel

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.

Cognitive Impairments After Stroke

259

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

262

Robinson and Jorge

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

Neuropsychiatric Disorders Following Stroke

263

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

264

Robinson and Jorge

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

Neuropsychiatric Disorders Following Stroke

265

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.

266

Robinson and Jorge

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].

Neuropsychiatric Disorders Following Stroke

267

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.)

268

Robinson and Jorge

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

Neuropsychiatric Disorders Following Stroke

269

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.)

270

Robinson and Jorge

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.

Neuropsychiatric Disorders Following Stroke

271

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.

272

Robinson and Jorge

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.)

Neuropsychiatric Disorders Following Stroke

273

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.)

274

Robinson and Jorge

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).

Neuropsychiatric Disorders Following Stroke

275

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

276

Robinson and Jorge

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.)

Neuropsychiatric Disorders Following Stroke

277

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

278

Robinson and Jorge

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.

Neuropsychiatric Disorders Following Stroke

279

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.

280

Robinson and Jorge

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.

Neuropsychiatric Disorders Following Stroke

281

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.

282

Robinson and Jorge

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

284

Davis

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.

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

285

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.

286

Davis

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

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

287

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

288

Davis

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

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

289

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

290

Davis

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

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

291

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

292

Davis

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

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

293

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

294

Davis

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.

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

295

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

296

Davis

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

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

297

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.

REFERENCES 1. Sacco RL. Extracranial carotid stenosis. N Engl J Med 2001; 345:1113–1118. 2. Biller J, Feinberg WM, Castaldo JE, Whittemore AD, Harbaugh RE, Dempsey RJ, Caplan LR, Kresowik TF, Matchar DB, Toole JF, Easton JD, Adams HP Jr, Brass LM, Hobson RW II, Brott TG, Sternau L. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation 1998; 97:501–509. 3. Perry JR, Szalai JP, Norris JW. Consensus against both endarterectomy and routine screening for asymptomatic carotid artery stenosis. Canadian Stroke Consortium. Arch Neurol 1997; 54:25–28. 4. Nicolaides AN. Asymptomatic carotid stenosis and risk of stroke. Identification of a high risk group (ACSRS). A natural history study. Int Angiol 1995; 14:21–23. 5. Heyman A, Wilkinson WE, Heyden S, Helms MJ, Bartel AG, Karp HR, Tyroler HA, Hames CG. Risk of stroke in asymptomatic persons with cervical arterial bruits: a population study in Evans County, Georgia. N Engl J Med 1980; 302:838–841.

298

Davis

6. Wolf PA, Kannel WB, Sorlie P, McNamara P. Asymptomatic carotid bruit and risk of stroke. The Framingham Study. JAMA 1981; 245:1442–1445. 7. Sandok BA, Whisnant JP, Furlan AJ, Mickell JL. Carotid artery bruits: prevalence survey and differential diagnosis. Mayo Clin Proc 1982; 57:227–230. 8. Shorr RI, Johnson KC, Wan JY, Sutton-Tyrrell K, Pahor M, Bailey JE, Applegate WB. The prognostic significance of asymptomatic carotid bruits in the elderly. J Gen Intern Med 1998; 13:86–90. 9. Sauve JS, Laupacis A, Ostbye T, Feagan B, Sackett DL. Does this patient have a clinically important carotid bruit? JAMA 1993; 270:2843–2845. 10. Sauve JS, Thorpe KE, Sackett DL, Taylor W, Barnett HJ, Haynes RB, Fox AJ. Can bruits distinguish high-grade from moderate symptomatic carotid stenosis? The North American Symptomatic Carotid Endarterectomy Trial. Ann Intern Med 1994; 120:633–637. 11. Davies KN, Humphrey PR. Do carotid bruits predict disease of the internal carotid arteries? Postgrad Med J 1994; 70:433–435. 12. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med 1986; 315:860–865. 13. Hennerici M, Hulsbomer HB, Hefter H, Lammerts D, Rautenberg W. Natural history of asymptomatic extracranial arterial disease: results of a long term prospective study. Brain 1987; 110:777–791. 14. Mackey AE, Abrahamowicz M, Langlois Y, Battista R, Simard D, Bourque F, Leclerc J, Cote R. Outcome of asymptomatic patients with carotid disease. Asymptomatic Cervical Bruit Study Group. Neurology 1997; 48:896–903. 15. Van Ruiswyk J, Noble H, Sigmann P. The natural history of carotid bruits in elderly persons. Ann Intern Med 1990; 112:340–343. 16. O’Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond G, Wolfson SK, Bommer W, Price TR, Gardin JM, Savage PJ, CHS Collaborative Research Group. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. Stroke 1992; 23:1752–1760. 17. Longstreth WT Jr, Shemanski L, Lefkowitz D, O’Leary DH, Polak JF, Wolfson SK Jr. Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly. The Cardiovascular Health Study. Stroke 1998; 29:2371–2376. 18. Fine-Edelstein JS, Wolf PA, O’Leary DH, Poehlman H, Belanger AJ, Kase CS, D’Agostino RB. Precursors of extracranial carotid atherosclerosis in the Framingham Study. Neurology 1994; 44:1046–1050. 19. Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PWF, Belanger AJ, O’Leary DH, Wolf PA, Schaeffer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332:286–291. 20. Mineva PP, Manchev IC, Hadjiev DI. Prevalence and outcome of asymptomatic carotid stenosis: a population-based ultrasonographic study. Eur J Neurol 2002; 9:383–388. 21. Kuller LH, Sutton-Tyrell K. Aging and cardiovascular disease. Cardiol Clin 1999; 17:51–65. 22. Norris JW, Zhu CZ, Bornstein NM, Chambers BR. Vascular risks of asymptomatic carotid stenosis. Stroke 1991; 22:1485–1490. 23. Nadareishvili ZG, Rothwell PM, Beletsky V, Pagniello A, Norris JW. Long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis. Arch Neurol 2002; 59:1162–1166. 24. Inzitari D, Eliasziw M, Gates P, Sharpe BL, Chan RKT, Meldrum HE, Barnett HJM. The North American Symptomatic Carotid Endarterectomy Trial Collaborators. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. N Engl J Med 2000; 342:1693–1701. 25. The European Carotid Surgery Trialists Collaborative Group. Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 1995; 345:209–212. 26. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421–1428.

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

299

27. The CASANOVA Study Group. Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke 1991; 22:1229–1235. 28. Sleight SP, Poloniecki J, Halliday AW. Asymptomatic carotid surgery trial. Asymptomatic carotid stenosis in patients on medical treatment alone. Eur J Vasc Endovasc Surg 2002; 23:519–523. 29. Powers WJ, Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, Grubb RL Jr. Benign prognosis of never-symptomatic carotid occlusion. Neurology 2000; 54:878–882. 30. Barnett HJ, Gunton RW, Eliasziw M, Fleming L, Sharpe B, Gates P, Meldrum H. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA 2000; 283:1429–1436. 31. Castaldo JE, Nelson JJ, Reed JF, Longnecker JE, Toole JF. The delay in reporting symptoms of carotid artery stenosis in an at-risk population. Arch Neurol 1997; 54:1267–1271. 32. Norris JW, Zhu CZ. Stroke risk and critical carotid stenosis. J Neurol Neurosurg Psychiatry 1990; 53:235–237. 33. Norris JW, Zhu CZ. Silent stroke and carotid stenosis. Stroke 1992; 23:483–485. 34. Lewis RF, Abrahamowicz M, Cote R, Battista RN. Predictive power of duplex ultrasonography in asymptomatic carotid disease. Ann Intern Med 1997; 127:13–20. 35. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation 2002; 106:3143. 36. Whitty CJM, Sudlow CLM, Warlow CP. Investigating individual subjects and screening populations for asymptomatic carotid stenosis can be harmful. J Neurol Neurosurg Psychiatry 1998; 64:619–623. 37. Clase CM, Cina CS. Medical management versus investigate-and-operate strategy in asymptomatic carotid stenosis: a decision analysis. J Vasc Surg 2002; 36:541–548. 38. Schulte-Altedorneburg G, Droste DW, Felszeghy S, Kellermann M, Popa V, Hegedus K, Hegedus C, Schmid M, Modis L, Ringelstein EB, Csiba L. Accuracy of in vivo carotid B-mode ultrasound compared with pathological analysis. Stroke 2001; 32:1520–1524. 39. Riley WA, Barnes RW, Applegate WB, Dempsey R, Hartwell T, Davis VG, Bond MG, Furberg CD. Reproducibility of noninvasive ultrasonic measurement of carotid artherosclerosis. The Asymptomatic Carotid Artery Plaque Study. Stroke 1992; 23:1062–1068. 40. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age. Circulation 2001; 104:2815–2819. 41. Malinow MR, Nieto FJ, Szklo M, Chambless LE, Bond G. Carotid artery intimal-medial wall thickening and plasma homocysteine in asymptomatic adults. Circulation 1993; 87:1107– 1113. 42. Stevens J, Tyroler HA, Cai J, Paton CC, Folsom AR, Tell GS, Schreiner PJ, Chambless LE. Body weight change and carotid artery wall thickness. The Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 1998; 147:563–573. 43. Chambless LE, Folsom AR, Davis V, Sharrett R, Heiss G, Sorlie P, Szklo M, Howard G, Evans GW. Risk factors for progression of common carotid atherosclerosis: the Atherosclerosis Risk in Communities Study, 1987–1998. Am J Epidemiol 2002; 55:38–47. 44. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfeson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340:14–22. 45. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, Clegg LX. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: The Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997; 146:483–494. 46. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction. The Rotterdam Study. Circulation 1997; 96:1432–1437.

300

Davis

47. Salonen JT, Salonen R. Ultrasound B-mode imaging in observational studies of artherosclerotic progression. Circulation 1993; 87(suppl II):56–65. 48. Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, Rosamond WD, Evans G. Carotid wall thickness is predictive of incident clinical stroke. Am J Epidemiol 2000; 151:478–487. 49. Touboul PJ, Elbaz A, Koller C, Lucas C, Adrai V, Chedru F, Amarenco P. Common carotid artery intima-media thickness and brain infarction. Circulation 2000; 102:313–318. 50. Davis PH, Dawson JD, Mahoney LT, Lauer RM. Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults: the Muscatine Study. Circulation 1999; 100:838–842. 51. Oei HH, Vliegenthart R, Hak AE, Iglesias dS, Hofman A, Oudkerk M, Witteman JC. The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study. J Am Coll Cardiol 2002; 39:1745–1751. 52. Zheng ZJ, Sharrett AR, Chambless LE, Rosamond WD, Nieto FJ, Sheps DS, Dobs A, Evans GW, Heiss G. Association of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis. Atherosclerosis 1997; 131:115–125. 53. Bots ML, Hofman A, Grobbe DE. Common carotid intima-media thickness and lower extremity arterial atherosclerosis. Arterioscler Thromb 1994; 14:1885–1891. 54. Mukherjee D, Yadav JS. Carotid artery intimal-medial thickness: indicator of atherosclerotic burden and response to risk factor modification. Am Heart J 2002; 144:753–759. 55. Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probtsfield J, Riley WA, Young B. Effect of lovastatin on early carotid artherosclerosis and cardiovascular events. Circulation 1994; 90:1679–1687. 56. Crouse JR III, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol 1995; 75:455–459. 57. Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Salonen JT. Koupio Atherosclerosis Prevention Study (KAPS): a population-based primary prevention trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995; 92:1758–1764. 58. Mack WJ, Selzer RH, Hodis HN, Erickson JK, Liu CR, Liu CH, Crawford DW, Blankenhorn DH. One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy. Stroke 1993; 24:1779–1783. 59. Lonn EM, Yusuf S, Dzavik V, Doris CI, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley WA, Teo KK. Effects of ramipril and vitamin E on atherosclerosis. Circulation 2001; 103:919–925. 60. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness. Circulation 2001; 103:1721– 1726. 61. Zanchetti A, Bond MG, Hennig M, Neiss A, Mancia G, Dal Palu C, Hansson L, Magnani B, Rahn KH, Reid JL, Rodicio J, Safar M, Eckes L, Rizzini Pon, on behalf of the ELSA investigators. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation 2002; 106:2422–2427. 62. Greenland PG, Abrams J, Aurigemma GP, Bond MG, Clark LT, Criqui MH, Crouse JR III, Friedman L, Fuster V, Herrington D, Kuller LH, Ridker PM, Roberts WC, Standford W, Stone N, Swan J, Taubert KA. Prevention Conference V: Beyond secondary prevention: identifying the high-risk patient for primary prevention. Noninvasive tests of atherosclerotic burden. Circulation 2000; 101:e16–e22. 63. Lonn E. Use of carotid ultrasound to stratify risk. Can J Cardiol 2001; 17:22A–25A. 64. Stamou SC, Hill PC, Dangas G, Pfister AJ, Boyce SW, Dullum MKC, Bafi AS, Corso PJ, Silver B. Stroke after coronary artery bypass: incidence, predictors, and clinical outcome. Stroke 2001; 32:1508–1513.

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

301

65. Naylor AR, Mehta Z, Rothwell PM, Bell PR. Carotid artery disease and stroke during coronary artery bypass: a critical review of the literature. Eur J Vasc Endovasc Surg 2002; 23:283–294. 66. McKhann GM, Grega MA, Borowicz LM Jr, Bechamps M, Selnes OA, Baumgartner WA, Royall RM. Encephalopathy and stroke after coronary artery bypass grafting: incidence, consequences, and prediction. Arch Neurol 2002; 59:1422–1428. 67. Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C, Ozanne G, Mangano D. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 1996; 335:1857–1863. 68. Goto T, Baba T, Yoshitake A, Shibata Y, Ura M, Sakata R. Craniocervical and aortic atherosclerosis as neurologic risk factors in coronary artery bypass patients. Ann Thorac Surg 2000; 69:834–840. 69. Brown KR, Kresowik TF, Chin MH, Kresowik RA, Grund SL, Hendel ME. Multistate population-based outcomes of combined carotid endarterectomy and coronary artery bypass. J Vasc Surg 2003; 37:32–39. 70. Ropper AH, Wechsler LR, Wilson LS. Carotid bruit and the risk of stroke in elective surgery. N Engl J Med 1982; 307:1388–1390. 71. Evans BA, Wijdicks EFM. High-grade carotid stenosis detected before general surgery: Is endarterectomy indicated? Neurology 2001; 57:1328–1330. 72. von Kemp K, van den BP, Peterson T, Waegeneers S, Scheerlinck T, Danau W, van Tussenbroek F, Debing E, Staelens I. Screening for concomitant diseases in peripheral vascular patients. Results of a systematic approach. Int Angiol 1997; 16:114–122. 73. Marek J, Mills JL, Harvich J, Cui H, Fujitani RM. Utility of routine carotid duplex screening in patients who have claudication. J Vasc Surg 1996; 24:572–577. 74. Pilcher JM, Danaher J, Khaw KT. The prevalence of asymptomatic carotid artery disease in patients with peripheral vascular disease. Clin Radiol 2000; 55:56–61. 75. Cina CS, Safar HA, Maggisano R, Bailey R, Clase CM. Prevalence and progression of internal carotid artery stenosis in patients with peripheral arterial occlusive disease. J Vasc Surg 2002; 36:75–82. 76. Ogren M, Hedblad B, Isacsson S, Janzon L, Jungquist G, Lindell S. Ten year cerebrovascular morbidity and mortality in 68 year old men with asymptomatic carotid stenosis. BMJ 1995; 310:1–8. 77. Haynes JC, Machtay M, Weber RS, Weinstein GS, Chalian AA, Rosenthal DI. Relative risk of stroke in head and neck carcinoma patients treated with external cervical irradiation. Laryngoscope 2002; 112:1883–1887. 78. Carmody BJ, Arora S, Avena R, Curry KM, Simpkins J, Cosby K, Sidawy AN. Accelerated carotid artery disease after high-dose head and neck radiotherapy: is there a role for routine carotid duplex surveillance? J Vasc Surg 1999; 30:1045–1051. 79. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103:1813–1818. 80. Rerkasem K, Shearman CP, Williams JA, Morris GE, Phillips MJ, Calder PC, Grimble RF. C-reactive protein is elevated in symptomatic compared with asymptomatic patients with carotid artery disease. Eur J Vasc Endovasc Surg 2002; 23:505–509. 81. Cote R, Wolfson C, Solymoss S, Mackey A, Leclerc JR, Simard D, Rouah F, Bourque F, Leger B. Hemostatic markers in patients at risk of cerebral ischemia. Stroke 2000; 31:1856– 1862. 82. Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke 1999; 30:1440–1443. 83. Silvestrini M, Vernieri F, Pasqualetti P, Matteis M, Passarelli F, Troisi E, Caltagirone C. Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA 2000; 283:2122–2127. 84. Markus H, Cullinane M. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001; 124:3–67.

302

Davis

85. AbuRahma AF, Wulu JT Jr, Crotty B. Carotid plaque ultrasonic heterogeneity and severity of stenosis. Stroke 2002; 33:1772–1775. 86. Gronholdt ML, Nordestgaard BG, Schroeder TV, Vorstrup S, Sillesen H. Ultrasonic echolucent carotid plaques predict future strokes. Circulation 2001; 104:68–73. 87. Hunt KJ, Evans GW, Folsom AR, Sharrett AR, Chambless LE, Tegeler CH, Heiss G. Acoustic shadowing on B-mode ultrasound of the carotid artery predicts ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2001; 32:1120–1126. 88. Cai JM, Hatsukami TS, Ferguson MS, Small R, Polissar NL, Yuan C. Classification of human carotid atherosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation 2002; 106:1368–1373. 89. Yuan C, Zhang S, Polissar NL, Echelard D, Ortiz G, Davis JW, Ellington E, Ferguson MS, Hatsukami TS. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. Circulation 2002; 105:181–185. 90. Bruno A, Jones WL, Austin JK, Carter S, Qualls C. Vascular outcome in men with asymptomatic retinal cholesterol emboli. Ann Intern Med 1995; 122:249–253. 91. Long A, Lepoutre A, Corbillon E, Branchereau A. Critical review of non- or minimally invasive methods (duplex ultrasonography, MR- and CT-angiography) for evaluating stenosis of the proximal internal carotid artery. Eur J Vasc Endovasc Surg 2002; 24:43–52. 92. Moneta GL, Edwards JM, Papanicolaou G, Hatsukami T, Taylor LM Jr, Strandness DE Jr, Porter JM. Screening for asymptomatic internal carotid artery stenosis: duplex criteria for discriminating 60% to 99% stenosis. J Vasc Surg 1995; 21:989–994. 93. Howard G, Baker WH, Chambless LE, Howard VJ, Jones AM, Toole JF, ACAS Investigators. An approach for the use of Doppler ultrasound as a screening tool for hemodynamically significant stenosis (despite heterogeneity of Doppler performance). Stroke 1996; 27:1951–1957. 94. Nederkoorn PJ, Mali WPT, Eikelboom BC, Elgersma OEH, Buskens E, Hunink MGM, Kappelle LJ, Buijs PC, Wust AFJ, van der Lugt A, van der Graaf Y. Preoperative diagnosis of carotid artery stenosis: accuracy of noninvasive testing. Stroke 2002; 33:2003–2008. 95. Johnston DCC, Eastwood JD, Nguyen T, Goldstein LB. Contrast-enhanced magnetic resonance angiography of carotid arteries: utility in routine clinical practice. Stroke 2002; 33: 2834–2838. 96. Patel SG, Collie DA, Wardlaw JM, Lewis SC, Wright AR, Gibson RJ, Sellar RJ. Outcome, observer reliability, and patient preferences if CTA, MRA, or Doppler ultrasound were used, individually or together, instead of digital subtraction angiography before carotid endarterectomy. J Neurol Neurosurg Psychiatry 2002; 73:21–28. 97. Johnston DCC, Goldstein LB. Clinical carotid endarterectomy decision making: Noninvasive vascular imaging versus angiography. Neurology 2001; 56:1009–1015. 98. Yucel EK, Anderson CM, Edelman RR, Grist TM, Baum RA, Manning WJ, Culebras A, Pearce W. Magnetic resonance angiography: update on applications for extracranial arteries. Circulation 1999; 100:2284–2301. 99. Chimowitz MI, Weiss DG, Cohen SL, Starling MR, Hobson RW. Cardiac prognosis of patients with carotid stenosis and no history of coronary artery disease. Veterans Affairs Cooperative Study Group. Stroke 1994; 25:759–765. 100. Gates PC, Eliasziw M, Algra A, Barnett HJM, Gunton RW. Identifying patients with symptomatic carotid artery disease at high and low risk of severe myocardial infarction and cardiac death. Stroke 2002; 33:2413–2416. 101. Markus RA, Mack WJ, Azen SP, Hodis HN. Influence of lifestyle modification on atherosclerotic progression determined by ultrasonographic change in the common carotid intima-media thickness. Am J Clin Nutr 1997; 65:1000–1004. 102. Cortellaro M, Cofrancesco E, Arbustini E, Rossi F, Negri A, Tremoli E, Gabrielli L, Camera M. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemostasis 2002; 88(1):41–47. 103. Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GBJ, Miller ME, Riley W. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000; 102:1503–1510.

Evaluation and Treatment of Asymptomatic Carotid Artery Disease

303

104. Cote R, Battista RN, Abrahamowicz M, Langlois Y, Bourque F, Mackey A, Asymptomatic Cervical Bruit Study Group. Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing. Ann Intern Med 1995; 123:649–655. 105. Results of a randomized controlled trial of carotid endarterectomy for asymptomatic carotid stenosis. Mayo Asymptomatic Carotid Endarterectomy Study Group. Mayo Clin Proc 1992; 67:513–518. 106. Hobson RW, Weiss DG, Fields WS, Goldstone J, Moore WS, Towne JB, Wright CB, Veterans Affair Cooperative Study Group. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 1993; 328:221–227. 107. Chambers BR, You RX, Donnan GA. Carotid endarterectomy for asymptomatic stenosis. Cochrane Database of Systematic Reviews 2002; 4. 108. Lanska DJ, Kryscio RJ. Endarterectomy for asymptomatic internal carotid artery stenosis. Neurology 1997; 48:1481–1490. 109. Benavente O, Moher D, Pham B. Carotid endarterectomy for asymptomatic carotid stenosis: a meta-analysis. BMJ 1998; 317:1477–1480. 110. Barnett HJM, Eliasziw M, Meldrum HE. Evidence based cardiology: prevention of ischaemic stroke. BMJ 1999; 318:1539–1543. 111. Baker WH, Howard VJ, Howard G, Toole JF, for the ACAS Investigators. Effect of contralateral occlusion on long-term efficacy of endarterectomy in the Asymptomatic Carotid Atherosclerosis Study (ACAS). Stroke 2000; 31:2330–2334. 112. Pettigrew LC, Thomas N, Howard VJ, Veltkamp R, Toole JF. Low mini-mental status predicts mortality in asymptomatic carotid arterial stenosis. Neurology 2000; 55:30–34. 113. Feasby TE, Quan H, Ghali WA. Hospital and surgeon determinants of carotid endarterectomy outcomes. Arch Neurol 2002; 59:1877–1881. 114. Cebul RD, Snow RJ, Pine R, Hertzer NR, Norris DG. Indications, outcomes, and provider volumes for carotid endarterectomy. JAMA 1998; 279:1282–1287. 115. Goldstein LB, Samsa GP, Matchar DB, Oddone EZ. Multicenter review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis. Stroke 1998; 29:750– 753. 116. Findlay JM, Nykolyn L, Lubkey TB, Wong JH, Mouradian M, Senthilselvan A. Auditing carotid endarterectomy: a regional experience. Can J Neurol Sci 2002; 29:326–332. 117. Warlow C. Carotid endarterectomy for asymptomatic carotid stenosis. Better data, but the case is still not convincing. BMJ 1998; 317:1468. 118. Chaturvedi S, Meinke JL, St Pierre E, Bertasio B. Attitudes of Canadian and US neurologists regarding carotid endarterectomy for asymptomatic stenosis. Can J Neurol Sci 2000; 27:116– 119. 119. Irvine CD, Baird RN, Lamont PM, Davies AH. Endarterectomy for asymptomatic carotid artery stenosis. BMJ 1995; 311:1113–1114. 120. Chaturvedi S, Halliday A. Is another clinical trial warranted regarding endarterectomy for asymptomatic carotid stenosis? Cerebrovasc Dis 1998; 8:210–213. 121. Barnett HJ. Decision-making for carotid endarterectomy. The trials are only the start. Can J Neurol Sci 2002; 29:302–304. 122. Barnett HJM, Eliasziw M, Meldrum HE, Taylor DW. Do the facts and figures warrant a 10fold increase in the performance of carotid endarterectomy on asymptomatic patients? Neurology 1996; 46:603–608. 123. Barnett HJM, Broderick JP. Carotid endarterectomy: another wake-up call. Neurology 2000; 55:746–747. 124. Brott T, Toole JF. Medical compared with surgical treatment of asymptomatic carotid artery stenosis. Ann Intern Med 1995; 123:720–722. 125. Castaldo JE. Is carotid endarterectomy appropriate for asymptomatic stenosis? Yes. Arch Neurol 1999; 56:877–879. 126. Findlay M, Tucker WS, Ferguson GG, Holness RO, Wallace MC, Wong JH. Guidelines for the use of carotid endarterectomy: current recommendations from the Canadian Neurosurgical Society. CMAJ 1997; 157:653–659.

304

Davis

127. Hart RG, Bailey RD. An assessment of guidelines for the prevention of ischemic stroke. Neurology 2002; 59:977–982. 128. Huber TS, Wheeler KG, Cuddeback JK, Dame DA, Flynn TC, Seeger JM. Effect of the Asymptomatic Carotid Atherosclerosis Study on carotid endarterectomy in Florida. Stroke 1998; 29:1099–1105. 129. Sarasin FP, Bounameaux H, Bogousslavsky J. Asymptomatic severe carotid stenosis: immediate surgery or watchful waiting? A decision analysis. Neurology 1995; 45:2147–2153. 130. Wholey MH, Wholey M, Mathias K, Roubin GS, Diethrich EB, Henry M, Bailey S, Bergeron P, Dorros G, Eles G, Gaines P, Gomez CR, Gray B, Guimaraens J, Higashida R, Ho DS, Katzen B, Kambara A, Kumar V, Laborde JC, Leon M, Lim M, Londero H, Mesa J, Musacchio A, Myla S, Ramee S, Rodriquez A, Rosenfield K, Sakai N, Shawl F, Sievert H, Teitelbaum G, Theron JG, Vaclav P, Vozzi C, Yadav JS, Yoshimura SI. Global experience in cervical carotid artery stent placement. Cath Cardiovasc Intervent 2000; 50:160–167. 131. Roubin GS, New G, Iyer SS, Vitek JJ, Al Mubarak N, Liu MW, Yadav J, Gomez C, Kuntz RE. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001; 103:532–537. 132. Yadov JS for the SAPPHIRE Investigators. Stenting and angioplasty with protection in patients at high risk for endarterectomy: The SAPPHIRE study. Circulation 2002; 106:2897a. 133. Brott TG. Angioplasty and stenting should be performed only in the setting of a clinical trial. Stroke 2002; 33:2519–2520. 134. Bettmann MA, Katzen BT, Whisnant J, Brant-Zawadzki M, Broderick JP, Furlan AJ, Hershey LA, Howard V, Kuntz R, Loftus CM, Pearce W, Roberts A, Roubin G. Carotid stenting and angioplasty: a statement for healthcare professionals from the Councils on Cardiovascular Radiology, Stroke, Cardio-thoracic and Vascular Surgery, Epidemiology and Prevention, and Clinical Cardiology, American Heart Association. Circulation 1998; 97:121– 123. 135. Davis SM, Donnan GA. Carotid stenting is unproven: randomization is a must. Stroke 2002; 33:2522–2523. 136. Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE, Simard D, Silver FL, Hachinski V, Clagett GP, Barnes R, Spence JD. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet 1999; 353:2179–2184. 137. Rothwell PM, Slattery J, Warlow CP. A systematic comparison of the risks of stroke and death due to carotid endarterectomy for symptomatic and asymptomatic stenosis. Stroke 1996; 27:266–269. 138. Kresowik TF, Bratzler D, Karp HR, Hemann RA, Hendel ME, Grund SL, Brenton M, Ellerbeck EF, Nilasena DS. Multistate utilization, processes, and outcomes of carotid endarterectomy. J Vasc Surg 2001; 33:227–234. 139. Karp HR, Flanders WD, Shipp CC, Taylor B, Martin D. Carotid endarterectomy among Medicare beneficiaries: a statewide evaluation of appropriateness and outcome. Stroke 1998; 29:46–52. 140. Bratzler DW, Oehlert WH, Murray CK, Bumpus LJ, Moore LL, Piatt DS. Carotid endarterectomy in Oklahoma Medicare beneficiaries: patient characteristics and outcomes. J Ok State Med Assoc 1996; 89:423–429. 141. Kucey DS, Bowyer B, Iron K, Austin P, Anderson G, Tu JV. Determinants of outcome after carotid endarterectomy. J Vasc Surg 1998; 28:1051–1058.

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

306

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

307

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].

308

Adams

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.

Antithrombotic Therapies for Prevention of Ischemic Stroke

309

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

310

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

311

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

Adams

Antithrombotic Therapies for Prevention of Ischemic Stroke

313

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-

314

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

315

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

316

Adams

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.

Antithrombotic Therapies for Prevention of Ischemic Stroke

317

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

318

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

319

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).

320

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

321

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-

322

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

323

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

324

Adams

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.

Antithrombotic Therapies for Prevention of Ischemic Stroke

325

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

326

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

327

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].

328

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

329

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

330

Adams

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-

Antithrombotic Therapies for Prevention of Ischemic Stroke

331

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

332

Adams

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

Antithrombotic Therapies for Prevention of Ischemic Stroke

333

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

334

Adams

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.

REFERENCES 1. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155–160. 2. Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356:359–365. 3. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353:611–616. 4. 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; 278:313– 321. 5. Crouse JR, Byington RP, Furberg CD. HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. Atherosclerosis 1998; 138:11–24. 6. Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999; 30:1969–1973. 7. Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. Stroke, statins, and cholesterol. Stroke 1997; 28:946–950. 8. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1026–1027. 9. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:145– 153. 10. Lindholm LH, Ibsen H, Beevers G, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359:1004–1010. 11. Dahlo¨f B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Lasartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:995–1003. 12. Enseleit F, Hurlimann D, Luscher TF. Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events. J Cardiovasc Pharmacol 2001; 37:S21– S30. 13. Leys D, Deplanque D, Mounier-Vehier C, Mackowiak-Cordoliani MA, Lucas C, Bordet R. Stroke prevention: management of modifiable vascular risk factors. J Neurol 2002; 249:507– 517. 14. Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000; 152:897–907.

Antithrombotic Therapies for Prevention of Ischemic Stroke

335

15. Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 2001; 86:3574–3578. 16. Kareinen A, Viitanen L, Halonen P, Lehto S, Laakso M. Cardiovascular risk factors associated with insulin resistance cluster in families with early-onset coronary heart disease. Arterioscler Thromb Vasc Biol 2001; 21:1346–1352. 17. Hevener AL, Reichart D, Janez A, Olefsky J. Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male wistar rats. Diabetes 2001; 50:2316–2322. 18. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284:2901–2906. 19. Norris JW. Risk of cerebral infarction, myocardial infarction and vascular death in patients with asymptomatic carotid disease, transient ischemic attack and stroke. Cerebrovasc Dis 1992; 2(suppl):2–5. 20. Chamorro A. Heparin in acute ischemic stroke: the case for a new clinical trial. Cerebrovasc Dis 1999; 9(suppl 3):16–23. 21. Castellanos M, Castillo J, Leira R, Serena J, Chamorro A, Da´valos A. Inflammationmediated damage in progressing lacunar infarctions: a potential therapeutic target. Stroke 2002; 33:982–987. 22. Chamorro A, Cervera A, Castillo J, Davalos A, Aponte JJ, Planas AM. Unfractionated heparin is associated with a lower rise of serum vascular cell adhesion molecule-1 in acute ischemic stroke patients. Neurosci Lett 2002; 328:232–299. 23. Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant therapy: heparin. Circulation 2001; 103:2994–3018. 24. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119:64S–94S. 25. Fareed J, Callas D, Hoppensteadt DA, Walenga JM, Bick RL. Antithrombin agents as anticoagulants and antithrombotics. Implications in drug development. Med Clin North Am 1998; 82:569–586. 26. Green D, Hirsh J, Heit J, Prins M, Davidson B, Lensing AW. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev 1994; 46:89–109. 27. Turpie AG, Gent M, Cote R, et al. A low-molecular-weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. A randomized, double-blind study. Ann Intern Med 1992; 117:353– 357. 28. Adams HP Jr. Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke 2002; 33:856–861. 29. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Frequency of major complications of aspirin, warfarin, and intravenous heparin for secondary stroke prevention. Ann Intern Med 1999; 130:14–22. 30. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114:511S–523S. 31. Becker RC, Ansell J. Antithrombotic therapy. An abbreviated reference for clinicians. Arch Intern Med 1995; 155:149–161. 32. Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a ‘‘standard care’’ nomogram. A randomized controlled trial. Ann Intern Med 1993; 119:874–881. 33. Toth C, Voll C. Validation of a weight-based nomogram for the use of intravenous heparin in transient ischemic attack or stroke. Stroke 2002; 33:670–674. 34. Ramirez-Lassepas M, Cipolle RJ, Rodvold KA, et al. Heparin induced thrombocytopenia in patients with cerebrovascular ischemic disease. Neurology 1986; 34:736–740. 35. Atkinson JL, Sundt TMJ, Kazmier FJ, Bowie EJ, Whisnant JP. Heparin-induced thrombocytopenia and thrombosis in ischemic stroke. Mayo Clin Proc 1988; 63:353–361. 36. Kappers-Klunne MC, Boon DM, Hop WC, et al. Heparin-induced thrombocytopenia and

336

37.

38. 39. 40.

41.

42.

43. 44. 45.

46.

47. 48. 49.

50. 51. 52.

53. 54. 55. 56. 57. 58.

Adams thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases. Br J Haematol 1997; 96:442–446. Boon DM, Michiels JJ, Tanghe HL, Kappers-Klunne MC. Heparin-induced thrombocytopenia with multiple cerebral infarctions simulating thrombotic thrombocytopenic purpura. A case report. Angiology 1996; 47:407–411. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344:1286–1292. Bergqvist D. Low molecular weight heparins. J Intern Med 1996; 240:63–72. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330–1335. Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127:804–812. Sallah S, Thomas DP, Roberts HR. Warfarin and heparin-induced skin necrosis and the purple toe syndrome: infrequent complications of anticoagulant treatment. Thromb Haemost 1997; 78:785–790. Putnam S, Adams HP Jr. Heparin in the early treatment of the patient with transient ischemic attacks. Arch Neurol 1985; 42:960–962. Biller J, Bruno A, Adams HP Jr, et al. A randomized trial of aspirin or heparin in hospitalized patients with recent transient ischemic attacks. A pilot study. Stroke 1989; 20:441–447. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349:1581. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998; 279:1265–1272. Chamorro A, Vila N, Saiz A, Alday M, Tolosa E. Early anticoagulation after large cerebral embolic infarction: a safety study. Neurology 1995; 45:861–865. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet 2001; 358:683–684. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355:1205–1210. Sandercock P. Is there still a role for intravenous heparin in acute stroke? No. Arch Neurol 1999; 56:1160–1161. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001; 119:300S–320S. Coull BM, Williams LS, Goldstein LB, et al. Anticoagulants and antiplatelet agents in acute ischemic stroke. Report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Neurology 2002; 59:13–22. Moonis M, Fisher M. Considering the role of heparin and low-molecular-weight heparins in acute ischemic stroke. Stroke 2002; 33:1927–1933. Counsell C, Sandercock P. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischemic stroke (Cochrane review). Stroke 2002; 33:1925–1926. Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1998; 114:524S– 530S. Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90:1522–1536. Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001; 119:95S–107S. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114:445S–469S.

Antithrombotic Therapies for Prevention of Ischemic Stroke

337

59. Hirsh J, Poller L. The International Normalized Ratio. A guide to understanding and correcting its problems. Arch Intern Med 1994; 154:282–288. 60. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999; 159:46–48. 61. Oates A, Jackson PR, Austin CA, Channer KS. A new regimen for starting warfarin therapy in out-patients. Br J Clin Pharmacol 1998; 46:157–161. 62. Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126:133– 136. 63. Gladman JR, Dolan G. Effect of age upon the induction and maintenance of anticoagulation with warfarin. Postgrad Med J 1995; 71:153–155. 64. Fagan SC, Kertland HR, Tietjen GE. Safety of combination aspirin and anticoagulation in acute ischemic stroke. Ann Pharmacother 1994; 28:441–443. 65. Loewen P, Sunderji R, Gin K. The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines. Can J Cardiol 1998; 14:717–726. 66. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336:1506–1511. 67. Hyman BT, Landas SK, Ashman RF, Schelper RL, Robinson RA. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987; 82:1233–1237. 68. Sallah S, Abdallah JM, Gagnon GA. Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency. Haemostasis 1998; 28:25–30. 69. Essex DW, Wynn SS, Jin DK. Late-onset warfarin-induced skin necrosis: case report and review of the literature. Am J Hematol 1998; 57:233–237. 70. Wynn SS, Jin DK, Essex DW. Warfarin-induced skin necrosis occurring four days after discontinuation of warfarin. Haemostasis 1997; 27:246–250. 71. Krahn MJ, Pettigrew NM, Cuddy TE. Unusual side effects due to warfarin. Can J Cardiol 1998; 14:90–93. 72. Sato Y, Tsuru T, Oizumi K, Kaji M. Vitamin K deficiency and osteopenia in disuse-affected limbs of vitamin D-deficient elderly stroke patients. Am J Phys Med Rehabil 1999; 78:317– 322. 73. Wehrmacher WH, Karlman RL, Scanlon P, Messmore HL Jr. Anticoagulant therapy of thromboembolic disease during pregnancy. Compr Ther 1998; 24:289–294. 74. Ginsberg JS, Barron WM. Pregnancy and prosthetic heart valves. Lancet 1994; 344:1170– 1172. 75. Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. Arch Intern Med 1999; 159:1322–1328. 76. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153:1557–1562. 77. Gitter MJ, Jaeger TM, Petterson TM, Gersh BJ, Silverstein MD. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc 1995; 70:725–733. 78. Petty GW, Lennihan L, Mohr JP, et al. Complications of long-term anticoagulation. Ann Neurol 1988; 23:570–574. 79. Hart RG. Oral anticoagulants for secondary prevention of stroke. Cerebrovasc Dis 1997; 7(suppl 6):24–29. 80. Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002; 59:193–197. 81. Pengo V, Legnani C, Noventa F, Palareti GISCOAT Study Group (Italian Study on Complications of Oral Anticoagulant Therapy). Oral anticoagulation therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding. A Multicenter Inception Cohort Study. Thromb Haemost 2001; 85:418–422.

338

Adams

82. Ortin M, Olalla J, Marco F, Velasco N. Low-dose vitamin K1 versus short-term with holding of acenocoumarol in the treatment of excessive anticoagulation episodes induced by acenocoumarol. A retrospective comparative study. Haemostasis 1998; 28:57–61. 83. Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997; 126:959–962. 84. Litin SC, Gastineau DA. Current concepts in anticoagulant therapy. Mayo Clin Proc 1995; 70:266–272. 85. Baglin C, Brown K, Luddington R, Baglin T. Risk of recurrent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors. East Anglian Thrombophilia Study Group. Br J Haematol 1998; 100:764–768. 86. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332:993– 997. 87. Hart RG, Sherman DG, Easton JD, Cairns JA. Prevention of stroke in patients with nonvalvular atrial fibrillation. Neurology 1998; 51:674–681. 88. Scardi S, Mazzone C, Pandullo C, Goldstein D, Poletti A, Humar F. Lone atrial fibrillation: prognostic differences between paroxysmal and chronic forms after 10 years of follow-up. Am Heart J 1999; 137:686–691. 89. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989; 1:175–179. 90. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus lowintensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348:633–638. 91. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343:687–691. 92. Stroke Prevention in Atrial Fibrillation Investigators. Preliminary report of the stroke prevention and atrial fibrillation study. N Engl J Med 1990; 322:863–868. 93. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study. Final results. Circulation 1991; 84:527–539. 94. The Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation. Analysis of pooled data from 3 randomized trials. Arch Intern Med 1997; 157:1237–1240. 95. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of lowdose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990; 323:1505–1511. 96. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349–355. 97. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992; 327:1406–1412. 98. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999; 281:1830–1835. 99. Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513–1521. 100. Koefoed BG, Feddersen C, Gullov AL, Petersen P. Effect of fixed minidose warfarin, conventional dose warfarin and aspirin on INR and prothrombin fragment 1
2 in patients with atrial fibrillation. Thromb Haemost 1997; 77:845–848. 101. Koefoed BG, Gullov AL, Petersen P. Prevention of thromboembolic events in atrial fibrillation. Thromb Haemost 1997; 78:377–381.

Antithrombotic Therapies for Prevention of Ischemic Stroke

339

102. Abdelhafiz AH. A review of anticoagulation with warfarin in patients with nonvalvular atrial fibrillation. Clin Ther 2002; 23:1628–1636. 103. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in nonrheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255–1262. 104. Feinberg WM. Anticoagulation for prevention of stroke. Neurology 1998; 51:S20–S22. 105. Blakely JA. Anticoagulation in chronic nonvalvular atrial fibrillation: appraisal of two metaanalyses. Can J Cardiol 1998; 14:945–948. 106. Anderson DC. Primary and secondary stroke prevention in atrial fibrillation. Semin Neurol 1998; 18:451–459. 107. Sparks PB, Mond HG, Kalman JM, Jayaprakash S, Lewis MA, Grigg LE. Atrial fibrillation and anticoagulation in patients with permanent pacemakers: implications for stroke prevention. Pacing Clin Electrophysiol 1998; 21:1258–1267. 108. Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:745–746. 109. Manning WJ, Douglas PS. Transesophageal echocardiography and atrial fibrillation: added value or expensive toy? Ann Intern Med 1998; 128:685–687. 110. Manning WJ, Silverman DI, Gordon SP, Krumholz HM, Douglas PS. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328:750–755. 111. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344:1411–1420. 112. Kinch JW, Davidoff R. Prevention of embolic events after cardioversion of atrial fibrillation. Current and evolving strategies. Arch Intern Med 1995; 155:1353–1360. 113. Fatkin D, Kuchar DL, Thorburn CW, Feneley MP. Transesophageal echocardiography before and during direct current cardioversion of atrial fibrillation: evidence for ‘‘atrial stunning’’ as a mechanism of thromboembolic complications. J Am Coll Cardiol 1994; 23:307–316. 114. Tanne D, Goldbourt U, Zion M, Reicher-Reiss H, Kaplinsky E, Behar S. Frequency and prognosis of stroke/TIA among 4808 survivors of acute myocardial infarction. The SPRINT Study Group. Stroke 1993; 24:1490–1495. 115. Maggioni AP, Franzosi MG, Farina ML, et al. Cerebrovascular events after myocardial infarction: analysis of the GISSI trial. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). BMJ 1991; 302:1428–1431. 116. Maggioni AP, Franzosi MG, Santoro E, White H, Van de Werf F, Tognoni G. The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico II (GISSI-2), and The International Study Group. N Engl J Med 1992; 327:1–6. 117. Asinger RW, Mikell FL, Elsperger J, Hodges M. Incidence of left-ventricular thrombosis after acute transmural myocardial infarction. Serial evaluation by two-dimensional echocardiography. N Engl J Med 1981; 305:297–302. 118. Martin R, Bogousslavsky J. Mechanism of late stroke after myocardial infarct: the Lausanne Stroke Registry. J Neurol Neurosurg Psychiatry 1993; 56:760–764. 119. Pullicino PM, Halperin JL, Thompson JLP. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000; 54:288–294. 120. Moore T, Eriksson P, Stegmayr B. Ischemic stroke after acute myocardial infarction. A population-based study. Stroke 1997; 28:762–767. 121. Moore T, Olofsson B-O, Stegmayr B, Eriksson P. Ischemic stroke. Impact of a recent myocardial infarction. Stroke 1999; 30:997–1001. 122. Smith P. Oral anticoagulants are effective long-term after acute myocardial infarction. J Intern Med 1999; 245:383–387. 123. Salem DN, Levine HJ, Pauker SG, Eckman MH, Daudelin DH. Antithrombotic therapy in valvular heart disease. Chest 1998; 114:590S–601S.

340

Adams

124. Altman R, Rouvier J, Gurfinkel E, et al. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg 1991; 101:427–431. 125. Stein PD, Alpert JS, Dalen JE, Horstkotte D, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1998; 114:602S–610S. 126. Tiede DJ, Nishimura RA, Gastineau DA, et al. Modern management of prosthetic valve anticoagulation. Mayo Clin Proc 1998; 73:665–680. 127. Sirajuddin RA, Miller AB, Geraci SA. Anticoagulation in patients with dilated cardiomyopathy and sinus rhythm: a critical literature review. J Cardiac Failure 2002; 8:48–53. 128. Nendaz MR, Sarasin FP, Junod AF, Bogousslavsky J. Preventing stroke recurrence in patients with patent foramen ovale: antithrombotic therapy, foramen closure, or therapeutic abstention? A decision analytic perspective. Am Heart J 1998; 135:532–541. 129. Serena J, Segura T, Perez-Ayuso MJ, Bassaganyas J, Molins A, Davalos A. The need to quantify right-to-left shunt in acute ischemic stroke: a case-control study. Stroke 1998; 29:1322–1328. 130. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in cryptogenic stroke study. Circulation 2002; 2002 105:2625–2631. 131. Mas J-L, Arquizan C, Lamay C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740–1746. 132. Halperin JL, Fuster V. Patent foramen ovale and recurrent stroke: another paradoxical twist. Circulation 2002; 105:2580–2582. 133. Dressler FA, Craig WR, Castello R, Labovitz AJ. Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke. J Am Coll Cardiol 1998; 31:134–138. 134. Blackshear JL, Zabalgoitia M, Pennock G, et al. Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. SPAF TEE Investigators. Stroke Prevention and Atrial Fibrillation. Transesophageal Echocardiography. Am J Cardiol 1999; 83:453–455. 135. Klijn CJ, Kappelle LJ, Algra A, van Gijn J. Outcome in patients with symptomatic occlusion of the internal carotid artery or intracranial arterial lesions: a meta-analysis of the role of baseline characteristics and type of antithrombotic treatment. Cerebrovasc Dis 2002; 12:228– 234. 136. Chimowitz MI, Kokkinos J, Strong J, et al. The Warfarin–Aspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488–1493. 137. Benesch CG, Chimowitz MI. for the WASID Investigators. Best treatment of intracranial arterial stenosis? 50 years of uncertainty. Neurology 2000; 55:465–466. 138. Schievink WI. The treatment of spontaneous carotid and vertebral artery dissections. Curr Opin Cardiol 2000; 15:316–321. 139. Schievink WI, Mokri B, Piepgras DG, Kuiper JD. Recurrent spontaneous arterial dissections: risk in familial versus nonfamilial disease. Stroke 1996; 27:622–624. 140. Leys D, Moulin T, Stojkovic T, Begey S, Chavot D. Follow-up of patients with history of cervical artery dissection. Cerebrovasc Dis 1995; 5:43–49. 141. Schievink WI. Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001; 344:898–905. 142. Algra A, De Schryver ELLM, van Gijn J, Kappelle LJ, Koudstaal PJ. Oral anticoagulants versus antiplatelet therapy for preventing further ascular events after transient ischaemic attach of minor stroke of presumed arterial origin. Cochrane Database of Systematic Reviews 2001; 4:CD001342. 143. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 1997; 42:857–865. 144. Mohr JP, Thompson JLP, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345:1444–1451. 145. Wakita M, Yasaka M, Minematsu K, Yamaguchi T. Effects of anticoagulation on infarct size and clinical outcome in acute cardioembolic stroke. Angiology 2002; 53:551–556. 146. Devereaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of

Antithrombotic Therapies for Prevention of Ischemic Stroke

147.

148. 149. 150. 151. 152. 153. 154. 155. 156.

157. 158. 159.

160. 161. 162.

163.

164. 165.

166.

167.

168.

169.

341

physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ 2001; 323:1218–1222. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71–86. Roth GJ, Calverley DC. Aspirin, platelets, and thrombosis: theory and practice. Blood 1994; 83:885–898. Lekstrom JA, Bell WR. Aspirin in the prevention of thrombosis. Medicine 1991; 70:161–178. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs. Chest 2001; 119:39S–63S. Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101:1206–1218. Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis 1998; 8(suppl 5):8–18. Weksler BB, Kent JL, Rudolph D, Scherer PB, Levy DE. Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia. Stroke 1985; 16:5–9. Pedersen AK, Fitzgerald GA. Dose-related kinetics of aspirin: presystemic acetylation of platelet cyclooxygenase. N Engl J Med 1984; 311:1206–1211. Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978; 61:314–319. Tohgi H, Tamura K, Kimura B, Kimura M, Suzuki H. Individual variation in platelet aggregability and serum thromboxane B2 concentrations after low-dose aspirin. Stroke 1988; 19:700–703. Helgason CM, Tortorice KL, Winkler SR, et al. Aspirin response and failure in cerebral infarction. Stroke 1993; 24:345–350. Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25:2331–2336. Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non responder. A pilot-study including 180 post-stroke patients. Thromb Res 1993; 71:397–403. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286:954–959. Isles C, Norrie J, Paterson J, Ritchie L. Risk of major gastrointestinal bleeding with aspirin. Lancet 1999; 353:148–150. Sze PC, Reitman D, Pincus MM, Sacks HS, Chalmers TC. Antiplatelet agents in the secondary prevention of stroke: meta-analysis of the randomized control trials. Stroke 1988; 19:436–442. Cappelleri JC, Lau J, Kupelnick B, Chalmers TC. Efficacy and safety of different aspirin dosages on vascular diseases in high-risk patients. A metaregression analysis. Online J Curr Clin Trials, 1995, 6442 Doc. No 174. Silagy CA, McNeil JJ, Donnan GA, Tonkin AM, Worsam B, Campion K. Adverse effects of low-dose aspirin in a healthy elderly population. Clin Pharmacol Ther 1993; 54:84–89. Stack WA, Atherton JC, Hawkey GM, Logan RF, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Alimen Pharmacol Ther 2002; 16:497–506. Cryer B, Feldman M. Effects of nonsteriodal anti-inflammatory drugs on endogenous gastrointestinal prostaglandins and therapeutic strategies for prevention and treatment of nonsteriodal anti-inflammatory drug-induced damage. Arch Intern Med 1992; 152:1145–1155. Hobson RW, Krupski WC, Weiss DG. Influence of aspirin in the management of asymptomatic carotid artery stenosis. VA Cooperative Study Group on Asymptomatic Carotid Stenosis. J Vasc Surg 1993; 17:257–263. Lanza FL, Royer GL, Nelson RS. Endoscopic evaluation fo the effects af aspirin, buffered aspirin, and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980; 303:136–138. He J, Whelton PK, Vu B. Aspirin and risk of hemorrhagic stroke. JAMA 1998; 280:1930– 1935.

342

Adams

170. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321:129–135. 171. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebocontrolled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349:1641–1649. 172. Taylor DW, Barnett HJM, Haynes RB, et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet 1999; 353:2179–2184. 173. Boysen G. Bleeding complications in secondary stroke prevention by antiplatelet therapy: a benefit-risk analysis. J Intern Med 1999; 246:239–245. 174. Kronmal RA, Hart RG, Manolio TA, Talbert RL, Beauchamp NJ, Newman A. Aspirin use and incident stroke in the cardiovascular health study. CHS Collaborative Research Group. Stroke 1998; 29:887–894. 175. Hart R, Halperin J, McBride R. Aspirin for the primary prevention of stroke and other major vascular events. Arch Neurol 2000; 57:326–332. 176. Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Part II: surgical group. Stroke 1978; 9:309–319. 177. Fields WS, Lemak NA, Frankowski RF, Hardy RJ, Bigelow RH. Controlled trial of aspirin in cerebral ischemia. Circulation 1980; 62:V90–V96. 178. Bousser M-G, Eschwage E, Hauenau M. ‘‘A.I.C.L.A.’’ controlled trial of aspirin and dipyridamole in the secondary prevention of atherothrombotic cerebral ischemia. Stroke 1983; 14:5–14. 179. The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299:53–59. 180. Lindblad B, Persson NH, Takolander R, Bergqvist D. Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial. Stroke 1993; 24:1125–1128. 181. The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338:1345– 1349. 182. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1–13. 183. UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. Br Med J 1988; 296:316–320. 184. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325:1261–1266. 185. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 1998; 114:470S–488S. 186. Adams HP Jr, Bendixen BH. Low- versus high-dose aspirin in prevention of ischemic stroke. Clin Neuropharmacol 1993; 16:485–500. 187. Grotta JC, Lemak NA, Gary H, Fields WS, Vital D. Does platelet antiaggregant therapy lessen the severity of stroke? Neurology 1985; 35:632–636. 188. Wilterdink JL, Bendixen B, Adams HP Jr, et al. Effect of prior aspirin use on stroke severity in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 2001; 32:2836– 2840. 189. De Keyser J, Herroelen L, De Klippel N. Early outcome in acute ischemic stroke is not influenced by the prophylactic use of low-dose aspirin. J Neurol Sci 1997; 145:93–96. 190. Karepov V, Bornstein NM, Hass Y, Korczyn AD. Does daily aspirin diminish severity of firstever stroke? Arch Neurol 1997; 54:1369–1371. 191. Sivenius J, Cunha L, Diener HC, et al. Antiplatelet treatment does not reduce the severity of subsequent stroke. Neurology 1999; 53:825–829.

Antithrombotic Therapies for Prevention of Ischemic Stroke

343

192. Gomes I. Aspirin: a neuroprotective agent at high doses? Natl Med J India 1998; 11:14–17. 193. Williams PS, Rands G, Orrel M, Spector A. Aspirin for vascular dementia. Cochrane Database of Systematic Reviews 2001; 4. 194. Chimowitz MI, Furlan AJ, Nayak S, Sila CA. Mechanism of stroke in patients taking aspirin. Neurology 1990; 40, 1682–1685. 195. Vaitkus PT, Barnathan ES. Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: a meta-analysis. J Am Coll Cardiol 1993; 22:1004–1009. 196. Moinuddeen K, Quin J, Shaw R, et al. Anticoagulation is unnecessary after biological aortic valve replacement. Circulation 1998; 98:II95–II98. 197. The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study Investigators. JAMA 1998; 279:1273–1277. 198. Multicentre Acute Stroke Trial—Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346:1509–1514. 199. Berge E. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2001; I4. 200. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40,000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31:1240–1249. 201. Rojas-Fernandez CH, Kephart GC, Sketris IS, Kass K. Underuse of acetylsalicylic acid in individuals with myocardial infarction, ischemic heart disease or stroke: data from the 1995 population-based Nova Scotia Health Survey. Can J Cardiol 1999; 15:291–296. 202. Segal JB, McNamara RL, Miller MR, Powe NR, Goodman SN, Robinson FA, Bass EB. Antiocoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter. Cochrane Database of Systematic Reviews 2004; 4. 203. Koudstaal PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2001; 4. 204. Massel D, Little SH. Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. J Am Coll Cardiol 2001;37569–578. 205. Rivey MP, Alexander MR, Taylor JW. Dipyridamole: a critical evaluation. Drug Intell Clin Pharm 1984; 18:869–880. 206. Fitzgerald GA. Dipyridamole. N Engl J Med 1987; 316:1247–1256. 207. Eisert WG. Near-field amplification of antithrombotic effects of dipyridamole through vessel wall cells. Neurology 2001; 57:S20–S23. 208. Diener HC, Darius H, Bertrand-Hardy JM, Humphreys M. Does early high dosage dipyridamole in prevention of secondary stroke induce cardiac events? Zeitschr Kardiol 2001; 90:348–351. 209. Gibbs CR, Lip GY. Do we still need dipyridamole? Br J Clin Pharmacol 1998; 45:323–328. 210. Redman AR, Ryan GJ. Analysis of trials evaluating combinations of acetylsalicylic acid and dipyridamole in the secondary prevention of stroke. Clin Ther 2001; 23:1391–1408. 211. The Persantine–Aspirin Reinfarction Study (PARIS) Research Group. The Persantine– Aspirin Reinfarction Study. Circulation 1980; 62:V85–V88. 212. The American–Canadian Co-Operative Study group. Persantine Aspirin Trial in cerebral ischemia. Part II: endpoint results. Stroke 1985; 16:406–415. 213. Sivenius J, Riekkinen PJ, Laakso M, Smets P, Lowenthal A. European Stroke Prevention Study (ESPS): antithrombotic therapy is also effective in the elderly. Acta Neurol Scand 1993; 87:111–114. 214. Sivenius J, Laakso M, Penttila IM. The European stroke prevention study: results according to sex. Neurology 1991; 41:1189–1192.

344

Adams

215. Easton JD. Antiplatelet therapy in the prevention of stroke. Drugs 1991; 42(suppl 5):39–50. 216. Forbes CD. Secondary stroke prevention with low-dose aspirin, sustained release dipyridamole alone and in combination. ESPS Investigators. European Stroke Prevention Study. Thromb Res 1998; 92:S1–S6. 217. Diener HC. Dipyridamole trials in stroke prevention. Neurology 1998; 51:S17–S19. 218. Sivenius J, Cunha L, Diener HC, et al. Second European Stroke Prevention Study: antiplatelet therapy is effective regardless of age. ESPS2 Working Group. Acta Neurol Scand 1999; 99:54–60. 219. Sullivan JM, Harken DE, Gorlin R. Pharmacologic control of thromboembolic complications of cardiac-valve replacement. N Engl J Med 1971; 284:1391–1394. 220. Shah H, Gondek K. Aspirin plus extended-release dipyridamole or clopidogrel compared with aspirin monotherapy for the prevention of recurrent ischemic stroke: a cost-effective analysis. Clin Ther 2000; 22:362–370. 221. Sarasin FP, Gaspoz JM, Bounameaux H. Cost-effectiveness of new antiplatelet regimens used as secondary prevention of stroke or transient ischemic attack. Arch Intern Med 2000; 160:2773–2778. 222. Dyken ML. Antiplatelet agents and stroke prevention. Semin Neurol 1998; 18:441–450. 223. Tijssen JG. Low-dose and high-dose acetylsalicylic acid, with and without dipyridamole: a review of clinical trial results. Neurology 1998; 51:S15–S16. 224. Easton JD. What have we learned from recent antiplatelet trials? Neurology 1998; 51:S36–S38. 225. Wilterkink JL, Easton JD. Dipyridamole plus aspirin in cerebrovascular disease. Arch Neurol 1999; 56:1087–1092. 226. Chambers M, Hutton J, Gladman J. Cost-effectiveness analysis of antiplatelet therapy in the prevention of recurrent stroke in the UK. Aspirin, dipyridamole and aspirin-dipyridamole. Pharmacoeconomics 1999; 16:577–593. 227. Verstraete M, Zoldhelyi P. Novel antithrombotic drugs in development. Drugs 1995; 49:856– 884. 228. Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 1998; 129:394–405. 229. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100:1667–1672. 230. Goto S, Tamura N, Sakakibara M, Ikeda Y, Handa S. Effects of ticlopidine on von Willebrand factor-mediated shear-induced platelet activation and aggregation. Platelets 2001; 12:406–414. 231. Saltiel E, Ward A. Ticlopidine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states. Drugs 1987; 34:222–262. 232. McTavish D, Faulds D, Goa KL. Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. Drugs 1990; 40:238–259. 233. Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321:501–507. 234. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1:1215–1220. 235. Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication: effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990; 227:301–308. 236. Sheikh RA, Romano PS, Prindiville TP, Yasmeen S, Trudeau W. Endoscopic evidence of mucosal injury in patients taking ticlopidine compared with patients taking aspirin/ nonsteroidal antiinflammatory drugs and controls. J Clin Gastroenterol 2002; 34:529–532. 237. Iqbal M, Goenka P, Young MF, Thomas E, Borthwick TR. Ticlopidine-induced cholestatic hepatitis: report of three cases and review of the literature. Digest Dis Sci 1998; 43:2223–2226. 238. Yim HB, Lieu PK, Choo PW. Ticlopidine induced cholestatic jaundice. Singapore Med J 1997; 38:132–133. 239. Persoz CF, Cornella F, Kaeser P, Rochat T. Ticlopidine-induced interstitial pulmonary disease: a case report. Chest 2001; 119:1963–1965.

Antithrombotic Therapies for Prevention of Ischemic Stroke

345

240. Pizarro AE, Andrade RJ, Garcia-Cortes M, et al. [Acute hepatitis due to ticlopidine. A report of 12 cases and review of the literature]. Rev Neurol 2001; 33:1014–1020. 241. Dakik HA, Salti I, Haidar R, Uthman IW. Drug points: ticlopidine associated with acute arthritis. BMJ 2002; 324:2727. 242. Alberti L, Alberti-Flor JJ. Ticlopidine-induced cholestatic hepatitis successfully treated with corticosteroids. Am J Gastroenterol 2002; 97:10721072. 243. Rosen H, el-Hennawy AS, Greenberg S, Chen CK, Nicastri AD. Acute interstitial nephritis associated with ticlopidine. Am J Kidney Dis 1995; 25:934–936. 244. Love BB, Biller J, Gent M. Adverse haematological effects of ticlopidine. Prevention, recognition and management. Drug Saf 1998; 19:89–98. 245. Bennett CL, Weinberg PD, Rozenberg-Bendror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenia purpura associated with ticlopidine. Ann Intern Med 1998; 128:541–544. 246. Mallet L, Mallet J. Ticlopidine and fatal aplastic anemia in an elderly woman. Ann Pharmacother 1994; 28:1169–1171. 247. Paradiso-Hardy FL, Angelo CM, Lanctot KL, Cohen EA. Hematologic dyscrasia associated with ticlopidine therapy: evidence for causality. CMAJ 2000; 163:1441–1448. 248. Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Curr Opin Hematol 2001; 8:286–293. 249. Naseer N, Aijaz A, Saleem MA, Nelson J, Peterson SJ, Frishman WH. Ticlopidine-associated thrombotic thrombocytopenic purpura. Heart Dis 2001; 3:221–223. 250. Liu ZC, Uetrecht JP. Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. Drug Metab Disposition 2000; 28:726–730. 251. Hung MJ, Wang CH, Cherng WJ. Granulocyte colony stimulating factor treatment for delayed recovery of ticlopidine-related neutropenia. Int J Clin Pract 2002; 56:70–71. 252. Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. JAMA 1999; 281:806– 810. 253. Moake JL. Thrombotic thrombocytopenic purpura today. Hospital Practice (Office Edition), 1999, 53–59. 254. Tsai HM, Rice L, Sarode R, Chow TW, Moake JL. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med 2000; 132:794– 799. 255. Eldor A. Thrombotic thrombocytopenic purpura: diagnosis, pathogenesis and modern therapy. Baillieres Clin Haematol 1998; 11:475–495. 256. George JN, Gilcher RO, Smith JW, Chandler L, Duvall D, Ellis C. Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: diagnosis and management. J Clin Apheresis 1998; 13:120–125. 257. Gordjani N, Sutor AH. Coagulation changes associated with the hemolytic uremic syndrome. Semin Thromb Hemost 1998; 24:577–582. 258. Orimo S, Ozawa E, Yagi H, Ishizashi H, Matsumoto M, Fujimura Y. Simple plasma exchange reduced autoantibody to von Willebrand factor-cleaving protease in a Japanese man with ticlopidine-associated thrombotic thrombocytopenic purpura. J Intern Med 2002; 251:280– 281. 259. Yang CW, Chen YC, Dunn P, Chang MY, Fang JT, Huang CC. Ticlopidine-induced thrombotic thrombocytopenic purpura: two case reports treated with plasma exchange plus steroids. Renal Failure 2001; 23:851–856. 260. Janzon L. The STIMS trial: the ticlopidine experience and its clinical applications. Swedish Ticlopidine Multicenter Study. Vasc Med 1996; 1:141–143. 261. Murray JC, Kelly MA, Gorelick PB. Ticlopidine: a new antiplatelet agent for the secondary prevention of stroke. Clin Neuropharmacol 1994; 17:23–31.

346

Adams

262. Scrutinio D, Cimminiello C, Marubini E, Pitzalis MV, Di Biase M, Rizzon P. Ticlopidine versus aspirin after myocardial infarction (STAMI) trial. J Am Coll Cardiol 2001; 37:1259–1265. 263. Steinhubl SR, Ellis SG, Wolski K, Lincoff AM, Topol EJ. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events: data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial. Circulation 2001; 103:1403–1409. 264. Machraoui A, Germing A, Lindstaedt M, et al. Efficacy and safety of ticlopidine monotherapy versus ticlopidine and aspirin after coronary artery stenting: follow-up results of a randomized study. J Invasive Cardiol 2001; 13:431–436. 265. Madan M, Marquis JF, de May MR, et al. Coronary stenting in unstable angina: early and late clinical outcomes. Can J Cardiol 1998; 14:1109–1114. 266. Walter H, Neumann FJ, Hadamitzky M, Elezi S, Muller A, Schomig A. Coronary artery stent placement with postprocedural antiplatelet therapy in acute myocardial infarction. Coronary Artery Dis 1998; 9:577–582. 267. Goods CM, al-Shaibi KF, Liu MW, et al. Comparison of aspirin alone versus aspirin plus ticlopidine after coronary artery stenting. Am J Cardiol 1996; 78:1042–1044. 268. Kitai T, Nishikawa M, Tanigawa T, et al. Inhibition by combined therapy with ticlopidine and aspirin of enhanced platelet aggregation during physical exercise in patients with coronary artery disease. Am Heart J 2001; 142:E1E1. 269. Schuhlen H, Kastrati A, Pache J, Dirschinger J, Schomig A. Incidence of thrombotic occlusion and major adverse cardiac events between two and four weeks after coronary stent placement: analysis of 5,678 patients with a four-week ticlopidine regimen. J Am Coll Cardiol 2001; 37:2066–2073. 270. Berger PB, Mahaffey KW, Meier SJ, et al. Safety and efficacy of only 2 weeks of ticlopidine therapy in patients at increased risk of coronary stent thrombosis: results from the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial. Am Heart J 2002; 143:841–846. 271. Harbison JW. Ticlopidine versus aspirin for the prevention of recurrent stroke. Analysis of patients with minor stroke from the Ticlopidine Aspirin Stroke Study. Stroke 1992; 23:1723– 1727. 272. Grotta JC, Norris JW, Kamm B. Prevention of stroke with ticlopidine: who benefits most? TASS Baseline and Angiographic Data Subgroup. Neurology 1992; 42:111–115. 273. Bellavance A. Efficacy of ticlopidine and aspirin for prevention of reversible cerebrovascular ischemic events. The Ticlopidine Aspirin Stroke Study. Stroke 1993; 24:1452–1457. 274. Hershey LA. Stroke prevention in women: role of aspirin versus ticlopidine. Am J Med 1991; 91:288–292. 275. Weisberg LA. The efficacy and safety of ticlopidine and aspirin in non-whites: analysis of a patient subgroup from the Ticlopidine Aspirin Stroke Study. Neurology 1993; 43:27–31. 276. Pryse-Phillips W. for the Ticlopidine Aspirin Stroke Study Group. Ticlopidine Aspirin Stroke Study: outcome by vascular distribution of the qualifying event. J Stroke Cerebrovasc Dis 1993; 3:49–56. 277. Gorelick PB, Leurgans SL, Richardson D. African American Antiplatelet Stroke Prevention Study: clinical trial design. J Stroke Cerebrovasc Dis 1998; 7:526–534. 278. Jarvis B, Simpson K. Clopidogrel: a review of its use in the prevention of atherothrombosis. Drugs 2000; 60:347–377. 279. Harker LA, Marzec UM, Kelly AB, et al. Clopidogrel inhibition of stent, graft, and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates. Circulation 1998; 98:2461–2469. 280. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84:891–896. 281. Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K, Boneu B. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation 2000; 101:2823–2828.

Antithrombotic Therapies for Prevention of Ischemic Stroke

347

282. Helft G, Osende JI, Worthley SG, et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol 2000; 20:2316–2321. 283. Gawaz M, Seyfarth M, Muller I, et al. Comparison of effects of clopidogrel versus ticlopidine on platelet function in patients undergoing coronary stent placement. Am J Cardiol 2001; 87:332–336. 284. Pache J, Kastrati A, Mehilli J, et al. Clopidogrel therapy in patients undergoing coronary stenting: value of a high-loading-dose regimen. Catheter Cardiovasc Interv 2002; 55:436– 441. 285. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494– 502. 286. Weber AA, Braun M, Hohlfeld T, Schwippert B, Tschope D, Schror K. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol 2001; 52:333–336. 287. Creager MA. Results of the CAPRIE trial: efficacy and safety of clopidogrel. Clopidogrel versus aspirin in patients at risk of ischaemic events. Vasc Med 1998; 3:257–260. 288. Miller L, Gupta A, Bertolet BD. Use of clopidogrel loading, enoxaparin, and double-bolus eptifibatide in the setting of early percutaneous coronary intervention for acute coronary syndromes. J Invasive Cardiol 2002; 14:247–250. 289. Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Am Heart J 2000; 140:67–73. 290. Fisher AA, Le Couteur DG. Intracerebral hemorrhage following possible interaction between celecoxib and clopidogrel. Ann Pharmacother 2001; 35:1567–1569. 291. Trivier JM, Caron J, Mahieu M, Cambier N, Rose C. Fatal aplastic anaemia associated with clopidogrel. Lancet 2001; 357:446. 292. Meyer B, Staudinger T, Lechner K. Clopidogrel and aplastic anaemia. Lancet 2001; 357:1446– 1447. 293. Bennett CL, Connors JM, Carwile MJ, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 325:1371–1372. 294. Hankey GJ. Clopidogrel and thrombotic thrombocytopenic purpura. Lancet 2000; 356:269– 270. 295. Elmi F, Peacock T, Schiavone J. Isolated profound thrombocytopenia associated with clopidogrel. J Invasive Cardiol 2000; 12:532–535. 296. Nara W, Ashley I, Rosner F. Thrombotic thrombocytopenic purpura associated with clopidogrel administration: case report and brief review. Am J Med Sci 2001; 322:170–172. 297. Reichenberger F, Wirtz H, Paschke R. Clopidogrel and side effects. Cardiology 1902; 96:51– 52. 298. Oomen PH, Tulleken JE, Zijlstra JG. Hemolytic uremic syndrome in a patient treated with clopidogrel. Ann Intern Med 2000; 132:1006. 299. Moy B, Wang JC, Raffel GD, Marcoux JP. Hemolytic uremic syndrome associated with clopidogrel: a case report. Arch Intern Med 2000; 160:1370–1372. 300. Chinnakotla S, Leone JP, Fidler ME, Hammeke MD, Tarantolo S. Clopidogrel-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in a kidney/pancreas transplant recipient. Transplantation 2000; 70:550–552. 301. Willens HJ. Clopidogrel-induced mixed hepatocellular and cholestatic liver injury. Am J Ther 2000; 7:317–318. 302. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329–1339. 303. Bhatt DL, Chew DP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103:363–368. 304. Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin

348

305.

306. 307.

308.

309.

310. 311. 312. 313. 314. 315. 316.

317.

318. 319.

320. 321.

322. 323.

324. 325.

Adams followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001; 358:527–533. Taniuchi M, Kurz HI, Lasala JM. Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation 2001; 104:539–543. Berger PB, Bell MR, Rihal CS, et al. Clopidogrel versus ticlopidine after intracoronary stent placement. J Am Coll Cardiol 1999; 34:1891–1894. Dangas G, Mehran R, Abizaid AS, et al. Combination therapy with aspirin plus clopidogrel versus aspirin plus ticlopidine for prevention of subacute thrombosis after successful native coronary stenting. Am J Cardiol 1907; 87:470–472. Muller C, Buttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000; 101:590–593. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102:624–629. Bhatt DL, Kapadia SR, Bajzer CT, et al. Dual antiplatelet therapy with clopidogrel and aspirin after carotid artery stenting. J Invasive Cardiol 2001; 13:767–771. Berglund U, Richter A. Clopidogrel treatment before percutaneous coronary intervention reduces adverse cardiac events. J Invasive Cardiol 2002; 14:243–246. Hacke W. From CURE to MATCH: ADP receptor antagonists as the treatment of choice for high-risk atherothrombotic patients. Cerebrovasc Dis 2002; 13(suppl 1):22–26. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002; 39:9–14. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001; 29:2271–2275. Albers GW, Amarenco P. Combination therapy with clopidogrel and aspirin: can the CURE results be extrapolated to cerebrovascular patients? Stroke 2001; 32:2948–2949. Dippel DW. The results of CAPRIE, IST and CAST Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events. International Stroke Trial. Chinese Acute Stroke Trial. Thromb Res 1998; 92:S13–S16. Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials. Stroke 2000; 31:1779–1784. Gaspoz JM, Coxson PG, Goldman PA, et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med 2002; 346:1800–1806. Bergamasco B, Benna P, Carolei A, Rasura M, Rudelli G, Fieschi C. A randomized trial comparing ticlopidine hydrochloride with indobufen for the prevention of stroke in high-risk patients (TISS Study). Ticlopidine Indobufen Stroke Study. Functi Neurol 1997; 12:33–43. The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke. A randomized, double-blind, placebo-controlled, dose-escalation study. Stroke 2000; 31:601–609. Junghans U, Seitz RJ, Aulich A, Freund H-J, Siebler M. Bleeding risk of tirofiban, a nonpeptide GPIIb/IIIa platelet receptor antagonist in progressive stroke: an open pilot study. Cerebrovasc Dis 2001; 12:308–312. Topol EJ, Easton JD, Amarenco P, et al. Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Am Heart J 2000; 139:927–933. Cannon CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000; 102:149–156. Schneider R. Results of hemorheologically active treatment with pentoxifylline in patients with cerebrovascular disease. Angiology 1989; 40:987–993. Apollonio A, Castignani P, Magrini L, Angeletti R. Ticlopidine–pentoxifylline combination in

Antithrombotic Therapies for Prevention of Ischemic Stroke

349

the treatment of atherosclerosis and the prevention of cerebrovascular accidents. J Int Med Res 1989; 17:28–35. 326. The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework. Lancet 1998; 351:233–241. 327. Hurlen M, Erikssen J, Smith P, Arnesen H, Rollag A. Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 outpatients. J Intern Med 1994; 236:299–304. 328. Lechat P, Lardoux H, Mallet A, et al. Anticoagulant (fluindione)–aspirin combination in patients with high-risk atrial fibrillation. A randomized trial (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane; FFAACS). Cerebrovasc Dis 2001; 12:245–252.

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

352

Snell et al.

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

Surgical Management Options to Prevent Ischemic Stroke

353

(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%

354

Snell et al.

(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

Surgical Management Options to Prevent Ischemic Stroke

355

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

356

Snell et al.

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.

Surgical Management Options to Prevent Ischemic Stroke

357

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].

358

Snell et al.

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

Surgical Management Options to Prevent Ischemic Stroke

359

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,

360

Snell et al.

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.

REFERENCES 1. American Heart Association. Heartfacts: 1994 Cardiovascular Statistics. Dallas: American Heart Association, 1994. 2. Blatter DD, Bahr AL, Parker DL, Robison RO, Kimball JA, Perry DM, Horn S. Cervical carotid MR angiography with multiple overlapping thin-stab acquisition: comparison with conventional angiography. Am J Roentgenol 1993; 161:1269–1277. 3. Zwiebel WJ. Duplex sonography of the cerebral arteries: efficacy, limitations, and indications [comments]. Am J Roentgenol 1992; 158:29–36. 4. Fleck JD, Biller J, Loftus CM. Medical and surgical management of stroke and extracranial carotid artery disease. In: Grossman RG, Loftus CM, eds. Principles of Neurosurgery. New York: Lippincott-Raven, 1999:271. 5. Caplan LR, Gorelick PB, Hier DB. Race, sex, and occlusive cerebrovascular disease: a review. Stroke 1986; 17:648–655. 6. Fisher CM, Gore I, Okabe N. Atherosclerosis of the carotid and vertebral arteries-extracranial and intracranial. J Neuropathol Exp Neurol 1965; 24:455–476. 7. Hutchinson HC, Yates PO. Carotico-vertebral stenosis. Lancet 1957; 1:2–8. 8. Warlow C. Disorders of the cerebral circulation. In: Walton J, ed. Brain’s Diseases of the Nervous System. Oxford, England: Oxford University Press, 1993:217. 9. Fisher M, Fieman S. Geometric factors of the bifurcation in carotid atherogenesis. Stroke 1990; 21:267–271. 10. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326:242–250. 11. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362:801– 809. 12. Drexler H. Endothelial dysfunction: clinical implications. Prog Cardiovasc Dis 1997; 39:287– 324. 13. Cybulsky MI, Gimbrone MA. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991; 251:788–791. 14. O’Brien KD, McDonald TO, Chait A, Allen MD, Alpers CE. Neovascular expression of Eselectin, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 1996; 93:582–672. 15. Schussheim AE, Fuster V. Antibiotics for myocardial infarction? A possible role of infection in atherogenesis and acute coronary syndromes. Drugs 1999; 57:283–291. 16. Adams RD, Victor M, Ropper AH. Principles of Neurology. 6th ed. New York: McGraw-Hill, 1997:779–780.

Surgical Management Options to Prevent Ischemic Stroke

361

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.

362

Snell et al.

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

364

Marler

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.

Thrombolysis for Acute Stroke

365

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

366

Marler

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

Thrombolysis for Acute Stroke

367

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.

368

Marler

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.

Thrombolysis for Acute Stroke

369

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

370

Marler

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

Thrombolysis for Acute Stroke

371

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

372

Marler

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.

Thrombolysis for Acute Stroke

373

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

374

Marler

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

Thrombolysis for Acute Stroke

375

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

376

Marler

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.

Thrombolysis for Acute Stroke

377

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].

378

Marler

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.

REFERENCES 1. Hippocrates. Aphorisms. Translated by Francis Adams. 400 B.C. The Internet Classics Archive. http://classics.mit.edu/Hippocrates/aphorisms.1.i.html. 2. Fagan SC, Morgenstern LB, Petitta A, Ward RE, Tilley BC, Marler JR, Levine SR, Broderick JP, Kwiatkowski TG, Frankel M, Brott TG, Walker MD. Cost-effectiveness of tissue plasminogen activator therapy for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology 1998; 50(4):883–890. 3. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995; 333:1581–1587. 4. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al., for the ECASS Study

Thrombolysis for Acute Stroke

5.

6.

7.

8.

9.

10.

11. 12. 13.

14.

15. 16.

17. 18. 19.

20.

21.

379

Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274:1017–1025. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. for the Second European-Australasian Acute Stroke Study Investigators. Randomized double-blind placebocontrolled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet 1998; 352:1245–1251. Clark WM, Albers GW, Madden KP, Hamilton S, for the Thrombolytic Therapy in Acute Ischemic Stroke Study Investigators. The rt-PA (alteplase ) 0- to 6-hour acute stroke trial, part a (a0267g): results of a double-blind, placebo-controlled, multicenter study. Stroke 2000; 31:811–816. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S for the ATLANTIS Study Investigators. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS study: a randomized controlled trial. JAMA 1999; 282(21):2019–2026. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S, ATLANTIS Trials Investigators, ECASS Trials Investigators, NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 Mar 6; 363(9411):768–774. Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, et al. for the NINDS rt-PA Stroke Study Group. Early stroke treatment associated with better outcome. The NINDS rt-PA Stroke Study. Neurology 2000; 55:1649–1655. Katzan IL, Hammer MD, Furlan AJ, Hixson ED, Nadzam DM, on behalf of the Cleveland Clinic Health System. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke 2003; 34:799–800. The Ancrod Stroke Study Investigators. Ancrod for the treatment of acute ischemic brain infarction. Stroke 1994; 25:1745–1759. Sherman DG, Atkinson RP, Chippendale T, et al. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. JAMA 2000; 283:2395–2403. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II Study: a randomized controlled trial. JAMA 1999; 282:2003–2001. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, and the PROACT investigators. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998; 29:4–11. GUSTO III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337:118–123. Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, StewartWynne EG, Tuck RR, for the Australian Streptokinase (ASK) Trial Study Group. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996; 276:961–966. Morris AD, Ritchie C, Grosset DG, Adams FG, Lees KR. A pilot study of streptokinase for acute cerebral infarction. Q J Med 1995; 88:727–731. Multicenter Acute Stroke Trial–Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335:145–150. Multicentre Acute Stroke Trial. Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346:1509–1514. Cornu C, Boutitie F, Candelise L, Boissel JP, Donnan GA, Hommel M, Jaillard A, Lees KR. Streptokinase in acute ischemic stroke: an individual patient data meta-analysis. The Thrombolysis in Acute Stroke Pooling Project. Stroke 2000; 31:1555–1560. Chapman DF, Lyden P, Lapchak PA, Nunez S, Thibodeaux H, Zivin J. Comparison of TNK

380

22.

23. 24.

25.

26.

27. 28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

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.

Thrombolysis for Acute Stroke

381

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

384

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

385

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.)

Anticoagulant and Antiplatelet Treatment

387

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

388

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

389

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].

390

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

391

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

392

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

393

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].

394

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

395

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

396

Berge and Sandercock

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.)

Anticoagulant and Antiplatelet Treatment

397

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

Anticoagulant and Antiplatelet Treatment

399

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.)

400

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

401

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

402

Berge and Sandercock

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

Anticoagulant and Antiplatelet Treatment

403

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.

REFERENCES 1. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project—1981– 86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1990; 53:16–22. 2. Broderick JP, Phillips SJ, Whisnant JP, O’Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline in stroke? Stroke 1989; 20:577–582. 3. Homer D, Whisnant JP, Schoenberg BS. Trends in the incidence rates of stroke in Rochester, Minnesota, since 1935. Ann Neurol 1987; 22:245–251. 4. Sandercock P, Celani MG, Ricci S. The likely public impact health impact of simple treatments for acute ischaemic stroke. Cerebrovasc Dis 1992; 2(suppl):234. 5. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349:1569–1581. 6. Warlow C, Dennis MS, van Gijn J, Hankey GJ, Sandercock P, Bamford J, Wardlaw JM. Stroke. A Practical Guide to Management. Oxford: Blackwell Science Ltd, 1996. 7. Wardlaw JM, del Zoppo GJ, Yamaguchi T. Thrombolysis in acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. 8. Gubitz G, Councell C, Sandercock P, Signorini D. Anticoagulants for acute ischaemic stroke (Cochrane Review). The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. 9. Bath PMW, Iddenden R, Bath FJ. Low-molecular-weight heparins and heparinoids in acute ischemic stroke. A meta-analysis of randomized controlled trials. Stroke 2000; 31:1770–1778. 10. Bath PM, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D, Marttila R, Olsson J, O’Neill D, Orgogozo J, Ringelstein B, van der SJ, Turpie AG. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet 2001; 358:702–710. 11. Berge E, Sandercock P. Anticoagulants versus antiplatelet agents for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library 2002, Issue 4. Oxford: Update Software, 2002. 12. Counsell C, Sandercock P. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. 13. Gubitz G, Sandercock P. Different doses of anticoagulant for acute ischaemic stroke (protocol for a Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. 14. Gubitz G, Sandercock P, Counsell C. Immediate anticoagulant therapy for acute ischaemic stroke: a systematic review of seven randomised trials directly comparing different doses of the same anticoagulant. Stroke 2000; 31:308. 15. Davenport R, Dennis M, Wellwood I, Warlow C. Complications after acute stroke. Stroke 1996; 27:415–420. 16. Moussouttas MM, Lichtman JH, Krumholtz HM, Cerese J, Brass LM. The use of heparin anticoagulation in acute ischemic stroke among academic medical centres. Stroke 1999; 30:265. 17. Al Sadat A, Sunbulli M, Chaturvedi S. Use of intravenous heparin by North American neurologists: do the data matter? Stroke 2002; 33:1574–1577. 18. Burgin WS, Staub L, Chan W, Wein TH, Felberg RA, Grotta JC, Demchuk AM,

404

19.

20.

21.

22.

23. 24. 25. 26. 27.

28.

29.

30. 31. 32.

33. 34.

35.

36. 37.

Berge and Sandercock Hickenbottom SL, Morgenstern LB. Acute stroke care in non-urban emergency departments. Neurology 2001; 57:2006–2012. Coull BM, Williams LS, Goldstein LB, Meschia JF, Heitzman D, Chaturvedi S, Johnston KC, Starkman S, Morgenstern LB, Wilterdink JL, Levine SR, Saver JL. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Stroke 2002; 33:1934–1942. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 2001; 32:2333–2337. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998; 279:1265–1272. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000; 355:1205–1210. Lyrer P, Erickson LP. Antithrombotic drugs for carotid artery dissection (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. Einhaupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, Haberl RL, Pfister HW, Schmiedek P. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597–600. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484–488. Stam J, de Bruijn STFM, Deveber G. Anticoagulants for cerebral sinus thrombosis (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. Randomised controlled trial of subcutaneous calcium-heparin in acute myocardial infarction. The SCATI (Studio sulla Calciparina nell’Angina e nella Trombosi Ventricolare nell’Infarto) Group. Lancet 1989; 2:182–186. Kontny F, Dale J, Abildgaard U, Pedersen TR. Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study. J Am Coll Cardiol 1997; 30:962–969. Collins R, MacMahon S, Flather M, Baigent C, Remvig L, Mortensen S, Appleby P, Godwin J, Yusuf S, Peto R. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials. BMJ 1996; 313:652–659. Cairns JA, Theroux P, Lewis HD Jr, Ezekowitz M, Meade TW. Antithrombotic agents in coronary artery disease. Chest 2001; 119:228S–252S. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke 2002; 33:2722–2727. Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA. 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; 25:1901–1914. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001; 119:300S–320S. Scottish Intercollegiate Guidlines Network. Antithrombotic Therapy. A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network, Royal College of Physicians, 1999. Scottish Intercollegiate Guidlines Network. Prevention of Venous Thromboembolism. A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network, Royal College of Physicians, 2000. Royal College of Physicians of Edinburgh. Consensus conference on medical management of stroke. J Neurol Neurosurg Psychiatry 1999; 66:128–129. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-

Anticoagulant and Antiplatelet Treatment

38. 39. 40. 41.

42.

43. 44.

45. 46.

47. 48. 49. 50.

51.

52. 53. 54.

55. 56.

57.

58.

405

rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255–1262. Sandercock P, Tangkanakul C. Very early prevention of stroke recurrence. Cerebrovasc Dis 1997; 7(suppl 1):10–15. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995; 26:1471–1477. Bousser MG. Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke 1999; 30:481–483. Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ 1994; 309:299–304. Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KA, Premmereur J, Bigonzi F. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337:447–452. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79:1–17. Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333:1588–1593. Hommel M. Fraxiparine in Ischaemic Stroke Study (FISS bis). Cerebrovasc Dis 1998; 8 (suppl 4):19. Turpie AGG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, Klimek M, Hirsh J. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993; 329:524–529. Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: a meta-analysis and hypothesis. Cerebrovasc Dis 1999; 9:215–217. Chamorro A. Heparin in acute ischemic stroke: the case for a new clinical trial. Cerebrovasc Dis 1999; 9(suppl 3):16–23. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71–86. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–106. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994; 308:235–246. van Kooten F, Ciabattoni G, Patrono C, Schmitz P, van Gijn J, Koudstaal P. Evidence for episodic platelet activation in acute ischaemic stroke. Stroke 1994; 25:278–281. Koudstaal P, Ciabattoni G, van Gijn J. Increased thromboxane biosynthesis in patients with acute cerebral ischaemia. Stroke 1993; 24:219–223. Lindley RI, Amayo EO, Marshall J, Sandercock PA, Dennis M, Warlow CP. Acute stroke treatment in UK hospitals: the Stroke Association survey of consultant opinion. J R Coll Physicians Lond 1995; 29:479–484. Ebrahim S, Redfern J. Stroke Care—A Matter of Chance. A National Survey of Stroke Services. London: The Stroke Association, 1999. Marsh EE III, Adams HP Jr, Biller J, Wasek P, Banwart K, Mitchell V, Woolson R. Use of antithrombotic drugs in the treatment of acute ischemic stroke: a survey of neurologists in practice in the United States. Neurology 1989; 39:1631–1634. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebocontrolled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349:1641–1649. Gubitz G, Sandercock P, Counsell C. Antiplatelet therapy for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002.

406

Berge and Sandercock

59. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40,000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31:1240–1249. 60. Bero LA, Grilli R, Grimshaw JM. Closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings. BMJ 1998; 317:465–468. 61. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential benefits, limitations and harms of clinical guidelines. BMJ 1999; 318:530. 62. Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346:1509–1514. 63. Patrono C, Coller B, Dalen JE, Fuster V, Gent M, Harker LA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 1998; 114(suppl 5):470S–488S. 64. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330:1287–1294. 65. van Gijn J. Aspirin: dose and indications in modern stroke prevention. Neurol Clin 1992; 10:193–209. 66. van Kooten F, Ciabattoni G, Patrono C, Dippel DW, Koudstaal PJ. Platelet activation and lipid peroxidation in patients with acute ischemic stroke. Stroke 1997; 28:1557–1563. 67. Born GVR, Collins R. Aspirin versus clopidogrel: the wrong question? Lancet 1997; 349:806. 68. D’Andrea G, Perini F, Hasselmark L, Alecci M, Cananzi AR. Effect of picotamide and aspirin, combined or alone, on platelet aggregation in patients with cerebral infarction. Funct Neurol 1995; 10:91–98. 69. Gao B. The effects of ligustrazine, aspirin and betahistidine on platelet aggregation in patients with acute ischaemic stroke. Chin J Neurol Psychiatry 1989; 22:148–151. 70. Kaye J. A Trial to Evaluate the Relative Roles of Dipyridamole and Aspirin in the Prevention of Deep Vein Thrombosis in Stroke Patients. Brackness (UK): Boehringer Ingelheim (Internal report trial no. CT 330/189), 2002. 71. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994; 330:956–961. 72. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, doseescalation study. The Abciximab in Ischemic Stroke Investigators. Stroke 2000; 31:601–609. 73. Lee KY, Heo JH, Lee SI, Yoon PH. Rescue treatment with abciximab in acute ischemic stroke. Neurology 2001; 56:1585–1587. 74. Kittusamy PK, Koenigsberg RA, McCormick DJ. Abciximab for the treatment of acute distal embolization associated with internal carotid artery angioplasty. Catheter Cardiovasc Interv 2001; 54:221–233. 75. Hofmann R, Kerschner K, Steinwender C, Kypta A, Bibl D, Leisch F. Abciximab bolus injection does not reduce cerebral ischemic complications of elective carotid artery stenting: a randomized study. Stroke 2002; 33:725–727. 76. Adams HP. Abciximab in Emergent Stroke Treatment Trial (AbESST). http://www. strokecenter.org/trials/. Date last accessed: December 30, 2002. 77. Junghans U, Seitz RJ, Ritzl A, Wittsack HJ, Fink GR, Freund HJ, Siebler M. Ischemic brain tissue salvaged from infarction by the GP IIb/IIIa platelet antagonist tirofiban. Neurology 2002; 58:474–476. 78. Cheung RT, Ho DS. Fatal hemorrhagic transformation of acute cerebral infarction after the use of abciximab. Stroke 2000; 31:2526–2527. 79. Ciuffetti G, Aisa G, Mercuri M, Lombardini R, Paltriccia R, Neri C, Senin U. Effects of ticlopidine on the neurologic outcome and the hemorheologic pattern in the postacute phase of ischemic stroke: a pilot study. Angiology 1990; 41:505–511. 80. Lowe G. The pharmacology of thrombolytic and fibrinogen-depleting agents in the treatment of acute ischaemic stroke. Cerebrovasc Dis 1998; 8(suppl 1):36–42.

Anticoagulant and Antiplatelet Treatment

407

81. Liu M, Counsell C, Wardlaw J. Fibrinogen depleting agents for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software, 2002. 82. Sherman DG, Atkinson RP, Chippendale T, Levin KA, Ng K, Futrell N, Hsu CY, Levy DE. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 2000; 283:2395–2403. 83. Orgogozo JM, Verstraete M, Kay R, Hennerici M, Lenzi GL. Outcomes of ancrod in acute ischemic stroke. Independent Data and Safety Monitoring Board for ESTAT. Steering Committee for ESTAT. European Stroke Treatment with Ancrod Trial. JAMA 2000; 284:1926–1927.

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

410

Wahlgren and Ahmed

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].

Neuroprotective Agents and Other Therapies for Acute Stroke

411

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.

412

Wahlgren and Ahmed

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

Neuroprotective Agents and Other Therapies for Acute Stroke

413

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.

414

Wahlgren and Ahmed

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-

Neuroprotective Agents and Other Therapies for Acute Stroke

415

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-

416

Wahlgren and Ahmed

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

Neuroprotective Agents and Other Therapies for Acute Stroke

417

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].

418

Wahlgren and Ahmed

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

Neuroprotective Agents and Other Therapies for Acute Stroke

419

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)

420

Wahlgren and Ahmed

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.

Neuroprotective Agents and Other Therapies for Acute Stroke

421

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].

422

Wahlgren and Ahmed

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.

Neuroprotective Agents and Other Therapies for Acute Stroke

423

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].

424

Wahlgren and Ahmed

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.

REFERENCES 1. Beal MF. Role of excitotoxicity in human neurological disease. Curr Opin Neurobiol 1992; 2:657–662. 2. Beal MF, Hyman BT, Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci 1993; 16:125–131. 3. Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 1988; 11:465–469. 4. Dietrich WD, Busto R, Halley M, Valdes I. The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990; 49:486– 497. 5. de Courten-Myers G, Myers RE, Schoolfield L. Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats. Stroke 1988; 19:623–630.

Neuroprotective Agents and Other Therapies for Acute Stroke

425

6. Hajat C, Hajat S, Sharma P. Effects of poststroke pyrexia on stroke outcome: a meta-analysis of studies in patients. Stroke 2000; 31:410–414. 7. Kammersgaard LP, Jorgensen HS, Rungby JA, Reith J, Nakayama H, Weber UJ, Houth J, Olsen TS. Admission body temperature predicts long-term mortality after acute stroke: the Copenhagen Stroke Study. Stroke 2002; 33:1759–1762. 8. Boysen G, Christensen H. Stroke severity determines body temperature in acute stroke. Stroke 2001; 32:413–417. 9. Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 2000; 31:1250–1255. 10. Pulsinelli WA, Waldman S, Sigsbee B, Rawlinson D, Plum F. Experimental hyperglycemia and diabetes mellitus worsens stroke outcome. In: Betz E, ed. Pathophysiology and Pharmacology of Cerebrovascular Disorders. Baden-Baden: Verlag Gerhard Witzstrock, 1980:196–199. 11. Heiss WD, Hayakawa T, Waltz AG. Cortical neuronal function during ischemia. Arch Neurol 1976; 33:813–820. 12. Hossman KA. Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. Brain Pathol 1994; 4:23–36. 13. Siesjo BK, Agardh CD, Bengtsson F. Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1989; 1:165–211. 14. Chan PH. Oxygen radicals in focal cerebral ischemia. Brain Pathol 1994; 4:59–65. 15. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981; 54: 773–782. 16. Morawetz RB, Crowell RH, DeGirolami U, Marcoux FW, Jones TH, Halsey JH. Regional cerebral blood flow thresholds during cerebral ischemia. Fed Proc 1979; 38:2493–2494. 17. Davalos A, Castillo J, Serena J, Noya M. Duration of glutamate release after acute ischemic stroke. Stroke 1997; 28:708–710. 18. Kuschinsky W, Gillardon F. Apoptosis and cerebral ischemia. Cerebrovasc Dis 2000; 10:165– 169. 19. Ernster L. Biochemistry of reoxygenation injury. Crit Care Med 1988; 16:947–953. 20. Lees KR. Neuroprotection. Br Med Bull 2000; 56:401–412. 21. Slikker W, Saran J, Auer RN, Palmer GC, Narahashi T, Youdim MBH, Maynard KI, Carbone KM, Trembly B. Neuroprotection: past successes and future challenges. Ann NY Acad Sci 2001; 939:465–477. 22. Liebeskind DS, Kasner SE. Neuroprotection for ischemic stroke: an unattainable goal? CNS Drugs 2001; 15:165–174. 23. DeGraba TJ, Pettigrew LC. Why do neuroprotective drugs work in animals but not humans? Neurol Clin 2000; 18:475–493. 24. Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work. Stroke 1999; 30:180–182. 25. Grotta J. Why do all drugs work in animals but none in stroke patients? 2. Neuroprotective therapy. J Intern Med 1995; 237:89–94. 26. Gorelick PB. Neuroprotection in acute ischemic stroke: a tale of for whom the bell tolls? Lancet 2000; 355:1925–1926. 27. Drummond JC, Piyash PM, Kimbro JR. Neuroprotection failure in stroke. Lancet 2000; 356:1032–1033. 28. Wardlaw JM, Warlow CP, Sandercock PA, Dennis MS, Lindley RI. Neuroprotection disappointment yet aGAIN. Lancet 2000; 356:597. 29. Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002; 33:2123–2136. 30. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Trust Study Group. Lancet 1990; 336:1205–1209. 31. Clinical trial of nimodipine in acute ischemic stroke. The American Nimodipine Study Group. Stroke 1992; 23:3–8.

426

Wahlgren and Ahmed

32. Bogousslavsky J, Regli F, Zumstein V, Kobberling W. Double-blind study of nimodipine in non-severe stroke. Eur Neurol 1990; 30:23–26. 33. Wahlgren NG, MacMahon DG, de Keyser J, Indredavik B, Ryman T, for the INWEST study group. The Intravenous Nimodipine West European Trial (INWEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis 1994; 4:204–210. 34. Sze KH, Sim TC, Wong E, Cheng S, Woo J. Effect of nimodipine on memory after cerebral infarction. Acta Neurol Scand 1998; 97:386–392. 35. Paci A, Ottaviano P, Trenta A, Iannone G, De Santis L, Lancia G, Moschini E, Carosi M, Amigoni S, Caresia L. Nimodipine in acute ischemic stroke: a double-blind controlled study. Acta Neurol Scand 1989; 80:282–286. 36. Norris JW, LeBrun LH, Anderson BA, The Canwin Study Group. Intravenous nimodipine in acute ischemic stroke. Cerebrovasc Dis 1994; 4:194–196. 37. Nag D, Garg RK, Varma M. A randomized double-blind controlled study of nimodipine in acute cerebral ischemic stroke. Indian J Physiol Pharmacol 1998; 42:555–558. 38. Martinez-Vila E, Guillen F, Villanueva JA, Matias-Guiu J, Bigorra J, Gil P, Carbonell A, Martinez-Lage JM. Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction. Angiology 1990; 41:1010–1016. 39. Kaste M, Fogelholm R, Erila T, Palomaki H, Murros K, Rissanen A, Sarna S. A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. Stroke 1994; 25:1348–1353. 40. Infeld B, Davis SM, Donnan GA, Yasaka M, Lichtenstein M, Mitchell PJ, Fitt GJ. Nimodipine and perfusion changes after stroke. Stroke 1999; 30:1417–1423. 41. Horn J, de Haan RJ, Vermeulen M, Limburg M. Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 2001; 32:461–465. 42. Heiss WD, Holthoff V, Pawlik G, Neveling M. Effect of nimodipine on regional cerebral glucose metabolism in patients with acute ischemic stroke as measured by positron emission tomography. J Cereb Blood Flow Metab 1990; 10:127–132. 43. Gelmers HJ, Gorter K, de Weerdt CJ, Wiezer HJ. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med 1988; 318:203–207. 44. Gelmers HJ. The effects of nimodipine on the clinical course of patients with acute ischemic stroke. Acta Neurol Scand 1984; 69:232–239. 45. Mohr JP, Orgogozo JM, Harrison MJG, Hennerici M, Wahlgren NG, Gelmers JH, MartinezVila E, Dycka J, Tettenborn D. Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cerebrovasc Dis 1994; 4:197–203. 46. Rosenbaum D, Zabramski J, Frey J, Yatsu F, Marler J, Spetzler R, Grotta J. Early treatment of ischemic stroke with a calcium antagonist. Stroke 1991; 22:437–441. 47. Limburg M, Hijdra A. Flunarizine in acute ischemic stroke: a pilot study. Eur Neurol 1990; 30:121–122. 48. Franke CL, Palm R, Dalby M, Schoonderwaldt HC, Hantson L, Eriksson B, Lang-Jenssen L, Smakman J. Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands. Acta Neurol Scand 1996; 93:56–60. 49. Azcona A, Lataste X. Isradipine in patients with acute ischemic cerebral infarction. An overview of the ASCLEPIOS Programme. Drugs 1990; 40:52–57. 50. Oczkowski WJ, Hachinski VC, Bogousslavsky J, Barnett HJ, Carruthers SG. A double-blind, randomized trial of PY108-068 in acute ischemic cerebral infarction. Stroke 1989; 20:604–608. 51. Horn J, Limburg M. Calcium antagonists for acute ischemic stroke. Cochrane Database Systematic Review 2000; 2:CD001928. 52. Chan SA, Reid KH, Schurr A, Miller JJ, Iyer V, Tseng MT. Fosphenytoin reduces hippocampal neuronal damage in rat following transient global ischemia. Acta Neurochir (Wien) 1998; 140:175–180. 53. Graham SH, Chen J, Lan J, Leach MJ, Simon RP. Neuroprotective effects of a use-dependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion. J Pharmacol Exp Ther 1994; 269:854–859.

Neuroprotective Agents and Other Therapies for Acute Stroke

427

54. The Internet Stroke Center. Washington University School of Medicine. URL: http://www. strokecenter.org/, in, 2002. 55. Muir KW, Hamilton SJ, Lunnon MW, Hobbiger S, Lees KR. Safety and tolerability of 619C89 after acute stroke. Cerebrovasc Dis 1998; 8:31–37. 56. Muir KW, Holzapfel L, Lees KR. Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke. Cerebrovasc Dis 2000; 10:431–436. 57. Grotta J, Clark W, Coull B, Pettigrew LC, Mackay B, Goldstein LB, Meissner I, Murphy D, LaRue L. Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. Stroke 1995; 26:602–605. 58. Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J. Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke 2000; 31:347–354. 59. Albers GW, Goldstein LB, Hall D, Lesko LM. Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 2001; 286:2673–2682. 60. Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM. Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Stroke 1995; 26:254–258. 61. Bullock MR, Merchant RE, Carmack CA, Doppenberg E, Shah AK, Wilner KD, Ko G, Williams SA. An open-label study of CP-101,606 in subjects with a severe traumatic head injury or spontaneous intracerebral hemorrhage. Ann NY Acad Sci 1999; 890:51–58. 62. Dyker AG, Lees KR. Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke. Stroke 1999; 30:1796–1801. 63. Harrison NL, Simmonds MA. Quantitative studies on some antagonists of N-methyl-Daspartate in slices of rat cerebral cortex. Br J Pharmacol 1985; 84:381–391. 64. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamateactivated channels in mouse central neurones. Nature 1984; 307:462–465. 65. Muir KW, Lees KR. A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Stroke 1995; 26:1183–1188. 66. Mitka M. News about neuroprotectants for the treatment of stroke. JAMA 2002; 287:1253– 1254. 67. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomized controlled trial. Lancet 2004; 363:439–445. 68. Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 1987; 325:529–531. 69. Sacco RL, DeRosa JT, Haley EC Jr, Levin B, Ordronneau P, Phillips SJ, Rundek T, Snipes RG, Thompson JL. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 2001; 285:1719–1728. 70. Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M, Orgogozo JM, Whitehead J. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet 2000; 355: 1949–1954. 71. Albers GW, Clark WM, Atkinson RP, Madden K, Data JL, Whitehouse MJ. Dose escalation study of the NMDA glycine-site antagonist licostinel in acute ischemic stroke. Stroke 1999; 30:508–513. 72. Lees KR. Cerestat and other NMDA antagonists in ischemic stroke. Neurology 1997; 49:S66– S69. 73. Lee JM, Zipfel GJ, Choi DW. The changing landscape of ischemic brain injury mechanisms. Nature 1999; 399:A7–A14. 74. Nicoletti F, Bruno V, Copani A, Casabona G, Knopfel T. Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders? Trends Neurosci 1996; 19:267–271. 75. ARTIST +: AMPA Receptor Antagonist Treatment in Ischemic Stroke Trial, YM872 + Alteplase. Ongoing Clinical Trials Session, in, 27th International Stroke Conference, URL: http://stroke.ahajournals.org/, 2002. 76. ARTIST MRI: AMPA Receptor Antagonist Treatment in Ischemic Stroke Trial-MRI. On-

428

77. 78.

79. 80.

81. 82. 83.

84.

85.

86. 87. 88.

89.

90.

91.

92.

93. 94. 95. 96.

97.

Wahlgren and Ahmed going Clinical Trials Session, in, 27th International Stroke Conference. URL: http://stroke. ahajournals.org/, 2002. Bassi S, Albizzati MG, Sbacchi M, Frattola L, Massarotti M. Double-blind evaluation of monosialoganglioside (GM1) therapy in stroke. J Neurosci Res 1984; 12:493–498. Argentino C, Sacchetti ML, Toni D, Savoini G, D’Arcangelo E, Erminio F, Federico F, Milone FF, Gallai V, Gambi D, et al. GM1 ganglioside therapy in acute ischemic stroke. Italian Acute Stroke Study—Hemodilution+ Drug. Stroke 1989; 20:1143–1149. Ganglioside GM1 in acute ischemic stroke. The SASS Trial. Stroke 1994; 25:1141–1148. Lenzi GL, Grigoletto F, Gent M, Roberts RS, Walker MD, Easton JD, Carolei A, Dorsey FC, Rocca WA, Bruno R, et al. Early treatment of stroke with monosialoganglioside GM-1. Efficacy and safety results of the Early Stroke Trial. Stroke 1994; 25:1552–1558. Candelise L, Ciccone A. Gangliosides for acute ischemic stroke. Cochrane Database Syst Rev:CD000094., 2001. Cross AJ, Jones JA, Baldwin HA, Green AR. Neuroprotective activity of chlormethiazole following transient forebrain ischemia in the gerbil. Br J Pharmacol 1991; 104:406–411. Cross AJ, Jones JA, Snares M, Jostell KG, Bredberg U, Green AR. The protective action of chlormethiazole against ischemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity. Br J Pharmacol 1995; 114:1625–1630. Snape MF, Baldwin HA, Cross AJ, Green AR. The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischemia in the rat. Neuroscience 1993; 53:837– 844. Sydserff SG, Cross AJ, Green AR. The neuroprotective effect of chlormethiazole on ischemic neuronal damage following permanent middle cerebral artery ischemia in the rat. Neurodegeneration 1995; 4:323–328. Sydserff SG, Cross AJ, West KJ, Green AR. The effect of chlormethiazole on neuronal damage in a model of transient focal ischemia. Br J Pharmacol 1995; 114:1631–1635. Hales TB, Lambert JJ. Modulation of GABAa and glycine receptors by clomethiazole. Eur J Pharmacol 1992; 210:239–246. Wahlgren NG, Ranasinha KW, Rosolacci T, Franke CL, van Erven PM, Ashwood T, Claesson L. Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke 1999; 30:21–28. Wahlgren NG, Matias-Guiu J, Lainez JM, Veloso F, Ranasinha K, Grossman E, Ashwood T, for the CLASS study Group. The clomethiazole acute stroke study (CLASS): Safety results in 1,356 patients with hemispheric stroke. J Stroke Cerebrovasc Dis 2000; 9:158–165. Wahlgren NG, Bornhov S, Bornhov S, Sharma A, Cederin B, Rosolacci T, Ashwood T, Claesson L, for the CLASS study group. The Clomethiazole Acute Stroke Study (CLASS): Efficacy results in 545 patients classified as total anterior circulation syndrome (TACS). J Stroke Cerebrovasc Dis 1999; 8:231–239. Wahlgren NG, Diez-Tejedor E, Teitelbaum J, Arboix A, Leys D, Ashwood T, Grossman E. Results in 95 hemorrhagic stroke patients included in CLASS, a controlled trial of clomethiazole versus placebo in acute stroke patients. Stroke 2000; 31:82–85. Lyden P, Shuaib A, Ng K, Levin K, Atkinson RP, Rajput A, Wechsler L, Ashwood T, Claesson L, Odergren T, Salazar-Grueso E. Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke 2002; 33:122–128. Early GABA-ergic Activation Study In Stroke (EGASIS). Stroke 2002; 33:646–655. BRAINS (Bayer Randomised Acute Ischemia Neuroprotectant Study). Stroke 2000; 31:2768– 2871. Repinotan in acute ischemic stroke—a randomized exposure controlled trial. On-Going Clinical Trials Session. Abstract of the 26th International Stroke Conference. Stroke 32, 2001. POST: double-blind, placebo controlled safety and efficacy trials of intravenous BMS-204352 in patients with acute stroke. On-going Clinical Trials Session, 25th International Stroke Conference, in, The Internet Stroke Center. URL: http://www.strokecenter.org/, 2002. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993; 262:689–695.

Neuroprotective Agents and Other Therapies for Acute Stroke

429

98. Kamii H, Mikawa S, Murakami K, Kinouchi H, Yoshimoto T, Reola L, Carlson E, Epstein CJ, Chan PH. Effects of nitric oxide synthase inhibition on brain infarction in SOD-1-transgenic mice following transient focal cerebral ischemia. J Cereb Blood Flow Metab 1996; 16:1153– 1157. 99. Ying W, Anderson CM, Chen Y, Stein BA, Fahlman CS, Copin JC, Chan PH, Swanson RA. Differing effects of copper, zinc superoxide dismutase overexpression on neurotoxicity elicited by nitric oxide, reactive oxygen species, and excitotoxins. J Cereb Blood Flow Metab 2000; 20:359–368. 100. Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, Chan PH. Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci 1998; 18:205–213. 101. Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 1998; 29:12–17. 102. Ogawa A, Yoshimoto T, Kikuchi H, Sano K, Saito I, Yamaguchi T, Yasuhara H. Ebselen in acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial. Cerebrovasc Dis 1999; 9:112–118. 103. A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). The RANTTAS Investigators. Stroke 1996; 27:1453–1458. 104. Haley EC Jr. High-dose tirilazad for acute stroke (RANTTAS II). RANTTAS II Investigators. Stroke 1998; 29:1256–1257. 105. Bath PM, Iddenden R, Bath FJ, Orgogozo JM. Tirilazad for acute ischemic stroke. Cochrane Database Syst Rev:CD002087, 2001. 106. Lees KR, Sharma AK, Barer D, Ford GA, Kostulas V, Cheng YF, Odergren T. Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke. Stroke 2001; 32:675– 680. 107. Lesage AS, Peeters L, Leysen JE. Lubeluzole, a novel long-term neuroprotectant, inhibits the glutamate-activated nitric oxide synthase pathway. J Pharmacol Exp Ther 1996; 279:759– 766. 108. Grotta J. Lubeluzole treatment of acute ischemic stroke. The US and Canadian Lubeluzole Ischemic Stroke Study Group. Stroke 1997; 28:2338–2346. 109. Diener HC, Cortens M, Ford G, Grotta J, Hacke W, Kaste M, Koudstaal PJ, Wessel T. Lubeluzole in acute ischemic stroke treatment: a double-blind study with an 8-hour inclusion window comparing a 10-mg daily dose of lubeluzole with placebo. Stroke 2000; 31:2543–2551. 110. Ford GA. Lubeluzole plasma concentrations and outcome in acute ischemic stroke. Cerebrovasc Dis 2000; 10:78. 111. Ay H, Ay I, Koroshetz WJ, Finklestein SP. Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc Dis 1999; 9:131–135. 112. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 2001; 57:1428–1434. 113. Wayne C, William E, Edward O, Eric R. Cervene in acute ischemic stroke: results of a double-blind, placebo-controlled, dose-comparison study. J Stroke Cerebrovasc Dis 1999; 8:224– 230. 114. Clark WM, Raps EC, Tong DC, Kelly RE. Cervene (Nalmefene) in acute ischemic stroke: final results of a phase III efficacy study. The Cervene Stroke Study Investigators. Stroke 2000; 31:1234–1239. 115. Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R. Effect of citicoline on ischemic lesions as measured by diffusionweighted magnetic resonance imaging. Citicoline 010 Investigators. Ann Neurol 2000; 48:713– 722. 116. Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA. A randomized doseresponse trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology 1997; 49:671–678.

430

Wahlgren and Ahmed

117. Clark WM, Williams BJ, Selzer KA, Zweifler RM, Sabounjian LA, Gammans RE. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999; 30:2592–2597. 118. Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001; 57:1595– 1602. 119. Role of Intravenous Citicoline for Supratentorial Hemorrhage (RICH Study). On-going Clinical Trials Session, in, 27th International Stroke Conference, URL: http://stroke.ahajournals. org/, 2002. 120. De Deyn PP, Reuck JD, Deberdt W, Vlietinck R, Orgogozo JM. Treatment of acute ischemic stroke with piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. Stroke 1997; 28:2347–2352. 121. Major Ongoing Stroke Trials: PASS II (Piracetam Acute Stroke Study II). Stroke 2000; 31: 2536–2542. 122. A study to evaluate the effects of ONO-2506 intravenous infusion in patients with acute ishemic stroke, in, http://www.clinicaltrials.gov, 2003. 123. Huber M, Kittner B, Hojer C, Fink GR, Neveling M, Heiss WD. Effect of propentofylline on regional cerebral glucose metabolism in acute ischemic stroke. J Cereb Blood Flow Metab 1993; 13:526–530. 124. Chen J, Nagayama T, Jin K, Stetler RA, Zhu RL, Graham SH, Simon RP. Induction of caspase3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 1998; 18:4914–4928. 125. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, Shimizu-Sasamata M, Yuan J, Moskowitz MA. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 1997; 94:2007– 2012. 126. Himi T, Ishizaki Y, Murota S. A caspase inhibitor blocks ischemia-induced delayed neuronal death in the gerbil. Eur J Neurosci 1998; 10:777–781. 127. MacManus JP, Buchan AM. Apoptosis after experimental stroke: fact or fashion? J Neurotrauma 2000; 17:899–914. 128. Rosenblum WI. Apoptosis and stroke pathogenesis. Stroke 1999; 30:1154–1156. 129. Fink K, Zhu J, Namura S, Shimizu-Sasamata M, Endres M, Ma J, Dalkara T, Yuan J, Moskowitz MA. Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation. J Cereb Blood Flow Metab 1998; 18:1071–1076. 130. Ladurner G. Neuroprotection in acute ischemic stroke (Abstracts of the International Stroke Conference 2001). Stroke 2001; 32:323-c. 131. Lyden P, Jacoby M, Schim J, Albers G, Mazzeo P, Ashwood T, Nordlund A, Odergren T. The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASST): final results. Neurology 2001; 57:1199–1205. 132. Grotta J. Combination Therapy Stroke Trial: rt-PA +/
lubeluzole. Stroke 2000; 31:278. 133. Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G, D’Alessandro R. Fever in acute stroke worsens prognosis. A prospective study. Stroke 1995; 26:2040–2043. 134. Jorgensen HS, Reith J, Pedersen PM, Nakayama H, Olsen TS. Body temperature and outcome in stroke patients. Lancet 1996; 348:193. 135. Reith J, Jorgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL, Olsen TS. Body temperature in acute stroke: relation to troke severity, infarct size, mortality, and outcome. Lancet 1996; 347:422–425. 136. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke 1998; 29:529–534. 137. Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke 2002; 33:519–524. 138. Dippel DW, van Breda EJ, van Gemert HM, van der Worp HB, Meijer RJ, Kappelle LJ,

Neuroprotective Agents and Other Therapies for Acute Stroke

139.

140.

141.

142.

143.

144.

145.

146.

147. 148. 149.

150.

151. 152.

153. 154. 155.

156.

157.

431

Koudstaal PJ. Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: a double-blind, randomized phase II clinical trial. Stroke 2001; 32:1607–1612. Kasner SE, Wein T, Piriyawat P, Villar-Cordova CE, Chalela JA, Krieger DW, Morgenstern LB, Kimmel SE, Grotta JC. Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Stroke 2002; 33:130–134. Knoll T, Wimmer ML, Gumpinger F, Haberl RL. The low normothermia concept— maintaining a core body temperature between 36 and 37 degrees C in acute stroke unit patients. J Neurosurg Anesthesiol 2002; 14:304–308. Kammersgaard LP, Rasmussen BH, Jorgensen HS, Reith J, Weber U, Olsen TS. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case-control study: the Copenhagen Stroke Study. Stroke 2000; 31:2251– 2256. Georgiadis D, Schwarz S, Kollmar R, Schwab S. Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. Stroke 2001; 32:2550–2553. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998; 29:2461– 2466. Schwab S, Schwarz S, Aschoff A, Keller E, Hacke W. Moderate hypothermia and brain temperature in patients with severe middle cerebral artery infarction. Acta Neurochir Suppl (Wien) 1998; 71:131–134. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke 2001; 32:2033–2035. Steiner T, Friede T, Aschoff A, Schellinger PD, Schwab S, Hacke W. Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke 2001; 32:2833–2835. Meden P, Kammersgaard L, Overgaard K. [Can acute stroke be treated with hypothermia?]. Nord Med 1998; 113(15):3–5. Correia M, Silva M, Veloso M. Cooling therapy for acute stroke. Cochrane Database Syst Rev:CD001247, 2000. Rieke K, Schwab S, Krieger D, von Kummer R, Aschoff A, Schuchardt V, Hacke W. Decompressive surgery in space-occupying hemispheric infarction: results of an open, prospective trial. Crit Care Med 1995; 23:1576–1587. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 1996; 53:309–315. Hacke W, Stingele R, Steiner T, Schuchardt V, Schwab S. Critical care of acute ischemic stroke. Intensive Care Med 1995; 21:856–862. Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O, Hacke W. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke 1998; 29:1888– 1893. Broderick JP, Hacke W. Treatment of acute ischemic stroke: Part II: neuroprotection and medical management. Circulation 2002; 106:1736–1740. Heros RC. Surgical treatment of cerebellar infarction. Stroke 1992; 23:937–938. Safety and Feasibility of Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage: The NovoSeven ICH Trial, in Ongoing Clinical Trials Session, 27th International Stroke Conference, 2002, URL: http://stroke.ahajournals.org/, 2002. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30:2752– 2758. Recommendations for Clinical Trial Evaluation of Acute Stroke Therapies. Stroke 2001; 32:1598–1606.

432

Wahlgren and Ahmed

158. Kidwell CS, Liebeskind DS, Starkman S, Saver JL. Trends in acute ischemic stroke trials through the 20th century. Stroke 2001; 32:1349–1359. 159. Grotta J. Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke 2002; 33:306–307. 160. Lees KR. Neuroprotection is unlikely to be effective in humans using current trial designs: an opposing view. Stroke 2002; 33:308–309. 161. Davis SM, Donnan GA. Neuroprotection: establishing proof of concept in human stroke. Stroke 2002; 33:309–310.

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

434

Chaloupka et al.

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.

PTA of Cerebrovascular Occlusive Disease

435

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

436

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

437

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

438

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

439

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

440

Chaloupka et al.

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’’

PTA of Cerebrovascular Occlusive Disease

441

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

442

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

443

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

444

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

445

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.

446

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

447

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

448

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

449

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.

450

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

451

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

452

Chaloupka et al.

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].

PTA of Cerebrovascular Occlusive Disease

453

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.

454

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

Figure 2 Continued.

455

456

Chaloupka et al.

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.

PTA of Cerebrovascular Occlusive Disease

457

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

458

Chaloupka et al.

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.

PTA of Cerebrovascular Occlusive Disease

Figure 3 Continued.

459

460

Figure 3 Continued.

Chaloupka et al.

PTA of Cerebrovascular Occlusive Disease

461

Figure 3 Continued.

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

462

Chaloupka et al.

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.

PTA of Cerebrovascular Occlusive Disease

463

Figure 4 Continued.

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].

464

Chaloupka et al.

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(1
A/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

PTA of Cerebrovascular Occlusive Disease

465

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,

466

Chaloupka et al.

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),

PTA of Cerebrovascular Occlusive Disease

467

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

468

Chaloupka et al.

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

PTA of Cerebrovascular Occlusive Disease

469

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

470

Chaloupka et al.

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.

REFERENCES 1. AbuRahma AF, Bates MC, Stone PA, Wulu JT. Comparative study of operative treatment and percutaneous transluminal angioplasty/stenting for recurrent carotid disease. J Vasc Surg 2001; 34:831–838. 2. Alazzaz A, Thornton J, Aletich VA, et al. Intracranial percutaneous transluminal angioplasty for arteriosclerotic stenosis. Arch Neurol 2000; 57:1625–1630. 3. 1999 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association, 1999. 4. Ahuja A, Guterman LR, Hopkins LN. Angioplasty for basilar artery atherosclerosis. J Neurosurg 1992; 77:941–944. 5. Al-Mubarak N, Roubin GS, Gomez CR, et al. Carotid artery stenting in patients with high neurological risks. Am J Cardiol 1999; 83:1411–1413. 6. Al-Mubarak N, Roubin GS, Iyer SS, et al. Carotid stenting for severe radiation-induced extracranial carotid artery occlusive disease. J Endovasc Surg 2000; 7:36–40. 7. Al-Mubarak N, Gomez CR, Vitek JJ, Roubin GS. Stenting of symptomatic stenosis of the intracranial internal carotid artery. AJNR Am J Neuroradiol 1998; 19:1949–1951. 8. Asymptomatic Carotid Atherosclerosis Study Executive Committee. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421–1428. 9. Audiffret A, Desgranges P, Kobeiter H, et al. Technical aspects and current results of carotid stenting. J Vasc Surg 2001; 33:1001–1007. 10. Autret A, Pourcelot L, Saudeau D, et al. Stroke risk in patients with carotid stenosis. Lancet 1987; 1:888–890. 11. Bharadvaj BK, Mabon RF, Giddens DP. Steady flow in a model of the human carotid bifurcation. Part I-laser-Doppler anemometer measurements. J Biomechanics 1982; 15(5):363–378. 12. Barnett HJ, Fox A, Hachinski VC, Haynes B, Peerless SJ, Sackett D, Taylor DW. Further conclusions from the extracranial-intracranial bypass trial. Surg Neurol 1986; 26:227–235. 13. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339:1415–1425.

482

Chaloupka et al.

14. Becker GI. Current and future treatment of carotid bifurcation atherosclerotic disease: a perspective. JVIR 1997; 8:3–8. 15. Beebe HG. Scientific evidence demonstrating the safety of carotid angioplasty and stenting: do we have enough to draw conclusions yet? J Vasc Surg 1998; 27:788–790. 16. Beebe HG, Kritpracha B. Carotid stenting versus carotid endarterectomy: update on the controversy. Semin Vasc Surg 1998; 11:46–51. 17. Bejjani GH, Monsein LH, Laird JR, et al. Treatment of symptomatic cervical carotid dissections with endovascular stents. Neurosurgery 1999; 44:755–761. 18. Bergeron P, Chambran P, Hartung O, Bianca S. Cervical carotid artery stenosis: which technique, balloon angioplasty or surgery? J Cardiovasc Surg (Torino) 1996; 37:73–75. 19. Bergeron P, Becquemin JP, Jausseran JM, et al. Percutaneous stenting of the internal carotid artery: the European CAST I study. J Endovasc Surg 1999; 6:155–159. 20. Bockenheimer SA, Mathias K. Percutaneous transluminal angioplasty in arteriosclerotic internal artery stenosis. AJNR Am J Neuroradiol 1983; 43:791–792. 21. Bogousslavsky J, Barnett HJM, Fox AJ, et al. Atherosclerotic diseases of the middle cerebral artery. Stroke 1986; 17:1112–1120. 22. Bonaldi G. Angioplasty and stenting of the cervical carotid bifurcation: report of a 4 year series. Neuroradiology 2002; 44:164–174. 23. Brooks WH, McClure RR, Jones MR, et al. Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital. J Am Coll Cardiol 2001; 38:1589– 1595. 24. Brott T, Thalinger K. The practice of carotid endarterectomy in a large metropolitan area. Stroke 1984; 15:950–955. 25. Brown MN. CAVATAS late results: does carotid balloon angioplasty fare well against endarterectomy? Proceedings of TCT 2002. Washington, DC: Cardiovascular Research Foundation, 2002:96. 26. Callahan AS, Berger BL. Basilar artery endoprosthesis placement: rescue therapy for recurrent thrombosis. J Neuroimaging 2000; 10:47–48. 27. Callahan BS, Berger BL. Balloon angioplasty of intracranial arteries for stroke prevention. J Neuroimaging 1997; 7:232–235. 28. Caplan L, Babikian V, Helgason C, et al. Occlusive disease of the middle cerebral artery. Neurology 1985; 35:975–982. 29. Chaloupka JC, Weigele JB, Mangla S, Lesley WS. Cerebrovascular angioplasty and stenting for the prevention of stroke. Curr Neurol Neuroscie Rep 2001; 1:39–53. 30. Chimowitz MI. Angioplasty or stenting is not appropriate as first-line treatment of intracranial stenosis. Arch Neurol 2001; 58:1690–1692. 31. Conners JJ, Wojak JC. Interventional Neurordiology: Part IV: Brachiocephalic Angioplasty and Stenting. Philadelphia: W.B. Saunders, 1999:431–555. 32. Conners JJ, Wojak JC. Percutaneous transluminal angioplasty for intracranial atherosclerotic lesions: evolution of technique and short term results. J Neurosurg 1999; 91:415–423. 33. Conners JJ, Seidenwurm DS, Wojak JC, et al. Treatment of atherosclerotic disease at the cervical carotid bifurcation: current status and review of the literature. AJNR Am J Neuroradiol 2000; 21:444–450. 34. Craig DR, Meguro K, Watridge C, et al. Intracranial internal carotid artery stenosis. Stroke 1982; 13:825–828. 35. Crawley F, Brown MM, Clifton AG. Angioplasty and stenting in the carotid arteries. Postgrad Med J 1998; 74:7–10. 36. Criado FJ, Lingelbach JM, Ledesma DF, Lucas PR. Carotid artery stenting in a vascular surgery practice. J Vasc Surg 2002; 35:430–434. 37. Criado FJ, Wellons E, Clark NS. Evolving indications for and early results of carotid artery stenting. Am J Surg 1997; 174:111–114. 38. Dorros G, Cohn JM, Palmer LE. Stent deployment resolves a petrous carotid artery angioplasty dissection. AJNR Am J Neuroradiol 1998; 19:392–394.

PTA of Cerebrovascular Occlusive Disease

483

39. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction: description of a new technique and a preliminary report of its application. Circulation 1964; 30:654–670. 40. Debakey MH. Carotid endarterectomy revisited. J Endovascular Surg 1996; 3:4. 41. Diethrich EB, Ndiaye M, Reid DB. Stenting in the carotid artery: initial experience in 110 patients. J Endovasc Surg 1996; 3:42–62. 42. Eastcott HHG, Pickering GW, Robb C. Reconstruction of internal carotid artery in a patient with intermittent attacks of hemiplegia. Lancet 1954; 2:994. 43. Eckard DA, Zarnow DM, McPherson CM, et al. Intracranial internal carotid angioplasty: technique with clinical and radiographic results and followup. AJR 1999; 172:703–707. 44. EC/IC Bypass Study Group. Failure of extracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985; 313:1191–1200. 45. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001; 357:1729–1737. 46. European Carotid Trialists Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70% to 99%) or with mild (0 to 29%) carotid stenosis. Lancet 1991; 337:1235–1243. 47. Feldman RL, Trigg L, Gaudier J, Galet J. Use of coronary Palmaz-Schatz stent in percutaneous treatment of an intracranial carotid artery stenosis. Catheterization Cardiovasc Diagn 1996; 38:316–319. 48. Feldmann E, Daneault N, Kwan E, et al. Chinese-white differences in the distribution of occlusive disease. Neurology 1990; 40:1541–1545. 49. Fessler RD, Lanzino G, Guterman LR, et al. Improved cerebral perfusion after stenting of a petrous carotid stenosis: technical case report. Neurosurgery 1999; 45:638–642. 50. Fisher CM. Occlusion of the carotid artery. Arch Neurol Psychiatry 1951; 69:346–377. 51. Fisher CM. Occlusion of the carotid artery; further experiences. Arch Neurol Psychiatry 1954; 72:187–204. 52. Fox DJ, Moran CJ, Cross DT, et al. Long-term outcome after angioplasty for symptomatic extracranial carotid stenosis in poor surgical candidates. Stroke 2002; 33:2877–2880. 53. Fung YC. Biomechanics: Circulation. 2d ed. New York: Springer-Verlag, 1997. 54. Fredricks H, Kievit J, Van Baalen JM, et al. Carotid recurrent stenosis and risk of ipsilateral stroke: a systematic review of the literature. Stroke 1998; 29:244–250. 55. Gil-Peralta A, Mayol A, Marcos JR, et al. Percutaneous transluminal angioplasty of the symptomatic atherosclerotic carotid arteries. Results, complications, and follow-up. Stroke 1996; 27:2271–2273. 56. Gomez GR. The role of carotid angioplasty and stenting. Semin Neurol 1998; 18:501–511. 57. Gomez CR, Misra VK, Liu MW, et al. Elective stenting of symptomatic basilar artery stenosis. Stroke 2000; 31:95–99. 58. Gondim AAA, Cruz-Flores S, Moore J, AL-Joundi T. Angioplasty and stenting for symptomatic basilar artery stenosis. J Neuroimaging 2002; 12:55–58. 59. Gorelick PB, Caplan LR, Hier DB, et al. Racial differences in the distribution of anterior circulation occlusive disease. Neurology 1984; 34:54–59. 60. Gorelick PB, Caplan LR, Hier DB, et al. Racial differences in the distribution of posterior circulation occlusive disease. Stroke 1985; 16:785–790. 61. Gress DR, Smith WS, Dowd CF, et al. Angioplasty for intracranial symptomatic vertebrobasilar ischaemia. Neurosurgery 2002; 51:23–29. 62. Gruntzig A, Hopff H. Perkutane Rekanalisation chronisher arterieller Verschlusse mit einem neuen Dilatationskatheter. Modifikation der Dotter-technik. Dtsch Med Wochenschr 1974; 99:2502–2505. 63. Hass WK, Fields WS, North RR, et al. Joint study of extracranial arterial occlusion. II. Arteriography, techniques, sites, and complications. JAMA 1968; 203:961–968. 64. Henry M, Amor M, Masson I, et al. Angioplasty and stenting of the extracranial carotid arteries. J Endovasc Surg 1998; 5:293–304.

484

Chaloupka et al.

65. Higashida RT, Hieshima GB, Tsai FY, et al. Transluminal angioplasty of the vertebral and basilar artery. AJNR Am J Neuroradiol 1987; 8:745–749. 66. Heyden S, Heyman A, Goree JA. Nonembolic occlusion of middle cerebral and carotid arteries—a comparison of predisposing factors. Stroke 1970; 1:363–369. 67. Hobson RW, Weiss DG, Fields WS, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis: The Veterans Affairs Cooperative Study group. N Engl J Med 1993; 328:221– 227. 68. Hobson RW. CREST (Carotid Revascularisation Endarterectomy versus Stent Trial): background, design, and current status. Semin Vasc Surg 2000; 13(2):139–143. 69. Hobson RW. Status of carotid angioplasty and stenting trials. J Vasc Surg 1998; 27:791. 70. Hobson RW, Goldstein JE, Jamil Z, et al. Carotid restenosis: operative and endovascular management. J Vasc Surg 1999; 29:228–238. 71. Hobson R. Regarding ‘‘randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial.’’ J Vasc Surg 2000; 31:622–623. 72. Horowitz MB, Pride GL, Graybeal DF, Purdy PD. Percutaneous transluminal angioplasty and stenting of midbasilar stenoses: three technical case reports and literature review. Neurosurgery 1999; 45:925–931. 73. Houdart E, Ricolfi F, Brugieres P, et al. Percutaneous transluminal angioplasty of atherosclerotic basilar artery stenosis. Neuroradiology 1996; 38:383–385. 74. Jiminez C, Duong H, Olarte M, Pile-Spellman J. Recurrent abrupt occlusion after transluminal angioplasty for basilar artery stenosis: case report. Neurosurgery 1999; 44:210–215. 75. Jordan WD, Roye GD, Fisher WS, et al. A cost comparison of balloon angioplasty and stenting versus endarterectomy for the treatment of carotid artery stenosis. J Vasc Surg 1998; 27:16–24. 76. Jordan WD, Voellinger DC, Fisher WS, et al. A comparison of carotid angioplasty with stenting versus endarterectomy with regional anesthesia. J Vasc Surg 1998; 28:397–403. 77. Kerber CW, Hornwell LD, Loeden OL. Catheter dilatation of proximal carotid stenosis during distal carotid endarterectomy. AJNR Am J Neuroradiol 1980; 1:348–349. 78. Kilaru S, Korn P, Kasirajan K. Is carotid angioplasty and stenting more cost effective than carotid endarterectomy? J Vasc Surg 2003; 37:331–339. 79. Ku DN, Giddens DP. Laser Doppler anemometer measurements of pulsatile flow in a model carotid bifurcation. J Biomechanics 1987; 20(4):407–421. 80. Lanzino G, Fessler RD, Miletich RS, et al. Angioplasty and stenting of basilar artery stenosis: technical case report. Neurosurgery 1999; 45:404–408. 81. Lanzino G, Mericle RA, Lopes DK, et al. Percutaneous transluminal angioplasty and stent placement for recurrent carotid artery stenosis. J Neurosurg 1999; 90:688–694. 82. Levy EI, Hanel RA, Bendok BR, et al. Staged stent-assisted angioplasty for symptomatic intracranial vertebrobasilar artery stenosis. J Neurosurg 2002; 97:1294–1301. 83. Levy EI, Horowitz MB, Kroebbe CJ, et al. Transluminal stent-assisted angioplasty of the intracranial vertebrobasilar system for medically refractory, posterior circulation ischaemia: early results. Neurosurgery 2001; 48(6):1215–1221. 84. Lylyk P, Cohen JE, Ceratto R, et al. Angioplasty and stent placement in intracranial atherosclerotic stenoses and dissections. Am J Neuroradiol 2002; 23:430–436. 85. Liu AY, Paulsen RD, Marcellus MK, et al. Long-term outcomes after carotid stent placement for treatment of carotid artery dissection. Neurosurgery 1999; 45:1368–1374. 86. Mackey AE, Abramowicz M, Laglois Y, et al. Outcome of asymptomatic patients with carotid disease. Neurology 1997; 48:896–903. 87. Malek AM, Higashida RT, Halbach VV, et al. Tandem intracranial stent deployment for treatment of an iatrogenic, flow-limiting, basilar artery dissection: technical case report. Neurosurgery 1999; 45:919–924. 88. Manninen HI, Rasanen HT, Vanninen RL, et al. Stent placement versus percutaneous transluminal angioplasty of human carotid arteries in situ: distal embolization and findings at intravascular US, MR imaging and histopathologic analysis. Radiology 1999; 212:483–492.

PTA of Cerebrovascular Occlusive Disease

485

89. Marks MP, Marcellus M, Norbash AM, et al. Outcome of angioplasty for atherosclerotic intracranial stenosis. Stroke 1999; 30:1065–1069. 90. Mathias KD. Angioplasty and stenting for carotid lesions: an argument for. Advances Surg 1999; 32:225–243. 91. Mathur A, Dorros G, Iyer SS, et al. Palmaz stent compression in patients following carotid artery stenting. Catheterization Cardiovasc Diagn 1997; 41:137–140. 92. Mayo Asymptomatic Carotid Endarterectomy Study Group. Results of a randomized controlled trial of carotid endarterectomy for asymptomatic carotid stenosis. Mayo Clin Proc 1992; 67:513–518. 93. McKenzie JD, Wallace RC, Dean BL, et al. Preliminary results of intracranial angioplasty for vascular stenosis caused by atherosclerosis and vasculitis. AJNR Am J Neuroradiol 1996; 17:263–268. 94. Moore WS, Barnett HJM, Beebe HG, et al. Guidelines for carotid endarterectomy: a multidisciplinary consensus statement from the Ad Hoc Committee, American Heart Association. Stroke 1995; 26:188–201. 95. Mori T, Mori K, Fukuoka M, Honda S. Percutaneous transluminal angioplasty for total occlusion of middle cerebral arteries. Neuroradiology 1997a; 39:71–74. 96. Mori T, Mori K, Fukuoka M, Honda S. Percutaneous transluminal cerebral angioplasty: serial angiographic follow-up after successful dilatation. Neuroradiology 1997b; 39:111– 116. 97. Mori T, Fukuoka M, Kazita K, Mori K. Follow-up study after intracranial percutaneous cerebral balloon angioplasty. AJNR Am J Neuroradiol 1998; 19:1525–1533. 98. Mori T, Kazita K, Mori K. Cerebral angioplasty and stenting for intracranial vertebral atherosclerotic stenosis. AJNR Am J Neuroradiol 1999; 20:787–789. 99. Mori T, Kazita K, Chokyu K, et al. Short-term arteriographic and clinical outcome after cerebral angioplasty and stenting for intracranial vertebrobasilar and carotid atherosclerotic occlusive disease. AJNR Am J Neuroradiol 2000; 21:249–254. 100. Morris PP, Martin EMM, Regan J, Braden G. Intracranial deployment of coronary stents for symptomatic atherosclerotic disease. AJNR Am J Neuroradiol 1999; 20:1668–1694. 101. Nahser HC, Henkes H, Weber W, et al. Intracranial vertebrobasilar stenosis: angioplasty and follow-up. Am J Neuroradiol 2000; 21:1293–1301. 102. Naylor AR, Bolia A, Abbott RJ, et al. Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial. J Vasc Surg 1998; 28:326–334. 103. Nakahara T, Sakamoto S, Hamasaki O, Sakoda K. Stent-assisted angioplasty for intracranial atherosclerosis. Neuroradiology 2002; 44:706–710. 104. Nakamaya T, Tanaka K, Kaneko M, et al. Thrombolysis and angioplasty for acute occlusion of intracranial vertebrobasilar arteries. J Neurosurg 1998; 88:919–922. 105. Nakatsuka H, Ueda T, Ohta S, et al. Successful percutaneous transluminal angioplasty for basilar artery stenosis: technical case report. Neurosurgery 1996; 39:161–164. 106. New G, Roubin GS, Iyer SS, et al. Safety, efficacy, and durability of carotid artery stenting for restenosis following carotid endarterectomy: a multicenter study. J Endovasc Ther 2000; 7:345–352. 107. Nomura M, Hashimoto N, Nishi S, Akiyama Y. Percutaneous transluminal angioplasty for intracranial vertebral and/or basilar artery stenosis. Clin Radiol 1999; 54:521–527. 108. Norris JW, Zhu CZ, Bornstein NM, et al. Stroke risks of asymptomatic carotid stenosis. Stroke 1991; 22:1485–1490. 109. 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. 110. O’Holleran LW, Kennelly MM, McClurken M, et al. Natural history of asymptomatic carotid plaque: five year follow-up study. Am J Surg 1987; 154:659–662. 111. O’Leary DH, Clouse MH. Percutaneous transluminal angioplasty of the cavernous carotid artery for recurrent ischemia. AJNR Am J Neuroradiol 1984; 5:644–645.

486

Chaloupka et al.

112. Ohki T, Marin ML, Lyon RT, et al. Ex vivo human carotid artery bifurcation stenting: correlation of lesion characteristics with embolic potential. J Vasc Surg 1998; 27:463–471. 113. Perry JR, Szalai JP, Norris JW. Consensus against both endarterectomy and routine screening for asymptomatic carotid artery stenosis: Canadian Stroke Consortium. Arch Neurol 1996; 54:25–28. 114. Phatouros CC, Higashida RT, Malek AM, et al. Clinical use of stents for carotid artery disease. Neuro Med Chir (Tokyo) 1999; 39:809–827. 115. Phatouros CC, Higashida RT, Malek AM, et al. Endovascular stenting of an acutely thrombosed basilar artery: technical case report and review of the literature. Neurosurgery 1999; 44:667–673. 116. Purdy PD, Devous MD, Unwin DH. Angioplasty of an atherosclerotic middle cerebral artery associated with improvement in regional cerebral blood flow. AJNR Am J Neuroradiol 1990; 11:878–880. 117. Qureshi AI, Luft AR, Janardhan V, et al. Identification of patients at risk for periprocedural neurological deficits associated with carotid angioplasty and stenting. Stroke 2000; 31:376–382. 118. Ramee SR, Dawson R, McKinley KL, et al. Provisional stenting for symptomatic intracranial stenosis using a multidisciplinary approach: acute results, unexpected benefit, and one-year outcome. Catheterisation Cardiovasc Intervent 2001; 52:457–467. 119. Rasmussen PA, Perl J, Barr JD, et al. Stent-assisted angioplasty of intracranial vertebrobasilar atherosclerosis: an initial experience. J Neurosurg 2000; 92:771–778. 120. Rosanio S, Tocchi M, Uretsky BF, Stouffer GA. Use of intraluminal stents in the treatment of carotid, renal and peripheral arterial disease. Am J Med Sci 2000; 319:111–117. 121. Rostomily RC, Mayberg MR, Eskridge Jr, et al. Resolution of petrous internal carotid artery stenosis after transluminal angioplasty. J Neurosurg 1992; 76:520–523. 122. Rothwell PM, Slattery J, Warlow CP. A systematic review of the risks of stroke and death due to endarterectomy for symptomatic carotid stenosis. Stroke 1996; 27:260–265. 123. Roubin GS, Yadav S, Iyer SS, Vitek J. Carotid stent-supported angioplasty: a neurovascular intervention to prevent stroke. Am J Cardiol 1996; 78:8–12. 124. Streifler JY, Eliasziw M, Benavente PR, et al. The North American Symptomatic Carotid Endarterectomy Trial, risk of stroke in patients with first ever retinal vs hemispheric transient ischemic attacks and high grade carotid stenosis. Arch Neurol 1995; 52:246–249. 125. Stroke and cerebrovascular disease. The National Advisory Neurological Disorders and Stroke Council. Status Report: Decade of the Brain. Bethesda, MD: National Institutes of Health, Public Health Services, 1992:26–27. 126. Sundt TM Jr, Sandok BA, Whisnant JP. Carotid endarterectomy: complications and preoperative assessment of risk. Mayo Clin Proc 1975; 50:301–306. 127. Sundt TM, Smith HC, Campbell JK, et al. Transluminal angioplasty for basilar artery stenosis. Mayo Clin Proc 1980; 55:673–680. 128. Sundt TM. Occlusive Cerebrovascular Disease. Diagnosis and Surgical Treatment. Philadelphia: WB Saunders, 1987:477–487. 129. Takis C, Kwan ES, Pessin MS, et al. Intracranial angioplasty: experience and complications. AJNR Am J Neuroradiol 1997; 18:1661–1668. 130. Teitelbaum GP, Lefkowitz MA, Gianotta SL. Carotid angioplasty and stenting in high-risk patients. Surg Neurol 1998; 50:300–311. 131. Terada T, Higashida R, Halbach VV, et al. Transluminal angioplasty for arteriosclerotic disease of the distal vertebral and basilar arteries. J Neurol Neurosurg Psychiatry 1996; 60:377–381. 132. The CASANOVA Study Group. Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke 1991; 22:1229–1235. 133. The European Carotid Surgery Trialists’ Collaborative Group. Randomized trial of endarterectomy for recently symptomatic carotid stenosis: final results of MRC European carotid surgery trial (ECST). Lancet 1998; 351:1379–1387. 134. The Executive Committee for the Asymptomatic Carotid Atherosclerosis Study: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421–1428.

PTA of Cerebrovascular Occlusive Disease

487

135. Biasi GM, Ferrari SA, Nicolaides AN, et al. The ICAROS Registry of Carotid Artery Stenting. J Endovasc Ther 2001; 8:46–52. 136. Theron J, Raymond J, Cassaco A, Courtheoux F. Percutaneous angioplasty of atherosclerotic and postsurgical stenosis of carotid arteries. AJNR Am J Neuroradiol 1987; 8:495–500. 137. Theron J, Courtheoux P, Alachkar E, et al. New triple coaxial catheter protection system for carotid angioplasty with cerebral protection. AJNR Am J Neuroradiol 1990; 11:869–874. 138. Theron J, Payelle GG, Coskin O, et al. Carotid artery stenosis: treatment with protected balloon angioplasty and stent placement. Radiology 1996; 201:627–636. 139. Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000; 55:490–497. 140. Tievsky AL, Druy EM, Mardiat JG. Transluminal angioplasty in postsurgical stenosis of the extracranial carotid artery. AJNR Am J Neuroradiol 1983; 4:800–802. 141. Tsai FY, Matovich V, Hieshima G, et al. Percutaneous transluminal angioplasty of the carotid artery. AJNR Am J Neuroradiol 1986; 7:349–358. 142. Touho H. Percutaneous transluminal angioplasty in the treatment of atherosclerotic disease of the anterior cerebral circulation and hemodynamic evaluation. J Neurosurg 1995; 82:953–960. 143. Vozzi CR, Rodriguez AO, Poalantonio D, et al. Extracranial carotid angioplasty and stenting: Initial results and hort-term follow-up. Tex Heart Inst 1997; 24:167–172. 144. Waigand J, Gross CM, Ulich F, et al. Elective stenting of carotid artery stenosis in patients with severe coronary artery disease. Eur Heart J 1998; 19:1365–1370. 145. Warfarin versus aspirin for intracranial disease [Major Ongoing Stroke Trials]. Stroke 1999; 30:2256–2261. 146. Webster WW, Makaroun MS, Steed DL, et al. Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease. J Vasc Surg 1995; 21:338–345. 147. Wennberg DE, Lucas FL, Birkmeyer JD, et al. Variation in carotid endarterectomy mortality in the medicare population: trial hospitals, volume and patient characteristics. JAMA 1998; 279:1279–1281. 148. Wholey MH, Wholey MH, Jarmolowski CR, et al. Endovascular stents for carotid artery occlusive disease. J Endovasc Surg 1997; 4:326–338. 149. Wholey MH, Wholey M, Bergeron P, et al. Current global status of carotid artery stent placement. Catheterization Cardiovas Diagn 1998; 44:1–6. 150. Wiggli U, Gratzl O. Transluminal angioplasty of stenotic carotid arteries: case reports and protocol. AJNR Am J Neuroradiol 1983; 4:793–795. 151. Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid arteries. Circulation 1997; 95:376–381. 152. Yokote H, Terada T, Ryujin K, et al. Percutaneous transluminal angioplasty for intracranial arteriosclerotic lesions. Neuroradiology 1998; 40:590–596.

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

490

Guillaume and Hitchon

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.

Medical and Surgical Management of Intracerebral Hemorrhage

491

492

Guillaume and Hitchon

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

Medical and Surgical Management of Intracerebral Hemorrhage

493

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.

Medical and Surgical Management of Intracerebral Hemorrhage

495

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.

496

Guillaume and Hitchon

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

Medical and Surgical Management of Intracerebral Hemorrhage

497

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)

498

Guillaume and Hitchon

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

Medical and Surgical Management of Intracerebral Hemorrhage

499

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

500

Guillaume and Hitchon

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

Medical and Surgical Management of Intracerebral Hemorrhage

501

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

502

Guillaume and Hitchon

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

Medical and Surgical Management of Intracerebral Hemorrhage

503

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%

504

Guillaume and Hitchon

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

Medical and Surgical Management of Intracerebral Hemorrhage

505

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.

506

Guillaume and Hitchon

REFERENCES 1. Adams R, Victor M, Ropper A. Cerebrovascular diseases. In: Wonsiewicz MJ, Narozov M, eds. Principles of Neurology. 6th ed. Vol II. New York: McGraw-Hill, 1997:834–840. 2. Sacco R, Wolf P, Bharuca N, Meeks SL, Kannel WB, Charette LS, McNamara PM, Palwer EP, D’Agostino R. Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and prescursive factors in the Framingham Study. Neurology 1984; 34:847–854. 3. Taylor TN, Davis PH, Torner JC. Projected number of strokes by subtype in the year 2050 in the United States. Stroke 1998; 29:322. 4. Broderick J, Brott T, Tomsick T, Miller R, Huster G. Intracerebral hemorrhage is more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993; 78:188–191. 5. Broderick J, Brott T, Tomsick T, Tew J, Duldner J, Huster G. Management of intracerebral hemorrhage in a large metropolitan population. Neurosurgery 1994; 34:882–887. 6. Broderick JP, Adams HP, Barsan W, Feinberg W, Feldman E, Grotta J, Kase C, Krieger D, Mayberg M, Tilley B, Zabramski J, Zuccarello M. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999; 30:905–915. 7. Giroud M, Gras P, Chadan N, Beuriat P, Milan C, Arveux P, Dumas R. Cerebral hemorrhage in a French prospective population study. J Neurol Neurosurg Psychiatry 1991; 54:595–598. 8. Fogelholm R, Nuutila M, Vuorela AL. Primary intracerebral hemorrhage in the Jyvaskyla region, Central Finland, 1985–1989: incidence, case fatality rate, and functional outcome. J Neurol Neurosurg Psychiatry 1992; 55:546–552. 9. Broderick JP, Phillips SJ, Whisnant JP, O’Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of a decline in stroke? Stroke 1989; 20:577–582. 10. Broderick J. Intracerebral hemorrhage. In: Gorelick PB, Alter M, eds. Handbook of Neuroepidemiology. New York: Marcel Dekker, 1994:141–167. 11. Bamford J, Sandercock P, Dennis M, Warlow C, Jones L, McPherson K, Vessey M, Fowler G, Molyneux A, Hughes T. A prospective study of acute cerebrovascular disease in the community: The Oxfordshire Community Stroke Project 1981–1986 1. Methodology, demography and incident rates of first-ever stroke. J Neurol Neurosurg Psychiatry 1988; 51:1373–1380. 12. Brott TG, Thalinger K, Hertzberg V. Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke 1986; 17:1078–1083. 13. Broderick JP, Brott TG, Kothari R, Miller R, Khoury J, Pancioli A, Gebel J, Mills D, Minneci L, Shukla R. The Greater Cincinnati-Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke 1998; 29:415–421. 14. Broderick J, Brott T, Tomsick T, Leach A. Lobar hemorrhage in the elderly: the undiminishing importance of hypertension. Stroke 1993; 24:49–51. 15. Broderick JP, Brott T, Tomsick T, Huster G, Miller R. The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. NEJM 1992; 326:733–736. 16. Anderson CS, Chakera TM, Stewart-Wynne EG, Jamrozik KD. Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, 1989–90: incidence and outcome. J Neurol Neurosurg Psychiatry 1994; 57:936–940. 17. Broderick JP. Natural history of primary intracerebral hemorrhage. In: Whisnant JP, ed. Population-Based Clinical Epidemiology of Stroke. Oxford, England: Butterworth Heinemann, 1993. 18. Counsell C, Boonyakarnkul S, Dennis M, Sandercock P, Bamford J, Burn J, Warlow C. Primary intracerebral hemorrhage in the Oxfordshire Community Stroke Project, 2: prognosis. Cerebrovasc Dis 1995; 5:26–34. 19. Cole FM, Yates PD. The occurrence and significance of intracerebral micro-aneurysms. J Pathol Bacteriol 1967; 93:393–411. 20. Fisher CM. Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 1971; 30:536–550.

Medical and Surgical Management of Intracerebral Hemorrhage

507

21. Takebayashi S. Ultrastructural morphometry of hypertensive medial damage in lenticulostriate and other arteries. Stroke 1985; 16:449–453. 22. Challa V, Moody DM, Bell MA. The Charcot-Bouchard aneurysm controversy: impact of a new histologic technique. J Neuropathol Exp Neurol 1992; 51:264–271. 23. McCoormick WF, Rosenfield DB. Massive brain hemorrhage: a review of 144 cases and an examination of their causes. Stroke 1973; 4:946–954. 24. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage: Facts and hypotheses. Stroke 1995; 26:1471–1477. 25. Furlan AJ, Whisnant JP, Elveback LR. The decreasing incidence of primary intracerebral hemorrhage: a population study. Ann Neurol 1979; 5:367–373. 26. DelZoppo GJ, Mori E. Hematologic causes of intracerebral hemorrhage and their treatment. Neurosurg Clin North Am 1992; 3:637–658. 27. Albers GW, Sherman DG, Gress DR, Paulseth JE, Petersen P. Stroke prevention in nonvalvular atrial fibrillation: a review of prospective randomized trials. Ann Neurol 1991; 30:511–518. 28. Dickenson LD, Miller LD, Patel CP, Gupta SK. Enoxiparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 1998; 43:1074–1081. 29. Harrington H, Heller HA, Dawson D, Caplan L, Rumbaugh C. Intracerebral hemorrhage and oral amphetamine. Arch Neurol 1983; 40:503. 30. Levine SR, Brust JCM, Futrell N, Ho KL, Blake D, Millikan CH, Brass LM, Fayad P, Schyultz LR, Selwa JF. Cerebrovascular complications of the use of crack form of alkaloid cocaine. NEJM 1990; 323:699–704. 31. Wakai S, Kumakura N, Nagai M. Lobar intracerebral hemorrhage: a clinical, radiographic, and pathological study of 29 consecutive operated cases with negative angiography. J Neurosurg 1992; 76:231–238. 32. Okazaki H, Whisnant J. Clinical pathology of hypertensive intracerebral hemorrhage. In: Mizukami M, Kogure K, Kanaya H, Yamori Y, eds. Hypertensive Intracerebral Hemorrhage. New York: Raven Press Publishers, 1983:177–180. 33. Vinters HV. Cerebral amyloid angiopathy: a critical review. Stroke 1987; 18:311–324. 34. Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr. Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 1991; 30:637–649. 35. Masuda J, Tanaka K, Ueda K, Omae T. Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan. Stroke 1988; 19:205–210. 36. Schutz H, Bodeker RH, Damain M, Krack P, Dorndorf W. Age-related spontaneous intracerebral hematoma in a German community. Stroke 1990; 21:1412–1418. 37. Langer DJ, Lasner TM, Hurst RW, Flamm ES, Zager EL, King JT Jr. Hypertension, small size and deep venous drainage are associated with risk of hemorrhagic presentation of cerebral arteriovenous malformations. Neurosurgery 1998; 42:481–489. 38. Halpin SF, Britton JA, Byrne JV, Clifton A, Hart G, Moore A. Prospective evaluation of cerebral angiography and computed tomography in cerebral hematoma. J Neurol Neurosurg Psychiatry 1994; 57:1180–1186. 39. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. NEJM 2001; 344:1450–1460. 40. Herman B, Leyton AC, Van Luijk JH, Frenken CW, Op de Coul AA, Schulte BP. Epidemiology of stroke in Tilburg, The Netherlands: The population-based stroke incidence register: 2. Incidence, initial clinical picture and medical care, and three-week case fatality. Stroke 1982; 13:629–634. 41. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prospective study of acute cerebrovascular disease in the community: The Oxfordshire Community Stroke Project—1981– 1986. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry 1990; 53:16–22.

508

Guillaume and Hitchon

42. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med 1999; 27:617–621. 43. Kwak R, Kadoya S, Suzuki T. Factors affecting the prognosis in thalamic hemorrhage. Stroke 1983; 14:493–500. 44. Diringer MN, Edwards DF, Zazulia AR. Hydrocephalus: a previously unrecognized predictor of poor outcome from supratentorial intracerebral hemorrhage. Stroke 1998; 29:1352–1357. 45. Gebelm JM, Sila CA, Sloan MA, Granger CB, Mahaffey KW, Weisenberger J, Green CC, White HD, Gore JM, Weaver WD, Califf RM, Topol EJ. Thrombolysis-related intracranial hemorrhage: a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation. Stroke 1998; 3:563–569. 46. Caplan L. General symptoms and signs. In: Kase CS, Caplan LR, eds. Intracerebral Hemorrhage. Boston: Butterworth-Heinemann, 1994:31–43. 47. Mayer SA, Sacco RL, Shi T, Mohr JP. Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology 1994; 44:1379–1384. 48. Qureshi AI, Safdar K, Weil EJ, Barch C, Bliwise DC, Colohan AR, MacKay B, Frankel MR. Predictors of early deterioration and mortality in black Americans with spontaneous intracerebral hemorrhage. Stroke 1995; 26:1764–1767. 49. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, Spilker J, Duldner J, Khouri J. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28:1–5. 50. Andrews BT, Chiles BW, Olsen WL, Pitts LH. The effect of intracerebral hematoma location on the risk of brain-stem compression and on clinical outcome. J Neurosurg 1988; 69:518–522. 51. Tanaka A, Yoshinaga S, Nakayama Y, Kimura M, Tomonaga M. Cerebral blood flow and clinical outcome in patients with thalamic hemorrhages: a comparison with putamenal hemorrhages. J Neurol Sci 1996; 144:191–197. 52. Ott KH, Kase CS, Ojeman RG, MOhr JP. Cerebellar hemorrhage: diagnosis and treatment. A review of 56 cases. Arch Neurol 1974; 31:160–167. 53. Zhu XL, Chan MSY, Poon WS. Spontaneous intracranial hemorrhage: which patients need diagnostic cerebral angiography? A prospective study of 206 cases and review of the literature. Stroke 1997; 28:1406–1409. 54. Channing L, Cummins RO. Advanced Cardiac Life Support Provider Manual. The American Heart Association, 2001, Dallas, TX. 55. Fujii Y, Shigekazu T, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke 1998; 29:1160–1166. 56. Kazui S, Hiroaki N, Yamamoto H, Sawada T, Yamaguchi Ta. Enlargement of spontaneous intracerebral hemorrhage. Stroke 1996; 27:1783–1787. 57. Powers WJ. Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993; 43:461–467. 58. Dandapani BK, Suzuki S, Kelley RE, Reyes-Iglesias Y, Duncan RD. Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995; 26:21–24. 59. Qureshi AI, Wilson DA, Hanley DF, Traystman RJ. Pharmacologic reduction of mean arterial pressure does not adversely affect regional cerebral blood flow and intracranial pressure in experimental intracerebral hemorrhage. Crit Care Med 1999; 27:965–971. 60. Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, Hensley MJ, Strom BL. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. NEJM 1987; 316:1229–1233. 61. Kassell NF, Hitchon PW, Gerk MK, Sokoll MD, Hill TR. Alterations in cerebral blood flow, oxygen metabolism, and electrical activity produced by high dose sodium thiopental. Neurosurgery 1980; 7:598–603. 62. Diringer MN, Edwards DF. Admission to a neurologic/neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage. Crit Care Med 2001; 29:635–640.

Medical and Surgical Management of Intracerebral Hemorrhage

509

63. Tellez H, Bauer R. Dexamethasone as treatment in cerebrovascular disease, 1: a controlled study in intracerebral hemorrhage. Stroke 1973; 4:541–546. 64. Italian Acute Stroke Study Group. Haemodilution in acute stroke: results of the Italian hemodilution trial. Lancet 1988; 1:318–321. 65. Yu YL, Kumana CR, Lauder IJ, Cheung YK, Chan FL, Kou M, Chang CM, Cheung RT, Fong KY. Treatment of acute cerebral hemorrhage with intravenous glycerol. A doubleblind, placebo-controlled, randomized trial. Stroke 1992; 7:967–971. 66. Fayad PB, Awad IA. Surgery for intracerebral hemorrhage. Neurology 1998; 51:S69–S73. 67. Hankey GJ, Hon C. Surgery for primary intracerebral hemorrhage: is it safe and effective? Stroke 1997; 28:2126–2132. 68. Prasad K, Browman G, Srivastava A, Menon G. Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand 1997; 95:103– 110. 69. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J. The ABCs of measuring intracerebral hematoma volumes. Stroke 1996; 27:1304–1305. 70. Lisk DR, Pasteur W, Rhoades H, Putnam RD, Grotta JC. Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation. Neurology 1994; 44:133–139. 71. Yamanaka R, Satoh S. Comparison of steriotactic aspiration, craniotomy, and conservative treatment for putaminal hemorrhage. Neurol Med Chir (Tokyo) 1988; 28:986–990. 72. Kaufman HH. Treatment of deep spontaneous intracerebral hematomas: a review. Stroke 1993; 24(suppl I):I-101–I-108. 73. Kase C, Mohr J, Caplan L. Intracerebral hemorrhage. In: Barnett H, Mohr J, Stein B, Yatsu F, eds. Stroke: Pathophysiology, Diagnosis, and Management. New York: Churchill Livingstone, 1992:561–616. 74. McKissock W, Richardson A, Taylor J. Primary intracerebral hemorrhage: a controlled trial of surgical and conservative treatment in 180 unselected cases. Lancet 1961; 2:222–226. 75. Auer L, Deinsberger W, Niederkorn K, Gell G, Kleinert R, Schneider G, Holzer P, Bone G, Mokry M, Korner E. Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study. J Neurosurg 1989; 70:530–535. 76. Juvela S, Heiskanen O, Poranen A, Valtonen S, Kourne T, Kaste M, Troupp H. The treatment of spontaneous intracerebral hemorrhage: a prospective randomized trial of surgical and conservative treatment. J Neurosurg 1989; 70:755–758. 77. Batjer HH, Reisch JS, Allen BC, Plaizier LJ, Su CJ. Failure of surgery to improve outcome in hypertensive putaminal hemorrhage: a prospective randomized trial. Arch Neurol 1990; 47:1103–1106. 78. Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology 1998; 51:1359–1363. 79. Fernandes H, Mendelow A. Spontaneous intracerebral hemorrhage: a surgical dilemma. Br J Neurosurg 1999; 13:389–394. 80. Saver JL. Surgical therapy. In: Feldmann E, ed. Intracerebral Hemorrhage. Armonk, NY: Futura Publishing Co, 1994:303–332. 81. International Surgical Trial in Intracerebral Hemorrhage. Presented at the British Association of Stroke Physicians, 2001. Stroke 2000; 31:2536. 82. Kanaya H. All Japan co-operative study on the treatment of hypertensive intracerebral hemorrhage. Jpn J Stroke 1990; 12:509–524. 83. Kaneko M, Koba T, Yokoyama T. Early surgical treatment for hypertensive intracerebral hemorrhage. J Neurosurg 1977; 46:579–583. 84. Kaneko M, Tanaka K, Shimada T, Sato K, Uemura K. Long-term evaluation of ultra-early operation for hypertensive intracerebral hemorrhage in 100 cases. J Neurosurg 1983; 58:838– 842. 85. Yokote H, Komai N, Nakai E, Ueno M, Hayashi S, Terashita T. Stereotactic evacuation of

510

86.

87.

88.

89. 90. 91. 92. 93. 94. 95.

96.

97. 98. 99.

100. 101. 102.

103.

104.

105. 106.

Guillaume and Hitchon hypertensive cerebellar hemorrhage using plasminogen activator. No Shinkei Geka 1989; 17:421–426. Fujitsu K, Muramoto M, Ikeda Y, Kim I, Kuwabara T. Indications for surgical treatment of putaminal hemorrhage: comparative study based on serial CT and time-course analysis. J Neurosurg 1990; 73:518–525. Volpin L, Cervellini P, Colombo F, Zanusso M, Benedetti A. Spontaneous intracerebral hematomas: a new proposal about the usefulness and limits of surgical treatment. Neurosurgery 1984; 15:663–666. Sawada T, Yamaguchi T, Kikuchi H. Comparison of medical and surgical treatments of hypertensive intracerebral hemorrhage. In: Mizukami M, Kogure K, Kanaya H, Yamori Y, eds. Hypertensive Intracerebral Hemorrhage. New York: Raven Press, 1983:233–238. Kalff R, Feldges A, Mehdorn HM, Grote W. Spontaneous intracerebral hemorrhage. Neurosurg Rev 1992; 15:177–186. Donauer E, Faubert C. Management of spontaneous intracerebral and cerebellar hemorrhage. In: Kaufman H, ed. Intracerebral Hematomas. New York: Raven Press, 1992:211–227. Zumkeller M, Hollerhage HG, Proschl M, Dietz H. The results of surgery for intracerebral hematomas. Neurosurg Rev 1992; 15:33–36. Firsching R, Huber M, Frowein RA. Cerebellar haemorrhage: management and prognosis. Neurosurg Rev 1991; 14:191–194. Da Pian R, Bazzan A, Pasqualin A. Surgical versus medical treatment of spontaneous posterior fossa haematomas: a cooperative study on 205 cases. Neurol Res 1984; 6:145–151. Kase C. Cerebellar hemorrhage. In: Kase C, Caplan L, eds. Intracerebral Hemorrhage. Boston: Butterworth-Heinemann, 1994:425–443. Kase C, Crowell R. Prognosis and treatment of patients with intracerebral hemorrhage. In: Kase C, Caplan L, eds. Intracerebral Hemorrhage. Boston: Butterworth-Heinemann, 1994:467–489. Luessenhop A. Hypertensive intracerebral hemorrhage in the United States: update on surgical treatment. In: Mizukami M, Kogure K, Kanaya H, Yamori Y, eds. Hypertensive Intracerebral Hemorrhage. New York: Raven Press, 1983:123–132. Sypert G, Arpin-Sypert E. Spontaneous posterior fossa hematomas. In: Kaufman H, ed. Intracerebral Hematomas. New York: Raven Press, 1992:187–196. Backlund EO, von Holst H. Controlled subtotal evacuation of intracerebral haematomas by stereotactic technique. Surg Neurol 1978; 9:99–101. Nguyen JP, Decq P, Brugieres P, Yepes C, Melon E, Gaston A, Keravel Y. A technique for stereotactic aspiration of deep intracerebral hematomas under computed tomographic control using a new device. Neurosurgery 1992; 31:330–335. Kaufman H. Stereotactic aspiration with fibrinolytic and mechanical assistance. In: Kaufman H, ed. Intracerebral Hematomas. New York: Raven Press, 1992:181–185. Niizuma H, Suzuki J. Stereotactic aspiration of putaminal hemorrhage using a double track aspiration technique. Neurosurgery 1988; 22:432–436. Iseki H, Amano K, Kawamura H, Tanikawa T, Kawabatake H, Notani M, Shiwaku T, Iwata Y, Taira T, Nagao H, Umezawa Y, Shimizzu T, Kitamura K. A new apparatus for CT-guided steriotactic surgery. Appl Neurophysiol 1985; 48:50–60. Kanaya H, Kuroda K. Development in neurosurgical approaches to hypertensive intracerebral hemorrhage. In: Kaufman H, ed. Intracerebral Hematomas. New York: Raven Press, 1992: 197–210. Montes JM, Wong JH, Fayad PB, Awad IA. Steriotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma: protocol and preliminary experience. Stroke 2000; 31:834–840. Matsumoto K, Hondo H. CT-guided stereotaxic evacuation of hypertensive intracerebral hematomas. J Neurosurg 1984; 61:440–448. Miller DW, Barnett GH, Kormos DW, Steiner CP. Steriotactically guided thrombolysis of deep cerebral hemorrhage: preliminary results. Cleve Clin J Med 1993; 60:321–324.

Medical and Surgical Management of Intracerebral Hemorrhage

511

107. Schaller C, Rohde V, Meyer B, Hassler W. Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissue-plasminogen activator. Neurosurgery 1995; 36:328–335. 108. Tzaan WC, Lee ST, Lui TN. Combined use of steriotactic aspiration and intracerebral streptokinase infusion in the surgical treatment of hypertensive intracerebral hemorrhage. J Formos Med Assoc 1997; 96:962–967. 109. Iseki H, Amano K, Kawamura H, Tanikawa T, Kawabatake H, Notani M, Shiwaku T, Iwata Y, Taira T, Nagao H, Umezawa Y, Shimizu T, Kitamura K. A new apparatus for CT-guided stereotactic surgery. Appl Neurophysiol 1985; 48:50–60. 110. Tanikawa T, Amano K, Kawamura H, Kawabatake H, Notani M, Iseki H, Shiwaku T, Nagao T, Iwata Y, Taira T, Umezawa Y, Shimizu T, Kitamura K. CT-guided stereotactic surgery for evacuation of hypertensive intracerebral hematoma. Appl Neurophysiol 1985; 48: 431–439. 111. Liu ZH, Kang GQ, Chen XH, Tian ZM, Cai HZ, Zhang Y, Li SY. Evacuation of hypertensive intracerebral hematoma by a stereotactic technique. Stereotact Funct Neurosurg 1990; 54– 55:451–452. 112. Kandel EI, Peresedov VV. Stereotaxic evacuation of spontaneous intracerebral hematomas. J Neurosurg 1985; 62:206–213. 113. Hokama M, Tanizaki Y, Mastuo K, Hongo K, Kobayashi S. Indications and limitations for CT-guided stereotaxic surgery of hypertensive intracerebral haemorrhage, based on the analysis of postoperative complications and poor ability of daily living in 158 cases. Acta Neurochir (Wien) 1993; 125:27–33. 114. Hondo H, Uno M, Sasaki K, Ebisudani D, Shichijo F, Toth Z, Matsumoto K. Computed tomography controlled aspiration surgery for hypertensive intracerebral hemorrhage: experience of more than 400 cases. Stereotact Funct Neurosurg 1990; 54:432–437. 115. Shitamichi M, Nakamura J, Sasaki T, Suematsu K, Tokuda S. Computed tomography guided stereotactic aspiration of pontine hemorrhages. Stereotact Funct Neurosurg 1990; 54–55:453– 456. 116. Ito H, Muka H, Kitamura A. Stereotactic aqua stream and aspirator for removal of intracerebral hematoma. Stereotact Funct Neurosurg 1990; 54–55:457–460. 117. Zong-hui L, Zeng-min T, Xiao-han C, et al. CT-guided stereotactic evacuation of hypertensive intracerebral hematoma. Chin Med J 1991; 104:387–391. 118. Niizuma H, Otsuki T, Johkura H, Nakazato N, Suzuki J. CT-guided stereotactic aspiration of intracerebral hematoma-result of a hematoma-lysis method using urokinase. Appl Neurophysiol 1985; 48:427–430. 119. Horimoto C, Yamaga S, Toba T, Tsujimura M. Stereotactic evacuation of massive hypertensive intracerebral hemorrhage. No Shinkei Geka 1993; 21:509–512. 120. Etou A, Mohadjer M, Braus D, Mundinger F. Stereotactic evacuation and fibrinolysis of cerebellar hematomas. Stereotact Funct Neurosurg 1990; 54–55:445–450. 121. Niizuma H, Yonemitsu T, Jokura H, Nakasato N, Suzuki J, Yoshimoto T. Stereotactic aspiration of thalamic hematoma: overall results of 75 aspirated and 70 nonaspirated cases. Stereotact Funct Neurosurg 1990; 54–55:438–444. 122. Lippitz B, Mayfrank L, Spetzger U, Warnke JP, Bertalanffy H, Gilsbach JM. Lysis of basal ganglia haematoma with recombinant tissue plasminogen activator (rtPA) after stereotactic aspiration: initial results. Acta Neurochir (Wien) 1994; 127:157–160. 123. Firsching R, Huber M, Frowein RA. Cerebellar haemorrhage: management and prognosis. Neurosurg Rev 1991; 14:191–194. 124. Broderick J, Brott T, Zuccarello M. Management of intracerebral hemorrhage. In: Batjer H, ed. Cerebrovascular Disease. Philadelphia: Lippincott-Raven, 1996:1–18. 125. vanLoon J, VanCalenbergh F, Goffin J, Plet C. Controversies in the management of spontaneous cerebellar haemorrhage: a consecutive series of 49 cases and review of the literature. Acta Neurochir (Wien) 1993; 122:187–193. 126. Naff NJ, Carhuapoma JR, Williams MA, Bhardwaj A, Ulatowski JA, Bederson J, Bullock R,

512

127.

128. 129. 130. 131.

Guillaume and Hitchon Schmutzhard E, Pfausler B, Keyl PM, Tuhrim S, Hanley DF. Treatment of intraventricular hemorrhage with urokinase: effects on 30-day survival. Stroke 2000; 31:841–847. SHEP Cooperative Research Group. Prevention of various stroke types by treatment of isolated systolic hypertension. Presented at International Stroke Society’s Second World Congress of Stroke; Washington, DC, September 1992. Wintzen AR, de Jonge H, Loeliger EA, Bots GT. The risk of intracerebral hemorrhage during oral anticoagulant treatment: a population study. Ann Neurol 1984; 16:553–558. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897–902. Tissue plasminogen activator for acute ischemic stroke: The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. NEJM 1995; 333:1581–1587. Gillman MW, Cupples LA, Gagnon D, Posner BM, Ellison RC, Castelli WP, Wolf PA. Protective effect of fruits and vegetables on development of stroke in men. JAMA 1995; 273:1113–1117.

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

514

van Gijn and Rinkel

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].

Management of Subarachnoid Hemorrhage

515

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.

516

van Gijn and Rinkel

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

Management of Subarachnoid Hemorrhage

517

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

518

van Gijn and Rinkel

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

Management of Subarachnoid Hemorrhage

519

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].

520

van Gijn and Rinkel

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.

Management of Subarachnoid Hemorrhage

521

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.

522

van Gijn and Rinkel

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.

Management of Subarachnoid Hemorrhage

523

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

524

van Gijn and Rinkel

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.

526

van Gijn and Rinkel

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

Management of Subarachnoid Hemorrhage

527

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

528

van Gijn and Rinkel

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.

Management of Subarachnoid Hemorrhage

529

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.

Management of Subarachnoid Hemorrhage

531

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

532

van Gijn and Rinkel

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 endotrache