Front Cover

Brain Edema

Copyright Page

Contents

Dedication

Acknowledgments

List of Contributors

Introduction: Brain Edema Formation—Significance for Patient Outcome

History of Brain Edema

Recent Advances in the Field of Brain Edema Research

The Physiology of Cerebral Blood Vessels and How to Investigate Them (Part 1 and 2)

Molecular Basis and Concepts in Brain Edema Formation (Part 3)

Brain Edema Process in Pre-Clinical Models (Part 4)

Clinical Features and Management of Brain Edema (Part 5)

Perspectives in Future Translational Research on Brain Edema

References

I. General Introduction

1 Physiology of Cerebral Blood Vessels

Introduction

Cerebrovascular Architecture and Principle of Blood Perfusion

Cellular Components of Cerebral Vasculature and the Neurovascular Unit

Cerebrovascular Endothelial Cells

Blood-Brain Barrier Function

Vasoactive Factors Released by Endothelial Cells: Endothelium-Dependent Cerebrovascular Reactivity

Mechanotransduction of Shear Stress

Cerebrovascular Smooth Muscle Cells

Principle Mechanisms of SMC Constriction or Relaxation

Potassium Channels on VSMCs

Role of Internal Ca2+ Stores

Mechanisms of NO-Induced Vasodilation

Concluding Remarks

Pericytes

Astrocytes

Perivascular Neurons—Extrinsic and Intrinsic

Autoregulation and Myogenic Tone

Further Mechanisms of Global Blood Flow Regulation: Reaction to pCO2/pH and pO2 Changes

Mechanisms of Local Blood Flow Regulation—Neurovascular Coupling

Summary

References

2 Blood–Brain Interfaces Organization in Relation to Inorganic Ion Transport, CSF Secretion, and Circulation

Introduction

Part I: Blood–Brain Barriers and Fluid Flow in the Brain

Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier Functions and Specificities

Cerebrospinal Fluid Circulation, CSF Brain Exchanges, and Perivascular Flow

Part II: Transport and Secretion Processes at the Brain Barriers

Influx of Organic Compounds, Polypeptides, and Proteins Into the Brain

Efflux of Organic Compounds, Polypeptides, and Proteins Out of the Brain

Transporters and Channels for Inorganic Ions at the Blood–Brain Barrier

Transporters and Channels for Inorganic Ions and Water at the Blood–Cerebrospinal Fluid Barrier in Relation to CSF Secretio ...

Conclusions

Acknowledgments

References

II. Techniques to Investigate Cerebral Blood

3 Noninvasive Imaging Techniques for Brain Edema: From Basic Science to the Clinic

Introduction

Compartments that Contribute to Water Movement in the Brain

Forms of Edema Relevant to Neuroimaging

Cytotoxic Edema

Vasogenic Edema

Interstitial or Ionic Edema

Neuroimaging Modalities for Edema

Magnetic Resonance Imaging

Computed Tomography

Ultrasound

Nuclear Medicine Techniques

Advanced and Emerging Imaging Approaches

Summary

Acknowledgments

References

4 Experimental Techniques to Investigate the Formation of Brain Edema In Vivo

Key Phrases

Introduction

Identification of Brain Edema

Measurement of Brain Water Content

Detection of Cytotoxic Brain Edema

Detection of Vasogenic Brain Edema

References

5 In Vitro Models of the Blood–Brain Barrier to Better Understand the Pathophysiology of Brain Edema

Introduction

In Vitro Blood–Brain Barrier: Experimental Setup and Techniques

Primary and Immortalized Brain Microvascular Endothelial Cells

Brain Microvascular Endothelial Cells Derived from Endothelial Progenitor and Stem Cell Sources

In Vitro Cocultures Model of the Blood–Brain Barrier

Flow-Based In Vitro Models of the Blood–Brain Barrier

In Vitro Models for Modeling Vasogenic Cerebral Edema

Concluding Remarks

References

III. Molecular Basis and Concepts in Brain Edema Formation for New Treatment Development

6 The Extracellular and Perivascular Spaces of the Brain

Components of the Central Nervous System (CNS)

The Ventricular System and CSF

The Extracellular Space

The Extracellular Space and Perivascular Space in Edema

Conclusions

References

7 Blood-Brain Barrier Mechanisms of Edema Formation: The Role of Ion Transporters and Channels

Abbreviations

Cytotoxic Versus Vasogenic Edema

Blood-Brain Barrier Ion Transporters and Channels in Cytotoxic Edema

Na+–K+–Cl− Cotransport

Na+/H+ Exchange

KCa3.1 Channel

Blood-Brain Barrier Ion Transporters and Channels in Vasogenic Edema

Effects of Elevated Intracellular [Ca2+] on BBB Tight Junctions and Permeability

Role of BBB Ion Transporters and Channels in Alteration of Intracellular [Ca2+] and Barrier Disruption

Conclusions

Acknowledgments

References

8 Mechanisms of Cell-Volume Regulation in the Central Nervous System

Key phrases

Introduction

Mechanisms of Cell-Volume Regulation in Vertebrates

Mechanisms of Physiological Cell-Volume Regulation in Astrocytes

Mechanisms of Physiological Cell-Volume Regulation in Neurons

Cell-Volume Changes in the CNS Under Pathological Conditions

References

9 Role of Aquaporins in the Formation and Resolution of Brain Edema

Abbreviations

Aquaporins

Family Members

From Genes to Arrays of Pores

Distribution in the CNS

Role of Aquaporins in Edema

Mechanisms of Regulation of Water Movement

Aquaporin Expression in Edema

Aquaporin-4 in Edema Formation

Aquaporins in Edema Resolution

Chronic Changes in Aquaporin-4 in Relation to Edema

AQPs as a Potential Link Between Neuroinflammation and Edema

Treatment of Edema: Drugs Against AQPs

Conclusions

Statement of Financial Support

References

10 Sur1–Trpm4-Promising Target for Brain Edema Treatment in Brain Edema: From Molecular Mechanisms to Clinical Practice

Introduction

SUR1–TRPM4

SUR1–TRPM4 in the Pathogenesis of Ischemic Brain Edema

Animal Models

Retrospective Clinical Studies

Prospective Clinical Studies

SUR1–TRPM4 in the Pathogenesis of Perihematomal Edema

SUR1–TRPM4 in the Pathogenesis of Edema After Subarachnoid Hemorrhage

SUR1–TRPM4 in the Pathogenesis of Edema and Hemorrhagic Progression of a Contusion After Traumatic Brain Injury

SUR1–TRPM4 in the Pathogenesis of Hemorrhagic Encephalopathy of Prematurity

Conclusions

References

11 Role of Matrix Metalloproteinases in Brain Edema

Introduction

Molecular Elements of the BBB: Proteins Composing the Tight Junctions, Adherens Junctions, and Extracellular Matrix

Matrix Metalloproteinases: Molecular Aspects and Regulation of their Function in Brain

Tight Junction Proteins and Extracellular Matrix Proteins as Molecular Targets of the MMPs: Implications for BBB Dysfunctio ...

Conclusions

References

IV. Brain Edema Process in Preclinical Models

12 Edema and BBB Breakdown in Stroke

Introduction

Physiologic Structure and Function of the Blood–Brain Barrier

The Phases of Edema in Stroke

Hyperacute Phase: The First Few Minutes

The Acute Phase: The First Hours

The Patient in the Clinic: Reperfusion and Edema

Edema

The Subacute Phase: 24–48 hours

The Chronic Phase: 3 Days–2 Weeks

Summary

References

Further Reading

13 Brain Edema Formation in Traumatic Brain Injury

Abbreviations

Traumatic Brain Injury Pathophysiology

Clinical Aspects of Traumatic Brain Injury

Pre-clinical Models and Edema Aspects

Pathophysiology of Edema Formation in Traumatic Brain Injury Models

Classification of the Different Forms of Edema

Vasogenic Edema Formation

Primary Vasogenic Edema After Mechanical Disruption of Cerebral Vessels

Delayed Vasogenic Edema After Later Blood–Brain Barrier Dysfunctions: Cellular and Molecular Events

Transcytosis and Caveolae

Tight Junction Degradation

Ionic and Cytotoxic Edema Formation after Traumatic Brain Injury

Ionic Edema Formation

Cytotoxic Edema Formation

Conclusions

Acknowledgments

References

14 Spinal Cord Edema After Spinal Cord Injury: From Pathogenesis to Management

Pathogenesis: Molecular Mechanisms of Spinal Cord Edema

Biphasic Nature of Spinal Cord Injury

Spinal Edema Exacerbates the Initial Injury

Spinal Edema Formation Is a Multifactorial Molecular Process

Management of Spinal Cord Edema: Bench to Bedside

General Management of Spinal Cord Injury

Edema-Specific Therapies Under Investigation

Aquaporins

Melatonin

Hormonal Therapies

Other Therapies

Conclusion

References

15 Brain Edema in Acute Liver Failure

Introduction

Mechanisms of Brain Edema in Acute Liver Failure

Ammonia

Cellular Transporter Proteins

Cellular Energy Metabolism, Lactate, and Cerebral Blood Flow

Neuroinflammation

Implications for Future Therapy in Acute Liver Failure

Ammonia-Lowering Strategies

N-Acetyl Cysteine

Mild Hypothermia

Phenytoin

Propofol

Antiinflammatory Agents

Indomethacin

Minocycline

Etanercept

Liver-Assist Devices, Blood Depuration Strategies

Summary

Acknowledgment

References

16 Blood–Brain Barrier and Edema in Brain Tumors

Introduction

The Healthy Blood–Brain Barrier

Water Movement in the Brain

Reactive Astrocytes

Brain Tumors and their Cellular Sources

BBB Changes in Brain Tumors and Edema Formation

General Observations

Tight Junctions in Glioblastoma

Aquaporins and Glioblastoma

Edema Formation in Glioblastoma

Model Systems to Study Changes of BBB in Tumors

In Vitro Models

Monocultures

Cocultures of Glioma and Endothelial Cells

Explant Cultures

In Vivo Models to Study Changes of BBB in Tumors

Conclusions

References

17 Water Homeostasis Dysfunction in Epilepsy

Water and Ion Homeostasis and Epilepsy

Aquaporins

AQP4−/− Mice

Altered Extracellular Space in AQP4−/− Mice

Seizure Phenotype of AQP4−/− Mice

Altered K+ Homeostasis in AQP4−/− Mice

Anchoring of AQP4 by the Dystrophin-Associated Protein Complex (DAPC)

Human Tissue Studies

Methodological Issues

Expression and Regulation of AQP4 During Epileptogenesis

Subcellular Alteration in AQP4 Distribution: A Common Disease Mechanism?

AQP4 and the Gliovascular Junction

A Role for AQP4 at the Synapse?

Genetic Studies of AQP4 and Epilepsy

Restoration of Water and Ion Homeostasis

Conclusions

References

18 Water Homeostasis Dysfunctions and Edema in Neuroinflammatory Disease

Introduction

Blood–Brain Barrier Function in Health and CNS Inflammation

AQP4 in Neuroinflammation

Tool Developments for In Vivo Monitoring the Dynamic Complexity of Vasogenic Edema

Conclusion

References

19 Experimental Therapies for Brain Edema and Intracranial Hypertension

Key Phrases

Abbreviations

Introduction

Surgical Treatment Options—Decompressive Craniectomy (DC)

Targeting Blood–Brain Barrier Permeability

The Kallikrein–Kinin System

Arginine Vasopressin V1a Receptors

Vascular Endothelial Growth Factor (VEGF)

Matrix Metalloproteinases (MMPs)

Endothelin

Vasodilator-Stimulated Phosphoprotein (VASP)

Reducing Cytotoxic Brain Edema

Na+/H+ Antiporter

Na+/K+/2Cl− Cotransporter

SUR1-TRPM4

Conclusion

References

V. Clinical Features and Management of Brain Edema

20 Clinical Monitoring of Brain Edema

Introduction

Pathogenesis

Indication for Intracranial Pressure Monitoring

Clinical Signs of Brain Edema

Noninvasive Techniques

Computed Tomography

Biomarkers

Noninvasive Monitoring of Intracranial Pressure

Intraocular Pressure

Ocular Sonography

Transcranial Doppler

Tissue Resonance Analysis

Invasive Techniques

Intraventricular

Intraparenchymal

Subarachnoid

Epidural

Secondary Effects of Elevated Intracranial Pressure

Microdialysis

Thermal Diffusion Flowmetry

Jugular Venous Oximetry

Brain Tissue Oxygen Tension

Conclusion

References

21 Brain Edema in Developing Brain Diseases

Introduction

Neonatal Encephalopathy (NE)

Stroke

Germinal Matrix Hemorrhage (GMH)

Traumatic Brain Injury (TBI)

Infectious Processes

Epilepsy

Diabetic Ketoacidosis (DKA)

Hereditary Encephalopathy/Leukodystrophies

CNS Tumors

Tools for Functional Edema Studies: MRI

Pathophysiology

The Molecular Protagonist of Edema Formation in the Developing Brain

The Neurovascular Unit (NVU)

Therapeutic Targets

Symptomatic Treatment and Current Treatment Strategies

Novel Treatments for the Developing Brain

Conclusion

References

22 Cerebral Edema in Cerebrovascular Diseases

Introduction

Pathophysiology of Cerebrovascular Edema in Ischemic Stroke

Clinical Aspects

Symptoms Related to the Extent of the Lesion

Symptoms Related to Compression by Brain Herniation

Symptoms Related to Intracranial Hypertension

Brain Imaging Diagnosis

Predictors of Cerebral Edema

Clinical Predictors

Influence of the Genetic Background

Influence of Stroke Mechanism

Should We Monitor Intracranial Pressure?

Biological Biomarkers

Electrophysiology

Brain Imaging

Stroke Volume and Severity of Ischemia

Imaging Markers of BBB Permeability

Perfusion Abnormalities

Pre-stroke Brain Morphological Structure

Vascular Imaging of Cerebral Arteries

Functional Prognosis

Ischemic Strokes

Hemispheric Infarction

Cerebellar Infarction

Hemorrhagic Transformation of Ischemic Stroke

Treatments

Prevention of Brain Edema Development After a Stroke

Mechanical Ventilation

Hemodynamic Support

Blood Pressure Control

Glucose Management

Temperature Management

Medical Treatment in a Deteriorated Patient

Elevated Head Position

Osmotherapy

Mannitol

Hypertonic Saline

Other Osmotic Agents

Steroids

Hypothermia

Barbiturates

Hyperventilation

Neurosurgical Options in a Deteriorated Patient

Malignant MCA Infarction

Brain Swelling Following Cerebellar Infarction

Conclusion

References

Further Reading

23 Traumatic Brain Injury and Edema Treatment

Introduction

Epidemiology

Pathophysiology

Brain Edema

Classification

Vasogenic Brain Edema

Cytotoxic Brain Edema

Traumatic Brain Edema

Focal Traumatic Brain Edema

Diffuse/Global Traumatic Brain Edema

Treatment of Traumatic Brain Edema

Clinical Management of Brain Edema and Increased Intracranial Pressure

Cerebral Perfusion Pressure

Osmotic Substances

Hyperventilation

Hypothermia

Barbiturates

Decompressive Surgery

Summary

References

Further Reading

24 Treatment of Edema Formation in Oncology

Introduction

Primary CNS Tumors

Tumor-Associated Brain Edema

Imaging of Brain Tumors and Tumor-Associated Edema

Anatomo-Functional Background

Medical Treatment of Brain Edema in Neurooncology

Corticosteroids

Boswellia

Antiangiogenic Therapy

Aquaporin

Osmodiuretic

Surgical Intervention

Management of Intracranial Pressure

Future Perspectives

Conclusion

References

25 Perspectives on Future Translational Research on Brain Edema

Introduction

Source of Brain Edema Fluid

Resolution of Edema: Where and How Is the Water Leaving the CNS?

The Link Between Cytotoxic Cell Swelling and Edema

Edema Formation in Different Regions of the CNS

Tumor and Immune Cell-Mediated Brain Edema

Molecular Targets for the Treatment of brain edema

References

Index

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