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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 recombinant 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 currently 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 resonance 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 genetically 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 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 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 benefit from its breadth and depth.

Myron D. Ginsberg, MD University of Miami, Miller School of Medicine, Miami, Florida, U.S.A.

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 refined 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 field. The purpose of this book is to bridge this gap and present relevant bench research of "translational" significance, as well as its logical import, to the bedside. Each of the first 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 significance 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

Contents

Foreword Myron D. Ginsberg . . . . v Preface . . . . vii Contributors . . . . xix

Section I. SUBARACHNOID HEMORRHAGE

  1. Animal Models of Subarachnoid Hemorrhage 1 Gustavo Pradilla, Quoc-Anh Thai, and Rafael J. Tamargo Introduction . . . . 1 In Vitro Models of Vasospasm . . . . 1 In Vivo Models of Vasospasm . . . . 2 Creation of SAH and Induction of Vasospasm . . . . 2 Monkey Models . . . . 2 Rabbit Models . . . .3 Dog Models . . . . 4 Cat Models . . . . 5 Rat Models . . . . 6 Mouse Models . . . . 7 Other Models . . . . 8 Conclusions . . . . 9 References . . . . 9
  2. Pathogenesis of Cerebral Aneurysm Growth and Rupture 15 Wesley Hsu and Richard E. Clatterbuck Introduction . . . . 15 Histology . . . . 15 Pathology . . . . 16

Theories of Saccular Aneurysm Etiology . . . . 17

Connective Tissue Disorders and Aneurysmal Formation . . . . 18

Familial Aneurysmal Formation . . . . 19

Mechanical Factors in Aneurysmal Formation . . . . 19

Vessel Wall Homeostasis and Aneurysmal Formation . . . . 22

Traumatic Intracranial Aneurysms . . . . 23

References . . . . 24

  1. Pathogenesis of Cerebral Vasospasm 29 Frederick W. Lombard and Cecil O. Borel Introduction . . . . 29 Etiology of Vasospasm . . . . 30 Endothelial Dysfunction . . . . 32 Vascular Remodeling Following SAH . . . . 37 Cerebral Blood Flow . . . . 38 Conclusions and Future Directions . . . . 39 References . . . . 39
  2. Surgical Management of Aneurysmal Subarachnoid Hemorrhage 45 Quoc-Anh Thai, Gustavo Pradilla, and Daniele Rigamonti Introduction . . . . 45 Clinical Presentation of aSAH . . . . 45

Diagnosis of Subarachnoid Hemorrhage and Aneurysms . . . . 45 Grading and Prognosis of aSAH . . . . 47

Complications After aSAH . . . . 47 Surgical Intervention . . . . 48 Conclusion . . . . 50 References . . . . 50

5. Endovascular Management of a Patient After Subarachnoid Hemorrhage 53 Stephen Chang, Abhishek Srinivas, and Kieran Murphy Introduction . . . . 53

Team- and Consensus-Based Approach to Aneurysm Care . . . . 53

Endovascular Management Following aSAH . . . . 53

Vessel Occlusion as a Method of Treating Aneurysms . . . . 57

Vertebral Dissecting Aneurysms . . . . 58

GDC Coiling and Intraventricular rtPA After Aneurysm . . . . 59 Intraoperative Angiography and Outcome of Clip

Position in the Operating Room . . . . 60 Postcoil Follow-Up—Coil Compression and Recanalization . . . . 60 New Aneurysms and the Need for Follow-Up . . . . 60 Acute vs. Chronic Aneurysms (Cocaine-Related Bleed Sites) . . . . 61 Our Philosophy on Aneurysms . . . . 61 References . . . . 61

B. Intraoperative Management of Aneurysmal Subarachnoidal Hemorrhage 6? Ansgar M. Brambrink and Jeffrey R. Kirsch Introduction . . . . 67

Routine Intraoperative Management . . . . 67 Special Problems and Techniques . . . . 73 Conclusion . . . . 76 References . . . . 76

7. Medical Management of Subarachnoid Hemorrhage 81 Yekaterina K. Axelrod and Michael N. Diringer

Evaluation and Initial Management . . . . 81

Early Critical Care Management . . . . 84

8. Clinical Trials in Subarachnoid Hemorrhage 93 Nader Pouratian, Aaron S. Dumont, and Thomas P. Bleck

Introduction . . . . 93 Prevention of Rebleeding . . . . 93 Prevention and Treatment of Vasospasm . . . . 95 Neuroprotection . . . . 98

Why Have Previous Clinical Trials in Aneurysmal Subarachnoid

Hemorrhage Failed? . . . . 99 Conclusion and Future Directions . . . . 99 References . . . . 100

9. Prognosis and Outcomes Following Aneurysmal Subarachnoid Hemorrhage 103 Richard E. Temes, J. Michael Schmidt, and Stephan A. Mayer

Introduction . . . . 103 Clinical Grading Scales . . . . 103

Delayed Cerebral Ischemia . . . . 103

Hierarchy of Clinical and Functional Outcomes After aSAH . . . . 104

Neurologic Impairment After aSAH . . . . 105

Disability and Handicap After aSAH . . . . 107

Conclusions and Future Directions . . . . 108

Section II. INTRACEREBRAL HEMORRHAGE

10. Animal Models of Intracerebral Hemorrhage 111 Kenneth R. Wagner and Thomas G. Brott Introduction . . . . 111 Models and Species: Overview . . . . 111 Intracerebral Blood Infusion ICH Models . . . . 112 Bacterial Collagenase Model . . . . 115 Ischemia-Reperfusion Hemorrhage Model . . . . 116 Brain Pathologic Response to ICH in Animal Models . . . . 116 Limitations of Animal Models . . . . 117

Summary of Animal Species and ICH Induction Methods . . . . 117 Overall Summary and Conclusions . . . . 118 References . . . . 118

11. Pathophysiologic Mechanisms of Brain Injury Following Intracerebral Hemorrhage 123

Gustavo J. Rodríguez, Jawad F. Kirmani, Mustapha A. Ezzeddine, and Adnan I. Qureshi Introduction . . . . 123

Pathology of Hematoma and Mechanical Compression . . . . 123

Pathology of the Perihematoma Region . . . . 124

Role of Cerebral Blood Flow Changes . . . . 124

Role of Thrombin and Blood Products . . . . 126

Role of Inflammation and Glutamate . . . . 127

Role of Matrix Metalloproteinases . . . . 127

Conclusions and Future Directions . . . . 127

12. Surgical Management of Intracerebral Hemorrhage 133 Gavin W. Britz and Arthur M. Lam Introduction . . . . 133

Etiologic Factors for Intracerebral Hemorrhage . . . . 133

Diagnosis of Intracerebral Hemorrhage . . . . 134

Indications for Surgical Therapy . . . . 136

Anesthetic Considerations . . . . 137

13. Medical Management of Intracerebral Hemorrhage 141 Neeraj S. Naval and J. Ricardo Carhuapoma Introduction . . . . 141 Diagnosis . . . . 141 Early Management . . . . 142 Coagulopathies . . . . 144 Activated Recombinant Factor VIIA . . . . 144 Intraventricular Thrombolysis . . . . 145 Surgical Treatment and ICH Thrombolysis . . . . 145 Increased Intracranial Pressure and Cerebral Edema . . . . 146 Seizures . . . . 146

Treatment of Precipitating Factors . . . . 147 Other General Medical Aspects . . . . 147

14. Clinical Trials in Intracerebral Hemorrhage 151 Alejandro A. Rabinstein and Eelco F. M. Wijdicks

Introduction . . . . 151 Surgical Evacuation . . . . 151 Medical Treatment . . . . 155 Future Trials . . . . 158 References . . . . 159

15. Prognosis and Outcomes Following Intracerebral Hemorrhage 161 Stanley Tuhrim

Prognosis by Specific Lesion Site . . . . 161

General Prognostic Features . . . . 162

Specific Prognostic Features . . . . 165

Section III. FOCAL ISCHEMIC STROKE

16. Animal Models of Ischemic Stroke 171 Turgut Tatlisumak, Fuhai Li, and Marc Fisher

Introduction . . . . 171 Animal Selection . . . . 171

Approaches for Inducing Focal Cerebral Ischemia . . . . 172

17. Pathogenesis of Brain Injury Following Ischemic Stroke 187 Xian Nan Tang, Zhen Zheng, and Midori A. Yenari Introduction . . . . 187

Excitotoxicity, Intracellular Calcium, and Ischemic Brain Injury . . . . 187 Oxidative Stress and Brain Ischemia . . . . 190 Ischemia-Induced Gene Expression . . . . 193 Apoptosis . . . . 194

Inflammation Following Cerebral Ischemia . . . . 196 Matrix Metalloproteinases . . . . 198 Conclusions and Future Directions . . . . 199 References . . . . 199

  1. Neuroimaging in Ischemic Stroke 205 José G. Merino and Steven Warach Introduction . . . . 205 MRI in Clinical Care . . . . 205 MRI in Stroke Research . . . . 208 References . . . . 212
  2. Thrombolytic Therapy for Acute Ischemic Stroke 217 Christopher V. Fanale and Patrick D. Lyden Introduction . . . . 217 Early Clinical Considerations . . . . 217 Intravenous Thrombolytics in Acute Stroke Therapy . . . . 219 Intra-arterial Thrombolytics in Acute Stroke Therapy . . . . 222 Other Thrombolytics for Acute Stroke . . . . 224 Emerging Technologies . . . . 224 Controversies in the Use of Intravenous rtPA . . . . 225 Stroke Centers . . . . 226 References . . . . 226
  3. Medical Management of Acute Ischemic Stroke 229 Kyra J. Becker Introduction . . . . 229 The Ischemic Penumbra . . . . 229 Blood Pressure and Stroke . . . . 229 Glucose and Ischemic Brain Injury . . . . 231 Temperature and Brain Injury . . . . 232 Infection . . . . 232

Viscosity and Red Blood Cell Mass in Stroke . . . . 233 Miscellaneous Drugs and Therapeutic Interventions . . . . 233 Intracranial Pressure and Malignant Cerebral Edema . . . . 233 Stroke Units . . . . 235 Summary . . . . 235 References . . . . 235

21. Clinical Neuroprotective Trials in Ischemic Stroke 243 Wayne M. Clark and Helmi L. Lutsep Introduction . . . . 243 Neuroprotection . . . . 243

Investigational Agents: Reperfusion Injury Agents . . . . 246 Conclusion . . . . 247 References . . . . 248

22. Prognosis and Outcomes Following Ischemic Stroke 251 L. Creed Pettigrew Introduction . . . . 251

Medical Risk Factors for Progressing Stroke . . . . 251 Radiographic Indicators of Progressing Stroke . . . . 252 Thrombolysis, Risk of Hemorrhage, and Modification of Outcome in Acute Ischemic Stroke . . . . 254 Conclusions and Future Directions . . . . 259 References . . . . 260

23. Venous Strokes and Venous Sinus Thrombosis 263 Izabella Rozenfeld, Madeline C. Fields, and Steven R. Levine Introduction . . . . 263 Clinical Presentation . . . . 263 Epidemiology and Risk Factors . . . . 264 Pathogenesis . . . . 266 Natural History/Prognosis . . . . 267 Cerebral Venous Thrombosis in Children . . . . 268 Imaging/Diagnosis . . . . 268 Anatomy . . . . 269 Treatment . . . . 270 Summary and Conclusions . . . . 272 References . . . . 272

Section IV. GLOBAL CEREBRAL ISCHEMIA

  1. Animal Models of Global Cerebral Ischemia 275 Thaddeus S. Nowak, Jr. Introduction . . . . 275 Histopathology of Global Ischemia . . . . 275 Global Ischemia Models . . . . 277 Control of Model Variability . . . . 281 Conclusions and Future Directions . . . . 286 References . . . . 286
  2. Pathogenic Mechanisms of Brain Injury Following Global Cerebral Ischemia 293 Raymond C. Koehler Sequence of Events During Complete and Incomplete Cerebral Ischemia . . . . 293

Sequence of Events During Reperfusion . . . . 294

Selective Vulnerability . . . . 294

Arachidonic Acid Metabolism . . . . 297

Conclusions and Future Directions . . . . 305 References . . . . 305

26. Management of Brain Injury Following Cardiopulmonary Arrest 313 Romergryko G. Geocadin

Introduction . . . . 313 Pathophysiologic Consideration . . . . 313 Controlled Clinical Trials of Brain-Directed Therapies

After Cardiac Arrest . . . . 314 Clinical Trials in Hypothermia and Cardiac Arrest . . . . 316 Secondary Injuries that Affect Neurologic Outcome . . . . 320 Conclusions . . . . 322 References . . . . 323

27. Prognosis and Neurologic Outcomes Following Cardiopulmonary Arrest 327 Robert J. Wityk

Introduction . . . . 327 Clinical Syndromes . . . . 327 Prognosis and Clinical Predictors . . . . 328 Summary . . . . 332 References . . . . 333

Section V. DOGMAS, CONTROVERSIES, AND FUTURE DIRECTIONS

28. Failure of Neuroprotective Agents to Show Benefit in Clinical Trials 335 Richard J. Traystman

Health Characteristics of Animals . . . . 339

29. Ischemic Preconditioning 345 Ines P. Koerner and Nabil J. Alkayed

Introduction . . . . 345 Clinical Relevance . . . . 345

Models of Preconditioning: Cross-Tolerance . . . . 346

Pharmacologic Preconditioning . . . . 346 Mechanisms of Ischemic Tolerance . . . . 346 Adenosine and KATP Channels . . . . 347 Mitochondrial KATP Channels . . . . 347 NMDA Receptors and Ca2+ . . . . 347 Nitric Oxide in Preconditioning . . . . 347 Apoptosis Inhibitors and Bcl-2 . . . . 347

Reactive Oxygen Species and Superoxide Dismutases . . . . 348 Inflammation in Ischemic Damage and Ischemic Tolerance . . . . 348

Preconditioning and Hibernation . . . . 348 Hypoxia-Inducible Factor 1 and Cytochrome P450 . . . . 349 Conclusion and Future Directions . . . . 349 References . . . . 349

30. Therapeutic Potential of Hypothermia in Acute Stroke 355 Carmelo Graffagnino

Background Pathophysiology of Ischemia . . . . 355 Mechanisms of Hypothermic Neuroprotection . . . . 355 Preclinical Work with Global Ischemia . . . . 356 Preclinical Work with Focal Ischemia . . . . 356 Human Experience with Hypothermia . . . . 357 Human Clinical Trials with Hypothermia for Global Ischemia

(Cardiac Arrest) . . . . 358 Human Clinical Trials with Hypothermia for Focal Ischemia . . . . 359 Conclusions and Future Directions . . . . 360 References . . . . 360

31. Decompressive Hemicraniectomy for Stroke: An Old Therapy Revisited 365 Suresh Subramaniam, Michael D. Hill, and Andrew M. Demchuk

Clinical Course of Massive Cerebral Infarction . . . . 365 Identification of Patients for Hemicraniectomy . . . . 366 Description of Surgical Technique for Hemicraniectomy and Duraplasty . . . . 366 Key Issues to Address Prior to Hemicraniectomy . . . . 368 Conclusion . . . . 371 References . . . . 371

32. Blood-Pressure Management in Subarachnoid Hemorrhage, Acute Ischemic Stroke, and Intracerebral Hemorrhage 375 Wendy C. Ziai

Introduction . . . . 375 Cerebrovascular Physiology . . . . 375 Subarachnoid Hemorrhage . . . . 376 Ischemic Stroke . . . . 378 Intracerebral Hemorrhage . . . . 381 References . . . . 384

33. Diagnosis and Treatment of Cerebral Arteriovenous Malformations 389 Abhishek Srinivas, Stephen Chang, and Philippe Gailloud

34. Endovascular Therapy for Carotid Stenosis 399 Alison J. Nohara

Preparation for Carotid Stenting . . . . 400

Routine Postprocedural Care . . . . 401

35. Acute Stroke Care Units: A Critical Appraisal 405 Paul A. Nyquist and Anish Bhardwaj

Introduction . . . . 405 Historic Perspective . . . . 405

ASU in the United States vs. Europe . . . . 406 European Literature and Databases . . . . 406 Need for ASU in the United States . . . . 407 ACUs: Definition and Composition . . . . 408 Human Resources in the ASU . . . . 410 Capabilities of an ASU . . . . 410 Configuration of ASU . . . . 410 Specific Issues Surrounding Care in ASUs . . . . 410 Summary and Conclusions . . . . 412 References . . . . 412

36. Telemedicine Applied to Stroke Care 415

Marian P. LaMonte, Mona N. Bahouth, Yan Xiao, Peter Hu, and Colin Mackenzie Introduction . . . . 415

Current Challenges in Providing Emergency Access to

Stroke Specialty Care . . . . 415 Telemedicine as a Bridge from On-Site Emergency Providers to Specialists . . . . 415 Fundamental Research Advancing Telemedicine for Stroke Care . . . . 416 Reimbursement Challenges and Alternatives for Renewable Funding for

Telemedicine Programs . . . . 418 Conclusions and Future Directions . . . . 418 References . . . . 419

37. Multimodality Neuromonitoring in Acute Stroke 421 Wolf-Dieter Heiss, Christian Dohmen, and Rudolf Graf Introduction . . . . 421

Studies in Experimental Stroke Models . . . . 421 Application of Multimodal Monitoring in the Neurologic

Intensive Care Unit . . . . 424 Comparison to Functional Imaging . . . . 427 Conclusions and Future Directions . . . . 429 References . . . . 429

38. Gender Differences in Stroke Pathobiology: Therapeutic Implications 433 Louise D. McCullough, Julia Kofler, and Patricia D. Hurn Introduction . . . . 433 Role of Biologic Sex . . . . 433

Estrogen: Multiple Actions, Current Controversies . . . . 436 Testosterone: Role in Male Sensitivity to Ischemia . . . . 439 Conclusions . . . . 439 References . . . . 440

39. Ultrasonography in the Management of Acute Stroke 443 Andrei V. Alexandrov and Marc Ribo Introduction . . . . 443

Transient Ischemic Attack vs. Stroke . . . . 443

Targets of Cerebrovascular Ultrasound Testing . . . . 444

Therapeutic Applications in Acute Ischemic Stroke . . . . 449

Conclusions and Future Directions . . . . 453

40. Acute Stroke in the Young 459

Heather J. Fullerton and Donna M. Ferriero Introduction . . . . 459

Terminology, Incidence, and Epidemiology . . . . 459 Mechanisms of Injury in Stroke . . . . 460 Distribution and Clinical Presentation . . . . 462 Etiologies and Risk Factors . . . . 462 Diagnostic Evaluation . . . . 465

Management . . . . 465 Conclusions . . . . 467 References . . . . 468

41. Functional Recovery After Stroke with Cell-Based Therapy 473 Michael Chopp and Yi Li Cell-Based Therapy: New Strategies for Stroke . . . . 473 Neurogenesis After Stroke . . . . 473 Sources of Cells for Treatment of Stroke . . . . 474 Modification of Cells in Stroke Research . . . . 475 Cell Therapy from the Laboratory to the Stroke Patient . . . . 476 Challenges in Cell-Based Therapy for Stroke: Determining the

Mechanism of Cell Therapy . . . . 477 References . . . . 478

42. Brain Attack 481

Chandrasekaran Sivakumar and Alastair M. Buchan Introduction . . . . 481 Imaging . . . . 481 Thrombolysis . . . . 483 Early Outcome . . . . 484 ICU Care . . . . 484 Decompressive Surgery . . . . 485 Neuroprotection . . . . 485 Acute Stroke Units . . . . 486 Biologic Markers . . . . 486 Telemedicine . . . . 486 Conclusions and Future Directions . . . . 486 References . . . . 487

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 a Core Molecular Laboratories and Training, b Department 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 Chairmana, Vice Chairmanb, Professor b a Department of Neurology, Evanston Northwestern Healthcare, b Departments 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, Harborview 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 a Department of Neurology, b Stroke 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

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 a Departments of Neurology and Neurological Surgery, b Neurocritical 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, b Neurosciences Critical Care Unit, Johns Hopkins Bayview Medical Center, and c Neurosciences 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 Department of Neurology and Neurosciences, Zeenat Qureshi Stroke Research Center, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, USA

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 Kofler, 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 a and b Co-Director a Department of Neurology, b Stroke Program, Oregon Stroke Center, Oregon Health & Science University, Portland, Oregon, USA

Patrick D. Lyden, MD, FAAN, Professor a and Director b a Department of Neurosciences, University of California-San Diego, b UCSD 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, b Neurological 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

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, b University 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 a Mayo Clinic College of Medicine, b Neurological-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

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

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

Richard J. Traystman, PhD, FCCM, Professor a, Associate Vice President b, and Associate Dean c a Department of Anesthesiology & Perioperative Medicine, b Research Planning and Development, c Research School of Medicine, Oregon Health & Science University, Portland, Oregon, USA

Stanley Tuhrim, MD, Director a, Professor b a Division of Cerebrovascular Diseases, b Department 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 a Cerebrovascular Division, b Department 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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