Stroke: Pathophysiology, Diagnosis, and Management, 5th Edition

STROKE Pathophysiology, Diagnosis, and Management 5TH EDITION J.P. Mohr, MD, MS Daniel Sciarra Professor of Neurolo...

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STROKE

Pathophysiology, Diagnosis, and Management 5TH EDITION

J.P. Mohr, MD, MS

Daniel Sciarra Professor of Neurology Department of Neurology Columbia University New York, New York

Philip A. Wolf, MD

Professor of Neurology, Medicine, and Public Health Boston University School of Medicine Principal Investigator Framingham Heart Study Boston, Massachusetts

James C. Grotta, MD

Professor of Neurology Chairman Department of Neurology Director Vascular Neurology Program University of Texas Medical School at Houston Houston,Texas

Michael A. Moskowitz, MD

Professor of Neurology Harvard-MIT Division of Health Science and Technology Boston, Massachusetts

Marc R. Mayberg, MD

Executive Director Seattle Neuroscience Institute at Swedish Medical Center Seattle, Washington

Rüdiger von Kummer, MD, FAHA

Professor of Diagnostic Radiology/Neuroradiology Head Department of Neuroradiology Technische Universität Dresden Director Dresden University Stroke Centre Dresden, Germany

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

STROKE: PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT Copyright © 2011, 2004, 1998, 1986 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/ permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Stroke : pathophysiology, diagnosis, and management / [edited by] J.P. Mohr . . .[et al.]—5th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-5478-8 (hardcover : alk. paper) 1. Cerebrovascular disease. I. Mohr, J. P. [DNLM: 1. Stroke. WL 355] RC388.5.S8528 2011 2011003851 616.8¢1—dc22

Acquisitions Editor: Charlotta Kryhl Developmental Editor: Joan Ryan Publishing Services Manager: Patricia Tannian Team Leader: Radhika Pallamparthy Senior Project Manager: Linda Van Pelt Project Manager: Anitha Sivaraj Design Direction: Ellen Zanolle

Printed in the United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2 1

ISBN 978-1-4160-5478-8

This book is dedicated to Joan Mohr, Kathryn Dreyfus, Mary Lou Weir, and Barbara Wolf, whose forbearance is herewith acknowledged with gratitude, and to our stroke patients and their families who consented to participate in the clinical research protocols that have provided us with so much of the information that is contained in this book.

CONTRIBUTORS Takato Abe, MD Division of Neurobiology Department of Neurology and Neuroscience Weill Cornell Medical College New York, New York Cerebral Ischemia and Inflammation Harold P. Adams, Jr., MD Professor and Director Division of Cerebrovascular Disorders University of Iowa Stroke Center Iowa City, Iowa Antithrombotic Therapy for Treatment of Acute Ischemic Stroke Clinical Scales to Assess Patients with Stroke Opeolu Adeoye, MD Assistant Professor of Emergency Medicine and Neurosurgery Department of Emergency Medicine University of Cincinnati Cincinnati, Ohio Prehospital and Emergency Department Care of the Patient with Acute Stroke Sachin Agarwal, MD Resident Department of Neurology Columbia University Medical Center New York, New York Collagen Vascular and Infectious Diseases Maria I. Aguilar, MD Assistant Professor Division of Cerebrovascular Disease Department of Neurology Mayo Clinic Arizona Phoenix, Arizona Secondary Prevention of Cardioembolic Stroke Lama Al-Khoury, MD Department of Neurology University of California, San Diego, School of Medicine San Diego, California Intravenous Thrombolysis

Adrià Arboix, MD, PhD Associate Professor of Neurology Cerebrovascular Division Department of Neurology Hospital Universitari del Sagrat Cor University of Barcelona Barcelona, Spain Microangiopathies (Lacunes) Roland N. Auer, MD, PhD Department of Pathology and Laboratory Medicine University of Calgary Health Science Center Calgary, Alberta, Canada Histopathology of Cerebral Ischemia Issam A. Awad, MD, MSc, FACS, MA (hon) Professor and Director Neurovascular Surgery Program Biological Sciences Division University of Chicago Chicago, Illinois Cerebral Cavernous Malformations and Venous Anomalies: Diagnosis, Natural History, and Clinical Management Dural Arteriovenous Malformations Alison E. Baird, MD Professor of Neurology, Physiology, and Pharmacology Director Division of Cerebrovascular Disease and Stroke State University of New York Downstate Medical Center Brooklyn, New York Magnetic Resonance Imaging of Cerebrovascular Diseases Selva Baltan, MD, PhD Associate Professor of Neurology Department of Neurology University of Washington Seattle, Washington Molecular Pathophysiology of White Matter AnoxicIschemic Injury Henry J.M. Barnett, MD, FRCPC, FACP Scientific Director and Co-founder The John P. Robarts Research Institute London, Ontario, Canada Spinal Cord Ischemia

vii

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CONTRIBUTORS

H. Hunt Batjer, MD Professor and Chair Department of Neurological Surgery Feinberg School of Medicine Northwestern University Chicago, Illinois Cerebral Cavernous Malformations and Venous Anomalies: Diagnosis, Natural History, and Clinical Management Oscar R. Benavente, MD, FRCPC Professor and Research Director of Stroke University of British Columbia Vancouver, British Columbia, Canada Antiplatelet Therapy for Secondary Prevention of Stroke Secondary Prevention of Cardioembolic Stroke Bernard R. Bendok, MD Associate Professor of Neurological Surgery and Radiology Northwestern University Feinberg School of Medicine Northwestern Medical Faculty Foundation Chicago, Illinois Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations Eric M. Bershad, MD Vascular Neurology and Neurocritical Care Baylor College of Medicine Houston,Texas Aneurysmal Subarachnoid Hemorrhage Jeffrey R. Binder, MD Professor of Neurology and Biophysics Director Stroke and Neurobehavior Programs Department of Neurology Medical College of Wisconsin Milwaukee, Wisconsin Posterior Cerebral Artery Disease Alan S. Boulos, MD Chairman Division of Neurosurgery Herman and Sunny Stall Chair of Endovascular Neurosurgery Associate Professor of Surgery and Radiology Albany Medical College and Hospital Albany, New York Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations Marie-Germaine Bousser, MD Service de Neurologie Université Hôpital Lariboisière–Fernand Widal Paris, France CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Frank J. Bova, PhD Department of Neurological Surgery University of Florida Gainesville, Florida Radiosurgery for Arteriovenous Malformations

Michael Brainin, MD, PhD, FESO, FAHA Professor of Neurology Chairman and Director Department of Clinical Neurosciences Donau-Universität Krems Head Department of Neurology Landesklinikum Donauregion Tulln, Austria Classification of Ischemic Stroke Jonathan L. Brisman, MD Neurological Surgery, PC Long Island, New York Indications for Carotid Endarterectomy in Patients with Symptomatic Stenosis Wendy Brown, MD Department of Neurology University of California, San Diego, School of Medicine San Diego, California Intravenous Thrombolysis John C.M. Brust, MD Professor of Clinical Neurology Columbia University College of Physicians and Surgeons New York, New York Anterior Cerebral Artery Disease Stroke and Substance Abuse Patrícia Canhão, MD, PhD Department of Neurosciences Hospital de Santa Maria University of Lisbon Lisbon, Portugal Cerebral Venous Thrombosis Louis R. Caplan, MD Professor of Neurology Harvard Medical School Senior Member Division of Cerebrovascular Disease Beth Israel Deaconess Medical Center Boston, Massachusetts Intracerebral Hemorrhage Vertebrobasilar Disease Mar Castellanos, MD Section of Neurology Hospital Universitari Doctor Josep Trueta Girona, Spain Antiplatelet Therapy for Secondary Prevention of Stroke Hugues Chabriat, MD, PhD Service de Neurologie Université Paris Hôpital Lariboisière–Fernand Widal Paris, France CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CONTRIBUTORS

Angel Chamorro, MD, PhD, FESO Director Comprehensive Stroke Center Hospital Clinic of Barcelona University of Barcelona and Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS) Barcelona, Spain Anterior Cerebral Artery Disease Jae H. Choi, MD Assistant Professor of Neurology Columbia University Medical Center New York, New York Arteriovenous Malformations and Other Vascular Anomalies Michael Chopp, PhD Scientific Director Neuroscience Research Henry Ford Health System Detroit, Michigan Enhancing Brain Reorganization and Recovery of Function after Stroke E. Sander Connolly, MD, FACS Bennett M. Stein Professor of Neurological Surgery Vice Chairman of Neurosurgery Director Cerebrovascular Research Laboratory Surgical Director Neuro-Intensive Care Unit Department of Neurological Surgery Columbia University Medical Center New York, New York Surgical Decision Making,Techniques, and Periprocedural Care of Cerebral Arteriovenous Malformations Bruce M. Coull, MD Professor of Neurology and Medicine Associate Dean of Clinical Affairs, COM Chief Medical Officer, UPH Plans The University of Arizona Tucson, Arizona Coagulation Abnormalities in Stroke Brett L. Cucchiara, MD Assistant Professor Department of Neurology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Treatment of “Other” Stroke Etiologies Turgay Dalkara, MD, PhD Professor of Neurology Department of Neurology Faculty of Medicine Director Institute of Neurological Sciences and Psychiatry Hacettepe University Ankara,Turkey Apoptosis and Related Mechanisms in Cerebral Ischemia

ix

Krishna A. Dani, MRCP Clinical Lecturer Institute of Neuroscience and Psychology University of Glasgow Glasgow, Scotland Magnetic Resonance Imaging of Cerebrovascular Diseases Mark J. Dannenbaum, MD Fellow Cerebrovascular and Skull Base Surgery Department of Neurosurgery Brigham and Women’s Hospital Harvard Medical School Boston, Massachusettts Surgical Management of Posterior Circulation Aneurysms Shervin R. Dashti, MD, PhD Fellow, Cerebrovascular and Skull Base Surgery Neurosurgical Institute of Kentucky Norton Neuroscience Institute Louisville, Kentucky Spinal Arteriovenous Malformations Patricia H. Davis, MD Professor University of Iowa Stroke Center Iowa City, Iowa Antithrombotic Therapy for Treatment of Acute Ischemic Stroke Ted M. Dawson, MD, PhD Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases Scientific Director Institute for Cell Engineering Professor Departments of Neurology and Neuroscience Johns Hopkins University School of Medicine Baltimore, Maryland Intracellular Signaling: Mediators and Protective Responses Valina L. Dawson, PhD Professor Departments of Neurology, Neuroscience, and Physiology Director Neuroregeneration and Stem Cell Programs Institute for Cell Engineering Johns Hopkins University School of Medicine Baltimore, Maryland Intracellular Signaling: Mediators and Protective Responses Arthur L. Day, MD Director of Cerebrovascular Center Brigham and Women’s Hospital Boston, Massachusetts Surgical Management of Posterior Circulation Aneurysms

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CONTRIBUTORS

Michael J. De Leo III, MD New England Center for Stroke Research Department of Radiology University of Massachusetts Medical School Worcester, Massachusetts Endovascular Treatment of Cerebral Aneurysms

Anne Ducros, MD, PhD Emergency Headache Centre and Department of Neurology University Hospital Lariboisière Paris, France Reversible Cerebral Vasoconstriction Syndromes

Gregory J. del Zoppo, MD Professor of Medicine (in Hematology) Adjunct Professor of Neurology University of Washington School of Medicine Harborview Medical Center Seattle, Washington The Cerebral Microvasculature and Responses to Ischemia Mechanisms of Thrombosis and Thrombolysis

Imanuel Dzialowski, MD Department of Neurology Dresden University Stroke Centre Technical University of Dresden Dresden, Germany Computed Tomography–Based Evaluation of Cerebrovascular Disease

Jennifer Diedler, MD Department of Neurology University of Heidelberg Heidelberg, Germany Critical Care of the Patient with Acute Stroke

Christopher S. Eddleman, MD, PhD Department of Neurological Surgery Feinberg School of Medicine Northwestern University Chicago, Illinois Cerebral Cavernous Malformations and Venous Anomalies: Diagnosis, Natural History, and Clinical Management

Hans C. Diener, MD Professor of Neurology and Chairman Department of Neurology University Duisburg-Essen Essen, Germany Migraine and Stroke

Mohamed Samy Elhammady, MD Department of Neurosurgery University of Miami Miller School of Medicine Lois Pope LIFE Center Miami, Florida Surgical Management of Asymptomatic Carotid Stenosis

Marco R. Di Tullio, MD Professor of Medicine Division of Cardiology Associate Director Cardiovascular Ultrasound Laboratories Columbia University Medical Center New York, New York Atherosclerotic Disease of the Proximal Aorta

Mitchell S.V. Elkind, MD, MS, FAAN Associate Professor of Neurology and Epidemiology Associate Chairman of Neurology for Clinical Research and Training Departments of Neurology and Epidemiology Columbia University Medical Center New York, New York Collagen Vascular and Infectious Diseases

Bruce H. Dobkin, MD, FRCP Neurologic Rehabilitation and Research Director University of California Los Angeles Stroke Center Los Angeles, California Rehabilitation and Recovery of the Patient with Stroke

J. Paul Elliott, MD Neurosurgeon Colorado Brain and Spine Institute, LLC, PC Englewood, Colorado Dural Arteriovenous Malformations

Kendra Drake, MD Department of Neurology The University of Arizona Tucson, Arizona Coagulation Abnormalities in Stroke

José M. Ferro, MD, PhD Director and Full Professor Department of Neurosciences Hospital de Santa Maria University of Lisbon Lisbon, Portugal Cerebral Venous Thrombosis

Rose Du, MD, PhD Assistant Professor of Surgery Department of Neurosurgery Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts Surgical Management of Posterior Circulation Aneurysms

J. Max Findlay, MD, PhD, FRCSC Division of Neurosurgery University of Alberta Edmonton, Alberta, Canada Intraventricular Hemorrhage

CONTRIBUTORS

William A. Friedman, MD Chairman Department of Neurosurgery University of Florida McKnight Brain Institute Gainesville, Florida Radiosurgery for Arteriovenous Malformations Karen L. Furie, MD Neurology Stroke Service Massachusetts General Hospital Boston, Massachusetts Cardiac Diseases Anthony J. Furlan, MD Professor and Chairman of Neurology Gilbert W. Humphrey Chair in Neurology Case Western Reserve School of Medicine University Hospitals–Case Medical Center Cleveland, Ohio Intraarterial Thrombolysis in Acute Ischemic Stroke Sasikhan Geibprasert, MD Department of Medical Imaging The Hospital for Sick Children Toronto, Ontario, Canada Interventional Therapy of Brain and Spinal Arteriovenous Malformations Y. Pierre Gobin, MD Professor of Radiology in Neurology and Neurosurgery Director Interventional Neurology Weill Cornell Medical Center New York Presbyterian Hospital New York, New York Cerebral Angiography Mark P. Goldberg, MD Professor and Chair Department of Neurology University of Texas Southwestern Medical Center Dallas,Texas Molecular Pathophysiology of White Matter AnoxicIschemic Injury Larry B. Goldstein, MD Professor of Medicine Division of Neurology Department of Medicine Director Duke Stroke Center Duke University Durham, North Carolina Primary Prevention of Stroke Nicole R. Gonzales, MD Assistant Professor of Neurology Department of Neurology University of Texas Medical School at Houston Houston,Texas Pharmacologic Modification of Acute Cerebral Ischemia

xi

Matthew J. Gounis, PhD Director New England Center for Stroke Research Assistant Professor Department of Radiology University of Massachusetts Medical School Worcester, Massachusetts Endovascular Treatment of Cerebral Aneurysms Steven M. Greenberg, MD, PhD Professor of Neurology Harvard Medical School Director Hemorrhagic Stroke Research Program Massachusetts General Hospital Boston, Massachusetts Intracerebral Hemorrhage David M. Greer, MD, MA, FCCM Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Associate Professor of Neurology Vice Chairman Department of Neurology Yale School of Medicine New Haven, Connecticut Cardiac Diseases Barbara A. Gregson, PhD Principal Research Associate Director of the Surgical Trial in Intracerebral Haemorrhage II (STICH II) Newcastle University Newcastle upon Tyne, United Kingdom Surgery for Intracerebral Hemorrhage James C. Grotta, MD Professor of Neurology Chairman Department of Neurology Director Vascular Neurology Program University of Texas Medical School at Houston Houston,Texas Pharmacologic Modification of Acute Cerebral Ischemia Werner Hacke, MD, PhD Professor and Chairman Department of Neurology University of Heidelberg Heidelberg, Germany Cerebral Infarction: Surgical Treatment Critical Care of the Patient with Acute Stroke John Hallenbeck, MD Senior Investigator Stroke Branch National Institute of Neurological Disorders and Stroke Bethesda, Maryland Cerebral Ischemia and Inflammation

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CONTRIBUTORS

Gerhard F. Hamann, MD Department of Neurology Horst-Schmidt-Kliniken Wiesbaden, Germany The Cerebral Microvasculature and Responses to Ischemia Andreas Hartmann, MD Associate Professor of Neurology Charité Berlin Department of Neurology Klinikum Frankfurt (Oder) Oder, Germany Arteriovenous Malformations and Other Vascular Anomalies Michael Hennerici, MD, PhD Professor of Neurology Chairman Department of Neurology University of Heidelberg Mannheim, Germany Ultrasonography Roberto C. Heros, MD Department of Neurosurgery University of Miami School of Medicine Lois Pope LIFE Center Miami, Florida Surgical Treatment of Asymptomatic Carotid Stenosis Randall Higashida, MD Clinical Professor of Radiology, Neurological Surgery, Neurology, and Anesthesiology Chief Division of Neurointerventional Radiology University of California, San Francisco, Medical Center San Francisco, California Intraarterial Thrombolysis in Acute Ischemic Stroke Shunichi Homma, MD Margaret Milliken Hatch Professor of Medicine Associate Chief Cardiology Division Director Noninvasive Cardiac Imaging Columbia University Medical Center New York, New York Atherosclerotic Disease of the Proximal Aorta Cardiac Diseases Kazuhiro Hongo, MD Department of Neurosurgery Shinshu University School of Medicine Matsumoto, Japan Cerebellar Infarction and Hemorrhage

L. Nelson Hopkins, MD, FACS Professor and Chairman of Neurosurgery Professor of Radiology University of Buffalo Director Toshiba Stroke Research Center State University of New York Department of Neurosurgery Millard Fillmore Gates Hospital Kaleida Health Buffalo, New York Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations Tetsuyoshi Horiuchi, MD Department of Neurosurgery Shinshu University School of Medicine Matsumoto, Japan Cerebellar Infarction and Hemorrhage George Howard, DrPH Department Chair Biostatistics School of Public Health University of Alabama at Birmingham Birmingham, Alabama Distribution of Stroke: Heterogeneity by Age, Race, and Sex Virginia J. Howard, PhD Associate Professor of Epidemiology School of Public Health University of Alabama at Birmingham Birmingham, Alabama Distribution of Stroke: Heterogeneity by Age, Race, and Sex Daniel Huddle, DO Interventional Neuroradiologist Colorado Brain and Spine Institute, LLC, PC Englewood, Colorado Dural Arteriovenous Malformations Costantino Iadecola, MD Cotzias Distinguished Professor of Neurology and Neuroscience Chief Division of Neurobiology Weill Cornell Medical College New York, New York Cerebral Ischemia and Inflammation Anne Joutel, MD Laboratoire de Génétique Université Hôpital Lariboisière–Fernand Widal Paris, France CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CONTRIBUTORS

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Eric Jüttler, MD, MSc Junior Professor of Neurology Center for Stroke Research Berlin Charité—Universitätsmedizin Berlin Berlin, Germany Cerebral Infarction: Surgical Treatment

Chelsea S. Kidwell, MD Professor of Neurology Medical Director of Georgetown Stroke Center Georgetown University Medical Center Washington, D.C. Magnetic Resonance Imaging of Cerebrovascular Diseases

Udaya K. Kakarla, MD Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Spinal Arteriovenous Malformations

Helen Kim, PhD Assistant Professor Departments of Anesthesia and Perioperative Care, and Epidemiology and Biostatistics Center for Cerebrovascular Research Institute for Human Genetics University of California, San Francisco San Francisco, California Genetics and Vascular Biology of Brain Vascular Malformations

Mary A. Kalafut, MD Co-Director Vascular Laboratory The Scripps Research Institute La Jolla, California Mechanisms of Thrombosis and Thrombolysis William B. Kannel, MD, MPH Senior Investigator Framingham Heart Study Professor Emeritus Boston University School of Medicine Framingham, Massachusetts Epidemiology of Stroke Carlos S. Kase, MD Professor of Neurology Boston University School of Medicine Neurologist-in-Chief Boston Medical Center Boston, Massachusetts Intracerebral Hemorrhage Scott E. Kasner, MD, MSCE Professor Department of Neurology University of Pennsylvania Philadelphia, Pennsylvania Treatment of “Other” Stroke Etiologies Markku Kaste, MD, PhD, FAHA, FESO Professor of Neurology Emeritus Chair of Department of Neurology Emeritus Head of Clinical Stroke Research Department of Neurology Helsinki University Central Hospital University of Helsinki Helsinki, Finland General Stroke Management and Stroke Units Alexander Khaw, MD Director of Stroke Research and Neurovascular Laboratory Department of Neurology University of Greifswald Greifswald, Germany Arteriovenous Malformations and Other Vascular Anomalies

Louis J. Kim, MD Assistant Professor of Neurological Surgery University of Washington School of Medicine Attending Neurosurgeon Harborview Medical Center Seattle, Washington Spinal Arteriovenous Malformations Stanley H. Kim, MD Neurosurgeon Neurosurgery, Endovascular, and Spine Center Austin,Texas Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations Catharina J.M. Klijn, MD, PhD Department of Neurology Rudolf Magnus Institute of Neuroscience University Medical Center Utrecht Utrecht,The Netherlands Genetics of Aneurysms and Arteriovenous Malformations Shigeaki Kobayashi, MD Department of Neurosurgery Stroke and Brain Center Aizawa Hospital Matsumoto, Japan Cerebellar Infarction and Hemorrhage Ricardo J. Komotar, MD Department of Neurological Surgery Neurological Institute Columbia University Medical Center New York, New York Surgical Decision Making,Techniques, and Periprocedural Care of Cerebral Arteriovenous Malformations

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CONTRIBUTORS

Timo Krings, MD, PhD, FRCP(C) Professor of Radiology—Neuroradiology Division of Neuroradiology Joint Department of Medical Imaging Toronto Western Hospital University Health Network and Hospital for Sick Children University of Toronto Toronto, Ontario, Canada Interventional Therapy of Brain and Spinal Arteriovenous Malformations Alexander Kunz, MD Division of Neurobiology Department of Neurology and Neuroscience Weill Cornell Medical College New York, New York Cerebral Ischemia and Inflammation Tobias Kurth, MD, ScD Director of Research Inserm Unit 708—Neuroepidemiology Paris, France Migraine and Stroke Catherine Lamy, MD Department of Neurology Hôpital Sainte-Anne Paris Descartes University Paris, France Hypertensive Encephalopathy Ronald M. Lazar, PhD, FAAN, FAHA Professor of Clinical Neuropsychology in Neurology and Neurological Surgery Director Levine Cerebral Localization Laboratory Neurological Institute Columbia University New York, New York Middle Cerebral Artery Disease Elad I. Levy, MD, FACS, FAHA Director of Neuroendovascular Fellowship Professor of Neurosurgery Professor of Radiology University of Buffalo Neurosurgery Co-director Toshiba Stroke Research Center Department of Neurosurgery Millard Fillmore Gates Hospital Kaleida Health Buffalo, New York Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations

David S. Liebeskind, MD Professor of Neurology Director Stroke Imaging Director Vascular Neurology Residency Co-Director Cerebral Blood Flow Laboratory Associate Director UCLA Stroke Center David Geffen School of Medicine at UCLA University of California, Los Angeles Los Angeles, California Cerebral Angiography Patrick D. Lyden, MD, FAAN, FAHA Chairman Department of Neurology Carmen and Louis Warschaw Chair in Neurology Cedars-Sinai Medical Center Los Angeles, California Intravenous Thrombolysis Joanne Markham, MS Research Associate Professor of Radiology Division of Radiological Sciences Washington University Medical School St. Louis, Missouri Cerebral Blood Flow and Metabolism in Human Cerebrovascular Disease Randolph S. Marshall, MD John and Elizabeth Katte Harris Professor of Neurology Division Head Stroke and Cerebrovascular Division Columbia University New York, New York Middle Cerebral Artery Disease J.L. Martí-Vilalta, MD Director Cerebrovascular Unit Department of Neurology Hospital de la Santa Creu i Sant Pau Barcelona, Spain Microangiopathies (Lacunes) Jean-Louis Mas, MD Professor of Neurology Department of Neurology Hôpital Sainte-Anne Paris Descartes University Paris, France Hypertensive Encephalopathy

CONTRIBUTORS

Henning Mast, MD Adjunct Associate Professor of Neurology Stroke Unit, Neurological Institute Columbia University New York, New York Arteriovenous Malformations and Other Vascular Anomalies Carotid Artery Disease Junichi Masuda, MD Department of Laboratory Medicine Shimane Medical University Shimane, Japan Moyamoya Disease Colin Mathers, PhD Coordinator Mortality and Burden of Disease Innovation, Information, Evidence and Research Cluster (IER) World Health Organization Geneva, Switzerland The Global Burden of Stroke Marc R. Mayberg, MD Executive Director Seattle Neuroscience Institute at Swedish Medical Center Seattle, Washington Indications for Carotid Endarterectomy in Patients with Symptomatic Stenosis Stephen Meairs, MD Professor of Neurology Coordinator of European Stroke Network University of Heidelberg Mannheim, Germany Ultrasonography Alexander David Mendelow, MD, PhD Department of Neurosurgery Newcastle General Hospital Newcastle upon Tyne, United Kingdom Surgery for Intracerebral Hemorrhage James F. Meschia, MD, FAAN Professor of Neurology Mayo Clinic Jacksonville, Florida Stroke Genetics Alyson A. Miller, PhD National Health and Research Council of Australia Career Development Award Fellow Department of Pharmacology Monash University Clayton,Victoria, Australia Vascular Biology and Atherosclerosis of Cerebral Arteries Takahiro Miyawaki, MD Department of Neuroscience Albert Einstein College of Medicine Bronx, New York Molecular and Cellular Mechanisms of Ischemia-Induced Neuronal Death

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J Mocco, MD, MS Department of Neurosurgery Toshiba Stroke Research Center School of Medicine and Biomedical Sciences State University of New York at Buffalo Department of Neurosurgery Millard Fillmore Gates Hospital Kaleida Health Buffalo, New York Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations J.P. Mohr, MD, MS Daniel Sciarra Professor of Neurology Department of Neurology Columbia University New York, New York Arteriovenous Malformations and Other Vascular Anomalies Carotid Artery Disease Classification of Ischemic Stroke Collagen Vascular and Infectious Diseases Columbia University Daniel Sciarra Professor of Neurology Department of Neurology Intracerebral Hemorrhage Microangiopathies (Lacunes) Middle Cerebral Artery Disease New York, New York Posterior Cerebral Artery Disease Spinal Cord Ischemia Ultrasonography Vertebrobasilar Disease Jacques J. Morcos, MD, FRCS(Eng), FRCS(Ed) Professor Departments of Neurosurgery and Otolaryngology Co-Director Microsurgery Training Center University of Miami Miller School of Medicine Lois Pope LIFE Center Miami, Florida Surgical Treatment of Asymptomatic Carotid Stenosis Lewis B. Morgenstern, MD Professor Neurology, Emergency Medicine, and Neurosurgery Director Stroke Program University of Michigan School of Public Health Ann Arbor, Michigan Medical Therapy of Intracerebral and Intraventricular Hemorrhage Michael A. Moskowitz, MD Professor of Neurology Harvard-MIT Division of Health Science and Technology Boston, Massachusetts Apoptosis and Related Mechanisms in Cerebral Ischemia

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CONTRIBUTORS

Brian V. Nahed, MD Department of Neurosurgery Massachusetts General Hospital Boston, Massachusetts Anterior Circulation Aneurysms David W. Newell, MD Executive Director Swedish Neuroscience Institute Seattle, Washington Extracranial to Intracranial Bypass for Cerebral Ischemia Dimitry Ofengeim, MD Department of Neuroscience Albert Einstein College of Medicine Bronx, New York Molecular and Cellular Mechanisms of Ischemia-Induced Neuronal Death Jun Ogata, MD Multiple Handicapped Children’s Hospital Hirakata Ryoikuen Tsuda-higashi Hirakata, Osaka, Japan Moyamoya Disease Christopher S. Ogilvy, MD Robert G. and A. Jean Ojemann Professor of Surgery (Neurosurgery) Director Endovascular and Operative Neurovascular Surgery Harvard Medical School Attending Neurosurgeon Massachusetts General Hospital Boston, Massachusetts Anterior Circulation Aneurysms Yuko Y. Palesch, PhD Professor Department of Medicine Division of Biostatistics and Epidemiology Medical University of South Carolina Charleston, South Carolina Conduct of Stroke-Related Clinical Trials Arthur Pancioli, MD Robert C. Levy Professor and Chair Department of Emergency Medicine University of Cincinnati College of Medicine Cincinnati, Ohio Prehospital and Emergency Department Care of the Patient with Acute Stroke Min S. Park, MD Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Spinal Arteriovenous Malformations

Ludmila Pawlikowska, PhD Assistant Professor Department of Anesthesia and Perioperative Care Center for Cerebrovascular Research University of California, San Francisco San Francisco, California Genetics and Vascular Biology of Brain Vascular Malformations John Pile-Spellman, MD Adjunct Professor of Radiology and Neurosurgery Columbia University Medical Center New York, New York Arteriovenous Malformations and Other Vascular Anomalies William J. Powers, MD H. Houston Merritt Distinguished Professor and Chairman Department of Neurology University of North Carolina, Chapel Hill Chapel Hill, North Carolina Cerebral Blood Flow and Metabolism in Human Cerebrovascular Disease Volker Puetz, MD Department of Neurology Dresden University Stroke Centre Technical University of Dresden Dresden, Germany Computed Tomography–Based Evaluation of Cerebrovascular Disease Bruce R. Ransom, MD, PhD Warren and Jermaine Magnuson Professor and Chair of Neurology Adjunct Professor of Physiology and Biophysics University of Washington School of Medicine Seattle, Washington Molecular Pathophysiology of White Matter Anoxic-Ischemic Injury Risto O. Roine, MD, PhD Associate Professor Department of Neurology Helsinki University Central Hospital University of Helsinki Helsinki, Finland General Stroke Management and Stroke Units Ynte M. Ruigrok, MD, PhD Department of Neurology Rudolf Magnus Institute of Neuroscience University Medical Center Utrecht Utrecht,The Netherlands Genetics of Aneurysms and Arteriovenous Malformations Tatjana Rundek, MD, PhD Associate Professor of Neurology Department of Neurology Miller School of Medicine University of Miami Miami, Florida Prognosis after Stroke

CONTRIBUTORS

Ralph L. Sacco, MS, MD, FAAN, FAHA Adjunct Professor Department of Neurology Columbia University New York, New York Professor and Chairman Department of Neurology Miller School of Medicine University of Miami Miami, Florida Prognosis after Stroke Primary Prevention of Stroke Classification of Ischemic Stroke Ronald J. Sattenberg, MD Assistant Professor of Radiology Department of Radiology University of Louisville Hospital Louisville, Kentucky Cerebral Angiography Jeffrey L. Saver, MD, FAHA, FAAN Professor of Neurology David Geffen School of Medicine at UCLA Director, UCLA Stroke Center University of California, Los Angeles Los Angeles, California Cerebral Angiography Sean I. Savitz, MD Associate Professor of Neurology University of Texas Medical School at Houston Houston,Texas Enhancing Stroke Recovery with Cellular Therapies Sudha Seshadri, MD Associate Professor Department of Neurology Boston University School of Medicine Investigator, The Framingham Heart Study Boston, Massachusetts Vascular Dementia and Vascular Cognitive Decline Jitendra Sharma, MD Fellow Interventional Neurology Case Western Reserve School of Medicine Cleveland, Ohio Intraarterial Thrombolysis in Acute Ischemic Stroke Gerald Silverboard, MD Atlanta Family Neurology Atlanta, Georgia Arterial Dissections and Fibromuscular Dysplasia Aneesh B. Singhal, MD Neurology Stroke Service Massachusetts General Hospital Boston, Massachusetts Reversible Cerebral Vasoconstriction Syndromes

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Christopher G. Sobey, PhD National Health and Medical Research Council of Australia Senior Research Fellow Department of Pharmacology Monash University Clayton, Victoria, Australia Vascular Biology and Atherosclerosis of Cerebral Arteries Robert F. Spetzler, MD Director J. N. Harber Chair of Neurological Surgery Barrow Neurological Institute Phoenix Professor Department of Surgery Section of Neurosurgery University of Arizona College of Medicine Tuscon, Arizona Spinal Arteriovenous Malformations Christian Stapf, MD Adjunct Assistant Professor of Neurology Division of Stroke Department of Neurology Columbia University Medical Center New York, New York Arteriovenous Malformations and Other Vascular Anomalies Robert M. Starke, BS Department of Neurological Surgery Neurological Institute Columbia University Medical Center New York, New York Surgical Decision Making,Techniques, and Periprocedural Care of Cerebral Arteriovenous Malformations Michael F. Stiefel, MD Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona Spinal Arteriovenous Malformations Kathleen Strong, MD Monitoring and Evaluation UNITAID Geneva, Switzerland The Global Burden of Stroke José I. Suarez, MD Head Vascular Neurology and Neurocritical Care Professor Neurology and Neurosurgery Baylor College of Medicine Houston,Texas Aneurysmal Subarachnoid Hemorrhage

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CONTRIBUTORS

Marek Sykora, MD Department of Neurology University of Heidelberg Heidelberg, Germany Department of Neurology Comenius University Bratislava Bratislava, Slovakia Critical Care of the Patient with Acute Stroke Gilda Tafreshi, MD Department of Neurology Scripps Mercy Medical Center San Diego, California Intravenous Thrombolysis Karel ter Brugge, MD, FRCP Professor of Radiology and Surgery The David Braley and Nancy Gordon Chair in Interventional Neuroradiology University of Toronto Head of Neuroradiology University Health Network and the Mount Sinai and Women’s College Hospitals Toronto Western Hospital Toronto, Ontario, Canada Interventional Therapy of Brain and Spinal Arteriovenous Malformations Barbara C. Tilley, MD, PhD Lorne C. Bain Distinguished Professor and Director Division of Biostatistics The University of Texas Health Science Center at Houston School of Public Health Houston,Texas Conduct of Stroke-Related Clinical Trials Danilo Toni, MD, PhD Professor of Neurology Director of Emergency Department Stroke Unit Department of Neurology and Psychiatry Sapienza University of Rome Rome, Italy Classification of Ischemic Stroke Elisabeth Tournier-Lasserve, MD Laboratoire de Génétique Université Hôpital Lariboisière–Fernand Widal Paris, France CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Marcelo D. Vilela, MD Chief of Neurosurgery Mater Dei Hospital Belo Horizonte Minas Gerais, Brazil Affiliated Assistant Professor Department of Neurological Surgery University of Washington Seattle, Washington Extracranial to Intracranial Bypass for Cerebral Ischemia

Rüdiger von Kummer, MD, FAHA Professor of Diagnostic Radiology/Neuroradiology Head Department of Neuroradiology Technische Universität Dresden Director Dresden University Stroke Centre Dresden, Germany Computed Tomography–Based Evaluation of Cerebrovascular Disease Ajay K. Wakhloo, MD, PhD Professor of Radiology, Neurology, and Surgery Director Neuroimaging and Intervention Director Clinical Research New England Center for Stroke Research University of Massachusetts Medical School Worcester, Massachusetts Endovascular Treatment of Cerebral Aneurysms Steven Warach, MD, PhD Senior Investigator Stroke Diagnostics and Therapeutic Section National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland Magnetic Resonance Imaging of Cerebrovascular Diseases Babette B. Weksler, MD, MS Professor of Medicine Weill Cornell Medical College Weill Cornell Cancer Care and Blood Disorders New York, New York Antiplatelet Therapy for Secondary Prevention of Stroke Joshua Z. Willey, MD, MS Assistant Professor of Neurology Division of Stroke Columbia University Medical Center New York, New York Spinal Cord Ischemia Max Wintermark, MD, MAS Associate Professor of Radiology, Neurology, Neurological Surgery, and Biomedical Engineering Chief of Neuroradiology Department of Radiology University of Virginia Charlottesville, Virginia Magnetic Resonance Imaging of Cerebrovascular Diseases Philip A. Wolf, MD Professor of Neurology, Medicine, and Public Health Boston University School of Medicine Principal Investigator Framingham Heart Study Boston, Massachusetts Epidemiology of Stroke

CONTRIBUTORS

Daniel Woo, MD, MS Professor Department of Neurology University of Cincinnati College of Medicine Cincinnati, Ohio Stroke Genetics Takenori Yamaguchi, MD, PhD Professor Emeritus National Cerebral and Cardiovascular Center Osaka, Japan Moyamoya Disease Masahiro Yasaka, MD Director Department of Cerebrovascular Disease National Hospital Organization Kyusyu Medical Center Kyushu, Japan Moyamoya Disease William L. Young, MD James P. Livingston Professor and Vice Chair Department of Anesthesia and Perioperative Care Professor of Neurological Surgery and Neurology Director Center for Cerebrovascular Research University of California, San Francisco San Francisco, California Genetics and Vascular Biology of Brain Vascular Malformations Darin B. Zahuranec, MD Assistant Professor of Neurology University of Michigan Medical School Ann Arbor, Michigan Medical Therapy of Intracerebral and Intraventricular Hemorrhage

xix

Allyson R. Zazulia, MD Associate Professor Department of Neurology Section of Cerebrovascular Disease Washington University School of Medicine St. Louis, Missouri Cerebral Blood Flow and Metabolism in Human Cerebrovascular Disease Zheng Gang Zhang, MD, PhD Department of Neurology Henry Ford Health System Detroit, Michigan Enhancing Brain Reorganization and Recovery of Function after Stroke R. Suzanne Zukin, PhD F.M. Kirby Professor of Neural Repair and Protection Dominick P. Pupura Department of Neuroscience Director Neuropsychopharmacology Center Albert Einstein College of Medicine New York, New York Molecular and Cellular Mechanisms of Ischemia-Induced Neuronal Death Richard M. Zweifler, MD Chief of Neurology Sentara Healthcare Professor of Neurology and Eastern Virginia Medical School Norfolk, Virginia Arterial Dissections and Fibromuscular Dysplasia

PREFACE The editors and the many contributors are grateful that their efforts have justified this, the fifth edition of this book, the first edition dating back 25 years. Further changes in the field of stroke are continuing to improve the knowledge of risk factors (modifiable or not); diagnosis, based not only on the clinical syndrome but also on greatly improved imaging; treatment to prevent the basic underlying disease and to stabilize and even to reverse the effects of acute stroke; and improvements in functional rehabilitation to improve the outcome. Michael Moskowitz now edits the expanded section on pathophysiology. Philip A. Wolf continues as editor for the section on epidemiology and stroke prevention. J.P. Mohr continues as editor for clinical manifestations and specific medical diseases and stroke. Advances in the field have radically altered the number and length of the sections. A new editor, Rüdiger von Kummer, has taken charge of the section on diagnostic studies. The ever-enlarging subject of therapy has prompted further modifications of the book’s structure. James C. Grotta continues as section editor for medical therapy. Reflecting the growing field of intravascular therapy and its multispecialty nature, Rüdiger

von Kummer overlaps as section editor for interventional neuroradiology, and another new editor, Marc Mayberg, edits the section on neurosurgery. We hope readers will be attracted to the important changes in scope of the subjects covered, with the inclusion of many new ones unknown or barely in existence when the original edition was brought forth. We continue the hope that the information contained in this edition makes for its rapid obsolescence, so great are our aspirations for continued rapid developments in our field. J.P. MOHR, MD, MS JAMES C. GROTTA, MD MARC R. MAYBERG, MD MICHAEL MOSKOWITZ, MD, PhD RÜDIGER VON KUMMER, MD, FAHA PHILIP A. WOLF, MD

xxi

section one

Pathophysiology MICHAEL A. MOSKOWITZ

The science of stroke has progressed rapidly. Neurogenesis, angiogenesis, brain plasticity, and new stem cell technologies have emerged to turn the field toward longer term strategies for stroke recovery. This section focuses on many of these advances and summarizes key principles that affect the translational aspects of stroke science. The basic science section focuses on vascular biology and atherosclerosis; the molecules and mechanisms that modulate vascular reactivity, vessel caliber, and ultimately blood flow; blood flow regulation, oxygen delivery and consumption, and hemodynamic and metabolic components that characterize brain before and after stroke; and pathologic conditions that modulate these mechanisms. Discussions of matrix molecules and responses of small blood vessels to stroke injury, as well as the biology of thrombus formation and clot lysis, are included. Classic histopathology of stroke follows, including the underlying dynamics of cell death inferred from pathologic descriptions, the cell and tissue mechanisms contributing to ischemic injury and cell death, and the complexity of tissue response to injury and entryways into the cell death process. Reviewed is the comprehensive literature about ion channels, glutamate receptors, hydrogen ions, oxygen radicals, and ways in which molecular and cellular pathways can be harnessed during the preconditioning process to reduce injury in the vulnerable brain.

1

Vascular Biology and Atherosclerosis of Cerebral Arteries ALYSON A. MILLER, CHRISTOPHER G. SOBEY

C

erebral perfusion is compromised by several pathophysiologic conditions that not only affect cerebrovascular reactivity and thrombosis but also are associated with an increased risk of stroke. Disease states may produce cerebrovascular abnormalities by a variety of mechanisms, including endothelial dysfunction, impaired relaxation of vascular muscle, and augmented vasoconstriction. Significant progress has been made in the understanding of mechanisms that normally regulate cerebral blood flow and abnormalities of cerebrovascular function in pathophysiologic states. This chapter summarizes the current understanding of some important mechanisms of cerebrovascular function and dysfunction. We do not, however, address other aspects of vascular biology, including vascular proliferation, remodeling, and formation of collateral vessels.

Physiologic Regulation of Cerebrovascular Tone Nitric Oxide and Cyclic Guanosine Monophosphate–Mediated Mechanisms Endothelium modulates vascular tone by producing and releasing potent vasoactive substances.1-3 One of these important substances is endothelium-derived nitric oxide (NO), which diffuses to vascular muscle and produces relaxation through activation of the soluble form of guanylyl cyclase, resulting in an increased intracellular concentration of cyclic guanosine monophosphate (cGMP) and relaxation. The NO–guanylyl cyclase mechanism represents a major mechanism of cerebral vasodilatation. NO is a potent dilator of cerebral vessels and may be produced by one of three isoforms of NO synthase (NOS) (neuronal/type 1 or nNOS, immunologic/type 2 or iNOS, and endothelial/type 3 or eNOS), each of which uses l-arginine as a substrate.1,2 In blood vessels, NO is generated under basal conditions in the endothelium by eNOS. Soluble guanylyl cyclase, which is cytosolic, can also be activated by pharmacologic agents, including nitroglycerin and sodium nitroprusside.2,4 The activity of NOS can be further stimulated by increases in intracellular calcium levels that occur in response to many receptor-mediated agonists, such as acetylcholine, or in response to rises in shear stress that are associated with increases in the velocity of blood flow.1

Under normal conditions, NO is released both intraluminally and abluminally by endothelium. Endothelial release of both NO and prostacyclin, a product of arachidonic acid metabolism, into the vascular lumen contributes to the antithrombogenic properties of endothelium because both of these substances inhibit aggregation of platelets and adherence of leukocytes to endothelium. Particulate guanylyl cyclase, the second form of guanylyl cyclase in vascular muscle, can be activated by members of the natriuretic peptide family: atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide.5 Administration of exogenous atrial and brain natriuretic peptides produces relaxation of cerebral blood vessels, but it is not clear whether endogenously produced natriuretic peptides contribute to regulation of cerebrovascular tone. Although the endothelial and neuronal isoforms of NOS are constitutively expressed in blood vessels, the inducible or “immunologic” isoform is probably not expressed under normal conditions; however, its expression may be induced in endothelium, vascular muscle, and other cell types in brain.1 This inducible isoform of NOS can produce large amounts of NO in pathophysiologic conditions, such as ischemia– reperfusion, subarachnoid hemorrhage (SAH), and meningitis. Cyclic Adenosine Monophosphate–Mediated Mechanisms Activation of adenylate cyclase and production of cyclic adenosine monophosphate (cAMP) in vascular muscle mediate relaxation of blood vessels in response to a variety of endogenous substances, and this mediation represents a second major mechanism of vasodilatation in cerebral vessels. Stimuli that activate adenylate cyclase include prostanoids (prostacyclin and prostaglandin E2), adenosine, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide, β-adrenergic agonists, pituitary adenylate cyclase activating peptide (PACAP), and adrenomedullin. A newer concept is that increases in intracellular cAMP in vascular muscle produce vasodilatation only in part by a direct effect and, in part, by activation of potassium ion (K+) channels (see later). 3

4

PATHOPHYSIOLOGY

K+ Channels and Endothelium-Derived Hyperpolarizing Factor (EDHF) Vasodilator mechanisms also present in cerebral vessels involve activation of K+ channels and, apparently to a much lesser extent than in systemic vessels, the release of an EDHF. Increases in the activity of K+ channels ultimately result in membrane hyperpolarization of vascular muscle cells.1,6,7 At least seven families of K+ channels are present in cerebral blood vessels: adenosine triphosphate (ATP)– sensitive K+ (K ATP) channels; large-(BKCa), intermediate(IKCa), and small-conductance (SKCa) calcium-activated K+ channels; voltage-dependent K+ (K V ) channels, inwardly rectifying K+ (K IR) channels, and two-pore domain K+ (K2P) channels. KATP Channels The activity of K ATP channels is inhibited by intracellular ATP or an increased ratio of ATP to adenosine diphosphate (ADP). The intracellular concentration of ATP is normally sufficient to prevent opening of K ATP channels, and in cerebrovascular muscle, these channels appear to be closed under normal conditions.8 Because intracellular ATP levels are tightly regulated, it is likely that K ATP channels are only rarely activated by reductions in ATP. Reductions in levels of intracellular pO2 and pH also open these channels and produce vasorelaxation. Thus, the activity of K ATP channels appears to reflect, at least in part, the metabolic state of cells.6 Several endogenous substances produce hyperpolarization and relaxation of cerebrovascular muscle that is mediated, either fully or partly, by activation of K ATP channels. These substances include CGRP, norepinephrine, and increased intracellular concentration of cAMP.7 The concept that K ATP channels may be activated by higher concentrations of cAMP is supported by evidence that dilatation of the basilar artery in response to forskolin, a direct activator of adenylate cyclase, can be attenuated with glibenclamide, a selective inhibitor of K ATP channels.9,10 In contrast, vasodilators that increase cGMP in cerebral vessels are usually not inhibited by glibenclamide in most studies.11,12 Systemic hypoxia is a potent cerebral dilator, and relaxation of cerebral vessels during hypoxia appears to involve activation of K+ channels.7,13 Relaxation during hypoxia of both large cerebral arteries in vitro and cerebral arterioles in vivo is inhibited by glibenclamide, suggesting that the response to hypoxia is mediated by activation of K ATP channels.8 BKCa Channels The activity of BKCa channels increases in response to elevations in intracellular calcium. In particular, this is now understood to be mediated by calcium sparks, which are transient local calcium-signaling events that deliver high (μM) local calcium levels from the opening of ryanodine-sensitive calcium release channels located in the sarcoplasmic reticulum to BKCa channels on the plasma membrane.14 BKCa channels in blood vessels appear to act as a negative feedback mechanism during increases in intracellular concentrations of calcium; thus these channels open more frequently during increases in blood

pressure and with membrane depolarization. The tone of cerebral vessels, particularly during elevations of arterial pressure, may potentially be influenced by the activity of BKCa channels (see later discussion of hypertension).13 In contrast to K ATP channels, BKCa channels may be active in large cerebral arteries under basal conditions, and selective inhibition of this channel (e.g., with tetraethylammonium [TEA] or iberiotoxin) leads to constriction of cerebral arteries.15,16 BKCa channels are responsive to other stimuli in addition to the intracellular concentration of calcium. Activation of BKCa channels appears to contribute to relaxation of cerebral arterioles in response to activation of adenylate cyclase and accumulation of cAMP.17 Because a variety of endogenous vasoactive stimuli raise the concentration of cAMP in vascular muscle, activation of BKCa channels by cAMP may play a major role in regulation of cerebrovascular tone. There is similar evidence that increases in cGMP, or of NO independent of cGMP, can increase the activity of BKCa channels in cerebral vessels.15,17 IKCa and SKCa Channels and EDHF Recent studies have established that both IKCa and SKCa channels are expressed in cerebral arteries.18 Both of these channels are well known to be expressed in endothelial cells of systemic arteries, where they mediate K+ efflux and hyperpolarization, resulting in EDHF-mediated vasodilatation. However, studies to clarify the functional roles of IKCa and SKCa channels and, indeed, the existence and nature of EDHF-mediated responses have been much fewer in cerebral arteries. There is evidence that just as in systemic arteries, the functional importance of EDHF in endothelium-dependent relaxation becomes more prominent (with the role of endothelium-derived NO diminishing) in smaller arteries.19 Although further study is clearly required in cerebral arteries, it appears that IKCa channel activation can fully mediate EDHF-dependent dilatation of the middle cerebral artery when NO is absent,18,20,21 whereas SKCa channels can also contribute to endothelium-dependent hyperpolarization of this vessel only when NO synthesis is present.18,21 KV Channels Voltage-dependent K+ (K V ) channels are activated in response to membrane depolarization, but this process occurs independently of the intracellular calcium concentration. These K+ channels are also activated by elevations in arterial blood pressure and may thus modulate pressure-induced increases in cerebral artery tone.22 Activation of K V channels may also contribute directly to mechanisms that produce cerebral vasorelaxation in response to NO and EDHF.23-25 KIR Channels The name inwardly rectifying K+ channels is based on the channels’ properties that enable conduction of K+ current into cells much more readily than K+ current out of cells.6,26,27 At physiologic membrane potential, however, a small rise above the normal extracellular K+ (≈3 mM in cerebrospinal fluid) leads to an increase in the resting outward K+ current through K IR channels. Hence, a modest increase in extracellular K+ (e.g., by 75 yr NIHSS score 0-9 (n = 46) 10-14 (n = 28) 15-20 (n = 43) >20 (n = 49)

t-PA

Placebo

59 38 41 22

42 18 27 12

60 25 0 7

37 25 25 0

50 39 26 8

54 27 0 0

67 27 23 0

36 15 6 0

*Favorable outcome = NIHSS score of 0 or 1 at 3 months. The categories for age and baseline NIHSS represent quartiles of the range of each variable. NIHSS, National Institutes of Health Stroke Scale; t-PA, tissue-type plasminogen activator. Data from The NINDS t-PA Stroke Study Group: Generalized efficacy of t-PA for acute stroke: Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 28:2119-2125, 1997.

(see later discussion of subgroups). Additionally, overly restrictive entry criteria may limit enrollment of older adults and minority populations more likely to have comorbidities and most in need of the new approaches to stroke prevention or therapy. Potential participants at higher risk of unfavorable outcomes are also potential “responders” to treatment. Table 60-1 shows published data from the NINDS t-PA Stroke Study.39 The percentage of participants with a favorable outcome decreased with age and with increasing NIHSS score, but the t-PA–treated group had a higher percentage of favorable outcomes in 14 of the 16 age-byNIHSS subgroups. In the oldest patients with the highest NIHSS scores, there were no favorable outcomes in either treatment group, but 74% of the t-PA–treated patients, versus 86% of the placebo-treated patients, experienced severe disability or death. To minimize problems with missing data (see discussions of adherence and analyses of missing data), investigators may consider excluding potential participants with characteristics that might prevent the participants from completing the study or from complying with the study medication. Stroke trials thus may exclude patients at imminent risk of death such as those with terminal cancer.

Randomization Randomization is the method of allocating participants to the different treatment arms of a randomized clinical trial. Simple randomization is similar to flipping an unbiased coin and using heads or tails to assign a participant to one of two treatment arms. Using alternating assignment of participants to treatment or control as they come in to a study is not a random assignment: If a participant’s treatment assignment in the sequence of alternating assignments is revealed, all other participants’ assignments can be ascertained. To ensure randomness, a random number generator, available in most statistical software packages, is generally used to conduct the randomization. Stratification Simple randomization may result in imbalances in the risk factors associated with outcome or in the number of participants in each treatment arm. In stroke treatment trials, as in all trials, investigators desire balance in factors associated with treatment outcome such as baseline NIHSS score and age to ensure that one group does not inadvertently have an advantage over another. To obtain balance, one solution is to stratify participants before randomization into specific subgroups and then randomly assign participants to treatment arms within each subgroup. Another goal of stratification is to improve the precision of the statistical analysis. The EC/IC Bypass Study stratified participants on the basis of clinical center, type of underlying vascular lesion (two categories), presence or absence of a related neurologic deficit; participants with internal carotid occlusion were stratified according to presence or absence of related symptoms after angiographic demonstration of occlusion.4,5 In therapeutic trials with smaller samples, a smaller number of strata must be used. For the NINDS rt-PA Stroke Study,9 there was limited knowledge about the predictors of stroke outcome in patients treated soon after stroke (within 180 minutes of stroke onset), so a decision was made to stratify only by clinical site and time from stroke outcome to treatment (0 to 90 minutes or 91 to 180 minutes). There is a rapid increase in the number of subgroups as the number of variables used for stratification rises. In a trial that is stratified on time from stroke onset (early, late), clinical center (8 locations), NIHSS score (3 levels), and age (3 levels), there would be 144 subgroups. Given a large number of subgroups and a small sample size, participants could be unequally assigned to treatment groups within strata, inducing an overall imbalance in the treatment arms. A complex randomization scheme also makes it more likely that clinics will make errors in the randomization. Most treatment trials and prevention trials have sufficient sample size to make stratification unnecessary except on the basis of one or two influential variables. There is little gain in statistical precision once the number of participants per group exceeds 50, with the greatest gains from stratification for trials with 20 or fewer participants per treatment arm.29 Generally, the most important stratifying variable in multiple-site trials is clinical site.

CONDUCT OF STROKE-RELATED CLINICAL TRIALS

When a study uses stratification, the stratifying variables should be included as covariates in the primary analysis. If the overall sample size is small and there is concern that stratification by site may lead to imbalances in treatment groups, one solution is to use a validated clinical index that takes into account several variables or to use minimization, a statistical approach to balancing the treatment arms to the extent possible after each participant’s entry criteria are ascertained.30 Blocking Blocking is the process of forcing the proportion in each of the two treatment arms within strata to be fixed through time, usually at 0.5; that is, blocking provides balance on unknown temporal variables. A block size of four in a trial with equal randomization to the two treatment arms would imply that after every four participants are randomly assigned within a block there would be two participants in each treatment arm. Generally, the selected block size is large enough to make it difficult for an investigator to guess the next treatment assignment. Often the block size is randomly chosen from a range of block sizes to make it more difficult to detect the end of a block.

Blinding Blinding (sometimes referred to as masking) is an approach to reduce bias in the assessment of the trial outcome measures. In a single-blind study, either the participant or the investigator is blinded to the treatment assignment before the end of the trial. In the more common double-blind study, neither the participant nor the investigator knows the treatment assignment. When the outcome is death, it is more difficult to introduce bias unless the outcome is classified as stroke-related death. Bias in classifying a participant as having a new stroke (or stroke-related death) could inadvertently be introduced if the rater assessing outcomes knows the treatment assignment or if differing amounts of effort were put into finding information about the event, depending on treatment group. For many of the other outcome measures of poststroke recovery, some inherent subjectivity is built into the scale assessment. Even if the rater does not introduce bias, there can be a perception of bias on the part of those who review the trial report if the study was not blinded. A traditional approach to blinding is to formulate the intervention in such a way that neither physician nor participant can determine what treatment is being given to the participant. If this approach is not possible (e.g., surgery versus medical care), efforts must be made to collect outcome data in as unbiased a way as possible, such as by using someone not present at the time of treatment, as in the NINDS t-PA stroke trial,9 or by using an independent adjudicator. In the WARSS,6 periodic dose adjustments were needed for many participants receiving warfarin. To maintain the blind, the coordinating center fabricated clinically plausible values for participants in the aspirin-placebo treatment arm. A message to change the placebo dose for

1197

some patients was sent from the laboratory to the investigator. The frequency and amount of change for participants receiving placebo was determined through the use of a complex algorithm that mimicked the frequency and direction of changes in the warfarin-treated group.

Recruitment Proper planning helps ensure recruitment on the timetable projected. This is particularly important for acute stroke therapy trials, in which participant eligibility must be quickly assessed and time from admission to treatment must be minimized. In the NINDS t-PA Stroke Study, methods of total quality improvement were used to flowchart the process in each emergency department and to engage those involved in the process (CT technicians, laboratory technicians, nurses, pharmacists, neurologists, emergency department physicians and staff) in helping determine how to enroll patients more quickly.31 Another important aspect of recruiting is engagement of the community. For acute stroke trials, cooperation of the community emergency medical services is essential in facilitating prompt arrival of prospective trial participants at participating emergency departments.32 In acute stroke trials, the yield of participants from community presentations is low, but communication remains important to create a climate of trust. Also, community consent may be needed in order to meet institutional review board (IRB) requirements for randomization in the emergency department (see later section on informed consent). For prevention trials, especially those conducted in groups of participants who are not acutely ill, the special efforts made to engage the community may have a greater effect on recruitment. In particular, some minority groups may be unwilling to participate in prevention trials unless a climate of trust has been developed in the community by the study investigators. There is a growing literature on recruitment of minority participants, but little rigorous research has been conducted to test recruitment methodologies. A 2000 survey of community members in San Francisco33 identified factors associated with willingness to participate, including altruism and tangible benefits to the participant.

Adherence to Treatment and Trial Follow-Up Adherence to treatment can be increased by simplifying study procedures and demands on participants, gathering sufficient information to enable close contact with participants after enrollment, and providing the patient, family, or both with sufficient information about the trial and its requirements before randomization. Conducting a “runin” period that mimics the study before randomization may eliminate “noncompliers” before they are entered into the trial, although using a run-in design could result in enrolling a less generalizable group of participants. A run-in period may be feasible for long-term stroke prevention trials but would not be possible in therapeutic trials for acute stroke, in which treatment must be given as quickly as possible. In both stroke prevention and therapeutic trials, all participants should be encouraged to return for a final

1198

THERAPY

trial visit even if they no longer take study medications or participate in other aspects of the intervention, to avoid the problem of missing outcome data (see later discussion on missing data). For an acute stroke trial with a one-time dose, the possibility of drop-out from therapy is minimal; however, completeness of follow-up remains an important issue. Measuring Adherence to Treatment If treatment is an educational intervention to reduce stroke risk factors or an exercise rehabilitation program, a participant’s adherence to the regimen can be estimated with process measures (e.g., number of sessions attended) or by changes in knowledge, attitudes, and beliefs. If laboratory tests are applicable, reliable, and affordable, the most accurate assessment of medication compliance may be measurement of blood, saliva, or urine levels of the drug; if, however, a participant is generally noncompliant but takes medication more often close to the next clinic visit, such a measurement does not reflect the true level of adherence. Other standard adherence measures for medication trials include pill counts of returned medication and counting the number of times the pill container was opened by means of a miniaturized electronic device in the lid of the pill bottle. Both methods are only estimates, subject to under- and overcounting or excess opening of the pill container, and can be expensive. Morisky and associates34 suggest posing a set of questions as a better measure of compliance than a pill count. The usefulness of these questions in stroke trials needs validation, although the approach has been validated in trials of Parkinson’s disease treatments.35 Counts of missed visits, missed forms, and missed items on forms may also be useful in monitoring adherence to treatment.

Data Collection and Quality Assurance General texts on clinical trials provide detailed plans for study data collection and quality assurance applicable to stroke trials. Key approaches include study documentation, timely applications of range and consistency checks, and prompt communication of data errors to the study coordinators for resolution. Protocol and Manual of Procedures A trial has two key documents, the protocol and the manual of procedures. Both are essential to trial management. The protocol is the blueprint for the trial. It is the document that is sent to the institutional review board and, when necessary, the FDA. Changes to the protocol and changes in data collected generally require new IRB approval and often notification to the FDA. Protocols should be kept as simple as possible, reflecting the primary aspects of study design with procedures being documented in the manual of procedures. Changes to the manual of procedures would not require a protocol change or new approvals. The manual of procedures contains study instruments (i.e., forms for data collection), detailed instructions for completing the study

instruments, and other instructions for data collection, follow-up, laboratory procedures, and so on. The manual documents answers to questions raised by investigators conducting the trial in the field so that answers to the same question are consistent over time. The protocol and manual of procedures provide sufficient detail to allow someone who has not been participating in the trial to replicate it in another setting. Training An important aspect of quality assurance is training of the people collecting data for the trial. Some trials have developed video training and testing programs for stroke outcomes such as the modified Rankin and NIHSS scales. The training and testing program for the NIHSS scale can be obtained through the National Stroke Association. To maintain consistency of NIHSS measurement over time, investigators are often recertified over the course of the trial.

Data Analyses Intent to Treat The guiding principle in clinical trials is the use of intentto-treat (ITT) analysis. When an ITT analysis is used, all participants undergoing randomization are included in the primary analysis, whether or not they withdraw or deviate from the protocol. In a surgical trial, under an ITT analysis, all participants randomly assigned to surgery would be analyzed in the surgical group, and all participants assigned to medical care would be analyzed in the medical care group. The EC/IC Bypass Study methodology paper describing the design suggested that the intentto-treat principle would not be followed. However, in the presentation of trial results, the analytic approach was changed, and the intent-to-treat principle was followed.5 The terms “completer analysis,” “on-treatment analysis,” and “analyzable population” are generally used to describe a situation in which participants who stop treatment, did not adhere to protocol, or have incomplete follow-up are excluded. These analyses are often conducted in addition to ITT analyses. If results of these ancillary analyses agree with the analyses of the full trial data set, the interpretation is clear. If results do not agree, emphasis should generally be placed on the ITT analysis. When some ineligible participants are expected to be enrolled, the effect on the trial sample size should be considered in the trial design. Although some biostatisticians suggest that no withdrawals be allowed and that analyses include all participants who underwent randomization, regardless of the circumstances, there are several other complex situations relevant to stroke trials.36 For example, if it is necessary to randomly assign participants to treatment before an entry criterion is completely ascertained—for example, before MRI can be performed a large number of participants are enrolled who do not meet the entry criteria. If the eligibility for study is determined on the basis of data collected prior to treatment and eligibility is defined by someone blinded to treatment assignment, the FDA has allowed the ITT analyses to include only eligible participants. Methods for imputing data in order to include participants with missing follow-up and


1199

adherence to the ITT principle are described in a later section in the chapter.

approach, which uses alpha divided by the number of comparisons.

General Approaches

Clustering

Textbooks on clinical trials summarize the analytic approaches used in clinical trials.1,37 These standard approaches, such as analyses of time to new stroke or death, are generally useful in prevention trials and intervention trials, in which the outcome is usually binary (yes/ no; each participant either survived stroke-free or had a new stroke or died). Treatment trials of acute therapy present a special problem. As noted previously, the outcome of therapeutic trials is often recovery from stroke, for which there is no one accepted measure. Thus, trials are usually designed with a set of correlated outcome measures. These measures can be analyzed separately, but interpretation of the set of outcomes with respect to an overall effect of treatment is difficult, particularly if some outcomes show a weak or negative effect. Additionally, having multiple outcome measures generally requires adjustment for multiple comparisons. For this reason some investigators choose a single primary outcome, even though the single outcome does not represent the multiple dimensions of recovery. Others use global tests for multiple outcomes.

Special analytic issues arise in the analyses of clustered data when there is some correlation or association among participants, such as a clinical trial in which the unit of randomization is a physician’s practice or an emergency department rather than a patient. In the analysis of clustered data, a positive correlation among patients in the provider’s practice or clinical site is often assumed, implying that patients in a practice or a clinical site are more like one another than like patients in different practices or sites. In the presence of a positive correlation, the variance unadjusted for clustering underestimates the true variance. Thus, by ignoring the clustering, the investigator may falsely reject a null hypothesis and claim treatment benefit.

Global Tests A composite outcome can be constructed identifying the results in a subject as a failure if any one of the set of primary outcomes occur.38 In stroke, the composite outcome is often new stroke or stroke-related death. This approach is most commonly used in cardiovascular disease. Another approach is the use of a global statistical test,39 such as in the NINDS t-PA Stroke Trial.9 Investigators chose dichotomization of each of the outcome measures into minimal or no disability (success/failure) to address the question of interest. Dichotomization also solved the statistical issue of the J-shaped distribution of the Barthel Index. When the outcome measures are dichotomous (binary), the global test is reported as an odds ratios. Odds ratios for the individual outcomes were also given to provide an interpretation of the global test outcome.9 Multiple Comparisons An argument has been made40 that if the comparisons represent separate questions (i.e., assessment of the impact of the intervention on two or three different outcomes), each comparison can be considered a separate experiment with no need for adjustment of the alpha level. When an overall hypothesis and a subgroup hypothesis are being tested (e.g., all patients with stroke and patients with severe NIHSS status at baseline), spending some alpha on this overall comparison (0.04) and less on the subgroups is another approach.41 When all possible pairwise comparisons are to be made among a series of treatments, a more stringent adjustment of the alpha level for multiple comparisons may be required. Hockberg’s correction,42 a step-down approach, is an example and is less conservative than the traditional Bonferroni

Missing Data Of particular concern in clinical trials is the biased use of only those participants for whom there is complete outcome data. Bias may arise because the participants who provided data may have a better response to treatment than those who did not, even those in the placebo group. Therefore, a subgroup of fully compliant participants (“completers”) is not a random sample of the original sample. Patterns of missing data (i.e., rate, time to withdrawal, and reason for withdrawal) may differ among treatment groups, contributing bias to study results. Furthermore, the amount of missing data may differ among treatment groups. If a substantial proportion of data (e.g., >20%) is unobserved, especially in the primary outcome of interest, the integrity and quality of the entire study could be questioned, regardless of the approach taken to adjust for the missing data. When data are missing, a variety of statistical methods may be used to perform an ITT analysis.37 There are two patterns of missing data in longitudinal clinical trials: intermittent (e.g., due to a single missed clinic visit) and monotone (e.g., due to participant withdrawal or loss to follow-up). Missing data have been classified as follows: • Missing completely at random (MCAR): Data that are missing because of an event, circumstances, or measure completely independent of the outcome of interest or other participant-specific measures collected in the study. For example, the absence of a participant’s 3-month NIHSS score is MCAR if (1) the investigational staff simply forgot to evaluate the participant on the NIHSS at 3 months or (2) the participant’s car broke down on his/her way to the clinic for the 3-month visit. • Missing at random (MAR): Data that are missing because of an event, circumstances, or measure independent of the outcome of interest but related to another participant-specific measure. If the 3-month NIHSS score is missing because the participant was feeling depressed and did not wish to make the clinic visit, it is MAR (depression is not measured by NIHSS score).

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• M issing not at random (MNAR or nonignorable): The data are missing because of the unobserved outcome of interest. If the 3-month NIHSS score is missing because the participant’s neurologic condition (which is measured by the NIHSS score) had deteriorated to the extent that the participant was unable to travel to the clinic, the missing data are nonignorable. Statistically, MCAR and MAR data are not problematic because standard statistical methods as well as various imputation methods can be applied with minimal or no bias because the missing data in this case are considered a representative sample of the observed data. If more than a minimal amount of data is missing, this approach leads to reduction in statistical power. For statistical analysis with MAR data, a multiple imputation method is recommended before analysis, because the method adds some uncertainty to the imputed value, thereby allowing for more appropriate variance estimation. Repeated measures analysis or survival analyses can be conducted with MAR data without imputing, if all other assumptions are met. Nonignorable missing (MNAR) data are more problematic for analysis. Application of standard statistical methods may yield biased results. If there are missing data, various multiple imputation methods are available to substitute values for the missing data items, many of which have good statistical properties.43 In clinical trials in which an event such as death or recurrent stroke is the primary outcome and are MNAR, using an approach to analysis that censors participants when they are lost to follow-up can introduce bias. Thus, approaches to multiple imputation specifically for survival data have been developed.44 When the reason for missing data is unknown, the most conservative approach is to assume it is MNAR. In the WARSS, the primary outcome (recurrent ischemic stroke or death from any cause) for 2173 of the 2206 participants was assessed at the end of the trial. For the remaining 33, an innovative approach to imputation was used. A senior clinician who was blinded to treatment assignments classified the participants with missing outcomes into three categories and the following decisions were made: 1. Endpoint eminent; an endpoint was assumed to have occurred at the time the participant was lost to followup (N = 1) (MNAR). 2. Data missing for reason unrelated to study (e.g., participant moved to Puerto Rico with daughter); participant was censored at the date of loss to follow-up (i.e., participant’s outcome was considered unknown after the date specified, and participant does not contribute information after that point in time) (N = 20) (MAR or MCAR). 3. Data missing for reason possibly related to study (MNAR). For example, a TIA occurred then a participant was lost to follow-up. For this type of participants, methods of multiple imputation are used to impute a value for time to outcome, taking into account baseline covariates (N = 12). Of the 12 participants for whom multiple imputation was used, a primary outcome was imputed for 2, and an event-free follow-up imputed for 10.46

Interim Analysis Almost all clinical trial participants are enrolled sequentially and followed up over some period. By conducting interim analyses during the course of the trial, investigators are better able to ensure participant safety. Stopping the study early because of overwhelming evidence of the efficacy of a drug means earlier access to an efficacious treatment for patients, less time receiving an ineffective treatment for controls, and earlier profit for the pharmaceutical industry. Stopping a study early because of negative results ensures that participants are not unnecessarily exposed to inferior or ineffective treatment and prevents wasting of resources. Interim analyses also allow the investigators and statisticians to evaluate assumptions made in the design of the trial, such as participant accrual rate and the parameters used for sample size estimation. Figure 60-2 gives examples of three different guidelines for stopping a trial.37 Peto et al46 and O’Brien and Fleming46 use more conservative guidelines early in their studies, so that the final alpha level for testing is close to the planned overall alpha (0.05). Pocock48 uses a less conservative guideline, but the final comparison for the trial would be made at an alpha level less than 0.05, potentially less acceptable to investigators. If all participants are quickly entered into the trial by the time the first or the second interim analysis is to be conducted, further interim analyses may be unnecessary. The Interventional Management of Stroke Study, a phase 2 5.0 4.0

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from Friedman LM, Furberg CD, DeMets DL: Fundamentals of clinical trials, ed 3, New York, 1998, Springer-Verlag.)


trial with a planned sample size of 80, included a planned interim analysis. Trial sites enrolled 10 patients per month and enrollment was completed in 8 months, making the planned interim analyses unnecessary.17 Stochastic curtailment originated in the quality control field for manufacturing, in which an entire batch of products would be rejected if a certain number of defective items were found; if and when that number was reached, the rest of the batch was not inspected. In clinical trials, stochastic curtailment is used to determine whether proceeding further with the study would be unlikely to provide a statistically significant result. These analyses are completed separately from analyses of efficacy, and usually implemented using the B statistic.49 Bayesian rules, derived from subjective prior information, have also been developed for stochastic curtailment and have been used more frequently in trials of cancer therapies than in trials of stroke prevention and therapy. Interim analyses, formal or informal, should be fully described in the study protocol. Analysis of Covariance Unless most participants in one treatment arm of a study have the risk factor and most participants in the other arm do not have the risk factor, it is possible to adjust statistically for imbalances between treatment groups by including the risk factor in a model testing for a treatment effect. If the imbalance in the risk factor explains away the treatment benefit, the benefit has been artificially enhanced by the imbalance. If a benefit of treatment remains or is enhanced after adjustment for the risk factor, the imbalance was not artificially inflating the treatment benefit. One danger in such post hoc analyses is that many variables may be tested in an attempt to bring out a positive treatment outcome, making the end result less credible. Investigators can avoid this “data dredging” by prespecifying the variables to be included as covariates.50 The odds ratio for a favorable outcome in the second NINDS rt-PA Stroke Study (part II) was 1.7 (95% confidence interval [CI], 1.2–2.6), adjusting for prespecified stratification variables. Post hoc analyses of covariance were also conducted with adjustment for the three variables (age, weight, and aspirin use before stroke) imbalanced (P < .05) between the two treatment groups at randomization. These post hoc analyses suggested an even greater benefit of t-PA (odds ratio for a favorable outcome 2.0 (95% CI, 1.3–3.1).9 Subgroup Analyses and Interactions After the completion of a trial, multiple analyses are often performed to determine whether there are subgroups in which the treatment might have been beneficial or harmful. To avoid bias, subgroups should be “proper”—that is, defined by characteristics measured at baseline—before treatment. For example, in the NINDS t-PA Stroke Study, each participant’s stroke subtype was determined 7 to 10 days after stroke from CT scans taken 24 hours after thrombolytic treatment and clinical data collected at baseline. The therapy could affect the 24-hour CT findings through both its clot-busting properties and its potential hemorrhagic side effects. The grouping of patients by this

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postrandomization classification of stroke subtype would not constitute a “proper” subgroup. The more subgroups examined, the more likely the analyses will lead to an alpha error, detection of a difference by chance alone. To protect against bias and alpha errors, the subgroups should be predefined, on the basis of a clearly justified rationale, and specified in the protocol before the start of the trial. These a priori subgroups are less subject to bias than subgroups defined after study results are known (post hoc). Analyses can be adjusted for multiple comparisons, with the potential for greatly reduced power, depending on the number of subgroups. Additionally, to protect against bias and inflated alpha error, particularly in the testing of post hoc hypotheses, testing for a treatment interaction before subgroup analyses are conducted provides a more stringent approach. An interaction between treatment and the subgrouping variable is present if (1) the treatment is harmful in one subgroup but beneficial in another or (2) the magnitude of treatment benefit differs among subgroups.51 Generally, interactions are tested at the 0.1 rather than 0.05 alpha level in recognition that most studies are not designed with sufficient power to test for interactions effects. Meade and Brennan52 conducted subgroup analyses of patients in a thrombosis prevention trial with emphasis on detecting subgroups who might derive the most benefit in terms of stroke prevention. The investigators presented analyses with tests of interactions suggesting that participants who had baseline systolic blood pressures 145 mm Hg and higher and were receiving aspirin therapy were at a higher risk of stroke than those with similar blood pressure levels who were receiving placebo, whereas participants with lower blood pressures experienced a protective effect (P value for the interaction, .006). The time-treatment interaction in the NINDS tPA Stroke Trial53 (Fig. 60-3) and a study of the effect of apolipoprotein-E on stroke outcomes in participants in the same stroke study54 provide other examples of treatment by covariate interactions.

Regulations and Guidelines Federal Regulations In the United States, the two main federal agencies responsible for regulation of stroke-related clinical trials are the U.S. Department of Health and Human Services (DHHS) and the FDA. Federal regulations apply to all clinical investigations and to studies involving FDA-regulated products. Additional regulations and policies (such as the Good Clinical Practice formulated by the International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, and those of the U.S. Department of Veterans Affairs and the Joint Commission on Accreditation of Health Care Organizations) may also apply, depending on the source of funding or the purpose of the investigation. Federal regulations govern all clinical trials that are funded by federal money or are conducted in institutions that (1) receive federal money, (2) have federal project-wide assurances, or (3) conduct studies of investigational drugs with human participants. Any clinical trial of drugs, biological products, or medical devices involving interstate shipping or marketing requires prior submission to and approval from

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Figure 60-3 Graph of model estimating

odds ratio for favorable outcome at 3 months in patients treated with recombinant tissue-type plasminogen activator (rt-PA) and in those given placebo by onset-to-treatment time (OTT) with 95% confidence intervals, after adjustment for the baseline National Institutes of Health (NIH) Stroke Scale score. Odds ratio >1 indicates greater odds that rt-PA–treated patients will have a favorable outcome at 3 months than the placebo-treated patients. Range of OTT was 58 to180 minutes with a mean (μ) of 119.7 minutes. (Aapted from Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome. Neurology 55:1649-1655, 2000.)

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the FDA. “Interstate shipping” is broadly defined; if the container or label or gel that holds the medication or anything related to the product is shipped across state lines, interstate shipping is considered to be involved. Ethics and the Protection of Human Subjects In clinical trials of stroke therapies, the informed consent process may be difficult because stroke may involve an emergency situation in which a participant’s life is in peril. In 1996, criteria to waive the informed consent requirement were established for research in emergency settings. These criteria provide exception to the requirement of informed consent from each participant or legally authorized representative before experimental intervention in situations in which the participant cannot provide informed consent because of a life-threatening medical condition and absence of his/her legally authorized representative. The IRB may permit informed consent waiver upon review of the life-threatening situation, existence of clinical equipoise (i.e., the relative benefits and risks of the proposed intervention, as compared with standard therapy, are unknown), and the need for the collection of valid scientific evidence to determine safety and effectiveness of the intervention under study. The IRB must also consider the feasibility, or lack thereof, of obtaining informed consent from the participant or legally authorized representative as well as the prospect of direct benefit to the participant through participation in the trial. Furthermore, for a waiver to be obtained, additional protection of the rights and welfare of participants must be provided, including at least a consultation with the representatives of the communities in which the study is to be conducted and from which the potential participants will be recruited (community consent). International Guidelines for Conducting Clinical Trials The International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, established in 1990, is a tripartite

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harmonization of technical requirements for the registration of pharmaceutical products in the United States, the European Union, and Japan. This Conference is the result of a need to standardize the regulatory requirements among the countries because of globalization of the pharmaceutical industry, arbitrary differences in regulations, and the need for a process to allow more timely access to new drugs for patients. Good Clinical Practice (GCP) is a set of guidelines for design, conduct, analysis, quality control, and reporting of clinical studies to achieve and maintain high-quality clinical research in a responsible and ethical manner. It is a part of the Conference’s document (section E6). Compliance with Good Clinical Practice ensures that the rights and safety of trial participants are guaranteed and that the results produced by the clinical trials are credible. All clinical trial personnel (i.e., clinicians, research nurse, study coordinators, statisticians, data managers, project managers, quality assurance personnel) should follow GCP. A copy of the GCP can be obtained online (http://www.fda.gov/oc/gcp/). REFERENCES 1. Cook TC, DeMets DL, editors: Introduction to statistical methods for clinical trials, New York, 2007, Chapman & Hall/CRC. 2. Gullov AL, Koefoed BG, Petersen P, et al: Fixed mini-dose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation, Arch Intern Med 158:1513– 1521, 1998. 3. Study design for randomized prospective trial of carotid endarterectomy for asymptomatic atherosclerosis. Asymptomatic Carotid Atherosclerosis Study Group, Stroke 20:844–849, 1989. 4. The International Cooperative Study of Extracranial/Intracranial Arterial Anastomosis (EC/IC Bypass Study): Methodology and entry characteristics. EC/IC Bypass Study Group, Stroke 16:397–406, 1985. 5. EC/IC Bypass Study Group: Failure of extracranial-intracranial arterial bypass to reduce risk of ischemic stroke. Results of an international randomized trial, N Engl J Med 313:1191–2000, 1985. 6. 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 345:1444–1451, 2001. 7. 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 13:120–126, 2002.

CONDUCT OF STROKE-RELATED CLINICAL TRIALS 8. Little KM, Alexander MJ: Medical versus surgical therapy for spontaneous intracranial hemorrhage, Neurosurg Clin North Am 13:339–347, 2002. 9. Tissue plasminogen activator for acute ischemic stroke: National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group, N Engl J Med 333:1581–1587, 1995. 10. Hacke W, Kaste M, Bluhmki E, et al: Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke, for the ECASS investigators, N Engl J Med 359:1317–1328, 2008. 11. Kwiatkowski TG, Libman RB, Frankel M, et al: Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group, N Engl J Med 340: 1781–1787, 1999. 12. Goldring S, Zervas N, Langfiti T: The Extracranial-Intracranial Bypass Study: A report of the committee appointed by the American Association of Neurological Surgeons to examine the study, N Engl J Med 316:817–820, 1987. 13. Ginsberg MD, Hill MD, Palesch YY, et al: The ALIAS Pilot Trial, A Dose-Escalation and Safety Study of Albumin Therapy for Acute Ischemic Stroke—I: Physiological responses and safety results, Stroke 37:2100–2106, 2006. 14. Garrett E-M: The continual reassessment method for dose-finding studies: a tutorial, Clinical Trials 3:57–71, 2006. 15. Tilley BC, Galpern W: Screening Potential Therapies: Lessons learned from new paradigms used in Parkinson’s disease, Stroke 38(Suppl):800–803, 2007. 16. Palesch YY, Tilley BC, Sackett DL, et al: Applying a Phase II Futility Study Design to Therapeutic Stroke Trials, Stroke 36:2410–2414, 2005. 17. IMS Study Investigators: Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The Interventional Management of Stroke (IMS), Stroke 35:904–911, 2004. 18. K aranjia PN, Nelson JJ, Lefkowitz DS, et al: Validation of the ACAS TIA/stroke algorithm, Neurology 48:346-351, 1997. 19. Brott T, Adams HP, Olinger CP: Measurements of acute cerebral infarction: A clinical examination scale, Stroke 20:864–870, 1989. 20. R ankin J: Cerebral vascular accidents in patient over the age of 60. II: Prognosis, Scott Med J 2:200–215, 1957. 21. Mahoney FI, Barthel DW: Functional evaluation: The Barthel Index, Md State Med J 14:61–65, 1965. 22. Jennet B, Bond M: Assessment of outcome after severe brain injury: A practical scale, Lancet 1:480–484, 1975. 23. Hanston L: Neurological scales in assessment of stroke. In Grotta J, Miller LP, Buchan AM, editors: Ischemic stroke: Recent advances in understanding stroke therapy, Southborough, MA, 1985, International Business Communications, pp 42–54. 24. Elashoff JD: NQuery Advisor® 4.0. Statistical Solutions Ltd, Boston, MA, [email protected], 2000. 25. Lesaffre E, Scheys I, Fröhlich J, Bluhmki E: Calculation of power and sample size with bounded outcome scores, Stat Med 12:1063– 1078, 1993. 26. Ebbutt AF, Frith L: Practical issues in equivalence studies, Stat Med 17:1691–1701, 1998. 27. Thall PF, Cook JD: Dose-finding based on efficacy-toxicity tradeoffs, Biometrics 60:684–693, 2004. 28. Chow SC, Chang M: Adaptive design methods in clinical trials—a review, Orphanet Journal of Rare Diseases 3:11, 2008. 29. Grizzle JE: A note on stratifying versus complete random assignment in clinical trials, Control Clin Trial 3:365–368, 1982. 30. Scott NW, McPherson GC, Ramsay CR, Campbell MK: The method of minimization for allocation to clinical trials: A review, Control Clin Trials 23:662–674, 2002. 31. Tilley BC, Lyden PD, Brott TG, et al: Total quality improvement methodology reduces delays between emergency department admission and treatment of acute ischemic stroke, Arch Neurol 54:1466–1474, 1997.

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32. National Institute of Neurologic Disorders and Stroke (NINDS) rt-PA Stroke Study Group: A systems approach to immediate evaluation and management of hyperacute stroke: Experience at eight centers and implications for community practice and patient care, Stroke 28:1530–1540, 1997. 33. Napoles-Springer AM, Grumbach K, Alexander M, et al: Clinical research with older African Americans and Latinos, Res Aging 22:668–691, 2000. 34. Morisky DE, Green LW, Levine DM: Concurrent and predictive validity of a self-reported measure of medication adherence, Med Care 24:67–74, 1986. 35. Gillings D, Koch G: The application of the principle of intention-totreat to the analysis of clinical trials, Drug Inf J 25:411–424, 1991. 36. Friedman LM, Furberg CD, DeMets DL: Fundamentals of clinical Trials, ed 3, New York, 1998, Springer-Verlag. 37. O’Brien PC, Tilley BC, Dyck PJ: Composite endpoints in clinical trials. In D’Agostino R, Sullivan L, Massaro J, editors: Wiley encyclopedia of clinical trials, New York, 2008, John Wiley & Sons. 38. T he NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke: Subgroup analysis of the NINDS t-PA stroke trial, Stroke 28:2119–2125, 1997. 39. Tilley BC, Huang P, O’Brien PC: Global Assessment Variables. In D’Agostino R, Sullivan L, Massaro J, editors: Wiley encyclopedia of clinical trials, Hoboken, NJ, 2008, John Wiley & Sons. 40. O’Brien P: The appropriateness of analysis of variance and multiple comparison procedures, Biometrics 39:787–794, 1983. 41. Moye LA: Alpha calculus in clinical trials: Considerations and commentary for the new millennium, Comment in Stat Med 19:763– 766, 2000. 42. Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance, Biometrika 75:800–802, 1988. 43. Schafer JL: Multiple imputation: A primer, Stat Methods Med Res 8:3–15, 1999. 44. Taylor JMG, Taylor S, Hsu C- H: Survival estimation and testing via multiple imputation, Statistics & Probability Letters 58:221–232, 2002. 45. Thompson JLP, Levin B, Sciacca RR, et al: Statistical Considerations in the WARSS Collaboration. Presented to American Heart Association Stroke Meeting, San Antonio, February 7-9, 2002. 46. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design, Brit J Cancer 34:585–612, 1976. 47. O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials, Biometrics 35:549–556, 1979. 48. Pocock SJ: Group sequential methods in the design and analysis of clinical trials, Biometrika 64:191–199, 1977. 49. Ellenberg S, Fleming TR, DeMets DL: Data monitoring committees in clinical trials: A practical perspective, Hoboken, John Wiley and Sons NJ, 2002, pp 129–133. 50. Koch GG, Davis SM, Anderson RL: Methodological advances and plans for improving regulatory success for confirmatory studies, Stat Med 17:1675–1690, 1998. 51. Yusuf S, Wittes J, Probstfield J, Tyroler HA: Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials, JAMA 266:93–98, 1991. 52. Meade T, Brennan PJ: Determination of who may derive most benefit from aspirin in primary prevention: Subgroup results from a randomised controlled trial, BMJ 321:13–17, 2000. 53. Marler JR, Tilley BC, Lu M, et al: Early stroke treatment associated with better outcome, Neurology 55:1649–1655, 2000. 54. Broderick J, Lu M, Jackson C, et al: Apolipoprotein E phenotype and the efficacy of intravenous tissue plasminogen activator in acute ischemic stroke, Ann Neurol 49:736–744, 2001.

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Interventional Neuroradiologic Therapy of Atherosclerotic Disease and Vascular Malformations J MOCCO, STANLEY H. KIM, BERNARD R. BENDOK, ALAN S. BOULOS, L. NELSON HOPKINS, ELAD I. LEVY

T

he treatment of vascular disease has undergone a revolution in the past decade. Previously, open surgical techniques were the only treatment modalities available for vascular disease that resulted in ischemic and hemorrhagic neurologic sequelae.Times have changed. Catheterbased treatment modalities have been developed that rival or surpass open surgical techniques for the treatment of these disease entities. Cerebral revascularization for the treatment of acute ischemic stroke has become a reality within the past decade. Site-specific intraarterial (IA) delivery of thrombolytic agents has enabled recanalization of occlusive lesions in the cerebrovasculature. The application of mechanical techniques to disrupt clot has pushed vessel recanalization rates as high as 90% as a matter of routine. Hemorrhagic complications still diminish the effectiveness of these techniques, yet a reduction in thrombolytic dosing and increased use of mechanical techniques may drive the clinical utility of IA stroke intervention forward. The primary problem is no longer whether a vessel can be recanalized but, rather, how rapidly recanalization can be achieved. With improving stroke education of the public (“brain attack”), the future may see relevant reductions in the time to treatment. Extracranial and intracranial revascularization for atherosclerotic disease has led the vascular revolution for ischemic cerebrovascular disease. Preliminary results suggest that the use of stents for revascularization of the cervical carotid bifurcation will likely supplant carotid endarterectomy (CEA) in the future. Multiple clinical trials are under way to compare the efficacy of stent placement with that of CEA. These trials will provide level 1 evidence within the next few years. Intracranial atherosclerotic disease is being discovered at an alarming rate through the use of noninvasive imaging techniques like MR and CT angiography. The application of angioplasty and stent techniques is gaining acceptance. Balloons and stents initially designed for the coronary circulation are being modified for delivery into the tortuous anatomy of the cerebral circulation. As a result, the location and scope of intracranial lesions that can be treated are increasing.

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The findings of initial trials have shown high rates of instent restenosis, but the use of drug coatings that inhibit fibrous tissue formation within cerebral vessels after manipulation may pave the way for broad application of these techniques for cerebral ischemia. Additionally, burgeoning technologies, such as flexible intracranialspecific balloon-mounted stents, may improve long-term results. Results of the initial clinical trial of the Guglielmi detachable coil (GDC, Boston Scientific Target, Fremont, CA) in 1990 led the way for a lasting and irreversible change in methods for the treatment of ruptured and unruptured intracranial aneurysms worldwide. At many centers, coil occlusion has become first-line therapy for all aneurysms. Initially, only one platinum coil was available. Today, several companies offer products used for endovascular treatment of intracranial aneurysms. Additionally, biologic modification of the platinum coil platform has been approved by the U.S. Food and Drug Administration (FDA). Coils with polymer and hydrogel modifications may promote complete aneurysm occlusion by inducing scar formation across the aneurysm neck. Intravascular stents have been used to provide critical assistance to coil techniques, thereby allowing successful treatment of previously untreatable aneurysms. Liquid polymers have been delivered directly into aneurysms to provide atraumatic methods for complete aneurysm filling. Perhaps most excitingly, early data with endoluminal flow diverters also point to an entirely new treatment modality for intracranial aneurysms. All of this explosive development in endovascular techniques comes on the heels of level 1 evidence indicating the superior effectiveness of aneurysm coiling over that of open surgical techniques in the majority of ruptured aneurysms. The treatment of cerebral arteriovenous malformations (AVMs) has benefited from catheter-based technology. Particles and silk, thread, and muscle fragments have been replaced as embolic agents by liquid polymers and sclerosing agents. Advances in catheter technology have enabled access of distal AVM feeding vessels, thereby enabling safer delivery of these substances. New liquid

INTERVENTIONAL NEURORADIOLOGIC THERAPY OF ATHEROSCLEROTIC DISEASE AND VASCULAR MALFORMATIONS

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TABLE 61-1 OUTCOME OF INTRAVENOUS ALTEPLASE FOR ACUTE ISCHEMIC STROKE Study*

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National Institute of Neurological Disorders and Stroke (NINDS)1 Second European Cooperative Acute Stroke Study (ECASS II)3 Standard Treatment with Alteplase to Reverse Stroke (STARS)2 *Superscript numbers indicate chapter references.

embolic agents show great promise for complete occlusion of AVMs, and multiple studies are now reporting the results of lasting AVM “cure” with the use of solely endovascular techniques, without the need for adjunctive radiosurgery or resection. This chapter presents advances in the use of catheterbased technology for the treatment of cerebrovascular disease and stroke, highlighting new techniques and recent technologic developments. Although many of the treatment modalities are considered investigational, they represent the current and future treatments for cerebrovascular disease.

Acute Ischemic Stroke Thrombolysis of Acute Ischemic Stroke In 1996, the FDA approved the use of intravenous (IV) recombinant tissue plasminogen activator (rt-PA, alteplase) in patients who present within 3 hours of the onset of acute ischemic stroke. This approval was based on the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) study.1 Currently, IV administration of t-PA within the 3-hour time window is the only treatment for acute ischemic stroke that is supported by level 1 evidence, recommended by the American Heart Association (AHA), and approved by the FDA. However, two major clinical trials and one prospective observational registry have reported outcomes of death or more than 50% functional dependency at the 3-month follow-up evaluation (Table 61-1).1-3 Moreover, six randomized trials failed to demonstrate a significant benefit for IV thrombolytic therapy initiated within 3 to 6 hours of stroke onset.3-8 Several randomized trials have evaluated the safety and efficacy of IA thrombolysis administered 3 to 6 hours from symptom onset.9,10 Additionally, a single-arm, prospective trial funded by the National Institutes of Health (NIH) of IA thrombolysis performed within 6 hours following a bridging dose (2/3 of normal) of IV t-PA within 3 hours demonstrated a benefit in comparison with results in the NINDS-NIH–funded t-PA trial control population and a suggestion of benefit in comparison with results in the NINDS-NIH–funded t-PA trial treatment population.11,12 In several case series, IA thrombolysis alone or in combination with mechanical thrombolysis has been reported as an alternative modality for treatment of acute ischemic stroke in a select group of patients.13-19 A randomized study is justified to determine whether IA thrombolysis with or without mechanical thrombectomy is superior to IV thrombolysis for acute ischemic stroke.

The IA approach to thrombolysis has theoretical advantages. First, angiographic evaluation helps determine whether an occlusion exists and local IA therapy is necessary. Second, the IA approach allows delivery of the thrombolytic agent (i.e., t-PA or reteplase [third- generation t-PA]) to the site of occlusion without excessive systemic administration (a lesser amount of the drug can actually be used). Third, the endovascular surgeon can titrate the dose of the agent through angiographic visualization of the clot response to lysis. Fourth, in patients showing a poor response to pharmacologic IA thrombolysis, angiographic evaluation aids in the selection of methods of mechanical thrombolysis or other endovascular intervention. For example, an acute ischemic stroke from occlusion of the M1 segment of the middle cerebral artery (MCA) may occur in the setting of severe pre-existing atherosclerotic stenosis or embolic plaque. A combination of pharmacologic and mechanical forms of IA thrombolysis by use of angioplasty, a stent, or a clot-retrieval device may be required for recanalization (Fig. 61-1). Disadvantages of the IA approach include longer potential time to treatment and significant resource requirements. With better patient education and earlier recognition of stroke symptoms, the time to treatment can be reduced. Although pharmacologic and mechanical forms of IA thrombolysis are promising novel therapies, patients with acute ischemic stroke still need to be transported expeditiously to an appropriate facility that can provide acute stroke therapy in a timely fashion. Time from onset to treatment is of paramount importance, regardless of the type of thrombolytic therapy used. Furthermore, advancements in imaging techniques, such as diffusion-weighted and perfusion-weighted MRI, xenonenhanced CT (XeCT), and CT perfusion scanning, may allow improved patient selection for thrombolysis in the future.20-28 Intraarterial Thrombolysis Trials The recanalization efficacy and safety of IA thrombolysis using recombinant pro-urokinase has been evaluated in two randomized, multicenter, placebo-controlled trials.9,10 In the Prolyse in Acute Cerebral Thromboembolism (PROACT) I and II trials, patients with acute ischemic stroke due to MCA occlusion and onset of symptoms within 6 hours underwent intra-arterial thrombolysis with recombinant pro-urokinase (r-pro-UK).9,10 The results of these trials are summarized in Table 61-2. Recanalization rates are based on the Thrombolysis in Myocardial

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A

C

B

Figure 61-1 A, Cerebral angiogram shows occlusion of the left M1 segment of the left middle cerebral artery (MCA). B, Persistent occlu-

sion of the M1 segment of the left MCA after administration of 4 units of reteplase. C, Recanalization of the left MCA after mechanical thrombolysis was performed via a 4-mm snare (Amplatz Goose-Neck Microsnare, Microvena, White Bear Lake, Minn).

TABLE 61-2 RESULTS OF PROLYSE IN ACUTE CEREBRAL THROMBOEMBOLISM (PROACT) TRIALS I AND II PROACT I

PROACT II

No. of patients CT scan exclusion

40 ICH, mass effect with midline shift, intracranial tumor, early changes of ischemia

Median National Institutes of Health Stroke Scale (NIHSS) score Heparin

r-Pro-UK, 17; placebo, 19

180 Same as PROACT I, hypodensity or effacement of sulci in more than 1/3 of the middle cerebral artery territory r-Pro-UK, 17; placebo, 17

Agent used Placebo group Mechanical thrombolysis % of TIMI grade 2 or 3 recanalization rate % Symptomatic ICH % Outcome at 90 days: mRS score 0-1 mRS score 0-2 % Mortality within 90 days

All patients received 2000-unit heparin bolus IV, then 500-unit/hour infusion for 4 hours

All patients received IV heparin; first 16 patients received 100-unit/kg bolus, then 1000-unit/ hour infusion during 4 hours; remaining patients received 4000-unit bolus followed by a 500-unit/hour infusion for 4 hours 6 mg of r-pro-UK; 9 mg over 2 hours Saline at 30 mL/hour over 2 hours Not permitted

9 mg of r-pro-UK over 2 hours and heparin IV heparin alone Not permitted

r-Pro-UK 58

r-Pro-UK 66

Placebo 14

15

7

31

21

27

43

Placebo 18

10

2

40 25

25 27

ICH, intracerebral hemorrhage; IV, intravenous; mRS, modified Rankin Scale; r-pro-UK, recombinant pro-urokinase; TIMI, Thrombolysis In Myocardial Infarction Study.

Infarction (TIMI) grading system (Table 61-3).29 Recanalization rates (TIMI 2 or 3) were 58% in the r-pro-UK group and 14% in the placebo group in the PROACT I trial. Because of the low number of patients in PROACT I, clinical efficacy of this treatment modality could not be established. However, because of the safety and recanalization rates observed in PROACT I, PROACT II was performed.

This trial was designed to assess the efficacy of intraarterial r-pro-UK (9 mg given over 2 hours as opposed to 6 mg in PROACT I) as measured by the modified Rankin scale (mRS) score of 2 or less at 90 days. For the primary outcome measure of efficacy in PROACT II, 40% of patients receiving r-pro-UK and 25% of those receiving placebo achieved an mRS score of 2 or less at 90 days


TABLE 61-3 DEFINITIONS OF PERFUSION IN THE THROMBOLYSIS IN MYOCARDIAL INFARCTION (TIMI) STUDY Grade

Definition

0 (no perfusion)

There is no antegrade flow beyond the point of occlusion. The contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming sequence. The contrast material passes across the obstruction and opacifies the coronary bed distal to the obstruction. However, the rate of entry of contrast material into the vessel distal to the obstruction or its rate of clearance from the distal bed (or both) is perceptibly slower than that of its entry into or clearance from comparable areas not perfused by the previously occluded vessel (e.g., other coronary artery or the coronary bed proximal to the obstruction). Antegrade flow into the bed distal to the obstruction occurs as promptly as antegrade flow into the bed proximal to obstruction and as clearance of contrast material from the involved bed in the same vessel or the opposite artery.

1 (penetration without perfusion)

2 (partial perfusion)

3 (complete perfusion)

(P = .04). Recanalization rates (TIMI 2 or 3) were 66% in the r-pro-UK group and 18% in the placebo group in this trial. A 15% absolute increase in favorable outcome was shown with r-pro-UK. For every seven patients treated with r-proUK, one would benefit. Despite being associated with an increased frequency of early symptomatic intracranial hemorrhage (ICH), intra-arterial r-pro-UK administered within 6 hours of symptom onset in stroke due to MCA occlusion significantly improved clinical outcome. PROACT II was a landmark trial in that, for the first time in a randomized study, IA thrombolysis demonstrated clinical efficacy and extended the time window for therapy to 6 hours in a homogeneous group of patients with acute ischemic stroke.10 This trial was conducted in a standardized fashion in terms of the technique of IA thrombolysis as well as the agent and the dose used. However, the FDA requested additional data to support the clinical efficacy and safety demonstrated in PROACT II before approving IA thrombolysis as a standard therapy for patients with acute ischemic stroke. The success of the PROACT II trial was not sufficient to gain FDA approval for pro-UK, but the trial paved the way for additional studies involving IA thrombolysis (with newer agents) in acute ischemic stroke. Several studies have evaluated the feasibility, safety, and recanalization rate of a combination of IV and IA pharmacologic thrombolysis in patients with acute ischemic stroke.11,12,30-34 The results are summarized in Table 61-4. The rationale for the combination approach is based on the fact that clinically severe strokes resulting from occlusion of large intracranial vessels respond poorly to IV thrombolysis. Combining the two therapies

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enables patients to receive IV therapy during the time required for initiation of IA thrombolysis, which may be more effective in opening large arteries. Direct comparison of these studies is difficult owing to heterogeneity of the study populations, dosages, and types of thrombolytic agents used as well as of patient selection criteria. Symptomatic ICH rates within 7 days of treatment range from 6% to 16%. Mortality rates range from 15% to 45%. TIMI 3 recanalization rates range from 4% to 55%. The Emergency Management of Stroke (EMS) Bridging Trial was designed to assess safety, feasibility, and recanalization efficacy of this combination approach.33 However, because of the small sample size (35 patients), the clinical efficacy of this therapy could not be determined. Suarez et al34 reported that 78% of patients treated by combination therapy had Barthel Index values higher than 95 at 3 months. Ernst et al30 reported mRS scores of 0 or 1 at or beyond 2-month follow-up for 44% of patients treated with combination therapy. The Interventional Management of Stroke (IMS) study, an NINDS-funded pilot study, was an open-label phase 2 study designed to provide preliminary results on the safety and efficacy of combination IV and IA t-PA therapies in 80 ischemic stroke patients with National Institutes of Health Stroke Scale (NIHSS) scores of 10 or higher.11 Patients received 0.6 mg/kg of intravenously administered t-PA over 30 minutes (15% as a bolus) followed by intraarterially administered t-PA at a dose of up to 22 mg over 2 hours if thrombus was identified on a cerebral angiogram. The study demonstrated a 16% rate of mortality at 3 months (compared with 24% in the NINDS placebo group) and a 6% rate of symptomatic ICH (compared with 1% in the NINDS placebo group). TIMI 2 and 3 recanalization rates of 40% and 10%, respectively, were observed. Favorable outcome at 3 months, as defined by an mRS score of 0 or 1, was observed in 30% of patients. On the basis of these encouraging results, the IMS II study was undertaken.12 The protocol was much the same as for IMS, except the use of a catheter with an ultrasonic tip was allowed (EKOS catheter, EKOS Corporation, Bothell, WA). Once again, the results were encouraging, with TIMI 2 or 3 recanalization in 60% of patients and 33% of patients experiencing an mRS score of 0 or 1 at 90 days. Qureshi et al19 evaluated the safety and efficacy of reteplase (the only third-generation thrombolytic agent available in addition to alteplase for the IA treatment of acute ischemic stroke) in 16 patients who were considered poor candidates for IV alteplase therapy because (1) the interval from symptom onset to presentation was 3 hours or more or (2) they had severe neurologic deficit on presentation (NIHSS scores ranged from 10 to 26). These investigators used a modified TIMI grading system (Table 61-5) and reported TIMI 3 or 4 (equivalent to the original TIMI grade 3) recanalization rates in 88% of patients. Such a high rate of recanalization was achieved even though 8 of 16 patients presented with occlusion of either the cervical (n = 4) or intracranial (n = 4) internal carotid artery (ICA). Early neurologic improvement (defined as a decrease of 4 or more points in the NIHSS score at 24 hours) was observed in 44% of patients. Qureshi35 developed a new grading scheme to account for more precise location of occlusion in the cerebral

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TABLE 61-4 RESULTS OF COMBINED INTRAVENOUS AND INTRAARTERIAL THROMBOLYSIS

Study* Emergency Management of Stroke (EMS) Bridging Trial33

Study Center —

Ernst et al30

University of Cincinnati

Keris et al32

Riga, Latvia

Hill et al31

University of Calgary, Alberta

Suarez et al34

University Hospitals of Cleveland, Case Western Reserve

Interventional Management of Stroke IMS Study11

—

IMS II Trial12

—

Design Double-blinded randomized placebo-controlled multicenter study comparing safety and feasibility of two treatment strategies Retrospective study to assess safety and feasibility of IV t-PA/IA t-PA within 3 hours of symptom onset

Symptomatic ICH within 7 Days 12% (2/17) IV/IA; 6% (1/18) placebo IA

6% (1/16)

Outcome Definition 3-month Glasgow Outcome Scale (GOS) score, Barthel Index, and mRS score mRS, follow-up range 2-100 months

Outcome

Mortality

No significant differences in outcome between treatment groups

At 90 days: 45% (5/11) in IV/IA; 10% (1/10) in placebo/IA

44% (7/16) had an mRS score of 0 or 1, 19% (3/16) an mRS score of 2, and 25% (4/16) an mRS score of 4 or 5 67% (8/12) mRS 0-3 at 1 month, 83% (10/12) mRS 0-3 at 12 months

13% (2/16)

17% at 12 months

Open-label prospective study to assess safety and efficacy of IV t-PA/IA t-PA within 6 hours of symptom onset Prospective, openlabel study to assess safety and feasibility of IV t-PA/IA t-PA within 3 hours of symptom onset Pilot study to assess feasibility of IV t-PA/IA UK or t-PA within 3 hours of symptom onset

None

mRS scores at 1 month and 12 months: good = mRS 0-3; poor = mRS 4-6

None

National Institutes of Health Stroke Scale (NIHSS) score 50%) rates of 7% and 3%, respectively, at 1 year have been reported.158-166 Rodriguez-Lopez et al165 reported a 3% incidence of postprocedural TIA in 37 patients after treatment with percutaneous balloon angioplasty and stenting of subclavian artery stenosis. In the occlusion group (15 of 37 patients), no postprocedural cerebrovascular events or deaths occurred. Ringelstein and Zeumer168 reported that a delay in the reversal of vertebral artery blood flow after percutaneous balloon angioplasty may account for such low rates of neurologic complications. Follow-up ultrasonography in these patients at 9 months showed no restenosis in the occlusion group. Additional studies are needed to determine the long-term morbidity and mortality of subclavian artery stenting for SSS.

Intracranial Aneurysms Approximately 30,000 Americans are afflicted with aneurysmal subarachnoid hemorrhage (SAH) yearly.169 The incidence of SAH has been reported to be between 6 and 16 per 100,000 persons in the United States, with higher numbers reported from Japan and Finland.169-172 Aneurysmal SAH accounts for 25% of cerebrovascular deaths and 8% of all strokes.173 Ruptured and unruptured aneurysms carry significantly different natural history risks. The risk of rupture has also been shown to be a function of aneurysm size and tobacco consumption.174,175 Although the natural history of ruptured aneurysms has been well defined, there is controversy regarding the natural history of unruptured aneurysms, particularly those less than 10 mm in diameter.169,174 We refer the reader to scholarly reviews of these issues by Weir169 and by the investigators of the International Study of Unruptured Intracranial Aneurysms (ISUIA).174

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The most common complication related to cerebral aneurysms is SAH.176 Other complications are cranial nerve deficits, symptoms related to mass effect,177 and strokes related to emboli released from thrombus within the aneurysm.178 Subarachnoid Hemorrhage Modern management of patients with SAH in the critical care unit, along with specialized microsurgical and endovascular expertise, contributes significantly to the prevention of recurrent hemorrhage and stroke following aneurysm rupture. Of paramount concern is the prevention of rehemorrhage because it is associated with a case-fatality rate of 70%.179 Juvela180 reported a 22.5% incidence of aneurysm rebleeding within 6 months of the primary hemorrhage in 236 untreated patients. Prevention of rebleeding through clip ligation of a ruptured aneurysm or through coil embolization are both accepted techniques for the treatment of ruptured aneurysms; however, with the publication of the results of the International Subarachnoid Aneurysm Trial (ISAT), evidence-based recommendations favor the use of coil embolization, particularly in patients older than 50 years.181,182 In addition to the morbidity associated with the initial hemorrhage, SAH can result in vasospasm, which can be neurologically detrimental. Seventy percent of patients with SAH demonstrate angiographic vasospasm; of these patients, approximately 50% have symptoms.183 Approximately 20% of symptomatic patients will experience stroke or die despite maximal modern therapy.183 Angiographically evident vasospasm usually peaks during days 5 to 14 after hemorrhage.179 Hypertension and hypervolemia have emerged as the first line of therapy for symptomatic vasospasm.184 IA administration of papaverine and balloon angioplasty have been used with some success to treat medically refractory vasospasm.176 Balloon angioplasty can be used for proximal vessel spasm of the supraclinoid carotid artery, A1 segment of the ICA, M1 segment of the MCA, vertebral artery, or basilar artery.185 If not performed carefully with avoidance of overdilation, the procedure can be associated with vessel rupture. Improvements in balloon technology may reduce this risk. It has been observed that balloon angioplasty can permanently relieve vasospasm symptoms in 60% to 70% of cases.185 Papaverine can be used for distal vessel spasm.186-188 Initial enthusiasm for IA papaverine has waned over the past several years, however, because it has been observed that the effects of papaverine are short lived. An alternative to papaverine, though likely one that is also subject to a short-lived effect, is verapamil. Mass Effect In a study by Malisch et al,177 in which the effect of coiling on symptoms related to the mass effect of aneurysms on cranial nerves was examined, symptoms resolved in 32% of patients and improved in 42% after coiling, with no change in 21% and worsening in 5%. It is believed that removing the pulsatility associated with an aneurysm after coiling may be responsible for symptom improvement.177

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Ischemic Complications

Fusiform Aneurysms

A paucity of data exists with respect to the embolic risk associated with the presence of an aneurysm. Clot can accumulate in the fundus of an aneurysm as a result of flow stasis, particularly in a large aneurysm. In a study by Qureshi et al,178 complications associated with embolization from the aneurysm fundus occurred in 3.3% of patients presenting with an unruptured aneurysm. In this study, clipping of the aneurysm was associated with a low risk of symptom recurrence. It should be noted that the presence of clot in an aneurysm might be a risk factor for thromboembolic complications during aneurysm coiling.

Fusiform aneurysms can lead to mass effect, hemorrhage, or both. The outcomes for patients with fusiform aneurysms remain poor, despite advances in microsurgical and endovascular treatment techniques.199 The treatment of fusiform aneurysms often requires vessel sacrifice. Over the past several years, stents have emerged as an option to treat certain fusiform aneurysms. Stents offer the advantage of maintaining patency of the parent vessel. Preliminary results suggest that stents may play a significant role in the management of this complex disease.200 Most excitingly, later case series have reported the use of endoluminal flow diversion, with excellent angiographic and clinical results.201

Technical Advances in Coil Treatment Although the results of coil treatment of small aneurysms (diameter less than 12 mm) and aneurysms with small necks (less than 5 mm) appear to be promising, lesser degrees of success have been observed with aneurysms with larger diameter size and wider necks.189 Technical advances have occurred over the past several years to improve the success rate with coiling of large and widenecked aneurysms. In the balloon-remodeling technique, which has been championed by Moret et al,190 more coils can be packed near the aneurysm neck because a balloon is inflated across the neck during coil placement (Fig. 61-2). The balloon is deflated after each coil is deployed to restore flow temporarily. Stent-assisted coiling appears to be another promising technique for certain wide-necked aneurysms (Fig. 61-3).191,192 The stent serves as scaffolding across the aneurysm neck, holding the coils within the aneurysm sac. Manufacturers have improved coils in an attempt to overcome some of the shortcomings associated with coil technology. Spherical coils (MicruSphere coils, Micrus Endovascular, San Jose, CA) and three-dimensional Guglielmi detachable coils (GDCs) appear to allow certain wide-necked aneurysms to be coiled more effectively. Newer technologies, such as coils made of bioactive materials and endoluminal flow diverters, are demonstrating early promise in continuing to advance endovascular aneurysm treatment.193-198

Figure 61-2 Balloon-assisted aneurysm coiling.

Arteriovenous Malformations Definition, Pathology, and Epidemiology An AVM is a congenital lesion that anatomically consists of a collection of abnormal arteries and veins lacking a normal capillary connection. The abnormal arteries form a conglomeration of vessels, which are referred to as the nidus. The nidus typically has little to no intervening brain tissue. The lack of a capillary bed causes early venous drainage, venous hypertension, and recruitment of arterial feeders. True arteriovenous shunts are occasionally noted in AVMs. Autopsy data suggest that AVMs occur in 4.3% of the general population.202 Between 1980 and 1990, the annual incidence of symptomatic AVMs in the Netherlands was 1.1 per 100,000 population.203 Aneurysms are commonly associated with AVMs. According to the literature, this association occurs in from 2.7%204 to 23%205 of patients. The four types of aneurysms observed in conjunction with AVMs are intranidal aneurysms, pedicular aneurysms, proximal aneurysms, and unassociated. Evidence suggests that the first three types of aneurysms occur as a result of the flow dynamics created by the AVM. Classification Although multiple classification systems for AVMs have emerged, the Spetzler-Martin grading system has remained the simplest and most practical to use.206 The

Figure 61-3 Stent-assisted aneurysm coiling.


TABLE 61-6 SPETZLER-MARTIN CLASSIFICATION OF ARTERIOVENOUS MALFORMATIONS OF THE BRAIN* Feature Size Small (6 cm) Eloquence of adjacent brain Noneloquent Eloquent Pattern of venous drainage Superficial only Deep

Points Awarded 1 2 3 0 1 0 1

*Grade = [size] + [eloquence] + [venous drainage], that is, [1, 2, or 3] + [0 or 1] + [0 or 1]. Adapted from Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:478, 1986.

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was 6%,211,216 and in one study, 17.8%.210 Certain radiologic findings appear to be associated with an increased hemorrhage risk. Among these findings are central venous drainage, intranidal aneurysm, periventricular or intraventricular location, arterial supply via perforators, multiple aneurysms, vertebrobasilar supply, basal ganglia location, single draining vein, impaired venous drainage, and deep venous drainage alone.199,217,218 Treatment The treatment of AVMs has dramatically evolved within the past 35 years as a result of advances in microsurgery, endovascular techniques (embolization), and radiation therapy. Embolization can play a role as a presurgical tool, as a pre–stereotactic irradiation tool, as sole therapy for a cure, as sole therapy for palliation, and to treat associated aneurysms. Embolization as a Preoperative Tool

system assigns AVMs to grades according to size, eloquence of brain surrounding the AVM, and presence or absence of deep venous drainage (Table 61-6). Increased surgical risk is associated with higher AVM grade. The grading system was initially designed to assess the safety and risk of AVM excision but is used by most practitioners regardless of treatment modality. One study suggests that this grading scheme may not have relevance to modern embolization strategies.207 Natural History AVMs have been associated with seizures, hemorrhage, headaches, and ischemia related to steal (see previous discussion of subclavian steal). In children younger than 2 years, congestive heart failure and hydrocephalus are common presentations. For the purpose of this chapter, we focus on the hemorrhagic and ischemic manifestations of AVMs. Stroke registries indicate that AVMs are responsible for the symptoms in more than 1% of patients who present with stroke.208 The risk of AVM hemorrhage is approximately 2% to 3% per year.202,209-212 Mortality from the first hemorrhage varies from 10% to 30%.199 An estimated 10% to 20% of survivors have long-term disability.199,212,213 Kondziolka et al214 proposed the following simplified equation to determine the hemorrhage risk in any given patient: Lifetime risk( % ) = 105 − patient’s age in years

This equation helps put the risk of hemorrhage in perspective when one is considering patients of varying ages. It is important to note, however, that there is a burgeoning belief that such rupture estimates are reflective not of incidental AVMs but rather of those that have previously ruptured only. To evaluate this hypothesis, there is an ongoing NIH-funded trial, A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), that seeks to observe the natural history of unruptured AVMs.215 The risk of hemorrhage appears to increase during the first year after a hemorrhage. In two studies, the increase

Microsurgery has been shown to be a safe and effective treatment for certain AVMs. The long-term protective effects of AVM surgery against hemorrhage risk have been established. In a study by Heros et al,219 excellent outcomes were achieved in 98.7% of patients with Spetzler-Martin grade I, II, or III AVMs at a mean follow-up of 3.8 years. Studies and empiric observations have suggested that AVM embolization reduces blood loss and enhances the ease of surgery.220 For large AVMs, embolization can achieve the goal of gradually decreasing the volume of the AVM before excision. Although it has never been proven, this strategy is believed to lower the risk of postoperative hemorrhage from normal perfusion pressure breakthrough.221 According to the normal perfusion pressure breakthrough theory, the increased flow of blood supplying a large AVM deprives the surrounding brain tissue of adequate blood supply. This deprivation creates a chronic ischemic state and loss of autoregulation. When a large AVM is resected, the surrounding tissue, which was previously ischemic, becomes perfused by a larger blood flow. The lack of autoregulation makes the small vessels vulnerable to hemorrhage. Gradual embolization of these large AVMs is thought to allow the surrounding brain tissue to adjust to gradually increasing amounts of perfusion, hence reducing the risk of hemorrhage after eventual resection of the AVM. Endovascular techniques performed before surgery can also be used to treat associated aneurysms, particularly if the aneurysm would be difficult to treat during surgical excision. Embolization Followed by Stereotactic Irradiation Radiosurgery has emerged as an attractive option for some AVMs, especially those located in surgically prohibitive deep locations. Stereotactic technology allows the delivery of radiation precisely and directly to the AVM while limiting exposure to surrounding brain tissue. Radiosurgery results in a 78% to 88% obliteration rate of AVMs with volumes equal to or less than 10 mm at 3 years.222 Lower obliteration rates and higher complication rates are associated with radiosurgery of larger AVMs. Over the

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past decade, several centers have reported on the strategy of embolization to reduce large AVMs to sizes amenable to radiosurgery.223,224 This is an attractive strategy for large AVMs for which surgical excision poses a high risk. Long-term outcomes associated with this type of treatment have not yet been determined, and recanalization remains a concern.224 Embolization Alone In the early 1990s only a small percentage of AVMs could be treated by endovascular techniques alone.225 However, this number has increased dramatically with the advent of the Onyx liquid embolic agent (ev3 Neurovascular, Irvine, CA).226-229 Such AVMs are typically small (less than 3 cm) and have a limited number (1 or 2) of arterial feeders. Embolization for Palliation Palliative embolization can be used in rare situations to decrease symptoms from large AVMs that are deemed untreatable by other means. Embolization can be used to reduce headaches and reversible neurologic deficits attributable to steal or venous hypertension or to occlude associated aneurysms. Embolization for palliation is only temporary, because the AVM can recur over time as a result of recanalization. No evidence exists that partial AVM embolization decreases the long-term risk of AVM hemorrhage.199

Conclusion Endovascular neurosurgery is evolving at a frantic pace. Although endovascular technology is still in its infancy, this field holds the promise to provide minimally invasive therapies for cerebrovascular disease resulting in ischemia and stroke. Clinicians are not yet able to predict the longterm effects of endovascular therapies, such as endoluminal responses to intracranial stent and coil implantations. However, short- and mid-term outcomes of existing technologies show substantial promise. Additionally, future transcatheter technologies may involve processes only hypothesized today, such as the delivery of growth factors able to reconstitute the vessel lumen across an aneurysm or even stem cells with the ability to repair and restore parenchyma destroyed by ischemic stroke. As medicine pushes toward the future, it appears that the most significant limitation of endovascular medicine may be the imagination of its physicians and the industry with which they collaborate. Disclosures The authors have the following financial relationships to disclose: Dr. Bendok has received research funding from Cordis; Dr. Mocco serves as a consultant to Actelion, Nfocus, and Lazarus Effect; his employer, The University of Florida, receives research funding from AccessClosure and Codman Neurovascular. Dr. Hopkins receives research study grants from Abbott (ACT 1 Choice), Boston Scientific (CABANA), Cordis (SAPPHIRE WW), and ev3/Covidien Vascular Therapies (CREATE) and a research grant from Toshiba (for the Toshiba Stroke

Research Center); has an ownership/financial interest in AccessClosure, Boston Scientific, Cordis, Micrus, and Valor Medical; serves on the Abbott Vascular Speakers’ Bureau; receives honoraria from Bard, Boston Scientific, Cordis, and from the following for speaking at conferences—Complete Conference Management, Cleveland Clinic, and SCAI; receives royalties from Cordis (for the AngioGuard device), serves as a consultant to or on the advisory board for Abbott, AccessClosure, Bard, Boston Scientific, Cordis, Gore, Lumen Biomedical, Micrus, and Toshiba; and serves as the conference director for Nurcon Conferences/Strategic Medical Seminars LLC. Dr. Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific and research support from Micrus Endovascular and ev3/Covidien Vascular Therapies; has ownership interests in Intratech Medical Ltd. and Mynx/AccessClosure; serves as a consultant on the board of Scientific Advisors to Codman & Shurtleff, Inc.; serves as a consultant per project and/or per hour for Micrus Endovascular, ev3/Covidien Vascular Therapies, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training from Abbott Vascular and ev3/ Covidien Vascular Therapies. Dr. Levy receives no consulting salary arrangements. All consulting is per project, per hour, or both. REFERENCES 1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke, N Engl J Med 333:1581–1587, 1995. 2. A lbers GW, Bates VE, Clark WM, et al: Intravenous tissue-type plasminogen activator for treatment of acute stroke: The Standard Treatment with Alteplase to Reverse Stroke (STARS) study, JAMA 283:1145–1150, 2000. 3. Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebo- controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators, Lancet 352:1245–1251, 1998. 4. 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 346:1509–1514, 1995. 5. Multicenter Acute Stroke Trial—Europe Study Group: Thrombolytic therapy with streptokinase in acute ischemic stroke, N Engl J Med 335:145–150, 1996. 6. Clark WM, Wissman S, Albers GW, et al: Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: A randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke, JAMA 282:2019–2026, 1999. 7. Donnan GA, Davis SM, Chambers BR, et al: Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group, JAMA 276:961– 966, 1996. 8. Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS), JAMA 274:1017–1025, 1995. 9. del Zoppo GJ, Higashida RT, Furlan AJ, 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 29:4–11, 1998. 10. Furlan A, Higashida R, Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism, JAMA 282:2003–2011, 1999.

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123. Ederle J, Dobson J, Featherstone RL, et al: Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): An interim analysis of a randomised controlled trial, Lancet 375:985–997, 2010. 124. Phatouros CC, Higashida RT, Malek AM, et al: Endovascular treatment of noncarotid extracranial cerebrovascular disease, Neurosurg Clin North Am 11:331–350, 2000. 125. Wityk RJ, Chang HM, Rosengart A, et al: Proximal extracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry, Arch Neurol 55:470–478, 1998. 126. Caplan LR, Amarenco P, Rosengart A, et al: Embolism from vertebral artery origin occlusive disease, Neurology 42:1505–1512, 1992. 127. Gomez CR, Cruz-Flores S, Malkoff MD, et al: Isolated vertigo as a manifestation of vertebrobasilar ischemia, Neurology 47:94–97, 1996. 128. Rocha-Singh K: Vertebral artery stenting: Ready for prime time? Catheter Cardiovasc Interv 54:6–7, 2001. 129. Crawley F, Brown MM, Clifton AG: Angioplasty and stenting in the carotid and vertebral arteries, Postgrad Med J 74:7–10, 1998. 130. Drescher P, Katzen BT: Percutaneous treatment of symptomatic vertebral artery stenosis with coronary stents, Catheter Cardiovasc Interv 52:373–377, 2001. 131. Storey GS, Marks MP, Dake M, et al: Vertebral artery stenting following percutaneous transluminal angioplasty. Technical note, J Neurosurg 84:883–887, 1996. 132. Chastain HD II, Campbell MS, Iyer S, et al: Extracranial vertebral artery stent placement: in-hospital and follow-up results, J Neurosurg 91:547–552, 1999. 133. Higashida RT, Tsai FY, Halbach VV, et al: Transluminal angioplasty for atherosclerotic disease of the vertebral and basilar arteries, J Neurosurg 78:192–198, 1993. 134. Mukherjee D, Roffi M, Kapadia SR, et al: Percutaneous intervention for symptomatic vertebral artery stenosis using coronary stents, J Invasive Cardiol 13:363–366, 2001. 135. SSYLVIA Study Investigators: Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): Study results, Stroke 35:1388–1392, 2004. 136. Wehman JC, Hanel RA, Guidot CA, et al: Atherosclerotic occlusive extracranial vertebral artery disease: Indications for intervention, endovascular techniques, short-term and long-term results, J Interv Cardiol 17:219–232, 2004. 137. Contorni L: Il circolo collaterale vertebro-vertebrale nella obliterazione dell’arterio subclavia all sua origine, Minerva Chir 15: 268–271, 1960. 138. Fisher C: Editorial: A new vascular syndrome: “the subclavian steal.”, N Engl J Med 265:912–913, 1961. 139. de Bray JM, Zenglein JP, Laroche JP, et al: Effect of subclavian syndrome on the basilar artery, Acta Neurol Scand 90:174–178, 1994. 140. Herring M: The subclavian steal syndrome: A review, Am Surg 43:220–228, 1977. 141. Piccone VA, Leveen HH: The subclavian steal syndrome, Ann Thoracic Surg 9:51–75, 1970. 142. Smith JM, Koury HI, Hafner CD, Welling RE: Subclavian steal syndrome. A review of 59 consecutive cases, J Cardiovasc Surg (Torino) 35:11–14, 1994. 143. Thomassen L, Aarli JA: Subclavian steal phenomenon. Clinical and hemodynamic aspects, Acta Neurol Scand 90:241–244, 1994. 144. Walker PM, Paley D, Harris KA, et al: What determines the symptoms associated with subclavian artery occlusive disease? J Vasc Surg 2:154–157, 1985. 145. Webster MW, Downs L, Yonas H, et al: The effect of arm exercise on regional cerebral blood flow in the subclavian steal syndrome, Am J Surg 168:91–93, 1994. 146. Fields WS, Lemak NA: Joint study of extracranial arterial occlusion. VII. Subclavian steal—a review of 168 cases, JAMA 222: 1139–1143, 1972. 147. Ackermann H, Diener HC, Seboldt H, Huth C: Ultrasonographic follow-up of subclavian stenosis and occlusion: natural history and surgical treatment, Stroke 19:431–435, 1988. 148. Drutman J, Gyorke A, Davis WL, Turski PA: Evaluation of subclavian steal with two-dimensional phase-contrast and two-dimensional time-of-flight MR angiography, AJNR Am J Neuroradiol 15:1642–1645, 1994.

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149. AbuRahma AF, Robinson PA, Jennings TG: Carotid-subclavian bypass grafting with polytetrafluoroethylene grafts for symptomatic subclavian artery stenosis or occlusion: A 20-year experience, J Vasc Surg 32:411–419, 2000. 150. Beebe HG, Stark R, Johnson ML, et al: Choices of operation for subclavian-vertebral arterial disease, Am J Surg 139:616–623, 1980. 151. Deriu GP, Milite D, Verlato F, et al: Surgical treatment of atherosclerotic lesions of subclavian artery: Carotid-subclavian bypass versus subclavian-carotid transposition, J Cardiovasc Surg (Torino) 39:729–734, 1998. 152. Owens LV, Tinsley EA Jr, Criado E, et al: Extrathoracic reconstruction of arterial occlusive disease involving the supraaortic trunks, J Vasc Surg 22:217–222, 1995. 153. Bachman DM, Kim RM: Transluminal dilatation for subclavian steal syndrome, AJR Am J Roentgenol 135:995–996, 1980. 154. Taylor CL, Selman WR, Ratcheson RA: Steal affecting the central nervous system, Neurosurgery 50:679–689, 2002. 155. Bornstein NM, Norris JW: Subclavian steal: A harmless haemodynamic phenomenon? Lancet 2:303–305, 1986. 156. Moran KT, Zide RS, Persson AV, Jewell ER: Natural history of subclavian steal syndrome, Am Surg 54:643–644, 1988. 157. Hennerici M, Klemm C, Rautenberg W: The subclavian steal phenomenon: A common vascular disorder with rare neurologic deficits, Neurology 38:669–673, 1988. 158. Farina C, Mingoli A, Schultz RD, et al: Percutaneous transluminal angioplasty versus surgery for subclavian artery occlusive disease, Am J Surg 158:511–514, 1989. 159. Hebrang A, Maskovic J, Tomac B: Percutaneous transluminal angioplasty of the subclavian arteries: long-term results in 52 patients, AJR Am J Roentgenol 156:1091–1094, 1991. 160. Mathias KD, Luth I, Haarmann P: Percutaneous transluminal angioplasty of proximal subclavian artery occlusions, Cardiovasc Interv Radiol 16:214–218, 1993. 161. Motarjeme A, Keifer JW, Zuska AJ, Nabawi P: Percutaneous transluminal angioplasty for treatment of subclavian steal, Radiology 155:611–613, 1985. 162. Selby JB Jr, Matsumoto AH, Tegtmeyer CJ, et al: Balloon angioplasty above the aortic arch: immediate and long-term results, AJR Am J Roentgenol 160:631–635, 1993. 163. Kumar K, Dorros G, Bates MC, et al: Primary stent deployment in occlusive subclavian artery disease, Cathet Cardiovasc Diagn 34:281–285, 1995. 164. Queral LA, Criado FJ: The treatment of focal aortic arch branch lesions with Palmaz stents, J Vasc Surg 23:368–375, 1996. 165. Rodriguez-Lopez JA, Werner A, Martinez R, et al: Stenting for atherosclerotic occlusive disease of the subclavian artery, Ann Vasc Surg 13:254–260, 1999. 166. Sueoka BL: Percutaneous transluminal stent placement to treat subclavian steal syndrome, J Vasc Interv Radiol 7:351–356, 1996. 167. Bogey WM, Demasi RJ, Tripp MD, et al: Percutaneous transluminal angioplasty for subclavian artery stenosis, Am Surg 60:103– 106, 1994. 168. Ringelstein EB, Zeumer H: Delayed reversal of vertebral artery blood flow following percutaneous transluminal angioplasty for subclavian steal syndrome, Neuroradiology 26:189–198, 1984. 169. Weir B: Unruptured intracranial aneurysms: A review, J Neurosurg 96:3–42, 2002. 170. Broderick JP, Brott T, Tomsick T, et al: Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage, J Neurosurg 78:188–191, 1993. 171. Kiyohara Y, Ueda K, Hasuo Y, et al: Incidence and prognosis of subarachnoid hemorrhage in a Japanese rural community, Stroke 20:1150–1155, 1989. 172. Sarti C, Tuomilehto J, Salomaa V, et al: Epidemiology of subarachnoid hemorrhage in Finland from 1983 to 1985, Stroke 22:848– 853, 1991. 173. Mohr JP, Caplan LR, Melski JW, et al: The Harvard Cooperative Stroke Registry: A prospective registry, Neurology 28:754–762, 1978. 174. International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention, N Engl J Med 339:1725–1733, 1998. 175. Qureshi AI, Suri MF, Yahia AM, et al: Risk factors for subarachnoid hemorrhage, Neurosurgery 49:607–613, 2001.

176. Bendok BR, Getch CC, Malisch TW, Batjer HH: Treatment of aneurysmal subarachnoid hemorrhage, Semin Neurol 18:521–531, 1998. 177. Malisch TW, Guglielmi G, Vinuela F, et al: Unruptured aneurysms presenting with mass effect symptoms: Response to endosaccular treatment with Guglielmi detachable coils. Part I. Symptoms of cranial nerve dysfunction, J Neurosurg 89:956–961, 1998. 178. Qureshi AI, Mohammad Y, Yahia AM, et al: Ischemic events associated with unruptured intracranial aneurysms: Multicenter clinical study and review of the literature, Neurosurgery 46:282–290, 2000. 179. Mayberg MR, Batjer HH, Dacey R, et al: Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association, Circulation 90:2592–2605, 1994. 180. Juvela S: Rebleeding from ruptured intracranial aneurysms, Surg Neurol 32:323–326, 1989. 181. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised trial, Lancet 360:1267–1274, 2002. 182. Molyneux AJ, Kerr RS, Yu LM, et al: International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion, Lancet 366:809–817, 2005. 183. Biller J, Godersky JC, Adams HP Jr: Management of aneurysmal subarachnoid hemorrhage, Stroke 19:1300–1305, 1988. 184. Origitano TC, Reichman OH, Anderson DE: Prophylactic hypervolemia without calcium channel blockers in early aneurysm surgery, Neurosurgery 31:804–806, 1992. 185. Newell DW, Eskridge JM, Mayberg MR, et al: Angioplasty for the treatment of symptomatic vasospasm following subarachnoid hemorrhage, J Neurosurg 71:654–660, 1989. 186. Coskun E: Papaverine and vasospasm, J Neurosurg 96:973–974, 2002. 187. Morgan MK, Jonker B, Finfer S, et al: Aggressive management of aneurysmal subarachnoid haemorrhage based on a papaverine angioplasty protocol, J Clin Neurosci 7:305–308, 2000. 188. Ohkuma H, Ogane K, Tanaka M, Suzuki S: Assessment of cerebral microcirculatory changes during cerebral vasospasm by analyzing cerebral circulation time on DSA images, Acta Neurochir Suppl 77:127–130, 2001. 189. Turjman F, Massoud TF, Sayre J, Vinuela F: Predictors of aneurysmal occlusion in the period immediately after endovascular treatment with detachable coils: A multivariate analysis, AJNR Am J Neuroradiol 19:1645–1651, 1998. 190. Moret J, Cognard C, Weill A, et al: Reconstruction technic in the treatment of wide-neck intracranial aneurysms. Long-term angiographic and clinical results. Apropos of 56 cases, J Neuroradiol 24:30–44, 1997. 191. Lanzino G, Wakhloo AK, Fessler RD, et al: Efficacy and current limitations of intravascular stents for intracranial internal carotid, vertebral, and basilar artery aneurysms, J Neurosurg 91:538–546, 1999. 192. Mocco J, Snyder KV, Albuquerque FC, et al: Treatment of intracranial aneurysm with the Enterprise stent: A multicenter registry, J Neurosurg 110:35–39, 2009. 193. Cekirge HS, Saatci I, Geyik S, et al: Intrasaccular combination of metallic coils and onyx liquid embolic agent for the endovascular treatment of cerebral aneurysms, J Neurosurg 105:706–712, 2006. 194. Cekirge HS, Saatci I, Ozturk MH, et al: Late angiographic and clinical follow-up results of 100 consecutive aneurysms treated with Onyx reconstruction: Largest single-center experience, Neuroradiology 48:113–126, 2006. 195. Cloft HJ: HydroCoil for Endovascular Aneurysm Occlusion (HEAL) study: periprocedural results, AJNR Am J Neuroradiol 27:289–292, 2006. 196. Cloft HJ: HydroCoil for Endovascular Aneurysm Occlusion (HEAL) study: 3-6 month angiographic follow-up results, AJNR Am J Neuroradiol 28:152–154, 2007.

INTERVENTIONAL NEURORADIOLOGIC THERAPY OF ATHEROSCLEROTIC DISEASE AND VASCULAR MALFORMATIONS 197. Fiorella D, Kelly ME, Albuquerque FC, Nelson PK: Curative reconstruction of a giant midbasilar trunk aneurysm with the Pipeline embolization device: Case report, Neurosurgery 64:212–217, 2009:discussion 217. 198. Murayama Y, Vinuela F, Ishii A, et al: Initial clinical experience with matrix detachable coils for the treatment of intracranial aneurysms, J Neurosurg 105:192–199, 2006. 199. Ogilvy CS, Stieg PE, Awad I, 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 32:1458–1471, 2001. 200. Chiaradio JC, Guzman L, Padilla L, Chiaradio MP: Intravascular graft stent treatment of a ruptured fusiform dissecting aneurysm of the intracranial vertebral artery: Technical case report, Neurosurgery 50:213–217, 2002. 201. Fiorella D, Woo HH, Albuquerque FC, Nelson PK: Definitive reconstruction of circumferential, fusiform intracranial aneurysms with the Pipeline embolization device, Neurosurgery 62:1115–1121, 2008. 202. Michelson W: Natural history and pathophysiology of arteriovenous malformations, Clin Neurosurg 26:307–313, 1978. 203. Jessurun GA, Kamphuis DJ, van der Zande FH, Nossent JC: Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations, Clin Neurol Neurosurg 95:193–198, 1993. 204. Patterson J, McKossoch W: A clinical survey of intracranial angiomas with special reference to their mode of progression and surgical treatment: A report of 110 cases, Brain 79:233–266, 1956. 205. Lasjaunias P, Piske R, Terbrugge K, Willinsky R: Cerebral arteriovenous malformations (C. AVM) and associated arterial aneurysms (AA). Analysis of 101 C. AVM cases, with 37 AA in 23 patients, Acta Neurochir 91:29–36, 1988. 206. Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations, J Neurosurg 65:476–483, 1986. 207. Hartmann A, Pile-Spellman J, Stapf C, et al: Risk of endovascular treatment of brain arteriovenous malformations, Stroke 33:1816– 1820, 2002. 208. Furlan AJ, Whisnant JP, Elveback LR: The decreasing incidence of primary intracerebral hemorrhage: A population study, Ann Neurol 5:367–373, 1979. 209. Brown RD Jr, Wiebers DO, Forbes G, et al: The natural history of unruptured intracranial arteriovenous malformations, J Neurosurg 68:352–357, 1988. 210. Fults D, Kelly DL Jr: Natural history of arteriovenous malformations of the brain: A clinical study, Neurosurgery 15:658–662, 1984. 211. Graf CJ, Perret GE, Torner JC: Bleeding from cerebral arteriovenous malformations as part of their natural history, J Neurosurg 58:331–337, 1983. 212. Ondra SL, Troupp H, George ED, Schwab K: The natural history of symptomatic arteriovenous malformations of the brain: A 24-year follow-up assessment, J Neurosurg 73:387–391, 1990.

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213. Hartmann A, Mast H, Mohr JP, et al: Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation, Stroke 29:931–934, 1998. 214. Kondziolka D, McLaughlin MR, Kestle JR: Simple risk predictions for arteriovenous malformation hemorrhage, Neurosurgery 37:851–855, 1995. 215. Hartmann A, Mast H, Choi JH, et al: Treatment of arteriovenous malformations of the brain, Curr Neurol Neurosci Rep 7:28–34, 2007. 216. Forster DM, Steiner L, Hakanson S: Arteriovenous malformations of the brain. A long-term clinical study, J Neurosurg 37:562–570, 1972. 217. Kader A, Young WL, Pile-Spellman J, et al: The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations, Neurosurgery 34:801–808, 1994. 218. Miyasaka Y, Yada K, Ohwada T, et al: An analysis of the venous drainage system as a factor in hemorrhage from arteriovenous malformations, J Neurosurg 76:239–243, 1992. 219. Heros RC, Korosue K, Diebold PM: Surgical excision of cerebral arteriovenous malformations: late results, Neurosurgery 26: 570–578, 1990. 220. Jafar JJ, Davis AJ, Berenstein A, et al: The effect of embolization with N-butyl cyanoacrylate prior to surgical resection of cerebral arteriovenous malformations, J Neurosurg 78:60–69, 1993. 221. Spetzler RF, Wilson CB, Weinstein P, et al: Normal perfusion pressure breakthrough theory, Clin Neurosurg 25:651–672, 1978. 222. Pollock BE, Lunsford LD, Flickinger JC, Kondziolka D: The role of embolization in combination with stereotactic radiosurgery in the management of pial and dural arteriovenous malformations. In Connors JJ, Wojak JC, editors: Interventional Neuroradiology., Philadelphia, 1999, WB Saunders, pp 267–275. 223. Fournier D, TerBrugge KG, Willinsky R, et al: Endovascular treatment of intracerebral arteriovenous malformations: experience in 49 cases, J Neurosurg 75:228–233, 1991. 224. Gobin YP, Laurent A, Merienne L, et al: Treatment of brain arteriovenous malformations by embolization and radiosurgery, J Neurosurg 85:19–28, 1996. 225. Vinuela F, Dion JE, Duckwiler G, et al: Combined endovascular embolization and surgery in the management of cerebral arteriovenous malformations: Experience with 101 cases, J Neurosurg 75:856–864, 1991. 226. Jahan R, Murayama Y, Gobin YP, et al: Embolization of arteriovenous malformations with Onyx: clinicopathological experience in 23 patients, Neurosurgery 48:984–997, 2001. 227. Song DL, Leng B, Xu B, et al: Clinical experience of 70 cases of cerebral arteriovenous malformations embolization with Onyx, a novel liquid embolic agent, Zhonghua Wai Ke Za Zhi 45:223– 225, 2007. 228. van Rooij WJ, Sluzewski M, Beute GN: Brain AVM embolization with Onyx, AJNR Am J Neuroradiol 28:172–178, 2007. 229. Weber W, Kis B, Siekmann R, Kuehne D: Endovascular treatment of intracranial arteriovenous malformations with Onyx: Technical aspects, AJNR Am J Neuroradiol 28:371–377, 2007.

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Intraarterial Thrombolysis in Acute Ischemic Stroke ANTHONY J. FURLAN, JITENDRA SHARMA, RANDALL HIGASHIDA

I

n the 1980s, several reports of intraarterial thrombolysis (IAT) as therapy for acute ischemic stroke were published.1-3 The thrombolytic agents used in these early series were urokinase (UK) and streptokinase (SK).Two decades later, advances in technique and microcatheter technology now allow superselective catheterization of even distal branches of occluded intracranial vessels. Importantly, rapid technical advances have prompted the Accreditation Council for Graduate Medical Education4 (ACGME) to standardize the training curricula in endovascular surgical neuroradiology (i.e., interventional neuroradiology) for neuroradiologists, neurosurgeons, and neurologists. Studies of IAT for acute ischemic stroke were initially limited to uncontrolled protocols.5,6 There was great variability in technique, and efficacy and complication rates varied among the reported series. As a result, in 1996, an American Heart Association (AHA) Special Writing Group published its recommendations for the use of thrombolytic agents in acute ischemic stroke. On the basis of the strength of the scientific evidence available at that time, the Group concluded that IAT “should be considered investigational and only used in the clinical trial setting,” recommending “further testing of” IAT.7 Subsequently, the results of the first randomized multicenter controlled trials of IAT, the Prolyse in Acute Cerebral Thromboembolism trials, PROACT I8 and PROACT II,9 were reported in 1998 and 1999, respectively. PROACT II remains the only randomized, controlled, multicenter clinical trial to demonstrate the efficacy of IAT in patients with acute ischemic stroke of less than 6 hours’ duration due to occlusion of the middle cerebral artery (MCA). Nonetheless, the U.S. Food and Drug Administration (FDA) has approved two stroke thrombectomy devices, and there is evidence that stroke IAT is being done routinely at most comprehensive stroke centers worldwide.

cervical segment of the vascular territory to be treated, followed by the introduction of a 2.3F coaxial microcatheter with a steerable microguidewire. Under direct fluoroscopic visualization, the microcatheter is gently navigated through the intracranial circulation until the tip is embedded within or through the central portion of the thrombus (Fig. 62-1). Many variations in catheter design and delivery technique have been described.10 Two types of microcatheters are being used most often for local cerebral thrombolysis, depending on the extent of clot formation. For the majority of intraarterial procedures, a single–end hole microcatheter is used, whereas for longer segments of clot formation, a microcatheter with multiple side holes is used. Superselective angiography through the microcatheter is performed at regular intervals to assess for extent of clot lysis and to adjust the dosage and volume of the thrombolytic agent. A superselective angiogram is performed, and if the clot is seen to be partially dissolved, the catheter is advanced into the remaining thrombus, where additional thrombolysis is performed.As the thrombus is dissolved, the catheter is advanced into more distal branches of the intracranial circulation, so that most of the thrombolytic agent enters the occluded vessel and is not washed preferentially into adjacent open blood vessels. The goal is to achieve rapid recanalization with as little thrombolytic agent as possible so as to limit the extent of brain infarction and reduce the risk of hemorrhage. Common experience shows, however, that it can take up to 2 hours to achieve recanalization after the procedure begins, that thrombolytic agents alone (i.e., without mechanical manipulation) rarely achieve recanalization in less than 30 minutes, and that recanalization is often incomplete. Among other factors, clot composition plays a key role in the rapidity and extent of recanalization achieved with IAT.

General Technique of Intraarterial Thrombolysis

Thrombolytic Agents

In patients with appropriate clinical and CT criteria, a complete four-vessel cerebral angiogram should be performed from a transfemoral approach to evaluate the site of vessel occlusion, the extent of thrombus, the number of territories involved, and the collateral circulation. In this procedure, a diagnostic catheter is guided into the high

Recombinant pro-urokinase (r-proUK), the thrombolytic agent used in PROACT II (see later), is currently not approved by the FDA and is not yet commercially available. Although some thrombolytic agents have theoretical advantages over others, there is no proof that one thrombolytic agent is superior to another in terms of safety, recanalization rate, or clinical efficacy in acute ischemic 1227

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Figure 62-1 Intraarterial thrombolysis, with 9 mg r-proUK, 5.5 hours from stroke onset. A, Diagnostic angiogram (AG) shows complete

Thrombolysis in Acute Myocardial Infarction (TIMI) 0 occlusion of the M1 middle cerebral artery; minimal early infarct signs on baseline CT. B, Tip of the microcatheter embedded within proximal thrombus. Partial clot lysis after 1-hour infusion. C, Complete TIMI 3 recanalization at 2 hours. 24-hour CT scan shows minimal infarction. 8-day CT scan shows slight asymptomatic hemorrhagic conversion. (From Furlan A, Higashida R, Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke: The PROACT II Study: A randomized controlled trial. JAMA 282:2003-2011, 1999.)

stroke. Therefore it is not clear whether the results of PROACT II are applicable when agents other than r-proUK are used for IAT. Commercially available agents include urokinase (UK), tissue-type plasminogen activator (t-PA), reteplase (recombinant t-PA [rt-PA]), and tenecteplase (tNKase). These thrombolytic agents differ in stability, half-life, and fibrin selectivity. UK is not fibrin selective and therefore can cause systemic hypofibrinoginemia. Both t-PA and r-proUK are fibrin selective and are active only at the site of thrombosis. However, r-proUK requires heparin for maximal thrombolytic effect. Newer agents have long half-lives, allowing bolus administration, such as rt-PA, or are more fibrin selective, such as tenecteplase. However, the efficacy of second- and third-generation thrombolytic agents in acute ischemic stroke has not been demonstrated in a randomized controlled trial (RCT).11 Adjunctive Therapy Intravenous (IV) heparin is given by most neurointerventionists during IAT for stroke. Systemic anticoagulation with heparin reduces the risk of catheter-related embolism. Also, the thrombolytic effect of some agents, such as

r-proUK, is augmented by heparin. Another rationale for antithrombotic therapy is prevention of early reocclusion, which is probably more common with atherothrombosis than with cerebral embolism. These indications are counterbalanced by the higher risk of brain hemorrhage when heparin is combined with a thrombolytic agent. The optimal dose of heparin during IAT for stroke has not been established. The PROACT I investigators reported a 27% rate of symptomatic brain hemorrhage when a conventional non–weight-adjusted heparin regimen (100 U/kg bolus followed by 1000 U/h for 4 hours) was used with intraarterial (IA) r-proUK.8 Subsequently, a low-dose heparin regimen (2000 U bolus followed by 500 U/h for 4 hours) was used with IA r-proUK, which reduced the rate of symptomatic brain hemorrhage to 7% in PROACT I and 10% in PROACT II. Unfortunately, the use of low-dose heparin therapy with IA r-proUK also cut the recanalization rate to half that for the original heparin regimen. Some neurointerventionists now employ the PROACT low-dose heparin regimen during IAT. However, this dose of heparin does not prolong the activated partial thromboplastin time (APTT) or activated clotting time (ACT). Other neurointerventionists employ

INTRAARTERIAL THROMBOLYSIS IN ACUTE ISCHEMIC STROKE

weight-adjusted heparin dosage, keeping the activated clotting time between 200 and 300 seconds. The safety and efficacy of platelet glycoprotein (GP) IIb/IIIa inhibitor agents in patients with acute ischemic stroke undergoing IAT are unclear. Coronary doses of IV abciximab appear to be relatively safe in patients with acute ischemic stroke.12 The risk of brain hemorrhage with the use of combined GP IIb/IIIa inhibitors and reduceddose thrombolytic agents may be higher in patients older than 75 years.13 The GP IIb/IIIa inhibitors abciximab and eptifibatide improve the efficacy of acute coronary interventions and have been used in patients undergoing cerebrovascular interventions.14-16 The GP IIb/IIIa inhibitor dose can be adjusted to keep the platelet inhibition value between 50% and 80% during the intervention through monitoring of the platelet activation units (PAU). However, GP IIb/IIIa inhibitors are not routinely employed during IAT for stroke. Adjunctive use of GP IIb/IIIa inhibition should be considered when the risk of acute reocclusion and endothelial injury is high, as in angioplasty and stenting for basilar artery atherothrombosis. Concomitant use of clopidogrel and aspirin is usually avoided in acute stroke interventions because of the risk of brain hemorrhage.

The Prolyse in Acute Cerebral Thromboembolism Trials Beginning in February 1994, patients were enrolled in the first placebo-controlled, double-blind multicenter trial of IAT in acute ischemic stroke, PROACT I.8 The results were published in 1998. The thrombolytic agent used in PROACT I was recombinant prourokinase (r-proUK), which is not yet commercially available. This agent is a recombinant, single-chain zymogen of an endogenous fibrinolytic, either UK or urokinase-type plasminogen activator (u-PA).17 Infusion of r-proUK does not lead to systemic dysfibrinogenemia with its associated higher risk of hemorrhagic side effects. Another clinically relevant characteristic of r-proUK is the facilitatory effect of coadministered heparin, which when given with r-proUK improves its fibrinolytic efficacy. In PROACT I, the safety and recanalization efficacy of 6 mg r-proUK given IA were compared with that of IA administration of saline placebo in 40 patients with acute ischemic stroke of less than 6 hours’ duration that was due to MCA occlusion. Only patients in whom diagnostic cerebral angiography showed Thrombolysis in Acute Myocardial Infarction (TIMI) grade 0 or grade 1 occlusion of the M1 or M2 segment of the MCA were included. Another major inclusion criterion was a minimum National Institutes of Health Stroke Scale (NIHSS) score of 4 (except for isolated aphasia or hemianopsia) and a maximum score of 30. Major exclusion criteria were uncontrolled hypertension (blood pressure >180 mm Hg systolic/100 mm Hg diastolic), a history of hemorrhage, and recent surgery or trauma. CT evidence of early ischemic changes was not an exclusion criterion. Mechanical disruption of the clot was not permitted because the goal of the trial was to demonstrate the efficacy and safety of r-proUK. Patients also received IV heparin. The first 16 patients received the “high-dose” heparin regimen already mentioned. It consisted of a bolus of 100 IU/kg followed by a 1000 IU/h

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infusion for 4 hours; anticoagulation was prohibited for the following 24 hours. On the basis of a recommendation from the external safety committee, the heparin regimen was changed after the first 16 patients to a 2000 IU bolus followed by a 500 IU/h infusion for 4 hours. The recanalization rate was 57.7% in the r-proUK group and only 14.3% in the placebo group. In the “high-dose heparin” group receiving r-proUK, the recanalization rate was 81.8%, but the rate of symptomatic intracranial hemorrhage (ICH) was 27%. In contrast, the patients receiving r-proUK and “low-dose heparin” had a recanalization rate of 40%, but the ICH rate was only 6%. Overall, symptomatic ICH occurred in 15.4% of patients receiving treatment and in 14.3% of patients receiving placebo. Although PROACT I was not a clinical efficacy trial, there appeared to be a 10% to 12% higher rate of excellent outcomes in the IA r-proUK group than in the control group. The follow-up clinical efficacy trial, PROACT II, was launched in February 1996, and the results were published in December 1999.9 PROACT II was a randomized, controlled, multicenter trial but differed from PROACT I in that it employed open-label design with blinded followup. Patient selection was essentially the same as in PROACT I, with the major exception that patients with early signs of infarction in more than one third of the MCA territory (the so-called ECASS [European Cooperative Acute Stroke Study] CT criterion)18 on the initial CT scan were excluded. Additionally, a dose of 9 mg r-proUK was used instead of 6 mg, and “low-dose heparin” was given to both the treatment and control groups. A total of 180 patients were randomly assigned to receive either 9 mg of IA r-proUK plus low-dose IV heparin or low-dose IV heparin alone. Baseline stroke severity in the PROACT II patients was very high, with a median NIHSS score of 17. The median time from onset of symptoms to initiation of IAT was 5.3 hours. The primary outcome measure was the proportion of patients who achieved a modified Rankin Scale score of 2 or less at 90 days, which signifies slight or no neurologic disability. For the group treated with r-proUK, there was a 15% absolute benefit (P = .043). The benefit was most noticeable in patients with a baseline NIHSS score between 11 and 20. On average, seven patients with MCA occlusion would require IAT for one of them to benefit. Recanalization rates were 66% at 2 hours for the treatment group and 18% for the placebo group (P < .001). Symptomatic brain hemorrhage occurred in 10% of the r-proUK group and 2% of the control group. Considering the later time to treatment and greater baseline stroke severity in PROACT II, the symptomatic brain hemorrhage rate compared favorably with that in the IV t-PA trials (6% in National Institutes of Neurological Disease and Stroke [NINDS],19 9% in ECASS,18 and 7% in Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS]).20 As in the NINDS trial, patients in PROACT II benefited overall from therapy despite the higher rate of brain hemorrhage, and there was no excess mortality (r-proUK, 24%; control, 27%). Despite these results, r-proUK did not receive FDA approval. However, PROACT II did establish the proof of the principle of IAT and also demonstrated its clinical efficacy up to 6 hours after stroke onset.

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Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial

very similar in the two trials (9% for MELT versus 10% for PROACT II).

The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) was a multicenter, randomized trial conducted at 57 centers in Japan (2002 to 2005) to evaluate the safety and efficacy of intraarterial UK to treat patients with MCA occlusion of less than 6 hours’ duration.21 Inclusion criteria were similar to those for PROACT II: age 20 to 75 years, MCA territory stroke within 6 hours from onset, baseline NIHSS score 5 or higher, and CT findings normal or showing only subtle signs of acute stroke in MCA territory. Angiographic inclusion criteria were complete occlusion of the M1 or M2 division of the MCA. Exclusion criteria included NIHSS score higher than 22, baseline modified Rankin Scale (mRS) score higher than 2, patients with high risk of hemorrhagic complication (platelet count < 100,000/mm3, heparin started within 48 hours, International Normalized Ratio [INR] > 1.7), history of head trauma or intracranial hemorrhage, history of stroke in last 3 months, and recent surgery or history of intracranial neoplasm. Clinical outcome was assessed at 7, 30, and 90 days by means of NIHSS, Barthel Index, and mRS. The primary outcome of MELT was favorable outcome at 90 days (mRS ≤ 2). Secondary outcomes were intracranial hemorrhage within 24 hours after start of treatment, death within 90 days, rate of recanalization, NIHSS scores of 0 and 1 at 24 hours, 30 days, and 90 days, Barthel Index more than 95, and mRS score less than 2 at 30 days and 90 days. MELT was stopped prematurely after approval of intravenous tissue plasminogen activator for stroke in Japan. At the time of discontinuation, 114 patients had been randomly assigned to treatment groups (mean age 66.9 versus 64.90 years, median NIHSS score 14 both arms). A nonsignificant improvement in clinical outcome (mRS score ≤ 2 at 90 days) was seen in the treatment arm over that in the control arm (49.1% and 38.6%, respectively; odds ratio [OR], 1.54; 95% confidence interval [CI], 0.73–3.23; P = .345); 73.7% of the patients (42/57) in the treatment arm had partial to complete recanalization. The rate of excellent functional outcome (mRS score ≤ 1 at 90 days) was greater in the treatment arm than in the control arm (41% and 22.8%, respectively; OR, 2.46; 95% CI, 1.09–5.54; P = .045). The 90-day mortality rates were 5.3% in the treatment group and 3.5% in the control arm (P = 1.000). The rates of intracerebral hemorrhage within 24 hours were 9% in the treatment group and 2% in the control group (P = .206). MELT was not able to show significant results possibly because of early termination of the trial but did suggest better clinical outcome at 90 days (mRS < 1). A metaanalysis that compared PROACT II and MELT showed that the two trials were comparable with slight differences in baseline clinical data (NIHSS scores 14 versus 17; CT signs of early infarct in 47% versus 76%) and time to initiation of therapy (3.8 versus 5.3 hours). MELT prohibited mechanical clot disruption except with the guidewire, but PROACT II allowed only chemical thrombolysis. The earlier start of IAT in MELT was one reason the recanalization rate was better in that trial than in PROACT II (73.7% versus 66%). The rates of intracranial hemorrhages were

Mechanical Thrombectomy in Acute Stroke Mechanical thrombectomy has become a new treatment option for strokes due to large vessel occlusion. Previous studies have shown that thrombus in large vessels is refractory to intravenous and intraarterial plasminogen activators.9,19,22,23 Later studies have shown that mechanical thrombectomy can improve recanalization rates, which are associated with better clinical outcomes.24-26 The Mechanical Embolus Removal in Cerebral Ischemia and Multi MERCI Trials The Merci retrieval system (Concentric Medical, Mountain View, Calif) consists of the Merci retriever, the Merci balloon guide catheter, and the Merci microcatheter. In 2004 the Merci retriever was the first device approved by the FDA as a mechanical thrombectomy device to remove clot in patients with acute ischemic stroke. The inclusion criteria specified that the Merci devices were for use in patients who were ineligible for intravenous t-PA or in whom it failed and that the devices could be used up to 8 hours from stroke onset. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial25 was a two-part multicenter nonrandomized trial designed to evaluate the safety and efficacy of the Merci retriever device. MERCI part 126 enrolled 30 patients in 7 U.S. centers with a baseline NIHSS score of 10 or higher and with stroke presentation more than 3 hours but within 8 hours of symptom onset or within 3 hours but with contraindications to IV thrombolysis. Patients were selected for treatment with the Merci device if brain CT showed early signs of infarction in less than one third of the MCA territory and diagnostic angiography showed an occlusion of the internal carotid artery, M1 segment of the middle cerebral artery, basilar artery, or vertebral artery. Twenty-eight patients were treated, and successful recanalization was achieved in 12 (43%) with mechanical thrombectomy alone and in 18 (64%) when additional intraarterial tissue plasminogen activator was used. At the 30-day evaluation, 50% (9/18) of patients with successful recanalization had made a significant recovery, defined as an mRS score less than 3. There was one procedure-related technical complication with no clinical consequences and 12 (43%) asymptomatic hemorrhages. MERCI part 1 demonstrated that the Merci retrieval system is safe and efficacious for clot removal within 8 hours of stroke symptom onset and suggested that recanalization is associated with improved clinical outcomes.27 MERCI part 225 was a single-arm prospective multicenter study that evaluated the safety and efficacy of mechanical thrombectomy within 8 hours of acute ischemic stroke onset. It was conducted at 25 centers between May 2001 and December 2003 and enrolled 151 patients. The inclusion criteria were similar to those for MERCI part 1. The primary outcomes for this study were the rates of vascular recanalization and device-related complications. Successful recanalization was defined as TIMI grades 2 and 3 flow assessed immediately after the treatment.


The device was deployed in 141 patients, and recanalization was achieved in 46% (69/151) on intention to treat analysis and in 48% (68/141) in whom the device was actually deployed. Ten patients (7.1%) had clinically significant complications, and symptomatic intracranial hemorrhage occurred in 7.8% (11/141). Although better clinical outcome (mRS score ≤ 2) was seen in patients with successful recanalization, the overall 90-day clinical efficacy for MERCI, reported as 27.7%, was similar to that for placebo in PROACT II, and the mortality rate for MERCI, reported as 43.5%, was higher than that in PROACT II. The Multi MERCI trial27 was designed to evaluate the safety and efficacy of a newer-generation thrombectomy device (L5 retriever) and to gain more experience with the first-generation Merci retrievers (X5 and X6). The inclusion criteria for the Multi MERCI trial were the same as those for MERCI, except that patients were also included if IV t-PA within 3 hours of stroke onset failed to open an intracranial large vessel occlusion confirmed by diagnostic angiography. Multi MERCI enrolled 177 patients, and a device was deployed in 164 patients; 131/164 patients were treated with the newer L5 retriever. The mean age was 68 ± 16 years, and the median baseline NIHSS score was 19 (15 to 23). The occlusion sites were internal carotid artery/terminus in 32% of patients, the MCA in 60%, and the posterior circulation in 8%. Forty-eight patients (29.3%) received IV rt-PA before intervention, 11 patients received GP IIB/ IIIa antagonists, and 14 received IA thrombolytics before or during mechanical thrombectomy. A 57.3% recanalization rate (75/131) was achieved with the retriever alone; the recanalization rate improved to 69.5% (91/131) with adjunctive IAT. A better recanalization rate was observed with the newer device (57.3%; 75/131) than with the older X5/X6 devices (45.5%; 15/33), but this difference did not reach statistical significance. Favorable outcome (mRS ≤ 2) was seen in 36% of patients, and the mortality rate was 34%. Both outcomes were significantly related to vascular recanalization. Symptomatic intracranial hemorrhage occurred in 16 patients (9.8%), and procedural-related complications occurred in 9 (5.5%) patients. The Multi MERCI trial showed that the newer device is safe and able to achieve somewhat better recanalization rates. Like MERCI, the Multi MERCI results suggested better outcomes in patients in whom recanalization was achieved. This study also suggested that mechanical thrombectomy after unsuccessful IV rt-PA (so-called rescue IA thrombectomy) is safe. The Penumbra System The Penumbra System (Penumbra, Inc., Alameda, CA) is a later-generation device designed to remove clot from large vessels in acute stroke settings.28 It consists of a reperfusion catheter, a separator, and a thrombus removal ring. The device removes clot by using an aspiration and extraction technique. If any residual thrombus is seen in the vessel after aspiration, a thrombus removal ring is used to remove residual thrombus. The first study to evaluate the safety and efficacy of the Penumbra System was a prospective multicenter, singlearm study that enrolled 23 patients from seven international centers.28 The primary endpoint of this study was

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the ability of the system to recanalize the affected vessel to TIMI grade 2 or higher within 8 hours of stroke onset. A secondary endpoint was clinical outcome 30 days after the procedure using an mRS score or 2 or less or a 4-point improvement in NIHSS score. The inclusion and exclusion criteria were similar to those for the Multi MERCI trial. The Penumbra System was used to treat 21 target vessels in 20 patients. The baseline mean age was 60 years, and the baseline mean NIHSS score was 21. Recanalization was achieved in all treated vessels. At 30-day follow-up, 45% of patients showed improvement in NIHSS score by at least 4 points or an mRS score of 2 or less. The mortality rate was 45%; 70% of deceased patients had a baseline NIHSS score higher than 20 or a basilar artery occlusion. This study demonstrated that the Penumbra System can open large vessel occlusions in acute stroke. This study was followed by a larger prospective single-arm multicenter trial to further assess the safety and efficacy of the Penumbra System.29 The baseline mean age was 63.5 years, and the mean NIHSS score was 17.6. The study enrolled 125 patients, and 125 target vessels were treated with the device.The recanalization rate was 81.6%, and the procedural complication rate was 12.8%. Intracranial hemorrhage was seen on 24-hour CT in 28% (35 patients), of which 11.2% (14) were symptomatic.The rate of 90-day mRS of 2 or less was 25%, and the mortality rate was 32.8%. At discharge, 41.6% of patients had good clinical outcome as defined by improvement in NIHSS score by at least 4 points or mRS score of 2 or less at 30-day followup. This study further confirmed the safety and efficacy of use of the Penumbra System in acute stroke and led to FDA and Center for Medicaid and Medicare Services (CMS) approval for its clinical use.29 Indications for and Drawbacks of Mechanical Thrombectomy Mechanical thrombectomy can be used in patients with acute stroke who are ineligible for IV or IA chemical thrombolytics, such as patients with recent surgery or other significant risk for hemorrhage. The MERCI trials included patients who were undergoing anticoagulation as long as the INR value was less than 3, the partial thromboplastin time (PTT) was less than 2 times that of controls, and the platelet count was higher than 30,000/mm3. Mechanical thrombectomy can also be used in combination with IV or IA therapy. The disadvantages of using mechanical thrombectomy include limited access to trained neurointerventionalists, technical difficulty with the navigating wire in delicate intracranial vessels, trauma to vessels, distal embolization, vessel dissection and vasospasm leading to worsening of stroke. The MERCI, Multi MERCI, and Penumbra studies were able to show that mechanical embolectomy can be effectively and safely used within 8 hours of stroke symptom onset as alternative treatment options for patients who are ineligible for thrombolytics. Because there were no randomized control groups, none of the trials was able to conclusively show that mechanical thrombectomy actually improves stroke clinical outcomes. Despite these limitations, the Merci retriever received approval from both

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the FDA and the CMS for clot removal up to 8 hours from acute stroke onset.30 Ongoing RCTs, including the Interventional Management of Stroke Study III (IMS3) and the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) study, will help answer questions regarding patient selection, comparative efficacy, and clinical outcomes for mechanical thrombectomy and IAT in patients with acute stroke.31

Drawbacks of Intraarterial Thrombolysis Access to facilities and a team of physicians (an interventionist and tertiary stroke team) capable of performing IAT is a limitation to the use of this procedure. Such expertise is not readily available in many developing countries or in communities across the United States, usually being limited to large academic centers. Treatment delays are also inherent to IAT. In PROACT II, the median time from stroke onset to drug infusion was 5.3 hours, and the average time from the patient’s arrival at the hospital to the initiation of IA r-proUK was 3 hours. IAT also involves costs and procedural risks not inherent to IV thrombolysis (IVT). However, serious procedural complications were uncommon in PROACT I and II; also, in experienced centers, cerebral angiography is associated with a morbidity of only 1.4% and with rates of permanent complications and death of 0.1% and 0.02%, respectively.32

Intraarterial versus Intravenous Thrombolysis IVT has the important advantages of speed, ease of administration, and widespread availability. Its efficiency is limited, however, by a number of factors. Intravenous thrombolytics achieve arterial recanalization in about 40% of patients. The recanalization rate may decrease with time owing to thrombus formation and growth, as in the proportion of patients with major stroke who have salvageable brain. ECASS I and II excluded patients with extended ischemic edema exceeding one third of the MCA territory.17,33 In the IVT trials, vascular imaging studies were not performed, so neither the sites of arterial occlusion nor the recanalization rates are known. Patients with ischemic stroke of less than 6 hours’ duration have a wide variety of occlusion sites, and 20% have no visible occlusion, despite similar neurologic presentations.34 Hence, the study populations in the IVT trials were relatively heterogeneous. Although there have been no randomized studies comparing recanalization rates with outcomes for IVT and IAT, recanalization rates for cerebrovascular occlusions average 70% for IAT and 34% for IVT.35 These differences in recanalization rates are most apparent with occlusions of large vessels, such as the internal carotid artery (ICA)—which is the vessel most resistant to thrombolysis—the carotid T segment, and the proximal (M1) segment of the MCA. The greater recanalization efficacy for large vessel occlusions may help explain why the time window for successful IAT may be longer than that for IVT. On the

basis of PROACT II, a 6-hour window appears to be a realistic goal for IAT in anterior circulation ischemia. For stroke in the vertebrobasilar circulation, there are some reports of successful therapy up to 48 hours after onset (see later).3,36 The factors that determine individual susceptibility to ischemia are not completely understood, and there is clearly a great deal of variability in time from onset to irreversible damage among individuals. Even though a longer time window may be offered by IAT, it is critical to understand that urgency is paramount in ischemic stroke intervention and that the earlier recanalization is achieved with either IVT or IAT, the better the neurologic outcome. IAT may be safer than IVT in patients with an excessive bleeding risk. Katzan et al37 reported the use of IAT in six patients with acute stroke after open heart surgery. Although this was only a small series, perioperative IAT appeared relatively safe, because only one minor bleeding complication occurred. There are other special situations in which IAT can be employed. Both Weber et al38 and Padolecchia et al39 showed the safety and efficacy of superselective IAT in cases of central retinal artery occlusion. Both studies reported significant improvements in visual acuity with no hemorrhagic complications. In the series reported by Weber et al,38 17.6% of patients recovered completely, a rate that is better than that in historical controls.

Combined Intravenous and Intraarterial Thrombolysis It may be feasible to combine IVT and IAT to take advantage of the early infusion possible with IV administration and the greater recanalization efficacy of IA therapy. Hospital systems are increasingly employing a “drip and ship” strategy, whereby IVT is initiated on site at the local community hospital and the patient is then transported to the regional neurointerventional stroke center for “rescue” IAT. This approach was studied in the pilot Emergency Management of Stroke (EMS) Bridging Trial.40 Patients with stroke of less than 3 hours’ duration were given a loading dose (0.6 mg/kg) of IV t-PA or placebo followed by angiography and IAT if a vascular occlusion remained. In 70% of all patients, angiography showed clot after IV therapy. MCA recanalization improved in patients who then received IA t-PA, but the risk of life-threatening bleeding complications also rose. The results of the follow-up IV plus IA t-PA trial (Interventional Management of Stroke [IMS]) have been reported.41 Among 62 patients with a baseline NIHSS score of 10 or more entered into the IMS study, 44 (71%) required both IV (0.6 mg/kg) and IA t-PA. The six symptomatic brain hemorrhages in the group receiving IV-IA combination therapy was 6.3%. A good outcome was achieved in 56% of patients younger than 80 years who received combination therapy, compared with 36% of patients with a baseline NIHSS score of 10 or higher who received IV t-PA alone in the NINDS t-PA Stroke Trial, and 40% in the PROACT II patients receiving IA r-proUK alone. Combined IV and IA stroke thrombolysis is still being investigated in the ongoing NIH-supported third Interventional Management of Stroke Study II (IMS3).


Recanalization of Acute Internal Carotid Occlusion ICA occlusion with distal embolization to the MCA is a common cause of acute stroke. The recanalization rate after IV thrombolytics for large vessel occlusions such as the ICA is generally poor.36,42-45 Several studies have shown higher mortality and morbidity rates for strokes secondary to large vessel occlusion.36,42-45 Jansen et al42 evaluated the role of early thrombolytics in treating acute carotid occlusion. This study enrolled 32 patients with a mean age of 56 years who were treated with IV alteplase (16), IA alteplase (8), and IA urokinase (8). Recanalization was achieved in only 12.5% of patients, and good clinical outcome was observed in only 16%; 53% had a fatal outcome. None of the therapies— IV or IA alteplase, IA urokinase—was able improve the recanalization rate or clinical prognosis.42 Zaidat et al46 reviewed a small series of 18 patients with distal ICA occlusion who were treated with either IA or combined IA-IV thrombolytic therapy. This study showed a higher recanalization rate with combined therapy (82%) than with IV therapy alone (62%) but no difference in the intracranial hemorrhage rate (20% versus 15%, respectively) or improvement in NIHSS score. This study also showed that time to treatment was the most powerful predictor of response to thrombolytic therapy (P < .001). Thrombolytics were least effective in patients with carotid T segment occlusion. Flint et al47 reviewed the data from the MERCI trial to evaluate the efficacy of mechanical thrombectomy in patients with acute carotid occlusion. Eighty patients with ICA occlusion (mean age 67 years, mean NIHSS score 20, mean time from stroke onset to treatment 4.1 hours) were treated with mechanical thrombectomy. Recanalization with the Merci retriever alone was successful in 53% of patients, and 63% underwent ICA recanalization with Merci retriever plus adjunctive endovascular treatment. Good clinical outcome (mRS ≤ 2 at 90 days) was seen in 39% (19/49 patients) after successful recanalization, but in only 3 of 30 patients without successful recanalization (P < .001). Patients with successful recanalization had a lower 90-day mortality rate, 30% (15/50), versus 73% (22/30) in the nonrecanalized group (P < .001). This pooled analysis was able to show that mechanical thrombectomy in combination with other endovascular approaches improved the recanalization rate and clinical outcome in patients with internal carotid occlusion.47 Jovin et al48 evaluated the role of emergency stenting in patients with acute stroke secondary to extracranial carotid artery occlusion. This study retrospectively reviewed 25 patients (mean age 62 years, median NIHSS score 14), of whom 15 presented within 6 hours of stroke symptom onset and 10 had fluctuating symptoms secondary to ICA occlusion. Twenty-three patients (92%) underwent recanalization by emergence stenting with only 2 clinically insignificant adverse events (1 asymptomatic ICH and 1 non–flow-limiting dissection). This study suggested that emergence stenting can be a treatment option in patients who present with stroke secondary to ICA occlusion.48 Acute stenting has also been proposed for MCA occlusion.49

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“Wake Up” Stroke Nogueira et al50 presented preliminary data from the DAWN (DWI/PWI [diffusion/perfusion-weighted imaging] and CTP [CT perfusion] Assessment in the triage of Wake-up and late-presenting strokes undergoing Neurointervention) trial. DAWN is a multicenter RCT that is evaluating the role of acute interventions based on imaging in treating stroke patients who present more than 8 hours after stroke symptom onset. The inclusion criteria for DAWN are a witnessed or nonwitnessed stroke in a patient who was last seen to be normal between 7 and 23 hours earlier, NIHSS score higher than 10, and MRI or angiography findings demonstrating a large vessel occlusion. DAWN requires perfusion imaging with an Albert Stroke Programme Early CT Score (ASPECTS) of 7 or higher on CT perfusion cerebral blood volume maps or a 20% mismatch on MRI. The acute intervention is at the discretion of the neurointerventionalist. The preliminary study evaluated 193 patients (mean age 64 years, NIHSS score 15, mean time from last seen well 16.3 hours) who were treated for large vessel occlusion: M1 segment of the MCA, 94 patients (49%); M2 segment of the MCA, 19 patients (10%); ICA, 43 patients (22%); and tandem ICA origin/MCA, 25 patients (13%). Multimodality acute interventions were performed to treat these patients with large vessel occlusions: IAT in 92 patients (48%), Merci retriever in 110 patients (57%), and other mechanical modalities in 56 patients (29%). Successful recanalization (TIMI grade 2 or 3) was achieved in 73% of patients (141). Long-term outcomes were available for 151 patients, of whom 45.7% had good outcome and 60.9% had acceptable outcome. The rates of ICH and mortality were 10.3% and 22.2%, respectively. DAWN showed direct significant correlation of favorable outcomes with age (OR, 0.96; 95% CI, 0.93–0.99; P = .026), time to treatment (OR, 1.11; 95% CI, 1.01– 1.21; P = .019), and successful recanalization (OR, 3.21; 95% CI, 1.21– 8.51; P = 0.018).

Vertebrobasilar Intraarterial Thrombolysis The natural history of basilar occlusion is extremely poor, with mortality rates ranging from 83% to 91%.3,47 Because of this poor natural history, IAT has been preferred in patients with acute basilar artery occlusion. Approximately 278 cases have been reported, with an overall basilar recanalization rate of 60%. Basilar artery occlusions have a high incidence of residual stenosis, which often requires adjuvant therapies such as angioplasty and antithrombotic and antiplatelet treatments. In a compilation of reported cases of vertebrobasilar thrombolysis, the mortality in patients in whom recanalization was not achieved was 90%, compared with 31% in patients in whom at least partial reperfusion was achieved. Good outcomes are strongly associated with recanalization after thrombolytic therapy. The majority of patients with successful vertebrobasilar recanalization had mild or moderate disability, compared with less than 14% of patients whose vessels remained occluded.51 Success of recanalization depends on the location of the vertebrobasilar occlusion. Distal occlusions have

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higher recanalization rates than proximal occlusions. Emboli, which often lodge in the distal basilar artery, are easier to lyse than atherosclerosis-related thrombi, the usual cause of proximal basilar occlusions.5,46 Short segment occlusions are easier to lyse than longer segment occlusions.46 Patients who are younger have higher recanalization rates,52,53 probably because they have a higher incidence of embolic occlusion. The time window for thrombolysis may be longer in the posterior circulation. The presence of coma or tetraparesis for several hours portends poor prognosis despite recanalization. However, prolonged vertebrobasilar occlusion symptoms do not preclude survival and recovery. Many series have included patients not treated until 24,3,54 48,46,55 or even 72 hours after symptom onset,3,52 or patients with prolonged, stuttering courses.56,57 An association between time to treatment and outcome has been suggested,58 but other series do not support the finding.46,59 This great variability makes it difficult to predict the timing and outcome of thrombolysis in the vertebrobasilar circulation. Patients with vertebrobasilar artery occlusion often have chronic atherothrombotic disease, which allows collateral vessels to develop over time. As hypothesized by Cross et al,52 there may be two distinct populations of patients with vertebrobasilar occlusion. Paradoxically, patients with a progressive stuttering course may have better collateral circulation and better outcome after IAT despite later treatment than patients with sudden onset of a severe deficit but with poor collateral vessels, who may actually be brought to treatment earlier. Despite the apparently longer time window, the rate of hemorrhagic transformation after vertebrobasilar thrombolysis appears lower than anterior circulation thrombolysis. The average rate of symptomatic brain hemorrhage after vertebrobasilar IAT is 6.5%, compared with 8.3% for IAT in the anterior circulation. A lower rate of hemorrhagic transformation after vertebrobasilar thrombolysis may be due to higher ischemic tolerance in the posterior circulation, improved collateral circulation, or an increased density of white matter tracts.60 There is no clear association between hemorrhage risk and time to treatment,52 although 3 of the 18 symptomatic hemorrhages reported in the literature occurred when thrombolysis was initiated more than 48 hours after symptom onset.3,59 Some investigators believe that patients with CT evidence of brainstem infarction are not candidates for thrombolytic therapy,3,46 but other researchers have found no correlation between this finding and neurologic outcome.52,59 In two separate series, none of the patients who had CT evidence of ischemia had hemorrhage. However, because of the experience in the anterior circulation, caution should be used when one is considering vertebrobasilar thrombolysis in patients in whom CT reveals signs of early infarction.

Risk Factors for Hemorrhagic Transformation Several series have found no relationship between recanalization and hemorrhage risk.61-63 However, these series do not address delayed recanalization or the status of recanalization at the time of brain hemorrhage.64

The amount of ischemic damage is a key factor in the development of hemorrhage after thrombolysis. Early extensive CT changes and severity of the initial neurologic deficit, both indicators of the extent of ischemic damage, are the best predictors of risk of hemorrhagic transformation (Fig. 62-2).63,65 In ECASS I,18 early CT changes in more than one third of the MCA territory correlated well with the frequency of hemorrhagic infarction. However, the socalled ECASS CT criterion is not present in all cases of hemorrhage, and there is considerable inter-reader variability in the interpretation of early CT changes. Furthermore, extensive early CT changes by themselves may be insufficient to exclude thrombolysis in specific patients.66,67 An analysis of the PROACT II data indicates that patients with early (i.e., < 6 hours) CT infarct volumes greater than 100 mL do poorly.68 However, estimated early CT changes (i.e., ECASS CT criterion) appear less predictive of outcome among homogeneous patients with MCA occlusion than in patients with mixed sites of arterial occlusion.69 Furthermore, time may also be a key factor in interpreting early CT changes. In the NINDS trial, patients with early CT changes still benefited from t-PA administration, perhaps because of the earlier treatment time window.63 Given the somewhat conflicting data, it would be prudent either (1) to avoid thrombolysis in patients with clear-cut and extensive early signs of infarction on CT and a NIHSS score higher than 20, especially those older than 75 years, or (2) to emphasize to the family of such a patient that the benefit-risk ratio is greatly reduced even if treatment is begun within 3 hours of onset. The amount of ischemic damage depends on the duration of occlusion and the amount of collateral blood flow. Both of these factors have been associated with increased risk of hemorrhage.61,63,70 Ueda et al70 found that the amount of residual blood flow, as determined by singlephoton emission CT (SPECT), was associated with hemorrhagic transformation, but they also used results of this assessment to extend the thrombolytic time window beyond 6 hours in three patients. Improved perfusion after 3 hours of IV r-tPA has also been demonstrated with single-photon emission CT.71 Other factors that have been associated with hemorrhage after thrombolysis for both stroke and myocardial infarction (MI) are thrombolytic dose,62,72 blood pressure,73,74 advanced age, prior head injury,63,75,76 and blood glucose level.64 Age was the most important risk factor in one of the largest series of thrombolysis-related ICH. Because of the increased risk in elderly patients, an upper age limit was initially instituted for patients being considered for coronary thrombolysis. Older patients with myocardial infarction were found to benefit from treatment, however, and the generally accepted age limit has been raised. A strong relationship between advanced age and hemorrhage was also demonstrated in the NINDS study and ECASS. Although there is no strict age cutoff, physicians must take into account the greater risk of hemorrhage in patients 75 years and older when choosing to administer thrombolysis for stroke. ICH after thrombolysis for stroke can occur at sites distant from the ischemic region.34 Cerebral amyloid angiopathy has been implicated as a causative factor in brain hemorrhages after thrombolysis for myocardial


A

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B

Figure 62-2 Early infarct signs on CT scans from a 67-year-old man with acute right hemiplegia and aphasia, National Institutes of Health

Stroke Scale (NIHSS) score 22, and internal carotid artery occlusion. A, Initial CT scan obtained 4 hours after stroke onset shows sulcal effacement, loss of gray-white matter distinction, and loss of insular ribbon in more than one third of the left middle cerebral artery territory (European Cooperative Acute Stroke Study [ECASS] CT criteria). B, Second CT scan obtained at 25 hours shows massive left cerebral and right anterior cerebral artery infarcts.

infarction.77 Amyloid angiopathy is a well known cause of spontaneous hemorrhage in the elderly and is associated with dementia of the Alzheimer’s type. Hence, thrombolytic therapy in elderly demented patients may carry a particularly high risk of brain hemorrhage. Hemorrhage into an arteriovenous malformation and unsuspected ischemic infarction have also been reported as causes of ICH after thrombolysis.77

Other Factors Affecting Outcomes with Thrombolysis Hacke78 has described the ideal candidate for thrombolysis as follows: a young person with good collateral circulation who has an MCA occlusion distal to the lenticulostriates due to a fresh fibrin-rich thrombus that passed through a patent foramen ovale. The presence of collateral flow is one of the primary determinants of outcome.79,80 Good leptomeningeal collaterals may limit the extent of ischemic damage and prolong the therapeutic window. Good collateral flow is also associated with higher rates of reperfusion, presumably because it allows a greater amount of thrombolytic agent to reach the clot. Clot composition is a neglected factor in recanalization success rates.81 Fresh thrombi, which are rich in fibrin and plasminogen, are easier to lyse than aged atherothrombi, which are more organized and have low fibrin and plasminogen contents and high amounts of platelets and cholesterol. Fresh cardiac emboli may therefore respond better to thrombolysis than atherothrombotic occlusion or calcific embolism.

Angiographic studies indicate that about 20% of patients presenting with a clinical picture consistent with acute ischemic stroke have no visible arterial occlusion.34 There is controversy regarding the utility of thrombolysis in patients who have no large vessel occlusion.82 The NINDS trial suggested a benefit of t-PA in patients with small vessel (i.e., lacunar) infarction, and it is possible that thrombolytic therapy may be effective in the recanalization of small vessels that are invisible on angiography. A meta-analysis of thrombolytic trials found no significant differences between results of studies that included patients with lacunar strokes and those of studies that excluded such patients.83

New Endovascular Therapies for Acute Stroke The technique used in IAT, unlike with IV administration, may be critical in achieving success and varies among interventionists. Direct intrathrombus delivery of thrombolytic agent is preferred over regional infusion. However, the infusion process has been variable, ranging from continuous to pulsed infusion both with and without bolus administration. In some series, clot disruption by the microcatheter has been included in the protocol, theoretically to improve exposure of the thrombus to the thrombolytic agent and thereby speed clot lysis. Mechanical clot manipulation was prohibited in PROACT I and PROACT II. In some series, IAT was followed by percutaneous transluminal angioplasty (PTA) of the recanalized vessel.84,85 To date, however, no prospective comparison

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of any of these techniques has been conducted, so their relative merits remain unclear. Several new interventional neuroradiologic techniques designed to improve the speed and completeness of recanalization in acute ischemic stroke have been described. These reports have all been individual case series from single institutions. The techniques include treatment of acute ischemic stroke by direct mechanical balloon angioplasty of the thrombus,85-88 mechanical snaring of clot from the MCAs,89 intravascular stenting of underlying occlusive atherosclerosis for restoring vessel patency,90 use of suction thrombectomy devices for establishing reperfusion, laser-assisted thrombolysis of acute emboli to the brain, and power-assisted Doppler ultrasound thrombolysis.91 As previously described, intravenous and intraarterial GP IIb/IIIa inhibitors have also been used to enhance the effects of clot lysis during acute stroke.12,15,16,92 These new technologies are in early feasibility and safety trials in both the United States and Europe and are still investigational. Phase 3 randomized controlled clinical trials must be performed before specific recommendations as to the safety and efficacy of any of these methods can be made.

Current Status of Intraarterial Thrombolysis and Need for More Evidence The fourth issue of the Cochrane Database of Systematic Reviews meta-analysis, which included data from PROACT I and PROACT II, concluded that overall, the risks of thrombolysis are offset by reductions in dependent survival, so that significantly more patients are alive and independent after treatment. Writers of this meta-analysis suggested, “The time window might extend to, or even beyond, six hours in selected patients.”93 On the basis of this available evidence, the Second American Heart Association International Evidence Evaluation Conference made a “major guideline change”94; IAT given within 3 to 6 hours after the onset of stroke symptoms is now a class IIb recommendation (acceptable, clinically useful, alternative or optional treatment supported by good evidence). IAT has also been endorsed by other major medical societies. Intraarterial stroke thrombolysis using clot retrieval devices is currently being performed routinely at most comprehensive stroke centers worldwide (Fig. 62-3). In the United States, the Merci retriever was used in 2300 ischemic stroke interventions in 2006, and the total number of IA ischemic stroke interventions was estimated to range from 3500 to 7200.95 Estimates of the potential annual number of IA stroke interventions in the United States alone range from 10,400 to 41,500, and comprehensive stroke centers use a clot retrieval device in approximately 65% of IA interventions. Importantly, although IA stroke intervention typically begins with mechanical clot retrieval, it frequently incorporates thrombolytic agents, antithrombotics, and platelet inhibition. As a result, there are no standard IA protocols or even standard criteria for device selection, and it is routine to make interventional decisions “on the table.” This fact reflects the complex technical heterogeneity of acute stroke arterial recanalization and further complicates the design of any potential RCTs.

There is a long history of surgical procedures being done without any RCT data whatsoever.96 At least for IA stroke thrombolysis, we have one phase 3 RCT demonstrating proof of principle and clinical efficacy.9 Of course the irony is that PROACT II used an unapproved drug (r-proUK) and specifically prohibited mechanical clot manipulation. The evolution of interventional neuroradiology has now introduced a new “twilight zone” of approved but unproven stroke clot retrieval devices. Both the Merci device and the Penumbra System were approved by the FDA and CMS without an RCT or definitive evidence of clinical efficacy.97 The ethics of performing IAT both outside and within a clinical trial have been extensively debated.98-100 Considering that the criteria for FDA approval were “safety and efficacy” and for CMS reimbursement “reasonable and necessary,” the use of stroke clot retrieval devices (in the USA) is not only legal but also ethical outside of a RCT. A compelling case can also be made that universal collective equipoise does not exist regarding IAT. U.S. Institutional Review Boards have required the inclusion of the availability of stroke clot retrieval devices in informed consents. This requirement further complicates recruitment into RCTs—the subtleties of clot retrieval versus an improved mRS at 90 days are likely to be lost on patients and families in the throes of dealing with an acute stroke. In the United States, ethics are conflated by CMS hospital reimbursement policies for IA stroke thrombolysis. CMS policies and off-label use of devices have posed tremendous recruitment barriers for RCTs.101 Another controversy relates to who should perform acute ischemic stroke interventions. Training and credentialing criteria have been published that have implications for vetting in RCTs.102 Certainly, clot retrieval devices have different technical training requirements from those of “simple” IAT. The need for more data is a separate issue from whether usage of clot retrieval devices or IAT should be restricted to clinical trials. The painfully slow recruitment in both the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) study and Interventional Management of Stroke Study III (IMS3) indicates how difficult such RCTs are to complete. Recruitment enthusiasm may depend on the clinical trial. For example, IMS3 has no competing trials and avoids the contentious issue of a “placebo.” Ten years after PROACT II, what question do we really want to answer? Is it simply “Does IA thrombolysis work?” or has it evolved to “On which patients does it work?” It is not widely known that 10 years ago the FDA approved a protocol for PROACT III with a sample size of 450—why wasn’t it done? The issues became cost, the ethics of a “placebo” control, recruitment, and, ultimately, feasibility. Indeed, the task became so daunting that the study’s funder, Abbott Laboratories, eventually abandoned the entire arena of stroke thrombolysis. In negotiations with Concentric Medical over the Merci retriever, at least one source reports that the FDA admitted another RCT like PROACT II was not feasible.103 At a minimum, this suggests that any additional IAT RCT will require international academic-industry collaboration and a novel design. In addition to recruitment, a major challenge for any new IAT RCT will be to tackle not only the technical


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Acute MCA syndrome NIHSS 4–30 –CT blood Risk stratification Cytoprotection

0–3 hrs

>3 hrs

3–6 hrs

+HDMCA

–HDMCA

IAT

IV t-PA 0.6 mg/kg

IV t-PA 0.9 mg/kg

+NIT

–NIT

IAT

IV t-PA 0.6 mg/kg

NIHSS 8–30 ANGIO

NIHSS 8–30 +NIT

+DW/ PWMR

–DW/ PWMR

MCA M1/M2

ANGIO

?? IAT or IVT

No thrombolysis

IAT Low-dose heparin

MCA M1/M2

IAT Low-dose heparin Key NINDS IV t-PA regimen PROACT II IA regimen

Figure 62-3 Potential treatment algorithm for acute middle cerebral artery syndrome. Plus sign indicates positive results, and minus sign negative results, of each test. ANGIO, angiography; DW/PWMR, diffusion/perfusion mismatch on MRI of the brain; ECASS, European Cooperative Acute Stroke Study; HDMCA, hyperdense middle cerebral artery; IAT, intraarterial thrombolysis; IV, intravenous; IVT, intravenous thrombolysis; NIHSS, National Institutes of Health Stroke (scale); NIT, noninvasive test; PROACT, Prolyse in Acute Cerebral Thromboembolism study; tPA, tissue-type plasminogen activator.

but also the physiologic heterogeneity of acute ischemic stroke. Recent mismatch imaging–based RCTs—such as the Desmoteplase in Acute Ischemic Stroke phase 2 (DIAS-2) study, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study, and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)—highlight the fact that acute ischemic stroke is even more physiologically heterogeneous than we thought.104,105 Unfortunately, from the pharmaceutical/medical device industry’s perspective, such heterogeneity reduces the potential market and increases the cost of an RCT. Nonetheless, in our view and the placebo issue aside, an IAT RCT that does not adequately account for stroke heterogeneity (both technical and physiologic) either will require a huge (and therefore not feasible) sample size or will be doomed to failure. Should we therefore put a moratorium on stroke clot retrieval devices and IAT and restrict their use to clinical trials? Aside from the fact that in the United States such restricted usage would not be legal, a “yes” answer exposes the conflict between academic altruism and a certain stroke realpolitik. So our answer to this question

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INTRAARTERIAL THROMBOLYSIS IN ACUTE ISCHEMIC STROKE 49. L evy E, Siddiqui A, Crumlish A, et al: First Food and Drug Administration-Approved Prospective Trial of Primary Intracranial Stenting for Acute Stroke, SARIS (Stent-Assisted Recanalization in Acute Ischemic Stroke), Stroke 40:3552–3556, 2009. 50. Nogueira R, Liebeskind D, Gupta R, et al: Preliminary data for the DAWN trial (DWI/PWI and CTP assessment in the triage of wakeup and late presenting strokes undergoing neurointervention): Imaging based endovascular therapy for proximal anterior circulation occlusions beyond 8 h from last seen well in 193 stroke patients. SNIS Annual Meeting oral abstracts, J NeuroInterv Surg 1:85, 2009. 51. K atzan IL, Furlan AJ: Thrombolytic therapy. In Fisher M, Bogousslavsky J, editors: Current review of cerebrovascular disease, ed 3, Boston, 1999, Butterworth Heinemann, pp 185–193. 52. Cross DT, Moran CJ, Akins P, et al: Relationship between clot location and outcome after basilar artery thrombolysis, AJNR Am J Neuroradiol 18:1221–1228, 1997. 53. Huemer M, Niederwieser V, Ladurner G: Thrombolytic treatment for acute occlusion of the basilar artery, J Neurol Neurosurg Psychiatry 58:227–228, 1995. 54. Matsumoto K, Satoh K, et al: Intra-arterial therapy in acute ischemic stroke. In Yamaguchi T, Mori E, Minematsu K, editors: Thrombolytic therapy in acute ischemic stroke III, Tokyo, 1995, Springer-Verlag, pp 279–287. 55. Clark W, Barnwell S, Nesbit G, et al: Efficacy of intra-arterial thrombolysis of basilar artery stroke [abstract], J Stroke Cerebrovasc Dis 6:457, 1997. 56. Wijdicks EF, Nichols DA, Thielen KR, et al: Intra-arterial thrombolysis in acute basilar artery thromboembolisms: The initial Mayo Clinic experience, Mayo Clin Proc 72:1005–1013, 1997. 57. Herderschee D, Limburg M, Hijdra A, et al: Recombinant tissue plasminogen activator in two patients with basilar artery occlusion, J Neurol Neurosurg Psychiatry 54:71–73, 1991. 58. Zeumer H, Freitag HJ, Grzyska U, et al: Local intra-arterial fibrinolysis in acute vertebrobasilar occlusion, Neuroradiology 31: 336–340, 1989. 59. Becker KJ, Monsein LH, Ulatowski J, et al: Intra-arterial thrombolysis in vertebrobasilar occlusion, AJNR Am J Neuroradiol 17:255–262, 1996. 60. Becker KJ, Purcell LL, Hacke W, et al: Vertebrobasilar thrombosis: Diagnosis, management, and the use of intra-arterial thrombolytics, Crit Care Med 24:1729–1742, 1996. 61. von Kummer R, Hacke W: Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery stroke, Stroke 23:646–652, 1992. 62. Mori E, Yoneda Y, Tabuchi M, et al: Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke, Neurology 42:976–982, 1992. 63. L evy DE, Brott TG, Haley EC, et al: Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke, Stroke 25:291–297, 1994. 64. K ase CS, Furlan AJ, Wechsler LR, et al: Hemorrhage after intraarterial thrombolysis for ischemic stroke: The PROACT II Trial, Neurology 57:1603–1610, 2001. 65. Bozzao L, Angeloni U, Bastianello S, et al: Early angiographic and CT findings in patients with hemorrhagic infarction in the distribution of the middle cerebral artery, AJNR Am J Neuroradiol 12:1115–1121, 1991. 66. Grotta JC, Choi D, Patel SC, et al: Agreement and variability in the interpretation of early CT changes in stroke patients qualifying for intravenous tPA therapy, Stroke 30:1528–1533, 1999. 67. Patel SC, Levine SR, Tilley JC, et al: Lack of clinical significance of early ischemic changes on computed tomography in acute stroke, JAMA 286:2830–2838, 2001. 68. Roberts HC, Dillon WP, Furlan AJ, et al: Angiographic collaterals in acute stroke—relationship to clinical presentation and outcome: The PROACT II trial [abstract], Stroke 32:336, 2001. 69. K idwell CS, Saver JL, Duckwiler G, et al: Predictors of hemorrhagic transformation following intra-arterial thrombolysis [abstract], Stroke 32:319, 2001. 70. Ueda T, Hatakeyama T, Kumon Y, et al: Evaluation of risk of hemorrhagic transformation in local intra-arterial thrombolysis in acute ischemic stroke by initial SPECT, Stroke 25:298–303, 1994.

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71. A lexandrov AV, Bratina P, Grotta JC: tPA associated reperfusion after acute stroke demonstrated by HMPAO-SPECT [abstract], Stroke 7:101–104, 1998. 72. Gore JM, Sloan M, Price TR, et al: Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study: Thrombolysis in Myocardial Infarction, Phase II, Pilot and Clinical Trial, Circulation 83:448–459, 1991. 73. Selker HP, Beshansky JR, Schmid CH, et al: Presenting pulse pressure predicts thrombolytic therapy-related intracranial hemorrhage. Thrombolytic Predictive Instrument (TPI) Project Results, Circulation 90:1657–1661, 1994. 74. Simoons ML, Maggioni AP, Knatterud G, et al: Individual risk assessment for intracranial haemorrhage during thrombolytic therapy, Lancet 342:1523–1528, 1993. 75. Gebel JM, Sila CA, Sloan MA, et al: Thrombolysis-related intracranial hemorrhage: A radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation, Stroke 29:563–569, 1998. 76. Larrue V, von Kummer R, del Zoppo G, et al: Hemorrhagic transformation in acute ischemic stroke, potential contributing factors in the European Cooperative Acute Stroke Study, Stroke 28: 957–960, 1997. 77. Sloan MA, Price TR, Petito CK, et al: Clinical features and pathogenesis of intracerebral hemorrhage after rt-PA and heparin therapy for acute myocardial infarction: The Thrombolysis in Myocardial Infarction (TIMI) II pilot and randomized clinical trial combined experience, Neurology 45:649–658, 1995. 78. Hacke W: Thrombolysis: Stroke subtype and embolus type. In del Zoppo GJ, Mori E, Hacke W, editors: Thrombolytic therapy in acute ischemic stroke II, Berlin, 1993, Springer-Verlag, pp 153–159. 79. von Kummer R, Holle R, Rosin L, et al: Does arterial recanalization improve outcome in carotid territory stroke? Stroke 26:581– 587, 1995. 80. R ingelstein EB, Biniek R, Weiler C, et al: Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization, Neurology 42: 289–298, 1991. 81. Chimowitz M, Pessin M, Furlan A, et al: The effect of source of cerebral embolus on susceptibility to thrombolysis [abstract], Neurology 44(Suppl 2):A356, 1994. 82. Caplan LR, Mohr JP, Kistler JP, Koroshetz W: Thrombolysis—not a panacea for ischemic stroke, N Engl J Med 337:1309, 1997. 83. Wardlaw JM, Warlow CP, Counsell C: Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke, Lancet 350:607–614, 1997. 84. Gönner F, Remonda L, Mattle H, et al: Local intra-arterial thrombolysis in acute ischemic stroke, Stroke 29:1894–1900, 1998. 85. Ueda T, Sakaki S, Nochide I, et al: Angioplasty after intra-arterial thrombolysis for acute occlusion of intracranial arteries, Stroke 29:2568–2574, 1998. 86. 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 21:249–254, 2000. 87. Nakayama T, Tanaka K, Kaneko M, et al: Thrombolysis and angioplasty for acute occlusion of intracranial vertebrobasilar arteries: Report of three cases, J Neurosurg 88:919–922, 1998. 88. Tsai FY, Berberaj B, Matovich V, et al: Percutaneous transluminal angioplasty adjunct to thrombolysis for acute middle cerebral artery rethrombosis, AJNR Am J Neuroradiol 15:1823–1829, 1994. 89. Chopko BW, Kerber C, Wong W, et al: Transcatheter snare removal of acute middle cerebral artery thromboembolism: Technical case report, Neurosurgery 40:1529–1531, 2000. 90. 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 44:667–673, 1999. 91. A lexandrov AV, Demchuk AM, Felberg RA, et al: High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial Doppler monitoring, Stroke 31:610–614, 2000. 92. Lempert TE, Halbach VV, Malek AM, et al: Rescue treatment of acute parent vessel thrombosis with glycoprotein IIb/IIIa inhibitor during GDC coil embolization, Stroke 30:693–695, 1999.

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93. Cochrane Database Syst Rev (4), 1999. 94. Emergency interventional stroke therapy: A statement from the American Society of Interventional and Therapeutic Neuroradiology and Society of Cardiovascular and Interventional Radiology, Am J Neuroradiol 22:54, 2001. 95. H irsch JA, Yoo AJ, Nogueira RG, et al: Case volumes of intraarterial and intravenous treatment of ischemic stroke in the USA, J NeuroInterv Surg 1:27–31, 2009. 96. Spodick DH: Numerators without denominators: There is no FDA for the surgeon, JAMA 232:35–36, 1975. 97. Furlan AJ, Fisher M: Devices, drugs, and the Food and Drug Administration: Increasing implications for ischemic stroke, Stroke 36:398–399, 2005. 98. Furlan AJ: Ethics and feasibility of placebo-controlled interventional acute stroke trials, Stroke 49:e533–e534, 2009. 99. Köhrmann M, Schwab S: Response to letter by Furlan, Stroke. Published online before print, July 23, 2009.

100. Grotta J, Barreto: A response to letters by Furlan, and Kohrmann and Schwab, Stroke. Published online before print July 23, 2009. 101. Off label practices plague circulatory system device randomized trials. The FDC Reports. The Gray Sheet. Vol 30, May 17, 2004. 102. Meyers PM, Schumacher HC, Alexander MJ, et al: Performance and training standards for endovascular ischemic stroke treatment, J NeuroInterv Surg 1:10–12, 2009. 103. Levin S: Concentric Medical: Breaking the stroke device barrier. In Vivo: The Business and Medicine Report, Vol 18, No 9, 2004. 104. L iebeskind DS: Reversing stroke in the 2010s. Lessons from Desmoteplase in Acute Ischemic Stroke-2 (DIAS-2), Stroke 40: 3156–3158, 2009. 105. Soares BP, Chien JD, Wintermark M: MR and CT monitoring of recanalization, reperfusion, and penumbra salvage: Everything that recanalizes does not necessarily reperfuse! Stroke 40: S24–S27, 2009.

63

Endovascular Treatment of Cerebral Aneurysms AJAY K. WAKHLOO, MATTHEW J. GOUNIS, MICHAEL J. DE LEO III

T

he field of endovascular surgical neuroradiology has emerged in the past few decades to provide safe and effective options for the treatment of intracranial aneurysms.The primary goal of aneurysm treatment, regardless of the means, is to prevent rupture or rerupture. Before endovascular techniques were developed, craniotomy with clip placement was the only definitive treatment for both ruptured and unruptured aneurysms. But as imaging and device technologies improved, endovascular approaches to intracranial aneurysms became widely available, especially for patients for whom surgery posed high risks. The first endovascular intracranial aneurysm occlusion was attempted in 1964 by Luessenhop and Velasquez.1 Though technically unsuccessful, this ground-breaking procedure provided a fundamental shift in the approach to treating intracranial disease. Contemporaries of Lussenhop and Velasquez investigated other technologies for aneurysm occlusion such as metallic2 and electric current thrombosis.3,4 However, the work of Fedor Serbinenko in Cold War–era Soviet Russia revolutionized this new field. Inspired by the sight of tethered helium balloons at a 1959 May Day celebration in Moscow’s Red Square,5 Serbinenko pioneered development of the first flowguided intraluminal balloon catheter.6 Not long after he performed the first therapeutic vessel occlusion in 1970, Serbinenko used a detachable balloon catheter to embolize an intracranial aneurysm.7 Widespread news of Serbinenko’s innovations at the Burdenko Neurosurgery Institute reached the West in 1974, when he summarized his experiences in English in the Journal of Neurosurgery.8 Serbinenko’s techniques immediately attracted curious minds from around the world. Among the pilgrims was Gerard Debrun, the French neuroradiologist who developed a latex balloon occlusion device.9 The detachable balloon method of aneurysm embolization underwent a period of growth over the next 15 years in the hands of numerous investigators.10-12 However, detachable balloon embolization was not without complications. For example, a detached balloon could act as a ball-valve within an aneurysm sac, leading to rapid aneurysm filling and rupture. Furthermore, the balloons would not appropriately appose to the aneurysm boundaries, resulting in dislodgement or suboptimal aneurysm occlusion. The detachable platinum coil, introduced in the 1990s, was developed to overcome the deficiencies of detachable

balloons and represented another fundamental shift in the neurointerventional treatment of intracranial aneurysms. When tightly packed into the aneurysmal sac, the coil mass prevented blood flow into the aneurysm, initiating intraaneurysmal clotting.13,14 Within days of coil embolization, macrophages and fibroblasts infiltrated into the dome of the aneurysm as endothelial cells began to proliferate across the neck. The long-term histopathologic findings showed that coil embolization promoted a vascularized fibrous connective tissue scar within the aneurysm dome and complete endothelialization of the neck.15-17 Early experiences with platinum coils revealed that they were difficult to control and that deployment of the coil within the aneurysm sac was unreliable. However, in 1991, Guido Guglielmi published two pivotal articles describing a novel electrolytic coil detachment technique from a stainless steel wire.18,19 Initial use of Guglielmi detachable coils (GDCs) in 15 patients demonstrated excellent aneurysm occlusion (70% to 100%).19 Periprocedural complications were limited to a single case of transient aphasia. The first multicenter trial of GDC treatment in 43 posterior circulation aneurysms showed a 7% combined morbidity and mortality, notably better than the 20% combined rate in reports of similarly sized trials that used detachable balloons.20,21

Endovascular Treatment of Ruptured Aneurysms: Evidence Without treatment, patients with aneurysmal subarachnoid hemorrhage (SAH) have a 19% risk of rebleeding within 2 weeks22 and a greater than 3% annual risk thereafter.23 Thus, isolating the aneurysm (i.e., the rupture site) from the circulation is the primary goal of treatment. Although endovascular embolization techniques found widespread use in the early 1990s, there was a lack of data comparing surgery with intervention. The International Subarachnoid Aneurysm Trial (ISAT) was the first large-scale prospective randomized trial to compare the safety and efficacy of endovascular coiling with surgical clipping for treatment of ruptured aneurysms.24 The primary endpoints of this international study were dependency and death at 1 year following treatment. Patient enrollment began in 1994 and was stopped in 2002 after 2143 patients had been randomly assigned to treatments because of significant freedom from death and disability in the endovascular group (22.6% relative risk reduction, 1241

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Cumulative percentage

25 20 Neurosurgery

15 10

Endovascular

5 Log-rank P = 0.03 0 0

12

24

36

48

60

72

84

215(6) 192(3)

103 98

Time since randomization (months) Annual number at risk (deaths): Endovascular 1073(85) 974(3) 887(5) Neurosurgery 1070(105) 944(10) 842(16)

717(8) 663(3)

541(4) 503(3)

373(5) 340(7)

Figure 63-1 Kaplan-Meier graph of cumulative mortality from the surgical and endovascular cohorts of the International Subarachnoid

Aneurysm Trial up to 7 years. (From Molyneux AJ, Kerr RS, Yu LM, et al: International subarachnoid aneurysm trial [ISAT] of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 366:809-817, 2005.)

6.9% absolute risk reduction). One year after treatment, the absolute risk reduction was 7.4% in the endovascular group in comparison with the clipping group, and the survival advantage continued for 7 years (Fig. 63-1).25 The ISAT demonstrated that coil embolization was superior in safety profile to surgical clipping for the treatment of ruptured aneurysms (Fig. 63-2). However, questions remained about the durability of aneurysm occlusion, that is, the efficacy of coils in preventing longterm rebleeding. Previous studies have demonstrated that angiographic follow-up is necessary after aneurysm treatment with detachable coils.26-28 Although there has been no widely accepted standard for defining recanalization, recanalization rates of aneurysms treated with detachable coils range from 4% to 60% depending on aneurysm size, neck width, and location.27,28 Recanalization may be associated with an increased risk of rebleeding in patients treated either endovascularly or surgically. The Cerebral Aneurysm Rerupture After Treatment (CARAT) study29,30 was an ambidirectional cohort study designed to compare rebleeding rates in 1001 patients with aneurysm rupture treated with either coil embolization or surgical clipping with an average of 3.6 years of follow-up. The total risk of rerupture after the initial treatment was 3.4% for coil embolization and 1.3% for surgical clipping.30 The rebleeding rate as a function of time from both treatments was reported to be 2.2% in the first year, 0.2% in the second year, and 0% thereafter. These findings were similar to those of the ISAT, which found an annual risk of rerupture 1 year after treatment to be 0.21% in the coiling group and 0.03% in the clipping group.25,31 In both the ISAT and the CARAT study, most rebleeds occurred in the first month after treatment. The latest ISAT analysis reports that with more than 8000 person-years of follow-up, aneurysms treated in the coiling and clipping arms rebled at a rate of 1.3% and 0.3%, respectively, after the first year (treatment received, P = .023).32 Although late rebleeding has been shown to be higher in the endovascular treatment arm

than the surgery arm, the ISAT investigators concluded the risk remains low and similar to the risk for SAH from either an existing or newly formed aneurysm. Longterm rebleeding rates were even lower in an impressive single-center experience of coil embolization of intracranial, berry aneurysms with 1810 patient-years of followup.33 This extensive experience from a Parisian hospital demonstrated that coiled aneurysms have a risk of early rebleeding of 0.94%, and only one case of late aneurysmal rebleed was observed (0.21%). Subsequent analysis by the CARAT investigators showed that the degree of initial aneurysm occlusion was the strongest predictor of rebleeding. Aneurysms that were completely occluded had a 1.1% risk of rebleeding, whereas the rebleeding risk was 17.6% for aneurysms with only partial initial occlusion.30 Although total occlusion was achieved in significantly more patients who underwent clipping (92%, compared with 39% with coiling), there were no cases of rerupture following early retreatment if deemed necessary. It should also be noted that retreatment of a previously embolized aneurysm is accompanied by low morbidity (1.1%) and low mortality (0%).33 These long-term data on the endovascular treatment of ruptured brain aneurysms confirm that risk of rebleeding from the treated aneurysms is extremely low and that patients have a good clinical outcome in comparison with surgical clipping. However, the recanalization rates have been the impetus for continuous developments in technologies to improve treatment durability. These technologies, which were not available during the ISAT trial, are discussed in subsequent sections.

Endovascular Treatment of Unruptured Aneurysms: Evidence The management of asymptomatic unruptured aneurysms is controversial.34-36 Primarily on the basis of the natural history data compiled by the International Study

ENDOVASCULAR TREATMENT OF CEREBRAL ANEURYSMS Risk ratio (95% Cl)

Number of events Endovascular Neurosurgery

1243

Test of interaction

Age (years) 15 (in nondominant-hemisphere infarction) or >20 (in dominanthemisphere infarction) Level of consciousness: score of ≥1 on item 1a of the NIHSS or 145 mL on DWI and/or >82 mL on apparent diffusion coefficient [ADC] maps (MRI)

Figure 78-1 Noncontrast CT scan of a patient with malignant left

middle cerebral artery (MCA) infarction plus infarction of the left posterior cerebral artery (PCA) 4 days after symptom onset under conservative treatment who died from transtentorial herniation.

buffers, hypothermia, osmotic therapy, steroids, and controlled hyperventilation.13,14 However, none of these therapies is supported by adequate evidence from randomized clinical trials of space-occupying cerebral ischemia.13-15 Several reports suggest that the measures are ineffective or even have harmful effects.13-20 There are various possible reasons why these therapies often fail or may even be detrimental. It has to be remembered that, for example, osmotic therapy is based on the presence of an intact blood-brain barrier, which, however, is largely disrupted in the infarct territory. From a pathophysiologic point of view, osmotic therapy is therefore of little value. ICP-lowering therapies are often used as escalating treatment options based on ICP measurement and are often not applied until increases of ICP are evident. However, in space-occupying ischemic stroke, early clinical deterioration is usually due not to increases of global ICP but to massive local swelling and brain tissue shifts. Increases of ICP usually occur late, when local mass effect has already led to severe compression and destruction of vital brain structures. Measurement of ICP therefore often does not help prevent these secondary complications, and herniation may occur even without previously increased global ICP. As a result, the value of therapies focusing on lowering ICP is limited and may come too late to be effective. Mild to moderate hypothermia is an exception and represents the most promising alternative treatment option, which, however, is currently not supported by evidence from larger clinical trials.21

In contrast to more complex pathophysiologic theories of conservative measures, decompressive surgery is based on pure mechanical thinking: The rationale of removing a part of the neurocranium is simply to create space for the expanding brain. The vector of brain extension is reverted from pressure on midline structures to extension into the newly created compensative spaces, thereby avoiding ventricular compression, reverting brain tissue shifts, and preventing mechanical damage of healthy brain tissue. Decreased ICP and, as a result, restored CBF is more or less a secondary effect, leading to increase in tissue oxygen supply and thereby avoiding secondary damage to the surrounding healthy tissue.22,23

Diagnosis Although the term malignant brain infarction was introduced in 1996, there is currently no generally accepted definition of this condition, especially in the early evaluation of patients with acute MCA infarction.5 The early prediction of a malignant course of the ischemic lesion would justify early and more aggressive intervention. On the other hand, the majority of patients who have acute MCA infarction do not experience a malignant course and probably do not profit from intensive care treatment or surgery and recover as well under conservative treatment. Currently the diagnosis of malignant brain infarction is based on (1) clinical neurologic findings, (2) a typical clinical course, and (3) neuroimaging findings (Table 78-1), as follows: 1. Clinically, patients with malignant MCA infarctions present with dense hemiplegia, head and eye deviation, multimodal hemineglect, and global aphasia when the dominant hemisphere is involved. It has to be noted that the National Institutes of Health Stroke Scale (NIHSS) underestimates the severity of nondominant infarction, an observation made by Krieger et al,24 who observed significant differences for NIHSS score as predictor for fatal brain swelling, depending on the

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Figure 78-2 Diagnosis of malignant middle cerebral artery (MCA) infarction by noncontrast CT scans, 3 hours (left) and 30 hours (right)

after symptom onset, showing infarction of the complete right MCA territory, including the basal ganglia, plus additional infarctions of the anterior cerebral artery and posterior cerebral artery territories, with incipient space-occupying effect indicated by narrowing of the frontal horn of the lateral ventricle.

side of the lesion. Therefore, NIHSS score typically ranges from higher than 16 to 20 when the dominant hemisphere is involved, and from higher than 15 to 18 when the nondominant hemisphere is involved.24-27 Furthermore, patients with malignant MCA infarction show an impaired level of consciousness, with score of at least 1 on item 1a of the NIHSS or less than 14 on the Glasgow Coma Scale.5,24-26 2. Patients with malignant MCA infarctions show a progressive deterioration of consciousness over the first 24 to 48 hours and frequently a reduced ventilatory drive requiring mechanical ventilation.5,25 3. Neuroimaging shows definite infarction of at least two thirds of the MCA territory, including the basal ganglia, with or without additional infarction or perfusion deficit of the ipsilateral ACA or the PCA territory.25-29 Measurement of early infarct volume in stroke MRI using diffusion-weighted imaging (DWI) or apparent diffusion coefficient (ADC) mapping has shown that early infarct volume has a highly predictive value for the development of a malignant course and may be used for early diagnosis in these patients instead of CT.27,30,31 Computed Tomography In clinical practice CT is widely available and in most cases offers the possibility to detect severe ischemic changes and brain edema formation early enough to predict the probability of a malignant course.32 In a systematic review by Hofmeijer et al,29 infarct size was the major determinant of the development of life-threatening edema after MCA infarction. Using noncontrast CT criteria, these researchers reported that infarct size more than 50% of the MCA territory, infarct size more than two thirds of the MCA territory, involvement of the complete MCA territory, involvement of other vascular territories (i.e., ACA and/or PCA), and early mass effect all are highly significant predictors for a malignant course, with infarct

size greater than two thirds of the MCA territory having the highest positive and negative predictive values (86% and 90%, respectively). Additional infarction of the ACA or PCA territory or both also has a high positive predictive value (86%) but a lower negative predictive value (69%) (Fig. 78-2). Advanced CT technologies using multimodal imaging including CT angiography (CTA) and perfusion CT may also help identify this condition. In studies using perfusion CT, perfusion deficits including more than two thirds of the MCA territory and low perfusion levels in the ACA and/or PCA territory or both were found to predict a malignant course with high positive predictive values of up to 90%, and negative predictive values between 40% and 85%, respectively.29,33-35 CTA allows fast and reliable evaluation of vessel patency in acute stroke; ICA occlusion is a significant predictor of a malignant course, although it has comparatively low positive predictive values.29 Magnetic Resonance Imaging Using DWI, apparent diffusion coefficient (ADC) mapping, and perfusion imaging, some studies have found early predictors for the development of life-threatening brain edema in acute MCA infarction. In two studies, lesion volume greater than 145 mL on DWI within 14 hours or greater than 82 mL on ADC maps within 6 hours after symptom onset predicted the development of a malignant course with positive predictive values of 91% and 82% and negative predictive values of 100% and 92%, respectively.30,31 In the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study, a DWI lesion volume greater than 100 mL also accurately predicted malignant MCA infarction.36 These positive and negative predictive values may be increased by a combined analysis of DWI and ADC measurements.30 The value of perfusion imaging for the prediction of a malignant course is still controversial (Fig. 78-3).

CEREBRAL INFARCTION: SURGICAL TREATMENT

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Figure 78-3 Diagnosis of malignant middle cerebral artery (MCA) infarction by MRI. Left, Diffusion-weighted imaging (DWI); right, perfusion imaging 4 hours after symptom onset. A diffusion lesion of >2/3 of the MCA territory and a perfusion deficit of the complete MCA territory can be seen. This constellation is highly predictive for a malignant course.

Single-Photon Emission Computed Tomography There are only few studies evaluating single-photon emission CT (SPECT) for the prediction of a malignant course in MCA infarction.37-39 Berrouschot et al37 performed CT and technetium Tc 99m–ethylcysteinate dimer (Tc 99m–ECD) SPECT within 6 hours of symptom onset in 108 patients with acute stroke, 11 of whom died owing to MCA infarction. The sensitivity of Tc 99m–ECD SPECT for predicting fatal outcome was 82% in both visual and semiquantitative analyses; specificity was 98% for visual analysis and 99% for semiquantitative analysis. These figures compared favorably with the sensitivity and specificity of baseline CT studies, which were 36% and 100%, respectively.37 In a study by Lampl et al,38 who performed Tc 99m diethylenetriaminepentaacetic acid (DTPA) SPECT in 25 patients with MCA infarction at 36 hours after symptom onset, 5 patients died of herniation. Whereas stroke volume on CT was only marginally increased in these 5 patients in comparison with the other 20 patients, the extent of DTPA distribution, including more than one vascular territory, significantly correlated with herniation.38 Positron Emission Tomography Positron emission tomography (PET) still represents the gold standard for defining the ischemic core, penumbra, and oligemia in acute stroke. However, PET is available in very few centers for patients with acute stroke and is therefore currently used mainly for scientific purposes and clinical studies. Only a few studies on malignant MCA infarction involve performance of PET.40-42 Dohmen et al43 investigated 34 patients with acute MCA infarction involving more than 50% of the MCA territory on noncontrast CT performed within 12 hours after symptom onset. PET was performed within 24 hours after symptom onset using flumazenil tagged with radioactive carbon (11C) to assess CBF and irreversible neuronal damage. Results showed significantly larger volumes of the ischemic core and larger volumes of irreversible neuronal

damage in patients with a malignant than in patients with a benign course (144.5 mL versus 62.2 mL and 157.9 mL versus 47.0 mL, respectively). In addition, mean CBF values within the ischemic core were significantly lower and the volume of the ischemic penumbra was significantly smaller in patients with malignant MCA infarction.40 Invasive Neuromonitoring Multimodal invasive monitoring, including the placement of probes allowing measurement of intracranial pressure, (ICP), CPP, microdialysis, and continuous electroencephalography (EEG) monitoring, is an interesting instrument for close observation in patients suffering from severe strokes. Yet, except for ICP and CPP measurement, multimodal invasive monitoring is currently also restricted to a few, mostly academic centers using these tools within clinical studies and is not available for routine use. There are several studies providing data on patients with malignant MCA infarction. Dohmen et al43 also performed microdialysis in addition to PET. They found close correlations between a number of parameters and the development of a malignant course after MCA infarction. These included increased ICP, decreased CPP and cerebral autoregulation, increased extracellular concentrations of transmitter amino acids and decreased extracellular concentrations of nontransmitter amino acids, increased concentrations of lactate, and decreased partial tissue oxygen pressure. In particular, increased ICP to more than 26.6 mm Hg and decreased CPP to less than 56 mm Hg both showed positive and negative predictive values of 100%.40,41,43 Animal Studies Several animal models of ischemic stroke provide evidence that decompressive surgery improves cerebral perfusion, reduces the volume of infarction, and significantly reduces mortality.44-49 Using an endovascular occlusion of the MCA technique, Forsting et al44 demonstrated an

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Figure 78-4 Different types of craniectomy: Upper row, from left to right, Unilateral frontotemporoparietal decompression (hemicrani-

ectomy) not exceeding the sinus sagittalis superior; frontotemporoparietal decompression exceeding the sinus sagittalis superior; temporal decompression (usually with resection of the temporal lobe). Middle row, from left to right, Bifrontal decompression not exceeding the sinus sagittalis superior; bifrontal decompression exceeding the sinus sagittalis superior; bilateral frontotemporoparietal decompression (bilateral hemicraniectomy); total calvarectomy. Lower row, from left to right, Unilateral suboccipital decompression; bilateral suboccipital decompression without opening of the foramen magnum; bilateral suboccipital decompression with opening of the foramen magnum; bilateral suboccipital decompression, without opening of the foramen magnum and resection of the atlantic arch.

absolute reduction in mortality of 35% after decompressive craniectomy in a rat model of focal cerebral ischemia. Furthermore, there were marked absolute reductions in average infarct volume compared with controls of 84% in animals subjected to craniectomy 1 hour after MCA occlusion and of 63% in animals subjected to craniectomy at 24 hours.44 Engelhorn et al47 compared reperfusion and craniectomy or both in a rat model of focal ischemia after MCA occlusion. They found significant absolute reductions in infarct volume by craniectomy at 1, 4, and 12 hours after MCA occlusion of 57%, 52%, and 33%, respectively. These results were comparable to those after reperfusion, probably owing to improved cerebral perfusion through collaterals after craniectomy.49 Interestingly, the combination of reperfusion and craniectomy was not significantly better than one treatment alone.47,48 Technical Aspects There are a variety of techniques for decompressive surgery. External (craniectomy, removal of the cranial vault) is differentiated from internal (removal of nonviable, edematous tissue) decompression. The two can be combined.50,51 In patients with diffuse brain edema without midline shift, bilateral craniectomy is a reasonable approach, whereas in patients with unilateral swelling of one hemisphere and midline shift, hemicraniectomy is the recommended procedure (Fig. 78-4). For hemicraniectomy, usually a large question mark– shaped skin incision based at the ear is made, and a

Figure 78-5 Bone defect after hemicraniectomy carried out over

the entire lateral temporal lobe down to the floor of the temporal fossa.

bone flap containing parts of the frontal, parietal, temporal, and occipital squama is removed.52 Alternatively, a T-shaped skin incision can be made in order to protect the occipital artery. Osteoplastic craniectomy should include parts of the frontal, parietal, and temporal squamae and should be performed to the base of the skull (Fig. 78-5). In the past, craniectomies were performed

1431


Dura (postoperative)

Additional volume Original volume h1

h2

r2

r1

Figure 78-7 Illustration of parameters for estimation of additional

volume created outside the skull by craniectomy in middle cerebral artery infarction with space-occupying edema, assuming that the brain takes an approximately spherical shape. h, height; r, radius.

of brain tissue to be allowed to shift outside the skull is directly related to the diameter of the removed bone flap and can be estimated using the following formula (Fig. 78-7):

without opening of the dura, but it is now recognized that decompression is achieved mainly by dural opening. Therefore, after dura enlargement, either an autologous or artificial dural patch should be inserted (Fig. 78-6). Some centers prefer to leave the dura open.53 The need for additional tissue removal (i.e., in the case of malignant MCA infarction, temporal lobectomy) has been discussed over the past years. Although, in theory, resection of the temporal lobe may reduce the risk of uncal herniation, this technique is much more complicated because it is difficult to distinguish between already infarcted and potentially salvageable tissue and a benefit has never been proven by clinical studies. Meanwhile, there is a broad consensus among neurosurgeons that external decompressive surgery by hemicraniectomy is sufficient.53 The bone flap is stored at −80° C and usually reimplanted after 6 weeks to 3 months. Alternatively, an artificial flap can be inserted. Serious or life-threatening complications of craniectomy are rare, including postoperative wound and bone infections, epidural or subdural hematomas, hygroma, and hydrocephalus.50,54-56 The most common, widely underestimated, but potentially detrimental complication of decompressive surgery arises from insufficient craniectomy, which leads to local shear stress and venous problems at the bone margins or, at worst, even to herniation through the craniectomy defect. Wagner et al57 analyzed postoperative CT scans of 60 patients in order to determine the occurrence of hemicraniectomy-associated infarcts and hemorrhages. Infarcts or hemorrhages of any size occurred in 70% of all patients; most lesions, however, were small (48-99 h Independent (%) Mild to moderate disability (%) Severe disability (%) Death (%)

Conservative Treatment

Decompressive Surgery

N = 512 1.0 11.2 37.8 50.0 N = 61 0.0 0.0 17.9 82.1 N = 65 0.0 24.6 12.3 63.1 N = 51 0.0 23.5 5.9 70.6 N = 14 0.0 28.6 35.7 35.7

N = 1212 6.1 25.6 43.5 24.9 N = 309 5.9 35.6 40.7 17.8 N = 69 0.0 37.7 40.6 21.7 N = 58 0.0 39.7 39.7 20.7 N = 11 0.0 27.3 45.5 27.3

Absolute Risk Reduction (%) 5.1 14.4 5.7 −25.1 5.9 35.6 22.8 −64.3 0.0 13.1 28.3 −41.4 0.0 16.2 33.8 −49.9 0.0 −1.3 9.8 −8.4

*Functional

outcome classified as (1) independent outcome (modified Rankin Scale [mRS] score 0 to 1; or Glasgow Outcome Scale [GOS] score 5; or Barthel Index [BI] ≥ 90); (2) mild to moderate disability (mRS score 2 to 3; or GOS score 4; or BI 60 to 85); (3) severe disability (mRS score 4 or 5; or GOS score 2 to 3; or BI < 60); and (4) death. In cases in which more than one outcome scale is given, outcome is classified according to the following priority: mRS/GOS/BI.

comparable because of higher age, more frequent lesions of the dominant hemisphere, different comorbidity, largely different conservative treatment concepts, and difference in operation techniques, cooling modes and durations of hypothermia, concomitant therapies, and patient monitoring. Most of all, however, inclusion criteria vary largely among these studies, because there is still no generally accepted definition for malignant MCA infarction. Clinical Randomized Trials Five randomized controlled trials were initiated between 2000 and 2004: The American Hemicraniectomy and Durotomy Upon Deterioration from Infarction-Related Swelling Trial (HeADDFIRST), which was completed in 2003, but has not been published yet as a written paper, the German DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY (DESTINY) trial, the French DEcompressive Craniectomy In MALignant middle cerebral artery infarcts (DECIMAL) trial, the Dutch Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial (HAMLET), and the Philippinian Hemicraniectomy for Malignant Middle Cerebral Artery Infarcts (HeMMI) trial.25-27,60-62 In 2007 the results of a prospectively planned pooled analysis including all patients from

DESTINY and DECIMAL and 23 patients from HAMLET treated by early hemicraniectomy within 48 hours were published.63 Mortality and Functional Outcome With all the results from nonrandomized studies taken together and reports on hypothermia excluded, hemicraniectomy is shown to reduce early mortality (in hospital) from 66.5% after conservative treatment to about 18.7% (−47.8%). If only patients for whom at least one followup is available are considered, this effect decreases, from 50% to 24.9% (−25.1%). If only reports with individual data are considered, 370 patients are available: The effect in reducing mortality after decompressive surgery is more obvious: 81.1% versus 12.6% for early mortality (−68.5%) and 82.1% versus 17.8% after 6 months (−64.3%) (there are no individual patient data after conservative treatment beyond 1 year).59 These results could be confirmed by the randomized trials: In the pooled analysis (and analyzing all patients from DESTINY, DECIMAL, and HAMLET) including patients treated within 48 hours, mortality at 1 year was significantly decreased from 71.4% (70.6%) in the conservative group to 21.6% (20.7%) in the surgery group (−49.8%; −49.9%).63 If surgery is delayed more than 48 and up to 99 hours after symptom onset, this effect cannot be observed anymore: Rates are 27.3%


after decompressive surgery and 35.7% after conservative treatment (−8.4%) (see Table 78-2).25,63 In nonrandomized studies, 31.7% of all patients undergoing decompressive surgery showed no or mild to moderate disability (modified Rankin Scale [mRS] score 0 to 3; Glasgow Outcome Scale [GOS] score 4 to 5; Barthel Index [BI] 60 or higher) at outcome visits, compared with 12.2% of patients undergoing conservative treatment (+19.5%). Taking into account individual patient data only, 41.5% of patients showed no or mild to moderate disability after decompressive surgery, compared with 0% after conservative treatment (+41.5%).59 In the pooled analysis of randomized trials on early hemicraniectomy, more patients in the surgery group had an mRS score of 4 or less (74.5% versus 23.8%; +50.7%) and an mRS score of 3 or less (43.1% versus 21.4%; +21.7%). The number needed to treat (NNT) was 2 for survival with a mRS score of 4 or less, 4 for survival with an mRS score of 3 or less, and 2 for survival irrespective of functional outcome.63 If surgery is delayed more than 48 and up to 99 hours after symptom onset, 67.2% of patients after surgical treatment, compared with 25.5% after conservative treatment, survive with a mRS score of 4 or less (+41.7%), and 39.7% after surgical treatment compared with 23.5% after conservative treatment survive with a mRS score of 3 or less (+16.2%) (see Table 78-2).25 However, in the nonrandomized studies, the number of severely disabled patients (mRS score, 4 to 5; GOS score 2 to 3; BI 3 cm) cerebellar hemorrhage or cerebellar hemorrhage with brainstem compression or hydrocephalus.1,5,8 Deterioration in the level of consciousness is a strong indication for emergency surgery. For hydrocephalus associated with a lesser degree of “tightness” of the posterior fossa, only ventricular drainage and careful observation are advocated (see case 2). Surgical Procedure of Hematoma Evacuation After induction of general anesthesia, the patient is placed in the prone position, and the head is fixed in a head frame with the neck slightly flexed. The head is elevated adequately to avoid development of venous congestion and edema during surgery. Unilateral suboccipital craniectomy is usually performed; the extent of the exposure

depends on the location and size of the hematoma. In larger or bilateral hemorrhages, bilateral suboccipital craniectomy with foramen magnum opening is sometimes needed. A linear or curved skin incision is usually placed between 2 cm above the inion and the spinous process of C2 (Fig. 79-1). With a curved skin incision, the postoperative scar is less visible. Other traditional incisions for this approach include hockey-stick and horseshoe incisions. When ventricular drainage is required because of obstructive hydrocephalus, a 3 cm–long linear incision is additionally placed at a point 5 to 6 cm above the orbitomeatal line and 5 cm posterior to the external auditory meatus, to allow insertion of a ventricular catheter (see Fig. 79-1). Skin flaps are reflected, and the nuchal fascia and muscles are exposed. The trapezius muscle has an attachment to the medial part of the superior nuchal line, and the sternocleidomastoid muscle has an attachment to its lateral part, extending to the mastoid process. An edge of the fascia and muscle is left at the upper incision to facilitate wound closure. The nuchal muscles are split at the midline, and the underlying semispinalis capitis muscle and rectus capitis posterior major and minor muscles are detached from the occipital bone. These muscles are retrogradely dissected from the inferior nuchal line by means of a periosteal elevator with minimum cautery, in the same manner as in a frontotemporal craniotomy.9 Gentle dissection of these muscles promotes wound healing and prevents postoperative muscle contraction headache. A craniectomy adequate to the size of the lesion is performed. It is sometimes widened with a drill and a rongeur laterally and superiorly up to the transverse sinus. After craniectomy, we frequently use ultrasonography to determine the location of the hematoma, and color Doppler ultrasonographic imaging with color-flow mapping system is helpful, especially when a vascular anomaly has

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Figure 79-2 CT scan (left) and MR images (center, fluid-attenuated inversion recovery [FLAIR] image; right, T2* image) showing a small cerebellar hematoma in the left dentate nuclei.

caused hematoma.10 Prior to the dural opening, a small durotomy is made, and a drainage tube is inserted into the hematoma cavity to evacuate the liquid clot. Then, the dura mater is widely opened and the occipital venous sinus is ligated or coagulated and sectioned. After introduction of the operating microscope, the cerebellar surface is inspected for a vascular anomaly. The corticotomy is extended around the drainage tube, and the hematoma is evacuated with suction. The hematoma is removed from the superficial region to the deeper region, and bleeding points are identified and coagulated. The wall of the hematoma cavity is covered with absorbable knitted fabric (Surgicel) to control oozing. After adequate removal of the clot, hemostasis should be completed. To confirm hemostasis, the intratracheal pressure is also raised to 30 cm H2O for 10 seconds (Valsalva maneuver), and the hematoma cavity is irrigated with saline solution. The dura is closed in a watertight fashion with continuous suture. In cases requiring further decompression, duraplasty is performed with either artificial dura, periosteum, or fascia harvested from the parietal region. To prevent venous sinus bleeding, several suspending dural stitches are placed at the edge of the craniectomy. Then the head frame is loosened and the head is refixed in a neck-extended position to facilitate approximation of the nuchal muscles and fascia easier to the fascia remaining at the superior nuchal line. The muscles are closed in two layers at the midline, and the skin is sutured. Epidural suction drainage is not recommended, so as to avoid accidental forced drainage of cerebrospinal fluid.

intravenously. The systolic blood pressure is maintained at less than 120 mm Hg for 24 hours. A CT scan is taken on day 1 after surgery to rule out rebleeding and cerebellar edema. Barbiturate or propofol is discontinued, and the patient is extubated after neurologic status has stabilized and a follow-up CT scan shows improvement in the “tightness” of the posterior fossa. Rehabilitation should start as soon as possible.

Postoperative Management

Case 3

Many centers perform CT in the operating room immediately after surgery, with general anesthesia maintained, to ensure adequate clot removal. The postoperative patient is managed in the intensive care unit with monitoring of vital signs. Laboratory data and neurologic signs are important. Auditory brainstem response is monitored when brainstem function is severely impaired. A patient who was comatose with or without dyspnea preoperatively is managed postoperatively with mechanical ventilation and short-acting barbiturate therapy. Corticosteroid, mannitol, and a histamine H2 blocker are administered

A 46-year-old man presented to the emergency room with consciousness disturbance following headache and vomiting. A CT scan demonstrated a large high-density area in the right cerebellum (>3 cm) (Fig. 79-4). The patient underwent emergency suboccipital craniectomy with evacuation of the hematoma. At operation, no vascular anomaly was detected. The postoperative CT scan showed complete removal of the hematoma (see Fig. 79-4). The truncal ataxia and right incoordination had resolved within 2 months, and the patient returned to previous daily life.

Illustrative Cases Case 1 A 67-year-old man suddenly complained of vertigo and nausea. CT and MRI showed a cerebellar hematoma (left dentate nucleus) without ventricular perforation (Fig. 79-2). The patient was conservatively treated with full recovery. Case 2 A 69-year-old man with a history of hypertension and diabetes mellitus had sudden onset of vomiting and ataxia of the right side. The patient was transferred to our hospital, where a CT scan demonstrated cerebellar hematoma extending to the fourth ventricle with mild ventriculomegaly (Fig. 79-3A). The patient became comatose 6 hours later, and a follow-up CT scan disclosed obstructive hydrocephalus (Fig. 79-3B). Emergency placement of a ventricular drain through the right anterior horn of the lateral ventricle was performed (see Fig. 79-3B); hematoma was not evacuated. Postoperative course was uneventful. The patient was sent to a rehabilitation hospital.

CEREBELLAR INFARCTION AND HEMORRHAGE

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A

Figure 79-3 A, CT scans on admission demonstrating a cerebellar hematoma extending to the fourth ventricle. B, Follow-up CT scan (left), obtained 6 hours after admission, showing a hydrocephalus. CT scan (right) after the placement of ventricular drain tube revealing resolution of the hydrocephalus.

B

Figure 79-4 CT scan before (left) and after (right) surgery showing that the right cerebellar hematoma is completely removed.

Cerebellar Infarction Clinical Features and Pathophysiology Before the introduction of CT scanning, correct diagnosis of cerebellar infarction was rarely made during life. With the improvement in CT and MRI, however, the diagnosis of cerebellar infarction was greatly facilitated. Amarenco et al11 studied arterial pathology of 88 cerebellar infarcts

in 56 patients. Cardiogenic embolism was the cause in 43% of the patients, and atherosclerotic occlusion in 35%. Emboli tend to lodge in the intracranial vertebral artery, resulting in infarction in the PICA territory; the SCA is rarely affected. The cerebellar infarction sometimes becomes hemorrhagic. Although the infarction is generally unilateral, bilateral cerebellar hemispheres can be affected owing to vascular variation.12

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Figure 79-5 Fluid-attenuated inversion recovery (FLAIR) (left and center) and diffusion (right) MR images showing bilateral cerebellar

infarction.

The initial symptoms include vertigo or dizziness, headache, nausea and vomiting, ataxia, and dysarthria. Approximately 13% to 39% of all patients with cerebellar infarction demonstrate mass effect in the posterior fossa.13,14 Large cerebellar infarcts cause edematous changes in the cerebellar hemisphere, resulting in compression of the brainstem typically starting on the third day after the ictus.15 Initially, sixth nerve palsy is likely to occur ipsilaterally, and facial weakness and Horner’s syndrome may be associated. Obstructive hydrocephalus sometimes develops because of compression of the fourth ventricle, leading to disturbance of consciousness that may be rapid. Patients become comatose over several hours once signs of brainstem compression appear and often demonstrate pinpoint pupils and decerebrate posturing from pontine compression. Ataxic respiration and apnea ultimately occur because of medullary compression from tonsillar herniation shortly before death. Indications for Surgery Patients with small cerebellar infarcts rarely become candidates for surgical treatment. Surgical treatment is necessary only in the patient with a rapidly progressing disturbance of consciousness caused by brainstem compression and/or fourth ventricle obstruction due to edematous change or hemorrhagic transformation.14-16 Treatment options are external ventricular drainage, posterior fossa decompressive craniectomy with duraplasty, resection of infarcted cerebellum, and combinations of those treatments.14-16 Detailed and frequent neurologic monitoring is essential to determine the necessity for surgery. Surgical Procedure Surgical decompression with extensive suboccipital craniectomy and duraplasty is the procedure of choice for massive cerebellar infarction. The craniectomy is essentially the same as that described previously for cerebellar hemorrhage. To achieve an effective decompression, the foramen magnum is widely opened, the craniectomy is extended bilaterally, and laminectomy of C1 is performed. When obstructive hydrocephalus is associated,

a ventricular catheter into the occipital horn of the lateral ventricle is placed at this stage. If the dura mater is extremely tense, ventricular drainage is not carried out until the dural opening is large enough to avoid upward herniation. The dura mater is incised first near the foramen magnum to drain the cerebrospinal fluid and then is widely opened. In cases associated with severe edematous change, grossly necrotic tissue of the cerebellum may be resected for internal decompression. Duraplasty is performed with artificial dura or a piece of fascia harvested from the parietal region. Illustrative Cases Case 4 A 50-year-old woman was admitted with the complaint of dizziness. MR images revealed bilateral cerebellar infarction (Fig. 79-5). These findings indicated that the right vermian branch might be fed by the left PICA. The symptom disappeared within 2 weeks. Case 5 A 68-year-old man presented with headache, dizziness, left ataxia, and nausea. MRI showed a high-intensity area in the territory of the left PICA (Fig. 79-6A). The patient was treated conservatively under the diagnosis of left cerebellar infarction. Five days after ictus, the patient progressively deteriorated. A CT scan disclosed a highdensity area corresponding to the territory of the PICA (Fig. 79-6B). The fourth ventricle was compressed, and the supratentorial ventricular system dilated. Diagnosis of hemorrhagic infarction was made. The patient underwent emergency surgery (suboccipital decompressive craniectomy with duraplasty, removal of the hemorrhagic portion of the infarcted cerebellum including the tonsil, and ventricular drainage through the right occipital horn). The patient was treated with propofol for 2 days after surgery. The postoperative CT scan showed the posterior fossa to be well decompressed as well as a reduction in ventricular size. The patient’s level of consciousness completely recovered, and the patient was discharged with mild ataxia and left dysmetria. Follow-up MRI performed 1 month after surgery showed a normal brainstem with a slack posterior fossa (Fig. 79-6C).

CEREBELLAR INFARCTION AND HEMORRHAGE

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A

B

C Figure 79-6 A, CT scan (left) and fluid-attenuated inversion recovery (FLAIR) MR image (right) demonstrating a cerebellar infarction in the left side. B, CT scans obtained at patient deterioration disclosing a hemorrhagic transformation and hydrocephalus. C, Axial FLAIR (left) and coronal T2-weighted (right) MR images, obtained 1 month after surgery, showing the posterior fossa slack with no evidence of brainstem injury.

Conclusion

REFERENCES

Management of cerebellar infarction and hemorrhage is described, with focus on the surgical indications and procedures. To achieve the best surgical outcome, timing of surgery is very important; surgical intervention should be performed without delay when indicated. Perioperative close observation and adequate medical management are important as well.

1. Kobayashi S, Sato A, Kageyama Y, et al: Treatment of hypertensive cerebellar hemorrhage: Surgical or conservative management? Neurosurgery 34:246–251, 1994. 2. Morioka J, Fujii M, Kato S, et al: Surgery for spontaneous intracerebral hemorrhage has greater remedial value than conservative therapy, Surg Neurol 65:67–73, 2006. 3. Little JR, Tubman DE, Ethier R: Cerebellar hemorrhage in adults. Diagnosis by computerized tomography, J Neurosurg 48:575–579, 1978.

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4. Luparello V, Canavero S: Treatment of hypertensive cerebellar hemorrhage: Surgical or conservative management? Neurosurgery 37:552–553, 1995. 5. Mayer SA, Rincon F: Treatment of intracerebral haemorrhage, Lancet Neurol 4:662–672, 2005. 6. Horiuchi T, Tanaka Y, Hongo K, et al: Characteristics of distal posterior inferior cerebellar artery aneurysm, Neurosurgery 53:589– 596, 2003. 7. Yamamoto T, Nakao Y, Mori K, et al: Endoscopic hematoma evacuation for hypertensive cerebellar hemorrhage, Minim Invasive Neurosurg 49:173–178, 2006. 8. Broderick J, Connolly S, Feldmann E, et al: Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: A guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group, Stroke 38:2001–2023, 2007. 9. Oikawa S, Mizuno M, Muraoka S, Kobayashi S: Retrograde dissection of the temporalis muscle preventing muscle atrophy for pterional craniotomy. Technical note, J Neurosurg 84:297–299, 1996. 10. Kitazawa K, Nitta J, Okudera H, Kobayashi S: Color Doppler ultrasound imaging in the emergency management of an intracerebral hematoma caused by cerebral arteriovenous malformations: Technical case report, Neurosurgery 42:405–407, 1998.

11. Amarenco P, Hauw JJ, Gautier JC: Arterial pathology in cerebellar infarction, Stroke 21:1299–1305, 1990. 12. Han SW, Cho GC, Baik JS, et al: Bilateral cerebellar infarction caused by dominant medial posterior inferior cerebellar artery, Neurology 66:1125–1126, 2006. 13. K ase CS, Norrving B, Levine SR, et al: Cerebellar infarction: Clinical and anatomic observation in 66 cases, Stroke 24:76–83, 1993. 14. Koh MG, Phan TG, Atkinson JLD, Wijdicks EFM: Neuroimaging in deteriorating patients with cerebellar infarcts and mass effect, Stroke 31:2062–2067, 2000. 15. Hornig CR, Rust DS, Busse O, et al: Space-occupying cerebellar infarction: Clinical course and prognosis, Stroke 25:372–374, 1994. 16. Adams HP Jr, del Zoppo G, Alberts MJ, et al: Guidelines for the early management of adults with ischemic stroke: A guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists, Stroke 38:1655–1711, 2007.

INDEX A ABC assessment (airway, breathing, circulation), 934–936, 935t Abciximab, 974, 978–979, 980t–982t, 983–985 in acute stroke, 1150, 1229 in aneurysm coiling, 1250 in basilar artery stenting, 1028 mechanism of action, 1150 Abulia (akinetic mutism), 370–373, 372f vs. locked-in syndrome, 457 Acetaminophen, for fever in acute stroke, 1003, 1024 in subarachnoid hemorrhage, 1035 Acetazolamide cerebral blood flow and, 50, 1000 in CADASIL, 270–271 in cerebral venous thrombosis, 1096 N-Acetyl-l-aspartate, 888, 893–894 Achromatopsia, 438 Acid sensing ion channels, 92–93 Acidophilia, neuronal, 69–70, 69f, 73t, 79–80 Acidosis, tissue infarction secondary to, 71–72 ischemia-induced, 92–93 in white matter, 125–126 Activated factor VII. See Recombinant activated factor VII. Activated partial thromboplastin time (aPTT), 972–973, 972t Activated protein C resistance, 773–775, 783 Activin-like kinase 1. See ALK-1 (activin-like kinase 1). Activities of Daily Living (ADLs), 1116 instrumental, 1116–1118 measurement of, 230–231, 230t, 231f scales for, 319, 321–322, 322t, 325, 1117 outcomes of rehabilitation and, 1119 prediction from impairments, 1116 rehabilitation for, 1127–1129 Acupuncture, and functional outcomes, 1127 Adamkiewicz, artery of, 644, 648–651, 654, 1269 Adaptive trial designs, 1195 ADC. See Apparent diffusion coefficient (ADC). Adenosine, white matter injury and, 132–134 Adenosine diphosphate (ADP) clopidogrel and, 1159–1160 platelet activation and, 1152 platelet aggregation and, 974, 1149–1151, 1150f Adenosine triphosphate (ATP), in white matter, 125–126, 130–131, 131f, 133f Adenylate cyclase, and vasodilatation, 3–4

Adhesion molecules in atherosclerosis, 695–697 in inflammatory response to ischemia, 101, 138–139, 139f, 139t therapy directed at, 145–147, 1066–1067 Adhesion receptors of cerebral microvessels, 17 focal ischemia and, 17, 19f, 20 for leukocytes, 17, 19f, 138 of platelets, 1149 ADLs. See Activities of Daily Living (ADLs). ADP. See Adenosine diphosphate (ADP). Adrenergic agents, for blood pressure control, 1014–1015 Advanced life support (ALS) units, 931, 934 Adventitial fibrosis, 485 Affective agnosia, 416 African Americans. See Black people. Age stroke epidemiology and, 191, 191f, 193–196, 196f stroke outcomes and, 221, 229 stroke recurrence and, 224–227 Aging, cerebral vessel wall thickness and, 23 Agrammatism, 399 AICA. See Anterior inferior cerebellar artery (AICA). AIDS (acquired immunodeficiency syndrome) apoptosis in brain tissue in, 116t lacunar infarcts in, 490 Air embolism, angiography-related, 911 Airway management, 934–935, 935t Akinetic mutism (abulia), 370–373, 372f vs. locked-in syndrome, 457 Akt (protein kinase B), in preconditioning, 156, 157f Albumin neuroprotective potential of, 1056t–1057t, 1069 in osmotherapy, 1110–1111 Alcohol consumption. See also Caffeinol. cognitive function and, 258 recurrent stroke risk and, 224–227 stroke risk and, 213, 243t, 244–245, 798–800 for intracerebral hemorrhage, 532–533 for subarachnoid hemorrhage, 213, 590 Alexia, 434–437, 435f–436f with agraphia, 403–405, 403f global, 434–437, 436f Alien hand syndrome, 369–371 ALK-1 (activin-like kinase 1) arteriovenous malformations and, 170f, 171–172, 177f experimental models and, 174–175 dural arteriovenous fistulas and, 180–181

Allergic angiitis, 693 Allesthesia, 415 Allochiria, 415 Alpha-galactosidase deficiency, 1089 ALS (advanced life support) units, 931, 934 Alteplase, 946. See also rt-PA (recombinant tissuetype plasminogen activator); Thrombolytic therapy. clinical trials of, 955–957 emergency department use of, 938 MRI-guided therapy with, 900 Altitudinal hemianopia, posterior cerebral artery infarction with, 430–431 Alzheimer’s disease. See also Dementia. amyloid angiopathy in, 275, 532–533 apoptotic biochemical alterations in, 116t historical concepts of, 252 imaging correlates of, 255 vascular dementia mixed with, 253, 255–257, 261, 261f, 502 Amaurosis fugax. See Transient monocular blindness (amaurosis fugax). American Heart Association’s Stroke Outcome Classification (AHA.SOC), 1117 American Indians, stroke risk in, 191–194, 191f ε-Aminocaproic acid, rebleeding and, after subarachnoid hemorrhage, 603, 1035–1036 Amitriptyline, for hyperpathia, 496–497 Amnesia after aneurysm rupture, of anterior communicating artery, 374–375 posterior cerebral artery infarction with, 440 Amnestic aphasia, 439–440 Amnestic color dysnomia, 438 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, 89–93, 91f blockade of, for cytoprotection, 1056t–1057t, 1061–1062 white matter excitotoxicity and, 132–134, 133f zinc and, 93–95 Amphetamines abuse of, 792–795, 1092 with aphasia therapy, 408–409, 1124t, 1125 intracerebral hemorrhage associated with, 546–547 with physical therapy, 1124t, 1128 Amusia, 415 Amyloid angiopathy, cerebral, 255 dementia secondary to, 502 genetics of, 273–274, 534–535, 534f granulomatous angiitis with, 552–553 histopathology of, 542–544, 543f–545f intracerebral hemorrhage in, 22–23, 255, 273–275, 1339

Page numbers followed by t indicate tables; page numbers followed by f indicate figures.

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Index

Amyloid angiopathy, cerebral (Continued) anticoagulation and, 550, 1185 lobar (white matter), 566–568, 568f, 568t magnetic resonance imaging of, 896, 896f as microbleeds, 554, 896f, 897 prevalence of, 532–533, 532t recurrent, 541 risk factors for, 532–533, 533t thrombolytic therapy and, 1234–1235 lacunar infarcts in, 490 nonhemorrhagic features of, 533 β-Amyloid peptide, 542–544 β-Amyloid precursor protein (APP), 22–23, 542–543 mutations affecting, 534–535, 534f, 543 Anagrelide, for essential thrombocytosis, 776 Analgesia in critical care of stroke, 1010–1012 after subarachnoid hemorrhage, 601 Anarthria, lacunar infarction with, 500 Ancrod, 949–950 Aneurysm(s) in arteriovenous malformations. See Arteriovenous malformations, brain, aneurysms associated with. dissecting, 661, 662f, 1085–1086. See also Arterial dissection. angiography of, 916f, 921 intracranial. See Intracranial aneurysms. microaneurysms in amyloid angiopathy, 543 in granulomatous angiitis, 552–553 in intracerebral hemorrhage, 535–536, 574 sites of, 566 miliary, 535–536 septic (mycotic), 591 injection drug abuse and, 790, 795 with intraparenchymal hemorrhage, 914 vertebrobasilar, 452–453, 452f–453f, 916f Aneurysm clips, 1302–1303, 1304f Aneurysmal subarachnoid hemorrhage. See also Intracranial aneurysms; Subarachnoid hemorrhage. angiography of aneurysm angiographically negative, 596 with catheter angiography, 594–595, 595f, 913–914, 922 with CT angiography, 595–596, 595f early need for, 594 with MR angiography, 596 rebleeding precipitated by, 911 blood flow and metabolism after, 58–60, 598 clinical presentation of, 593, 593t diagnostic testing and radiography of, 593–594, 594f MR angiography in, 887–888 differential diagnosis of, 591, 591t vs. reversible vasoconstriction syndrome, 769 emergency department management of, 940–941 endovascular treatment of, 1217–1218, 1218f antithrombotic therapy in, 1035 evidence for, 1241–1242, 1242f–1243f epidemiology of, 589–591 genetics of, 1292 grading scales for, 309, 313, 313t, 596–597, 596t radiologic, 596–597, 596t historical aspects of, 589

Aneurysmal subarachnoid hemorrhage (Continued) intensive care management of, 1035–1039 antifibrinolytics in, 1035–1036 extracranial complications in, 1038–1039 general, 1035 hydrocephalus in, 1036 invasive monitoring in, 1039 rebleeding and, 1035 vasospasm in, 1036–1038, 1036t with intraventricular hemorrhage, 1349, 1351f management of, 597–607 general measures in, 597–601, 597t hypertension and, 935 of neurologic complications, 597t, 602–606, 602f, 602t securing the aneurysm in, 601, 601t of systemic complications, 597t, 603t, 606–607 misdiagnosis of, 593 in moyamoya disease, 1088 outcomes of, 607, 1035 overview of, 589 pathophysiology of, 591–592, 592t risk factors for, 590–591 smoking as, 211 vasospasm secondary to, 10–11, 10f, 58–60, 604–606, 1086–1087 angiography of, 922 angioplasty for, 922, 1038, 1217 blood flow and metabolism with, 58–59 blood pressure and, 598 catecholamine levels and, 1039 extracranial-intracranial bypass for, 1418–1419 Fisher scale and, 597 intensive care management of, 1036–1038, 1036t in moyamoya disease, 1088 multimodal MRI of, 898 pathophysiology of, 1036 PET studies in, 51f–52f ultrasound monitoring of, 850, 1036, 1036t Angiitis of central nervous system. See Primary (isolated) angiitis of central nervous system; Vasculitis. Angiogenesis arteriovenous malformations and, 174–176 in atherosclerotic lesions, 841 cell therapies for induction of, 1139f, 1140 definition of, 163–164 functional recovery from stroke and, 164–165 of microvessels, 21–22, 170 in remodeling after stroke, 162–165 Angiography, cerebral, 910. See also Computed tomographic angiography (CTA); Magnetic resonance angiography (MRA). anatomy in common variants, 911, 912f normal, 911, 912f of aneurysms, intracranial, 913–914, 913f–916f of arterial dissection, 666–667, 670f–671f, 671, 921 of arteriovenous malformations, 622, 914–915, 917f, 921 to confirm obliteration, 1362 of basilar artery occlusion, 456, 457f beading seen in with drug abuse, 546–548, 547f in granulomatous angiitis, 552–553

Angiography, cerebral (Continued) in brain death, 923–924 in CADASIL, 760 “caput medusae” in venous phase of, 1388, 1390f, 1394–1395 of carotid artery stenosis external carotid, 335, 336f internal carotid, 337, 338f, 917–918, 918f stroke risk and, 353–354 transient ischemic attack and, 352–353, 353f, 918 in cerebral ischemia, 916–919, 918f–919f of cerebral venous thrombosis, 523, 523f, 923–924, 924f in cryptogenic infarction, 301–302 current status of, 910 of dural arteriovenous fistula, 913f, 1282, 1283f–1287f, 1289 of embolism, 297, 299, 301–302 of fibromuscular dysplasia, 678, 679f–680f, 921–922 in giant cell arteritis, 688 in granulomatous angiitis, 690, 690f of intracerebral hemorrhage, 556, 911–915, 1338 of intracranial atherosclerotic stenosis, 918–919, 918f–919f of intracranial hemorrhage, 911–915 intraoperative, in aneurysm clipping, 1303 in ischemic stroke, acute, 919–920, 919f–921f lacunar infarcts and, 301, 506, 506f in moyamoya disease, 703, 704f, 705t, 712, 715f, 922, 922f radiosurgery follow-up and, 1377 radiosurgery treatment planning and, 1375, 1375f regression of intracranial stenosis in, 1210 in reversible cerebral vasoconstriction syndromes, 766f, 768–769, 768f risks of, 910–911 blindness as, 430, 460 contrast-related, 460, 911 migraine-like, 725, 727 stroke as, 725 of subarachnoid hemorrhage, 594–596, 595f, 913 subdural hematoma and, 911–913 technique of, 910 of vasculitis, 921, 922f of vasospasm, after subarachnoid hemorrhage, 605, 922 Angioma. See Cavernous malformations, cerebral; Hereditary neurocutaneous angiomatosis; Venous anomalies. Angioplasty, balloon. See also Stenting. for arterial dissection, 673, 678f, 1084 for atherosclerotic disease, intracranial, 1211–1212 carotid. See Carotid artery disease, angioplasty and stenting for. for delayed cerebral ischemia, 605–606 in fibromuscular dysplasia, 680, 1086 glycoprotein IIb/IIIa receptor antagonists with, 983–984 intraarterial thrombolysis combined with, 1235–1236 in moyamoya disease, 1088 for radiation-induced vasculopathy, 1087

Index 1449 Angioplasty, balloon (Continued) in reversible cerebral vasoconstriction syndromes, 770 for subclavian steal, 1216–1217 for vasospasm, 921, 1038, 1217 vertebral artery, extracranial, 1215–1216 Angiotensin receptor antagonists, 245–246 Angiotensin-converting enzyme gene, lacunar infarction and, 507 Angiotensin-converting enzyme inhibitors, 245–246 in acute stroke, 1000 in diabetic patients, 247 in hypertensive encephalopathy, 738 in intensive care unit, 1015 intracerebral hemorrhage risk and, 531 in migraine patients, 729 Anisoylated plasminogen-streptokinase activator complex (APSAC), 32t, 35, 948–949 inhibitors of, 36 Anistreplase. See Anisoylated plasminogenstreptokinase activator complex (APSAC). Anomic aphasia, 439–440 functional imaging in, 406 natural history of, 407 Anosognosia, 412f, 413, 414f thalamic hemorrhage with, 563–564 Anoxic-ischemic injury. See White matter anoxicischemic injury. Anterior cerebral artery anatomy of, 362–366, 363f–364f aneurysms of distal, surgery for, 1303f, 1314–1317, 1316f ruptured, 368 visual loss caused by, 375 anomalies of, 364–366, 365f infarction in patients with, 368–369 borderzone anastomoses of, 427 collateral flow in, from carotid stenosis, 339–340, 339f cortical distribution of, 364, 364f dissecting aneurysms of, 362 saccular aneurysm of, 362, 365–366 species differences in, 366 Anterior cerebral artery infarction angiography in, 920f etiologies of, 362 middle cerebral artery infarction with, 1024–1025 symptoms and signs of, 362 akinetic mutism (abulia), 370–373, 372f autonomic changes, 375 callosal disconnection signs, 369–370, 372, 374–375 incontinence, 375 language disturbance, 372–374, 373f in neonate, 375 other mental abnormalities, 374–375 seizures during menses, 375 visual loss, 375 weakness and sensory loss, 366–369, 367f–368f Anterior choroidal artery aneurysms of with intraventricular hemorrhage, 1350 surgery for, 1310–1312, 1312f hemorrhage from, 558 occlusion of, clinical syndromes in, 345–346

Anterior communicating artery anatomy of, 362, 363f aneurysms of, 374–375, 913f–914f ruptured, 1338f, 1349–1350, 1351f surgery for, 1313–1314, 1315f anomalies of, 364–366 Anterior inferior cerebellar artery (AICA), 446–448, 448f–449f, 1440 atherosclerosis of, 451 hemorrhage from branches of, 535 occlusions of, 463t, 465, 468 Anterior spinal artery syndrome, 651–652, 652t after aortic surgery, 649 Anticardiolipin antibody test, 777–779, 778t Anticoagulant agents, 971–973, 972t. See specific agents. Anticoagulant proteins. See Protein C; Protein S. Anticoagulation. See Antithrombotic therapy; Heparin; Intracerebral hemorrhage (ICH), anticoagulant-associated; Warfarin. aortic plaques and, 751 for arterial dissection, 672–673, 1084–1085 in cardioembolic stroke, 816, 816t, 820, 985–986 in acute stroke, 1185–1186 in cerebral venous thrombosis, 1096–1097 in fibromuscular dysplasia, 1086 for migraine patients, 729 thrombolysis in patient with, 961, 967 Anticonvulsants in acute stroke, 937, 1002 prophylactic, 1023 intracerebral hemorrhage and, 1108 for migraine patients, 729–730, 730t subarachnoid hemorrhage and, 1035 Antidiuretic hormone. See SIADH (syndrome of inappropriate antidiuretic hormone). Antiemetic agents in acute stroke, 601 after subarachnoid hemorrhage, 601 Antifibrinolytic therapy, rebleeding and, after subarachnoid hemorrhage, 603, 1035–1036 Antihypertensive treatment. See also Blood pressure management. in acute stroke, 1000–1001 dementia risk and, 258 in hypertensive encephalopathy, 738–739 in intensive care unit, 1014–1016 in intracerebral hemorrhage, 939 in pregnancy, 738–739 for stroke prevention, 245–246, 245t with borderline hypertension, 215, 215f in diabetics, 247 with hypertension, 531 in subarachnoid hemorrhage, 941, 1035 for thrombolysis candidate, 961–962, 966, 966t Antioxidants, cognitive function and, 257 Antiphospholipid antibodies, 777–779, 778t, 1092–1093 catastrophic syndrome caused by, 1093 lacunes associated with, 489–490 in Sneddon’s syndrome, 694, 780 in systemic lupus erythematosus, 692, 777–778 Libman-Sacks endocarditis and, 822, 1180 α2-Antiplasmin, 31–32, 32t, 36, 945 microplasmin and, 947 therapeutic plasminogen activation and, 37

Antiplatelet therapy. See also Antithrombotic therapy; Aspirin; Clopidogrel. in acute ischemic stroke agents for, 972t, 973–975 complications of, 976t, 977–979 efficacy of, 980t–982t, 983–985 in aneurysm therapy, endovascular, 1247–1250 of ruptured aneurysm, 1249 aortic plaques and, 751 for arterial dissection, 672–673, 1084–1086 in atrial fibrillation, stroke risk and, 248 in cerebral venous thrombosis, 526 cognitive function and, 260 for dissecting aneurysm, 1085–1086 drugs for, 1154t bleeding risks with, 1154 settings least appropriate for, 1154–1155 in fibromuscular dysplasia, 1086 in intracerebral hemorrhage, 1108 intracerebral hemorrhage secondary to, 940 with aspirin, 1159 microbleeds and, 1167–1168 for migraine patients, 729 for primary prevention of stroke, 248–249, 1147, 1160–1162, 1168 for secondary prevention of stroke, 1147 agents for, 1154–1155, 1154t anticoagulants combined with, 1147, 1166–1167 aspirin for, 1155–1159 aspirin vs. warfarin for, 1162–1163 aspirin with clopidogrel for, 1159, 1164–1166 cardioembolic stroke and, 1147, 1164, 1183 in carotid endarterectomy, 1165 in carotid stenting, 1165–1166 cerebral microbleeds and, 1167–1168 clopidogrel for, 1159–1160 concluding summary on, 1168 early recurrence and, 1161–1162 investigational agents for, 1167 noncardioembolic stroke and, 1162–1163, 1164t physiologic basis of, 1147–1153, 1148f, 1149t, 1150f platelets of patients at risk and, 1153–1154 rationale for, 1147 in subarachnoid hemorrhage aneurysmal, 599–600 for vasospasm, 1037 for thrombosis, 776 in toxin-related vasculitis, 1092 Antithrombin, as anticoagulant, 972t, 977 Antithrombin III, 772 abnormalities of, 772, 774, 774t assays for, 774–775 Antithrombotic therapy. See also Anticoagulation; Antiplatelet therapy. in acute ischemic stroke, 971 with arterial dissection, 986 complications of, 975–979, 976t conclusions of studies on, 984–985 current status of, 986 efficacy of, 979–985, 980t–982t future of, 986–987 overview of, 971 pharmacology of, 971–975, 972t in arterial dissection, 1084–1086 in atrial fibrillation, 248, 1175–1176

1450

Index

Antithrombotic therapy (Continued) in cardioembolic stroke, 816, 816t, 985–986 in cerebral venous thrombosis, 525–526, 525t in fibromuscular dysplasia, 1086 to prevent deep vein thrombosis, 979, 985 to prevent reocclusion after thrombolysis, 986 in temporal arteritis, 1091 during warfarin initiation, 985–986 Aorta spinal cord arterial supply from, 644 Takayasu’s arteritis of, 691–692 Aortic aneurysm, and spinal cord ischemia secondary to dissection, 648–649 secondary to surgery, 649–650, 650f, 654 Aortic arch plaques. See also Aortic plaques, of proximal aorta. emboli derived from, 299, 302 lacunar infarcts caused by, 489–490 in posterior circulation, 450–451 transcranial Doppler monitoring of, 846 in vertebrobasilar infarction, 456 posterior circulation ischemia and, 450 risk of recurrent stroke and, 227 stroke prevention with, 1182 transesophageal echocardiography of, lacunar stroke and, 506 Aortic coarctation, spinal cord ischemia in, 649 iatrogenic, 650 steal phenomenon and, 650–651 Aortic dissection, thoracic, acute stroke secondary to, 936–937 Aortic endarterectomy, 752 Aortic plaques, of proximal aorta, 741. See also Aortic arch plaques. carotid artery disease and, 749 coronary artery disease and, 749 frequency in population, 741 future directions in imaging of, 752–753, 753f ischemic stroke and atheroembolism and, 749–751 cardiac catheterization and, 750–751 cardiac surgery and, 750 case-control studies and, 743–744, 744t pathology studies and, 741 plaque morphology and, 745–747, 746t, 747f prospective studies and, 744–745, 744t race/ethnicity and, 747–748 summary of, 753 natural history of, 747 risk factors for, 748–749 stroke prevention with, 1182 transesophageal echocardiography of, 741–743, 742f–743f lacunar stroke and, 506 vs. newer methods, 752–753, 753f treatment of, 751–752 Aortic stenosis, 823 Aortic stiffness, cognitive function and, 259 Aphasia. See also Language disorders. with middle cerebral artery infarction, 396–409 conduction aphasia, 404–405, 405f efficacy of therapy for, 407–408 epidemiology of, 407 functional imaging in, 397, 405–407, 411f global or total, 397, 398f. See also Global aphasia. innovative therapies for, 408–409 motor aphasia, 397–401, 398f–400f

Aphasia (Continued) natural history of, 407 right-sided, 413 sensory aphasia, 401–405, 401f–403f transcortical aphasia, 405 with posterior cerebral artery infarction, 439–440 thalamic hemorrhage with, 563–564 therapies for, 1124, 1124t Aphemia, 400 Aphonia, lacunar infarction with, 500 Apixaban, 973, 1183t, 1184 Apolipoprotein E arteriovenous malformations and, 172–173 intracerebral hemorrhage and, 275, 533–535 in amyloid angiopathy, 542–543, 566–567 recurrent, 541 warfarin-related, 550 Apoptosis, 79, 107. See also Ischemic cell death; Necroptosis (programmed necrosis). aneurysm rupture and, 591–592 in cerebral ischemia, 113–114 vs. autophagy, 107–108, 113 calcium and, 93 focal, 88 global, 88 around hemorrhage, 1338–1339, 1339f inhibition of, 115 vs. necrosis, 73, 73t, 107–108 rarity of, 71f, 72–73, 73t in human brain, 115–116, 115t–116t molecular mechanisms of, 80–88, 82f–84f, 108–113, 110f–112f, 156–157 caspase-independent, 86–88, 87f inflammation and, 140–141 inhibitors of, 84–86 survival pathways and, 111–113, 112f protective responses against, 157–158, 158f in spinal cord ischemia, 114–115, 646 Apoptosome, 81, 85f, 96, 143–144 Apoptotic bodies, 80 APP. See β-Amyloid precursor protein (APP). Apparent diffusion coefficient (ADC), 883f, 885 in cerebral venous thrombosis, 899–900 in hypertensive encephalopathy, 736, 736f intracerebral hemorrhage and, 896 in ischemic stroke, 891 age of lesion and, 893 hemorrhagic transformation and, 897 salvageable penumbra and, 901 in malignant middle cerebral artery infarction, 1428 Apraxias, 409–410 constructional, 415 for dressing, 412f, 414 of speech, 400 Aprosody, 415–416 APSAC (anisoylated plasminogen-streptokinase activator complex), 32t, 35, 948–949 inhibitors of, 36 Aptiganel (Cerestat), 1056t–1057t, 1059 aPTT (activated partial thromboplastin time), 972–973, 972t Arachidonic acid cerebral vasodilatation caused by, 5–6 platelet activation and, 1151–1152 platelet aggregation and, 1149–1151, 1150f

Argatroban, 973, 976 complications of, 977, 979 efficacy of, 983, 985 l-Arginine for MELAS, 1095–1096 nitric oxide synthesis from, 3, 6–9 platelet aggregation and, 1152 Arrhythmias, cardiac. See also Atrial fibrillation. in acute stroke, 1000 brainstem infarction with, 456 cardioembolic stroke associated with, 819–820 emergency department evaluation of, 936 subarachnoid hemorrhage with, 593, 606, 941, 1039 Arterial dissection, 453–454, 661–675. See also Aneurysm(s), dissecting. angiography of, 666–667, 670f–671f, 671, 921 antithrombotic therapy in, 986 aortic. See Aortic aneurysm. carotid. See Carotid artery(ies), dissection of. clinical manifestations of, 664–666, 666t, 668t course and prognosis of, 674–675, 679t, 680f development of, 661, 662f diagnostic imaging of, 666–672 epidemiology of, 661 in fibromuscular dysplasia, 662, 671, 671f, 1086 mechanisms of ischemia in, 664 middle cerebral artery, 388–389, 663–666 pathogenesis of, 661–662, 664t pathology of, 661–664, 662f–663f sites of, 662–663 treatment of, 672–674, 1084–1086 endovascular, 673, 674f–678f medical, 672–673 surgical, 673–674, 679f vertebral. See Vertebral arteries, dissection of. Arterial occlusive disease. See also Atherosclerosis. hemodynamic effects of, 49–50, 50f tenuous equilibrium in, 456t Arterial spin labeling methods, 887, 887f Arterioles, 485 Arteriovenous fistulas carotid, in capillary–arteriovenous syndrome, 180 spinal, 1366–1367, 1367f–1369f, 1367t. See also Arteriovenous malformations, spinal. traumatic, 632 venous thrombosis leading to, 632 Arteriovenous malformations, brain, 616–632. See also Dural arteriovenous malformations. aneurysms associated with, 617–620, 619f, 626, 915, 917f, 921, 1218–1219 endovascular therapy and, 1256–1260, 1260f, 1263–1268, 1361f radiosurgery and, 1381–1382, 1384 surgery for, 1361 angiography of, 622, 914–915, 917f, 921 in capillary malformation–arteriovenous malformation syndrome, 180 in children, 1362–1363 classification of, 1218–1219, 1219t, 1255–1260 angioarchitectonic, 1256–1260, 1259f–1261f, 1259t pathomechanical, 1256, 1257f–1258f, 1259t by risk of hemorrhage, 1255–1257, 1256f Spetzler-Martin, 1359–1360, 1359t, 1363 treatment-based, 1257–1260, 1260t diagnosis of, 622–625, 622f–623f, 623t

Index 1451 Arteriovenous malformations, brain (Continued) differential diagnosis of, 617t endovascular treatment of, 1204–1205, 1219–1220 architectonic features and, 1256–1260, 1259f–1262f, 1259t–1260t in cerebrofacial metameric syndromes, 1265, 1268f in children, 1362–1363 concepts of, 1260–1263, 1262f–1263f with false aneurysms, 1262f–1263f, 1265–1267 with flow-related aneurysms, 1263–1264, 1268 indications for and contraindications to, 1265–1269 microsurgery combined with, 1360–1363 outcomes of, 1362 proliferative angiopathy and, 1264–1265, 1266f–1267f radiosurgery following, 1219–1220, 1260–1261, 1267, 1374, 1379–1380, 1383–1384 of single-hole macrofistulas, 1264, 1264f, 1267 epidemiology of, 169, 620–622, 621f etiology of, 169–170, 176, 177f, 616–618 experimental models of, 174–176, 175f–176f, 175t genetics of, 170, 622, 1293 approaches to studies of, 1293–1294 association studies of, 1297 candidate gene studies and, 172–173 concluding summary of, 1298 familial aggregation and, 172, 1297 genome-wide association studies of, 173, 1297 genome-wide gene expression studies of, 1297–1298 linkage studies of, 1297 in mendelian disease, 171–172 next-generation sequencing and, 173 paradominant inheritance in, 173–174 headache associated with, 631 hemodynamics of, 57 hemorrhage secondary to, 169, 544–545, 625 vs. aneurysmal hemorrhage, 626 angiography and, 913 cerebellar, 570, 1361, 1361f in children, 1362–1363 clinical presentation of, 625–626 clinically silent, 626 with concurrent aneurysms, 629–630 epidemiology of, 620–622, 621f, 1293 factors predisposing to, 625 genetics of, 172–173, 1297 lesion location and, 626 medullary, 579 mesencephalic, 572–574 model systems and, 174 pregnancy and, 626 rehemorrhage risk with, 628 risk of, 625, 1219, 1358 with seizures, 630–631, 630t setting of rupture and, 626 severity and course of, 627–628 surgery for, 1343 as surgical complication, 631

Arteriovenous malformations, brain (Continued) on surgical follow-up, 1359 syndrome types with, 626–627, 627f–629f historical understanding of, 616 intraventricular hemorrhage secondary to, 626, 627f, 1262f, 1350–1352 language function and, 406–407 limited understanding of, 169 locations of, 624–625, 624f–625f clinical presentation and, 626 seizures and, 630 microsurgery for, 1358 anesthesia for, 1360 architecture of lesion in, 1359 associated aneurysms and, 1361 basal ganglia region, 1361 edema and hemorrhage following, 1362 embolization and, 1360–1362 guidelines for, 1363 in multimodality treatment, 1358–1363 operative procedure in, 1360–1361 patient-related factors in, 1358–1359 of pediatric lesions, 1362–1363 posterior fossa, 1361, 1361f postoperative care in, 1362 pregnancy and, 1363 radiosurgery and, 1361–1362 risk classification for, 1359–1360, 1359t timing of, 1359 morphology of, 169, 618–620, 618f–620f moyamoya-type changes in, 619, 636–637 multiple, 625, 625f natural history of, 1219 with neurologic deficit, 631 pathogenesis of, 169–170, 176, 177f, 618 physiologic studies of, 631–632 pregnancy and, 626, 1363 radiosurgery for, 1361–1363, 1374 advantages and disadvantages of, 1374 brainstem, 1361, 1377–1378 concluding summary of, 1385 dose selection for, 1376 embolization prior to, 1219–1220, 1260–1261, 1267, 1374, 1379–1380, 1383–1384 failed, reasons for, 1379–1380 failed, retreatment for, 1379, 1383 follow-up to, 1377 fundamental elements of, 1374 with Gamma Knife, 1374–1378, 1376f, 1378t, 1380–1384 grading of lesions and, 1360 head ring application for, 1374–1375 hemorrhagic complications of, 1378t, 1380–1382 in hereditary hemorrhagic telangiectasia, 1385 image acquisition for, 1375, 1375f with linear accelerator, 1374–1379, 1376f, 1378t, 1379f, 1381, 1383–1384 with particle beams, 1378, 1378t, 1381 pathologic mechanism of, 1374 patient selection for, 1374 radiation complications of, 1378t, 1382–1383 radiation delivery in, 1376–1377 reported efficacy of, 1377–1379, 1378t treatment planning for, 1375–1376, 1376f very late complications of, 1383 seizures associated with, 630–631, 630t, 1358–1359

Arteriovenous malformations, brain (Continued) settings for rupture of, 626 signaling pathways relevant to, 170, 170f size of, 623–624, 623f–624f surgical specimens from, 170, 175 symptoms of, 169 transcranial ultrasonography of, 622, 623f, 848–849 treatment of, 1219–1220 underdiagnosis or misdiagnosis of, 626 vasospasm associated with, 626, 628–629, 628f venous drainage of, 620, 620f, 623–624 Arteriovenous malformations, spinal, 1366 anatomic basis of, 1269 classification of, 1269, 1366, 1367t angiomorphologic, 1269–1271, 1270f–1273f pathophysiologic, 1271–1273 of conus medullaris, 1370, 1372f endovascular treatment of, 1273–1277, 1275f–1277f, 1366 conus medullaris, 1370, 1372f extradural, 1366 extradural-intradural, 1367 indications for, 1277 intradural, 1366–1367 intramedullary, 1367–1370, 1370f–1371f extradural, 1366, 1367f intradural, 1366–1367, 1368f–1369f, 1369t intramedullary, 1367–1370, 1370f–1371f subacute necrotic myelitis caused by, 652 transient ischemic attacks caused by, 650–651 treatment concepts for, 1273–1277, 1274f– 1278f treatment strategies for, 1366–1370, 1368f– 1371f Arteritis. See also Vasculitis. amphetamine abuse and, 546–547 lacunar infarcts associated with, 490, 508 Asian people. See also Chinese people; Japanese people; Korean people. cryptogenic infarction in, 302 intracerebral hemorrhage in, 531 paradoxically high stroke risk in, 199–200 Asian/Pacific Islanders, stroke risk in, 191–193, 191f Aspergillosis, of posterior circulation, 455 Aspiration pneumonia, 1001 prevention of, 935, 1001–1002 during rehabilitation, 1121 Aspirin, 1156. See also Antiplatelet therapy. in acute ischemic stroke, 288, 973–974 complications of, 977–979 current status of, 986, 996 efficacy of, 980t–982t, 983–985 after aneurysm coiling, 1249–1250 antiplatelet activity of, 776, 973–974, 1155–1156 aortic plaques and, 751 in atrial fibrillation, 819–820, 1175–1176 in carotid artery disease, 1404 in carotid artery stenting, 1165–1166 in carotid endarterectomy, 1165, 1400, 1412 for deep vein thrombosis prophylaxis, 985 dipyridamole combined with, 729 for carotid artery stenosis, 1404 dose-response effects with, 1155–1156 hemorrhagic stroke risk and, 532 mechanism of action, 1150–1151 microembolic signals and, 846

1452

Index

Aspirin (Continued) microhemorrhages associated with, 553–554 for migraine patients, 729–730, 729t intravenous, 729–730 pharmacokinetics of, 1155 for primary stroke prevention, 248–249, 1160–1162, 1168 in diabetic patients, 1161 in middle cerebral artery atherosclerosis, 918–919 in women, 1160–1161 with prosthetic valves, 821 resistance to, 1149, 1156–1159 management of, 1159 for secondary stroke prevention, 779, 1163, 1164t, 1168, 1210 of cardioembolic stroke, 816, 1164, 1183 clopidogrel combined with, 1159, 1164–1166 early recurrence and, 1161–1162 vs. warfarin, 1162–1163 thrombolytic therapy combined with, 967, 977–978 toxicity of, 1159 warfarin-associated hemorrhage and, 549 Assessment. See Stroke scales. Association studies, 1293–1294 of arteriovenous malformations, 1297 genome-wide, 1294, 1296 of intracranial aneurysms, 1295–1296 Asterixis, lacunar infarct causing, 500 Astrocytes, 16, 18f, 122–123 axonal regeneration inhibited by, 165 blood-brain barrier and, 16–17 focal ischemia and, 17–20, 19f in inflammatory reaction, 101, 138 in light microscopy, 69f necrosis of, 114 population size of, 165 secondary neuronal death and, 20 stem cells derived from, 162 tissue factor expressed by, 21 Ataxia basilar artery occlusion with, 457 lateral medullary infarction with, 471 Ataxic hemiparesis anterior cerebral artery infarction with, 368 dysarthria–clumsy hand syndrome and, 499 lacunar infarction with, 492, 498 sensory, thalamic hemorrhage with, 565 Ataxic nystagmus, 458–459 Atherosclerosis. See also Coronary artery disease. alcohol consumption and, 800 aneurysms associated with, 591 of anterior cerebral artery, 362 aortic. See Aortic plaques, of proximal aorta. branch occlusion mechanisms in, 451–452, 451f carotid artery. See Carotid artery atherosclerosis. dementia secondary to, 502–504 diffuse vascular, 202 bruits and, 202 endothelium-dependent relaxation in, 6–7 homocysteine and, 781–782 inflammation in, 695–698, 697f intracranial, 1210–1212 endovascular techniques for, 1210–1212 lacunar infarction secondary to, 299, 507 medical management of, 1210–1211 natural history of, 1210–1211 race/ethnicity and, 302

Atherosclerosis (Continued) in microcirculation, 485 of middle cerebral artery, 388–389 platelet and leukocyte products in, 7 premature, homocystinemia and, 781 “response to injury” theory of, 695–696, 697f smoking and, 801 of spinal cord vessels, 646 ultrasonographic techniques for power Doppler, 834f real-time compound imaging, 832 three-dimensional, 833 ultrasonography of, 833–841 in advanced disease, 836–841, 837f–840f, 837t early plaque in, 835–836 flow-mediated dilation in, 836 intima-media thickness in, 833–835, 835f vertebrobasilar, 450–452, 451f, 460 Atherothrombosis, 776 Atherothrombotic stroke. See also Ischemic stroke. in autopsy series, 299–300 large artery, 295–297 diffusion-weighted MRI and, 893 in TOAST classification, 318–320, 318t of posterior cerebral artery, 428, 428f prognosis of, 222–223, 222f recurrence risk after, 224–226, 225f–226f, 225t ATP (adenosine triphosphate), in white matter, 125–126, 130–131, 131f, 133f Atrial fibrillation, 819–820, 1173–1176. See also Cardioembolic stroke. atrial appendage thrombi in, 1174 cardioversion for, embolization secondary to, 1176 carotid territory TIAs and, 341 cognitive impairment and, 260 hemostatic system in, 775, 823 after intracerebral hemorrhage, anticoagulation and, 820, 1111 prevalence of, 1173, 1174f prevention of stroke in, 819–820, 1147, 1166–1167, 1175–1176 prognosis after stroke and mortality and, 223, 229 recurrence risk and, 225–227, 1175 stroke risk and, 209–210, 209f, 210t, 248, 819–820, 1173–1174, 1175t cardiac failure and, 210 gene variant and, 275 lacunar, 491 transesophageal echocardiography and, 819–820 types of, 1173 von Willebrand factor and, 773 warfarin in, 1175–1176 with antiplatelet agents, 1166–1167 after intracerebral hemorrhage, 820, 1111 vs. newer agents, 1183–1184, 1183t stroke risk and, 248, 819–820 Atrial flutter, 820 Atrial natriuretic peptide cerebrovascular tone and, 3 subarachnoid hemorrhage and, 607 Atrial septal aneurysm, 1181 Autonomic disturbances anterior cerebral artery infarction with, 375 middle cerebral artery infarction with, 396, 396f

Autophagy (autolysis), 79, 88, 157 of ischemic neurons, 71–73, 107–108, 113 Autoregulation of cerebral blood flow, 48–49, 48f arterial occlusive disease and, 49 with arteriovenous malformations, 57, 631, 1362 fibrinoid necrosis and, 489 hypertensive encephalopathy and, 734, 735f, 736–738 after intracerebral hemorrhage, 56–57, 1030–1031 intracranial pressure and, 1018, 1019f after ischemic stroke, 53 after subarachnoid hemorrhage, 59, 598 of spinal blood flow, 645 Axonal remodeling, 162, 165 Azathioprine for giant cell arteritis, 1090t, 1091 for inflammatory vasculopathies, 1090t

B Baclofen, for spasticity, 1122t, 1123 Barbiturates abuse of, 798 intracranial pressure and, 1022 for neuroprotection in aneurysm surgery, 1302 in carotid endarterectomy, 1407–1408 Barthel Index (BI), 230–231, 230t, 231f, 321–322, 322t, 1116, 1117t extended, 322 inpatient rehabilitation and, 1119 Basal ganglia arteriovenous malformations, 1361 Basal ganglia hemorrhage, 556 recurrent, 540 Basal ganglia stroke, neuronal cell transplantation after, 164 Basal lamina, microvascular, 16–17, 18f angiogenesis and, 21–22 focal cerebral ischemia and, 17–21, 37–38 plasmin activity and, 31, 36–37 Basilar artery anatomy of, 448–450, 450f–451f of apex region, 1322–1323, 1323f–1324f paramedian branches in, 488 aneurysms of, 452–453, 452f angiography of, 915f aneurysms of apex of, 452, 452f, 1322–1323, 1323f with intraventricular hemorrhage, 1350 surgery for, 1322–1330, 1323f–1324f, 1326f–1327f, 1329f aneurysms of trunk of, surgery for, 1334 atherosclerosis of, 450–452, 451f dissection of, 453–454, 666 prognosis of, 674 fibromuscular dysplasia of, 454 neck trauma and, 454 neurofibromatosis affecting, 455 Basilar artery migraine, 474–476, 726–727 Basilar artery occlusive disease. See also Vertebrobasilar disease. angiography in, 920f–921f of branches. See Basilar branch disease. clinical course with, 457 clinical presentation of, 456–457

Index 1453 Basilar artery occlusive disease (Continued) clinical syndromes of, 457–460 diagnostic imaging in, 456, 457f with CT modalities, 878, 879f historical aspects of, 456 imaging results with, 297 intraarterial thrombolysis in, 1233–1234 lacunar, 461–462 of long circumferential branches, 462–468 management of, 1028 patterns of infarction in, 456 posterior cerebral artery stem in, 429, 429f temporal course of, 455–456 at top of artery, 460–461, 460f transcranial Doppler ultrasonography of, 843 contrast-enhanced, 848 vertebral artery syndrome indistinguishable from, 468 Basilar branch disease, 461–462, 462f, 463t. See also Anterior inferior cerebellar artery (AICA); Posterior inferior cerebellar artery (PICA); Superior cerebellar artery. bat-PA (vampire bat salivary plasminogen activator), 35 Bcl-2 family of proteins, 81–84, 82f, 108–113, 110f calpains and, 93 cavernous angiomas and, 179 in cerebral ischemia, 114–115 erythropoietin and, 156 in human brain, 115t–116t preconditioning and, 157–158, 157f–158f zinc and, 95 Behçet’s disease, 455, 694–695 Benzodiazepines in critical care, 1010 for seizure control, 1023 Berry aneurysms. See Saccular (berry) aneurysms. β-blockers in acute stroke, 1000 in hypertensive encephalopathy, 738 in migraine patients, 729–730, 730t bFGF (trafermin), 1056t–1057t, 1072 BI. See Barthel Index (BI). Bicaudate index, 603–604, 604t Bilirubin oxidized products, in subarachnoid hemorrhage, 11 Binswanger’s disease, 253, 502–504 vs. CADASIL, 762 Bivalirudin, 973 Black people aortic plaques in, 747–748 basilar artery stenosis in, 450 cryptogenic infarction in, 302 intracerebral hemorrhage in putaminal-thalamic, 559 rate of, 531 lacunar infarction in, 202, 300, 490–491 microbleeds in, 897 sickle cell trait in, 782 stroke outcomes in, 202–203, 220–222 stroke risk in, 189–196, 191f–192f, 195f, 202, 203f stroke types in, 202 subarachnoid hemorrhage in, 589–590 Bladder dysfunction, after stroke, 1119–1120, 1120t Bland infarction, 293 Bleeding globes, 541

Blinded clinical trials, 1197 Blindness. See also Transient monocular blindness (amaurosis fugax). giant cell arteritis with, 687–689 posterior cerebral artery infarction with, 430–431 Blindsight, 431 Blood glucose. See also Hyperglycemia after stroke; Hypoglycemia. in acute stroke, 1003–1004 cerebral blood flow and, 47–48 in intensive care unit, 1024 Blood pressure invasive monitoring of, 1016 lability of, with brainstem lesions, 456 Blood pressure management. See also Antihypertensive treatment. in acute stroke, 1000–1001 after carotid endarterectomy, 1413 in emergency department with acute stroke, 935–936 with intracerebral hemorrhage, 938–939 with subarachnoid hemorrhage, 941 in intensive care unit, 1014–1016, 1027–1028 with intracerebral hemorrhage, 1030–1031, 1107 in emergency department, 938–939 in reversible cerebral vasoconstriction syndromes, 770 with subarachnoid hemorrhage, 598, 941, 1035 in thrombolytic therapy, 961–962, 965–966, 966t Blood-brain barrier, 16–17, 163–164. See also Permeability barrier, microvascular. disrupted by plasminogen activators, 967 disrupted in acute stroke, 140–141 FLAIR imaging of, 884, 884f, 893 gadolinium enhancement and, 893 hemorrhagic transformation and, 897 disrupted in cerebral venous thrombosis, 899 drug delivery systems and, 1072 focal ischemia and, 17–18, 19f osmotherapy and, 1019–1020 ultrasound for permeation of, 859 white matter microangiopathy and, 23 B-mode ultrasonography, 831–832, 833f of atherosclerotic plaques, 839–840, 840f Borderzone collaterals, 427 in carotid stenosis, 340 Borderzone infarction carotid disease and, 340 cerebellar, 474, 475f–476f in reversible cerebral vasoconstriction syndromes, 767–769, 768f in sickle cell disease, 782 Borderzone region, arteriovenous malformations in, 616–617, 624–625, 625f Botulinum toxin, for spasticity, 1122t, 1123 Brachial artery reactivity, 836 Brain death, diagnosis of, 923–924 Brain natriuretic peptide cerebrovascular tone and, 3 fluid/electrolyte balance and, 1012 subarachnoid hemorrhage and, 606–607 Brainstem. See also Medulla; Pons. arteriovenous malformations involving, 1361, 1377–1378 cavernous malformation in, 1393f–1394f, 1394 cerebellar infarction with compression of, 456, 1444

Brainstem hematoma. See also Medullary hemorrhage; Pontine hemorrhage. surgical treatment of, 576–579, 1033 Brainstem infarction. See also Basilar artery occlusive disease; Medullary infarction; Pontine infarction; Vertebral artery occlusive disease. basilar artery dissection with, 454 basilar migraine and, 727 blood pressure and blood flow lability in, 456 confabulation in, 461 hallucinations in, 461 herniation with, 460 in meningitis, 455 palatal myoclonus in, 457–458 posterior inferior cerebellar artery and, 466 rare causes of, 455 skew deviation of gaze in, 458 in syphilis, 455 thrombolytic therapy in, 1234 vertebral artery dissection with, 453–454, 678f ultrasonography and, 841 vertebral artery occlusion with, 473 Broca’s aphasia, 397–398, 398f. See also Motor aphasia. functional imaging in, 406 natural history of, 407 Bromocriptine, aphasia recovery and, 409 Brucellosis, posterior cerebral artery infarction in, 428–429 Bruits, 202, 354 subclavian steal and, 1216

C CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), 255, 270–271, 485, 502, 507, 758 cholinesterase inhibitors and, 261 clinical presentation of, 759–760, 760f concluding summary of, 762 diagnosis of, 762 differential diagnosis of, 762 familial hemiplegic migraine and, 726 genetics of, 761–762 historical understanding of, 758–759 microbleeds in, 897 migraine attacks in, 721 natural history of, 759–760, 760f neuroimaging in, 760, 761f pathology of, 760–761 Caffeinol, 1056t–1057t, 1074 Calcitonin gene–related peptide, 3–4 Calcitonin gene–related peptide antagonists, for migraine, 729–730 Calcium anoxic-ischemic white matter injury and, 128–131, 128f, 131f, 133–134, 133f ischemic neuronal death and, 93 potassium ion channels and, 4–5, 9–10, 9f vascular smooth muscle and, 6, 9f Calcium channel blockers, 245–246 for cytoprotection in ischemic stroke, 1055–1058 for elevated blood pressure in acute stroke, 1001 in intensive care unit, 1015

1454

Index

Calcium channel blockers (Continued) in hypertensive encephalopathy, 738 in migraine-related stroke, 1095 in moyamoya disease, 1088 in reversible cerebral vasoconstriction syndromes, 766f, 770, 1087 for vasospasm, in subarachnoid hemorrhage, 1037 Calcium sparks, 4–5 Call-Fleming syndrome. See Reversible cerebral vasoconstriction syndromes. Callosal apraxia, 410 Callosomarginal artery, 363–364 Calpains, 93, 1067–1068 cAMP. See Cyclic adenosine monophosphate (cAMP). Canadian Neurological (Stroke) Scale (CNS), 308, 312–314, 314t Candidate gene studies, 172–173, 1294 of arteriovenous malformations, 1297 of intracranial aneurysms, 1295–1296 Cangrelor, 974 Capillaries cerebral. See Microvasculature, cerebral. spinal cord, 645 Capillary malformation–arteriovenous malformation syndrome, 180 CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), 271, 762 Carbamazepine, white matter protection and, 134 Carbon dioxide partial pressure (Pco2), arterial, cerebral blood flow and, 47 Carboxyl-terminal modulator protein, 96 Cardiac arrest amnesia following, 73 global ischemia in, 73, 75 animal models of, 76 necrosis in, 88 hypothermia following, 1073, 1075, 1111 Cardiac catheterization atheroembolism secondary to, 750–751 ischemic stroke secondary to, 823 Cardiac disease prognosis after stroke and, 223 recurrent stroke risk and, 224–227 stroke risk associated with, 208–210, 208f–209f Cardiac enzymes, 1000 Cardiac events, after stroke, 228–229, 1000 Cardiac output, cognitive function and, 260 Cardiac shunts, right-to-left. See also Patent foramen ovale. diagnosis of, 816, 847 Cardiac surgery, atheroembolism secondary to, 750 Cardiac tumors, 818, 819f, 823, 1180 Cardioembolic stroke, 297–299, 814. See also Atrial fibrillation. anticoagulation in, 816, 816t, 820, 985–986 in acute stroke, 1185–1186 cardiac conditions associated with, 299, 814, 814t, 816–823, 1173, 1174f. See also specific conditions. dysrhythmias, 819–820 structural defects, 816–819, 817f–819f valvular disease, 821–823, 821f–822f cardiac procedures associated with, 823 carotid artery stenosis with, 340–341 cerebellar, 1443

Cardioembolic stroke (Continued) clinical features of, 298–299, 814–815, 815f, 815t lacunar syndromes and, 300 diagnostic studies in, 299, 815–816 diffusion-weighted MRI as, 893 emboli in, properties of, 297–298, 814, 815t, 1173 hemorrhagic transformation in, 814–815, 815f, 897 hemostatic system and, 823 management approach in, 816, 816t percentage of, in NOMASS study, 222f prevalence of, 1173 prevention of, 816, 1147, 1164, 1168, 1173. See also specific conditions. anticoagulant-related hemorrhage in, 1184–1186 anticoagulants for, 1182–1184, 1183t with aortic arch disease, 1182 in atrial fibrillation, 1173–1176 basic concepts for, 1173, 1174f, 1174t with cardiac tumors, 1180 in cardiomyopathies, 1176–1177 in myocardial infarction, 1177–1178 with patent foramen ovale, 1180–1182 in valvular disease, 1178–1180 prognosis after, 814 functional status in, 231 mortality in, 222–223 recurrence risk in, 225–226, 225t, 226f in systemic lupus erythematosus, 692, 822 in TOAST classification, 318–320, 318t Cardiomyopathy, 223, 816–817, 1176–1177 Caribbean-Hispanics, early death after ischemic stroke in, 220 Carotid artery(ies) anatomy of, 334, 335f aneurysms of bifurcation, 914f, 1312–1313, 1312f–1314f cavernous, 1305–1306 intraventricular hemorrhage secondary to, 1350 paraclinoid, 1306–1308, 1309f–1310f petrous, 1305 anomalies of, aneurysms associated with, 592 dissection of, 662–663, 665f antithrombotic therapy in, 986 catheter-related, 911 clinical manifestations of, 664–666, 666t course and prognosis of, 674–675 epidemiology of, 661 imaging of, 666–672, 668f–672f magnetic resonance imaging/angiography of, 898, 898f mechanisms of ischemia in, 664 mimicking migraine, 722 pathology of, 662, 663f with subarachnoid hemorrhage, 661 treatment of, 672–674, 674f–677f, 679f, 1084–1086 ultrasonography of, 841 giant cell arteritis in, 688 intima-medial thickness of, 259 kinking of, 336 persistent primitive connections of, 450 pseudoocclusion of, 847–848

Carotid artery atherosclerosis. See also Carotid artery disease. angiography in, 917–918, 918f anterior cerebral artery infarction and, 362 extracranial, 334–336, 335f–336f fibromuscular dysplasia with, 1086 high-resolution MRI of plaque in, 899 intracranial, 337, 338f plaque morphology in, 1405–1406 irregular, 346, 346f ultrasonography of, 839–840, 840f, 1405 stroke mechanisms and, 340–341, 342f, 347 t-PA elevation in, 775 transient ischemic attack and, 349–350, 352 Carotid artery disease, 334. See also Carotid artery atherosclerosis; Large artery thrombosis with infarct. anatomic basis of, 334, 335f angioplasty and stenting for, 354–355, 1204, 1213–1215 in acute occlusion, 1233 angiography and, 917–918, 918f antiplatelet therapy with, 1165–1166 embolization at time of, 846 vs. endarterectomy, 1400–1401, 1404–1405, 1405t, 1414 in migraine patients, 729 ulcer healing after, 354 anterior cerebral artery infarction in, 362 aortic plaques coexisting with, 749 asymptomatic, 341, 353–355 bruit in, 202, 354 bypass for. See Extracranial-intracranial bypass. clinical significance of, 334 clinical syndromes in, 344. See also Transient ischemic attacks (TIAs), in carotid artery disease. anterior choroidal artery and, 345–346 cerebral infarction, 346–348, 348f dementia, 348 ocular, 344–345, 344f–345f reversible ischemic neurologic deficit, 348 transient ischemic attacks, 336, 347–353, 353f collateralization in, 844 contralateral, 1406 with distal insufficiency, 342–344, 343f, 346–348, 348f extracranial lesions in, 334–337, 336f asymmetry of, 334 CT angiography of, 874, 875f hemodynamically significant, 335, 335f–336f not atherosclerotic, 336–337 plaque rupture of, 335–336 tempo of development of, 334 in fibromuscular dysplasia, 1086 hemodynamic effects of, 49, 50f stroke risk and, 50 intracranial lesions in, 337, 338f lacunar infarcts in, 490 magnetic resonance angiography of, 898 mechanical thrombectomy in, 1233 medical management of, 1403–1404 microemboli associated with, 845–846 in moyamoya disease, 703, 709–710, 712–715, 714f–715f, 922 pathophysiology of ischemia in, 337–344 collateral pathways in, 337–340, 339f distribution of lesions and, 339f

Index 1455 Carotid artery disease (Continued) stroke mechanisms in, 340–344, 341f–343f transient ischemic attacks and, 340–342 posterior cerebral artery occlusion in, 427–428 radiation-induced, 337, 1087 Takayasu’s arteritis in, 691–692 thrombolytic therapy in, 1233 thrombosis of, cerebral infarction and, 340–343, 346–347 ulceration of, 335, 341, 343f asymptomatic, 354, 1403 transient ischemic attack and, 352–353 ultrasonography in, 831–833, 833f–834f in advanced atherosclerosis, 836–840, 837f–838f, 837t, 840f contrast-enhanced, 847–848 early plaque in, 835–836 intima-media thickness in, 833–835, 835f of plaque angiogenesis, 841 of plaque morphology, 839–840, 840f, 1405 of plaque motion, 840–841 transcranial, 337, 354, 842t, 845–848 Carotid artery stump pressure measurement, 1408 Carotid endarterectomy antiplatelet therapy with, 1165 for asymptomatic stenosis, 353–354 concluding summary on, 1414 with contralateral occlusion, 1406 coronary artery bypass grafting and, 1406–1407 decision making for, 1405–1407 vs. medical management, 1403–1404 natural history and, 1403 vs. stenting, 1404–1405, 1405t, 1414 clinical trials of, 1213, 1398–1400 vs. angioplasty and stenting, 1214–1215, 1400–1401, 1404–1405, 1405t Doppler ultrasonography after, 354–355 magnetic resonance spectroscopy after, 894 mental function and, 348 microemboli and, 845–846 operative considerations for anesthesia in, 1407–1408 complications in, 1412–1414 monitoring in, 1408 neuroprotection in, 1407–1408, 1410–1411 patch grafting in, 1409 postoperative care in, 1412–1414 shunting in, 1408–1409, 1411–1412, 1412f surgical technique in, 1409–1412, 1410f– 1411f pathology specimens from, 341, 342f, 352–353 stroke after, heparin-induced thrombocytopenia and, 777 for symptomatic stenosis vs. angioplasty and stenting, 1400–1401 concluding summary on, 1401 published guidelines for, 1400 randomized trials of, 1398–1401 after transient ischemic attack, 349 with anterior cerebral artery anomaly, 369 Carotid patch grafting, 1409 Carotid-cavernous fistula, 633, 633f Caspase-independent apoptosis, 86–88, 87f, 109 Caspases, 80–81, 82f–84f, 108–110, 110f–111f in cerebral ischemia, 88, 113–114 endoplasmic reticulum and, 111 heat shock proteins and, 113

Caspases (Continued) in human brain, 115t–116t inflammation and, 143 inhibitors of, 83–84, 113, 115 as potential neuroprotection target, 1067–1068 preconditioning response and, 156–158 in spinal cord ischemia, 114–115 Catheter-based treatment. See Endovascular therapies. Cauda equina, claudication of, 651 Caudate hemorrhage, 559–561, 561f gross anatomy of, 538–539, 539f Caudate infarction, clinical features of, 372, 374–375 Cavernous angiomas cerebral. See Cavernous malformations, cerebral. spinal cord, 651 Cavernous malformations, cerebral, 169, 176–180, 634–635, 634f, 1388 clinical presentation of, 1390–1391 diagnostic classification of, 634–635, 635t diagnostic imaging of, 545, 546f, 1391–1392 epidemiology of, 1389 future studies needed on, 180, 1396 genetics of, 176–180, 178f, 178t, 274, 545, 634, 1389–1390 genotype–phenotype correlation with, 180 with intracerebral hemorrhage, 544–545, 546f, 546t, 634–635 thalamic, 561 management of, 1392–1394, 1393f–1395f radiosurgery in, 1384–1385, 1391, 1394, 1395f multifocal, 1389–1390, 1391f overview of, 176 pathogenesis of, 179, 1389–1390 pathologic features of, 1388, 1389f–1390f Cavernous sinus thrombosis, 519–520. See also Cerebral vein and dural sinus thrombosis. CBF. See Cerebral blood flow (CBF). CD36 scavenger receptor, 143, 143f, 143t CD95. See Fas (CD95) and Fas ligand. Cell death pathways, 156–157. See also Ischemic cell death. tolerance and, 157–158 Cell-based therapies, 1134. See also Stem cells, neural. cells used in, 1135–1140, 1135t alternative adult stem cells, 1136–1140, 1139f, 1140t embryonic, 1135 neural, 1135–1136, 1137f–1138f complexity of stroke and, 1134 concluding summary on, 1144 goals of, 1134 guidelines for, 1144 historical background of, 1134 mechanisms of, 1140–1141 pilot clinical trials on, 1141 recent and ongoing studies of, 1141–1142, 1142t safety issues in, 1143 translational barriers in, 1142–1143 Central pain, 1120. See also Dejerine-Roussy syndrome; Thalamic pain syndrome. Central venous line, 1016 Central volume principle, 44–45

Centrum semiovale infarcts lacunar, 300–301, 495, 502 pathogenesis of, 300, 502 pure sensory stroke with, 301 Cerebellar hemorrhage, 569–572, 1440–1442 arteriovenous malformation leading to, 570, 1361, 1361f causes of, 570, 1440 clinical course with, 571–572, 572f clinical features of, 570–571, 571t, 1440–1441 gross anatomy of, 535, 539–540, 541f illustrative cases of, 1442, 1442f–1443f intraventricular extension of, 570, 570f, 572, 573f, 1355f postoperative management with, 1442 rates of, 570 sites of, 570, 570f, 573f, 575f surgery for, 569–570, 572, 1033, 1112, 1336– 1337, 1340, 1341f, 1343–1344, 1343f, 1441 indications for, 1441 technique of, 1441–1442, 1441f warfarin-associated, 548–549 Cerebellar infarction, 1443–1444. See also Anterior inferior cerebellar artery (AICA); Posterior inferior cerebellar artery (PICA); Superior cerebellar artery. ataxic hemiparesis in, 498 borderzone, 474, 475f–476f causes of, 1443 arterial dissection as, 669f, 670–671 vertebral artery occlusion as, 473, 1443 clinical features of, 1444 cord infarction combined with, 653 edema secondary to, 456, 1434–1435 illustrative cases of, 1444, 1444f–1445f management of, 1028–1029 decompressive surgery in, 1430f, 1434–1435, 1444 treatment options in, 1444 multiple, 474 pathophysiology of, 1443–1444 syndromes of, 463t Cerebellum anatomy of, 1440 arterial supply of, 447–448, 448f–449f, 1440. See also specific arteries. arteriovenous malformations involving, 1361, 1361f hemorrhagic, 544–545 Cerebral arteries, anatomy of, 334, 335f. See also Cerebral vasculature; specific arteries. Cerebral blood flow (CBF), 44. See also Autoregulation, of cerebral blood flow. alcohol consumption and, 800 in arterial occlusive disease, 49–50, 50f arterial Pco2 and, 47 arterial Po2 and, 47 with arteriovenous malformations, 57 after brainstem infarction, 456 control of, 46–47 energy metabolism and, 46–49, 48f glucose concentration and, 47–48 hemoglobin concentration and, 47 after intracerebral hemorrhage, 56–57, 56f, 59–60 after ischemic stroke, angiogenesis and, 163–164 in ischemic stroke, acute, 50–54, 51f–53f, 59 lacunar infarcts and, 507

1456

Index

Cerebral blood flow (Continued) measurement methods for, 44–46 in CT perfusion imaging, 877 in intensive care unit, 1018 in large artery occlusive disease, 49 in MR perfusion imaging, 885–887, 892 metabolic demand and, 47 in moyamoya disease, 713 revascularization and, 714–716 normal values of, 46 oxygen content and, 47 perfusion pressure and, 46–49, 48f statins and, 7 after subarachnoid hemorrhage, aneurysmal, 58–60 summary of, 59–60 viscosity and, 46–47 Cerebral blood volume in arterial occlusive disease, 49–50 in CT perfusion imaging, 877 in MR perfusion imaging, 885–887, 892 in acute stroke, 900–901 of cerebral venous thrombosis, 899–900 perfusion pressure and, 48–49, 48f subarachnoid hemorrhage and, 58–59 Cerebral edema. See also Cytotoxic cerebral edema; Ionic cerebral edema; Vasogenic edema. in acute stroke, 998–999 blood pressure management and, 1000 course of, 1020f hyperglycemia and, 1003–1004 hypothermia for, 1003 middle cerebral artery, 1025, 1426–1427, 1427f after arteriovenous malformation surgery, 1362 in cerebellar infarction, 456, 1434–1435 in cerebral venous thrombosis, 19–20, 517–518, 522–523, 527 magnetic resonance imaging and, 899–900 treatment of, 1096, 1435–1436 classification of, 1426 focal cerebral ischemia leading to, 17–19 in hypertensive encephalopathy, 734–735, 737–738 in eclampsia, 737 imaging of, 735–737 intracerebral hemorrhage with, 1029–1031, 1109, 1339 osmotherapy for, 998–999, 1019–1021 perihematomal, 896 in reversible cerebral vasoconstriction syndromes, 767–769 after subarachnoid hemorrhage, 606, 1038 thrombolytic therapy leading to, 967 in traumatic brain injury, 1435 Cerebral hyperperfusion syndrome, 1413 Cerebral infarction. See also Infarct age; Infarct core; Ischemic stroke; Necrosis. early CT signs of, 870–871, 871f–872f focal ischemia as, 75–76. See also Focal cerebral ischemia. histopathology of, 68–69, 69f, 71–73 initial development of, 76 sharp border of, 69f, 72–73 after subarachnoid hemorrhage, 604

Cerebral ischemia. See also Delayed cerebral ischemia (DCI); Focal cerebral ischemia; Global cerebral ischemia; Ischemic stroke. animal models of, 73, 1051 white matter injury and, 124–125 in atherosclerosis, pathophysiology of, 7 cell death pathways in, 107. See also Apoptosis; Necrosis. classification of, 75 experimental, plasminogen activators in, 37–38 histopathology of, 68 apoptosis and, 71f, 72–73, 73t infarction in, 68–69, 69f, 71–73 levels of organization and, 68, 69t selective neuronal necrosis in, 68–73, 69f–72f, 73t selective vulnerability and, 69 in moyamoya disease, 711, 713, 715–716 platelet activation in, 776 tolerance to, inflammation and, 138, 143–145 unstable phase of, before recanalization, 997 mobilization and, 1002 white matter. See White matter anoxic-ischemic injury. Cerebral metabolic rate of glucose (CMRglc) after intracerebral hemorrhage, 56, 57f in ischemic stroke, acute, 52–53 remote effects in, 54–55 measurement of, 46 metabolic demand and, 47 normal values of, 46 Cerebral metabolic rate of oxygen (CMRO2) in arterial occlusive disease, 49, 50f cerebral blood volume and, 48–49 hyperventilation and, 47 after intracerebral hemorrhage, 56, 56f in ischemic stroke, acute, 50–54, 51f–53f remote effects in, 54–55, 55f measurement of, 46 metabolic demand and, 47 normal values of, 46 subarachnoid hemorrhage and, aneurysmal, 58–59 Cerebral metabolism, 46 blood flow and, 46–49, 48f in ischemic stroke, acute, 50–54, 51f–53f remote effects in, 54–55, 55f measurement methods for, 46 normal values of, 46 summary of, 59–60 surgical retraction of brain tissue and, 59 Cerebral perfusion pressure, 46–49, 48f in arterial occlusive disease, 49–50 in intracerebral hemorrhage, 1030–1031 intracranial pressure management and, 998–999, 1016, 1018–1019, 1019f Cerebral salt wasting syndrome, 607, 999, 1012, 1039 Cerebral vasculature, 16. See also Cerebral arteries, anatomy of; Microvasculature, cerebral. Cerebral vein and dural sinus thrombosis, 516. See also Venous thrombosis. anatomic basis of, 516–517, 517f angiography of, 523, 523f, 922–923, 923f clinical aspects of, 519–520 contraception and, 527 decompressive surgery in, 1096, 1435–1436 diagnosis of, 520–523, 521f–523f

Cerebral vein and dural sinus thrombosis (Continued) dural arteriovenous fistulas and, 180–181, 1280–1281 epidemiology of, 516 etiology of, 518–519, 518t factor V Leiden and, 773 future pregnancy and, 524, 527 heparin-induced thrombocytopenia and, 777 hypercoagulable states and, 783 magnetic resonance imaging of, 521–523, 522f, 899–900, 899f microvascular damage in, 19–20 overview of, 516 pathophysiology of, 517–518 prognosis of, 523–525 transcranial Doppler ultrasonography of, 849 treatment of, 525–527, 525t, 1096–1097 Cerebrofacial arteriovenous metameric syndromes, 1265, 1268f Cerebrolysin, 1056t–1057t, 1070 Cerebrospinal fluid (CSF) dural sinus thrombosis and, 518 with intracerebral hemorrhage, 555–556 protein level in in Behçet’s disease, 694–695 in primary angiitis, 689–690 after subarachnoid hemorrhage bilirubin oxidized products in, 11 endothelin in, 11 hemoglobin in, 10–11, 10f Cerebrospinal fluid management. See also Ventricular catheter. in aneurysm surgery, 1320 after hematoma evacuation, 1342 Cerebrovascular resistance, 46–47 arterial Pco2 and, 47 autoregulation and, 48 Cerebrovascular tone alcohol consumption and, 800 angiographic effect on, 911 arterial Pco2 and, 47 arterial Po2 and, 47 pathophysiology of, 6–12 regulation of, 3–6, 16 reversible cerebral vasoconstriction syndromes and, 769–770 smoking and, 801–802 viscosity of blood and, 47 Cerestat. See Aptiganel (Cerestat). Certoparin, 977, 980t, 982t Cervical spine manipulation, cord infarction associated with, 652 Cervical spondylosis, vertebral artery occlusion in, 454 Cervicothoracic arterial territory, 643 cGMP. See Cyclic guanosine monophosphate (cGMP). Charcot-Bouchard aneurysms, 489–490, 490f Children cerebral arteriovenous malformations in, 1362–1363 ischemic stroke in, classification of, 321 Chinese people alcohol consumption in, 799 genetics of intracerebral hemorrhage in, 534 Chiropractic manipulation arterial dissection associated with, 453, 661–662 ischemic stroke associated with, 454

Index 1457 Chlamydia pneumoniae, in carotid artery disease, 336 Cholesterol, serum. See also Low-density lipoprotein (LDL). cognitive impairment and, 259 stroke risk and, 204–205, 205f in men of Japanese origin, 532 Cholesterol emboli from aorta, 749, 751 lacunar infarcts caused by, 489–490 in retinal circulation, 344, 350–351 Cholesterol-lowering therapy, cerebrovascular effects of, 7, 8f Choline, in infarct, 888, 894 Cholinesterase inhibitors with aphasia therapy, 1124t, 1125 with physical therapy, 1124t, 1129 for vascular dementia, 261, 1124 Churg-Strauss syndrome, 693 Cigarette smoking. See also Smoking. aneurysm development and, 592 carotid atherosclerosis and, 334 endothelial dysfunction and, 836 as risk factor for stroke, 211, 212f, 212t, 242–243, 243t as intracerebral hemorrhage, 531–532 as subarachnoid hemorrhage, 211–212, 590 Cilostazol, for secondary prevention of stroke, 729, 1167 Cincinnati Prehospital Stroke Scale, 309–310, 310t, 932, 934t Cingulate gyrus lesions, clinical features of, 371–375 Circle of Willis, 16 collateral flow in, 337–340, 339f spontaneous occlusion of. See Moyamoya disease. Cirrhosis, and risk of intracerebral hemorrhage, 532 Citalopram, for poststroke depression, 1002, 1121 Citicoline, 1056t–1057t, 1070–1071, 1071t, 1075 Claudication of cauda equina, 651 cerebral, in carotid stenosis, 343 of spinal cord, 651 Clazosentan, for vasospasm, in subarachnoid hemorrhage, 1037 Clinical scales. See Stroke scales. Clinical trials, 1192 adaptive designs in, 1195 adherence to treatment in, 1197–1198 blinding in, 1197 data analyses in, 1198–1201, 1200f, 1202f data collection in, 1198 definition of, 1192 ethics in, 1192–1193, 1202 federal regulations for, 1201–1202 follow-up of patients in, 1197–1198 inclusion and exclusion criteria in, 1195–1196, 1196t informed consent in, 1202 international guidelines for, 1202 outcome measures in, 1192–1194, 1199 prevention trials, 1192 quality assurance in, 1198 randomization in, 1196–1197 recruitment for, 1197 sample size in, 1194–1195, 1195f stopping, 1200, 1200f therapeutic trials, 1192 three phases of, 1193–1194 when to conduct, 1192–1193

Clips, aneurysm, 1302–1303, 1304f Clomethiazole, 968, 1056t–1057t, 1064 Clonidine, in critical care, 1010, 1014 Clopidogrel, 974, 1159–1160. See also Antiplatelet therapy. in acute ischemic stroke, 983, 985 aortic plaques and, 751 in atrial fibrillation, 819–820 in carotid artery stenting, 1165–1166 in carotid endarterectomy, 1165 complications of, 978 microembolic signals and, 846 for migraine patients, 729 in minor stroke or transient ischemic attack, 1162 pharmacokinetics and dosing of, 1160 platelet activation and, 776, 1159 resistance to, 1160 after stent placement, 1247–1249 for secondary stroke prevention aspirin combined with, 1159, 1164–1166 of cardioembolic stroke, 1164 of noncardioembolic stroke, 1163, 1164t summary of, 1168 Clot burden score, 10-point, 874, 874f, 876 CMRglc. See Cerebral metabolic rate of glucose (CMRglc). CMRO2. See Cerebral metabolic rate of oxygen (CMRO2). CNS (Canadian Neurological Scale), 308, 312–314, 314t Coagulation abnormalities, 772. See also Hypercoagulable states; Platelet activation; Prothrombotic states; Thrombosis. acquired deficiencies, 774, 774t alcohol consumption and, 800 antiphospholipid antibodies and, 777–780, 778t fibrinolysis and, 775–776 heparin-induced thrombocytopenia as, 776–777 hereditary deficiencies, 772–774 homocysteine and, 780–782, 780f intraventricular hemorrhage in, 1349 ischemic stroke and, 775, 1085t, 1092–1095 laboratory tests for, 774–775 platelets and, 776 screening of stroke patients for, 783, 784t smoking and, 801 terminology of, 772 in warfarin-associated intracerebral hemorrhage, 940 Coagulation pathways, 29, 30f, 945, 946f. See also Hemostasis. plasminogen activation and, 31–32 Cocaine abuse, 795–797, 1092 intracerebral hemorrhage in, 547–548, 547f, 561, 1354f Codeine abuse, 791 Coenzyme Q10, for MELAS, 1095–1096 Cognitive rehabilitation, 1123–1125, 1123t–1124t Cohort studies, of stroke distribution, 189–190, 193–195 Coil embolization, 1241. See also Endovascular therapies. of arteriovenous malformations, brain, 1263 as single-hole macrofistulas, 1264, 1264f of arteriovenous malformations, spinal, 1274, 1274f of dural arteriovenous malformations, 1286–1288, 1287f

Coil embolization (Continued) of intracranial aneurysms, 1217–1218, 1218f balloon-assisted, 1246, 1247f intraventricular fibrinolysis following, 1354 ruptured, 1242, 1243f, 1249–1250, 1342–1343 stent-assisted, 1218, 1218f, 1246–1247, 1248f, 1249–1250 technology for, 1244–1247 Collagen type 1 A2 gene, 1296 Collagen type IV alpha 1 mutations, 272 Collagen vascular disease. See also Systemic lupus erythematosus. cerebral vasculitis in, 1090t, 1091 Sjögren’s syndrome as, 693–694 Collateral circulation ischemic stroke and, 919–920 revascularization and, 919–920 transcranial Doppler ultrasonography of, 844 Collier’s sign, 461 Color disconnection syndrome, 438 Color Doppler flow imaging, 831–832, 832f, 833t of carotid artery stenosis, 837–838, 838f in giant cell arteritis, 688 transcranial, 842–843 of cerebral venous thrombosis, 849 contrast-enhanced, 848 flow obstruction score in, 850, 850t of vertebral artery stenosis, 838–839 Color dysnomia, 438, 439f Coma anterior inferior cerebellar artery and, 465 basilar artery occlusion with, 457, 464 Community surveillance studies, of stroke distribution, 189–190, 193–194 Compartmental models, 44–45 Compensatory strategies, 1117–1118 Computed tomographic angiography (CTA), 873–877 of aneurysmal subarachnoid hemorrhage, 595–596, 595f of arterial dissection, 666–667, 672, 672f contraindications to, 877 contrast media in, 877 diagnostic accuracy of, 871f–876f, 873–874 diagnostic impact of, 874 of extracranial carotid artery disease, 874, 875f feasibility and technical capacity, 871f, 873 of intracerebral hemorrhage, 537–538, 537f, 878, 1109 of intracranial arterial occlusion, 871f, 873–874, 877 of intracranial arterial stenosis, 873–874 of intracranial thrombus, 873–874, 873f–874f of ischemic brain tissue, 874, 875f–876f of malignant middle cerebral artery infarction, 1428 in moyamoya disease, 273 of posterior circulation ischemia, 878, 879f radiation dose in, 877–878 therapeutic impact of, 876–877 Computed tomographic (CT) venography, of cerebral venous thrombosis, 521, 522f Computed tomography (CT), 870 of aortic plaques, 753 of carotid plaques, 1405–1406 of cavernous malformations, 1391 of cerebellar arteries, 448, 449f

1458

Index

Computed tomography (CT) (Continued) of cerebral infarction, 870–873, 871f of cerebral perfusion. See Perfusion CT imaging. of cerebral venous thrombosis, 520–521, 521f of early ischemic changes, 870–871, 871f–872f of hemorrhagic transformation, 897 in hypertensive encephalopathy, 736–737 of infarct core, 870 of intracerebral hemorrhage, 553, 878, 1337, 1338f lobar, 569, 569t vs. MRI, 895–897, 895f warfarin-associated, 549–550, 551f of ischemic penumbra, 870, 872f of lacunar infarcts, 504–505, 509 of malignant middle cerebral artery infarction, 1427f–1428f, 1428 of migraine patients, 724 in moyamoya disease, 712 noncontrast, 870–873 diagnostic impact of, 871 feasibility and technical capacity, 870–871, 871f–872f prognostic impact of, 872–873 therapeutic impact of, 872 of posterior circulation ischemia, 878, 879f for radiosurgery treatment planning, 1375, 1375f in spinal cord ischemia, 652–653 of subarachnoid hemorrhage, 593–594, 594f, 596 grading scale based on, 596–597, 596t hydrocephalus and, 603–604, 604t thrombolytic therapy decision and, 963–964, 963f–964f of thrombus, with hyperdense artery sign, 870–871, 871f Conduction aphasia, 404–405, 405f functional imaging in, 406 putaminal hemorrhage with, 559 Confabulation, 411, 415, 461 Confusion clinical features of, 414 after right middle cerebral artery infarction, 414–415 Congestive heart failure. See Heart failure. Conjugate horizontal gaze palsy, in basilar artery occlusion, 459 Connective tissue disease aneurysm development and, 592 arterial dissection and, 662 Consciousness, reduced, in cardioembolic infarction, 299 Constraint-induced language therapy, 408 Constraint-induced movement therapy, 1127–1128 Constructional apraxia, 415–416 Continuous-wave Doppler systems, 831, 832f Contrast agents for angiography, risks of, 460, 911 in aneurysm coiling, 1249 for computed tomographic angiography, 877 gadolinium, caution with, 888–889 for ultrasonography, 847 molecular imaging with, 858–859 stroke therapy using, 855–858 Contrast harmonic imaging, 851 Conus medullaris, arteriovenous malformations of, 1370, 1372f Core. See Infarct core.

Corona radiata, lesions of with aphasia, 500 with ataxic hemiparesis, 498 with dysarthria-clumsy hand syndrome, 499 with hemichorea–hemiballismus, 499 Coronary artery bypass surgery carotid endarterectomy and, 1406–1407 embolism secondary to, 823 stroke risk in, 750 Coronary artery disease. See also Myocardial infarction. aortic plaques coexisting with, 749 cognitive impairment and, 259–260 flow-mediated vasodilation measurements in, 836 lateral medullary infarction with, 471–472 migraine-stroke association and, 723–724 stroke prognosis and, 202 stroke risk and, 199–200, 200f, 202, 208, 209f Corpus callosum arterial supply of, 364 disconnection signs of, in anterior cerebral artery infarction, 369–370, 372, 374–375 lesions of, in Susac’s syndrome, 695, 696f lexical information and, 435 sectioning of, hemidyslexia secondary to, 437 Cortical deafness, 403 Cortical spreading depression delayed cerebral ischemia and, 604 migraine and, 728, 1095 Corticosteroid therapy in acute stroke, 1022, 1056t–1057t, 1068 antiphospholipid antibodies and, 779 for Behçet’s disease, 695 for giant cell arteritis, 689, 1090–1091, 1090t for inflammatory vasculopathies, 1090t in intracerebral hemorrhage, 1108 in moyamoya disease, 714, 1088 for primary (isolated) angiitis, 1089–1090, 1090t relative contraindication in cerebral edema, 998–999 reversible cerebral vasoconstriction syndromes and, 1087 after subarachnoid hemorrhage, 599 for Susac’s syndrome, 695 Covert brain infarcts, 255–256 COX-1. See Cyclooxygenase-1 (COX-1). COX-2. See Cyclooxygenase-2 (COX-2). Cranial nerve palsies, carotid artery dissection with, 664 Craniectomy, decompressive. See Decompressive surgery. Craniotomy far lateral suboccipital, 1332–1333 for hematoma evacuation, 1341–1342 pterional for anterior circulation aneurysms, 1302–1305, 1303f, 1305f–1308f for basilar apex aneurysms, 1323–1325, 1326f suboccipital, 1333–1334 for cerebellar hematoma evacuation, 1441–1442, 1441f for cerebellar infarction, 1444 C-reactive protein alcohol consumption and, 800 in giant cell arteritis, 688 prognosis after stroke and, 201–202, 224, 697 recurrent stroke risk and, 227, 775 stroke risk and, 207, 697–698 vascular dementia and, 259 Creatine, in infarct, 888, 894

CREB (cAMP response element binding protein), 75, 89–90, 92, 98 Critical care after microsurgery, 1362 Critical care in acute stroke, 1008 analgesia in, 1010–1012 blood glucose management in, 1024 blood pressure control in, 1014–1016 clinical examinations in, 1008 diagnostic tests requiring transport, 1008 fluid and electrolyte balance in, 1012, 1012t initial assessment in, 1008 intracranial pressure elevation in, 1018–1023, 1019f invasive monitoring in, 1016–1018 mechanical ventilation in, 1008–1010, 1009t pulmonary function in, 1008–1009 sedation in, 1010–1012, 1011t for specific syndromes, 1024–1039 basilar artery occlusion, 1028 cerebellar infarction, 1028–1029 intracerebral hemorrhage, spontaneous, 1029–1035 middle cerebral artery stroke, large, 1024–1028, 1025f subarachnoid hemorrhage, 1035–1039 temperature management in, 1024 venous thromboembolism prophylaxis in, 1023–1024 Crossed cerebellar diaschisis, 54–55, 55f Cross-tolerance, 155 Cryoglobulinemia, 695 Cryptogenic infarction (undetermined cause), 301–302 carotid artery disease and, 336 causes of uncertainty in, 301–302 clinical features of, 302 diagnostic tests in, 302 potential explanations for, 302 in TOAST classification, 318–320, 318t CSF. See Cerebrospinal fluid (CSF). CT. See Computed tomography (CT). CTA. See Computed tomographic angiography (CTA). C-type natriuretic peptide, cerebrovascular tone and, 3 Cutaneomucosal venous malformations, 180 Cyclic adenosine monophosphate (cAMP) platelet aggregation and, 1152 vasodilatation and, 3–4, 8 Cyclic guanosine monophosphate (cGMP) cerebral vasodilatation and, 3–4, 8 platelet activation and, 1152 Cyclin-dependent kinase inhibitor 2A and 2B, 1296 Cyclooxygenase-1 (COX-1), and aspirin, 1150–1151, 1155 Cyclooxygenase-2 (COX-2), 1155 postischemic inflammation and, 140t, 141–142 Cyclooxygenase-2 (COX-2) inhibitors, 1156 Cyclophilin D, 80, 88, 93 Cyclophosphamide for inflammatory vasculopathies, 1090t for primary (isolated) angiitis, 1089–1090, 1090t Cytokines. See also Tumor necrosis factor (TNF). in atherosclerosis, 695–697 in cerebral ischemia, 138–141, 139f, 140t inflammation and, 101 preconditioning associated with, 145 as therapeutic targets, 147 in moyamoya disease, 711 in rheumatoid arthritis, 693

Index 1459 Cytoprotection, 1049 clinical trials of, 1055–1075, 1056t–1057t, 1058f of anti-inflammatory strategies, 1065–1069 of blood substitutes, 1074–1075 of caffeinol, 1074 of calcium antagonists, 1055–1058 future issues for, 1053–1055 of glutamate antagonists, 1058–1061 of hypothermia, 1072–1074 of indirect glutamate-acting agents, 1061–1063 of membrane stabilizers, 1069–1072 of other neurotransmitter modulators, 1063–1065 of trophic factors, 1072 concluding summary on, 1075 definition of, 1049 preclinical testing of, 1051–1053 animal models for, 1051–1053 role of, 1049–1050 targets of, 1050 Cytotoxic cerebral edema, 870, 1426 in cerebral venous thrombosis, 899–900 in diffusion-weighted imaging, 885, 891, 893, 900–901

D Dabigatran, 973, 1183–1184, 1183t Dalteparin, 977, 980t–982t, 981–982 DALYs. See Disability-adjusted life years (DALYs). Danaparoid complications of, 976–977, 976t, 979 efficacy of, 980t–982t, 982, 985 pharmacology of, 971–973 unavailability of, 977 DCI. See Delayed cerebral ischemia (DCI). DDAVP (desmopressin), 1012 D-dimer levels, 32–33, 775 in cerebral venous thrombosis, 523 dementia risk and, 260 after stroke, 775 stroke risk and, 775 Death receptor pathway of apoptosis, 81, 82f–83f, 107, 109–110, 110f, 156–157 in cerebral ischemia, 114 Decerebrate responses, in basilar artery occlusion, 457 Decompression sickness, spinal cord ischemia in, 648 Decompressive surgery, 1426. See also Hemicraniectomy. animal studies of, 1429–1430 in cerebellar infarction, 1430f, 1434–1435, 1444 in cerebral venous thrombosis, 1096, 1435–1436 complications of, 1431 controversial aspects of, 1426 internal, 1430–1431 cerebellar, 1444 in intracerebral hemorrhage, 1341 in middle cerebral artery infarction. See Malignant middle cerebral artery infarction. pathologic basis of, 1426–1427, 1427f posterior fossa, 1028–1029 in subarachnoid hemorrhage, 1038, 1435 techniques of, 1430–1431, 1430f–1431f in traumatic brain injury, 1435 volume of expansion and, 1431, 1431f Decubitus ulcers, 1002, 1121–1122

Deep dyslexia, 399 Deep penetrating arteries, 485 Deep vein thrombosis, prevention of, 1002 antithrombotic therapy for, 979, 985 in critical care patients, 1023–1024 in intracerebral hemorrhage, 1108 Deferoxamine, in intracerebral hemorrhage, 1109 Dehydration, on admission to facility, 999 Dejerine-Roussy syndrome, 430, 496–497. See also Thalamic pain syndrome. Delayed cerebral ischemia (DCI), in subarachnoid hemorrhage, 591, 593–594, 597, 604–606 blood pressure management and, 598, 605 fluid management and, 598, 605 intensive care management of, 1036–1038 with intraventricular hemorrhage, 1352 pulmonary dysfunction and, 606 Delirium, 1002 after right middle cerebral artery infarction, 414–415 Dementia. See also Alzheimer’s disease; Vascular dementia. anterior cerebral artery infarction with, 375 arteriovenous malformations with, 1259t in CADASIL, 758–760 carotid artery disease with, 348 in Sneddon’s syndrome, 780 thalamic, 501, 504 Dendritic swelling, 70–71, 70f, 72f Depression in CADASIL, 759 dementia risk and, 260 poststroke, 232–233, 1002, 1120–1121, 1124t aphasia with, 407 with left caudate lesions, 375 quality-of-life scales and, 324–325 reversible vasoconstriction syndromes and, 770 Desmodus salivary plasminogen activator. See Desmoteplase. Desmopressin (DDAVP), 1012 Desmoteplase, 35, 949 MRI-guided therapy with, 900 Dexamethasone, in ischemic stroke, 146t, 1068 Dexfenfluramine, 794 Dextran, in osmotherapy, 1110–1111 Dextromethorphan, 794 Dextrorphan, 1056t–1057t, 1059 Diabetes insipidus in acute stroke, 999 in critical care patients, 1012 Diabetes mellitus alcohol consumption and, 800 cerebrovascular dysfunction in, 11–12 cognitive decline in, 259 lacunar infarction associated with, 490–491 primary prevention of stroke in, 246–247 antiplatelet agents for, 1161 prognosis after stroke and mortality and, 223–224, 229 recurrence risk and, 224–225, 227 stroke risk and, 205–206, 206f sulfonylureas for, stroke presentation and, 1069–1070 thiazolidinediones for, postischemic inflammation and, 144, 1069 Diaschisis, 54–55, 55f Diazepam, cytoprotective trial of, 1056t–1057t, 1064 Dichloroacetate, for MELAS, 1095–1096

Diet. See also Nutrition. in primary prevention of stroke, 243t, 244 stroke risk and, 214–215 vascular cognitive impairment and, 257 Diet pills, 547, 794 Diffusion tensor imaging, 885 Diffusion-weighted imaging (DWI), 882, 883f, 885, 886f, 888t of cerebral venous thrombosis, 899–900 hemorrhagic transformation and, 897 of intracerebral hemorrhage, 1337–1338 in ischemic acute stroke, 891–893, 894f with cerebral edema, 998 with malignant infarct, 998, 1428, 1429f therapy guided by, 900–902, 900f of lacunar infarcts, 505–506 outcome prediction models and, 229 of silent angiography complications, 911 transient ischemic attacks and, 889–891, 889f–890f Dilated cardiomyopathy, 223, 816–817, 1176–1177 Dimethylarginine, asymmetrical, 6–7 Diplopia, lateral medullary infarction with, 471 Dipyridamole for migraine patients, 729 in moyamoya disease, 1087–1088 platelet activation and, 776, 974 recurrent stroke and, 974 in secondary stroke prevention, 729, 1163, 1164t, 1168 Direct thrombin inhibitors, 973 Disability assessment scales for, 319, 321–322, 322t definition of, 1116 Disability-adjusted life years (DALYs), 279–287, 285t DISC (death-inducing signaling complex), 80–81, 82f–83f Dissection. See Aneurysm(s), dissecting; Arterial dissection. Disseminated intravascular coagulation, 1093–1094 Distribution of stroke, 189 age and, 191, 191f, 193–196, 196f comparison of indices of, 189–191, 190f geographic variations in, 192–195, 193f by incidence rates, 189–190, 193–195, 195f by mortality rates, 189–193, 191f–193f, 219–221 by prevalence, 190–191, 195, 196f race or ethnicity and, 189–196, 198–200, 202–203, 203f, 220 sex discrepancies in, 192–193, 192f, 195–196, 195f–196f summary of, 195–196 temporal decline in, 191–192, 192f, 219–221 Divalproex, contraindicated in hemorrhagic stroke, 937 Dizziness. See Vertigo. Do not resuscitate (DNR) orders, with intracerebral hemorrhage, 1113 Dolichoectasia, intracranial arterial in Fabry disease, 1089 lacunes and, 489–490 transcranial Doppler ultrasonography of, 847 Dolichoectatic aneurysms. See Fusiform aneurysms. Donepezil aphasia recovery and, 409 for CADASIL symptoms, 270–271

1460

Index

Dopamine, aphasia recovery and, 409 Doppler frequency shift, 831 Doppler ultrasonography. See also Color Doppler flow imaging; Power Doppler imaging; Transcranial Doppler (TCD) ultrasonography. of carotid artery disease in advanced atherosclerosis, 836–838, 837f–838f, 837t after angioplasty, 354–355 asymptomatic, 353–354 with dissection, 666–668, 668f, 841 after endarterectomy, 354–355 for cerebral blood flow measurement, 45 technology of, 831, 832f–834f, 833t of vertebral artery stenosis, 838–839, 839f Dorsal lateral medullary syndrome, 467 Doxycycline, focal cerebral ischemia and, 20 Dressing apraxia, 412f, 414 Drug abuse. See Substance abuse. Drug-induced stroke, migraine-related, 724–725 DSC (dynamic susceptibility contrast) imaging, 885–887, 887f Dulteplase, 946 Duplex ultrasonography, 831, 832f–833f. See also Color Doppler flow imaging. Dural arteriovenous fistulas. See Dural arteriovenous malformations. Dural arteriovenous malformations, 175, 180–181, 632–633, 633f, 1280 angiography of, 913f, 1282, 1283f–1287f, 1289 classification of, 1282–1284, 1282t, 1283f– 1286f clinical presentation of, 1280–1281 diagnosis of, 1282 distinguishing features of, 1280, 1281f epidemiology of, 1280 etiology of, 1280 evolution of, 1281–1282 pathophysiology of, 1281–1282 summary of, 1289–1290 treatment of endovascular, 1287–1288, 1287f–1288f indications for, 1283–1285 management strategy in, 1289 options for, 1285 palliative, 1285, 1287–1289 radiosurgical, 1288, 1385 surgical technique for, 1285–1289 venous hypertension and, 175, 180, 911–913, 1280–1282, 1289 Dural venous sinuses anatomic variations of, 517 anatomy of, 516–517, 517f thrombosis of. See Cerebral vein and dural sinus thrombosis. Duret hemorrhages, 460 DWI. See Diffusion-weighted imaging (DWI). Dynamic susceptibility contrast (DSC) imaging, 885–887, 887f Dysarthria–clumsy hand syndrome, 499, 576 Dyschromatopsia, 437–438 Dysexecutive syndrome, 503 Dysgeusia, 430 Dyslexia, 434 color discrimination impairment with, 438 deep, 399 with dysgraphia, 403–404, 403f as hemidyslexia, 437

Dyslexia (Continued) for numbers, 437 verbal, 436–437, 436f without visual field defect, 437 Dysphagia lateral medullary infarction with, 470 after stroke, 1121 Dysphasia, 396–397 Dyspraxia, 409 Dysrhythmias. See Arrhythmias, cardiac. Dystonia hemiplegia with, 394 lacunar causes of, 499–500 Dystroglycan, of astrocytes, focal ischemia and, 17–18, 20

E Ebselen, 1056t–1057t, 1065 ECG. See Electrocardiography (ECG). Echocardiography. See also Transesophageal echocardiography (TEE). after cardioembolic stroke, 816 after embolic stroke, 299 three-dimensional, of aortic plaques, 752–753, 753f Echoplanar imaging (EPI), 882, 884–888, 895 Eclampsia hypertensive encephalopathy in, 736f, 737–739 reversible cerebral vasoconstriction syndromes and, 1087 Economic costs of stroke, 194–195, 198, 219 “Ecstasy,” 794 Edaravone, 1065–1066 Edema. See Cerebral edema; Peripheral edema; Pulmonary edema; Spinal cord edema. Edoxaban, 973 EEG. See Electroencephalography (EEG). Ehlers-Danlos syndrome, 1292 Elastin gene, 1295–1296 Electrocardiography (ECG) in acute stroke, 936, 1000 after cardioembolic stroke, 815–816 after embolic stroke, 299 after subarachnoid hemorrhage, 593, 1039 Electroencephalography (EEG) lacunes and, 506–507 for monitoring in acute stroke, 1018, 1023 of comatose patients, 937 not routine after stroke, 1002 in moyamoya disease, 713 Electrolyte balance. See also Fluid management. in critical care patients, 1012 in general stroke management, 999 Eliprodil, 1056t–1057t, 1061 Embolic agents. See Liquid embolic agents. Embolism. See also Cardioembolic stroke; Cholesterol emboli; Microemboli. angiography-related, 911 of anterior choroidal artery, 345 from aortic plaques, 749–751 artery-to-artery, 295–296 clinical features with, 296 imaging and, 296–297 in carotid artery disease extracranial, 336 intracranial, 337, 346–347

Embolism (Continued) ischemic stroke and, 340–342, 344, 346–347, 346f retinal artery occlusion and, 344, 350–351 transient ischemic attack and, 348–352 infarcts of undetermined cause and, 294, 302 lacunes caused by, 489–490 of middle cerebral artery, 386–388, 387f–388f of posterior cerebral artery, 427–428, 428f properties of emboli in, 297–298 spinal cord ischemia secondary to, 646, 648t with unobvious source, 297, 302 of vertebrobasilar arteries, 450–451, 456, 460 Embolization techniques. See Arteriovenous malformations, brain, endovascular treatment of; Coil embolization; Liquid embolic agents. Emergency department. See also Prehospital care of stroke. concluding summary on, 942 course of events in, 929–930 disposition from, 941–942 to stroke unit, 997 initial preventive measures in, 938 initial stabilization and management in, 934–937 airway in, 934–935, 935t breathing in, 935 cardiac evaluation in, 936 circulation in, 935–936 diagnostic studies in, 937 emesis in, 937 hyperglycemia in, 936 hyperpyrexia in, 936 hypertension in, 935–936 hypotension in, 936 seizures in, 936–937 management pathways in, 937–941 for hemorrhagic stroke, 938–940, 1106, 1107t for herniation, 941 for ischemic stroke, 937–938 for stroke mimics, 937 for subarachnoid hemorrhage, 940–941 notification of pending arrival in, 932 rapid stroke evaluation guidelines for, 929, 929t time delays in, 929t, 932–934 triage in, 932–934 Emergency medical services (EMS), 929. See also Prehospital care of stroke. activation of, 930–931 dispatch of, 931 notification of hospital by, 932 stroke scales for use by, 309–311, 309t–311t, 932, 933f, 934t taskforce recommendations for, 929 Enalapril, in acute stroke, 1001, 1015 Enalaprilat, in hypertensive encephalopathy, 738 Endocarditis infective, 821, 822f, 1180 in heroin users, 790 Libman-Sacks, 822, 1180 nonbacterial thrombotic, 821–822, 822f, 1180 Endoglin (ENG), arteriovenous malformations and, 170f, 171–172, 177f experimental models and, 174–175, 175f Endoplasmic reticulum pathway, apoptotic, 111, 156–157 Endoplasmic reticulum stress, 156–157 Endoscopic hematoma removal, 1342

Index 1461 Endothelial cells, cerebral, 16, 18f. See Leukocyte adhesion receptors, endothelial cell; Vascular endothelial growth factor (VEGF). angiogenesis and, 164 antithrombotic properties of, 31 arteriovenous malformations and, 164, 170f blood-brain barrier and, 16–17, 163–164 focal cerebral ischemia and, 17, 19–20, 19f angiogenesis and, 21–22 neurogenesis and, 164–165 plasminogen activators from, 29–31 turnover rate of, 163–164 Endothelial dysfunction, 3 in atherosclerosis, 6–7 cardiac embolism and, 823 in diabetes mellitus, 11–12 in hyperhomocysteinemia, 11 in hypertension, chronic, 8–9, 9f in hypertensive encephalopathy, 734, 737–738 measurement of, ultrasonographic, 836 platelets and leukocytes in, 6–7, 1148–1149 in preeclampsia/eclampsia, 737 smoking and, 836 after subarachnoid hemorrhage, 10, 10f vascular cognitive impairment and, 259 Endothelin, 11 vasospasm after subarachnoid hemorrhage and, 10f, 11, 1037 Endothelium, vascular atherothrombosis and, 776 hemostasis and, 772 von Willebrand factor in, 773 nonthrombogenic properties of, 1147–1148 tobacco smoke and, 801 Endothelium-dependent relaxation. See Endothelial dysfunction; Nitric oxide. Endothelium-derived hyperpolarizing factor, 4–5 Endovascular cooling, 1027, 1057t, 1073–1074 Endovascular therapies. See also Angioplasty, balloon; Stenting; Thrombectomy, mechanical; Thrombolytic therapy, intraarterial; Thrombolytic therapy, intravenous. for aneurysmal subarachnoid hemorrhage, 1217–1218, 1218f antithrombotic therapy in, 1035 evidence for, 1241–1242, 1242f–1243f for aneurysms. See Intracranial aneurysms, endovascular treatment of. for arterial dissection, 673, 674f–678f for arteriovenous malformations. See Arteriovenous malformations, brain, endovascular treatment of; Arteriovenous malformations, spinal, endovascular treatment of. for atherosclerotic disease extracranial carotid, 1213–1215 extracranial vertebral artery, 1215–1216 intracranial, 1210–1212 for delayed cerebral ischemia, 605–606 for dural arteriovenous malformations, 1287–1288, 1287f–1288f for fibromuscular dysplasia, 680 new technologies for, in acute stroke, 1236 overview of, 1204–1205 serial angiography with, 919–920 for subarachnoid hemorrhage antithrombotic therapy with, 1035 vs. surgery, 601, 601t for subclavian steal syndrome, 1216–1217

ENG. See Endoglin (ENG). Enlimomab, 145–147, 146t, 1056t–1057t, 1067 Enoxaparin, 977 to prevent deep vein thrombosis, 985, 1108 Eosinophilia, 69–70 in spinal cord ischemia, 646, 647f EP1 receptor, 141–142, 147. See also Prostaglandin E2. Ephedra alkaloids, 794 Ephedrine, 794 EPI. See Echoplanar imaging (EPI). Epidemiology of stroke, 198, 219. See also Distribution of stroke; Risk factors for stroke. diffuse atherosclerosis and, 202 bruits and, 202 economic costs and, 198 frequency by type of stroke in, 200–203, 201t global burden in, 279 disability in, 283–285, 284t–285t discussion and conclusions on, 287–288 in disease burden of2004, 285, 285t incidence and prevalence in, 281–283, 283t introduction to, 279 methods for assessing, 280–283 mortality estimates in, 280–281, 281f–282f, 281t projections to 2030, 286–287, 287f, 287t risk factors in, 285–286, 286f, 288 studies including, 279–280 incidence in, 198–200, 199t, 200f magnitude of the problem and, 198 mortality in, 198 overview of, 198 of recurrent stroke, 201–202 of silent stroke, 201 Epidural catheter, 1017 Epidural hemorrhage, 911 magnetic resonance imaging of, 898 Epigenetic mechanisms, of ischemic cell death, 99–101, 100f Epilepsy. See also Seizures. apoptotic biochemical alterations in, 116t arteriovenous malformations with, 1259t cavernous malformations and, 1391–1392 dendritic swelling in, 70–71 in moyamoya disease, 711 necrosis of substantia nigra in, 71–72 venous anomalies and, 1395–1396 Epinephrine, abuse of, 795 Eptifibatide, 974, 978–979, 983–984, 1150, 1229 Ergot derivatives contraindicated in ischemic stroke, 1095 contraindicated in vasoconstriction syndromes, 770 stroke risk and, 724–725, 729–730 Errorless learning procedures, 408 Erythrocyte sedimentation rate, prognosis after stroke and, 224 Erythropoietin clinical trials of, 1056t–1057t, 1072 in preconditioning response, 156, 157f stroke recovery fostered by, 165 Escitalopram, for poststroke depression, 1002 Esmolol, for blood pressure control, in intracerebral hemorrhage, 939 Estradiol, microvascular density and, in focal cerebral ischemia, 22

Estrogen cerebral blood vessels and, 592 neuroprotective effect of, 1071 État criblé, 485, 486f Ethics in clinical trials, 1192–1193, 1202 Etomidate for neuroprotection, in carotid endarterectomy, 1407–1408 for rapid sequence intubation, 935, 935t, 1009 European Stroke Scale, 313–314 EuroQol scale, 324–325 Evoked potentials, lacunes and, 507 Evolving stroke, 348 Excitotoxicity, 112–113 glutamate, 88–93, 91f in white matter, 131–132, 133f nitric oxide and, 97 in reperfusion, 967 spinal cord ischemia and, 646 Extinction, 411, 412f Extracellular matrix, microvascular, 16 blood-brain barrier and, 16–17 focal cerebral ischemia and, 17–20, 19f, 37–38 plasmin activity and, 31, 36–37 Extracranial-intracranial bypass, 1417, 1418f–1419f for acute ischemic stroke, 1418, 1422 as aneurysm treatment adjunct, 1423 arterial kinking secondary to, 336 for carotid dissection, intracranial, 1086 in cerebral vasospasm, 1418–1419 concluding summary on, 1423 Doppler ultrasonography prior to, 353 hemodynamic effects of, 50f, 1420–1421 historical aspects of, 1210, 1417–1418 mental function and, 348 in moyamoya disease, 273, 1088, 1422–1423 for occlusive cerebrovascular disease, 1419–1422 optic neuropathy and, 344–345 for radiation-induced vasculopathy, 1087 revival of, 343 surgical technique in, 1421–1422 Eye deviation, 394 Eye movements. See Oculomotor dysfunction.

F Fabry disease, 269–270, 1089 Facial pain, lateral medullary infarction with, 469 Facial weakness cerebellar hemorrhage with, 571 lateral medullary infarction with, 471 Faciobrachial paresis, 391–392 Factor II G20210A, 773–774 Factor V Leiden, 773–774 Factor VII. See Recombinant activated factor VII. False aneurysm, arteriovenous malformation with. See also Pseudoaneurysm. cerebral, 1262f–1263f, 1265–1267 spinal, 1277f Family history of stroke, 207 Far lateral suboccipital craniotomy, 1332–1333 Fas (CD95) and Fas ligand, 81, 82f–83f, 109, 110f, 111–113 in cerebral ischemia, 88, 114, 140–141 FOXO-3A transcription factor and, 98–99, 99f in human brain, 115t–116t in spinal cord ischemia, 114–115

1462

Index

FAST scale (Face, Arm, and Speech Test), 309–310 Fasudil, for vasospasm, after subarachnoid hemorrhage, 11 Fatigue, after stroke, 1121 Federal regulations for clinical trials, 1201–1202 Femoral bruits, 202 Fenestrations, vascular, 911, 912f Fenfluramine, 794 Fenofibrate, postischemic inflammation and, 144 Fenoldopam, in hypertensive encephalopathy, 738 Fentanyl in critical care, 1011–1012 prior to laryngoscopy, 935 Fever. See also Hyperthermia. in acute stroke, 936, 1003, 1024 intracerebral hemorrhage with, 1106–1107 prognosis after stroke and, 222 subarachnoid hemorrhage with, 598, 1035 Fibrin deposition in microvessels, 21–22 formation of, 773f, 775 plasmin formation and, 31, 945–946 in thrombus formation, 29, 30f, 945, 946f cross-linking of, 29, 31f, 945 Fibrin globes, 541, 574 Fibrin split products, 945 Fibrinogen ancrod treatment and, 949–950 aortic plaques and, 748 coagulation and, 773f, 775 dementia risk and, 260 platelets and, 1149–1151, 1150f, 1153 prognosis after stroke and, 224 recurrent stroke risk and, 227 in smokers, 801 stroke risk and, 207, 773, 775 Fibrinoid microangiopathy, hypertension with, 23 Fibrinoid necrosis, 488–489, 489f in cerebral amyloid angiopathy, 542–543, 543f–544f Fibrinolysis. See also Antifibrinolytic therapy; Plasminogen activators. endogenous, 29–33, 31f, 775–776, 945–946 in cerebrospinal fluid, 1352 embolization secondary to, 31 platelet participation in, 1152 regulation of, 36, 945–946 intracisternal, 1038 Fibrocartilaginous emboli, spinal cord ischemia and, 646–648, 653–654 Fibromuscular dysplasia, 272, 675–680 angiography of, 678, 679f–680f, 921–922 arterial dissection in, 662, 671, 671f, 1086 carotid artery, 272, 336, 676–677, 679f–680f vein graft for, 679f clinical manifestations of, 677 diagnosis of, 677–678, 679f–680f epidemiology of, 675 pathogenesis of, 676 pathology of, 675–676 sites of, 676–677 treatment of, 678–680, 1086 vertebrobasilar, 454 Fick principle, 44, 46 FIM. See Functional Independence Measure (FIM). Fish oil, 257 Fisher scale, 596–597, 596t FK506. See Tacrolimus (FK506).

FLAIR (fluid-attenuated inversion recovery) images, 883f–885f, 884, 888t diffusion-weighted imaging and, 885 hemorrhage on, 895t in ischemic stroke, 891, 891t, 893 FLIP Fas inhibitor protein, 107, 109–110, 110f in normal human brain, 115t Flow-mediated vasodilation, 836 Fluid management in critical care patients, 1012, 1012t in general stroke management, 999 in prehospital stroke management, 931–932, 999 in subarachnoid hemorrhage, 598, 1035 Flunarizine, 729–730 Focal cerebral ischemia, 75–76. See also Focal noreflow phenomenon. acidosis secondary to, 92–93 animal models of, 73, 76, 77f, 78, 1051 white matter injury and, 124–125 apoptosis and, 113–115 calcium and, 93 cell death pathways in, 88 D dimer elevation and, 32–33 definition of, 75 erythropoietin and, 156 etiologies of, 75–76 experimental models of, 76, 77f, 78 glutamate excitotoxicity and, 89 histopathology of, 69f, 71, 73 inflammation in cellular events in, 139f interventions aimed at, 139t–140t mechanisms of injury in, 138–143 transcription factors and, 143–144 metabolic stress in, 96 microvasculature and, 16–20, 19f, 22–23 amyloid deposition and, 22–23 angiogenesis and, 22 extracellular matrix and, 37–38 lipohyalinosis and, 23 plasmin generation and, 36–37 neurogenesis induced by, 162 NF-κB (nuclear factor-κB) and, 98 nitric oxide and, 97 NMDA receptors and, 89–90 pathways of cell death in, 107 plasminogen activators for, 29, 37–38 hemorrhage risk with, 39 plasminogen activators of cerebral tissue in, 37–38 preconditioning and, 154–155 pretreatment for prevention of, 20 tissue acidosis in, 71–72 zinc and, 95 Focal no-reflow phenomenon, 17, 20–21 Folic acid, homocysteine level and, 11, 781–782, 1088–1089 Foramen ovale. See Patent foramen ovale. Forkhead transcription factors, 98–99, 99f Forskolin, 4 Fosphenytoin neuroprotection trial of, 1056t–1057t, 1062 for seizures in acute stroke, 937, 1002 in intracerebral hemorrhage, 1108 Four-dimensional ultrasonography, of plaque motion, 840–841

Four-vessel occlusion (4-VO) model in rats, 76–78, 77f FOXO-3A transcription factor, 98–99, 99f Framingham Stroke Profile, 242, 243t Free radical scavengers, 1056t–1057t, 1065–1066 Free radicals. See also Reactive oxygen species (ROS). ischemic cell death and, 97–98 wine drinking and, 800 Frenchay Activities Index, 321, 1116 Fresh frozen plasma, for warfarin-associated intracerebral hemorrhage, 940, 1031, 1111, 1184 Frontosubcortical syndrome, 491 Fugl-Myer scale, 321, 1116 Functional disability, after stroke, 230–231, 230t, 231f Functional Independence Measure (FIM), 319, 321–322, 1116, 1117t inpatient rehabilitation and, 1119, 1119t Functional recovery angiogenesis and, 164–165 neurogenesis and, 164–165 remodeling of cerebral tissue and, 162, 164–165 transcranial Doppler monitoring of, 851 Furosemide, in osmotherapy, 1110–1111 Fusiform aneurysms, 591 of posterior inferior cerebellar artery, 1332f, 1334f stent-assisted coiling of, 1246–1249 vertebrobasilar, 452–453, 1322

G GABA (γ-aminobutyric acid), white matter injury and, 132–134, 134f Gabapentin, white matter protection and, 134 Gadolinium contrast agents caution with, 888–889 for enhancement of infarct, 893 Gait disturbance, anterior cerebral artery infarction with, 368–369 α-Galactosidase deficiency, 1089 Gamma Knife radiosurgery for arteriovenous malformations, 1374–1378, 1376f, 1378t, 1380–1384 for cavernous malformations, 1394 Gangliosides, neuroprotective potential of, 1070 Gastrointestinal bleeding antithrombotic therapy and, 975 aspirin and, 1159 prophylaxis of, 1108 thrombolytic therapy and, 962 Gastrostomy tube, 1121 Gavestinel, 1056t–1057t, 1061 Gaze palsy. See also Oculomotor dysfunction. cerebellar hemorrhage with, 571 horizontal, in basilar artery occlusion, 459 pontine hemorrhage with, 576–577, 578t upward, thalamic hemorrhage with, 562 GCS. See Glasgow Coma Scale (GCS). G-CSF. See Granulocyte colony-stimulating factor (G-CSF). Gender stroke epidemiology and, 192–193, 192f, 195–196, 195f–196f stroke outcomes and, 221

Index 1463 Gene expression studies, 1294 Gene therapy, ultrasound-enhanced, 859–860 General stroke management, 996–1004. See also Critical care in acute stroke; Stroke units. blood glucose and, 1003–1004 body temperature and, 1003 deterioration in, causes of, 997–998, 998t edema in, 998–999 general medical management in, 999–1002 blood pressure, 1000–1001 cardiovascular function, 1000 decubitus ulcer, 1002 deep venous thrombosis, 1002 delirium, 1002 depression, 1002 fluids and electrolytes, 999 mobilization, 1002 pulmonary embolism, 1002 pulmonary function, 1001–1002 seizures, 1002 urinary tract infection, 1002 goals of, 996, 996t hemorrhagic transformation and, 998–999 intracranial pressure elevation in, 998–999 recanalization in, 997 unstable cerebral ischemia in, 997 vital functions in, 997 Genetics of intracranial aneurysms. See Intracranial aneurysms, genetics of. Genetics of stroke, 268 basic concepts for, 268, 269f family history and, 207, 268–269 genome-wide association studies of, 274–275 inherited disorders and, 269–274, 269t–270t. See also specific disorders. intracerebral hemorrhage and, 275, 534–535, 534f ischemic, 275 lacunar infarction and, 507 optimizing drug therapy and, 275–276 Genetics of vascular cognitive impairment, 257 Genetics of vascular malformations. See Arteriovenous malformations, brain, genetics of; Cavernous malformations, cerebral, genetics of. Genitourinary bleeding antithrombotic therapy and, 975 thrombolytic therapy and, 962 Genome-wide association studies, 1294 Genome-wide gene expression studies, 1294 Giant aneurysms, 1318–1320 Giant cell arteritis, 687–689, 688f, 1090–1091, 1090t stroke in, 687–689 Giant lacunes, 301 with speech disturbance, 400–401 Glasgow Coma Scale (GCS), 308–309, 309t Intracerebral Hemorrhage Scale and, 312–313, 313t outcomes after hematoma surgery and, 1345, 1345f WFNS subarachnoid hemorrhage scale and, 313, 313t, 596–597, 596t Glasgow Outcome Scale (GOS), 322–323, 323t with intracerebral hemorrhage, 1344–1345 Glasgow Outcome Scale, extended (GOS-E), 1345

Glia. See also Astrocytes; Oligodendrocytes. of human infarcts, NF-κB activation in, 143–144 lost in pannecrosis, 71 NMDA receptors of, 90 spared by selective neuronal necrosis, 68–69, 69f Glia limitans, 16 Glial scar, 165 Glibenclamide, 4, 1069 Glioblastoma multiforme, hemorrhagic, 548, 549f–550f Global aphasia, 397 functional imaging in, 406 natural history of, 407 transcortical aphasia and, 405 Global cerebral ischemia, 75 AMPA receptors and, 89, 91–92, 91f animal models of, 73, 76–78, 77f, 1051 apoptosis in, 113–116 caspase 3 and, 83–84 inhibitory proteins and, 85–86 piddosome and, 81 calcium and, 93 causes of, 75 cell death pathways in, 88 cell populations affected by, 75 definition of, 75 glutamate excitotoxicity and, 89 histopathology of, 69f, 75 kainate receptors and, 92 metabolic stress in, 96 necrosis in, 73 neurogenesis following, 164 NMDA receptors and, 90 pathophysiology of, 75 preconditioning and, 145, 154–155 transcription factors and, 98–101, 99f–100f transient receptor potential channels and, 92 in vitro models of, 76, 78–79, 79f zinc and, 94f–95f, 95 Global outcomes, rating scales for, 322–323, 323t Glomuvenous malformations, 180 Glucose. See Blood glucose; Cerebral metabolic rate of glucose (CMRglc). Glucose extraction fraction, 47 Glue. See Liquid embolic agents. Glutamate agents acting indirectly on, 1056t–1057t, 1061–1063 measurement of, in brain tissue, 1018 Glutamate antagonists. See NMDA (N-methyl-daspartate) receptor antagonists. Glutamate excitotoxicity. See Excitotoxicity. Glycerol, for cerebral edema, 998–999, 1020–1021 in cerebral venous thrombosis, 1096 in intracerebral hemorrhage, 1109 Glycoprotein IIb/IIIa receptor, 1149–1151, 1150f Glycoprotein IIb/IIIa receptor antagonists, 974, 978–979, 983–985, 1150 current status of, 986, 1150 in thrombolytic therapy, 1229, 1236 GOS. See Glasgow Outcome Scale (GOS). GPIIb/IIIa. See Glycoprotein IIb/IIIa receptor. Gradient echo sequences, 883 Gradient recalled echo (GRE) imaging, 883f, 888, 888t of acute thrombus, 891, 892f hemorrhage on, 895, 895f–896f, 895t lobar, in amyloid angiopathy, 567–568, 568f

Grange syndrome, 272 Granulocyte colony-stimulating factor (G-CSF), 165, 1057t, 1072 Granulomatous angiitis. See Primary (isolated) angiitis of central nervous system. Guanylyl cyclase particulate, 3 soluble, 3 atherosclerosis and, 6–7 after subarachnoid hemorrhage, 10–11

H Hallucinations, brainstem infarction with, 461 Haloperidol, for delirium, 1002 Handicap, poststroke, 231, 1116 assessment scales for, 322–323, 323t HARM (hyperintense acute reperfusion marker) sign, 884f, 893 Head and neck cancer, carotid artery disease secondary to, 337 Head deviation, 394 Head trauma apoptotic biochemical alterations in, 116t exclusion from thrombolysis for, 961 Headache. See also Migraine. arteriovenous malformations with, 1259t lateral medullary infarction with, 470 thunderclap differential diagnosis of, 769 in reversible vasoconstriction syndromes, 765–767, 766f, 769–770 of vascular disease, 724 Health Utilities Index, 325 Heart failure cognitive function and, 260 prognosis after stroke and, 223, 229 recurrent stroke risk and, 226–227 stroke associated with, 816–817 hemostasis and, 823 stroke prevention in, 1177 stroke risk and, 209f, 210, 1177 Heat shock proteins, 113 postischemic inflammation and, 142, 145 spinal cord infarction and, 646 tolerance and, 158, 158f Hematocephalus, 1349 Hemiamblyopias, 431 Hemianalgesia, lateral medullary infarction with, 470–471 Hemianopia altitudinal, posterior cerebral artery infarction with, 430–431 anosognosia for, 413 homonymous. See Homonymous hemianopia. macular, posterior cerebral artery infarction with, 431, 437 middle cerebral artery infarcts with, 395–396 migraine with, 720, 725–726 right alexia with, 435 hemidyslexia with, 437 verbal dyslexia with, 436–437 Hemiballism, 461 Hemichorea–hemiballism, 499 putaminal hemorrhage causing, 557

1464

Index

Hemicraniectomy, 1022. See also Decompressive surgery. complications of, 1431 for intracerebral hemorrhage, 1033, 1111 for middle cerebral artery infarction. See Malignant middle cerebral artery infarction. in subarachnoid hemorrhage, 1038 technique of, 1430–1431, 1430f–1431f volume of expansion and, 1431, 1431f Hemidyschromatopsia, 438 Hemidyslexia, 437 Hemiinattention, 411. See also Neglect. Hemineglect. See Neglect. Hemiparesis, 389–392. See also Ataxic hemiparesis. anosognosia for, 413 in basilar artery occlusion, 457 hemimedullary infarction with, 472 with impersistence, 414 infarcts without, 393 lobar hemorrhage with, 567 migraine with, 725–726 “recovery” from, 393 thalamic hemorrhage with, 562 Hemiplegia, 389–391, 391f cerebellar hemorrhage with, 571 with dystonia, 394 pontine hemorrhage with, 576 Hemiplegic migraine, 725–726 Hemisensory syndromes, 495–496 Hemispherectomy, sensory disturbances following, 394–395 Hemodilution, for cerebral edema, in intracerebral hemorrhage, 1109 Hemoglobin breakdown products of, MRI appearance and, 895 cerebral blood flow and, 47 in cerebrospinal fluid, after subarachnoid hemorrhage, 10–11, 10f diaspirin–cross-linked, 1074–1075 in neuroprotective solutions, 1056t–1057t, 1074–1075 Hemorrhage, extracranial antithrombotic therapy and, 975, 976t, 977, 979 thrombolytic therapy and, 962 Hemorrhage, intracranial. See Intracerebral hemorrhage (ICH); Intracranial hemorrhage (ICH); Intraventricular hemorrhage; Subarachnoid hemorrhage. Hemorrhagic infarction, 293. See also Hemorrhagic transformation. embolism with, 299 Hemorrhagic stroke. See also General stroke management; Intracerebral hemorrhage (ICH). acute management of, 938–940, 1106, 1107t. See also Emergency department. emesis in, 937 clinical scales for to differentiate from ischemic stroke, 311 on quality of life, 324, 1116–1117 to quantify severity, 312–313, 313t diet pills and, 794 Hemorrhagic transformation, 897, 1185. See also Hemorrhagic infarction. angiography-related, 911 asymptomatic, 998–999, 1185

Hemorrhagic transformation (Continued) of cardioembolic infarction, 814–815, 815f, 897, 1185 anticoagulant resumption with, 1186 cerebellar infarction with, 1443–1444, 1445f definition of, 1185 early computed tomography and, 963–964, 964f, 1185 hyperglycemia and, 1003–1004 magnetic resonance imaging of, 897, 1185 with diffusion or perfusion MRI, 901 with FLAIR imaging, 893 microvasculature in in focal cerebral ischemia, 17–20, 19f, 37–39 hypothermia and, 20 thrombolytic therapy and, 39 in venous sinus thrombosis, 19–20 NIHSS score and, 317 vs. primary hematoma, 897 after thrombolytic therapy, 317, 897 hypertension and, 961–962 intraarterial, 897, 1234–1235, 1235f in preclinical studies, 950–951 recanalization and, 998–999 vertebrobasilar, 1234 venous, 899 Hemorrhagic venous infarction of spinal cord, 652 Hemostasis, 772. See also Coagulation pathways; Platelet(s). activation of, 775 cardiac embolism and, 823 inflammation and, 1152–1153 microvessel wall and, 21 regulation of, 772, 773f Heparin, 1182 in acute ischemic stroke complications of, 975–976, 976t, 979 efficacy of, 979–983, 980t–982t, 985 hemorrhage associated with, 550–551 in aneurysm coiling, 1247–1249 for arterial dissection, 672, 1084–1085 in carotid endarterectomy, 1410–1412 for cerebral venous thrombosis, 525–526, 525t, 1096–1097 as contraindication to thrombolysis, 961, 967 endogenous, 772 after experimental stroke, 21 in intraarterial thrombolysis, 1228–1229 intracerebral hemorrhage secondary to, 550–551, 940, 1031 low-molecular-weight, 971–973 in cerebral venous thrombosis, 1096–1097 complications of, 976–977, 976t, 979 efficacy of, in acute stroke, 980t–982t, 981–983, 985 to prevent deep vein thrombosis, 985, 1023–1024 in subarachnoid hemorrhage, 1035 pharmacology of, 971–973 with plasminogen activator, 38–39 t-PA activity and, 946 for venous thromboembolism prophylaxis, 985 in intracerebral hemorrhage, 1108 in ischemic stroke, 1002 after subarachnoid hemorrhage, 600, 1035 in warfarin initiation, 985–986 weight-based dosing of, 972, 972t Heparin cofactor activity assay, 774–775

Heparin-induced thrombocytopenia, 776–777, 976 with low-molecular-weight heparins, 977 Hepatitis B, polyarteritis nodosa and, 692 Hereditary hemorrhagic telangiectasia, 171–172, 177f, 274 cerebral arteriovenous malformations in, 622, 634 endovascular treatment of, 1264, 1264f radiosurgery for, 1385 experimental model of, 174, 175f genetics of, 1293 spinal arteriovenous malformations in, 1269–1271, 1271f, 1274, 1276f Hereditary neurocutaneous angiomatosis, 1293 Herniation. See also Decompressive surgery. brainstem infarction secondary to, 460 cerebellar infarction with, 1434–1435, 1444 cerebral venous thrombosis and, 1096, 1435–1436 emergency department management and, 939 intracranial pressure monitoring and, 1111 middle cerebral artery infarction with, 389, 390f, 998, 1024, 1426–1427, 1427f SPECT imaging and, 1429 posterior cerebral artery infarction caused by, 428–429 pupillary abnormalities in, 460–461 HERNS (hereditary endotheliopathy, retinopathy, nephropathy, and stroke), 274 Heroin, 790–792 adulterants in, 791 myelopathy caused by, 791–792 stroke caused by, 790–792 Heubner’s artery, 362, 363f anomalies of, 364–365 infarction in territory of, 366–368, 368f, 372 Hiccups, lateral medullary infarction with, 470 High-convexity infarction, in carotid syndromes, 347–348, 348f High-intensity transient signals (HITS), ultrasonographic, 844–846, 844f Hippocampus global ischemia models and, 114–115 in vitro, 79, 79f plasminogen activators affecting, 37 selective neuronal necrosis in, 73 Hirudin, 973, 976–977 Hirulog, 973 Hispanics. See also Caribbean-Hispanics; MexicanAmericans. aortic plaques in, 747–748 cavernous malformations in, 634 cryptogenic infarction in, 302 lacunar infarction in, 300 stroke outcomes in, 221–222 stroke risk in, 191–194, 191f, 203f Histidine-rich glycoprotein, 945–946 HITS. See High-intensity transient signals (HITS), ultrasonographic. HMG (3-hydroxy-3-methylglutaryl)–coenzyme A reductase inhibitors. See Statins. Hoarseness, lateral medullary infarction with, 470 Homocysteine, 780–782, 780f alcohol consumption and, 800 aortic plaques and, 748 in CADASIL, 759 stroke risk and, 207–208, 207f vascular cognitive impairment and, 257

Index 1465 Homocystinuria, 271, 780, 1088 Homonymous hemianopia, posterior cerebral artery infarction with, 431, 433–434. See also Hemianopia. color discrimination impairment with, 438 fibromuscular dysplasia and, 454 global alexia and, 436 hemidyslexia and, 437 Homonymous sectoranopia, posterior cerebral artery infarction with, 431 Homunculus, capsular lesions and, 494 Horizontal gaze palsy, in basilar artery occlusion, 459 Hormone replacement therapy risk of subarachnoid hemorrhage and, 590–591 stroke risk and, 213 Horner’s syndrome carotid artery dissection with, 664 lateral medullary infarction with, 471 Hunt and Hess scale, 308, 313, 313t, 596–597, 596t Huntington’s disease, apoptosis in, 116t Hydralazine, 1014 avoided in intracerebral hemorrhage, 939 in hypertensive encephalopathy, 738 Hydrocephalus anterior cerebral artery ischemia with, 368 arteriovenous malformation and, 1359 cerebellar infarction with, 1028–1029, 1444, 1445f interstitial edema and, 1426 intracerebral hemorrhage with, 1029, 1034– 1035, 1109–1110 caudate, 560–561 cerebellar, 572, 1340, 1341f, 1343–1344, 1343f thalamic, 565, 566t intraventricular hemorrhage with, 1109–1110, 1349, 1352 lacunar infarction with, 491 after subarachnoid hemorrhage, 603–604, 604t and aneurysm surgery, 1320 intensive care management of, 1036 Hydrogen peroxide, cerebral vasodilatation and, 5–6 Hydromorphone abuse, 791 Hydroxyethyl starch carotid-cross clamping end, 1407 in osmotherapy, 1110–1111 Hydroxyurea for essential thrombocytosis, 776 for sickle cell patients, 783, 1094–1095 Hyperbaric oxygen, 1075 Hypercholesterolemia endothelium-dependent relaxation in, 6–7 recurrent stroke risk and, 225–226 therapy for, cerebrovascular effects of, 7, 8f Hypercoagulable states. See also Antiphospholipid antibodies; Coagulation abnormalities. aortic plaques and, 748 cryptogenic infarction in, 302 definition of, 772 genetic factors in, 272–273 ischemic stroke and, 1092–1093 moyamoya disease and, 711 posterior cerebral artery infarction in, 428–429 Hyperdense artery sign, in computed tomography posterior circulation, 878, 879f thrombolytic therapy decision and, 963–964, 964f with thrombus, 870–871, 871f

Hyperdense dot sign, in computed tomography, 964, 964f Hyperglycemia after stroke, 1003–1004 in acute setting, 936 in intensive care unit, 1013–1014, 1024 intracerebral hemorrhage and, 1107 prognosis and, 223–224 recurrence risk and, 224–225, 227 with subarachnoid hemorrhage, 599, 1035 thrombolytic therapy and, 962 Hyperhidrosis, contralateral to infarction, 396, 396f Hyperhomocyst(e)inemia, 11, 781–782 in alcoholics, 800 cryptogenic infarction in, 302 treatment of, 1088–1089 Hyperintense acute reperfusion marker (HARM) sign, 884f, 893 Hyperintense vessel sign, on FLAIR imaging, 884, 885f, 893 Hyperpathia, 496–497 treatment of, 508 Hyperperfusion syndrome, cerebral, 1413 Hypertension. See also Antihypertensive treatment; Blood pressure management. in acute stroke, 223, 935–936 aneurysms associated with, 591–592 chronic autoregulation of cerebral blood flow in, 48 Charcot-Bouchard aneurysms in, 489–490, 490f endothelial function in, 8–9, 9f intracerebral hemorrhage and, 535 intraventricular hemorrhage associated with, 1349, 1350f, 1353, 1353t lipohyalinosis in, 488–489 microatheroma in, 488 potassium ion channels in, 9–11, 9f classification of, 245t episodic, after middle cerebral artery infarction, 396 exclusion from thrombolysis for, 961–962 extreme, fibrinoid necrosis in, 488–489, 489f global prevalence of, 286, 286f induced during carotid endarterectomy, 1407, 1410–1412 in stroke, to increase blood flow, 1028 for vasospasm, 598, 605, 1036–1037 intracerebral hemorrhage in. See Intracerebral hemorrhage (ICH), hypertension-related. intracerebral hemorrhage presenting with, 555 lacunar infarction associated with, 490–491, 507–508 antihypertensive therapy and, 508 basilar branches and, 461–462 Binswanger’s disease and, 503–504 in pure motor stroke, 493 lipohyalinosis secondary to, 23 in migraine patients, 729 prognosis after stroke and mortality and, 223 recurrent stroke and, 224–226 renovascular in fibromuscular dysplasia, 1086 in moyamoya disease, 709–710 risk of stroke and, 203–204, 204f diastolic pressure and, 203–204

Hypertension (Continued) in global population, 285–286, 286f isolated systolic hypertension and, 204 for subarachnoid hemorrhage, 590 smoking and, 801 subarachnoid hemorrhage with, 1039 vascular cognitive impairment and, 258 Hypertensive encephalopathy, 734 causes of, 737–738 clinical features of, 735 definition of, 734 neuroradiologic features of, 735–737, 736f pathogenesis of, 734–735, 735f pathologic features of, 735 treatment of, 738–739 Hyperthermia. See also Fever. in acute stroke, 936, 1003, 1024 pontine hemorrhage with, 575 preconditioning induced by, 154–155 prognosis after stroke and, 222 Hypertonic saline for cerebral edema, 998–999, 1021 for impending herniation, 939, 941 Hyperventilation cerebral blood flow and, 47 for elevated intracranial pressure, 1021–1022, 1110 for impending herniation, 939, 941 Hypoglossal artery, 450 Hypoglycemia dendritic swelling in, 70–71 neuronal apoptosis in, 71f prehospital stroke management and, 931–932 thrombolytic therapy and, 962 Hyponatremia in acute stroke, 999 in intensive care unit, 1012 after subarachnoid hemorrhage, 607, 1039 Hypotension in acute stroke, 936 in intensive care unit, 1015–1016 intracranial pressure and, 1019 Hypothermia in acute stroke, 1003 by endovascular cooling, 1027, 1057t, 1073–1074 focal cerebral ischemia and, 20 global cerebral ischemia and, 1049–1050 intracranial pressure elevation and, 1111 for large middle cerebral artery infarction, 1026–1027, 1426–1427 neuroprotective, 1023, 1026–1027, 1056t–1057t, 1072–1074 during aneurysm surgery, 1302 with caffeinol, 1074 in subarachnoid hemorrhage, 1035, 1038 preconditioning induced by, 154–155 thrombolysis combined with, 968 Hypoxia acute stroke management and, 1001 cerebral blood flow and, 47 cerebral vasodilatation caused by, 4 chronic hypertension and, 9 oxidative stress and, 9 local, angiogenesis and, 21–22 preconditioning induced by, 154–155 Hypoxia/ischemia. See also White matter anoxicischemic injury. animal models of, 76, 78

1466

Index

I ICAM-1 (intercellular adhesion molecule-1), 138, 139t, 144–147, 146t ICD (International Classification of Diseases) codes, 189, 190f ICH. See Intracerebral hemorrhage (ICH); Intracranial hemorrhage (ICH). ICH (Intracerebral Hemorrhage) Scale, 312–313, 313t ICP. See Intracranial pressure (ICP). ICU (intensive care unit). See Critical care in acute stroke. Ideational apraxia, 410 Ideomotor apraxia, 409–410 Idraparinux, 973 Immunologic tolerance to brain antigens, induction of, 147 Immunosuppressive drugs, for inflammatory vasculopathies, 1090t Impairments, 1116 Impersistence, 412f, 414 IMT. See Intima-media thickness (IMT). Incidence of stroke. See Distribution of stroke. Incontinence, anterior cerebral artery infarction with, 375 Indicator dilution methods, 45 Indocyanine green angiography of intracranial aneurysms, 1303 of spinal arteriovenous malformations, 1366, 1368f–1369f Infarct age, magnetic resonance imaging and, 893 Infarct core, 76 in animal models, 77f, 78 computed tomography of, 870 CT perfusion imaging of, 877 metabolic changes in, 96, 893 volume of hyperglycemia and, 1003 prediction of, MRI studies and, 901–902 temperature and, 1003, 1024 thrombolytic therapy and, 901 Infarct of undetermined cause. See Cryptogenic infarction. Infection cerebral vasculitis in, 1090t, 1091–1092 intraventricular catheter–associated, 1017 moyamoya disease and, 711 poststroke, 140–141 primary angiitis and, 689, 690f stroke associated with, fibrinogen and, 775 after subarachnoid hemorrhage, 606 Inflammation in amyloid angiopathy, 533 aneurysm development and, 592 aneurysm rupture and, 592 arteriovenous malformations and, 171, 176 in atherosclerosis, 695–698, 697f positron emission tomography of, 753 cerebral cavernous malformations and, 179 dementia risk and, 259 hemostasis and, 772–773 ischemic cell death and, 101 spinal cord, 646 platelet activation and, 1152–1153 smoking and, 802 Inflammation, postischemic, 138 cellular events in, 138, 139f interventions aimed at, 138, 139t–140t

Inflammation, postischemic (Continued) focal cerebral ischemia and, 17, 19f, 20–21, 23 in ischemic necrosis, 73, 73t, 108 in ischemic stroke, 138, 139f mechanisms of ischemic injury in, 138–141 cyclooxygenase-2 in, 140t, 141–142 nitric oxide in, 140t, 141 scavenger receptors in, 142–143, 143f, 143t toll-like receptors in, 142–143, 142f–143f, 143t transcription factors in, 143–144 preconditioning and, 144–145 therapeutic approaches to, 145–148 clinical trials of, 145–147, 146t, 1056t–1057t, 1065–1069 PPAR agonists in, 144 Inflammatory biomarkers prognosis after stroke and, 224 recurrent stroke risk and, 227 stroke risk and, 207 Inflammatory diseases, 687, 1085t, 1089–1092, 1090t. See also Vasculitis; specific diseases. Infliximab for giant cell arteritis, 689, 1091 for Takayasu’s arteritis, 692 Informed consent in clinical trials, 1202 for thrombolytic therapy, 963 Inhalant abuse, 798 Inhalational anesthetics, preconditioning induced by, 155 Innominate artery occlusion, 474 Insulin therapy in acute stroke, 1003–1004 with intracerebral hemorrhage, 1107 in intensive care unit, 1013–1014, 1024 in subarachnoid hemorrhage, 1035 Integrins arteriovenous malformations and, 170f, 173–174 cerebral cavernous malformations and, 178–179, 178f of cerebral microvessels, 17 angiogenesis and, 21–22 focal ischemia and, 17–18, 19f, 20–21 Intensive care unit (ICU). See Critical care in acute stroke. Intent-to-treat analysis, 1198–1199 Interferon regulatory factor 1 (IRF-1), in postischemic inflammation, 139–140, 142–144, 147 Interferon-β, 1057t, 1067 neuroprotection studies of, 1057t, 1067 Interleukin-1 arteriovenous malformations and, 173 in atherosclerosis, 695–696 in cerebral ischemia, 138–140, 140t, 145 Interleukin-1 receptor antagonists, in ischemic stroke, 146–147, 146t Internal capsule arterial supply of, 384 lacunar infarcts in, 488. See also Lacunes. lesions of, clinical features of, 373, 375 putaminal hemorrhage with extension to, 557–558, 558f–559f International Classification of Diseases (ICD) codes, 189, 190f Internuclear ophthalmoplegia, in basilar artery occlusion, 458–459

Interpeduncular cistern anatomy of, 1322–1323, 1324f approaches to, 1325, 1328, 1330 Interstitial cerebral edema, 1426 Interventional therapies. See Endovascular therapies. Intervertebral disks, herniated, and spinal cord ischemia, 646–648 Intima-media thickness (IMT) in atherosclerosis, 833–835, 835f in Takayasu’s arteritis, 842 Intracerebral hemorrhage (ICH), 531. See also Hemorrhagic stroke; Intracranial hemorrhage (ICH); Microbleeds, cerebral. amyloid angiopathy with. See Amyloid angiopathy, cerebral, intracerebral hemorrhage in. anticoagulant resumption with, 1186 anticoagulant-associated, 548–551, 550f–551f, 940, 1031, 1111, 1184–1185 amyloid angiopathy and, 552 atrial fibrillation and, 820 cerebellar, 570 microhemorrhages and, 553–554 antithrombotic therapy and, 1336 blood flow and metabolism in, 56–57, 56f–57f, 59–60 blood pressure management in, 1030–1031, 1107 in emergency department, 938–939 after carotid endarterectomy, 1413 causes of, 914, 1337t. See also specific causes. nonhypertensive, 544 cerebellar. See Cerebellar hemorrhage. clinical and laboratory features of, 554–556 cocaine abuse and, 547–548, 547f, 561, 1354f diagnosis of, vs. infarction, 293–294 emergency department management of, 938–940, 1106, 1107t genetics of, 275, 534–535, 534f hematoma expansion in, 536–538, 536f–537f, 939 anticoagulant-associated, 549–550, 550f, 940, 1031 blood pressure and, 1030 CT angiography of, 878 lobar, 569 prevention of, 1108–1109 after surgical evacuation, 1344 hydrocephalus and, 1029, 1034–1035, 1109–1110 with caudate hemorrhage, 560–561 with cerebellar hemorrhage, 572, 1340, 1341f, 1343–1344, 1343f with thalamic hemorrhage, 565, 566t hypertension-related, 531 in amyloid angiopathy, 533 cerebellar, 570 in chronic hypertension, 535 in hypertensive encephalopathy, 736 lobar, 566–567, 567t medullary, 579 mesencephalic, 572–573 as microbleeds, 897 MRI of, 896–897, 896f pathogenesis of, 535–536, 538–539 pontine, 574–575 recurrent, 540 thalamic, 561

Index 1467 Intracerebral hemorrhage (Continued) imaging of, 553–554 angiography in, 556, 911–915, 1338 computed tomography in, 549–550, 551f, 553, 878, 1337, 1338f CT angiography in, 537–538, 537f, 878, 1109 MRI in, 553–554, 555f, 895f, 896, 1337–1338, 1338t incidence rates of, 531, 532t intensive care management of, 1029–1035, 1106 blood pressure control in, 1030–1031 coagulation status in, 1031 with hydrocephalus, 1034–1035 with intraventricular hemorrhage, 1033–1034, 1034f medical, 1029–1030 pathophysiologic principles of, 1029 standard orders for, 1107t surgical, 1031–1033, 1032t–1033t medical therapy of, 1106 for cerebral edema, 1109 concluding summary of, 1113 general measures in, 1106–1108 for hydrocephalus, 1109–1110 intracranial pressure and, 1109–1111, 1110f overview of, 1106 rebleeding prevention in, 1108–1109 standard orders for, 1106–1107, 1107t medullary, 577–579, 578f midbrain, 572–574, 573f migraine treatment in patient with, 730 migraine-related, 725 in moyamoya disease, 706, 708–709, 708f management of, 1088 prognosis and, 713 multiple simultaneous, 540–541 pathologic features of active bleeding in, 536–538, 536f–538f arteries involved in, 535 gross anatomy in, 538–540, 539f–541f histopathology in, 541–544, 542f–545f vascular rupture in, 535–536 pontine. See Pontine hemorrhage. prognosis of, 939–940, 1029, 1112–1113 recurrence of, 540–541, 541f in reversible cerebral vasoconstriction syndromes, 767–769, 768f risk factors for, 531–533 seizures associated with, 555, 936–937, 1108, 1344 in lobar hemorrhage, 567, 567t in sickle cell disease, 782 sites of, 535, 535t, 556, 1337 supratentorial, 556. See also Caudate hemorrhage; Lobar (white matter) hemorrhage; Putaminal hemorrhage; Thalamic hemorrhage. surgery for, 1031–1033, 1032t–1033t, 1111– 1112, 1112f, 1336 for aneurysmal hemorrhage, 1336–1338, 1338f, 1340, 1342–1343 in anticoagulated patient, 1336 with arteriovenous malformation, 1343 aspects amenable to, 1336 in brainstem, 576–579, 1033 cerebellar. See Cerebellar hemorrhage, surgery for. controversies about, 1336, 1337f, 1339–1340

Intracerebral hemorrhage (Continued) craniotomy for, 1341–1342 vs. endoscopic removal, 1342 evidence for, 1340–1341, 1340f–1341f imaging prior to, 1336–1338, 1338f, 1338t indications for, 1339–1340 vs. intracavity thrombolysis, 1342 lobar, 569 penumbra and, 1338–1339, 1339f, 1342 prognosis of, 1344–1345, 1344t, 1345f for traumatic hemorrhage, 1340 vs. ultrasonic aspiration, 1342 underlying pathology and, 1339 sympathomimetic drugs causing, 546–548, 547f thrombolytic therapy and, 37–39, 38t, 551–552, 553f–554f amyloid angiopathy and, 552 with thalamic hemorrhage, 561 traumatic, surgery for, 1340 tumor-related, 548, 548f–550f vascular malformations with. See also Arteriovenous malformations, brain, hemorrhage secondary to. cavernous, 544–545, 546f, 546t, 634–635 small, 544–545 telangiectases, 633–634 volume of, estimating, 538, 538f, 939, 1337 withdrawal of care in, 939–940, 1112–1113 Intracerebral Hemorrhage (ICH) Scale, 312–313, 313t Intracisternal fibrinolysis, 1038 Intracranial aneurysms. See also Aneurysm(s); Aneurysmal subarachnoid hemorrhage; Saccular (berry) aneurysms. anatomic distribution of, 591 posterior circulation, 1322 angiography of, 913–914, 913f–916f arteriovenous malformations with. See Arteriovenous malformations, brain, aneurysms associated with. CT angiography of, 878 development of, 591–592 endovascular treatment of, 1204, 1217–1218, 1218f, 1241 antithrombotic therapy in, 1035, 1247–1249 evidence, ruptured aneurysms, 1241–1242, 1242f–1243f evidence, unruptured aneurysms, 1242–1244, 1244f extracranial-intracranial bypass with, 1423 flow diversion for, 1250, 1251f historical development of, 1241 intraventricular fibrinolysis following, 1351f, 1354 periprocedural complications of, 1250 periprocedural management of, 1247–1250 vs. surgery, 1301–1302, 1322 techniques of, 1244–1247, 1247f–1248f fibromuscular dysplasia with, 454 genetics of, 1292–1293 approaches to studies of, 1293–1294 association studies of, 1295–1296 concluding summary of, 1298 genome-wide association studies of, 1296 genome-wide gene expression studies of, 1296–1297 linkage studies of, 1294–1295, 1295t giant, 1318–1320

Intracranial aneurysms (Continued) intracerebral hemorrhage caused by, 914, 1336 surgery for, 1336–1338, 1338f, 1340, 1342–1343 intraventricular, 1349 in moyamoya disease, 708–709, 709f, 712, 1088 MR angiography of, 898–899 natural history of, 1217 polycystic kidney disease with, 274, 591 prevalence of, 590 rupture of, 592. See also Aneurysmal subarachnoid hemorrhage. critical size and, 1336 with hydrocephalus, 1352 with intraventricular hemorrhage, 1349–1350, 1351f, 1352–1354, 1353t subdural hematoma secondary to, 911–913 surgery for, anterior circulation, 1301 anterior cerebral artery, distal, 1303f, 1314–1317, 1316f anterior choroidal artery, 1310–1312, 1312f anterior communicating artery, 1313–1314, 1315f carotid bifurcation, 1312–1313, 1312f–1314f cavernous internal carotid, 1305–1306 cerebrospinal fluid management after, 1320 clip types available for, 1302–1303, 1304f decision for, 1301–1302 extracranial-intracranial bypass with, 1423 for giant aneurysms, 1318–1320 historical perspective on, 1301 middle cerebral artery, 1303f, 1317–1318, 1317f–1319f operating room setup for, 1302, 1303f paraclinoid internal carotid, 1306–1308, 1309f–1310f patient positioning for, 1302, 1302f petrous internal carotid, 1305 posterior communicating artery, 1308–1310, 1311f surgical approaches for, 1302–1305, 1303f, 1305f–1308f surgical technique in, 1302–1303 surgery for, posterior circulation, 1322 anterior subtemporal approach to, 1323, 1323f–1324f, 1325–1330, 1327f, 1329f basilar apex region, 1322–1330, 1323f–1324f, 1326f–1327f, 1329f basilar trunk, 1334 posterior cerebral artery, distal, 1330–1332, 1331f posterior inferior cerebellar artery, 1332– 1334, 1332f–1334f selection criteria for, 1322 superior cerebellar artery, 1330–1332, 1332f temporopolar approach to, 1323, 1323f– 1324f, 1329–1330, 1329f transsylvian approach to, 1323–1325, 1323f–1324f, 1326f, 1330 vertebral artery, 1332–1333, 1333f types of, 591 ultrasonography of, contrast-enhanced, 848 Intracranial hemorrhage (ICH). See also Intracerebral hemorrhage (ICH); Intraventricular hemorrhage; Subarachnoid hemorrhage; Thrombolytic therapy, intravenous, intracranial hemorrhage secondary to.

1468

Index

Intracranial hemorrhage (Continued) cavernous malformations leading to, 176, 180 cerebral venous thrombosis leading to, 899 cocaine-related, 795–796 dural arteriovenous malformations leading to, 180, 1280–1282 immobilization of patient with, 1002 in moyamoya disease, 706, 711 surgical treatment and, 714–716 risk factors for low serum cholesterol as, 205 smoking as, 211 Intracranial pressure (ICP) emergency department management of, 939 monitoring of herniation and, 1111 invasive, 1016–1018 ultrasound, 850–851 postoperative management of, with aneurysm surgery, 1320 Intracranial pressure elevation in cerebral venous thrombosis, 518–520 treatment of, 525, 525t, 527, 1435–1436 visual loss and, 524 dural arteriovenous malformation with, 1281, 1289 intracerebral hemorrhage with, 1110–1111, 1110f intraventricular hemorrhage with, 1034–1035, 1110 after aneurysm rupture, 1350 after stroke basic management of, 998–999, 1019 basic physiology of, 1018, 1019f critical care management of, 1018–1023 edema with, 998, 1019f emesis with, 937 hypothermia for, 1003 in intubated patient, 935 large middle cerebral artery, 1024, 1026–1027, 1426–1427 in traumatic brain injury, 1435 vasodilator-induced, 1014 Intraparenchymal hemorrhage. See Intracerebral hemorrhage (ICH). Intraparenchymal microtransducer, 1017–1018 Intraventricular catheter. See Ventricular catheter. Intraventricular hemorrhage, 1349 aneurysmal, 1349–1350, 1351f, 1352–1354, 1353t arteriovenous malformation with, 626, 627f, 1262f, 1350–1352 causes of, 1349 clinical features of, 1352 diagnosis of, 1352 grading system for, 1350t, 1352 hydrocephalus in, 1109–1110, 1349, 1352 hypertensive, 1349, 1350f, 1353, 1353t intracerebral hemorrhage complicated by, 1349, 1350f, 1352 caudate, 560–561, 561f CSF examination and, 555–556 lobar, 569 management of, 1033–1034, 1034f, 1355f pontine, 574–576 prognosis and, 1029 putaminal, 538, 558–559, 560f putaminal-thalamic, 558 thalamic, 563–566, 564f–565f, 566t

Intraventricular hemorrhage (Continued) medical therapy of, 1106. See also Intracerebral hemorrhage (ICH), medical therapy of. in moyamoya disease, 706, 708, 1349 natural clearance of, 1352 primary, 1033, 1349, 1350f, 1352, 1354 prognosis of, 1354, 1355f subarachnoid hemorrhage with, 1033, 1036, 1038, 1352, 1354 treatment of, 1352–1354, 1353t, 1354f–1355f Intraventricular thrombolysis, 1034, 1034f, 1110, 1342, 1351f, 1353–1354, 1353t, 1354f–1355f in subarachnoid hemorrhage, 1036, 1038 Intubation, endotracheal, 934–935, 935t, 997, 1001, 1009 indications for, 1001 with intracerebral hemorrhage, 1108 laryngeal complications of, 1009–1010 Ionic cerebral edema, 870–871 diffusion-weighted imaging and, 885 IRF-1 (interferon regulatory factor 1), in postischemic inflammation, 139–140, 142–144, 147 Iron chelation, in intracerebral hemorrhage, 1109 Ischemia, definition of, 75 Ischemic cascade, 1050, 1052, 1065, 1067–1068 Ischemic cell change, 69–70 Ischemic cell death, 75. See also Cell death pathways. classification of ischemia and, 75–76 experimental models of, 76–79, 77f, 79f mechanisms of, 95–101 epigenetic, 99–101, 100f free radicals and lipid peroxidation, 97–98 inflammation, 101 metabolic stress, 95–96 mitochondrial permeabilization, 96 nitric oxide, 96–97 transcriptional, 98–101, 99f modalities of, 79. See also Apoptosis; Autophagy (autolysis); Necrosis. in focal ischemia, 88 in global ischemia, 88 spinal cord, 646 triggers of, 88–95 calcium, 93 glutamate excitotoxicity, 88–92, 91f nonexcitotoxic mechanisms, 92–93 zinc, 93–95, 94f–95f Ischemic optic neuropathy, 344–345, 344f–345f Ischemic penumbra, 59, 76 in animal models, 77f, 78 apoptosis in, 88 computed tomography of, 870 extracranial-intracranial bypass and, 1422 of intracerebral hemorrhage, 1338–1339, 1339f, 1342 magnetic resonance imaging of, 900–901, 1053–1054 metabolic changes in, 96, 894 narrow, 69f, 72 as target of drug therapies, 1051 thrombolytic therapy and, with desmoteplase, 949 Ischemic preconditioning, 144–145. See also Preconditioning. Ischemic stroke. See also Atherothrombotic stroke; Cardioembolic stroke; Cerebral infarction; Cerebral ischemia; General stroke management; Lacunes.

Ischemic stroke (Continued) acute management of, 937–938. See also Emergency department; General stroke management. angiogenesis following, 163–165 angiography in, 919–920, 919f–921f anti-inflammatory approaches to, 145–147 clinical trials of, 145–147, 146t PPAR agonists in, 144 aortic plaques and. See Aortic plaques, of proximal aorta, ischemic stroke and. cerebral blood flow and metabolism in, 50–54, 51f–53f, 59 thresholds of function in, 53–54 cerebral edema in, 1426–1427 classification of, 294, 294f. See also specific subtypes. algorithm for, 295f bland vs. hemorrhagic infarction in, 293 as cardioembolism, 297–299 in children, 321 as cryptogenic infarction, 301–302 diagnostic problems in, 294 inherited risk and, 269 vs. intracerebral hemorrhage, 293–294 as lacunar infarction, 299–301 as large artery thrombosis, 295–297 need for, 293 OCSP scale for, 311–312, 312t TOAST system for, 308, 318–321, 318t coagulation abnormalities and, 775, 1085t, 1092–1095 collateralization in, 919 deterioration in, causes of, 997–998, 998t extracranial-intracranial bypass in, 1418, 1422 genetics of risk factors for, 275 hemorrhage in. See Hemorrhagic transformation. vs. hemorrhagic stroke, rating instruments for, 311 inflammatory reaction in, 138, 139f cytokines in, 138 nitric oxide synthase in, 141 magnetic resonance imaging in, 883f, 885f, 891–895, 891t, 892f, 894f microbleeds in, 897 neurogenesis following, 162–165 outcomes of. See Prognosis after ischemic stroke. pharmacologic therapy of, 1049. See also Anticoagulation; Cytoprotection; Neuroprotection; Preconditioning; Thrombolytic therapy. scales to quantify severity of, 313–317, 314t–316t worsening after, 227–228 antithrombotic therapy and, 981t, 984–985 Isoflurane, preconditioning induced by, 155 Isolated angiitis. See Primary (isolated) angiitis of central nervous system. Isotropic diffusion-weighted imaging, 885 Israeli Vertebrobasilar Stroke Scale, 317

J Japan Coma Scale, 309 Japanese people CARASIL in, 271, 762 moyamoya disease in, 273, 636, 703–704, 710

Index 1469 Japanese people (Continued) stroke risk in, 199–200, 205, 211, 213 alcohol consumption and, 799 cholesterol level and, 532 smoking and, 531–532 Japanese Stroke Scale, 308, 313–314 Jugular massage, with dural arteriovenous malformation, 1285

K Kainate receptors, 92 white matter excitotoxicity and, 132–134, 133f Kallikrein gene, 1296 Katz Index, 325 Ketamine, in critical care, 1010 Ketosis, diet-induced, microvascular density and, 22 Kety-Schmidt method, 44, 46 Kidney disease. See Renal dysfunction. Klüver-Bucy syndrome, 371–372, 440–441 Korean people, moyamoya disease in, 704–705

L Labetalol for blood pressure control in acute stroke, 1001 in hypertensive encephalopathy, 738 in intensive care unit, 1015 in intracerebral hemorrhage, 939, 1107 in hypertensive encephalopathy, 738 for pulmonary edema, in acute stroke, 1001 Lactate anoxia and, 125–126 astrocytes and, 122–123 in infarct, 888, 894, 894f measurement of, in brain tissue, 1018 in penumbra of hemorrhage, 1339 Lactic acidosis. See MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes). Lacunar hypothesis, 300 Lacunar state, 491, 502–503 Lacunar syndrome, 300 Lacunes, 299–301, 485. See also Microangiopathies. arteriopathies underlying, 488–490, 489f–490f in basilar branch disease, 461–462 in CADASIL, 759–760, 761f cardioembolism and, 814–815 carotid bruit and risk of, 202 clinical features of, 300, 490–491 clinical syndromes with, 491–504 ataxic hemiparesis, 492, 498–499 atypical syndromes, 499 Binswanger’s disease, 502–504 centrum semiovale infarcts, 300–301, 495, 502 dysarthria–clumsy hand syndrome, 499 lacunar state, 491, 502–503 movement disorders, 499–500 pure motor stroke, 489–490, 490f, 492–494, 492f, 494f, 501 pure sensory stroke, 301, 494–497, 495f sensorimotor stroke, 497–498, 497f speech and language disorders, 500–502, 501f strategic infarcts, 504 vascular dementia, 502–503, 507–508

Lacunes (Continued) definitions of, 486, 487f diagnostic approach to, 508–509 diagnostic studies in, 300–301, 504–507, 506f genetics of, 507 glucose levels and, 936 historical aspects of, 485–486, 486f inflammation and, 697 lipohyalinosis leading to, 452 in moyamoya disease, 712 pathoanatomy of, 486–488 location of, 488 pathologic series of, 487t size of, 486–488 vascular territories involved by, 488 procollagen mutations and, 23 prognosis of, 507–508 with asymptomatic infarcts, 508 cardiovascular events in, 228–229 dementia in, 507–509 functional, 231 mortality in, 222, 507 progression and worsening in, 228 recurrence risk in, 225t, 226f, 507 secondary prevention of, 1165, 1168 spinal cord, 651 thrombolytic therapy with, 508, 1235 in TOAST classification, 318t treatment of, 508–509 types of, 486 Lambl’s excrescences, 819, 1178 Lamotrigine for central pain, 1120 in rodent ischemia model, 1062 Landmark agnosia, 434 Language disorders. See also Aphasia. anterior cerebral artery infarction with, 372–374, 373f lacunar infarction with, 500–501, 501f Lanoteplase, 36 Large artery thrombosis with infarct clinical features of, 296 lacunar syndromes and, 300 imaging results with, 296–297 mechanisms of, 295–296 in TOAST classification, 318–320, 318t Lateral geniculate body arterial supply to, 425, 426f color discrimination and, 437 infarction of, 431 Left atrial myxoma, 818, 819f, 1180 Left ventricular dysfunction embolic stroke risk and, 1177 in subarachnoid hemorrhage patients, 941 Left ventricular hypertrophy dementia risk and, 259 stroke risk and, 210 Left ventricular thrombus, 817, 1177–1178 Lens, dislocation of, 271 Lenticulostriate branches anatomy of, 384, 485, 488 lacunes in territories of, 488, 500 magnetic resonance angiography of, 506 rupture of, 558–559 supplying arteriovenous malformation, 915, 917f Lepirudin, 973 LeukArrest. See Rovelizumab (LeukArrest).

Leukoaraiosis, 502–504, 507. See also White matter hyperintensities. microbleeds associated with, 897 warfarin-associated hemorrhage and, 549 Leukocyte adhesion receptors, endothelial cell, 17, 19f Leukocyte count, prognosis of ischemic stroke and, 224 Leukocytes. See also Neutrophils. in bland infarction, 293 in ischemic brain, 19f, 20–21, 138–139, 139f, 139t therapeutic targets related to, 146–147 platelets and, 1152–1153 vasoactive agents produced by, 6 in atherosclerosis, 7 Levodopa/carbidopa with aphasia therapy, 1124t, 1125 with physical therapy, 1124t, 1129 Libman-Sacks endocarditis, 822, 1180 Lidocaine, prior to laryngoscopy, 935 Lifarizine, neuroprotection pilot study of, 1056t–1057t, 1062 Lifestyle modification. See Primary prevention of stroke. Limb shaking transient hemispheric attack with, 352 transient ischemic attack with, 369 anterior cerebral artery infarction and, 368 Limb-kinetic apraxia, 410 Lindegaard ratio, 605 Linear accelerator, for radiosurgery of arteriovenous malformations, 1374–1379, 1376f, 1378t, 1379f, 1381, 1383–1384 of cavernous malformations, 1394 Linkage studies, 268, 269f, 274–275, 1293–1294 of arteriovenous malformations, 1297 of intracranial aneurysms, 1294–1295, 1295t Lipid peroxidation, ischemic cell death and, 97–98 Lipid-lowering therapy, in primary prevention, 205, 247–248 Lipids, serum levels of, stroke risk and, 204–205, 205f Lipohyalinosis, microvascular, 23, 299, 485, 488–489 intracerebral hemorrhage and, 536, 538–539, 574 pure sensory stroke caused by, 495 vertebrobasilar, 452 Lipopolysaccharide (LPS) postischemic inflammation and, 141–142, 145 preconditioning induced by, 154–155 Lipoprotein (a) aortic plaques and, 748–749 fibrinolysis and, 775–776 Lipoprotein-associated phospholipase A2 first stroke risk and, 201–202 recurrent stroke risk and, 201–202, 227 stroke prognosis and, 224 Liquid embolic agents. See also Endovascular therapies. for aneurysms, 1246 for cerebral arteriovenous malformations, 1259–1263 as single-hole macrofistulas, 1264, 1264f for dural arteriovenous malformations, 1286–1288, 1287f for spinal arteriovenous malformations, 1273–1277, 1275f–1277f intramedullary, 1367–1370

1470

Index

Livedo reticularis, 694, 780–781, 783 Lobar (white matter) hemorrhage, 535, 556, 566–569 amyloid angiopathy and, 566–568, 568f, 568t anatomy of, 566, 566t cerebrospinal fluid and, 555–556 clinical features of, 567, 567t computed tomography of, 569, 569t drug abuse and, 546–548 etiology of, 566–567 gross anatomy of, 539, 540f metastatic tumors with, 548, 548f microhemorrhages and, 553–554 prognosis of, 568–569 recurrent, 540–541, 541f seizures and, 555 small vascular malformations and, 544–545 surgery for, 569 thrombolytic agents and, 551–552 Locked-in syndrome in basilar artery occlusion, 457 midbrain lesions with, 457 Lorazepam for delirium, 1002 for seizures, 1002 Los Angeles Prehospital Stroke Scale, 309–310, 310t, 932, 933f Loss of consciousness, 389 Lotrafiban, 1150 Lovastatin, in neuroprotection trials, 1057t, 1069 Low blood pressure prognosis after stroke and, 223 recurrence risk after stroke and, 224–226 Low-density lipoprotein (LDL), 775–776 alcohol consumption and, 799–800 Lp(a). See Lipoprotein (a). LPS. See Lipopolysaccharide (LPS). LSD (lysergic acid diethylamide), 797 Lubeluzole, 968 clinical trials of, 1056t–1057t, 1062–1063 Lumbar drainage, of hydrocephalus, 1034–1035 in subarachnoid hemorrhage, 1036 Lumbar puncture, with subarachnoid hemorrhage, 594, 596 and normal imaging, 940–941 Lupus anticoagulant, 777 Lupus anticoagulant test, 777, 778t Luxury perfusion, 51–52, 51f after ischemic stroke, angiography of, 919 after subarachnoid hemorrhage, 52f, 58 after surgical retraction of brain tissue, 59 Lymphocytes in postischemic inflammation, 138–139, 147 in poststroke autoimmune response, 140–141 Lymphomatoid granulomatosis, 693

M Ma huang, 794 α2-Macroglobulin, 32, 32t, 36 Maeda syndrome, 271 Magnesium for cytoprotection, in ischemic stroke, 1056t– 1057t, 1059–1060, 1075 for reversible cerebral vasoconstriction syndromes, 1087 for vasospasm, in subarachnoid hemorrhage, 1037

Magnetic resonance angiography (MRA), 882, 883f, 887–888, 888t aneurysmal subarachnoid hemorrhage and, 596 of arterial dissection, 666–671, 670f, 898, 898f of arterial stenosis or occlusion, 898 of dural arteriovenous malformations, 1282, 1284f of fibromuscular dysplasia, 678 in hypertensive encephalopathy, 737 of intracranial aneurysms, 898–899 lacunar infarcts and, 506 in moyamoya disease, 273, 703, 704f, 705t, 712–713, 714f in reversible cerebral vasoconstriction syndromes, 766f, 768–769 of vertebrobasilar aneurysms, 452–453 Magnetic resonance imaging (MRI), 882. See also Perfusion MR imaging; White matter hyperintensities. advanced techniques in, 884–888, 886f–887f of aortic plaques, 753, 754f of arterial dissection, 666–671, 667f, 669f, 672f of arteriovenous malformations, 622, 622f basic pulse sequences in, 883–884 of basilar artery occlusion, 456 in CADASIL, 760, 761f, 762 of carotid plaques, 1406 of cavernous malformations, 545, 546f, 634–635, 634f, 1389f–1391f, 1392, 1393f–1395f of cerebellar arteries, 448, 449f of cerebral microhemorrhages, 255, 553–554, 555f of cerebral venous thrombosis, 521–523, 522f, 899–900, 899f functional of arteriovenous malformations, 622, 622f recovery from hemiparesis and, 393 general principles of, 882–883 in giant cell arteritis, 688 of hemorrhage, 895–898, 895f–896f, 895t in hypertensive encephalopathy, 736–737, 736f in inherited disorders, 270–273 of intracerebral hemorrhage, 553–554, 555f, 895f, 896, 1337–1338, 1338t in ischemic stroke, 883f, 885f, 891–895, 891t, 892f, 894f of lacunar infarcts, 505–506, 509 of malignant middle cerebral artery infarction, 1428, 1429f of migraine patients, 724 in moyamoya disease, 703, 705t, 712–713, 712f, 714f multimodal stroke examination in, 882, 883f, 888–889, 888t therapy guided by, 900–902, 900f overview of, 882 regional metabolism and, 46 in reversible cerebral vasoconstriction syndromes, 766f, 767–768, 768f safety issues in, 888–889 in spinal cord ischemia, 652–653, 653f of subarachnoid hemorrhage, 594, 884, 884f, 893, 897–898 transient ischemic attacks and, 889–891, 889f–890f vascular cognitive impairment and, 252, 255–256

Magnetic resonance spectroscopy (MRS), 888, 893–895, 894f Magnetic resonance venography (MRV), 887–888 of cerebral venous thrombosis, 521, 522f, 523, 899, 899f of dural arteriovenous malformation, 1287f Major motor aphasia. See Broca’s aphasia. Malignant atrophic papulosis, 694 Malignant infarction, 389, 390f, 394–395 Malignant middle cerebral artery infarction clinical course of, 1024–1025 definition of, 998, 1427 diagnosis of, 1427–1429, 1427t glycerol therapy in, 999 hemicraniectomy for, 998–999, 1022, 1025–1026, 1025f animal studies and, 1429–1430 clinical studies of, 1431–1434, 1432t complications of, 1431 controversial aspects of, 1426 dominant-hemisphere, 1434 in elder patients, 1434 vs. hypothermia, 1027 indications for, 1427t pathologic basis of, 1426–1427, 1427f technique of, 1430–1431, 1430f–1431f timing of, 1434 volume of expansion and, 1431, 1431f hypothermia for, 1003, 1026–1027, 1073 monitoring in of intracranial pressure, 1018, 1429 multimodal invasive, 1429 prediction of, 998, 1428 Mannitol for cerebral edema, 998–999, 1020–1021 with cerebral venous thrombosis, 1096 with intracerebral hemorrhage, 1110–1111 for impending herniation, 939, 941 for neuroprotection during aneurysm surgery, 1302 during hematoma evacuation, 1341–1342 MAP (mean arterial pressure), calculation of, 941 Marfan’s syndrome, 1292 Marijuana, 797–798 Marrow stromal cell therapy, after stroke, 164–165 Mass effect, 1426. See also Cerebral edema; Decompressive surgery. Mathew Scale, 313–314 Matrix metalloproteinases in arteriovenous malformations, 170–171, 170f, 177f in focal cerebral ischemia, 17–20, 37–38 in ischemic stroke, FLAIR imaging and, 893 neuroblast migration after stroke and, 163–165 plaque rupture and, 753 in Takayasu’s arteritis, 692 MDMA (3,4-methylenedioxymethamphetamine), 794 Mean arterial pressure (MAP), calculation of, 941 Mean transit time (MTT) in CT perfusion imaging, 877 in MR perfusion imaging, 883f, 885–887, 887f, 892 of cerebral venous thrombosis, 899–900 Mean vascular transit time, 48–49

Index 1471 Mechanical ventilation, 997, 1008–1010. See also Intubation, endotracheal. indications for, 1008–1009, 1009t after intracerebral hemorrhage, 1108 after intraventricular hemorrhage, 1108 after subarachnoid hemorrhage, 600 Medical Outcomes Short Form-36 (SF-36), 324–325, 325t, 1116–1117 Medulla arterial territories in, 462f cavernous malformation in, 1394f Medullary hemorrhage, 577–579, 578f Medullary infarction hemimedullary, 472 lateral, 466–472, 469f medial, 472 MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), 271, 1095–1096 Memantine, 261 Memory impairment in anterior cerebral artery infarction, 374–375 in posterior cerebral artery infarction, 440 remediation of, 1123–1124, 1124t MEND (Miami Emergency Neurologic Deficit), 309–310, 310t Meningioma, with supplementary motor area lesions, 373–374 Meningitis lacunar infarcts in, 490 vascular effects of, 455 Meperidine abuse, 791 Merci retrieval system, 1230–1232, 1236. See also Thrombectomy, mechanical. Mesencephalon, arterial territories in, 462f Metabolic stress, ischemic cell death and, 95–96 Metabolites, of infarcted tissues, 888, 893–895, 894f Metamorphopsia, 434 Metformin, contrast media and, 877, 1249 Methamphetamine. See Amphetamines, abuse of. Methotrexate for giant cell arteritis, 1090t, 1091 for inflammatory vasculopathies, 1090t Methylenetetrahydrofolate reductase gene, 724 Methylphenidate abuse of, 794–795 for depression, 1121 Methylprednisolone for acute visual loss, in giant cell arteritis, 689, 1090–1091 for Behçet’s disease, 695 for inflammatory vasculopathies, 1090t for primary (isolated) angiitis, 1089–1090, 1090t in spinal cord ischemia, 654 Mexican-Americans. See also Hispanics. cavernous malformations in, 545 stroke risk in, 194 subarachnoid hemorrhage in, 589–590 Miami Emergency Neurologic Deficit (MEND), 309–310, 310t Microaneurysms in amyloid angiopathy, 543 in granulomatous angiitis, 552–553 in intracerebral hemorrhage, 535–536, 574 sites of, 566

Microangiopathies. See also Lacunes. dementia caused by, 502 fibrinoid, hypertension with, 23 hypertensive, 503 percentage of strokes caused by, 485 types of, 485 white matter, 23, 485 Microatheroma, 485, 488–489, 489f in basilar artery branches, 451–452 intracerebral hemorrhage and, 538–539 thalamic lacune caused by, 495 Microbleeds, cerebral, 255–256, 505. See also Microhemorrhages, cerebral. amyloid angiopathy with, 275, 567–568 in anticoagulated patients, 1184–1185 antithrombotic therapy and, 1167–1168 in CADASIL, 760 definition of, 896–897 magnetic resonance imaging of, 505, 896–897, 896f in moyamoya disease, 273, 712–713 Microbubbles. See Ultrasonography, contrast agents for. Microdialysis, cerebral, 1018, 1039 in malignant middle cerebral artery infarction, 1429 Microemboli injection drug abuse and, 791, 794 lacunar infarction caused by, 299, 301, 489–490 transcranial Doppler ultrasonography of, 844–847, 844f–845f in arterial dissection, 1084–1085 thrombolysis and, 850 Microglia in arteriovenous malformations, 170 in inflammatory reaction, 138–140, 139f to ischemia, 101 scavenger receptors in, 143, 143f Microhemorrhages, cerebral. See also Microbleeds, cerebral. at lobar hemorrhage presentation, 566–567 magnetic resonance imaging of, 255, 553–554, 555f Microplasmin, 947 Micropsia, 434 Microthrombi, in moyamoya disease, 710–711 Microvasculature, cerebral, 16. See also Focal cerebral ischemia, microvasculature and; Permeability barrier, microvascular. amyloid deposition in, 22–23 anatomy of, 16, 18f angiogenesis and, 21–22, 170 brain areas mainly supplied by, 485 flow regulation in, arteriovenous shunts and, 171 lipohyalinosis in, 23, 485 microangiopathy in, 23 neurovascular unit and, 16 overview of, 485 plasmin activity in, 31 plasminogen activator associated with, 37 postischemic inflammation and, 138–139 remodeling of walls in, 22 secondary injury processes and, 20–21 summary of, 23 Midazolam in critical care, 1010 reemergence of aphasia with, 409

Midbrain hemorrhage, 572–574, 573f Midbrain infarction, 427 Middle cerebral artery anatomical description of, 384–386, 385f anomalies in, 386 borderzone anastomoses in, 385–386, 385f, 427 segments in, 385–386, 386f aneurysms of, 915f distribution of, 1317, 1317f ruptured, 1338f, 1349–1350 surgery for, 1303f, 1317–1318, 1317f–1319f bypass surgery to. See Extracranial-intracranial bypass. collateral flow in, from carotid stenosis, 339, 339f dissection of, 388–389, 663 clinical manifestations of, 664–666 histology of, 386 structures supplied by, 384 Middle cerebral artery infarction, 384 arterial territories and, 389, 390f lacunar, 299–300, 389 as super lacune, 486–488 large, 1024–1028 blood pressure management for, 1027–1028 clinical course of, 1024–1025 hemicraniectomy for, 1025–1027, 1025f hypothermia for, 1026–1027 malignant. See Malignant middle cerebral artery infarction. pathology of, 386–389 carotid dissection in, 664, 667–668 dissection in, 388–389 embolism in, 386–388, 387f–388f other disorders in, 389 stenosis in, 388 thrombosis in, 388 perfusion imaging of, ultrasonographic, 856f remote metabolic effects of, 55 syndromes of dominant hemisphere. See Aphasia; Apraxias. syndromes of either hemisphere, 389–396 autonomic disturbances, 396 dizziness and vertigo, 394 eye and head deviation, 394 hemiplegia and hemiparesis, 389–393, 391f–392f loss of consciousness, 389 movement disorders, 393–394 sensory disturbances, 394–395 visual field disturbances, 395–396 syndromes of nondominant hemisphere, 411–416, 412f–414f Middle cerebral artery occlusion angiography of, 919f–920f cerebral hemodynamics in stroke risk and, 50 transcranial Doppler measurement of, 59 extracranial-intracranial bypass for, 1419–1420, 1422 microvasculature in adhesion receptors and, 17, 20 angiogenesis and, 21–22 focal no-reflow phenomenon and, 20–21 proteolysis and, 17–19, 21, 37–38 plasminogen activators for, 38 transcranial Doppler ultrasonography of, 59, 843

1472

Index

Middle cerebral artery stenosis, atherosclerotic, angiography in, 918–919 Midline shift, ultrasound monitoring of, 850 Migraine arterial dissection associated with, 454 arteriovenous malformations and, 631, 721 basilar artery, 474–476, 726–727 in CADASIL, 759 cardiovascular risk factors and, 723–724 classification of, 720, 721t clinical features of, 720 in unrelated pathology, 721 without headache, 725 hemiplegic, 725–726 overview of, 720 patent foramen ovale and, 728–729 reversible vasoconstriction syndromes and, 769–770 treatment of, 729–730, 729t–730t Migraine-induced stroke, 720–721, 727–728, 1095 Migraine-stroke association, 210–211, 720, 1095 classification of, 720–722 clinical features and, 720 with drug-induced stroke, 724–725 epidemiology of, 722–724 mechanisms of, 727–728 migraine that mimics stroke, 725–727 neuroimaging and, 724 in posterior cerebral artery infarction, 428–429 stroke prevention and, 729 stroke that mimics migraine, 722 treatment of migraine and, 729–730, 729t–730t treatment of stroke and, 1095 Migrainous cerebral infarction, 720 Mild cognitive impairment, 252–254 lacunar infarction with, 503 Miliary aneurysms, 535–536 Milrinone, for vasospasm, in subarachnoid hemorrhage, 1038 Mini Mental State Examination, 321 Minocycline in ischemic stroke, 146–147, 146t, 1057t, 1068 stroke recovery fostered by, 165 for Takayasu’s arteritis, 692 Minor motor aphasia, 400, 400f Misery perfusion, 49, 54 carotid stenosis and, 343 symptomatic carotid occlusion and, 1420–1421, 1423 Mitochondrial encephalomyelopathies. See also MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). acidotic brain infarcts in, 72 Mitochondrial flocculent densities, 71, 71f–72f, 73t Mitochondrial (intrinsic) pathway of apoptosis, 81, 83–84, 84f–85f, 107, 109, 110f, 113, 156–157 in cerebral ischemia, 88, 114 Mitochondrial permeability transition pore, 107 Mitochondrial permeabilization, and ischemic cell death, 96 Mitogen-activated protein kinase pathway, 111–112, 112f erythropoietin and, 157f intracranial aneurysms and, 1297 neuroprotection and, 1067–1068 Mitral annular calcification, 821 Mitral regurgitation, 823, 1178–1179 Mitral stenosis, 821, 821f, 1178–1179

Mitral valve disease, rheumatic, 1178–1179 Mitral valve papillary fibroelastoma, 823 Mitral valve prolapse, 823 Mitral valve strands, 1178 in transesophageal echocardiography, 819 Mixed aphasia, 397 Mobile stroke teams, 992–993, 1004 Mobility training, 1125–1127, 1125t Mobilization, 1002 contraindications to, 1002 Modified Rankin Scale (mRS), 307–309, 322–323, 323t Molecular imaging, with ultrasound, 858–859 Monoplegia, 392–393, 392f Monosodium glutamate neurotoxicity, dendritic swelling in, 70–71 Monteplase, 36 Mood disturbances. See also Depression. in CADASIL, 759 Morning glory disc anomaly, 273 Morphine abuse, 791 Mortality. See Distribution of stroke; Prognosis after ischemic stroke. Motor aphasia, 397–401, 398f–400f. See also Broca’s aphasia. bromocriptine and recovery from, 409 transcortical, 405 Motor apraxia, 409–410 Motor neglect, 414 anterior cerebral artery infarction with, 371 Movement disorders lacunar infarcts with, 499–500 middle cerebral artery infarcts with, 393–394 in superior cerebellar artery syndrome, 463–464 Movements, involuntary, with lesions of subthalamic nucleus, 461 Moyamoya disease, 273, 636–637, 636f, 703 diagnostic guidelines for, 703, 704f, 705t diagnostic testing for angiography in, 703, 704f, 705t, 712, 715f, 922, 922f electroencephalography in, 713 imaging modalities in, 712–713 laboratory findings in, 711 physiologic methods in, 713 disease progression and prognosis of, 713 epidemiology of, 703–705, 706f etiology and pathogenesis of, 710–711 future prospects for, 716 intraventricular hemorrhage in, 706, 708, 1349 introduction to, 703 oral contraceptives and, 802 pathology of, 706–710 aneurysm formation in, 708–709, 709f, 1349 in circle of Willis and branches, 706–708, 707f extracranial and systemic arteries in, 709–710 in leptomeningeal vessels, 708 in perforating arteries, 708, 708f smoking and, 802 symptoms and signs of, 711 treatment of, 713–716, 1087–1088 extracranial-intracranial bypass in, 273, 1088, 1422–1423 medical, 713–714, 1088 surgical, 713–716, 716f, 1088 Moyamoya syndrome, 273, 636, 1087 in sickle cell disease, 271–273, 782, 1095

Moyamoya vessels, 708, 708f, 710, 712 after revascularization, 715–716 MRA. See Magnetic resonance angiography (MRA). MRI. See Magnetic resonance imaging (MRI). MRS. See Magnetic resonance spectroscopy (MRS). mRS (Modified Rankin Scale), 307–309, 322–323, 323t MRV. See Magnetic resonance venography (MRV). MTT. See Mean transit time (MTT). Multiinfarct dementia, 252, 502 Multimodality brain monitoring, 1018 in subarachnoid hemorrhage, 1039 Mutism, lacunar infarction with, 500 Mycotic (septic) aneurysms, 591 injection drug abuse and, 790, 795 with intraparenchymal hemorrhage, 914 Myelin basic protein, induction of tolerance to, 147 Myelinated axons injury to. See White matter anoxic-ischemic injury. metabolism of, 123 regional differences of, 122 Myelination, poststroke therapies and, 165 Myelopathy, subacute progressive, 651 Myeloproliferative disease antiplatelet therapy in, 776, 1153 stroke in, 776, 1153 Myocardial infarction. See also Coronary artery disease. after carotid endarterectomy, 1414 genetics of stroke and, 275 migraine-stroke association and, 723–724 recent, intracerebral thrombolysis and, 962 stroke prevention with, 1177–1178 stroke secondary to, 208, 228–229, 817, 936 thrombolytic therapy for, 949 intracerebral hemorrhage secondary to, 551, 946–947 Myocardial ischemia in acute stroke, 1000–1001 hypotension secondary to, 1015–1016 respiratory function and, 1001 subarachnoid hemorrhage with, 1039 Myogenic tone, regulation of, 6 Myxoma, left atrial, 818, 819f, 1180

N N-acetyl-l-aspartate, 888, 893–894 NADPH oxidases atherosclerosis and, 6–7 cerebral vasodilatation caused by, 5–6 cerebral vasospasm and, 10 hypertension and, 9 postischemic inflammation and, 6–7 Nadroparin for cerebral venous thrombosis, 525–526, 1096–1097 complications of, 977 efficacy of, 980t–982t, 981–983 Nalmefene, cytoprotection trials of, 1056t–1057t, 1064 Naloxone, cytoprotection trials of, 1056t–1057t, 1064 Nasogastric feeding, 1121

Index 1473 National Institutes of Health Stroke Scale (NIHSS), 314–317, 316t emergency department use of, 937 hemispheric bias of, 308, 315–316, 1427–1428 intracerebral hemorrhage and, 312–313 paramedics’ use of, 309–310 prognosis and, 222, 229 rehabilitation and, 1116 Scandinavian Stroke Scale and, 314 training and certification for, 308–309, 315 Natriuretic peptides cerebrovascular tone and, 3 subarachnoid hemorrhage and, 606–607 Nausea and vomiting. See also Antiemetic agents. in acute stroke, 937 lateral medullary infarction with, 470 Near-infrared spectroscopy, cerebral, 1408 Neck rotation or trauma arterial dissection in, 661–663, 665f vertebral artery, 453, 662–663, 665f vertebrobasilar occlusion in, 454 C1-C2 subluxation and, 693 Necroptosis (programmed necrosis), 79–80, 107–111, 111f, 113, 157 calcium and, 93 inhibitor of, 113 Necrosis, 79–80. See also Cerebral infarction. vs. apoptosis, 73, 73t, 107–108, 113 calcium and, 93 cell survival pathways and, 111–113 death receptors in, 109–110, 113 diffusion-weighted imaging and, 885, 893 in focal ischemia, 88 in global ischemia, 88, 96 inflammation and, 143 secondary, 108 selective neuronal, histopathology of, 68–73, 69f–72f, 73t zinc and, 95 Necrostatin, 80 Neglect, 411–413, 412f–413f hemianopia associated with, 395 putaminal hemorrhage with, 563 thalamic hemorrhage with, 563–564 treatment of, 416, 1123–1124, 1123t–1124t Neonatal brain cocaine and, 796–797 codeine and, 791 hypoxic-ischemic injury to cell therapy in rat model, 1139f neuroprotection against, 113 pathways of ischemic cell death in, 107 periventricular hemorrhage in, 375 periventricular leukomalacia in, 375 thresholds for ischemic injury, 54 Neoplasms. See also Tumors, intracranial. cerebral vasculitis related to, 1090t, 1092 intraventricular hemorrhage associated with, 1349, 1350f Neural plasticity cholinergic mechanisms in, 409 pharmacotherapy and, 1128–1129 Neuroblasts generation of, 162–163 migration to ischemic boundary, 162–163 angiogenesis and, 164–165 Neurofibromatosis, basilar artery compression in, 455

Neurogenesis. See also Neuroblasts; Stem cells, neural. angiogenesis and, 162, 164–165 cell therapies for induction of, 1139f, 1140 functional recovery from stroke and, 164–165 preconditioning and, 157f, 158 in subventricular zone, 162–163 Neurogenic stunned myocardium, subarachnoid hemorrhage with, 606 Neurologic examination, in critical care patient, 1008 Neuromuscular blockade, for endotracheal intubation, 935, 1009 Neuronal acidophilia, 69–70, 69f, 73t, 79–80 Neuronal cell transplantation, after basal ganglia stroke, 164 Neuronal survival pathways, 98, 111–113, 112f Neuropil in pannecrosis, 72 selective necrosis of, in Wernicke’s encephalopathy, 72 in selective neuronal necrosis, 69–71, 69f Neuroprotection, 1049. See also Cytoprotection; Preconditioning. combined with thrombolysis, 967–968 after subarachnoid hemorrhage, 599–600 Neurosyphilis, lacunar infarcts in, 490 Neurotrophins, 111–112 in preconditioning response, 156 Neurovascular unit, 16, 255 Neutrophils. See also Polymorphonuclear leukocytes. in arteriovenous malformations, 170 in postischemic inflammation, 101, 138–139, 139t, 141, 144, 146–147 as target of phase 2 trial, 1067 stroke risk and, 697 NF-κB (nuclear factor-κB), 98 in postischemic inflammation, 142–145, 142f–143f, 147 in preconditioning response, 157f–158f, 158 programmed cell death and, 81–82, 87f Niacin, extended-release, stroke recovery fostered by, 165 Nicardipine for blood pressure control in acute stroke, 1001, 1015 in hypertensive encephalopathy, 738 in intracerebral hemorrhage, 939, 1107 in subarachnoid hemorrhage, 1035 for cytoprotection in ischemic stroke, 1056t– 1057t, 1058 for vasospasm, 922 intraventricular, 1038 as prolonged-release implant, 1037–1038 Nicotine patch, 801 Nidus, of arteriovenous malformation, 169 Nifedipine, 1001, 1015, 1027–1028 NIHSS. See National Institutes of Health Stroke Scale (NIHSS). Nimodipine for blood pressure control in acute stroke, 1001 in subarachnoid hemorrhage, 1035 for cytoprotection in ischemic stroke, 1056t– 1057t, 1057–1058, 1058f for neuroprotection, after subarachnoid hemorrhage, 599, 604

Nimodipine (Continued) in reversible cerebral vasoconstriction syndromes, 766f, 770, 1087 vasospasm and, in subarachnoid hemorrhage, 604, 1038 Nitric oxide cerebral vasodilatation and, 3–4 atherosclerosis and, 6–7 chronic hypertension and, 8–9, 9f hyperhomocysteinemia and, 11 leukocytes and, 6 platelet activation and, 6–7 subarachnoid hemorrhage and, 10, 10f superoxide and, 5 ischemic cell death and, 96–97 neuroprotection strategies and, 1065 platelet activation and, 1152 postischemic inflammation and, 141, 145 in preconditioning response, 155–156, 156f Nitric oxide synthase aneurysm rupture and, 592 cerebral ischemic damage and, 140t isoforms of, 3, 141 postischemic inflammation and, 140t, 141, 145 therapy directed at, 147 statins and, 7 superoxide and, 5 in hereditary hemorrhagic telangiectasia, 171 Nitroglycerin for elevated blood pressure, 1001, 1014 nitric oxide synthesis and, 3 Nitroprusside. See Sodium nitroprusside. NMDA (N-methyl-d-aspartate) receptor antagonists caspase inhibitors and, 115 for cytoprotection in ischemic stroke, 1056t–1057t, 1058–1061 memantine as, 261 side effects of, 92 NMDA (N-methyl-d-aspartate) receptors calpains and, 93 intracellular signaling and, 98 ischemic neuronal death and, 89–90, 92–93, 97 in spinal cord, 646 neuroprotection and, 112–113, 115 nitric oxide and, 96–97 of oligodendrocytes, 90, 132 zinc and, 95 Nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin combined with, 1156 Normobaric hyperoxia, 1075 NOTCH3 gene, and CADASIL, 270, 726, 758–759, 761–762 Notch signaling arteriovenous malformations and, 174 intracranial aneurysms and, 1297 Nuclear factor-κB. See NF-κB (nuclear factor-κB). Numbers, dyslexia for, 437 Nutrition. See also Diet. in intensive care unit, 1012–1014 during rehabilitation, 1121 after subarachnoid hemorrhage, 599 Nystagmus in basilar artery occlusion ataxic, 458–459

1474

Index

Nystagmus (Continued) convergence and, 461 vertical, 459 impaired opticokinetic, 395–396, 411 lateral medullary infarction with, 471 posterior inferior cerebellar artery and, 467

O Obesity endothelial dysfunction and, 836 stroke risk and, 206–207, 244 vascular cognitive impairment and, 258 OCSP (Oxford Community Stroke Project) Classification, 311–312, 312t Ocular bobbing basilar artery occlusion with, 458 pontine hemorrhage with, 576–577, 578t Ocular convergence abnormalities, basilar artery occlusion with, 461 Ocular migraine, 725 Oculomotor dysfunction in basilar artery occlusion, 459, 461 cerebellar hemorrhage with, 571 pontine hemorrhage with, 575–577, 578t in posterior cerebral artery disease, 430 pure motor stroke and, 493 thalamic hemorrhage with, 562–564, 562t OEF. See Oxygen extraction fraction (OEF). Olfactory bulb, stem cell migration to, 162 Oligodendrocytes, 122–123 ischemic injury to in cell culture, 124 excitotoxicity and, 131–132, 133f in tissue preparation, 127f NMDA receptors of, 90, 132 origin of, 162, 165 One-and-a-half syndrome in basilar artery occlusion, 459 in pontine hemorrhage, 576–577, 578t Ophthalmic artery amaurosis fugax and, 350 arising from anterior cerebral artery, 365 collateral flow in, 337–338, 339f, 340 Doppler ultrasonography of, 836–837 Ophthalmic migraine, 725 Ophthalmoplegia dural arteriovenous malformation with, 1289 in giant cell arteritis, 688 internuclear, in basilar artery occlusion, 458–459 mesencephalic hemorrhage with, 572–574 Opiate abuse, 790–792 Opiate antagonists, cytoprotection trials of, 1056t–1057t, 1064 Opioids, in critical care, 1011–1012 Optic aphasia, 433 Optic disc, morning glory anomaly of, 273 Optic neuropathy, ischemic, 344–345, 344f–345f Opticocerebral syndrome, 344, 346 Opticokinetic nystagmus, impaired, 395–396, 411 Oral contraceptives moyamoya disease and, 802 stroke risk and, 211–212 with cerebral venous thrombosis, 1096 in migraine sufferers, 722–723, 1095 vertebrobasilar occlusion and, 455 Oral-bucco-lingual apraxia, 410 Orgogozo Scale, 313–314

Orpington Prognostic Scale, 313–314, 1116 Osmotherapy, 998–999, 1019–1021 with cerebral venous thrombosis, 1096 with intracerebral hemorrhage, 1110–1111 questionable efficacy of, 1426–1427 Otic artery, 450 Outcome measures in clinical trials, 1192–1194, 1199 Oxford Community Stroke Project (OCSP) Classification, 311–312, 312t Oxidative stress. See also Reactive oxygen species (ROS); Superoxide. hyperhomocysteinemia and, 11 in hypertension, 9 neuron adaptations to, 154 platelet reactivity and, 1153–1154 Oxygen consumption. See Cerebral metabolic rate of oxygen (CMRO2). Oxygen content, arterial, cerebral blood flow and, 47 Oxygen extraction fraction (OEF), 47–48, 48f in arterial occlusive disease, 49–50, 50f carotid, 1420–1421, 1423 after intracerebral hemorrhage, 56, 56f in ischemic stroke, acute, 50–54, 51f–53f subarachnoid hemorrhage and, 58–59 Oxygen partial pressure (Po2) arterial, cerebral blood flow and, 47 brain tissue, monitoring of, 1018, 1039 Oxygen saturation, regional cerebral, 1408 Oxygen supplementation, 931, 931t, 935, 1001 with large hemispheric infarct, 1025 Oxygen-glucose deprivation, in vitro, 78–79, 79f, 92 Oxymetazoline abuse, 795

P p53 apoptosis and, 81, 87f, 110–111 cerebral ischemia and, 113 tolerance and, 157–158 in human brain, 115t–116t Pain central, 1120. See also Dejerine-Roussy syndrome; Thalamic pain syndrome. during rehabilitation, 1120 PAIs. See Plasminogen activator inhibitors (PAIs). Palatal myoclonus in basilar artery occlusion, 457–458 in superior cerebellar artery syndrome, 463–464 Palatal paralysis, lateral medullary infarction with, 471 Palinopsia, 433–434 Pamiteplase, 36 Pannecrosis, 71–73 Papaverine, for vasospasm, 922, 1038, 1217 Papillary fibroelastoma, 1180 mitral valve, 823 Paracetamol, for fever in acute stroke, 1003, 1024 in subarachnoid hemorrhage, 1035 Paradominant inheritance, 173–174, 179 Paradoxic embolus, 299, 302. See also Patent foramen ovale. Paralytic pontine exotropia, 576

Paraparesis, anterior cerebral artery infarction with, 368 Paraptosis, 157 Parenteral nutrition, 1013 Parkinson’s disease, apoptosis in, 116t PARP-1, 86–88, 87f Parthanatos, 86–88, 157 Particle beam radiosurgery, 1378, 1378t, 1381 Patch graft angioplasty, carotid, 1409 Patent foramen ovale, 817–818, 817f–818f, 1180–1182 in CADASIL, 760 detection of, ultrasonographic, 818, 818f, 847, 1180–1181 migraine and, 728–729, 1095 paradoxic embolus and, 299, 302, 817–818, 847, 1180–1181 recurrent stroke risk and, 224–225, 227, 1181 Pco2 (carbon dioxide partial pressure), arterial, cerebral blood flow and, 47 PCP (phencyclidine), 797 Penetrating arteries, 485, 488 Pentazocine, 791 Penumbra. See Ischemic penumbra. Penumbra System, 1231–1232, 1236. See also Thrombectomy, mechanical. Perfusion CT imaging, 870, 876f, 877–878 of cerebral vasospasm, 605 of malignant middle cerebral artery infarction, 1428 Perfusion failure with distal insufficiency, carotid territory, 342–344, 343f, 346–348, 348f Perfusion MR imaging, 882, 883f, 885–887, 887f, 888t in ischemic acute stroke, 892 therapy guided by, 900–902, 900f of malignant middle cerebral artery infarction, 1428, 1429f transient ischemic attacks and, 890f, 891 of vasospasm, 898 Perfusion pressure. See Cerebral perfusion pressure. Perfusion ultrasound imaging, 851 in acute ischemic stroke, 854–855, 856f contrast specific techniques in, 851, 851f–852f kinetics of, 853, 854f–856f high mechanical index, 852–853 low mechanical index, 852–853, 853f–854f power modulation in, 851–852, 852f safety of, 853–854 Perfusion-weighted imaging (PWI), 883f, 888t Pericallosal artery, 363–364 anomalies of, 365 Pericytes, 16, 18f in angiogenesis, 21–22 tissue factor expressed by, 21 Perimesencephalic nonaneurysmal subarachnoid hemorrhage, 591 angiography and, 913 vasospasm risk and, 604 Peripheral arterial disease stroke risk and, 208–209 vascular dementia risk and, 260 Peripheral edema, after middle cerebral artery infarction, 396, 396f Periventricular leukomalacia of infancy, 375 Perlecan gene, 1295

Index 1475 Permeability barrier, microvascular, 16–17 focal cerebral ischemia and, 17–18, 19f hemostasis and, 21 VEGF expression and, 22 white matter microangiopathy and, 23 Peroxisome proliferator-activated receptors (PPARs) ischemic stroke and, 1069 oxidative stress and, 9 postischemic inflammation and, 144 Peroxynitrite, 97 in reperfusion, 155–156 PET. See Positron emission tomography (PET). Phase 1 trials, 1193 Phase 2 trials, 1193–1194 Phase 3 trials, 1193–1194 inclusion and exclusion criteria for, 1195–1196, 1196t Phencyclidine (PCP), 797 Phenoxazoline abuse, 795 Phentermine, 794–795 Phenylpropanolamine, 794 intracerebral hemorrhage associated with, 547, 547f Phenytoin preclinical neuroprotection studies of, 1062 for seizures in acute stroke, 937, 1023 in intracerebral hemorrhage, 1108 white matter protection and, 134 Phosphatidylinositol-3-kinase (PI3K), 111–112, 112f in preconditioning response, 156, 157f Phosphodiesterase-5 inhibitors, stroke recovery fostered by, 165 Physical activity cognitive function and, 257–258 in primary prevention of stroke, 243–244, 243t PICA. See Posterior inferior cerebellar artery (PICA). Piddosome, 81, 86f, 144 Pioglitazone, 1069 Piritramid, 1011–1012 Placebo, 1193 Plasmin, 31–33, 31f, 945–946 in cerebrospinal fluid, 1352 microvascular integrity and, 36–37 platelet activation and, 1152 Plasmin inhibitors, 32t, 36 Plasminogen, 31–33, 31f, 32t, 945–946 in cerebrospinal fluid, 1352 platelets and, 1152 structure of, 31, 33f Plasminogen activator inhibitor type 1, 775–776, 945–946 in focal cerebral ischemia, 18–19, 37–38 smoking and, 801 Plasminogen activator inhibitors (PAIs), 31f, 32t, 36 Plasminogen activators, endogenous, 29–34, 31f, 32t, 34f–35f, 945–946. See also Fibrinolysis; scu-PA (single-chain urokinase-type plasminogen activator); t-PA (tissue-type plasminogen activator); u-PA (urokinase-type plasminogen activator). in cerebral tissue, 37 in focal cerebral ischemia, 18–19, 36–37 mutant forms of, 946–947, 948f

Plasminogen activators, exogenous, 32t, 33, 35–36, 948–950. See also APSAC (anisoylated plasminogen-streptokinase activator complex); rt-PA (recombinant tissue-type plasminogen activator); Staphylokinase; Streptokinase; Thrombolytic therapy; TNK-tPA (tenecteplase). clinical consequences of, 37 commercially available, 1227–1228 contraindications to use of, 37 in experimental cerebral ischemia, 37–38 Platelet(s). See also Antiplatelet therapy. in patients at risk of stroke, 1153–1154 physiologic overview of, 1147–1153, 1148f, 1149t, 1150f Platelet activation, 776, 1148–1150, 1150f antiphospholipid antibodies and, 778–779 blood coagulation in, 1152 in focal cerebral ischemia, 20–21 in heparin-induced thrombocytopenia, 776–777 inflammation and, 1152–1153 limiting mechanisms in, 1152 measurement of, 1156–1157 in patients at risk of stroke, 1153–1154 in therapeutic thrombolysis, 1152 in thrombus formation, 29, 945 transient ischemic attacks and, 7 vasoactive substances released in, 1148, 1149t, 1151–1152 vasomotor response to, 6 in atherosclerosis, 7 in chronic hypertension, 8 Platelet aggregation, 776, 1148–1151, 1148f, 1150f alcohol consumption and, 800 antiplatelet agents and, 776, 974 cocaine abuse and, 796 inhibiting mechanisms in, 1152 measurement of, 1156–1157 plasminogen activators and, 37 after stroke, 1153–1154 vasoactive substances released in, 1151 Platelet count exclusion from thrombolysis and, 961 stroke risk and, 1153 Pneumonia, aspiration, 1001 prevention of, 935, 1001–1002, 1121 Po2. See Oxygen partial pressure (Po2). Polar artery, 449–450 Polyarteritis nodosa, 692 infantile, 692 lacunar strokes in, 490 Polycystic kidney disease, autosomal dominant, 1293 intracranial aneurysms in, 274, 1293 subarachnoid hemorrhage and, 274, 591 Polycythemia, lacunes caused by, 489–490 Polycythemia rubra vera, stroke in, 776 Polymorphonuclear leukocytes, in focal cerebral ischemia, 19f, 20–21, 37. See also Neutrophils. Polymyalgia rheumatica, 687, 1091 Polyunsaturated fatty acids in fish oils, 257 potassium channels activated by, 5 Pons arterial territories in, 462f in CADASIL, 760 cavernous malformations in, 545, 1393f

Pontine hemorrhage, 535, 540, 541f, 574–576, 575f with dysarthria–clumsy hand syndrome, 499, 576 lateral tegmental, 577, 578t unilateral basal or basotegmental, 576, 577f Pontine infarction. See also Basilar artery occlusive disease. anterior inferior cerebellar artery and, 463t, 465 in heroin user, 792 intracranial vertebral artery and, 472 lacunar, 488 with ataxic hemiparesis, 498 pupillary disturbances in, 459 vertical nystagmus in, 459 Port-wine stain, 180 Positron emission tomography (PET) of amyloid angiopathy, 255–256, 568 of aortic arch plaques, 753, 754f in aphasia, 405–406 after intracerebral hemorrhage, 56, 56f–57f in ischemic stroke, acute, 51f–53f, 52 with crossed cerebellar diaschisis, 55f in large artery occlusive disease, 49, 50f of malignant middle cerebral artery infarction, 1429 of migraine patients, 724 in neglect syndrome, with frontal lesion, 412–413 of penumbra around hemorrhage, 1338 regional metabolism and, 46 of subarachnoid hemorrhage, 58–59 in vasculitis, 691–692 as giant cell arteritis, 688 Posterior cerebral artery anatomy of, 425–427, 426f brainstem and thalamic territory in, 425–426, 426f collateral linkages in, 427 cortical territory in, 426–427, 427f aneurysms of, distal, surgery for, 1330–1332, 1331f collateral flow in, from carotid stenosis, 339–340, 339f hyperdense sign in, with computed tomography, 878 occlusion of, CT angiography of, 878 Posterior cerebral artery infarction causes of, 427–429, 428f clinical syndromes in, 429–441 aphasia, 439–440 color dysnomia and dyschromatopsia, 437–439, 439f with distal basilar and PCA stem occlusion, 429, 429f Klüver-Bucy syndrome, 440–441 memory disorders, 440 motor syndromes, 430 oculomotor and pupillary disturbances, 430 reading disorders, 434–437, 435f–436f sensory syndromes, 429–430, 429f topographical disorientation, 434, 434f visual agnosia, 433 visual field disturbances, 430–433, 432f visual perception distortions, 433–434 middle cerebral artery infarction with, 1024 regional distribution of, 427, 427t

1476

Index

Posterior choroidal artery, 450, 451f rupture of branches of, 564 Posterior communicating artery, aneurysms of intraventricular hemorrhage secondary to, 1350, 1351f surgery for, 1308–1310, 1311f Posterior fossa, 1440 Posterior fossa pressure cone, lateral medullary infarction and, 471 Posterior inferior cerebellar artery (PICA), 446–448, 448f–449f, 1440 aneurysms of, 916f, 1322 with intraventricular hemorrhage, 1349 surgery for, 1332–1334, 1332f–1334f atherosclerosis of, 451 hemorrhage from branches of, 535 infarctions associated with, 456, 463t, 466–468, 466f–467f vertebral artery occlusion and, 468, 1443 Posterior reversible encephalopathy syndrome, 737–738 Posterior spinal artery syndrome, 652, 652t Postmenopausal women, cerebral blood vessels in, 592 Postpartum cerebral angiopathy, transcranial Doppler ultrasonography of, 847 Potassium ion channels cerebral vasodilatation associated with, 4–5 in diabetes mellitus, 12 hypertension and, 9–10, 9f after subarachnoid hemorrhage, 10–11, 10f families of, 4–5 focal cerebral ischemia and, 17 Power Doppler imaging, 832, 833t, 834f of intracranial aneurysms, 848 transcranial three-dimensional, 843–844, 848 of vertebrobasilar system, 848 Power modulation ultrasound imaging, 851–852, 852f PPARs. See Peroxisome proliferator-activated receptors (PPARs). Prasugrel, 974, 978 Preconditioning, 144–145, 154–158, 155f, 158f, 1049. See also Neuroprotection. Prednisone for Behçet’s disease, 695 for giant cell arteritis, 689, 1090–1091 for granulomatous angiitis, 690–691 for inflammatory vasculopathies, 1090t for primary (isolated) angiitis, 1089–1090, 1090t Preeclampsia hypertensive encephalopathy in, 737–739 soluble endoglin in, 171 Pregnancy. See also Neonatal brain. antihypertensive treatment in, 738–739 antiphospholipid antibodies and, 777–778, 778t arteriovenous malformations and, 626, 1363 cerebral venous thrombosis and, 524, 527, 1096–1097 cocaine abuse in, 795 reversible cerebral vasoconstriction syndromes and, 767t, 769 Prehospital care of stroke, 929. See also Emergency department. concluding summary of, 942 course of events in, 929–930 dispatch of providers in, 931 evaluation and management in, 931–932, 931t

Prehospital care of stroke (Continued) first medical contact in, 930–931 fluid management in, 931–932, 999 notification of hospital in, 932 recognition by patient or family in, 930 recognition of stroke in, 932 taskforce recommendations for, 929 Prevalence of stroke. See Distribution of stroke; Epidemiology of stroke. Prevention. See Primary prevention of stroke; Secondary prevention of stroke. Primary (isolated) angiitis of central nervous system, 455, 552–553, 689–691, 690f–691f, 1090t hemorrhage in, 552–553 vs. reversible vasoconstriction syndrome, 765, 769 vs. Susac’s syndrome, 695 Primary prevention of stroke, 242 antiplatelet agents in, 248–249, 1147, 1160– 1162, 1168 atrial fibrillation and, 248 clinical trials of, 1192 diabetes and, 246–247 hypertension and, 245–246, 245t identification of high-risk candidates for, 214–215, 215f lifestyle modification in, 242–245, 243t alcohol consumption and, 243t, 244–245 cigarette smoking and, 242–243, 243t drug abuse and, 243t, 245 nutrition and, 243t, 244 physical activity and, 243–244, 243t weight management and, 243t, 244 lipid-lowering therapy in, 247–248 in migraine patients, 729 risk assessment for, 242, 243t Progenitor cells, neural, 162 proliferation after stroke, 162–164 Prognosis after ischemic stroke, 219. See also Distribution of stroke, by mortality rates; Recurrent stroke. antithrombotic therapy and, 982t, 985 cardiac events in, 228–229 depression in, 232–233 diffusion-weighted imaging and, 902 functional disability or handicap in, 230–231, 230t, 231f initial stroke severity and, 222, 229 initial stroke syndrome and, 222 mortality in, 219–224 early, 219–220, 220t late, 220–221, 220t predictors of, 221–224, 221t nutrition and, 1012–1013 prediction models for, 229 public health implications of, 219 quality of life in, 231–232 recurrence in, 224–227 early, 225–226, 225f, 225t late, 225f–226f, 225t, 226–227 predictors of, 224–227 by subtypes mortality and, 222–223, 222f recurrence and, 224–226, 225f–226f, 225t worsening and, 228 worsening in, 227–228 antithrombotic therapy and, 981t, 984–985

Programmed cell death, 107–108. See also Apoptosis; Necroptosis (programmed necrosis). paraptosis as, 157 Progressing stroke, 997–998 Progressive inhibitory activity assay, 774–775 Progressive stroke, 348 Proliferative angiopathy, cerebral, 1264–1265, 1266f–1267f Propofol in critical care, 1010 intracranial pressure and, 999, 1110 Propranolol, 1014 Propylhexedrine abuse, 795 Prosopagnosia, 433–434 color blindness with, 438 Prostacyclin antithrombogenic properties of, 3 platelet activation and, 1152 vasodilatation associated with, 3 Prostaglandin E2 ischemic injury mediated by, 141–142, 147 vasodilatation associated with, 3 Prosthetic heart valves, 821, 1179–1180, 1186 infectious endocarditis of, 1180 Protamine sulfate, 975, 1031 Protease-activated receptor1, antagonist of, 974–975 Protective responses. See Preconditioning. Protein C, 772, 773f acquired deficiencies of, 774, 774t, 1092 functional assays of, 774–775 hereditary deficiencies of, 772–773, 1092 Protein kinase B (Akt), in preconditioning, 156, 157f Protein S, 772 acquired deficiencies of, 774, 774t, 1092 functional assays of, 774–775 hereditary deficiencies of, 772–773, 1092 Protein Z, 772–773 Prothrombin, 773–774, 773f Prothrombin complex concentrates, for warfarinassociated hemorrhage, 940, 1031, 1111 Prothrombin G20210A mutation, 773–774 Prothrombotic states. See also Hypercoagulable states. acquired deficiencies in, 774, 774t in cerebrovascular disease, 775, 1092–1093 definition of, 772 Proton density images, 883–884 proUK (pro-urokinase). See r-proUK (recombinant pro-urokinase). P-selectin, measurement of, 1156–1157 Pseudoaneurysm, 661, 662f, 1085–1086. See also Aneurysm(s), dissecting; Arterial dissection; False aneurysm. Pseudobulbar syndrome, in Binswanger’s disease, 504 Pseudochoreoathetosis, 500 Pseudoephedrine, 546, 794 Pseudoophthalmoplegia, 394 Pseudothalamic syndrome, 395 Pseudoxanthoma elasticum, 1292–1293 Pterional craniotomy for anterior circulation aneurysms, 1302–1305, 1303f, 1305f–1308f for basilar apex aneurysms, 1323–1325, 1326f

Index 1477 Ptosis in basilar artery occlusion, 459, 461 in lateral medullary infarction, 471 Pulmonary edema in acute stroke, 1001 after subarachnoid hemorrhage, 606 Pulmonary embolism, after stroke, 985, 1002, 1023 in heart failure, 1177 prophylaxis of, 985, 1002, 1023–1024 Pulmonary function. See Respiratory function. Pulse contour analysis, 1016 Pulse inversion in contrast harmonic imaging, 851 in power modulation imaging, 852 Pulsed-wave Doppler systems, 831, 832f Pupillary abnormalities in pontine hemorrhage, 575–576 in pontine infarction, 459 in posterior cerebral artery disease, 430 in top of basilar artery occlusion, 460–461 Pure motor hemiparesis. See Pure motor stroke. Pure motor stroke, 489–490, 490f, 492–494, 492f, 494f with confusion, 501 putaminal hemorrhage causing, 557 treatment of, 508 Pure sensory stroke, 301, 494–497, 495f putaminal hemorrhage causing, 557 thalamic hemorrhage causing, 565 Pure word deafness, 403 Pusher syndrome, 366 Putaminal hemorrhage, 535, 556–559, 556f–560f angiography in, 556 crack cocaine and, 547–548, 547f gross anatomy of, 538, 539f histopathology of, 536 neglect associated with, 563 PWI (perfusion-weighted imaging), 883f, 888t Pyribenzamine (tripelennamine), 791

Q Quadrantanopia inferior, 395, 395f upper, 431–434, 432f color blindness with, 438 verbal dyslexia with, 436–437 Quadriplegia, pontine hemorrhage with, 576 Quality of life, after stroke, 231–232 scales for assessment of, 323–326, 325t, 1116–1117 Quasimoyamoya disease. See Moyamoya syndrome.

R Race or ethnicity. See also American Indians; Asian people; Asian/Pacific Islanders; Black people; Hispanics. alcohol consumption and stroke risk with, 799 aortic plaques and, 747–748 distribution of stroke and, 189–196, 198–200, 202–203, 203f, 220 microbleed prevalence and, 897 stroke outcomes and, 221 Radial glial cells, 162 Radiation therapy carotid artery disease secondary to, 337, 1087 vasculopathy secondary to, 1087

Radicular arteries, 643–644, 645f infarction associated with, 651 Radicular veins, 645 Radiosurgery for cavernous malformations, 1384–1385, 1391, 1394, 1395f for cerebral arteriovenous malformations. See Arteriovenous malformations, brain, radiosurgery for. concluding summary of, 1385 for dural arteriovenous malformations, 1288, 1385 for spinal arteriovenous malformations, absence of role for, 1273 for venous malformations, 1385, 1395–1396 Raeder’s syndrome, 345 RAGE receptor, 142–143, 143t Randomization in clinical trials, 1196–1197 Rankin Scale, 230–231, 230t, 1117 Rapid sequence intubation, 934–935, 935t, 1009, 1108 Reactive oxygen species (ROS). See also Free radicals. bilirubin oxidized products secondary to, 11 cerebrovascular tone and, 5–6 in hypertension, 9 ischemic cell death and, 97–98 ischemic injury and, 138–142, 145 in preconditioning response, 155–156, 156f Reading disorders. See also Alexia; Dyslexia. posterior cerebral artery infarction with, 434–437, 435f–436f Real-time compound imaging, 832 Recanalization, 997 vs. reperfusion, 919–920 by thrombolytic therapy, 298, 965–967 monitoring of, 997 unstable cerebral ischemia and, 997, 1002 Recanalization time, 849–850, 849f Receptor interacting protein 1 (RIP1), 80–81, 108–111, 111f, 113 Receptor interacting protein 3 (RIP3), 80–81, 107, 109–110, 111f Recognition of Stroke in the Emergency Room (ROSIER) Scale, 310–311, 311t Recombinant activated factor VII, for intracerebral hemorrhage, 939, 1029–1031, 1109 warfarin-associated, 940, 1184 Recurrent stroke. See also Secondary prevention of stroke. antithrombotic therapy and, 980t, 983–984 aspirin resistance and, 1158 in carotid artery disease, 334 plaque vulnerability and, 335–336 dementia risk and, 253 diffusion-weighted imaging and, 892–893 with patent foramen ovale, 224–225, 227, 1181 risk of, 201–202, 224–227 antihypertensive therapy and, 246 antiphospholipid antibodies and, 778–779 early, 225–226, 225f, 225t late, 225f–226f, 225t, 226–227 predictors of, 224–227 Reduplication, 415 Rehabilitation, 1116 assessment measures in, 321, 1116–1117, 1117t cognitive, 1123–1125, 1123t–1124t concluding summary on, 1129

Rehabilitation (Continued) duration of, 1118 mechanisms for gains in, 1117–1118 medical complications during, 1119–1123 bladder dysfunction, 1119–1120, 1120t depression, 1120–1121 dysphagia, 1121 fatigue, 1121 pain, 1120 sexual dysfunction, 1122 skin ulcers, 1121–1122 sleep disorders, 1122 spasticity, 1122–1123, 1122t mobility training in, 1125–1127, 1125t organization of services for, 1118 outcomes of, 1119, 1119t speech and language, 1124 stroke units and, 992–993, 994t–995t terminology for, 1116 upper extremity and self-care skills in, 1127–1129 Remifentanil, in critical care, 1011–1012 Remodeling of cerebral tissue, 162 Renal dysfunction cognitive impairment and, 260 hypertensive encephalopathy and, 737 prognosis after stroke and, 224 Reorganization of brain, language therapy and, 406–408 Repair. See Angiogenesis; Neurogenesis. Reperfusion injury, 1051–1052, 1054 reactive oxygen species in, 155–156 in thrombolytic therapy, 967 Repinotan, 1056t–1057t, 1064 Respiratory abnormalities in basilar artery occlusion, 460 in medial medullary infarction, 472 pontine hemorrhage with, 575, 577 type of stroke and, 1001 Respiratory function in acute stroke care, 1001–1002 in critical care patient, 1008–1009 in emergency department, 935 REST/NRSF gene silencing factor, 100–101, 100f Reteplase, 36 Retinal arteriovenous malformation, 1265, 1268f Retinal artery assessment, and cognitive function, 259 Retinal artery occlusion, 344, 350. See also Transient monocular blindness (amaurosis fugax). intraarterial thrombolysis for, 1232 Retinal infarction, 344, 350 in drug abusers, 795 Retinocochleocerebral vasculopathy, 695, 696f Reversible cerebral vasoconstriction syndromes, 765 brain imaging in, 766f, 767–769, 768f clinical features of, 766–767 conditions associated with, 765, 767t, 1087 demographics of, 766 diagnostic criteria for, 765, 767t differential diagnosis of, 769 drugs associated with, 1087, 1087t etiology of, 769–770 historical background of, 765 laboratory findings in, 767 management of, 770, 1087 outcome of, 770 pathophysiology of, 769–770 prognosis of, 770 typical case of, 765, 766f

1478

Index

Reversible ischemic neurologic deficit, 348 Reversible posterior leukoencephalopathy syndrome, 737–738 overlap with vasoconstriction syndromes, 767–768, 767t Rheumatic mitral valve disease, recurrent stroke and, 227 Rheumatoid arthritis, 693 Rho-kinase pathway in diabetes mellitus, 12 hypertension and, 9 smooth muscle contractility and, 6 statins and, 7, 8f after subarachnoid hemorrhage, 11 Riddoch phenomenon, 431 RIP1. See Receptor interacting protein 1 (RIP1). RIP3. See Receptor interacting protein 3 (RIP3). Risk factors for atherosclerosis, aortic, 748–749 Risk factors for stroke, 203–215 blood lipids, 204–205, 205f cognitive impairment associated with, 257–259 diabetes, 205–206, 206f environmental factors, 211–215 alcohol consumption, 213 cigarette smoking, 211, 212f, 212t diet, 214 hormone replacement therapy, 213 oral contraceptives, 211–212 physical activity, 213–214 family history of stroke, 207 fibrinogen level, 207, 775. See also Coagulation abnormalities. genetics of, for common ischemic stroke, 275 global population data and, 285–286, 286f heart disease and dysfunction, 208–210, 208f atrial fibrillation, 209–210, 209f, 210t cardiac failure, 209f, 210 coronary disease, 208, 209f left ventricular hypertrophy, 210 peripheral artery disease, 208–209 homocysteine levels, 207–208, 207f, 781–782 hypertension, 203–204, 204f, 215, 215f identification of high-risk candidates and, 214–215, 215f inflammation, 207 migraine, 210–211 obesity, 206–207 subtypes of stroke and, 203 Rivaroxaban, 973, 1183t, 1184 Rolandic infarction lower, 400 upper, 392, 392f, 396 ROS. See Reactive oxygen species (ROS). ROSIER (Recognition of Stroke in the Emergency Room) Scale, 310–311, 311t Rosiglitazone, 1069 Rostral basilar artery syndrome, 463t, 464 Rovelizumab (LeukArrest), 1056t–1057t, 1067 r-proUK (recombinant pro-urokinase), 1205–1207, 1206t, 1227–1229. See also scu-PA (singlechain urokinase-type plasminogen activator); Urokinase. with heparin, 1228–1229 intracerebral hemorrhage secondary to, 552, 554f

rt-PA (recombinant tissue-type plasminogen activator), 29, 33, 946. See also Alteplase; Thrombolytic therapy; t-PA (tissue-type plasminogen activator). cerebral hemorrhage secondary to, 38–39, 38t clotting factors and, 33–34 contraindications to, 37 in experimental cerebral ischemia, 37 FDA approval of, 945, 957 intracisternal, 1038 for intraventricular thrombolysis, 1034, 1110, 1351f, 1353–1354, 1353t, 1354f–1355f in subarachnoid hemorrhage, 1036, 1038 platelet function and, 37 recanalization in ischemic stroke and, 38, 38t variants of, 36

S Saccular (berry) aneurysms. See also Aneurysm(s); Intracranial aneurysms. anatomical distribution of, 591, 913 of anterior cerebral artery, 362, 365–366 development of, 591–592 in fibromuscular dysplasia, 1086 in moyamoya disease, 709 rupture of, 591–592, 592t clinical syndromes related to, 593, 593t vertebrobasilar, 452, 452f Salt wasting syndrome, cerebral, 607, 999, 1012, 1039 Sarpogrelate, 1167 Scandinavian Stroke Scale (SSS), 312–314, 315t Scavenger receptors, 142–143, 143f, 143t, 147 Scleroderma, 693 Scopolamine, language function and, 409 scu-PA (single-chain urokinase-type plasminogen activator). See also r-proUK (recombinant pro-urokinase); u-PA (urokinase-type plasminogen activator); Urokinase. endogenous, 29–34, 32t, 35f, 945–946 inhibitors of, 36 recombinant, 33–34, 36 hemorrhage risk with, 39 recanalization in ischemic stroke and, 38, 38t Secondary prevention of stroke antiphospholipid antibodies and, 779 antiplatelet agents for. See Antiplatelet therapy, for secondary prevention of stroke. cardioembolic. See Cardioembolic stroke, prevention of. clinical trials of, 1192 factors affecting success of, 219 prevalence data and, 195 risk stratification for, 229 Sedation of critical care patients, 1010–1012, 1011t scales for evaluation of, 1012 after subarachnoid hemorrhage, 600–601 Seizures. See also Anticonvulsants; Epilepsy. in acute stroke, 936–937, 1002, 1023 thrombolytic therapy and, 962 arteriovenous malformations with, 630–631, 630t, 1358–1359 after carotid endarterectomy, 1413 cavernous malformations with, 1391–1392 cerebral venous thrombosis with, 519–520, 525t, 527

Seizures (Continued) in hypertensive encephalopathy, 734–735, 738 intracerebral hemorrhage and, 555, 936–937, 1108, 1344 lobar, 567, 567t pontine, 575 in reversible vasoconstriction syndromes, 766–767 after subarachnoid hemorrhage, 604 venous anomalies with, 1390–1391, 1395–1396 Selective serotonin reuptake inhibitors (SSRIs), in rehabilitation, 1124t, 1129 Selfotel, 1056t–1057t, 1059 Sensorimotor stroke, 497–498, 497f Sensory aphasia, 401–404, 401f, 403f. See also Wernicke’s aphasia. conduction aphasia as form of, 405 large lesion with absence of, 402, 402f transcortical, 405, 439 Sensory ataxic hemiparesis, thalamic hemorrhage with, 565 Sensory findings, 394–395 in basilar artery occlusion, 459–460 in thalamic hemorrhage, 564–566 Septic (mycotic) aneurysms, 591 injection drug abuse and, 790, 795 with intraparenchymal hemorrhage, 914 Serotonin, and vasoconstriction, 6–8 in reversible syndromes, 769–770 Serotonin agonist, for cytoprotection, 1063–1064 Sexual dysfunction, after stroke, 1122 SF-36. See Medical Outcomes Short Form-36 (SF-36). Shoulder pain, at hemiparetic arm, 1120, 1128 Shunt, ventriculoperitoneal. See also Ventricular catheter. after aneurysm surgery, 1320 Shunts, right-to-left. See also Patent foramen ovale. diagnosis of, 816, 847, 1180–1181 SIADH (syndrome of inappropriate antidiuretic hormone), 999, 1012 subarachnoid hemorrhage with, 1039 Sick sinus syndrome, 820 Sickle cell disease, 271–272, 455, 782–783, 783f, 1094–1095 moyamoya syndrome in, 271–273 transcranial Doppler ultrasonography in, 271–272, 782–783, 847, 1094–1095 Sickness Impact Profile (SIP), 324, 1116–1117 Signaling, intracellular, neuroprotective. See Preconditioning. Sildenafil, stroke recovery fostered by, 165 Silent infarcts cardiac catheterization with, 823 migraine-associated, 723–724 in sickle cell disease, 782, 1095 Silent stroke, 201 Single nucleotide polymorphisms (SNPs), 1294 Single-photon emission computed tomography (SPECT) in aphasia, 405–406 in hypertensive encephalopathy, 736–737 of malignant middle cerebral artery infarction, 1429 of penumbra around hemorrhage, 1338 Sipatrigine, phase 2 clinical trials of, 1056t–1057t, 1062 Sjögren’s syndrome, 693–694

Index 1479 Skew deviation in basilar artery occlusion, 458 lateral medullary infarction with, 471 Skin ulcers, 1002, 1121–1122 Sleep apnea, in acute stroke, 1001 Sleep disorders, during rehabilitation, 1122 Slipping clutch syndrome, 368 SMA. See Supplementary motor area (SMA). Smokeless tobacco, 801 Smoking, 800–802. See also Cigarette smoking. migraine-stroke association and, 722–724 recurrent stroke risk and, 224–225, 227 stroke risk and, 800–802 vascular cognitive impairment and, 258 Smooth muscle. See Vascular smooth muscle. Sneddon’s syndrome, 694, 780 SNPs (single nucleotide polymorphisms), 1294 Snuff, 801 Sodium nitroprusside, 1014 avoided in acute stroke, 935–936, 939, 1001 in hypertensive encephalopathy, 738 vs. nicardipine, 1015 nitric oxide synthesis and, 3 Somatosensory evoked potentials, 1408 Sonothrombolysis, 855–857 Sorbit solution, for cerebral edema, 1021 Spasticity, after stroke, 1122–1123, 1122t Spatial localization disorders, 414 SPECT. See Single-photon emission computed tomography (SPECT). Spectacular shrinking deficit, 387–388, 388f Speech and language therapies, 1124 Speech disorders. See also Aphasia. lacunar infarction with, 500 Speech dyspraxia, 398–399 Spetzler-Martin grade, 1359–1360, 1359t, 1363 radiosurgery outcome and, 1379–1380 Spin echo sequences, 883 Spinal arteriovenous malformations. See Arteriovenous malformations, spinal. Spinal cord arterial supply of, 643–645, 644f–645f, 1269 blood flow in, 645–646 primary angiitis of, 689 venous system of, 645, 1269 Spinal cord edema, infarction with, 646 Spinal cord infarction, 643 anatomic basis of, 643–645, 644f–645f in aortic coarctation, 649 in aortic dissection, 648–649 clinical presentation of, 650–652, 652t collateral segmental arteries and, 644 diagnostic tests in, 652–653, 653f differential diagnosis of, 652, 653t etiology of, 646–650, 648t, 650f in heroin user, 791–792 historical aspects of, 643 pathology of, 646, 647f–648f physiologic basis of, 645–646 prognosis of, 654 segments most affected by, 645–646 in systemic hypoperfusion, 649 treatment of, 653–654 zolmitriptan use and, 652, 724–725 Spinal cord ischemia apoptosis in, 114–115, 646 causes of, 646, 648, 648t iatrogenic, 649–650, 650f

Spontaneous recovery, 1117 Spot sign, in CT angiography, of acute intracerebral hemorrhage, 537–538, 537f, 878, 1109 SS-QOL (Stroke-Specific Quality of Life) scale, 324, 325t, 1116–1117 SSRIs (selective serotonin reuptake inhibitors), in rehabilitation, 1124t, 1129 SSS (Scandinavian Stroke Scale), 312–314, 315t SSS-TOAST classification, 320–321 Staphylokinase, 32t, 35, 949 inhibitors of, 36 STAT3 (signal transducer and activator of transcription 3), 99–100 Statins in aneurysmal subarachnoid hemorrhage, 599, 1037 angiographic improvement with, 1210 aortic plaques and, 752–753 carotid artery disease and, 334 clopidogrel metabolism and, 1160 cognitive function and, 259 C-reactive protein and, 698 focal cerebral ischemia and, 20 lacunar infarction and, 508 myopathy caused by, inherited risk of, 276 neuroprotective potential of, 1057t, 1068–1069 for primary prevention of stroke, 205, 247–248 in persons with diabetes, 247 stroke recovery fostered by, 165 vascular function and, 7, 8f Status epilepticus, 1023 Steal phenomena with arteriovenous malformations, 57, 1256, 1258f with calcium channel blockers, 1001 coarctation of aorta and, 650–651 after ischemic stroke, 53 in large artery occlusive disease, 49 subclavian, 473–474 angioplasty and stenting for, 1216–1217 with vasodilators, 1014 Stem cells adult nonneural, 1136–1140, 1139f, 1140t embryonic, 1135 neural, 158, 162, 1136, 1137f–1138f. See also Cell-based therapies. migration toward infarct, 1134, 1135f proliferation after stroke, 163–164 types under investigation, 1135t Stent, low-porosity, for flow diversion, 1250, 1251f Stent-assisted aneurysm coiling, 1218, 1218f, 1246–1250, 1248f Stenting. See also Angioplasty, balloon. for acute stroke, 1209 for arterial dissection, 673, 674f–678f, 1084–1086 for basilar artery occlusion, 1028 carotid. See Carotid artery disease, angioplasty and stenting for. in fibromuscular dysplasia, 680, 1086 of fusiform aneurysms, 1218 glycoprotein IIb/IIIa receptor antagonists in, 983–984 intracranial in acute ischemia, 919 for atherosclerotic disease, 1211–1212 for radiation-induced vasculopathy, 1087

Stenting (Continued) for subarachnoid hemorrhage, antiplatelet therapy with, 1035 for subclavian steal, 1216–1217 for vasospasm, 1038 vertebral artery, extracranial, 1215–1216 Stereotactic radiosurgery. See Radiosurgery. Stereotactic surgery for cavernous malformations, 1392–1394 for intracerebral hemorrhage endoscopic, 1342 with thrombolysis, 1112 with ultrasonic aspiration, 1342 Steroid therapy. See Corticosteroid therapy. Strategic infarct dementia, 373, 504 Strategic infarcts, 504 Streptokinase, 29, 32t, 35, 948 antithrombotic therapy combined with, 967 clinical consequences of, 37 clinical trials of, 955 contraindications to, 37 hemorrhage risk with, 552, 950–951, 950t inhibitors of, 36 Stress proteins, 158, 158f Stress ulcer prophylaxis, after subarachnoid hemorrhage, 600 Striate arteries bleeding from, 538–539 in white matter, 123 Stroke. See also Cardioembolic stroke; Epidemiology of stroke; General stroke management; Hemorrhagic stroke; Ischemic stroke. classification of, 294f diagnostic algorithm for, 295f uncommon causes of, 1084, 1085t Stroke and Aphasia Quality of Life Scale-39, 325 Stroke belt, of United States, 192–195 Stroke center, 992, 993t–994t emergency services and, 932 transport to, 929, 932 Stroke Impact Scale, 325, 1117 Stroke risk. See Distribution of stroke. Stroke scales, 307 on cause of ischemic stroke, 317–321, 318t in clinical trials, 1194 desired qualities of, 307–309 to differentiate stroke hemorrhagic vs. ischemic, 311 ischemic syndromes, 311–312, 312t for emergency medical services, 309–311, 309t–311t, 932, 933f, 934t on outcomes (disability), 319, 321–322, 322t on outcomes (global or handicap), 322–323, 323t on quality of life, 323–326, 325t to quantify severity of hemorrhagic stroke, 312–313, 313t of ischemic stroke, 313–317, 314t–316t of subarachnoid hemorrhage, 313, 313t on responses to rehabilitation, 321, 1116–1117, 1117t training and certification in, 308–310, 315, 322 types and goals of, 307, 308t Stroke team, in emergency department treatment, 934, 937

1480

Index

Stroke units. See also General stroke management. availability of, 996 components of, 992–993, 993t–994t concluding summary on, 1004 vs. conventional care, 993–995, 995t patient subgroups and, 995, 996t evidence for effectiveness of, 992–995, 995t evidence for long-term benefits, 995–996 goals of care in, 996, 996t history of, 992 intracerebral hemorrhage patients in, 1106– 1107, 1107t types of, 992–993 Stroke-in-evolution, antithrombotic therapy and, 984–985 Stroke-Specific Quality of Life (SS-QOL) scale, 324, 325t, 1116–1117 Subarachnoid hemorrhage. See also Aneurysmal subarachnoid hemorrhage. in amyloid angiopathy, 567 arterial dissection with, 661, 664–666, 670–671, 674, 1086 basilar artery, 454, 666 vertebral artery, 453–454, 661, 666 arteriovenous malformation with, 625–626, 628f, 913 causes of, 591, 591t, 913 cerebral ischemia in. See Delayed cerebral ischemia (DCI), in subarachnoid hemorrhage. cerebral venous thrombosis with, 520–521, 521f cerebrovascular dysfunction after, 3, 10–11, 10f, 598 computed tomography of, 940–941 definition of, 589 drug abuse and, 546–547 with cocaine, 547–548, 795–796 emergency department management of, 940–941 hydrocephalus secondary to, 603–604, 604t intensive care management of, 1036 with intraventricular hemorrhage, 1033, 1036, 1038, 1352, 1354 magnetic resonance imaging of, 594, 884, 884f, 893, 897–898 migraine treatment in patient with, 730 in moyamoya disease, 706, 708–709 in reversible cerebral vasoconstriction syndromes, 767–769 risk factors for, 211–213, 590 genetic marker as, 1296 seizures associated with, 936–937 spinal, 1271–1273 Subclavian artery spinal arteries and, 644 vertebral arteries arising from, 446, 447f Subclavian steal, 473–474 angioplasty and stenting for, 1216–1217 Subclavian-innominate artery disease, 473–474 Subcortical dementia, 502–504. See also Binswanger’s disease; Strategic infarct dementia. Subcortical white matter hemorrhage. See Lobar (white matter) hemorrhage. Subdural hemorrhage angiography of, 911–913 magnetic resonance imaging of, 884, 884f, 893, 898

Subhyaloid hemorrhages, 555, 571 Suboccipital craniotomy, 1333–1334 Substance abuse, 243t, 245, 790. See also Alcohol consumption; Cocaine abuse; Smoking. amphetamines and related drugs, 792–795, 1092 barbiturates, 798 cerebral vasculitis related to, 1092 definition of, 790 inhalants, 798 lysergic acid diethylamide, 797 marijuana, 797–798 opiates, 790–792 phencyclidine, 797 Substantia nigra, necrosis of, tissue acidosis in, 71–72 Subventricular zone neurogenesis in, 162–163 oligodendrocyte progenitor cells in, 165 Sufentanil in critical care, 1011–1012 for rapid sequence intubation, 1009 Sulcal arteries, of spinal cord, 645, 645f, 651–652 Sulcal veins, 645 Sulfonylureas, 1069–1070 Sumatriptan contraindicated with stroke risk, 729–730, 729t, 769–770 stroke associated with, 724–725 Super lacunes, 301, 486–488, 500 Superficial temporal artery to middle cerebral artery bypass. See Extracranial-intracranial bypass. Superior cerebellar artery anatomy of, 447–449, 448f–450f, 1440 branches in, 456, 462, 463f aneurysms of, 1322 surgery for, 1330–1332, 1332f cardioembolism of, 451, 462 hemorrhage from branches of, 535, 539–540 occlusions of, 462–464, 463t, 468 Superoxide atherosclerosis and, 6–7 cerebrovascular tone and, 5–6 cyclooxygenase-2 and, 141–142 hereditary hemorrhagic telangiectasia and, 171 in hypertension, 9 postischemic inflammation and, 145 in preconditioning response, 155–156 after subarachnoid hemorrhage, 10, 10f Superoxide dismutases, 5 atherosclerosis and, 6–7 cerebral ischemia and, 145 cerebral vasospasm and, 10 in hypertension, 9 preconditioning response and, 155–156 Supplementary motor area (SMA) functional neuroanatomy of, 374 lesions of, 371, 373–374, 373f Surgical retraction of brain tissue, metabolism and, 59 Susac’s syndrome, 695, 696f Susceptibility-weighted imaging (SWI), 882, 888 of hemorrhage, 553, 895, 895f Sylvian lip syndrome, 399 Sympathomimetic drugs. See also Amphetamines; Cocaine abuse; Phenylpropanolamine. intracerebral hemorrhage associated with, 546–548, 547f

Synaptogenesis, 162 Syndrome of inappropriate antidiuretic hormone (SIADH), 999, 1012 subarachnoid hemorrhage with, 1039 Syphilis brainstem infarction in, 455 spinal cord infarction in, 646, 651–652 Systemic lupus erythematosus, 455, 692–693 antiphospholipid antibodies in, 692, 777–778 Libman-Sacks endocarditis in, 822, 1180

T T1-weighted imaging, 883 hemorrhage on, 895, 895t in ischemic stroke, 893 T2-weighted imaging, 882–883, 883f, 888t diffusion-weighted imaging and, 885 FLAIR imaging and, 884 hemorrhage on, 895, 895t in ischemic stroke, 891–893 Tachycardia, lateral medullary infarction with, 471 Tachycardia-bradycardia syndrome, 820 Tacrolimus (FK506), 1056t–1057t, 1068 Takayasu’s arteritis, 455, 691–692 angiography in, 921, 922f ultrasonography in, 842 Talc microemboli, in intravenous drug abusers, 794 TCD. See Transcranial Doppler (TCD) ultrasonography. TEE. See Transesophageal echocardiography (TEE). Telangiectases, 633–634. See also Hereditary hemorrhagic telangiectasia. Telegraphic speech, 399 Telemedicine, 938 Telodiencephalic syndrome, 347 Temperature, body, in acute stroke, 1003, 1024. See also Hyperthermia; Hypothermia. Temporal arteritis. See Giant cell arteritis. Tenecteplase. See TNK-t-PA (tenecteplase). Terutroban, 1167 TGF. See Transforming growth factor (TGF)-β superfamily. Thalamic hemorrhage, 535 causes of, 561 clinical features of, 561–566, 562t aphasia in, 563–564 hemiparesis in, 561–562 neglect in, 563–564 oculomotor and pupillary, 562–564 topography and, 563–564 unusual sensory syndromes in, 564–566 CT aspects of, 565, 566t gross anatomy of, 539, 540f mortality rate of, 565–566 prognosis of, 566 putaminal-thalamic, 558–559, 560f topography of, 561, 563–564, 564f–565f, 566 Thalamic pain syndrome, 563–565. See also Central pain; Dejerine-Roussy syndrome. Thalamogeniculate arteries, 450, 451f rupture of, 563–564 Thalamoperforating arteries anatomy of, 449–450, 451f, 485, 488 lacunes in territories of, 488 rupture of, 563

Index 1481 Thalamus anterior cerebral artery infarction and, with dementia, 373 arterial territories of, 425–426, 426f, 429f hypertension and, 494–495 internal capsule and, 498 lacunar infarcts in, 488. See also Lacunes. posterior cerebral artery infarction and, 427 anterograde amnesia in, 440 aphasia in, 439–440 motor syndromes in, 430 sensory syndromes in, 429–430, 429f stem of PCA and, 429, 429f Tham. See Tromethamine (Tham). Thermal hypesthesia, lacunar infarction with, 494 Thiamine, for delirium prevention, 1002 Thiazolidinediones, postischemic inflammation and, 144, 1069 Thienopyridines, 974, 979. See also Clopidogrel; Ticlopidine. Thiopental intracranial pressure and, 999, 1022 for neuroprotection, during aneurysm surgery, 1302 for rapid sequence intubation, 935 Thoracolumbar arterial territory, 644–645 Three-dimensional ultrasonography, 833, 834f, 838, 840–841 transcranial, 843–844, 848 Thrombectomy, mechanical, 919, 1209 in acute carotid occlusion, 1233 in acute stroke, 1230–1232 for cerebral venous thrombosis, 1097 current status of, 1236–1237 with intraarterial thrombolysis, 1205, 1206f in late-presenting stroke, 1233 Thrombin, 29–31, 30f, 945, 946f plasminogen activation and, 31–32, 34 platelets and, 1148–1149, 1150f, 1151–1152 aspirin and, 1156 Thrombin-activatable fibrinolysis inhibitor, 36 Thrombocythemia, essential hydroxyurea for, 776 stroke in, 776 Thrombocytopenia, heparin-induced, 776–777, 976 with low-molecular-weight heparins, 977 Thromboembolism. See also Venous thrombosis. delayed cerebral ischemia and, 604 venous, prophylaxis of, after subarachnoid hemorrhage, 600 Thrombogenesis, endothelial properties and, 3 Thrombolysis, mechanical. See Thrombectomy, mechanical. Thrombolysis in Myocardial Infarction (TIMI) grading system, 1205–1209, 1207t modified, 1207–1209, 1209t Thrombolytic system. See Fibrinolysis. Thrombolytic therapy, intraarterial, 1205, 1227 adjunctive therapy for, 1228–1229 algorithm for, middle cerebral artery, 1237f in arterial dissection, 1084, 1086 for basilar artery occlusion, 1028 in carotid occlusion, acute internal, 1233 in carotid stenosis, 343 clinical trials of, 1205–1209, 1206t, 1208t, 1227, 1229–1230 potential, 1236–1237

Thrombolytic therapy, intraarterial (Continued) combined with intravenous thrombolysis, 1205, 1207, 1208t, 1232–1233 current status of, 1227, 1236–1237 diffusion-perfusion MRI data in, 901 drawbacks of, 1232 failures of, 1209 hemorrhagic transformation and, 1234–1235, 1235f hyperglycemia and hemorrhage with, 1003 ideal candidate for, 1235 intracerebral hemorrhage secondary to, 551–552, 554f vs. intravenous thrombolysis, 1232 postischemic hyperperfusion in, 901–902 technique of critical aspects of, 1235–1236 general, 1227–1229, 1228f thrombolytic agents for, 1227–1228 time window for, 872, 876, 1207, 1232, 1236 vertebrobasilar, 1233–1234 in wake-up and late-presenting strokes, 1233 Thrombolytic therapy, intravenous, 945. See also Plasminogen activators, exogenous; rt-PA (recombinant tissue-type plasminogen activator). antiphospholipid antibodies and, 1093 for aortic plaques, 752 in arterial dissection, 673, 1084 for basilar artery occlusion, 1028 blood pressure management during, 965–966, 966t catheter and line placement during, 966 for cerebral venous thrombosis, 526, 1097 clinical studies in acute stroke, 951–957 feasibility studies, 951–952 large randomized trials, 952–957, 952f–954f, 953t, 958t observational studies, 957–960, 958t combined with intraarterial thrombolysis, 1205, 1207, 1208t, 1232–1233 combined with other treatments, 967–968 anticoagulants, 979, 986–987 antiplatelet agents, 978–979, 983–984, 986–987 hypothermia, 1073–1074 concluding summary on, 968 cost-effectiveness of, 967 C-reactive protein and, 697 emergency department role in, 937–938 extracranial hemorrhage secondary to, 966–967 guidelines for acute stroke, 960–967 applicability to all subgroups, 965 consent required, 963 early CT findings and, 963–964, 963f–964f exclusion criteria, 953t, 960–962 expedited protocol, 960–963 facilities required, 963 management during and after, 963, 965–967, 966t off-label use and, 961 protocol, 960 time to treatment and, 964–965, 965f hemorrhagic transformation secondary to, 897 ideal candidate for, 1235 immobilization following, 1002 indications for, 945 vs. intraarterial thrombolysis, 1232

Thrombolytic therapy, intravenous (Continued) intracranial hemorrhage as contraindication to, 945, 953t, 962 intracranial hemorrhage secondary to, 551–552, 553f–554f amyloid angiopathy and, 552 antithrombotic therapy and, 967 in clinical trials, 552, 553f, 951–955, 954f, 967 in community studies, 957–960, 958t hyperglycemia and, 1107 management of, 966, 1031 as microhemorrhages, 553–554 platelet function and, 37 prediction of, 871 preexisting microbleeds and, 897 surgery for, 1111 in ischemic stroke, 29 cerebral hemorrhage and, 37–39, 38t contraindications to, 37 factors affecting efficacy of, 29 outcomes of, 1205, 1205t recanalization by, 38, 38t tenecteplase trials of, 36 with lacunar infarction, 508, 1235 late secondary ischemic injury in, 901–902 magnetic resonance imaging and HARM sign in, 884f, 893 therapy guided by, 900–902, 900f NIHSS score and response to, 316–317 patient selection for, 293 computed tomography in, 872–873, 963–964, 963f–964f CT angiography in, 874, 876–878 CT perfusion imaging in, 877 diffusion-perfusion MRI in, 900–901, 949 platelet activation in, 1152 posterior circulation, 878 preclinical studies in acute stroke, 950–951, 950t predictors of good outcome with, 967 prior stroke and, 961 recanalization following, 298, 965–967 hemorrhagic transformation and, 998–999 monitoring of, 997 reocclusion after, 965–967 antithrombotic therapy and, 986 risks of, 967 in sickle cell disease, 1094 in smokers, 801 telemedicine role in, 938 time window for, 964–965, 965f clinical trials and, 956–957 in toxin-related vasculitis, 1092 ultrasound monitoring of, 849–850, 849f, 850t ultrasound-enhanced, 855–858 emerging applications of, 860 Thrombolytic therapy, intraventricular, 1034, 1034f, 1110, 1342, 1351f, 1353–1354, 1353t, 1354f–1355f in subarachnoid hemorrhage, 1036, 1038 Thrombolytic therapy, local, in cerebral venous thrombosis, 1097 Thrombomodulin, 772, 773f Thrombophilias. See Hypercoagulable states. Thrombosis. See also Antiphospholipid antibodies; Coagulation abnormalities; Large artery thrombosis with infarct; Venous thrombosis. atherothrombosis, 776 cerebral microvasculature and, 23

1482

Index

Thrombosis (Continued) in heparin-induced thrombocytopenia, 777 middle cerebral artery occlusion in, 388–389, 388f–389f physiologic process of, 945–950, 946f platelets in, 776 spinal cord ischemia caused by, 646, 648 vascular injury and, 772 Thrombospondin, 945 Thrombotic thrombocytopenic purpura, 692 Thromboxane A2, 7 measurement of metabolites of, 1156 platelet activation and, 1148–1152, 1150f vasoconstriction associated with, 6, 11 Thrombus(i) acute, gradient recalled echo imaging of, 891, 892f in basilar artery, 450–451 dissolution of, 32–33. See also Fibrinolysis. formation of, 29–31, 945 intraarterial, computed tomography of, 870–871, 871f, 997 relative platelet–fibrin composition of, 945, 1147 remodeling of, 29, 31, 945 TIAs. See Transient ischemic attacks (TIAs). Ticagrelor, 974, 978 Ticlopidine, 776, 974, 1159–1160 with carotid artery stenting, 1165–1166 Time-of-flight MR angiography, 883f, 887–888 TIMI. See Thrombolysis in Myocardial Infarction (TIMI) grading system. Tinnitus, dural arteriovenous malformations with, 1280, 1285, 1289 Tinzaparin, 977–979, 980t–982t, 981–982 Tirilazad neuroprotection trials of, 1056t–1057t, 1065 for vasospasm, in subarachnoid hemorrhage, 1037 Tirofiban, 974, 978–979, 984 in basilar artery occlusion, 1028 mechanism of action, 1150 TMS. See Transcranial magnetic stimulation (TMS). TNF. See Tumor necrosis factor (TNF). TNK-t-PA (tenecteplase), 36, 946–947, 948f, 1227–1228 TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, 308, 318–321, 318t Tolerance, 154. See also Preconditioning. Toll-like receptors, 80, 142–143, 142f–143f, 143t, 147 Topographic memory loss, 414 Topographical disorientation, 434, 434f color blindness with, 438 Total aphasia, 397. See also Global aphasia. Toxins, cerebral vasculitis related to, 1090t, 1092 t-PA (tissue-type plasminogen activator), 29–34, 32t, 34f, 775, 945–946, 947f. See also rt-PA (recombinant tissue-type plasminogen activator); Thrombolytic therapy. in cerebral tissue, 37 amyloid angiopathy and, 543 in cerebrospinal fluid, 1352 in focal cerebral ischemia, 18–19, 36–38 inhibitors of, 36 mutant versions of, 35–36, 946–947 stroke risk and, 775 Tracheostomy, for mechanical ventilation, 1010

Trafermin. See bFGF (trafermin). Tramadol, 1011–1012 Tranexamic acid, rebleeding and, after subarachnoid hemorrhage, 603, 1035–1036 Transcortical aphasia, 405 functional imaging in, 406 mixed, 405 motor, 405 sensory, 405, 439 Transcranial direct current stimulation, hemiparesis and, 393 Transcranial Doppler (TCD) ultrasonography, 842–847 of arterial dissection, 666–668 vertebral artery, 841–842 of arteriovenous malformations, 622, 623f, 848–849 basic principles of, 831, 842–843, 842f, 842t–843t cardiac shunts detected by, 847, 1180–1181 in cardioembolic stroke, 816 in carotid artery disease, 337, 354, 842t, 845–848 in carotid endarterectomy, 1408 for cerebral perfusion monitoring, 999–1000 of cerebral vasospasm, 605–606 after subarachnoid hemorrhage, 850 in vasopressor therapy, 999 of cerebral venous thrombosis, 523 of collateralization, 844 contrast-enhanced, 843–844, 847–849 for cardiac shunt detection, 847 of dolichoectatic arteries, 847 for functional recovery monitoring, 851 with insufficient bone windows, 848 for intracranial pressure monitoring, 850–851 lacunar infarcts and, 506 of microemboli, 844–847, 844f–845f thrombolysis and, 850 of middle cerebral artery embolism, 746–747, 747f of midline shift, 850 of postpartum cerebral angiopathy, 847 of recanalization, 997 in reversible cerebral vasoconstriction syndromes, 768–769, 1087 in sickle cell disease, 271–272, 782–783, 847, 1094–1095 of stenosis and occlusion, 843–844 after subarachnoid hemorrhage, 59, 1036, 1036t technological advances in, 842 three-dimensional, 843–844, 848 thrombolytic therapy enhanced with, 857–858 of vasospasm, 1036, 1036t Transcranial magnetic stimulation (TMS) with aphasia therapy, 408 for hemineglect, 416 recovery from hemiparesis and, 393 Transcription factors, ischemic cell death and, 98–101, 99f Transesophageal echocardiography (TEE) of aortic plaques, 741–743, 742f–743f lacunar stroke and, 506 vs. newer methods, 752–753, 753f atrial fibrillation and, 819–820 in cardioembolic stroke, 816, 819 lacunar stroke and, 506 mitral valve strands in, 819

Transesophageal echocardiography (Continued) of patent foramen ovale, 1180–1181 right-to-left cardiac shunts detected by, 818, 818f, 847 spontaneous echo contrast in, 819 Transforming growth factor (TGF)-β superfamily arteriovenous malformations and, 170f, 171, 173–174, 177f cavernous angiomas and, 179 platelets and, 1153 Transient global amnesia, 440 Transient hemispheric attacks, 341, 351–352 Transient ischemic attacks (TIAs) vs. amyloid angiopathy symptoms, 533 angiography in evaluation of, 918–919, 918f–919f antiplatelet therapy following, 1162 in arterial dissection, 664, 666, 679t in CADASIL, 759 cardioembolic, clinical features of, 814 in carotid artery disease, 336, 347–353 angiographic correlations with, 352–353, 353f, 918 with arterial dissection, 664 brachial monoplegia in, 392–393 duration of, 348–349 of intracranial internal carotid, 350 with nonstenosing lesions, 352–353 pathophysiology of, 340–342 as transient hemispheric attacks, 341, 351–352 as transient monocular blindness, 341, 344, 350–352 cerebral venous thrombosis with, 519 C-reactive protein as risk factor for, 207 definition of, 938 differential diagnosis of, 349–350, 938 emergency department management of, 938 disposition of patient and, 941–942, 996 incidence of, 200 lacunar infarction following, 491, 507–508 lacunar source of, 496 magnetic resonance imaging in, 889–891, 889f–890f in migraine patients, 729–730, 729t–730t in moyamoya disease, 711 platelets in pathogenesis of, 7 posterior cerebral artery stem occlusion with, 428 preconditioning associated with, 144–145, 154 risk of cardiovascular events following, 229 of spinal cord, 650–651 thrombolytic therapy in, 962 in vertebral artery occlusion, 472 vertebrobasilar territory, 727 Transient monocular blindness (amaurosis fugax), 341, 344, 350–352 migraine with, 725 unilateral carotid stenosis with, 1000 Transient monocular vertical hemianopia, 351 Transient receptor potential (TRP) superfamily, 5–6, 92 Transsylvian approach. See Pterional craniotomy. Transthyretin gene mutations, 274, 534 Traumatic brain injury. See also Head trauma; Neck rotation or trauma. arteriovenous fistula caused by, 632 decompressive surgery in, 1435 intracerebral hemorrhage in, surgery for, 1340

Index 1483 Trazodone, 1056t–1057t, 1064 TREK-1 potassium channels, 5 Tremor, unilateral, lacunar infarct causing, 500 Tricyclic antidepressants for central pain, 1120 for depression, 1121 Triflusal, 1167 Trigeminal artery, 450 persistent, 340, 340f embolism in, 341 Tripelennamine (pyribenzamine), 791 Triple-H therapy, for cerebral vasospasm, 598, 605, 1036–1037 in moyamoya disease, 1088 Triptans, contraindications to in ischemic stroke, 1095 with stroke risk, 729–730, 729t, 769–770 after subarachnoid hemorrhage, 730 Tromethamine (Tham), for intracranial pressure elevation, 1021 Troponin elevation, after subarachnoid hemorrhage, 606 TRP (transient receptor potential) superfamily, 5–6, 92 Ts and Blues, 791 Tuberculous meningitis, vascular effects of, 455 Tumor necrosis factor (TNF) apoptosis and, 109–110, 111f, 114 in atherosclerosis, 695–697 in inflammatory response to ischemia, 138–141, 140t, 143–144 preconditioning associated with, 145 lacunar stroke prognosis and, 697 necroptosis and, 80, 111f necrosis and, 107–110 in stroke autopsy specimens, 115–116 Tumors, intracranial. See also Neoplasms. hemorrhagic, 548, 548f–550f, 1339 vascular, carotid artery disease and, 336–337 TUNEL labeling, 72–73, 113–116 Two-vessel occlusion (2-VO) models, 78

U Ultrasonic hematoma aspiration, 1342 Ultrasonography, 831. See also Doppler ultrasonography; Echocardiography; Perfusion ultrasound imaging; Transcranial Doppler (TCD) ultrasonography. in acute stroke, 849–855 of brain perfusion. See Perfusion ultrasound imaging. with contrast, 851, 851f–852f of functional recovery, 851 of intracranial pressure, 850–851 of midline shift, 850 with power modulation, 851–852, 852f of thrombolysis, 849–850, 849f, 850t of vasospasm, 850 of arterial dissection, 666–668, 668f–669f, 841–842 of atherosclerosis. See Atherosclerosis, ultrasonography of. basic imaging techniques in, 831–833, 832f–834f, 833t basic principles of, 831, 832f contrast agents for, 847

Ultrasonography (Continued) molecular imaging with, 858–859 stroke therapy using, 855–858 contrast-enhanced. See also Perfusion ultrasound imaging. of plaque angiogenesis, 841 transcranial, 843–844, 847–849 emerging applications of, 858–860 for drug delivery, 860 in gene therapy, 859–860 in molecular imaging, 858–859 for opening blood-brain barrier, 859 intraoperative, in aneurysm surgery, 848 in moyamoya disease, 713, 715f in Takayasu’s arteritis, 842 three-dimensional, 833, 834f, 838, 840–841 transcranial, 843–844, 848 Ultrasound stroke therapy, 38, 855–858 Umbilical cord blood, 1138, 1140, 1143 Undetermined cause, infarct of. See Cryptogenic infarction. Unfolded-protein response, 157 Unilateral spatial neglect, 411–412, 412f–413f u-PA (urokinase-type plasminogen activator). See also scu-PA (single-chain urokinase-type plasminogen activator); Urokinase. endogenous, 31–34, 32t, 945–946 in cerebral tissue, 37 in focal cerebral ischemia, 18–19, 37–38 inhibitors of, 36 exogenous, 33, 946 clinical consequences of, 37 contraindications to, 37 hemostatic consequences of, 34 mutant versions of, 35–36 recanalization in ischemic stroke and, 38, 38t Upper extremity rehabilitation, 1127–1129 Urapidil, 1014 in hypertensive encephalopathy, 738 Urate, serum, prognosis after stroke and, 224 Urinary incontinence, after stroke, 1119–1120, 1120t Urinary tract infection, 1002, 1119 Urokinase, 946, 1227–1228. See also r-proUK (recombinant pro-urokinase); scu-PA (singlechain urokinase-type plasminogen activator); u-PA (urokinase-type plasminogen activator). intraventricular, 1110, 1342, 1353, 1353t local, for cerebral venous thrombosis, 1097

V Valproic acid, for migraine prophylaxis, 730, 730t Valvular heart disease, 821–823, 821f–822f, 1178–1180 in heroin users, 790 Vampire bat salivary plasminogen activator (batPA), 35 Varicella zoster infection, cerebral vasculopathy in, 690f Vascular cognitive impairment. See also Vascular dementia. clinical diagnosis of, 253–254 common disease states and, 259–260 definition of, 253 epidemiology of, 253, 254f historical concepts of, 252 imaging correlates of, 255–256

Vascular cognitive impairment (Continued) mild, 252–254 neuropathology of, 256–257 neuropsychological assessment of, 254 overview of, 253 pathophysiology of, 255 prevention of, 257–260 risk factor management in, 260–261 risk factors for, 257–259 summary of, 261, 261f vascular disease severity measures and, 259 Vascular dementia, 502–503, 507–508. See also Vascular cognitive impairment. alcohol consumption and, 799 Alzheimer’s disease mixed with, 253, 255–257, 261, 261f, 502 amyloid angiopathy in, 255, 273 Binswanger’s disease as, 253, 502–504 classification of, 502 clinical diagnosis of, 253–254 definition of, 502 diagnostic criteria for, 252–253 epidemiology of, 252 historical evolution of concept of, 252 neuropathology of, 256–257 poststroke, 253, 502 risk factors for, 257–259 strategic infarcts with, 252, 373, 504 as subclass of vascular cognitive impairment, 253 treatment of, 260 pharmacologic, 261, 1124 Vascular endothelial growth factor (VEGF) angiogenesis and, 21–22 in remodeling after stroke, 163–165 in arteriovenous malformations, 170–172, 177f experimental models and, 174–175, 175f–176f in cavernous angiomas, 179 focal cerebral ischemia and, 17 neuroblast migration after stroke and, 163 Vascular injury, thrombosis secondary to, 772 Vascular malformations, brain arteriovenous. See Arteriovenous malformations, brain; Dural arteriovenous malformations. capillary-arteriovenous, 180 cavernous. See Cavernous malformations, cerebral. hemorrhagic. See Intracerebral hemorrhage (ICH), vascular malformations with. overview of, 616, 617f, 1388 venous. See Venous anomalies. Vascular malformations, spinal. See Arteriovenous malformations, spinal. Vascular smooth muscle calcium ions in, 6, 9f of cerebral arteries, 16 vascular endothelial growth factor and, 21 Vascular smooth muscle cells, in CADASIL, 760–762 Vasculitis, 687, 1085t, 1089–1092. See also Arteritis; Primary (isolated) angiitis of central nervous system; specific diseases. amphetamine-induced, 793–795 angiography of, 921, 922f immunosuppressive drugs for, 1090t

1484

Index

Vasculogenesis, definition of, 163–164 Vasoconstriction. See Cerebrovascular tone; Reversible cerebral vasoconstriction syndromes. Vasodilatation. See Cerebrovascular tone; Flowmediated vasodilation. Vasodilators for blood pressure control, 1014 for delayed cerebral ischemia, 605, 1038 in migraine-related stroke, 1095 Vasogenic edema, 1426 in cerebral venous thrombosis, 899–900 in hypertensive encephalopathy, 734–738 magnetic resonance imaging and, 885, 893 Vasopressin, t-PA and, 34 Vasopressors, in intensive care unit for hypotension, 1015–1016, 1019 thrombosis prophylaxis and, 1024 Vasospasm, cerebral cocaine-induced, 796 after intraventricular hemorrhage, 1352 posterior cerebral artery infarction caused by, 428–429 after subarachnoid hemorrhage. See Aneurysmal subarachnoid hemorrhage, vasospasm secondary to. Vault moyamoya, 708 VEGF. See Vascular endothelial growth factor (VEGF). Vein of Galen malformation, 169, 616, 617t, 633, 1280 prenatal diagnosis of, 1293 Veins, cerebral, anatomy of, 516–517, 517f Venous anomalies, 180, 635, 636f clinical presentation of, 1390–1391 diagnostic imaging of, 1390f, 1394–1395 epidemiology of, 1389 future understanding of, 1396 genetics of, 1389–1390 management of, 1395–1396 radiosurgery for, 1385, 1395–1396 pathologic features of, 1388 Venous hypertension arteriovenous malformations and, 175–176 dural arteriovenous fistulas and, 175, 180, 911–913, 1280–1282, 1289 magnetic resonance imaging and, 899 subdural hemorrhage secondary to, 911–913 Venous infarction cerebral venous thrombosis with, 1096–1097 magnetic resonance imaging of, 899 of spinal cord, 651–652 Venous sinuses. See Dural venous sinuses. Venous thromboembolism, prophylaxis of, after subarachnoid hemorrhage, 600 Venous thrombosis. See also Cerebral vein and dural sinus thrombosis; Thrombosis. arteriovenous fistula caused by, 632 Factor II G20210A and, 774 factor V Leiden and, 773 fibrinolysis and, 775 in heparin-induced thrombocytopenia, 777 transcranial Doppler ultrasonography of, 849 Ventilator. See Mechanical ventilation. Ventricular catheter, for pressure monitoring, 1016–1018

Ventricular drain, external in aneurysm surgery, 1306–1307, 1320 with cerebellar hematoma, 1441–1442, 1443f with cerebellar infarction, 1444 after hematoma evacuation, 1342 in intraventricular hemorrhage, 1352–1353, 1353t in subarachnoid hemorrhage, 1036, 1038 Ventricular hemorrhage. See Intraventricular hemorrhage. Ventriculoperitoneal shunt after aneurysm surgery, 1320 aneurysmal intraventricular hemorrhage and, 1349 Ventriculostomy in cerebellar hemorrhage, 1341f, 1343 in cerebellar infarction, 1028–1029, 1434–1435 in intracerebral hemorrhage or intraventricular hemorrhage, 1109–1110 in subarachnoid hemorrhage, 1036 Venules, postcapillary, 16, 18f, 485 fibrin deposition in, 21 Verapamil, in reversible cerebral vasoconstriction syndromes, 1087 Versican gene, 1295 Vertebral arteries anatomy of, 446, 447f aneurysms of, 452–453, 1322 surgery for, 1332–1333, 1333f atherosclerosis of, 450–452 cervical spondylosis occluding, 454 dissection of, 453–454, 662–663, 665f catheter-related, 911 clinical manifestations of, 666, 668t course and prognosis of, 674–675 epidemiology of, 661–662 imaging of, 666–672, 669f, 671f magnetic resonance imaging/angiography of, 898, 898f spinal cord ischemia secondary to, 646 with subarachnoid hemorrhage, 661 treatment of, 673, 678f, 1084–1086 ultrasonography of, 841–842 fibromuscular dysplasia of, 676–677 fibrous bands constricting, 455 giant cell arteritis in, 688, 688f neck trauma and, 453–454 Takayasu’s arteritis of, 691–692 Vertebral artery occlusive disease. See also Vertebrobasilar disease. angiography of, 919f angioplasty and stenting for, 1215–1216 bilateral, 473 CT angiography of, 878 extracranial, 472–473, 473f intracranial, 468–472, 469f, 473f spinal cord infarction in, 653 ultrasonography of, 838–839, 839f contrast-enhanced, 848 Vertebral subluxation, at C1-C2, 693 Vertebrobasilar disease, 446 anatomic basis of, 446–450 basilar artery in, 448–450, 450f–451f cerebellar arteries in, 446–448, 448f–450f embryology of, 446 persistent fetal anastomoses in, 446, 447f, 449–450 thalamic arteries in, 449–450, 451f vertebral arteries in, 446, 447f

Vertebrobasilar disease (Continued) clinical findings in basilar artery and. See Basilar artery occlusive disease. with migraine, 474–476 with multiple infarcts, 474, 475f–476f in subclavian-innominate artery disease, 473–474 vertebral artery and. See Vertebral artery occlusive disease. historical aspects of, 446 migraine-associated stroke in, 727 moyamoya disease and, 712 pathology of, 450–455 aneurysms in, 452–453, 452f–453f, 916f arterial dissection in, 453–454 atherosclerosis in, 450–452, 451f C1-C2 subluxation in, 693 cervical spondylosis in, 454 fibromuscular dysplasia in, 454 less common diseases in, 455 lipohyalinosis in, 452 neck rotation or trauma in, 453–455 temporal arteritis in, 455 pathophysiology of, 455–456, 456t power Doppler imaging of, 848 prognosis of, 222–223 transcranial Doppler ultrasonography in, 843 Vertigo, 394 anterior inferior cerebellar artery and, 465 lateral medullary infarction with, 469–470 posterior inferior cerebellar artery and, 467–468 Virchow-Robin spaces, 16 dilated, 486 Viscosity, cerebral blood flow and, 46–47 Visual agnosia, in posterior cerebral artery disease, 433 Visual field defects. See also Hemianopia; Quadrantanopia. lobar hemorrhage with, 567 in middle cerebral artery disease, 395–396, 395f in posterior cerebral artery disease, 430–433, 432f Visual perception distortions, in posterior cerebral artery disease, 433–434 Vitamin B6 for homocystinuria patients, 271, 1088 hyperhomocyst(e)inemia and, 1088–1089 Vitamin B12, homocysteine and, 781–782, 1088–1089 Vitamin D deficiency, cognitive function and, 257 Vitamin K, for warfarin-associated intracerebral hemorrhage, 940, 1111, 1184 Vitamin K antagonists, 973. See also Warfarin. Vocal cord paralysis, lateral medullary infarction with, 471 Vomiting. See Antiemetic agents; Nausea and vomiting. von Willebrand factor, 773

W Wallenberg syndrome, 463t, 466–468 Wallerian degeneration, 72f on sequential MRI, 893 Warfarin, 1182–1183. See also Anticoagulation; Cardioembolic stroke, prevention of. antiphospholipid antibodies and, 1093

Index 1485 Warfarin (Continued) aortic plaques and, 751 for arterial dissection, 672–673 in atrial fibrillation. See Atrial fibrillation, warfarin in. in cardiomyopathy, 816–817 after cerebral venous thrombosis, 526–527, 1097 genetics for dosing of, 275–276 heparin during initiation of, 985–986 heparin-induced thrombocytopenia and, 777 intracerebral hemorrhage associated with, 548–550, 550f–551f, 940, 1031, 1111, 1184–1185 amyloid angiopathy and, 552 aspirin and, 549 after myocardial infarction, with left ventricular thrombus, 817 with prosthetic valves, 821 for secondary stroke prevention, 779 of cardioembolic stroke, 816, 818, 1164 for Sneddon’s syndrome, 694 for stroke prevention vs. aspirin, 1162–1163, 1210 with aspirin, 1166–1167, 1183 thrombolysis in patient using, 961 Watershed areas cerebral. See Borderzone region. spinal cord, 644 infarction and, 651 ischemia of, 648–649 Weakness, in basilar artery occlusion, 457 Weber-Osler-Rendu syndrome. See Hereditary hemorrhagic telangiectasia.

Wegener’s granulomatosis, 693 Weight management, for primary prevention of stroke, 243t, 244 Wernicke’s aphasia, 401–404, 401f, 403f. See also Sensory aphasia. conduction aphasia as form of, 405 embolic event leading to, 298–299 functional imaging in, 406 large lesion with absence of, 402, 402f natural history of, 407 Wernicke’s encephalopathy, tissue acidosis in, 71–72 WFNS. See World Federation of Neurological Surgeons (WFNS) Scale. White matter anatomic distribution of, 122 metabolism of, 122–123 vascular supply of, 123, 124f White matter anoxic-ischemic injury, 122 anatomic and physiologic basis of, 122–123, 123f–124f autoprotection and, 132–134, 134f clinical protective strategies in, 133–134 effects of ischemia and, 125–129, 126f–129f mechanisms of injury in, 129–132, 129f, 131f, 133f model systems for studying, 123–125 overview of, 122 White matter hyperintensities. See also Leukoaraiosis. in amyloid angiopathy, 533 in CADASIL, 270, 760, 761f in CARASIL, 271 incidental, 893 vascular cognitive impairment and, 252–253, 255–256, 259

White matter lesions in amyloid angiopathy, 533 in anticoagulated patients, 1184–1185 in CADASIL, 758–760, 761f, 762 in hypertensive encephalopathy, 734–736 in migraine patients, 724 in posterior reversible encephalopathy syndrome, 737 White matter (lobar) hemorrhage. See Lobar (white matter) hemorrhage. White matter microangiopathy, 23 White matter remodeling, in ischemic brain, 165 Willbrand’s sign, 435–436 Withdrawal of care, with intracerebral hemorrhage, 939–940, 1112–1113 World Federation of Neurological Surgeons (WFNS) Scale, 309, 313, 313t, 323 subarachnoid hemorrhage and, 596–597, 596t Wyburn-Mason syndrome, 622

X Ximelagatran, 973 in atrial fibrillation, 1166

Z Zeiosis, 80 Zinc, ischemic cell death and, 93–95 Zolmitriptan contraindicated with stroke risk, 729–730, 729t spinal cord infarction associated with, 652, 724–725

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