Table of Contents
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Foreword
List of Contributors
Stroke and Hypertension
Abstract
INTRODUCTION
STROKE EPIDEMIOLOGY
PATHOPHISIOLOGY OF BRAIN VASCULAR DAMAGE INDUCED BY HIGH BLOOD PRESSURE
RELATIONSHIP BETWEEN HIGH BLOOD PRESSURE AND RISK OF STROKE
HYPERTENSION THERAPY AND CEREBROVASCULAR DAMAGE PREVENTION
Primary Stroke Prevention
A Special Situation: Primary Stroke Prevention in the Very Elderly
Secondary Stroke Prevention
Hypertension Therapy and Early Cerebral Damage
EVIDENCE OF THE RELATIONSHIP BETWEEN TREATMENT OF OTHER ASSOCIATED RISK FACTORS AND STROKE PREVENTION
Type 2 Diabetes Mellitus
Dyslipidemia
IS THERE A NEUROPROTECTIVE EFFECT OF RENIN-ANGIOTENSIN SYSTEM BLOCKADE?
CONCLUSION
TAKE HOME MESSAGES
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Autonomic Nervous System Dysfunction and Risk of Stroke
Abstract
INTRODUCTION
Stroke Subtypes
Cerebral Blood Vessels Innervation
Sympathetic Innervation
Parasympathetic Innervation
Cerebral Blood Flow Auto-regulation
Sympathetic Regulation of CBF
Parasympathetic Regulation of Cerebral Blood Flow
Vagal Modulation of Neuro-inflammation
Baroreflex Modulation of Cerebral Blood Flow
Autonomic Nervous System and the Risk of Stroke
Blood Pressure Level, Blood Pressure Variability and Risk of Stroke
Autonomic Nervous System Dysfunction and the Development of Hypertension
Autonomic Nervous System Dysfunction Alters BP Variability
Autonomic Nervous System Activity and Dynamic Regulation of Cerebral Blood Flow
Summary
Methodological Aspects and Future Perspectives
CONCLUSION
TAKE HOME MESSAGES
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
Reference
Stroke and the Immune System: Therapeutic Targeting of Toll-Like Receptors
Abstract
1. INTRODUCTION
2. INNATE IMMUNE CELLS AND THEIR REGULATION IN THE CNS
3. TLRs: STRUCTURE, ROLE AND EXPRESSION IN CNS
4. GENERAL CHARACTERISTICS AND IMMUNOLOGICAL ASPECTS OF STROKE
5. ROLE OF TLRs IN ISCHEMIC EVENTS
6. TLR TARGETING AS A PROMISING THERAPY IN CEREBRAL ISCHEMIA
CONCLUSION AND FUTURE DIRECTIONS
TAKE HOME MESSAGE:
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Intracerebral Bleeding and Oral Anticoagulant Therapies: Clinical Relevance and Management
Abstract
1. VKA-ASSOCIATED CEREBRAL HEMORRHAGES
1.1. Warfarin: Mechanism of Action and Main Characteristics
1.2. Monitoring Warfarin, and Risk of Intracerebral Bleeding
1.3. Reversal of VKA Effect and Management of VKA-Associated ICH
1.3.1. Vitamin K
1.3.2. FFP (Fresh Frozen Plasma)
1.3.3. About PCC (Prothrombin Complex Concentrates)
2. NON VITAMIN K ANTICOAGULANTS ASSOCIATED CEREBRAL HEMORRHAGES
2.1. DOACs Pharmacology
2.1.1. Dabigatran
2.1.2. Rivaroxaban
2.1.3. Apixaban
2.1.4. Edoxaban
2.2. DOACs Indications, Main Efficacy and Safety Data
2.3. DOACs Monitoring
2.3.1. Monitoring of Dabigatran
2.3.2. Monitoring of Direct Xa Inhibitors
2.4. DOACs Reversal and Management of Life Threatening Bleeding
2.4.1. General Principles for Managing Bleeding Related to Anticoagulants
2.4.2. Traditional Reversal Agents
2.4.2.1. Dabigatran Reversal
2.4.2.2. Factor Xa Inhibitors Reversal
2.4.3. Novel Reversal Strategies
2.4.3.1. Idarucizumab
2.4.3.2. Andexanet Alfa
CONCLUSION
TAKE HOME MESSAGES:
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Cerebral Collateral Circulation in Acute Ischemic Stroke: Translational Evidence for Outcome Prediction and Modulation Strategies
Abstract
INTRODUCTION
Cerebral Collateral Circulation in Humans and Rodents
Assessment of Cerebral Collateral Flow in Acute Stroke Patients
Cerebral Collateral Flow as Stratification Factor in Pre-Clinical Neuroprotection Studies
Acute Therapeutic Modulation of Cerebral Collateral Flow
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
DISCLOSURE
ACKNOWLEDGEMENTS
References
Life in the Penumbra with the BRODERICK PROBE®
Abstract
INTRODUCTION
METHODS
In vitro Calibration Procedures
In vivo Surgical Procedures
Image Scanning Procedures
Interpretation and Analysis of Data via Electrochemical Methods
Middle Cerebral Artery Occlusion According to the Method of Zea Longa et al., 1989
Preparation of the Monofilament Nylon Suture
Dual Laser Doppler Flowmetry (DLDF)
RESULTS AND DISCUSSION
NMI Data, Quantitative Histopathologic, and DLDF Data
SUMMARY AND CONCLUSION
Notes for Table 2
Appendix: Overview of Nanotechnology Platforms for Stroke Diagnosis and Treatment
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
On the Influence of Normalization Strategies for Perfusion MRI in Acute Stroke
Abstract
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION AND CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Genetic Causes of Ischemic Stroke
Abstract
INTRODUCTION
MONOGENIC STROKE DISORDERS
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) (OMIM 125310-600276)
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) (OMIM 192315)
Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL) (OMIM 192315)
Fabry Disease (OMIM #301500)
COL4A1/A2 related Arteriopathy (OMIM 605595-120130)
Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) (OMIM 540000)
Multifactorial Stroke
Stroke Subtypes Associations
Limits of GWAS and Next Generation Studies
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Diagnostic Challenges: Cryptogenic Ischemic Stroke
Abstract
ATRIAL FIBRILLATION: PREVALENCE AND THROMBOEMBOLIC RISK
MECHANISM OF THROMBOSIS AND THROMBO-EMBOLI IN NON-VALVULAR ATRIAL FIBRILLATION
CRYPTOGENIC STROKE AND ATRIAL FIBRILLATION
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Emerging Concepts for Neuroprotection
Abstract
INTRODUTION
Neuroprotection
Double Sword Process
Systemic Variables
Examples of Potential Neuroprotective Approaches
Preconditioning and Ischemic Tolerance
Hypothermia
Minocycline
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Pharmacological and Endovascular Recanalization Therapy
Abstract
INTRODUCTION
Systemic Thrombolysis
Indications for Intravenous Reperfusion Therapy
Endovascular Treatment of Stroke (Thrombolysis, Thrombectomy, Thrombus Aspiration)
Indications for Endovascular Therapy
Post Treatment Phase
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Neuroregeneration after Stroke
Abstract
INTRODUCTION
Reparative Processes after Stroke
Inflammation
Neurogenesis
Angiogenesis
Astrogliosis
Neuronal Plasticity Processes
Axonal Sprouting
Dendritic Remodelling
Spine Remodelling
Post-Stroke Adaptive Plasticity Processes
Re-emergence of a Critical Period after Stroke
Brakes of Plasticity after Stroke
Alteration of Brain Excitability after Stroke
GABA Signalling in Stroke
Glutamate Signalling in Stroke
Approaches to Modulate Neural Plasticity
Rehabilitation
Non-Invasive Transcranial Stimulation
Pharmacological Modulation of Neural Plasticity
Modulation of GABA Signalling to Promote Plasticity
Modulation of Glutamate Homeostasis to Promote Plasticity
Neural Stem Cell-based Therapies
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Post-Stroke Rehabilitation
Abstract
POST-STROKE REHABILITATION: ACUTE PHASE MANAGEMENT
Prognosis
Recovery of Independence in ADL and Social Participation
Gait
Upper Limb
Continuity of Care Management
POST-STROKE REHABILITATION: SUB-ACUTE PHASE MANAGEMENT
Main Sub-acute Phase Issues
Post-stroke Cognitive Impairment
Depression
Spasticity
Pain
POST-STROKE REHABILITATION: CHRONIC PHASE MANAGEMENT
WHAT’S NEW IN STROKE REHABILITATION
Constraint Induced Movement Therapy (CIMT)
Body Weight-Supported Treadmill Training (BWSTT)
Robotic Devices
Virtual Reality (VR)
Action Observation (AO)
Non-Invasive Brain Stimulation (NIBS)
CONCLUSION
TAKE HOME MESSAGE
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Current Developments in Stroke
(Volume 1)
(New Concepts in Stroke Diagnosis and Therapy)
Edited by
Alberto Radaelli
Division of Cardiac Rehabilitation,
San Gerardo Hospital,
Monza,Italy
GiuseppeMancia
University of Milano-Bicocca and
IRCCS Istituto Auxologico Italiano,
Milan,Italy
Carlo Ferrarese
Department of Neurology, San Gerardo Hospital,
University of Milano Bicocca,
Monza,Italy
&
Simone Beretta
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Foreword
Stroke is likely the neurological disease with the most relevant developments in all the research fields, from knowledge of the mechanisms leading to brain tissue death to codification of rehabilitation mainstays, through better definition of risk factors and consequent improvement of primary and secondary prevention, diagnosis with advanced imaging or by identification of genetic mechanisms in rare cases, treatments of the acute phase of ischemic events, with the well-established role of i.v. thrombolysis now backed up by combined endovascular treatments and with the potentialities of neuroprotection and neuroregeneration, or of iatrogenic hemorrhagic stroke, with the advent of antidotes for the new generation of direct oral anticoagulants.
As a consequence, a terribly huge literature on stroke has been produced: by typing the word “stroke” one may find approximately 140000 papers indexed in PubMed in the last 20 years. Hence, a book summarizing all the “new concepts in stroke diagnosis and therapy” is highly appreciated. The Authors report the present knowledge on all the above mentioned issue, with updated and well selected reference literature. The book can be a good “traveling companion” for neurologists working daily on stroke patient management and having little time to look for scientific literature, but also a guide for stroke basic and clinical researchers to pick up the most recent information and to get suggestions for further research.
My compliments to the Authors and “enjoy the reading” to all the readers.
Prof. Danilo Toni, MD
Associate Professor of Neurology
Director Emergency Department Stroke Unit
Hospital Policlinico Umberto I
Dept. of Neurology and Psychiatry, Sapienza Univerisity.
Preface 1
Stroke prevention, diagnosis and therapy are all evolving fields that give us the idea of how in progress is the clinical job and the scientific work. Stroke in particular deserves a special mention as it is perceived both by patients and by physicians and it is one of the most feared and invalidating condition.
In this regard, every single step able to improve prevention, accelerate diagnosis and therapy is welcome and need to be rapidly shared with all the scientific community.
On the one hand, despite the stabilization of stroke events in civilized countries other emerging countries contribute to new events so keeping a high prevalence of stroke worldwide. In this regard, stroke prevention still represents one of the missing opportunities and the recognition and treatment of old and new risk factors are mandatory. On the other hand, imaging and therefore diagnosis and therapeutic opportunities are now available to treat faster than ever ischemic events in order to reduce overall cerebral damage and therefore disability. These new possibilities nevertheless should not remain restricted to few golden clinical and scientific realities but be rapidly shared and diffused to the emerging countries where the prevalence of stroke is growing.
This book aims to be an aid to the diffusion and discussion of what is new in the field and what are some of the new directions of prevention, diagnosis and therapy. At least, eighty five per cent of strokes are of ischemic origin and are therefore the results of a missed prevention in vascular atherosclerosis and thrombosis. This has always been a “cardiology” field. It is evident that a tighter cooperation between cardiologists and neurologists is needed in order to share expertise and to create more powerful tools to improve prevention, diagnosis and therapy of vascular events that involve in a similar dramatic way both the heart and the brain.
Dr. Alberto Radaelli
Director of the Division of Cardiac Rehabilitation,
San Gerardo Hospital,
Monza,
Italy
Preface 2
Only few decades ago stroke was considered a devastating condition with high mortality, high disability, without adequate prevention strategies, any tool to perform accurate diagnosis and consequently without any effective treatment available.
Scientific and technological advances in the last few years have dramatically changed the scenario: epidemiologic, genetic, imaging, biological and therapeutic advances have made it possible to effectively prevent strokes, to perform accurate differential diagnosis of stroke type and of location of vessel occlusion and new treatments for acute phase have recently demonstrated dramatic results.
In the context of this new scenario, new concepts for stroke diagnosis and therapy emerged, and this book specifically addresses this point.
Major experts and opinion leaders in respective fields extensively review and discuss new advances in the knowledge of the role of stroke risk factor for their prevention; new technological tools to perform in vivo imaging of cerebral collateral circulation and ischemic penumbra are widely described and their relevance for more accurate diagnosis and prognosis is discussed.
Diagnostic challenges in rare aethiologies of stroke are described in detail and new studies on recanalization and neuroprotection strategies are reported, with analysis of their impact on stroke health organization.
Finally, the hemorrhagic risk associated to older and new anticoagulants is discussed and new studies on stroke recovery are presented.
The reader of this new book may obtain a state-of-the-art knowledge of stroke diagnosis and treatment options to address the challenges of this severe, but now treatable disease.
Dr. Carlo Ferrarese,
Professor of Neurology. Director of the Department of Neurology,
San Gerardo Hospital,
University of Milano Bicocca,
Monza,
Italy
List of Contributors
Antonio CocaHypertension and Vascular Risk Unit. Department of Internal Medicine, Institute of Medicine and Dermatology, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona, SpainAlberto RadaelliDivision of Cardiac Rehabilitation, San Gerardo Hospital, Monza, ItalyAlessandro VersaceLaboratory of Experimental Stroke Research, School of Medicine, University of Milano Bicocca, Monza, ItalyAnna BersanoCerebrovascular Unit, IRCCS Foundation Neurological Institute “C. Besta”, Via Celoria 11, Milan 20133, ItalyAntonio VincentiElectrophysiology Unit, Multimedica IRCCS Sesto San Giovanni, Milan, ItalyBarbara CasollaNESMOS (Neuroscience Mental Healt and Sensory Organs) Department, School of Medicine and Psychology, Sapienza University, Rome, ItalyCarlo FerrareseDepartment of Neurology, Director of the Department of Neurology, San Gerardo Hospital, University of Milano Bicocca, Monza, ItalyCarole FrindelUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Claude Bernard Lyon 1, FranceCristina SierraHypertension and Vascular Risk Unit. Department of Internal Medicine, Institute of Medicine and Dermatology, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona, Spain,David CaroneLaboratory of Experimental Stroke Researc, School of Medicine, University of Milano-Bicocca, Monza, Italy
Milan Center for Neuroscience (NeuroMi), Milan, ItalyDavid RousseauUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Claude Bernard Lyon 1, FranceElio Clemente AgostoniDepartment of Neuroscience, Neurology and Stroke Unit of the ASST: “Grande Ospedale Metropolitano Niguarda”, Milan, ItalyElisa CuccioneLaboratory of Experimental Stroke Research, School of Medicine, University of Milano Bicocca, Monza, ItalyFausto De AngeliLaboratory of Experimental Stroke Research, School of Medicine, University of Milano Bicocca, Monza, ItalyFrancesco OrziNESMOS (Neuroscience Mental Health and Sensory Organs) Department, School of Medicine and Psichology, Sapienza University, Rome, ItalyFrancesca Maria SalmeriDepartment of Biomedical, Dental Sciences and Morphological and Functional Images, University of Messina, Messina, ItalyGiuseppe ManciaUniversity of Milano-Bicocca and IRCCS Istituto Auxologico Italiano, Milan, ItalyGianvito MartinoInstitute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, ItalyGiada PadovanoLaboratory of Experimental Stroke Research, School of Medicine, University of Milano Bicocca, Monza, ItalyGianluca Luigi RussoInstitute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, ItalyGiuliano SetteNESMOS (Neuroscience Mental Healt and Sensory Organs) Department, School of Medicine and Psichology, Sapienza University, Rome, ItalyGiulia SoraciUniversity of “La Cattolica Sacro Cuore”, Rome, ItalyLeandro ProvincialiDepartment of Experimental and Clinical Medicine, Neurological Section, Marche Polytechnic University, Ancona, ItalyLeslie WenningDepartment of Physiology, Pharmacology and Neuroscience, The City University of New York School of Medicine, The Sophie Davis School of Biomedical Education, The City College of New York, New York, NY USA; Department of Anesthesiology, NYU Langone Medical Center, New York, NY, USALuca SoraciDepartment of Biomedical, Dental Sciences and Morphological and Functional Images, University of Messina, Messina, ItalyMarco LongoniDepartment of Neuroscience, Neurology and Stroke Unit of the ASST: “Grande Ospedale Metropolitano Niguarda”, Milan, ItalyMaria Elas GambuzzaMinistry of Health, Messina, ItalyMarco BacigaluppiNeuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, ItalyMathilde GiacaloneUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Claude Bernard Lyon 1, FranceMichela CocciaDepartment of Experimental and Clinical Medicine, Neurological Section, Marche Polytechnic University, Ancona, ItalyMichela RanieriCerebrovascular Unit, IRCCS Foundation Neurological Institute “C. Besta”, Via Celoria 11, Milan 20133, ItalyMonica CarpenedoHematology and Transplant Unit, San Gerardo Hospital, Monza, ItalyNorbert NighoghossianUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon;Université Claude Bernard Lyon 1, FrancePatricia Ann BroderickDepartment of Physiology, Pharmacology and Neuroscienc, The City University of New York School of Medicine, The Sophie Davis Program in Biomedical Education, The City College of New York, New York, NY, USA
Department of Biology, CUNY Grad. Ctr., New York, NY, USA
Department of Neurology, NYU Langone Medical Center and Comprehensive Epilepsy Center, New York, NY, USAPaolo CastiglioniIRCCS Fondazione Don Carlo Gnocchi, Milan, ItalyPaolo La SpinaDepartment of Clinical and Experimental Medicine, University of Messina, Messina, ItalyRobin ZagalaUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Claude Bernard Lyon 1, FranceSimone BerettaLaboratory of Experimental Stroke Research, School of Medicine, University of Milano Bicocca, Monza, ItalySerena CandelaNESMOS (Neuroscience Mental Health and Sensory Organs) Department, School of Medicine and Psichology, Sapienza University, Rome, ItalyTae-Hee ChoUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Claude Bernard Lyon 1, FranceVincenza SofoDepartment of Biomedical, Dental Sciences and Morphological and Functional Images, University of Messina, Messina, ItalyYves BerthezèneUniversité de Lyon, CREATIS, CNRS UMR5220, Inserm U1206, INSA-Lyon, Université Claude Bernard Lyon 1, FranceYong-Sheng LiDepartment of Physiology, Pharmacology and Neuroscienc, The City University of New York School of Medicine, The Sophie Davis Program in Biomedical Education, The City College of New York, New York, NY, USA
Department of Anesthesiology, NYU Langone Medical Center, New York, NY, USA
Stroke and Hypertension
Cristina Sierra,Antonio Coca*
Hypertension and Vascular Risk Unit. Department of Internal Medicine, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona, Spain
Abstract
Stroke, the third most-common cause of mortality after cancer and heart disease in developed countries, is one of the most common causes of cognitive impairment and vascular dementia. Stroke pathogenesis and its consequences are not completely elucidated, with various factors and biological mechanisms probably having a role. After age, hypertension is the leading modifiable cardiovascular risk factor for ischaemic/haemorrhagic stroke, small vessel disease predisposing to lacunar infarction, cerebral white matter lesions (cWML), and cerebral microbleeds. Primary stroke prevention, involving hypertension therapy and blood pressure (BP) control is now standard. At the same time, elevated post-stroke BP levels increase the risk of recurrent stroke, with recent trials suggesting that BP reduction with combinations of hypertension therapy reduces stroke recurrence. This chapter reviews the evidence on hypertension as a stroke risk factor and the part played by hypertension therapy in first/recurrent stroke prevention.
Keywords: Cerebral microbleeds, Cerebral small vessel disease, Cognitive impairment, Hemorrhagic stroke, Hypertension, Hypertension therapy, Ischemic stroke, Lacunar infarction, Recurrent stroke, Vascular dementia, White matter lesions.
*Corresponding author Antonio Coca: Hypertension and Vascular Risk Unit, Hospital Clinic., Villarroel 170, Barcelona 08036, Spain, Tel: + 34 932275759, E-mail:
[email protected]CONFLICT OF INTEREST
The authors confirm that they have no conflict of interest to declare for this publication.
ACKNOWLEDGEMENTS
Declared none.
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