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 Acute Stroke

DK9870_C000a.indd 1 08/14/2006 2:43:43 PM

 NEUROLOGICAL DISEASE AND THERAPY

Advisory Board

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

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

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

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

Louis R. Caplan, M.D.

Professor of Neurology
Harvard University School of Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts, U.S.A.

Mark A. Stacy, M.D.

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

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

Professor of Neurosciences
Director, Center for Neural Repair
University of California—San Diego
La Jolla, California, U.S.A.

DK9870_C000a.indd 2 08/14/2006 2:43:43 PM

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

DK9870_C000a.indd 3 08/14/2006 2:43:43 PM

 23. Handbook of Myasthenia Gravis and Myasthenic
Syndromes, edited by Robert P. Lisak
24. Handbook of Neurorehabilitation, edited by
David C. Good and James R. Couch, Jr.
25. Therapy with Botulinum Toxin, edited by Joseph Jankovic
and Mark Hallett
26. Principles of Neurotoxicology, edited by Louis W. Chang
27. Handbook of Neurovirology, edited by
Robert R. McKendall and William G. Stroop
28. Handbook of Neuro-Urology, edited by David N. Rushton
29. Handbook of Neuroepidemiology, edited by
Philip B. Gorelick and Milton Alter
30. Handbook of Tremor Disorders, edited by Leslie J. Findley
and William C. Koller
31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up
and Management, edited by Ronald J. Tusa
and Steven A. Newman
32. Handbook of Olfaction and Gustation, edited by
Richard L. Doty
33. Handbook of Neurological Speech and Language
Disorders, edited by Howard S. Kirshner
34. Therapy of Parkinson’s Disease: Second Edition,
Revised and Expanded, edited by William C. Koller
and George Paulson
35. Evaluation and Management of Gait Disorders, edited by
Barney S. Spivack
36. Handbook of Neurotoxicology, edited by Louis W. Chang
and Robert S. Dyer
37. Neurological Complications of Cancer, edited by
Ronald G. Wiley
38. Handbook of Autonomic Nervous System Dysfunction,
edited by Amos D. Korczyn
39. Handbook of Dystonia, edited by Joseph King Ching Tsui
and Donald B. Calne
40. Etiology of Parkinson’s Disease, edited by
Jonas H. Ellenberg, William C. Koller
and J. William Langston
41. Practical Neurology of the Elderly, edited by Jacob I. Sage
and Margery H. Mark
42. Handbook of Muscle Disease, edited by Russell J. M. Lane
43. Handbook of Multiple Sclerosis: Second Edition,
Revised and Expanded, edited by Stuart D. Cook
44. Central Nervous System Infectious Diseases and Therapy,
edited by Karen L. Roos

DK9870_C000a.indd 4 08/14/2006 2:43:43 PM

 45. Subarachnoid Hemorrhage: Clinical Management,
edited by Takehiko Yanagihara, David G. Piepgras,
and John L. D. Atkinson
46. Neurology Practice Guidelines, edited by
Richard Lechtenberg and Henry S. Schutta
47. Spinal Cord Diseases: Diagnosis and Treatment, edited by
Gordon L. Engler, Jonathan Cole, and W. Louis Merton
48. Management of Acute Stroke, edited by Ashfaq Shuaib
and Larry B. Goldstein
49. Sleep Disorders and Neurological Disease, edited by
Antonio Culebras
50. Handbook of Ataxia Disorders, edited by
Thomas Klockgether
51. The Autonomic Nervous System in Health and Disease,
David S. Goldstein
52. Axonal Regeneration in the Central Nervous System,
edited by Nicholas A. Ingoglia and Marion Murray
53. Handbook of Multiple Sclerosis: Third Edition, edited by
Stuart D. Cook
54. Long-Term Effects of Stroke, edited by
Julien Bogousslavsky
55. Handbook of the Autonomic Nervous System in Health
and Disease, edited by C. Liana Bolis, Julio Licinio,
and Stefano Govoni
56. Dopamine Receptors and Transporters: Function, Imaging,
and Clinical Implication, Second Edition, edited by
Anita Sidhu, Marc Laruelle, and Philippe Vernier
57. Handbook of Olfaction and Gustation: Second Edition,
Revised and Expanded, edited by Richard L. Doty
58. Handbook of Stereotactic and Functional Neurosurgery,
edited by Michael Schulder
59. Handbook of Parkinson’s Disease: Third Edition, edited by
Rajesh Pahwa, Kelly E. Lyons, and William C. Koller
60. Clinical Neurovirology, edited by Avindra Nath
and Joseph R. Berger
61. Neuromuscular Junction Disorders: Diagnosis
and Treatment, Matthew N. Meriggioli,
James F. Howard, Jr., and C. Michel Harper
62. Drug-Induced Movement Disorders, edited by
Kapil D. Sethi
63. Therapy of Parkinson’s Disease: Third Edition,
Revised and Expanded, edited by Rajesh Pahwa,
Kelly E. Lyons, and William C. Koller
64. Epilepsy: Scientific Foundations of Clinical Practice,
edited by Jong M. Rho, Raman Sankar,
and José E. Cavazos

DK9870_C000a.indd 5 08/14/2006 2:43:43 PM

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

DK9870_C000a.indd 6 08/14/2006 2:43:44 PM

 87. Handbook of Dementing Illnesses, Second Edition,
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

DK9870_C000a.indd 7 08/14/2006 2:43:44 PM

DK9870_C000a.indd 8 08/14/2006 2:43:44 PM
 Acute Stroke
Bench to Bedside

edited by
Anish Bhardwaj
Oregon Health & Science University
Portland, Oregon, U.S.A.

Nabil J. Alkayed
Oregon Health & Science University
Portland, Oregon, U.S.A.

Jeffrey R. Kirsch
Oregon Health & Science University
Portland, Oregon, U.S.A.

Richard J. Traystman
Oregon Health & Science University
Portland, Oregon, U.S.A.

New York London

DK9870_C000a.indd 9 08/14/2006 2:43:44 PM

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DK9870_C000a.indd 10 08/14/2006 2:43:44 PM

To our families.
 Foreword

In the field 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 field 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 mecha-
nisms 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 neuro-
protection 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 sub-
arachnoid 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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