Stroke Revisited: Pathophysiology of Stroke: From Bench to Bedside

Preface
Acknowledgment
Contents
Editors and Contributors
	Editor
	Associate Editor
	Contributors
Part I: Introduction on Stroke
	1: General Facts of Stroke
		1.1	 Introduction
		1.2	 Burden of Stroke
		1.3	 Epidemiologic Differences According to the Region and Sex
		1.4	 Definition of Stroke
		1.5	 Classification of Stroke
		1.6	 Conclusion
		References
	2: Cerebral Vascular Anatomy
		2.1	 Introduction
		2.2	 Internal Carotid Artery
			2.2.1	 Segments of the ICA
				2.2.1.1	 Cervical Segment
				2.2.1.2	 Petrous Segment
				2.2.1.3	 Lacerum Segment
				2.2.1.4	 Cavernous Segment
				2.2.1.5	 Clinoidal Segment
				2.2.1.6	 Ophthalmic Segment
				2.2.1.7	 Communicating Segment
			2.2.2	 Anatomic Variants of the ICA
			2.2.3	 Carotid-Basilar Anastomoses
		2.3	 Anterior Cerebral Artery
			2.3.1	 Perforating Branches
			2.3.2	 Cortical Branches
			2.3.3	 Anomalies of the ACA
		2.4	 Middle Cerebral Artery
			2.4.1	 Perforating Branches
			2.4.2	 Cortical Branches
			2.4.3	 Anomalies of the MCA
		2.5	 Posterior Cerebral Artery
			2.5.1	 Perforating Branches
			2.5.2	 Ventricular Branches
			2.5.3	 Cortical Branches
		2.6	 Basilar Artery
			2.6.1	 Cerebellar Branches
			2.6.2	 Perforating Branches
		2.7	 Vertebral Artery
			2.7.1	 Intracranial Branches
		2.8	 External Carotid Artery
			2.8.1	 Superior Thyroid Artery
			2.8.2	 Ascending Pharyngeal Artery
			2.8.3	 Lingual Artery
			2.8.4	 Facial Artery
			2.8.5	 Occipital Artery
			2.8.6	 Posterior Auricular Artery
			2.8.7	 Superficial Temporal Artery
			2.8.8	 Internal Maxillary Artery
		References
Part II: Clinical Science: Large Artery Atherothrombosis
	3: Concept of Large Artery and Small Vessel
		3.1	 Histological Classification of Arteries
		3.2	 Differentiation of Large Arteries and Small Vessels
		3.3	 Conclusions
		References
	4: Pathophysiology of Large-Artery Atherosclerosis
		4.1	 Atherosclerosis: A General Concept
			4.1.1	 Formation of Atherosclerosis
			4.1.2	 Classification of Atherosclerosis
				4.1.2.1	 Plaque Rupture
				4.1.2.2	 Plaque Erosion
				4.1.2.3	 Calcified Nodule
		4.2	 Large Artery Atherosclerosis: Intracranial Versus Extracranial
			4.2.1	 Epidemiology of Intracranial Atherosclerosis
			4.2.2	 Histologic Comparisons of Normal Arteries
			4.2.3	 Pathologic Comparisons of Atherosclerosis
		4.3	 Thrombus Formation in Large Artery Atherosclerosis
			4.3.1	 The Formation of Platelet Thrombus
				4.3.1.1	 Two Independent Pathways for Platelet Activation
				4.3.1.2	 Thrombus Propagation
			4.3.2	 Blood Coagulation
				4.3.2.1	 Contact Activation Pathway (Intrinsic Pathway)
				4.3.2.2	 TF Pathway (Extrinsic Pathway)
				4.3.2.3	 Common Pathway
				4.3.2.4	 Cofactors and Modulators
		4.4	 Conclusions
		References
	5: Pathophysiology of Stroke Resulting from Large-Artery Atherothrombosis
		5.1	 Introduction
		5.2	 Territorial Infarct
		5.3	 In Situ Thrombosis and Artery-to-Artery Embolism
		5.4	 Hemodynamic (Watershed) Infarction
		5.5	 Branch Atheromatous Disease
		References
Part III: Clinical Science: Small Vessel Disease
	6: Cerebral Small Vessel Disease
		6.1	 Underlying Pathologic Findings: Arteriolosclerosis
			6.1.1	 Lipohyalinosis
			6.1.2	 Microatheroma
			6.1.3	 Microaneurysm
			6.1.4	 Fibrinoid Necrosis
			6.1.5	 Is Arteriosclerosis Found Only in the Brain?
		6.2	 Clinical Manifestations of Small Vessel Disease
			6.2.1	 Lesions Identified by Acute Stroke Symptoms
				6.2.1.1	 Lacunar Infarction
				6.2.1.2	 ICH
				6.2.1.3	 Cerebral Microinfarct (Fig. 6.4e)
			6.2.2	 Lesions Found on Brain Imaging Without Acute Stroke Symptoms
				6.2.2.1	 Lacunes
				6.2.2.2	 WMHs
				6.2.2.3	 Microbleeds
				6.2.2.4	 ePVS
		6.3	 Risk Factors
		6.4	 Pathophysiology of SVD
		6.5	 Therapeutic Perspectives and Conclusion
		References
	7: Cerebral Amyloid Angiopathy: Emerging Evidence for Novel Pathophysiology and Pathogenesis
		7.1	 Introduction
		7.2	 Sporadic Aβ-Type CAA: General Aspects
			7.2.1	 Pathology, Pathogenesis, and Pathophysiology
			7.2.2	 Risk Factors
			7.2.3	 CAA-Related Cerebrovascular Disorders
				7.2.3.1	 Hemorrhagic Disorders
				7.2.3.2	 Ischemic Disorders
			7.2.4	 Biomarkers and Diagnosis
				7.2.4.1	 Biomarkers
				7.2.4.2	 Diagnosis
		7.3	 CAA-Related Cognitive Impairment and Neurodegeneration
			7.3.1	 Dementia Incidence in Non-demented Patients with CAA
			7.3.2	 CAA in Patients with Alzheimer’s Disease or Cognitive Impairment
			7.3.3	 Pathological Studies of Dementia and Cognitive Impairment in CAA
			7.3.4	 CAA-Related Neurodegeneration
		7.4	 CAA-Related Inflammation and Aβ Immunotherapies for AD and CAA
			7.4.1	 CAA-Related Inflammation
			7.4.2	 Aβ Immunotherapies for AD and CAA
		7.5	 Transmission of Aβ Pathology and CAA
		7.6	 Future Perspectives
		References
	8: Cerebral Autosomal Dominant Arteriopathy with Subcortical Ischemic Strokes and Leukoencephalopathy (CADASIL)
		8.1	 Molecular Genetic Analysis
		8.2	 Clinical Presentation
			8.2.1	 Subcortical Ischemic Stroke
			8.2.2	 Intracerebral Hemorrhagic Stroke
			8.2.3	 Migraine
			8.2.4	 Cognitive Impairment
			8.2.5	 Other Clinical Manifestations
		8.3	 Neuroimaging
		8.4	 Characteristic Differences Between Caucasians and Asians
		8.5	 Cystein Sparing CADASIL Mutations
		8.6	 Treatment
		References
Part IV: Clinical Science: Cardioembolism
	9: Pathophysiology of Cardioembolism
		9.1	 Introduction
		9.2	 Mechanism of Thrombus Formation in CE
			9.2.1	 Platelet Aggregation
			9.2.2	 Coagulation Cascade
				9.2.2.1	 Contact Activation Pathway (Intrinsic Pathway)
				9.2.2.2	 Tissue Factor Pathway (Extrinsic Pathway)
			9.2.3	 Other Factors Involved in Blood Coagulation
			9.2.4	 Blood Coagulation and CE
		9.3	 Features of CE
		9.4	 Noteworthy CE Points
		9.5	 Conclusions
		References
	10: Atrial Fibrillation and Other Cardiac Dysfunctions Related with Stroke
		10.1	 Introduction
		10.2	 Diagnosis and Treatment of Stroke Patients with AF
			10.2.1	 Stepwise Diagnostic Approach to Detect AF in Stroke Patients
				10.2.1.1	 Initial Step: History Taking
				10.2.1.2	 Second Step: Suspecting Stroke with AF
				10.2.1.3	 Third Step: Baseline ECG, Telemonitoring, 24-h Holter Monitoring, and Long-Term Monitoring
			10.2.2	 Neuroimage and Blood Biomarkers of AF-Related Stroke
				10.2.2.1	 Imaging Biomarkers
				10.2.2.2	 Blood Biomarkers of Cardioembolic Stroke and AF-Related Stroke
			10.2.3	 Risk Assessment and Treatment of AF-Associated Stroke
				10.2.3.1	 Risk Assessment
				10.2.3.2	 Antithrombotic Treatment for Stroke Patients with Atrial Fibrillation
					Vitamin K Antagonist Versus NOACs
					Timing of OAC Therapy Initiation
					Optimal Dose or Intensity of Anticoagulants
				10.2.3.3	 Non-OAC Treatment for Stroke with AF
		10.3	 Patent Foramen Ovale and Other Stroke-Related Cardiac Diseases
		References
Part V: Clinical Science: Pathophysiology of Specific Causes
	11: Cerebral Vessel Wall Diseases
		11.1	 Introduction
		11.2	 Anatomy of the Cerebral Vessel Wall
			11.2.1	 Common Arterial Structure
			11.2.2	 Characteristics of the Intracranial Arteries
			11.2.3	 Embryological Origins of Cerebral Smooth Muscle Cells
		11.3	 Common Pathway for Cerebral Vessel Wall Disease
			11.3.1	 Endothelial Dysfunction
			11.3.2	 Phenotypic Switching of Smooth Muscle Cells
			11.3.3	 Extracellular Matrix Degradation
			11.3.4	 Inflammation
			11.3.5	 Hemodynamic Change on the Wall
		11.4	 Pathophysiology of Cerebral Vessel Wall Diseases
			11.4.1	 Moyamoya Disease
			11.4.2	 Cerebral Artery Dissection
			11.4.3	 Primary Central Nervous System Vasculitis
		11.5	 Future Directions
		References
	12: Hemorrheologic Disease
		12.1	 Antiphospholipid Syndrome
			12.1.1	 Epidemiology of APS
			12.1.2	 Pathophysiology of APS
			12.1.3	 Diagnosis of APS
			12.1.4	 Treatment of APS Treatment
		12.2	 Cancer-Related Stroke
			12.2.1	 Epidemiology of Cancer-Related Stroke
			12.2.2	 Pathophysiology of Cancer-Related Stroke
			12.2.3	 Diagnosis of Cancer-Related Stroke
			12.2.4	 Treatment of Cancer-Related Stroke
		12.3	 Cerebral Venous Thrombosis
			12.3.1	 Epidemiology of CVT
			12.3.2	 Pathophysiology of CVT
			12.3.3	 Diagnosis of CVT
			12.3.4	 Treatment of CVT
		12.4	 Other Hypercoagulability-Related Conditions
			12.4.1	 Myeloproliferative Disorder
			12.4.2	 Pregnancy-Related Stroke
			12.4.3	 Oral Contraceptives and Hormonal Therapy
		References
	13: Paradoxical Embolic Stroke
		13.1	 Paradoxical Embolism
		13.2	 Source of Embolus
		13.3	 Right-to-Left Shunt
			13.3.1	 Patent Foramen Ovale
			13.3.2	 Atrial Septal Defect and Other Intracardiac Shunt
			13.3.3	 Pulmonary Arteriovenous Malformation, Extracardiac Shunt
		13.4	 Diagnosis
			13.4.1	 Brain Image
			13.4.2	 Study for Shunt
		13.5	 Treatment and Prevention for Paradoxical Embolism
			13.5.1	 Patent Foramen Ovale
			13.5.2	 Arterial Septal Defect and Ventricular Septal Defect
			13.5.3	 Pulmonary Arteriovenous Malformation
			13.5.4	 Antiplatelet or Anticoagulation for Paradoxical Embolization
		References
	14: Hemorrhagic Diseases
		14.1	 Intracerebral Hemorrhage
			14.1.1	 Epidemiology
			14.1.2	 Classification
			14.1.3	 Pathophysiology
				14.1.3.1	 Hypertensive Vascular Change
				14.1.3.2	 Cerebral Amyloid Angiopathy (CAA)
			14.1.4	 Risk Factors
			14.1.5	 Diagnosis and Imaging
			14.1.6	 Clinical Manifestation
			14.1.7	 Management
				14.1.7.1	 Emergent Management and Prevention of Hematoma Expansion
				14.1.7.2	 Management of Hypertension
				14.1.7.3	 Reversal Strategies for Vitamin K Antagonists
				14.1.7.4	 Reversal of Non-vitamin K Antagonist Oral Anticoagulants (NOACs)
				14.1.7.5	 Reversal of Antiplatelets
				14.1.7.6	 Management of IVH
				14.1.7.7	 Surgical Intervention
				14.1.7.8	 Critical Care of Intracerebral Hemorrhage
				14.1.7.9	 Prognosis and Outcomes
		14.2	 Subarachnoid Hemorrhage
			14.2.1	 Epidemiology
			14.2.2	 Clinical Manifestations
			14.2.3	 Grading Scales Used with Aneurysmal SAH
			14.2.4	 Diagnostic Evaluation
			14.2.5	 Management
				14.2.5.1	 Management Prior to Secure of the Ruptured Aneurysm
					Seizure; Antiepileptic Drugs
					Hypertension
					Antifibrinolytic Therapy
					Other Medical Management
				14.2.5.2	 Securing the Ruptured Aneurysm
					External Ventricular Drainage
					Microsurgical Clipping
					Endovascular Treatment
				14.2.5.3	 Management After Securing the Ruptured Aneurysm
					Cerebral Edema
					Vasospasm and Delayed Cerebral Ischemia
					Hydrocephalus
					Medical Complication
				14.2.5.4	 Guidelines
		14.3	 Cerebral Arteriovenous Malformation
			14.3.1	 Etiology
			14.3.2	 Epidemiology and Presentation
			14.3.3	 Risk of Hemorrhage of Untreated AVMs
			14.3.4	 Radiologic Findings
			14.3.5	 Classification
			14.3.6	 Treatment
				14.3.6.1	 Observation
				14.3.6.2	 Embolization
				14.3.6.3	 Microsurgical Resection
				14.3.6.4	 Stereotactic Radiosurgery
		14.4	 Cerebral Dural Arteriovenous Fistula
			14.4.1	 Epidemiology and Pathophysiology
			14.4.2	 Imaging and Classification
			14.4.3	 Clinical Manifestations
			14.4.4	 Natural History
			14.4.5	 Treatment
		References
Part VI: Brain Hemodynamics
	15: Brain Hemodynamics
		15.1	 Hemodynamics of Cerebral Blood Flow
			15.1.1	 Normal Hemodynamics and Autoregulation
			15.1.2	 Hemodynamic Failure in Cerebrovascular Disease
			15.1.3	 Collateral Circulation
			15.1.4	 Venous Hemodynamics
		15.2	 Measurement of Cerebral Blood Flow: Brain SPECT, PET, MRI, and CT
			15.2.1	 SPECT and PET
			15.2.2	 Perfusion MRI and CT
			15.2.3	 Measuring Core and Penumbra
		15.3	 Core and Penumbra
		15.4	 Conclusions
		References
Part VII: Basic Aspect: Cell Death and Neurorepair
	16: Pathophysiology of Neuronal Cell Death After Stroke
		16.1	 General Principles of Cell Death Mechanisms: Necrosis, Necroptosis, Apoptosis, and Autophagy
		16.2	 Mechanism of Cell Death Caused by Ischemic Stroke Versus Hemorrhagic Stroke
		16.3	 Excitotoxic Cell Death
		16.4	 Apoptosis Induced by Stroke
		16.5	 Free Radicals as a Therapeutic Target
		16.6	 Conclusion
		References
	17: Emerging Mechanism of Cell Death Caused by Stroke: A Role of Neurovascular Unit
		17.1	 Introduction
		17.2	 The Neurovascular Unit (NVU) and Its Components
			17.2.1	 Neurons
			17.2.2	 Vascular Endothelial Cells
			17.2.3	 Astrocytes
			17.2.4	 Pericytes
			17.2.5	 Microglia
			17.2.6	 Oligodendrocytes
			17.2.7	 Basement Membranes
		17.3	 Stroke Pathophysiology and NVU
			17.3.1	 NVU Dysfunction in Acute Phase of Stroke
			17.3.2	 NVU Remodeling in Chronic Phase of Stroke
		17.4	 White Matter Injury
		17.5	 Conclusions
		References
	18: Basic Aspect: Neurorepair After Stroke
		18.1	 Stem Cell Biology and Endogenous Neurogenesis in Brain
			18.1.1	 Stem Cell Biology: General Principles
				18.1.1.1	 Tracking Cell Generation
			18.1.2	 Endogenous Neurogenesis
				18.1.2.1	 Stem Cells in Brain Development and Adulthood
				18.1.2.2	 Molecular Basis for Self-Renewal and Fate Determination of NSCs
				18.1.2.3	 Neurogenesis in the Injured Brain
				18.1.2.4	 Stimulating Endogenous Neurogenesis After Stroke
				18.1.2.5	 Therapeutic Implications of Endogenous Neurogenesis
		18.2	 Conclusion
		References
	19: Mechanism of Recovery After Stroke
		19.1	 Plasticity of the Brain After Stroke
		19.2	 Regeneration of the Brain After Stroke
		19.3	 Conclusions
		References
	20: Neurorepair Strategies After Stroke
		20.1	 Introduction
		20.2	 Experimental Rehabilitation
			20.2.1	 Enriched Environment
			20.2.2	 Forced Physical Training Versus Voluntary Physical Exercise
			20.2.3	 Constraint-Induced Movement Therapy
			20.2.4	 Skilled Forelimb Use
		20.3	 Stem Cell Transplantation
		20.4	 Pharmacotherapies
			20.4.1	 Noradrenergic Pharmacotherapy
			20.4.2	 Selective Serotonin Reuptake Inhibitors
			20.4.3	 Other Drugs
		20.5	 Other Neurorepair Strategies
		20.6	 Conclusions and Future Perspectives
		References