Ischemic Stroke Therapeutics: A Comprehensive Guide

Preface
Contents
Part I: Acute Therapeutics
	1: Prehospital Stroke Care
		Prehospital Stroke Management
		911 Activation
		Prehospital Stroke Assessment
		Prehospital Transport
		Prehospital to Emergency Department Transition in Stroke Management
		Interhospital Transfers
		Future of Prehospital Stroke Care
		Case Presentation: EMS Stroke Evaluation and Triage from Activation to Treatment
		Summary
		References
	2: Neuroprotectants
		Introduction
		Pathophysiology and Mechanisms of Ischemic Injury
			Bioenergetic Failure Initiates the Ischemic Cascade
			Excitotoxicity
			Oxidative Stress
			Regulated Neuronal Death
			Inflammation
		Stroke Trials of Neuroprotective Strategies: Mechanistic Perspectives and Insights
			Mitigating Bioenergetic Failure
			Dampening Excitotoxicity
			Antioxidant Therapies
			Immunomodulatory Therapies
		Prospects for the Future of Neuroprotection
			Reviving Prior Failed Neuroprotectant Therapeutics for Intra-Arterial Stroke Therapies
			Bridging the Basic and Clinical Science Divide with Precision Neuromonitoring and Biomarkers
			Building the Case for Rational Combinations of Neuroprotective Therapies in Preclinical Models
		Conclusion
		References
	3: Acute Blood Pressure Management
		Introduction
		Blood Pressure After an Acute Ischemic Stroke: Pathophysiology
		Association of Blood Pressure Levels with Clinical Outcomes
		Blood Pressure Management
			Blood Pressure Management in the Prehospital Setting
			Blood Pressure Management in Patients Not Receiving Acute Reperfusion Therapies
			Blood Pressure Management in Patients Eligible for Intravenous Thrombolysis
			Blood Pressure Management in Patients Eligible for Mechanical Thrombectomy
		Conclusions
		References
	4: Intravenous Thrombolysis
		Case Vignette
		Introduction
		Rationale for IV Thrombolysis
		Evidence of Efficacy
			Recombinant Tissue Plasminogen Activator (rtPA)
				0–3 H
				3–4.5 H
				0–6 H
				4.5–9 H and Wake-Up Stroke
				Dose Conundrum: 0.6 mg/kg Vs. 0.9 mg/kg
			Tenecteplase
			Other IV Thrombolytics
				Streptokinase
				Desmoteplase
			Thrombolysis in Stroke Ambulance
			Minor Stroke
			Adjunct Therapies with Thrombolysis
				Antithrombotics
				Matrix Metalloprotease Inhibitor
				Remote Ischemic Conditioning
			Bridging Therapy (IV Thrombolysis + EVT) Vs. Direct EVT, Where Are We Headed?
		Practical Steps for IV Thrombolysis
			Pre-Thrombolysis
			Peri-Thrombolysis
			Post-Thrombolysis
		Practical Considerations
			Anterior Vs. Posterior Circulation Strokes
			Etiology of Ischemic Stroke
			Pregnancy
			Patients on Anticoagulation
			Intracranial Aneurysms and Vascular Malformation
		Conclusions
		References
	5: Endovascular Therapy for Acute Ischemic Stroke
		Introduction
		The Basis of EVT for AIS
		Development of Devices for EVT
			Development and Approval of New Devices
			Fibrinolytics
			MERCI Retrievers
			Suction Thrombectomy System
			Retrievable Stents
			Future Directions: The First-Pass Effect
		Clinical Evidence for EVT
			Early Window Trials
			Extended Time Window Trials
			Current Guidelines for Endovascular Therapy
			Posterior Circulation Occlusions
			Large Infarct Volume at Baseline
		Patient Triage and Selection
		Workflows from Onset to Treatment
			Time from Onset to Door
			Time from Door to EVT
			Procedural Time
		Summary and Future Perspectives
		References
	6: Advanced Imaging for Extended Window Stroke Therapy
		Introduction
		Stroke Time Window Definitions
		Intravenous Thrombolysis
			Early Time Window Treatment
			Extended Time Window Treatment
			Intravenous Thrombolysis AIS Treatment Summary
		Endovascular Thrombectomy
			Early Time Window Treatment
			Extended Time Window Treatment
		Uncertainty Beyond 24 Hours
		Conclusions
		References
	7: Acute Antithrombotic Therapy
		Introduction
		Aspirin
		Clopidogrel
			Chronic Clopidogrel Therapy
			Chronic Clopidogrel-Aspirin Therapy
			Acute Clopidogrel-Aspirin Therapy
			Optimal Duration of Acute Clopidogrel-Aspirin Therapy
			The Time Course of Benefit for Starting DAPT in POINT
			Clopidogrel and CYP2C19 Loss-of-Function Alleles
		Ticagrelor
			Acute Ticagrelor Monotherapy
			Acute Ticagrelor-Aspirin Therapy
		Dipyridamole
		Cilostazol
		Acute Anticoagulation
		Future Directions
		References
	8: Decompressive Hemicraniectomy and Suboccipital Craniectomy for Acute Ischemic Stroke
		Introduction
		Pathophysiology
		Clinical Presentation
		Radiologic Findings
		Timing of Surgery
		Surgical Technique of Decompressive Hemicraniectomy
		Complications
		Outcomes of Decompressive Hemicraniectomy
		Factors to Consider Before Hemicraniectomy
		Suboccipital Decompressive Craniectomy
		Current Recommendations
		Conclusion
		References
	9: Supportive Care and Management of Inhospital Complications
		Triage of the Patient with Acute Stroke
		Supporting the Ischemic Penumbra
		“Neuroworsening”
		Cerebral Edema
		Reperfusion Injury and Hemorrhagic Transformation
		Seizures and Epilepsy
		Psychiatric Complications of Stroke
			Depression
			Delirium
		Cardiovascular Management of Stroke Patients
			Blood Pressure Control
			Hypotension
			Atrial Fibrillation/Flutter
			Myocardial Ischemia
		Respiratory Management of Stroke Patients
			Oxygen and Ventilation
			Stroke-Associated Pneumonia
		Nutrition for Stroke Patients
			Nutritional Requirements While Hospitalized
			Long-Term Nutrition
		Fluid and Electrolyte Management in Stroke Patients
			Intravenous Fluids and Electrolytes
			Acute Renal Insufficiency
			Chronic Renal Disease
		Infections and the Inflammatory Response in Stroke Patients
			Fever
			Infections
		Hematologic Considerations for Stroke Patients
		Glucose Management in Stroke Patients
			Hypoglycemia
			Hyperglycemia
		Prophylaxis in Stroke Patients
			Deep Vein Thrombosis
			Stress Ulcer Prevention
			Decubitus Ulcers
		Summary
		References
	10: Postdischarge Complications of Stroke
		Introduction
		Fatigue
		Depression
		Seizures
		Sleep-Related Disorders
		Pain and Spasticity
		Other Poststroke Complications
		Conclusion
		References
Part II: Primary Prevention Therapeutics
	11: “Management of Emerging or Unconventional Risk Factors”
		Introduction
		Cancer
			Cancer Is Both a Risk Factor and an Emerging Stroke Subtype
			Anticoagulation Therapies to Control Cancer-Associated Coagulopathy
			Summary and Perspectives
		Infectious and Inflammatory Diseases
			Infection Is a Risk Factor and Can Directly Cause Acute Ischemic Stroke
			Inflammation Is a Risk Factor for Atherosclerosis and Stroke
			Summary and Perspectives
		Sleep Disorders
			Sleep Disorders Are a Prevalent Risk Factor for Ischemic Stroke
			CPAP May Reduce Stroke Risk
			Summary and Perspectives
		Air Pollution
			Air Pollution Is Both a Risk Factor and a Triggering Factor for Ischemic Stroke
			Individual, Regional, and International Effects to Reduce Air Pollution-Related Health Problems
			Summary and Perspectives
		Conclusion
		References
	12: “Management of Emerging or Unconventional Risk Factors-2”
		Chronic Kidney Disease and Stroke
		Diet, Nutrition, Obesity, and Stroke
			Diet and Nutrition
				Specific Nutrients
				Individual Foods
				Dietary Pattern
			Obesity
			Metabolic Syndrome
		Stroke with Genetic Etiologies
			Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
			Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL)
			HTRA1-Autosomal Dominant Disease (HTRA1-AD)
			Retinal Vasculopathy with Cerebral Leukodystrophy and Systemic Manifestations (RVCL-S)
			COL4A1/COL4A2-Associated Syndromes
			Pontine Autosomal Dominant Micro Angiopathy with Leukoencephalopathy (PADMAL)
			Cathepsin-A-Related Arteriopathy with Strokes and Leukoencephalopathy (CARASAL)
			Fabry Disease
		References
	13: Asymptomatic Carotid Artery Stenosis
		Prevalence of Asymptomatic Carotid Artery Stenosis
		Pathophysiology of the Asymptomatic Carotid Plaque
		Clinical Manifestations of Asymptomatic Carotid Stenosis
		Modalities for Detection of Carotid Artery Stenosis
		Prognosis and Treatment of Asymptomatic Carotid Stenosis
		References
Part III: Secondary Prevention Therapeutics
	14: Tailored Approach to Secondary Prevention After Stroke
		Introduction
			Small Vessel Occlusive Ischemic Strokes
			Evidence for Approach
				Antithrombotic Therapy
				Blood Pressure Control
			Cardioembolic Ischemic Strokes
			Evidence for Approach
				Anticoagulant Therapy or Antiplatelet Therapy
				DOACs for Secondary Prevention in Stroke or TIA Patients with AF
				Clinical Applications
				Approach to Antithrombotic Therapy for Other Causes of Cardioembolic Ischemic Strokes
				Approach to Antithrombotic Therapy for Embolic Strokes of Undetermined Source (ESUS)
		Large Artery Atherosclerotic Ischemic Strokes
			Extracranial Disease
				Carotid Endarterectomy (CEA) Versus Best Medical Therapy
				Carotid Endarterectomy (CEA) Versus Carotid Artery Stenting (CAS) for Symptomatic Carotid Disease
				Carotid Endarterectomy (CEA) Versus Carotid Artery Stenting (CAS) for Asymptomatic Carotid Disease
				Intensive Reduction in LDL Cholesterol after Ischemic Stroke
			Intracranial Atherosclerotic Disease (ICAD)
				Best Medical Therapy Versus Interventional Approaches
				Antithrombotic Therapy
				Risk Factor Management
			Strokes from Dissection
		Conclusion
		References
	15: Antithrombotic Therapy for Heterogeneous Causes of Stroke
		Introduction
		Principles of Antithrombotic Pharmacotherapy
		Antiplatelet Agents Used in the Secondary Prevention of Stroke/Transient Ischemic Attacks (TIA)
			Aspirin
			Clopidogrel
			Dipyridamole and Aspirin Plus Dipyridamole (DP-ASA)
			Cilostazol
			Ticlopidine
			Triflusal
			Sarpogrelate
		Mono, Dual, and Triple Therapy
		Laboratory Assessment of Antithrombotic Therapies
		Recommendations
			Acute Ischemic Stroke
			Secondary Prevention
			Secondary Prevention for Patients with Associated Hemorrhage (Intracranial or Other)
			Secondary Prevention for Patients on Antithrombotics Requiring Routine or Emergent Surgery
			Antiplatelet Agents and Cerebral Microbleeds
			Ischemic Stroke in the Setting of SARS-COV2 (COVID19) Infection
		Conclusion
		References
	16: Subclinical Vascular Brain Injury
		Introduction
		Epidemiology
		Pathophysiology
		Clinical Manifestations
		Diagnosis
		Clinical Implications and Management
		Case Presentation 1: An Ischemic Stroke Patient with Atrial Fibrillation and Cerebral Microbleeds
			Details of the Case
		Case Presentation 2: Incidentally Discovered Silent Lacunes and White Matter Hyperintensity
			Details of the Case
		Case Presentation 3: A Patient with Cognitive Impairment and Previously Unrecognized Vascular Brain Injury
			Details of the Case
		Conclusions
		References
	17: Secondary Prevention After Cardioembolic Stroke
		Patient Case
		Epidemiology
		Clinical and Radiographic Features
		Diagnostic Approach to Cardioembolic Stroke
		Atrial Fibrillation
		Antithrombotic Therapy for Stroke Prevention with AF
		Ischemic Cardiomyopathy
		Heart Failure and Reduced Left Ventricular Pump Function
		Patent Foramen Ovale
		Aortic Arch Atherosclerosis
		Valvular Disease
		Cardiac Tumors
		Left Atrial Cardiopathy
		Other Arrhythmia
		Summary
		References
	18: Secondary Prevention of Lacunar Stroke
		Introduction
			Definitions
			Clinical Features
			Pathophysiology and Therapeutic Implications
		Vascular Risk Factor Control in Patients with Previous Lacunar Stroke
			Blood Pressure Control
			Lipid Control
			Antiplatelet Therapy
			Anticoagulation Therapy
			Carotid Disease and Endarterectomy
		Conclusions and Future Directions
		References
	19: Symptomatic Extracranial Large Artery Disease
		Introduction
		Atherosclerotic Stenosis
			Symptomatic Carotid Stenosis
			Endarterectomy Versus Stenting
			Symptomatic, Non-Stenotic Carotid Atherosclerosis (SNSCA)
			Carotid Artery Occlusion
		Carotid Web Disease
		Cervical–Extracranial Artery Dissection
		Vasculitis
			Giant Cell Arteritis
			Takayasu Arteritis
			Radiation-Induced Vasculopathy
		External Carotid Artery
		Vertebral Artery
			Traumatic Vertebrobasilar Ischemia
		Subclavian Artery Disease
			Subclavian Stenosis
			Pseudonormotension
			Diagnosis of Subclavian Stenosis
			Other Subclavian Diseases
			Aneurysm
		Conclusion
		References
	20: Symptomatic Intracranial Atherosclerotic Disease
		Introduction
		Antithrombotic Therapy
			Aspirin Versus Oral Anticoagulants
			Cilostazol Plus Aspirin
			Clopidogrel Plus Aspirin
			Ticagrelor
		Percutaneous Transluminal Angioplasty and Stenting
		Surgery
		Risk Factor Control
		Conclusions
		References
	21: Non-atherosclerotic Cerebral Vasculopathies
		Introduction
		Cervicocephalic Arterial Dissection
		Fibromuscular Dysplasia
		Moyamoya Disease
		Radiation-Induced Vasculopathy
		Reversible Cerebral Vasoconstriction Syndrome
		Central Nervous System Vasculitides
			Primary Angiitis of the Central Nervous System
			Cerebral Amyloid Angiopathy-Related Inflammation and Amyloid βeta-Related Angiitis
			Systemic Vasculitides
		Other Less Common Non-atherosclerotic Vasculopathies
			Severe Acute Respiratory Syndrome Coronavirus 2 Vasculopathy
			Anatomical Vascular Anomalies
		Conclusion
		References
Part IV: Rehabilitation and Recovery
	22: Botulinum Toxin for Post-Stroke Limb Spasticity
		Case Presentation
		Introduction
		Pathophysiology and Anatomy
		Presentation and Evaluation
		Treatment Options
		Botulinum Toxin
		Dosing
		Timing
		Conclusion
		References
	23: Selective Serotonin Reuptake Inhibitors
		Introduction
			Pharmacology
			Clinical Indications
			Side Effects
		Overall Functional Improvement
			Post-Stroke Depression Treatment
			Risk Factors
			Effect on Outcomes
			Primary Prevention
			Treatment of Depression
			Psychotherapy Plus Pharmacotherapy
			Limitations
			Conclusion
		Neuroplasticity and Post-Stroke Motor Recovery
			Neuroplasticity
			FLAME Trial
			FOCUS Trial
			EFFECTS and AFFINITY Trial
			Limitations
			Conclusions
		Pain Management
		Other Potential Beneficial Effects of SSRIs Following Stroke
		Summary
		References
	24: Constraint-Induced Therapies
		Background
		Mechanism of Action
			Learned Nonuse
			Neuroplasticity
			Relative Importance of Protocol Components
		Clinical Applications
			Timing
			Applications in Special Populations
		Barriers to Implementation
			Generalizability
			Resource Intensity
			Therapist Factors
			Patient Factors
			Alternative Methods of Delivery
			Combining CIMT with Other Interventions
		Conclusion
		References
	25: Virtual Reality for Motor Recovery in Stroke Rehabilitation
		What Is Virtual Reality?
			Virtual Reality: Immersion, Presence, and Embodiment
			Virtual Reality: Reinforced Feedback
			Virtual Reality: What Kind of Systems Are Used?
				Specific Rehabilitation VR Systems
				Commercial VR Video Game Consoles
		Virtual Reality in Post-Stroke Motor Recovery
		Which Motor Outcomes Show Scientific Evidence?
			Gait
			Balance
			Upper-Limb Motor Function
			Upper-Limb Muscle Strength
			Quality of Life
		Conclusions
		References
	26: Transcranial Magnetic Stimulation
		Introduction
			Basic Principles
			Techniques
		Potential Therapeutic Applications of rTMS and TBS
			Motor Function
				Upper Limb
				Lower Limb
			Spasticity
			Dysphagia
			Language
			Neglect
			Depression
			Safety
		Cost-Effectiveness
		Future Perspectives
		Conclusions
		References
	27: Brain-Computer Interfaces for Rehabilitation After Stroke
		Introduction
		General Goals for BCIs
		Development of BCIs
		Tailoring BCIs to Stroke
		Neurophysiology of Motor Recovery and Neurofeedback
		BCIs as a Rehabilitation Device
		BCI Use as an Assistive Device to Restore Network Dynamics
		Summary and Future Directions
		References
Part V: Special Populations
	28: Pediatric Arterial Ischemic Stroke
		Introduction
		Perinatal Stroke
		Pre-Hospital Triage and Systems of Care for Childhood Stroke
		Diagnostic Neuroimaging
		Intravenous Thrombolysis
		Endovascular Therapy for Acute Ischemic Stroke
		Laboratory Studies
		Cardiac Evaluation
		Acute Management
		Seizures
		Hemicraniectomy
		Primary and Secondary Stroke Prevention Therapeutics
		Sickle Cell Disease (SCD)
		Congenital and Acquired Heart Disease
		Arteriopathy
		Hypercoagulable States
		Early Rehabilitation and Recovery
		Conclusion
		References
	29: Stroke in the Very Elderly
		Introduction
		Age-Specific Risk Factors in the Elderly
		Primary Prevention
			Hypertension
			Dyslipidemia
			Antiplatelet Therapy
			Atrial Fibrillation
		Acute Stroke Therapy
			Intravenous Alteplase
			Mechanical Thrombectomy
		Secondary Prevention
			Blood Pressure Reduction
			Statin Therapy
			Antithrombotic Therapy
			Carotid Stenosis
		Stroke Recovery and Complications
			Stroke Complications
			Stroke Recovery
		Conclusion and Future Directions
		References
	30: Vascular Cognitive Impairment
		Nosology and Diagnostic Criteria
		Emerging VCID Pathophysiology
			Endothelial Inflammation
			Blood-Brain Barrier Dysfunction
			Neuronal Network Disruption
			AD Biomarkers: Amyloid and Tau
			Macroscopic Disease
		Findings from Epidemiological and Pathological Studies
		The Role of Genetics
		Clinical History and Physical Examination
			Neuropsychological Profile
		Diagnostics
		Therapeutics
		Risk Factors and Prevention
		Conclusions and Future Directions
		References
Part VI: Systems of Care
	31: Stroke Systems of Care and Stroke Centers
		Introduction
		Basic Concepts and Scope of Stroke Care
		Elements of an SSoC
		Stroke Centers
			Acute Stroke Ready Hospital (ASRH)
			Primary Stroke Center (PSC)
			Thrombectomy-Capable Stroke Center (TSC)
			Comprehensive Stroke Center (CSC)
		Stroke Center Certification
		Conclusions
		References
	32: Telemedicine in Stroke Systems of Care
		Introduction
			Telestroke Models
		Evidence in Support of Telestroke
			Acute Ischemic Stroke
			Post-Stroke and Rehabilitation
			Tele-Health Economic Analyses
		Telemedicine Technology
		Medical Legal and Legislative Issues
			Licensure
			Privacy
			Stakeholder Satisfaction with Telestroke
		Summary
		References
	33: Broadly Bridging the Breach: Stroke Disparities
		Racial and Ethnic Disparities
			Disparities in Stroke Incidence and Mortality
			Disparities in Stroke Risk Factor Prevalence and Control
			Disparities in Acute Stroke Care
			Disparities in Post-Acute Care and Secondary Prevention
		Geographic Disparities (Urban and Rural)
		Socioeconomic Inequities
		References
	34: Stroke Systems of Care
		Introduction
		Structure and Organization of National-Level Stroke Registries and Other Community Models in Developed Countries
		Findings of the Major National Stroke Registries and Other Community Models in Developed Countries
			Contribution of Registries to Improvement in the Quality of Stroke Care
			Assessment of the Relationship between Quality of Care and Outcomes
			Evaluation of Stroke Systems of Care
		Value, Contributions, Challenges, and Opportunities of Stroke Registries
		Conclusions
		References
	35: Systematically Addressing Stroke Burden in the Developing World: A Framework for Effective Implementation
		Introduction
		The Need for Scientific Approach
		The World Stroke Organization-World Health Organization (WHO-WSO) Lancet Commission on Stroke
		Contextual and Pragmatic Approach
		Novel Dissemination and Implementation Plans
		Critical Areas to Address
		Conclusion
		References
Index