Primer on Cerebrovascular Diseases

Section I. Anatomy and Physiology

Chapter 1. Cerebrovascular Anatomy and Hemodynamics

• Introduction
• Anatomical Considerations
• Overview of Cerebral Hemodynamics
• Conclusion

Chapter 2. Cerebral Microcirculation

• Introduction
• Anatomy and Physiology of Microcirculation
• Neurovascular Unit and Coupling
• Microcirculation After Stroke and Thrombolysis
• Microvascular Dysfunction and Dementia
• Capillary Transit Time Heterogeneity as a Measure of Capillary Dysfunction

Chapter 3. The Glymphatic System and Brain Interstitial Fluid Homeostasis

• Introduction
• Interstitial Solute Clearance
• Perivascular Bulk Flow and the Glymphatic System
• Terminal Efflux Routes
• Physiological Roles of Perivascular Exchange and Cerebral Lymphatics
• Pathological Roles of Perivascular Cerebrospinal Fluid–Interstitial Fluid Exchange
• Conclusion

Chapter 4. Cerebrospinal Fluid: Formation, Absorption, Markers, and Relationship to Blood–Brain Barrier

• Introduction
• Blood–Brain Interfaces
• Blood–CSF Interface
• CSF–Blood Interface
• CSF Pressure
• Blood–Brain Barrier Interface
• Pathological Changes in the Capillary
• Conclusion

Chapter 5. Anatomy of Cerebral Veins and Dural Sinuses

• Introduction
• Dural Venous Sinuses
• Cerebral Veins

Chapter 6. Cerebral Vasa Vasorum

• Introduction
• Structure, Function, and Localization
• Cerebral Vasa Vasorum Neovascularization
• Molecular Imaging and Detection
• Clinical Significance in Disease

Chapter 7. Cerebral Vascular Muscle

• Introduction
• Myogenic Tone: Role of TRP Channels
• Mechanisms Underlying Vasodilation
• CADASIL: A Vascular Muscle Defect That Reduces Cerebral Blood Flow and Impairs Cognitive Function
• Summary

Chapter 8. Endothelium

• Introduction
• Endothelium and Vascular Tone
• Endothelium and Thrombosis
• Endothelium and Oxidative Stress
• Endothelium and Inflammation
• Endothelium and the RhoA/Rho-Kinase Pathway
• Endothelium and Angiogenesis
• Therapeutic Strategies to Maintain Cerebral Endothelial Function
• Funding Statement

Chapter 9. Development and Maintenance of the Blood–Brain Barrier

• Introduction
• Cell Types of the Neurovascular Unit
• Development
• Conclusion

Chapter 10. Cerebral Autoregulation

• Introduction: From Static to Dynamic
• Mechanisms Underlying Cerebral Autoregulation
• Cerebral Autoregulation in Hypertension and Neurological Diseases

Chapter 11. Cerebral Blood Flow Regulation (Carbon Dioxide, Oxygen, and Nitric Oxide)

• Introduction
• Physiological Responses of CO₂
• Mechanisms of Action of CO₂
• Conclusion
• Physiological Responses of O₂
• Mechanisms of Action of O₂
• Conclusion
• Physiological Responses of Nitric Oxide
• Conclusion

Chapter 12. CBF–Metabolism Coupling

• Introduction
• CBF Measurements
• CBF and Metabolism Coupling
• Neuronal Coupling to CBF and Metabolism
• Role of Astrocytes
• Uncoupling Between CBF and Metabolism

Chapter 13. Perivascular Neurotransmitter Regulation of Cerebral Blood Flow

• Introduction
• Sensory Nervous System

Chapter 14. Adenosine and Its Receptors Update: Influence on Cerebral Blood Flow (CBF)

• Introduction
• Adenosine Background
• Data Supporting Ado’s Role in Cerebral Blood Flow Regulation
• Conclusion

Chapter 15. Cerebrovascular Activity of Peptides Generated by Central Nervous System

• Introduction
• Endothelins
• The Kallikrein–Kinin System

Chapter 16. Eicosanoids in Cerebrovascular Diseases

• Introduction
• Production of Eicosanoids
• The Eicosanoid-Producing Enzymes
• Contributions to Stroke Injury
• Conclusion and Outlook

Chapter 17. Neurogenesis in Cerebrovascular Disease

• Introduction
• Adult Neurogenesis
• Cerebrovascular Disease and Neurogenesis
• Functional Significance of Neurogenesis in Cerebrovascular Disease
• Mechanisms of Neurogenesis-Mediated Repair
• Conclusion

Chapter 18. Gliogenesis

• Introduction
• Radial Glia Gives Rise to Neurons and Glial Cells During Development
• Adult Neurogenesis and Gliogenesis Take Place in SVZ or SGZ in Adult Brain
• Intrinsic Factors for Gliogenesis Regulation
• Gliogenesis After Brain Injury
• Conclusion

Chapter 19. Vascular Remodeling After Cerebral Ischemia

• Neovascularization After Cerebral Ischemia and Hypoxia
• Angiogenesis After Ischemia and Hypoxia
• Vasculogenesis and the Role of Endothelial Progenitor Cells
• Arteriogenesis and the Remodeling of Collateral Vessels After Stroke or Cerebral Hypoperfusion
• Therapies to Promote Poststroke Neovascularization

Section II. Pathophysiology

Chapter 20. An Overview of Atherosclerosis

• Introduction
• Cellular and Molecular Mechanisms in Atherosclerosis
• Pathology

Chapter 21. Thrombosis

• Introduction
• Physiology: Homeostatic System
• Role of Platelets
• Role of Vascular Endothelium
• Fibrinolysis
• Thrombotic Mechanisms
• Antithrombotic Treatment of Ischemic Stroke

Chapter 22. Histopathology of Cerebral Ischemia and Stroke

• Introduction
• Cerebral Infarction
• Astrocyte and Vascular Changes
• Inflammatory Events
• White Matter Changes
• Ischemic Penumbra
• Selective Ischemic Cell Death
• Summary

Chapter 23. Histopathology of Intracerebral Hemorrhage

• Introduction
• Histopathological Changes
• Summary

Chapter 24. Pathophysiology of Ischemia-Reperfusion Injury and Hemorrhagic Transformation in the Brain

• Introduction
• Cellular and Molecular Mechanisms of Ischemia-Reperfusion Injury and Hemorrhagic Transformation
• Intervention Strategies for Ischemia-Reperfusion Injury
• Conclusion

Chapter 25. Pathophysiology of Subarachnoid Hemorrhage, Early Brain Injury, and Delayed Cerebral Ischemia

• Introduction
• Aneurysm Formation
• Etiology of SAH
• Early Brain Injury
• Delayed Cerebral Ischemia
• Conclusion

Chapter 26. Pathophysiology of Ischemic White Matter Injury

• Cellular Anatomy of White Matter

Chapter 27. Central Neuroinflammation in Cerebral Ischemia: The Role of Glia

• Introduction
• Neuroinflammatory Response of Microglia to Cerebral Ischemia
• Neuroinflammatory Response of Astrocytes to Cerebral Ischemia
• Astrocyte–Microglia Cross Talk Following Cerebral Ischemia
• Conclusions

Chapter 28. Pathophysiology of the Peripheral Immune Response in Acute Ischemic Stroke

• Cerebral Ischemia and Inflammation
• Immune Cells Participating in Ischemic Injury and Tissue Repair
• Immune Cell Entry Into the Ischemic Brain
• Alterations of the Peripheral Immune System After Stroke
• Conclusion

Chapter 29. Cytotoxic and Vasogenic Brain Edema

• Introduction
• Normal Fluid Movement in the Brain
• Cerebral Edema
• Imaging and Monitoring Brain Edema
• Treatment
• Conclusion

Chapter 30. Spreading Depolarizations

• Basic Characteristics
• Impact on Injury Outcome
• Natural History of SDs in Injured Brain
• Trigger Factors and Modulators
• Detection of SDs
• Therapeutic Targeting of SDs
• Conclusion

Chapter 31. Hypertension

• Introduction
• Vascular Function
• Blood–Brain Barrier
• Vascular Structure
• Consequences of Vascular Disease During Hypertension

Chapter 32. Risk Factors: Diabetes

• Introduction
• Diabetes and Stroke
• Diabetes and Cognitive Impairment
• Cerebrovascular Function and Structure in Diabetes—Lessons From Preclinical Models
• A Unifying Hypothesis: Relevance of Microcerebrovascular Disease to Ischemic Stroke and Cognitive Impairment
• Conclusion

Chapter 33. Risk Factors: Aging

• Introduction
• Aged Blood–Brain Barrier and Neuroinflammation-aging
• Stroke
• Vascular Dementia
• Therapeutic Targets
• Research Disconnect
• Conclusion

Chapter 34. Risk Factors: Gender and Sex

• Introduction
• Examples of Traditional, Well-Studied Risk Factors: Hypertension and Hyperlipidemia
• Clinical Risk Factors More Prevalent in Women: Atrial Fibrillation, Diabetes Mellitus, Migraine With Aura, and Depression
• Female-Specific Clinical Risk Factors: Menopause, Hormone Replacement Therapy, Oral Contraceptives, and Pregnancy
• Role of Sex in Fundamental Stroke Pathobiology

Chapter 35. Mechanisms of Stroke Recovery

• Introduction
• Timeline for Stroke Recovery
• Excitatory Neuronal Signaling
• Promotion of Growth Programs
• Conclusions

Section III. Neuroprotection

Chapter 36. N-Methyl-D-Aspartate Receptors Remain Viable Therapeutic Targets for Stroke

• Introduction
• N-Methyl-d-Aspartate Subtype Glutamate Receptors at the Acute Phase of Stroke
• N-Methyl-d-Aspartate Subtype Glutamate Receptors and the Late Consequences of Stroke
• Conclusion

Chapter 37. Neuroprotectants: Reactive Oxygen Species (ROS) Based

• Introduction
• Sources of Reactive Oxygen Species in Cerebral Ischemia and SAH
• Basics of Free-Radical-Induced Lipid Peroxidation
• Mechanisms for Pharmacologic Inhibition of Oxidative Damage in Acute Ischemic or Hemorrhagic Stroke
• New Antioxidant Approaches
• Conclusion

Chapter 38. Neuroprotectants: Cell-Death Based

• Introduction
• Caspase
• Mitochondrial Pathway
• Bcl-2 Family
• Extrinsic Pathway
• Inhibitor of Apoptosis
• Caspase-Independent Cell Death
• Conclusion

Chapter 39. Comprehensive Concept of Regenerative Medicine for Ischemic Stroke With Bone Marrow Stromal Cells

• Introduction
• BMSC Transplantation for Ischemic Stroke
• Muse Cell Transplantation for Ischemic Stroke
• Conclusion

Chapter 40. Neuroprotectants: Temperature

• Introduction
• Therapeutic Hypothermia for Ischemia
• Therapeutic Hypothermia for Intracerebral Hemorrhage
• Conclusion

Chapter 41. Drug Delivery to the Central Nervous System

• Introduction
• Crossing the BBB
• Circumventing the BBB
• Conclusion

Chapter 42. Ischemic Tolerance: In Situ and Remote Pre- and Postconditioning

• Introduction
• In Situ PreC and PostC
• Cross-tolerance Induced by Heterologous Conditioning
• Remote Conditioning
• The Underlying Protective Mechanisms of In Situ and Remote Conditioning
• In Situ PreC
• In Situ PostC
• Remote PreC and PostC
• Conclusion

Section IV. Molecular Mechanisms

Chapter 43. Mechanisms of Neuron Death (Necrosis, Apoptosis, Autophagy) After Brain Ischemia

• Introduction
• Apoptosis, Necrosis, and Autophagy After Brain Ischemia
• Mechanisms of Selective Neuronal Death After Brain Ischemia

Chapter 44. Mechanisms of Glial Death and Protection

• Introduction
• Glia Metabolism
• Oligodendrocytes Are Vulnerable to Excitotoxicity Following Ischemia
• Mechanisms of Oligodendrocyte Damage, Protection, and Repair in Stroke
• Mechanisms of Astrocyte Damage and Protection in Stroke
• Conclusion

Chapter45. Mechanisms of Endothelial Injury and Blood–Brain Barrier Dysfunction in Stroke

• Introduction
• Disruption of the Blood–Brain Barrier in Ischemic Stroke
• Pathological Mechanisms of Endothelial Injury in Ischemic Stroke
• Therapeutic Opportunities
• Summary

Chapter 46. The Neurovascular Unit

• Introduction
• The Neurovascular Unit in CNS Function
• The Neurovascular Unit in Acute Stroke
• The Neurovascular Unit in Stroke Recovery
• Summary

Chapter 47. Mitochondrial Mechanisms During Ischemia and Reperfusion

• Introduction
• Adenosine Triphosphate and Energy Metabolisms
• Ion Channel Regulation of Mitochondrial Calcium
• Cell Death and Mitophagy
• Mitochondrial Transfer and Biogenesis
• Overview
• Abbreviations

Chapter 48. Excitotoxicity and Stroke

• Introduction
• What Is Excitotoxicity?
• How Excitotoxicity Kills Neurons
• Ischemia Initiates Excitotoxicity
• Clinical Disappointment—and Possible Explanations
• Possible Paths Forward—Maybe Still Starting With NMDA Antagonists

Chapter 49. Oxidative and Nitrosative Stress

• Oxidative Stress in Ischemic Stroke
• The Superoxide Radical
• Hydrogen Peroxide: A Superoxide Dismutant
• Nitric Oxide
• Peroxynitrite
• Iron and Oxidative Stress
• Reactive Oxygen Species and Cell Signaling Pathways
• Glutamate Excitotoxicity
• Sex Differences in Oxidative Stress and Stroke
• Oxidative Stress During Various Stages of Ischemia
• Antioxidants: Defense Against Reactive Oxygen Species

Chapter 50. Protein Kinases in Cerebral Ischemia

• Introduction
• Conclusion

Chapter 51. Ischemia Regulated Transcription Factors: Hypoxia Inducible Factor 1 and Activating Transcription Factor 4

• Introduction
• Hypoxia-Mediated Transcription Changes During Stroke
• Hypoxia Regulates Hypoxia-Inducible Factor System
• Regulation of Adaptive Transcription by HIF–Prolyl Hydroxylases
• Inhibiting HIF-PHDs as a Therapeutic Strategy
• HIF-PHD Inhibition to Prevent Oxidative Stress
• ATF4 is an Oxidative Stress–Inducible Transcription Factor Regulated by HIF-PHDs
• Glucose Deprivation and HIF Activity
• Conclusion

Chapter 52. Lipid Mediators

• Platelet-Activating Factor and Other Bioactive Lipids
• Platelet-Activating Factor Contributes to Excitotoxicity by Enhancing Glutamate Release
• Omega-3 Polyunsaturated Fatty Acids
• Docosahexaenoic Acid is Neuroprotective in Cerebral Ischemia
• Docosanoids: Neuroprotectin D1
• Concluding Remarks

Chapter 53. Mitogen-Activated Protein Kinase Signaling in Cerebrovascular Disease

• Mitogen-Activated Protein Kinase Signaling
• Ischemic Stroke
• Hemorrhagic Stroke
• Summary

Chapter 54. Rho-Associated Kinases in Cerebrovascular Disease

• Introduction
• Rho-Associated Kinases
• Rho-Associated Kinase Inhibitors
• Rho-Associated Kinase Inhibition in Experimental Models of Cerebrovascular Diseases
• Rho-Associated Kinase Inhibitors in Clinical Use for Cerebrovascular Diseases
• Conclusion

Chapter 55. Akt-GSK3β Pro-survival Signaling Pathway in Cerebral Ischemic Injury

• Introduction
• Akt Activation and Regulation
• Activation and Regulation of Akt in Cerebral Ischemic Injury
• Akt Regulates Transcriptional Machinery Leading to an Environment Supporting Cell Survival
• Glycogen Synthase Kinase 3β
• Other Akt Targets Impacting Transcription
• Summary

Chapter 56. Heat Shock Proteins and the Stress Response

• Introduction
• Heat Shock Proteins
• The Heat Shock Response
• Hsp70 in Ischemic Stroke
• Other Heat Shock Proteins
• Conclusion

Chapter 57. Noncoding RNAs and Stroke

• Introduction
• Noncoding RNAs
• miRNAs and Ischemic Brain Damage
• LncRNAs in the Post-Ischemic Brain
• piRNAs in the Post-Ischemic Brain
• Concluding Remarks

Chapter 58. Cytokines and Chemokines in Stroke

• Introduction
• Cytokines as Signaling Molecules in the Innate Immune Response of the Ischemic Brain
• Cytokines and Neuroinflammation
• The Role of Chemokines After Stroke
• Implication of Chemokines and Cytokines in Neurorepair Mechanisms After Stroke: Focus on Neurogenesis and Angiogenesis
• Therapeutic Approaches and Future Directions

Chapter 59. Growth Factors and Cerebrovascular Diseases

Chapter 60. Tissue Plasminogen Activator Signaling in the Normal and Diseased Brain

• Signaling in the Normal CNS
• Signaling in the Diseased CNS
• Conclusion

Chapter 61. Matrix Metalloproteinases and Extracellular Matrix in the Central Nervous System

• Introduction
• Basal Lamina and Endothelial Cells
• Common Features of the MMPs in Nervous Tissues and Cerebral Blood Vessels
• Enzymes and ECM
• Conclusion

Section V. Models and Methods

Chapter 62. Animal Models of Focal Ischemia

• Approaches to Inducing Focal Ischemia
• Induction of Middle Cerebral Artery Occlusion: Considerations for Anesthesia and Monitoring Physiological Variables
• Monitoring Cerebral Blood Flow During Middle Cerebral Artery Occlusion and Reperfusion
• Common Outcome Measures
• Use of Stroke Models for Understanding Pathophysiology Versus Treatments
• Comorbidities and Sex Differences

Chapter 63. Animal Models: Global Ischemia

• Introduction
• Rodent Models: Mice, Rats, Gerbils, and the Arctic Ground Squirrel
• Larger Animals: Dogs, Cats, and Monkeys
• Comparing Global Cerebral Ischemia With Cardiac Arrest
• Conclusion and Outlook

Chapter 64. Animal Models: Cerebral Hemorrhage

• Introduction
• Blood Injection Model
• Collagenase Injection Model
• Comparison of Blood and Collagenase Models
• Conclusion

Chapter 65. Animal Models of Neonatal Stroke/Ischemia

• Introduction
• Developmental Patterns of Ischemia-Associated Brain Damage in Preterm and Term Infants
• Large Animal Models of Ischemia-Related Injury
• Rodent Models of At-Term/Neonatal Focal Stroke and Hypoxia-Ischemia
• Method for Induction of tMCAO in P7 Rats
• Method for Induction of tMCAO in P10 Rats
• Method for Induction of tMCAO in P9–P10 Mice
• Model-Specific Oxidative and Inflammatory Mechanisms of Ischemic Injury in Neonates

Chapter 66. Animal Models: Vascular Models of Cognitive Dysfunction

• Introduction
• Cognitive Dysfunction of Vascular Origin in Human
• Animal Models: Advantages and Limitations
• Commonalities and Pathophysiology
• Conclusion

Chapter 67. Animal Models: Nonhuman Primates

• Introduction
• The Choice of Species
• Methods of Stroke Creation
• Assessment of Functional Outcome
• Surrogate Outcome Measures
• Conclusion

Chapter 68. Cerebral Blood Flow Methods

• Introduction
• Methods Requiring Brain Penetration
• Methods Requiring the Injection of a Radioactive Tracer
• Optical Techniques
• Conclusion

Chapter 69. Magnetic Resonance Imaging of Stroke

• Introduction
• T₁-, T₂-, and T₂∗-Weighted MRI
• Diffusion-Weighted MRI
• MR Angiography and Perfusion MRI
• Perfusion-Diffusion Mismatch
• Tissue Classification and Prediction

Chapter 70. Principles and Methods of Molecular Imaging in Stroke

• Imaging Agents and Modalities
• Imaging Plaque Vulnerability
• Imaging Thrombus
• Imaging Apoptonecrosis
• Imaging Neuroinflammation
• Imaging Stem Cells
• Conclusion

Chapter 71. Experimental Methods for Measuring Blood Flow in Brain Capillaries

• Two-Photon Microscopy of Fluorescent Signals
• Line-Scans Overcome Limitations of Measurement Speed
• Analysis Methods
• Viewing Stalled Vessels
• Other Methods and Future Outlook

Chapter 72. Genomic Tools

• Introduction
• Ischemic Stroke Versus Controls and Intracerebral Hemorrhage
• mRNA Profiles for Causes of Stroke
• Transient Ischemic Attacks
• Hemorrhagic Transformation
• micro RNA Regulation of mRNA
• Alternative Splicing of mRNA and the Future

Chapter 73. Proteomes and Biomarkers of the Neurovascular Unit

• Introduction
• Neurovascular Unit “Carta”
• Brain Endothelial Cell “Carta”
• Proteome of Cerebral Vessels
• Translational Proteomics: Biomarkers for Cardiovascular Diseases
• Quantitative Targeted Proteomics: From Discovery to Application
• Conclusion

Chapter 74. Blood Biomarkers in Acute Stroke

• Introduction
• Methodological Aspects
• Identification of Patients With Ischemic Stroke
• Differentiation Between Intracerebral Hemorrhage and Ischemic Stroke
• Predicting Bleeding Complications After Thrombolysis
• Identifying Ischemic Stroke Etiology
• Predicting Recurrent-Events in Patients With Transitory Ischemic Attack
• Summary

Chapter 75. Rodent Behavioral Tests Sensitive to Functional Recovery and Compensation

• Introduction
• Forelimb Function Tasks
• Hind Limb Function Tasks
• Cognitive Tasks Overview
• Conclusion

Clinical Chapters

Section VI. Clinical Aspects: Medical and Surgical

Chapter 76. Transient Focal Neurological Events

• Transient Ischemic Attacks
• Seizures
• Migraine
• Transient Global Amnesia
• Vertigo
• Hypoglycemia
• Functional Neurological Disorders
• Neuromuscular Conditions
• Brain Tumors, Subdural Hematomas, and Space-Occupying Lesions
• Syncope and Vertebrobasilar Insufficiency
• Primary Ophthalmologic Conditions
• Demyelinating Conditions

Chapter 77. Types of Stroke and Their Differential Diagnosis

• Introduction
• Ischemic Stroke
• Hemorrhagic Stroke

Chapter 78. Small Artery Occlusive Diseases

• Introduction
• Characteristics of Small Artery Occlusive Diseases on Specific Arteries

Chapter 79. Anterior Circulation: Large Artery Occlusive Disease and Embolism

• Introduction
• Vascular Anatomy and Pathology

Chapter 80. Carotid Artery Disease

• Introduction
• Pathology
• Mechanisms of Symptoms From Carotid Occlusive Disease
• Cerebral Hemispheric Syndromes
• Retinal Ischemia
• The Carotid Bruit
• Other Less Common Clinical Features of Carotid Artery Occlusive Disease
• Carotid Dissection and Moyamoya Disease

Chapter 81. Posterior Circulation: Large Artery Occlusive Disease and Embolism

• Introduction
• Vascular Anatomy of the Posterior Circulation
• Subclavian Artery Disease
• Vertebral Artery Origin Disease
• Extracranial Vertebral Artery Dissection
• Intracranial Vertebral Occlusion
• Basilar Artery Disease
• Cerebellar Infarction
• Thalamic Infarction
• Posterior Cerebral Artery Territory Infarction
• Posterior Circulation Embolism
• Imaging Studies

Chapter 82. Primer in Cerebrovascular Disease: Innominate and Subclavian Disease

• Introduction
• Evaluation and Workup
• Subclavian and Innominate Stenosis
• Subclavian and Innominate Aneurysmal Disease

Chapter 83. Vertebral Artery Disease

• Vascular Anatomy
• Extracranial Vertebral Artery
• Intracranial Vertebral Artery

Chapter 84. Basilar Artery Disease

• Anatomy
• Pathology and Pathophysiology
• Other Less Common Pathophysiologic Findings of the Basilar Artery
• Clinical Syndromes of Basilar Artery Ischemia
• Clinical Presentation and Outcomes From the Registry Data: NEMC-PCR and BASICS

Chapter 85. The Heart and Stroke

• Overview
• Stroke Classification
• Direct Cardiogenic Brain Embolism
• Brain Hypoperfusion Due to Cardiac Pump Failure
• Neurological Effects From Cardiac Drugs
• Neurological Complication From Endovascular Cardiac Procedure
• Cardiac Complications Associated With Brain Lesions
• Coexistent Vascular Diseases Affecting Both Heart and Brain

Chapter 86. Aortic Arch Artherosclerotic Disease

• Introduction
• Complex Atheromatous Plaques in the Descending Aorta and Stroke
• Stroke Prevention in Patients With Aortic Arch Atherosclerosis
• Conclusion

Chapter 87. Brain Injury From Cerebral Hypoperfusion

• Introduction
• Syncope
• Watershed Territory Infarcts
• Hypoxic-Ischemic Encephalopathy

Chapter 88. Stroke and Eye Findings

• Introduction
• Conclusion

Chapter 89. Spinal Cord Strokes

• Spinal Cord Vascular Supply
• Spinal Cord Ischemia and Infarction
• Causes of Spinal Ischemia
• Spinal Vascular Malformations
• Diagnostic Evaluation of Patients Presenting With Spinal Cord Ischemia
• Spinal Hemorrhages

Chapter 90. Unique Features of Aneurysms by Location

• Introduction
• Internal Carotid Artery Aneurysms
• Anterior Communicating Artery Aneurysms
• Middle Cerebral Artery Aneurysms
• Vertebrobasilar and Cerebellar Artery Aneurysms
• Conclusions

Chapter 91. Clinical Aspects of Subarachnoid Hemorrhage

• Introduction
• Epidemiology
• Diagnosis
• Clinical Course
• Vasospasm
• Treatment of Cerebral Aneurysms
• Conclusion

Chapter 92. Clinical Aspects of Intracerebral Hemorrhage

• Introduction
• Classification
• Clinical Presentation
• Radiologic Findings
• Management
• Conclusion

Chapter 93. Clinical Aspects of Intraventricular Hemorrhage

• Introduction
• Etiology of Intraventricular Hemorrhage in Infants
• Clinical Presentation of Intraventricular Hemorrhage in Infants
• Grading of Intraventricular Hemorrhage in Infants
• Diagnosis of Intraventricular Hemorrhage in Infants
• Treatment of Intraventricular Hemorrhage in Infants
• Etiology of Intraventricular Hemorrhage in Adults
• Symptoms of Intraventricular Hemorrhage in Adults
• Diagnosis of Intraventricular Hemorrhage in Adults
• Grading of Intraventricular Hemorrhage in Adults
• Treatment of Intraventricular Hemorrhage in Adults
• Prognosis

Chapter 94. Clinical Aspects of Subdural Hemorrhage (SDH)

• Acute Subdural Hematoma
• Chronic Subdural Hematomas

Chapter 95. Cerebral Venous Thrombosis

• Introduction
• Epidemiology
• Etiology
• Clinical Presentation
• Diagnosis
• Treatment
• Prognosis

Chapter 96. Developmental Venous Anomalies

• Introduction
• Radiopathological Characteristics
• Classification and Key Descriptive Attributes
• Presentation and Natural History
• Treatment Options
• Considerations for Management

Chapter 97. Vein of Galen Arteriovenous Malformations

• Embryology
• Anatomy and Classification
• Clinical Presentation
• Prognosis
• Goals of Treatment
• Treatment Options
• Ongoing Challenges

Chapter 98. Carotid Cavernous and Other Dural Arteriovenous Fistulas

• Introduction
• Carotid Cavernous Fistulas
• Other Dural Arteriovenous Fistulas

Chapter 99. Cavernous Malformations

• Introduction
• Genetics
• Pathology
• Clinical Presentation
• Natural History
• Diagnosis
• Indications for Treatment
• Timing of Surgical Treatment
• Choice of Operative Approach
• Radiosurgery
• Principles of Surgical Treatment
• Cavernous Malformations Associated With Seizures
• Future Directions

Chapter 100. Spinal Vascular Malformations

• Spinal Vascular Anatomy
• Classification and Epidemiology
• Pathophysiology, Hemodynamics, and Natural History
• Radiological Features
• Treatment
• Conclusion

Chapter 101. Reversible Cerebral Vasoconstriction Syndromes

• Introduction
• Epidemiology
• Risk Factors and Pathophysiology
• Clinical Features
• Laboratory Test Results
• Brain Imaging Results
• Diagnostic Approach
• Management
• Prognosis and Counseling

Chapter 102. Spontaneous Dissections of Cervicocephalic Arteries

• Etiology and Physiopathology
• Epidemiology
• Clinical Presentation
• Diagnosis
• Management

Chapter 103. Stroke Secondary to Trauma

• Introduction
• Ischemic Stroke
• Decreased Cerebral Perfusion Pressure
• Vasospasm
• Vascular Injury
• Hemorrhagic Stroke
• Delayed Traumatic Intracerebral Hemorrhage
• Hemorrhagic Progression
• Conclusion

Chapter 104. Vascular Cognitive and Behavioral Disorders

• Introduction

Section VII. Medical Conditions and Stroke

Chapter 105. Stroke in Children

• Introduction
• Epidemiology
• Perinatal and Neonatal Stroke
• Stroke in Children
• Work-Up
• Stroke Mimics
• Treatment
• Conclusion

Chapter 106. Ischemic Stroke in the Young

• Introduction
• Epidemiology of Stroke in the Young
• Causes of Ischemic Stroke in the Young
• Clinical Clues Suggesting Specific Causes of Stroke
• An Approach to Diagnostic Testing in Young Stroke Patients
• Treatment and Prognosis in Young Stroke Patients

Chapter 107. Rare Genetic Causes of Stroke

• Introduction
• Monogenic Diseases
• Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)
• Hereditary Endotheliopathy With Retinopathy, Nephropathy, and Stroke (HERNS)
• Type IV Collagen α1-Chain Mutation (COL4A1)
• Homocystinuria
• Marfan Syndrome and Vascular Ehlers–Danlos Syndrome
• Moyamoya Disease
• Polygenic Diseases
• Conclusions

Chapter 108. Stroke in Fabry Disease

• Epidemiology
• Pathophysiology
• Clinical Features
• Stroke Pathogenesis
• Neuroimaging
• Diagnosis
• Treatment

Chapter 109. Moyamoya Disease and Syndrome

• Introduction
• Epidemiology
• Pathology and Pathogenesis
• Clinical Features
• Diagnosis
• Prognosis and Treatment

Chapter 110. Varicella Zoster Virus and Stroke

• Introduction
• Epidemiology
• Clinical Features, Laboratory Abnormalities, and Diagnosis of VZV Vasculopathy
• Treatment of VZV Vasculopathy
• VZV in Giant Cell Arteritis
• Pathogenesis
• Conclusions

Chapter 111. Stroke and Migraine

• Introduction
• What Is Migraine?
• What Is the Relationship of Migraine to Stroke?
• Diagnosis and Prevention

Chapter 112. Cerebrovascular Complications of Cancer

• Stroke Directly Due to Tumor
• Stroke Due to Remote Effects of Tumor: Coagulopathy
• Hypercoagulability and Thrombosis
• Combined Hypercoaguability/Bleeding Diathesis
• Stroke in the Setting of Tumor, But Not Related to Tumor
• Sequelae of Cancer Treatment

Chapter 113. Radiation Vasculopathy

• Introduction
• Pathophysiology
• Incidence
• Radiological Manifestations
• Monitoring
• Treatment Options
• Cerebrovascular Complications of Cardiac Radiation
• Therapeutic Effects of Radiation on Cerebral Blood Vessels
• Future Prospects

Chapter 114. Aortic Dissection and Stroke

• Introduction

Chapter 115. Coagulopathies and Ischemic Stroke

• Introduction
• Antithrombin
• Protein C and Protein S
• Activated Protein C Resistance
• Fibrinogen and Fibrinolytic Abnormalities
• Homocyst(e)inemia
• Other Coagulation Abnormalities
• Who Should Be Evaluated for Coagulopathies?
• Summary

Chapter 116. Antiphospholipid Antibody Syndrome

• Introduction
• What Are Antiphospholipid Antibodies?
• Clinical and Laboratory Features of Antiphospholipid Antibody Syndrome
• Diagnosis of Antiphospholipid Antibody Syndrome
• Epidemiology
• When to Screen for aPL in Patients with Cerebrovascular Disease
• Predicting Thrombosis Risk in APS and aPL-Positive Patients
• Mechanisms of Antiphospholipid Antibody-Associated Disease
• Treatment

Chapter 117. Primary Platelet Disorders

• Introduction
• Thrombocytosis and Ischemic Stroke
• Thrombocytopenia and Ischemic Stroke
• Platelet Disorders and Hemorrhagic Stroke
• Conclusion

Chapter 118. Stroke and Sickle Cell Disease

• Introduction
• Silent Cerebral Infarctions
• Overt Cerebral Ischemic Infarction
• Intracranial Hemorrhage
• Other Neurological Problems
• Conclusion

Chapter 119. Pregnancy, Hormonal Contraception, and Postmenopausal Estrogen Replacement Therapy

• Stroke in Pregnancy
• Hormonal Contraception
• Hormone Replacement Therapy

Chapter 120. Toxicity/Substance Abuse

• Introduction
• Cannabis
• Amphetamines
• Cocaine
• Heroin
• Alcohol
• Cigarettes
• Conclusion

Chapter 121. Functional Disorders Presenting to the Stroke Service

• Introduction
• Etiology
• Diagnosis
• Management
• Prognosis
• Conclusion

Chapter 122. CADASIL

• Introduction
• Clinical Manifestations
• Imaging
• Pathological Data
• Diagnosis
• Treatment

Chapter 123. Stroke and Infection: Tuberculosis, Brucellosis, Syphilis, Lyme Disease and Listeriosis

• Neurosyphilis
• Neurobrucellosis
• Neuroborreliosis
• Neurotuberculosis
• Neuroinvasive Listeriosis

Chapter 124. HIV and Stroke

• Introduction
• Causes of Stroke in HIV Infection
• Cerebral Infections
• Cardiac Embolism
• Prothrombotic States
• Substance Abuse
• HIV-Associated Vasculopathy and Vasculitis
• Small Vessel HIV-Associated Vasculopathy
• Large- and Medium-Vessel HIV-Associated Vasculopathy
• Accelerated Atherosclerosis
• Approach to Stroke Therapy in the HIV-Positive Patient

Chapter 125. Stroke-Induced Immunodepression and Clinical Consequences

• Introduction
• Pathways of Stroke-Induced Immunodepression Syndrome
• Laboratory Markers for Stroke-Induced Immunodepression
• Sense and Nonsense of Stroke-Induced Immunodepression
• Therapeutic Implications
• Conclusions

Chapter 126. Cerebrovascular Complications of Cardiac Surgery

• Background
• Cardiac Surgical Procedures
• Minimally Invasive Cardiac Surgical Procedures
• Percutaneous Cardiac Surgical Procedures
• Mechanism of Stroke in Cardiac Surgery
• Acute Ischemic Stroke Treatment in Cardiac Surgery Patients
• Other Cerebrovascular Complications and Stroke Mimics

Section VIII. Diagnostic Testing

Chapter 127. Clinical Stroke Diagnosis

• Information Used for Stroke Diagnosis
• The Inductive Method—Sequential Hypothesis Generation and Testing and Pattern Matching
• Impact of Various Findings on the “What” Diagnosis
• Localization and Detection of the Vascular Lesion
• Stroke Localization
• Imaging and Laboratory Evaluation

Chapter 128. Cardiac Electrophysiology in Stroke Investigation: Holter, Event Monitor, and Long-Term Monitoring

• Background
• Optimizing Detection
• Relevance of Monitor Findings
• Evaluation
• Summary

Chapter 129. Cardiac Ultrasound in Stroke Investigation

• Major Sources of Emboli
• Imaging Procedures

Chapter 130. Overview of Neuroimaging of Stroke

• Introduction
• Commonly Used Imaging Modalities
• Ischemic Stroke
• Angiographic Assessment of Cerebral Vasculature
• Imaging Utilized for Endovascular Intervention
• Imaging Modalities to Assess Collateral Circulation
• Neuroimaging to Assess Cerebral Perfusion
• Intracerebral Hemorrhage
• Distinct Cases Associated With Ischemia/Infarction

Chapter 131. CT, CT-Angiography, and Perfusion-CT Evaluation of Stroke

• Introduction
• Hemorrhagic Stroke
• Arterio-occlusive Ischemic Stroke
• Veno-occlusive Ischemic Stroke

Chapter 132. MRI and MRA of Ischemic Stroke

• Introduction
• MRI of Brain Ischemia
• Diffusion MRI
• Magnetic Susceptibility Imaging
• FLAIR/T2- and T1-Weighted Imaging
• Contrast-Enhanced T1-Weighted Imaging
• MR Angiography
• Time-of-Flight and Phase-Contrast MRA
• Perfusion MRI
• MR in Acute Ischemic Stroke Triage
• The MGH Stroke Imaging Algorithm
• Conclusions

Chapter 133. Transcranial and Cervical Ultrasound in Stroke

• Introduction
• Transcranial Doppler Ultrasonography
• Cervical Duplex Ultrasonography
• Summary

Chapter 134. Conventional Cerebral Arteriography

• Introduction
• Indications
• Basic Concepts
• Safety
• Present and Future

Chapter 135. Ultrasound Examination of the Aortic Arch in Stroke

• Introduction
• Transesophageal Echocardiography
• Proximal Aortic Atheromas and Ischemic Stroke
• Arch Atheromas and Stroke After Cardiac Surgery or Aortic Procedures
• Considerations on Therapy and Prevention of Recurrent Events

Section IX. Management

Chapter 136. Thrombolysis for Acute Ischemic Stroke

• Intravenous Tissue Plasminogen Activator
• Extended Time Window to 4.5h
• Time to Treatment Effects
• Large Vessel Occlusion Strokes
• Mechanical Thrombectomy
• Conclusions

Chapter 137. General Treatment of Stroke in Intensive Care Setting

• Introduction
• General Critical Care
• Neurocritical Care
• Decompressive Craniectomy

Chapter 138. Physiological Monitoring of Stroke in the Intensive Care Setting

• Noninvasive Monitoring
• Oximetry
• End-Tidal CO₂ Monitoring
• Blood Pressure
• Temperature Management
• Water Hemostasis
• Glycemic Control
• Invasive Monitoring
• Pulmonary Artery Catheterization
• Cerebrovascular Physiology and Intracranial Pressure Monitoring
• Conclusion

Chapter 139. Hypertensive Encephalopathy

• Introduction
• Pathophysiology
• Imaging Characteristics
• Management of Hypertensive Encephalopathy
• Conclusion

Chapter 140. Management of Cerebral Edema/Intracranial Pressure in Ischemic Stroke

• Introduction
• Pathophysiology
• Assessment of Cerebral Edema
• Conclusion

Chapter 141. Surgery for Ischemic Strokes

• Introduction

Chapter 142. Clinical Status of Neuroprotection in Cerebral Ischemia

• Introduction
• Primary Stroke Prevention During Interventions
• Penumbra Salvage
• Prevention of Secondary Brain Injury
• Neuroprotection From Vasospasm-Related Ischemia
• Conclusion

Chapter 143. Cardiac Complications and ECG Abnormalities After Stroke

• Introduction
• Ischemia and Heart Failure
• ECG Abnormalities and Arrhythmias
• Summary

Chapter 144. Management of Hypertension in Stroke

• Introduction
• Management of Hypertension in the Acute Stroke Period
• Management of Chronic Hypertension in Patients With Cerebrovascular Disease

Chapter 145. Management of Diabetes in Stroke

• Introduction
• Diabetes as a Risk Factor for Stroke
• Pathophysiology of Stroke in Diabetes
• Diabetes and Stroke Outcomes
• Management

Chapter 146. Management of Atrial Fibrillation

• Frequency and Pathogenesis
• The Role of Echocardiography in Estimating Stroke Risk
• Ischemic Stroke Risk Factors and Bleeding Risk
• Antithrombotic Strategies for Stroke Prevention
• Evaluation and Management of Patients With Ischemic Stroke
• Summary

Chapter 147. Depression, Psychosis, and Agitation in Stroke

• Introduction
• Poststroke Depression
• Poststroke Psychosis
• Poststroke Anxiety and Agitation
• Summary

Chapter 148. Treatment of Vasculitis

• Introduction
• Large-Vessel Vasculitis
• Medium-Vessel Vasculitis
• Small-Vessel Vasculitis
• Variable Vessel Vasculitis
• Single-Organ Vasculitis
• Vasculitis Associated With Systemic Disease

Chapter 149. Endovascular Therapy for the Treatment of Cerebrovascular Disease

• Introduction
• Stroke
• Intracranial Aneurysms
• Intracranial Arteriovenous Malformations
• Conclusion

Chapter 150. Surgery for Ischemic Infarcts

• Introduction
• Malignant MCA Stroke
• Cerebellar Stroke

Chapter 151. Carotid Endarterectomy and Carotid Angioplasty and Stenting

• Introduction
• Carotid Endarterectomy
• Carotid Angioplasty and Stenting
• Carotid Endarterectomy or Carotid Angioplasty and Stenting

Chapter 152. Management of Asymptomatic Extracranial Carotid Artery Disease

• Introduction
• Epidemiology
• Revascularization
• Official Guidelines and Current Status of Practice
• Subgroup Analyses, Pitfalls, and Other Limitations of Published Randomized CEA Trials in ACS
• Risk Stratification: Identifying Patients at High Risk
• Conclusion
• List of Commonly Used Abbreviations

Chapter 153. Management of Cerebellar Hematomas and Infarcts

• Cerebellar Hemorrhage
• Diagnosis
• Treatment
• Cerebellar Infarction

Chapter 154. Surgical and Endovascular Management of Ruptured Posterior Circulation Aneurysms

• Introduction
• Presentation and Diagnosis
• Natural History
• Treatment Options
• Surgical Approaches
• Endovascular Treatments
• Endovascular Technique
• Stent-Assisted Coiling
• Balloon Remodeling
• Flow Diversion
• Multidisciplinary Approaches
• Clip Versus Coiling

Chapter 155. Surgical and Endovascular Management of Patients With Unruptured Aneurysm

• Introduction
• Epidemiology
• Clinical Presentation
• Imaging
• Risk Factors for Rupture
• Management
• Follow-Up

Chapter 156. Surgical and Endovascular Management of Patients With Giant Cerebral Aneurysms

• Introduction
• Microsurgery
• Endovascular Surgery
• Conclusion

Chapter 157. Surgical and Endovascular Management of Aneurysms in the Pediatric Age Group

• Introduction
• Epidemiology and Pathophysiology
• Presentation and Evaluation
• Treatment and Surgical/Endovascular Indications
• Initial Management of Ruptured Aneurysm Cases (Surgical and Endovascular)
• Complications
• Posttreatment Care and Follow-Up
• Outcomes
• Common Clinical Questions
• Conclusions

Chapter 158. Surgical Management of Pituitary Apoplexy

• Introduction
• Pathophysiology
• Clinical Presentation
• Management
• Surgical Technique
• Postoperative Management and Outcome
• Conclusion

Chapter 159. Surgical and Endovascular Management of Acutely Ruptured Arteriovenous Malformations

• Introduction
• AVM Grading Systems
• Microsurgical Resection
• Endovascular Embolization
• Stereotactic Radiosurgery
• Conclusions

Chapter 160. Surgical and Endovascular Management of Unruptured Arteriovenous Malformations

• Introduction
• Epidemiology and Natural History
• Management
• Conclusions

Chapter 161. Surgical and Endovascular Management of Vertebrobasilar Atherosclerosis

• Introduction
• General Features of Vertebrobasilar Atherosclerosis
• Management of Vertebrobasilar Atherosclerosis
• Endovascular Revascularization
• Microsurgical Revascularization
• Conclusion

Chapter 162. Extracranial–Intracranial Bypass Procedures

• Introduction
• EC–IC Bypass for Flow Replacement
• EC–IC Bypass for Flow Augmentation
• Conclusion

Chapter 163. Surgical Aspects of Moyamoya Disease

• Surgical Management
• Operative Technique: Direct STA–MCA Bypass
• Indirect Bypass Technique
• Operative Results
• Conclusion

Chapter 164. Prevention of Ischemic Stroke

• Introduction
• AHA/ASA Guideline Recommendations for Management of Lifestyle and Vascular Risks for Ischemic Stroke Prevention
• AHA/ASA Guideline Recommendations for Management of Antithrombotics, Oral Anticoagulants, PFO Closure and Related Surgery, Carotid Endarterectomy, and Prevention
• Conclusion

Chapter 165. Management of Lipid Metabolism

• Introduction
• Pathophysiology of Lipid Metabolism in Cerebrovascular Disease
• Lipids and Atherosclerosis and Their Interaction With Other Risk Factors
• Recommendation for Prevention and Treatment of Lipid-Associated Cerebrovascular Disease

Chapter 166. Antiplatelet Agents: Mechanisms and Their Role in Stroke Prevention

• Introduction
• Pathogenesis of Stroke and Contributing Disease States
• Antiplatelet Agents: Mechanisms and Role in Stroke Prevention

Chapter 167. Anticoagulants in Stroke Treatment

• Introduction
• Anticoagulants for Secondary Stroke Prevention
• Ischemic Stroke
• Initiation and Discontinuation of Anticoagulation After Stroke
• Anticoagulation: Intracranial Hemorrhage and Microbleeds

Chapter 168. Rehabilitation for Disabling Stroke

• Scientific Bases
• Rehabilitation Outcome Measures
• Stages of Rehabilitation
• Specific Interventions
• Conclusion

Chapter 169. Magnetic and Direct Current Stimulation for Stroke

• Introduction
• Historical Background
• Brain Plasticity in Stroke
• Transcranial Magnetic Stimulation
• Repetitive TMS
• Transcranial Direct Current Stimulation
• Safety Considerations for NIBS
• Limitations of NIBS
• Future Directions

Chapter 170. Management of Aneurysms and Vascular Malformations During Pregnancy and Puerperium

• Neurosurgical Procedures During Pregnancy
• Radiation Exposure
• Recommendations for the Management of Vascular Malformations
• Conclusion