Acute Stroke

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Acute Stroke

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Advisory Board

Gordon H. Baltuch, M.D., Ph.D.

Department of Neurosurgery University of Pennsylvania Philadelphia, Pennsylvania, U.S.A.

Cheryl Bushnell, M.D., M.H.S.

Duke Center for Cerebrovascular Disease Department of Medicine, Division of Neurology

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

Louis R. Caplan, M.D.

Professor of Neurology Harvard University School of Medicine

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

Mark A. Stacy, M.D.

Movement Disorder Center Duke University Medical Center Durham, North Carolina, U.S.A.

Mark H. Tuszynski, M.D., Ph.D.

Professor of Neurosciences Director, Center for Neural Repair University of California—San Diego

La Jolla, California, U.S.A.

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William C. Koller

2. Medical Therapy of Acute Stroke, edited by Mark Fisher 3. Familial Alzheimer’s Disease: Molecular Genetics

and Clinical Perspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner

4. Alzheimer’s Disease: Treatment and Long-Term Management,edited by Jeffrey L. Cummings and Bruce L. Miller

5. Therapy of Parkinson’s Disease, edited by William C. Koller and George Paulson

6. Handbook of Sleep Disorders, edited by Michael J. Thorpy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers

and Paul L. Schraeder

8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice,

edited by Takehiko Yanagihara and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by

Stanley R. Resor, Jr., and Henn Kutt

11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, Walter H. Moos,

and Elkan R. Gamzu

12. Handbook of Amyotrophic Lateral Sclerosis, edited by Richard Alan Smith

13. Handbook of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller 14. Handbook of Pediatric Epilepsy, edited by

Jerome V. Murphy and Fereydoun Dehkharghani 15. Handbook of Tourette’s Syndrome and Related Tic

and Behavioral Disorders, edited by Roger Kurlan 16. Handbook of Cerebellar Diseases, edited by

Richard Lechtenberg

17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr.

18. Parkinsonian Syndromes, edited by Matthew B. Stern and William C. Koller

19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg

20. Brain Tumors: A Comprehensive Text, edited by Robert A. Morantz and John W. Walsh

21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa B. H. Youdim, and Keith Tipton

22. Handbook of Dementing Illnesses, edited by John C. Morris

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Syndromes,edited by Robert P. Lisak 24. Handbook of Neurorehabilitation, edited by

David C. Good and James R. Couch, Jr.

25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett

26. Principles of Neurotoxicology, edited by Louis W. Chang 27. Handbook of Neurovirology, edited by

Robert R. McKendall and William G. Stroop

28. Handbook of Neuro-Urology, edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by

Philip B. Gorelick and Milton Alter

30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller

31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management, edited by Ronald J. Tusa

and Steven A. Newman

32. Handbook of Olfaction and Gustation, edited by Richard L. Doty

33. Handbook of Neurological Speech and Language Disorders,edited by Howard S. Kirshner

34. Therapy of Parkinson’s Disease: Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson

35. Evaluation and Management of Gait Disorders, edited by Barney S. Spivack

36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S. Dyer

37. Neurological Complications of Cancer, edited by Ronald G. Wiley

38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn

39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B. Calne

40. Etiology of Parkinson’s Disease, edited by Jonas H. Ellenberg, William C. Koller and J. William Langston

41. Practical Neurology of the Elderly, edited by Jacob I. Sage and Margery H. Mark

42. Handbook of Muscle Disease, edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition,

Revised and Expanded, edited by Stuart D. Cook

44. Central Nervous System Infectious Diseases and Therapy, edited by Karen L. Roos

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edited by Takehiko Yanagihara, David G. Piepgras, and John L. D. Atkinson

46. Neurology Practice Guidelines, edited by Richard Lechtenberg and Henry S. Schutta

47. Spinal Cord Diseases: Diagnosis and Treatment, edited by Gordon L. Engler, Jonathan Cole, and W. Louis Merton 48. Management of Acute Stroke, edited by Ashfaq Shuaib

and Larry B. Goldstein

49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras

50. Handbook of Ataxia Disorders, edited by Thomas Klockgether

51. The Autonomic Nervous System in Health and Disease, David S. Goldstein

52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. Ingoglia and Marion Murray 53. Handbook of Multiple Sclerosis: Third Edition,edited by

Stuart D. Cook

54. Long-Term Effects of Stroke, edited by Julien Bogousslavsky

55. Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefano Govoni

56. Dopamine Receptors and Transporters: Function, Imaging, and Clinical Implication, Second Edition, edited by

Anita Sidhu, Marc Laruelle, and Philippe Vernier 57. Handbook of Olfaction and Gustation: Second Edition,

Revised and Expanded, edited by Richard L. Doty 58. Handbook of Stereotactic and Functional Neurosurgery,

edited by Michael Schulder

59. Handbook of Parkinson’s Disease: Third Edition, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 60. Clinical Neurovirology, edited by Avindra Nath

and Joseph R. Berger

61. Neuromuscular Junction Disorders: Diagnosis and Treatment, Matthew N. Meriggioli, James F. Howard, Jr., and C. Michel Harper 62. Drug-Induced Movement Disorders, edited by

Kapil D. Sethi

63. Therapy of Parkinson’s Disease: Third Edition, Revised and Expanded, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller

64. Epilepsy: Scientific Foundations of Clinical Practice, edited by Jong M. Rho, Raman Sankar,

and José E. Cavazos

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and Behavioral Disorders: Second Edition, edited by Roger Kurlan

66. Handbook of Cerebrovascular Diseases: Second Edition, Revised and Expanded, edited by Harold P. Adams, Jr.

67. Emerging Neurological Infections, edited by Christopher Power and Richard T. Johnson

68. Treatment of Pediatric Neurologic Disorders, edited by Harvey S. Singer, Eric H. Kossoff, Adam L. Hartman, and Thomas O. Crawford

69. Synaptic Plasticity : Basic Mechanisms to Clinical Applications,edited by Michel Baudry, Xiaoning Bi, and Steven S. Schreiber

70. Handbook of Essential Tremor and Other Tremor Disorders,edited by Kelly E. Lyons and Rajesh Pahwa 71. Handbook of Peripheral Neuropathy, edited by

Mark B. Bromberg and A. Gordon Smith 72. Carotid Artery Stenosis: Current and Emerging

Treatments, edited by Seemant Chaturvedi and Peter M. Rothwell

73. Gait Disorders: Evaluation and Management, edited by Jeffrey M. Hausdorff and Neil B. Alexander

74. Surgical Management of Movement Disorders (HBK), edited by Gordon H. Baltuch and Matthew B. Stern 75. Neurogenetics: Scientific and Clinical Advances, edited by

David R. Lynch

76. Epilepsy Surgery: Principles and Controversies, edited by John W. Miller and Daniel L. Silbergeld

77. Clinician's Guide To Sleep Disorders, edited by Nathaniel F. Watson and Bradley Vaughn 78. Amyotrophic Lateral Sclerosis, edited by

Hiroshi Mitsumoto, Serge Przedborski and Paul H. Gordon 79. Duchenne Muscular Dystrophy: Advances in Therapeutics,

edited by Jeffrey S. Chamberlain and Thomas A. Rando 80. Handbook of Multiple Sclerosis, Fourth Edition, edited by

Stuart D. Cook

81. Brain Embolism, edited by Louis R. Caplan and Warren J. Manning

82. Handbook of Secondary Dementias, edited by Roger Kurlan

83. Parkinson's Disease: Genetics and Pathogenesis, edited by Ted M. Dawson

84. Migraine, Russell Lane and Paul Davies

85. Migraine and Other Headache Disorders, edited by Richard B. Lipton and Marcelo Bigal

86. Restless Legs Syndrome, edited by William G. Ondo

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edited by John C. Morris, James E. Galvin, and David M. Holtzman

88. Acute Stroke: Bench to Bedside, edited by

Anish Bhardwaj, Nabil J. Alkayed, Jeffrey R. Kirsch, and Richard J. Traystman

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edited by

Anish Bhardwaj

Oregon Health & Science University Portland, Oregon, U.S.A.

Nabil J. Alkayed

Jeffrey R. Kirsch

Richard J. Traystman

New York London

Acute Stroke

Bench to Bedside

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270 Madison Avenue New York, NY 10016

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Foreword

In the fi eld of stroke, we are living in interesting—indeed, exhilarating—but also challenging times. One needs merely to consider the following:

■ A sense of discouragement over the pitiable infrequency with which the only yet proven ameliorative therapy for acute ischemic stroke—intravenous tissue recombi- nant plasminogen activator—is actually being applied in clinical practice has begun to motivate stroke clinician-investigators to both develop strategies for widening the application of this therapy and validate other acute therapeutic approaches.

■ Clinical-trial methodology as applied to stroke has improved greatly in both its sophistication and rigor, and many randomized clinical trials in stroke are cur- rently ongoing, supported by the federal, pharmaceutical, and biotech sectors. (The superb website www.strokecenter.org provides a comprehensive status-report of completed and ongoing clinical trials in stroke.)

■ Remarkable advances in clinical neuroimaging now permit us to observe the ongoing pathophysiology of ischemic and hemorrhagic stroke in real time and with dazzling clarity and spatial resolution. Diffusion- and perfusion-weighted magnetic reso- nance imaging and computed tomography perfusion and computed tomography angiography deserve particular mention.

■ The fi eld of neurointensive care has emerged as a key subspecialty of neurology, with much to offer in the management of acute stroke syndromes.

■ Public awareness of the symptoms and signs of stroke and of the necessity for rapid intervention (the “therapeutic window”) is slowly but surely growing. The laudable efforts of the American Heart Association (via its American Stroke Association) in this regard deserve particular recognition.

■ In the laboratory, spectacular advances in molecular biology have shaped current directions in stroke research. It is now possible to investigate the effects of single-gene over- or underexpression on stroke pathophysiology by producing stroke in geneti- cally altered murine strains and to survey the panoply of altered gene expression in stroke by the use of microarray technology. Intracellular molecular signaling mechanisms and their alterations in stroke are being extensively investigated. The potential of stem-cell approaches to recovery of brain function is also under current study.

■ Animal models of ischemic and hemorrhagic stroke, which closely mimic relevant features of the human clinical disorders, are being studied with ever-increasing sophistication, and attention is being brought to bear on careful physiologic monitoring and a broad repertoire of tools for measuring functional and structural injury.

■ Perhaps the most exciting recent development is the successful translation of laboratory advances to the bedside, particularly evident in ongoing clinical trials of neuroprotection that are being driven by the successful results emerging from studies in animal stroke models.

The guiding philosophy of the present volume, assembled under the wise editorship of Drs. Bhardwaj, Alkayed, Kirsch, and Traystman, is to emphasize translationally important topic areas in cerebrovascular disease, where advances at the bench lead to advances at the bedside. Both hemorrhage (subarachnoid and intracerebral) and ischemia (focal and global) are considered. In subarachnoid hemorrhage, despite sophisticated surgical and endovascular therapies, vexatious problems remain: prerupture aneurysmal growth and posttreatment vasospasm. In intracerebral hemorrhage, key issues include pharmacologic approaches to thwart hemorrhage expansion and to combat secondary-injury processes. In both focal and global ischemia, the challenge remains to translate laboratory successes in neuroprotection to the clinic. A potpourri of other key mechanistic, therapeutic, and stroke-management topics is also considered in this volume

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under the section “Dogmas, Controversies, and Future Directions.” Taken together, the contributors to this timely volume offer the reader a rich menu to savor. Clinician-investigators will benefi t from its breadth and depth.

Myron D. Ginsberg, MD University of Miami, Miller School of Medicine,

Miami, Florida, U.S.A.

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Preface

As the third leading cause of death in the United States, stroke constitutes a national health problem. Stroke accounts for 1 in every 15 deaths and is the major cause of disability in the country. Presently, in excess of 4 million Americans are stroke survivors. In the past, care for stroke patients had been mixed with an element of nihilism. However, over the last 2 decades, major advances have been made, and practices that were largely based on anecdotal experiences and physiologic inferences have evolved into more refi ned procedures and protocols in the management of this patient population.

Laboratory-based research in animal models has enhanced our understanding of patho- physiologic mechanisms of brain injury and provided important insights for possible therapeutic strategies and targets. Advances in neuroimaging and neurointerventional techniques have provided multiple avenues and improved approaches to early diagnosis and therapy in the acute phase of stroke. Clinical research with neuroprotective trials in focal ischemic stroke, though disappointing thus far, have further heightened the need for a multifaceted approach that concentrates equally on early recognition, diagnosis, and aggressive treatment.

But stroke is more than just cerebral ischemia. Our understanding of the pathophysiology of brain injury following intracerebral and subarachnoid hemorrhage continues to grow from laboratory-based experimental work. Collaborative care by a specially trained team of neuro- intensivists, neurosurgeons, anesthesiologists, and nurses, and the advent of newer monitoring techniques in a dedicated neuro-intensive care unit have improved outcomes in patients with these subtypes of stroke.

While numerous textbooks on stroke are available, a large gap exists between basic science bench research and its translation into patient care in the fi eld. The purpose of this book is to bridge this gap and present relevant bench research of “translational” signifi - cance, as well as its logical import, to the bedside. Each of the fi rst 4 sections of the book begins with a chapter that covers research in the particular subarea, using appropriate animal models, and progresses through a continuum of the disease, from pathophysiology to clinical management to prognosis. The last section discusses controversies and future directions in stroke care, and it is hoped that the reader will be stimulated to investigate the many unanswered questions. Our intent with this book is to present a comprehensive review on the subject and provide clinicians, neuroscientists, and clinician scientists with a guide that will foster research of translational signifi cance from bench to bedside and vice versa in this important area. We hope that we have achieved our goal.

We, the editors, are indebted to the authors for their valuable contributions. Special thanks are due to Tzipora Sofare, MA, for her efforts in editing this volume. Her close attention to detail and never-ending quest for accuracy and consistency have greatly contributed to its quality. We would also like to particularly express our thanks to the Johns Hopkins Clinician Scientist Program, the American Heart Association, the National Stroke Association, and the National Institutes of Health extramural programs, which have supported our investigative work and fellowship training programs in stroke and neurosciences critical care.

Anish Bhardwaj, MD, FAHA, FCCM Nabil J. Alkayed, MD, PhD Jeffrey R. Kirsch, MD Richard J. Traystman, PhD , FCCM

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Contributors

Andrei V. Alexandrov, MD, Director Stroke Research and Neurosonology Program, Barrow Neurological Institute, Phoenix, Arizona, USA

Nabil J. Alkayed, MD, PhD, Director ^a, Associate Professor ^b ^aCore Molecular Laboratories and Training, ^bDepartment of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA

Yekaterina K. Axelrod, MD, Fellow Department of Neurosciences Critical Care, Washington University School of Medicine, St. Louis, Missouri, USA

Mona N. Bahouth, MSN, CRNP, Director Department of Neurology, University of Maryland School of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA Kyra J. Becker, MD, Associate Professor Departments of Neurology and Neurological Surgery, Harborview Medical Center, University of Washington School of Medicine, Seattle, Washington, USA Anish Bhardwaj, MD, FAHA, FCCM, Professor ^a and Director ^b ^a Departments of Neurology, Neurological Surgery, and Anethesiology & Perioperative Medicine, ^b Neurosciences Critical Care Program, Oregon Health & Science University, Portland, Oregon, USA

Thomas P. Bleck, MD, FCCM, Ruth Cain Ruggles Chairman^a, Vice Chairman^b,

Professor ^b ^aDepartment of Neurology, Evanston Northwestern Healthcare, ^bDepartments of Neurology, Neurosurgery, and Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Cecil O. Borel, MD, Associate Professor Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA

Ansgar M. Brambrink, MD, PhD, Associate Professor Department of Anesthesiology &

Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA

Gavin W. Britz, MD, MPH, Assistant Professor Department of Neurological Surgery, Harbor view Medical Center, University of Washington, Seattle, Washington, USA

Thomas G. Brott, MD, Professor Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, Florida, USA

Alastair M. Buchan, MD, Professor Acute Stroke Programme, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK

J. Ricardo Carhuapoma, MD, Assistant Professor Division of Neurosciences Critical Care, Departments of Neurology, Neurological Surgery, and Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Stephen Chang, MD, Resident Division of Interventional Neuroradiology, The Johns Hopkins Hospital, Baltimore, Maryland, USA

Michael Chopp, PhD, Professor and Director Department of Neurology, Henry Ford Health System, Wayne State University, Detroit, and Department of Physics, Oakland University, Rochester, Michigan, USA

Wayne M. Clark, MD, Professor ^a and Director ^b ^aDepartment of Neurology, ^bStroke Program, Oregon Stroke Center, Oregon Health & Science University, Portland, Oregon, USA

Richard E. Clatterbuck, MD, PhD, Assistant Professor Departments of Neurosurgery and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Andrew M. Demchuk, MD, FRCPC, Associate Professor Department of Clinical Neurosciences, Calgary Stroke Program, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada Michael N. Diringer, MD, Professor ^a and Director ^b ^aDepartments of Neurology and

Neurological Surgery, ^bNeurocritical Care Unit, Washington University School of Medicine, St. Louis, Missouri, USA

Christian Dohmen, MD Department of Neurology, Max-Planck Institute for Neurological Research, University of Cologne, Cologne, Germany

Aaron S. Dumont, MD, Fellow Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, Virginia, USA

Mustapha A. Ezzeddine, MD, Assistant Professor Department of Neurology and Neurosciences, Zeenat Qureshi Stroke Research Center, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, USA

Christopher V. Fanale, MD, Associate Stroke Program Director Colorado Neurological Institute–Swedish Medical Center, Englewood, Colorado, USA

Donna M. Ferriero, MD, Professor Departments of Neurology and Pediatrics, University of California–San Francisco, San Francisco, California, USA

Madeline C. Fields, MD, Resident Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA

Marc Fisher, MD, Professor Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Heather J. Fullerton, MD, MAS, Assistant Professor Departments of Neurology and Pediatrics, University of California–San Francisco, San Francisco, California, USA

Philippe Gailloud, MD, Associate Professor Division of Interventional Neuroradiology, The Johns Hopkins Hospital, Baltimore, Maryland, USA

Romergryko G. Geocadin, MD, Assistant Professor ^a, Director ^b, Associate Director ^c

a Departments of Neurology, Anesthesiology/Critical Care Medicine, and Neurosurgery, Johns Hopkins University School of Medicine, ^bNeurosciences Critical Care Unit, Johns Hopkins Bayview Medical Center, and ^cNeurosciences Critical Care Division, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Rudolf Graf, PhD, Assistant Professor Department of Neurology, Max-Planck Institute for Neurological Research, University of Cologne, Cologne, Germany

Carmelo Graffagnino, MD, FRCPC, Associate Clinical Professor Department of Medicine/Neurology, Duke University Medical Center, Durham, North Carolina, USA

Wolf-Dieter Heiss, MD, Professor Department of Neurology, Max-Planck Institute for Neurological Research, University of Cologne, Cologne, Germany

Michael D. Hill, MD, MSc, FRCPC, Associate Professor ^a and Director ^b ^a Department of Clinical Neurosciences, Heart and Stroke Alberta Professorship in Stroke Research, ^b Foothills Medical Centre Stroke Unit, University of Calgary, Calgary, Alberta, Canada

Wesley Hsu, MD, Resident Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Peter Hu, MS, CNE, Instructor Department of Anesthesiology, University of Maryland School of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA

Patricia D. Hurn, PhD, Professor and Vice Chairman of Research Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA

Jawad F. Kirmani, MD, Assistant Professor

Zeenat Qureshi Stroke Research Center, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, USA

Department of Neurology andNeurosciences,

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Jeffrey R. Kirsch, MD, Professor and Chairman Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA

Raymond C. Koehler, PhD, Professor Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Ines P. Koerner, MD, Fellow Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, USA

Julia Kofl er, MD, Resident Department of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Arthur M. Lam, MD, FRCPC, Professor, Anesthesiologist-in-Chief Departments of

Anesthesiology and Neurological Surgery, Harborview Medical Center, University of Washington, Seattle, Washington, USA

Marian P. LaMonte, MD, MSN, Associate Professor Departments of Neurology and Emergency Medicine, University of Maryland School of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA

Steven R. Levine, MD, Professor The Stroke Center, Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA

Fuhai Li, MD, Resident Department of Neurology, Duke University School of Medicine, Duke University Medical Center, Durham, North Carolina, USA

Yi Li, MD, Senior Staff Department of Neurology, Henry Ford Health System, Wayne State University, Detroit, Michigan, USA

Frederick W. Lombard, MBChB, FANZCA, Assistant Professor Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA

Helmi L. Lutsep, MD, Associate Professor â and ^b Co-Director âDepartment of Neurology, ^b Stroke Program, Oregon Stroke Center, Oregon Health & Science University, Portland, Oregon, USA Patrick D. Lyden, MD, FAAN, Professor â and Director ^b âDepartment of Neurosciences, University of California–San Diego, ^bUCSD Stroke Center, San Diego, California, USA

Colin Mackenzie, MBChB, Professor and Director Department of Anesthesiology, University of Maryland School of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA Stephan A. Mayer, MD, Associate Clinical Professor ^a and Director ^b ^a Departments of Neurology and Neurosurgery, ^bNeurological Intensive Care Unit, Columbia University College of

Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA Louise D. McCullough, MD, PhD, Assistant Professor and Director of Stroke Research Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut, USA

José G. Merino, MD, MPhil, Staff Clinician Section on Stroke Diagnostics and Therapeutics, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA

Kieran Murphy, MD, FRCPC, Associate Professor Director of Interventional Neuroradiology, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Neeraj S. Naval, MD, Instructor Division of Neurosciences Critical Care, Departments of Neurology, Neurological Surgery, and Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Alison J. Nohara, MD, Medical Director Interventional Neuroradiology, Eden Medical Center, Castro Valley, California, USA

Thaddeus S. Nowak, Jr., PhD, Professor Department of Neurology, University of Tennessee Memphis, Tennessee, USA

,

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Paul A. Nyquist, MD, MPH, Assistant Professor of Neurology Neurosciences Critical Care Division, Departments of Neurology, Neurological Surgery, Anesthesiology, and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

L. Creed Pettigrew, MD, MPH, Professor ^a, Director ^b ^a Department of Neurology,

bUniversity of Kentucky Stroke Program, University of Kentucky Chandler Medical Center, Lexington, Kentucky, USA

Nader Pouratian, MD, PhD, Resident Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, Virginia, USA

Gustavo Pradilla, MD, Resident Department of Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Adnan I. Qureshi, MD, Professor of Neurology and Radiology Department of Neurology and Neurosciences, Zeenat Qureshi Stroke Research Center, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, USA

Alejandro A. Rabinstein, MD, Associate Professor of Neurology ^a, Consultant ^b ^aMayo Clinic College of Medicine, ^bNeurological–Neurosurgical Intensive Care Unit, Saint Mary’s Hospital, Rochester, Minnesota, USA

Marc Ribo, MD, Stroke Neurologist Unitat Neurovascular Hospital Vall d’Hebron, Universitat Autónoma de Barcelona, Barcelona, Spain

Daniele Rigamonti, MD, FACS, Vice-Chairman and Professor Department of Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Gustavo J. Rodríguez, MD, Vascular Neurology Fellow Department of Neurology and Neurosciences, Zeenat Qureshi Stroke Research Center, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, USA

Izabella Rozenfeld, MD, Resident Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA

J. Michael Schmidt, PhD, Assistant Professor of Neuropsychology (in Neurology) Neurological Intensive Care Unit, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA

Chandrasekaran Sivakumar, MD, Fellow Calgary Stroke Program, Foothills Medical Center, University of Calgary, Calgary, Alberta, Canada

Abhishek Srinivas, MD,Division of Interventional Neuroradiology, The Johns Hopkins Hospital, Baltimore, Maryland, USA

Suresh Subramaniam, MD, MSc Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

Xian Nan Tang, MD, Fellow Department of Neurology, University of California–San Francisco, Veterans Affairs Medical Center, San Francisco, and Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA

Turgut Tatlisumak, MD, Associate Professor and Vice Chairman Department of Neurology, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland

Richard E. Temes, MD, Fellow Neurological Intensive Care Unit, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA Quoc-Anh Thai, MD, Assistant Chief of Service, Instructor Department of Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore,

Maryland, USA

Rafael J. Tamargo, MD, FACS Walter E. Dandy Professor a and Director b a Departments of Neurosurgery, Otolaryngology, and Neck Surgery, b Department of Cerebrovascular Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland , USA

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Richard J. Traystman, PhD, FCCM, Professor ^a, Associate Vice President ^b, and Associate Dean ^c

a Department of Anesthesiology & Perioperative Medicine, ^bResearch Planning and Development,

c Research School of Medicine, Oregon Health & Science University, Portland, Oregon, USA Stanley Tuhrim, MD, Director ^a Professor ^b ^aDivision of Cerebrovascular Diseases, ^bDepartment of Neurology, Mount Sinai School of Medicine, New York, New York, USA

Kenneth R. Wagner, PhD, Research Associate Professor Department of Neurology, University of Cincinnati College of Medicine, and Veterans Affairs Medical Center, Medical Research Service, Cincinnati, Ohio, USA

Steven Warach, MD, PhD, Chief Section on Stroke Diagnostics and Therapeutics, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA

Eelco F. M. Wijdicks, MD, Professor of Neurology and Chair Division of Critical Care

Neurology, Mayo Clinic College of Medicine, and Neurological–Neurosurgical Intensive Care Unit, Saint Mary’s Hospital, Rochester, Minnesota, USA

Robert J. Wityk, MD, Director ^a, Associate Professor ^b ^aCerebrovascular Division, ^bDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Yan Xiao, PhD, Associate Professor Department of Anesthesiology, University of Maryland School of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA Midori A. Yenari, MD, Associate Professor Department of Neurology, University of California–San Francisco, Veterans Affairs Medical Center, San Francisco, and Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA

Zhen Zheng, MD, PhD, Fellow Department of Neurology, University of California–San Francisco, Veterans Affairs Medical Center, San Francisco, and Department of Anesthesia,

Stanford University School of Medicine, Stanford, California, USA

Wendy C. Ziai, MD, Assistant Professor Departments of Neurology, Neurosurgery, and Anesthesia /Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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1 Animal Models of Subarachnoid Hemorrhage

Gustavo Pradilla, MD, Resident

Quoc-Anh Thai, MD, Assistant Chief of Service, Instructor Department of Neurosurgery , Johns Hopkins University School of Medicine , Johns Hopkins Medical Institutions, Baltimore , Maryland , USA

Rafael J. Tamargo, MD, FACS Walter E. Dandy Professor ^a and Director ^b

a Departments of Neurosurgery, Otolaryngology, and Neck Surgery,

b Department of Cerebrovascular Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland , USA

INTRODUCTION

Cerebral vasospasm is the delayed narrowing of cerebral arteries exposed to blood. Although vasospasm typically occurs after subarachnoid hemorrhage (SAH) from rupture of a cerebral aneurysm, it can also develop after trauma ( 1,2 ) and infections ( 3 ). In humans, vasospasm presents as a biphasic phenomenon. Whereas acute vasospasm generally presents immediately after SAH and typically resolves within hours, chronic vasospasm occurs at 4 to 21 days and peaks 7 to 10 days after hemorrhage, with an overall angiographic incidence of 67% ( 4 ) and a clinical incidence of 37% ( 4 ). Chronic vasospasm causes delayed ischemic defi cits, stroke, and death.

The etiology of vasospasm remains unclear. Current hypotheses include endothelial dysfunction secondary to infl ammation of the arterial wall and transendothelial migration of macrophages and neutrophils ( 5,6 ), nitric oxide (NO) scavenging by such blood-degradation products as oxy-hemoglobin ( 7 ), depletion of NO secondary to NO synthase dysfunction ( 8 ), direct vasoconstriction due such to spasmogenic proteins as endothelin-1 ( 9 ), and dysregulation of electrolyte channels in the smooth muscle cell, such as K ⁺ ( 10 ) and Mg ²⁺ ( 11 ).

In 1949, Robertson at the Royal Melbourne Hospital in Melbourne, Australia, was the fi rst to describe delayed ischemia after SAH and to suggest that the ischemic changes could be related to temporary spasm of the supplying vessels ( 12 ). The fi rst angiographic description of cerebral vasospasm after SAH was reported in 1951 ( 13 ). Since then, this condition has been studied extensively in experimental models.

Studies on the pathophysiology of cerebral vasospasm in humans have been attempted using postmortem specimens ( 14–18 ). Delayed postmortem artifacts, however, have prevented adequate analyses of genomic and proteomic variables, as well as testing of physiologic responses.

To study cerebral vasospasm under more physiologic conditions, several experimental models have been developed. We present an overview of the different experimental models that have been used to date and comment on their technical and scientifi c characteristics.

IN VITRO MODELS OF VASOSPASM

In vitro models of vasospasm typically use an intracranial vessel that is harvested and either placed in a physiologic environment attached to a fi xation device for recording of tension and other variables, or prepared for extraction of endothelial and smooth muscle cells for culture.

The vessels can be harvested after exposure to blood in vivo or they can be harvested from a healthy animal for further experimental manipulation in vitro. Using these models, several pro- vasospastic agents have been characterized and some pharmacologic interventions have been proposed ( 19–24 ). Advantages of these in vitro models include a well-controlled environment, real-time observation of vascular tone and electrolyte changes, low cost, and an abundance of tissue for testing. Disadvantages include removal of the vessel from its natural environment, denervation of the arterial wall, absence of innate immunologic stimulus, and lack of prolonged injury and recovery periods. Due to these observations, the relevance of these models to human

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Acute Stroke

Acute Stroke

edited by

Anish Bhardwaj

Nabil J. Alkayed

Jeffrey R. Kirsch

Richard J. Traystman

Acute Stroke

Bench to Bedside

Foreword

Preface

Contents

Contributors

1 Animal Models of Subarachnoid Hemorrhage