Brain Edema

From Molecular Mechanisms to Clinical Practice

Jerome Badaut, Nikolaus Plesnila

• Publisher: Academic Press
• Year: 2017
• Print ISBN: 9780128031964
• eBook ISBN: 9780128031971
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Brain Edema: From Molecular Mechanisms to Clinical Practice brings together the most widely recognized experts in experimental and clinical brain edema research to review the current knowledge gathered on the molecular and cellular pathophysiology and clinical management of brain edema. This timely book also discusses future directions of research and treatment.Brain edema is an integral and acutely life-threatening part of the pathophysiology of multiple cerebral and non-cerebral disorders, including traumatic brain injury, cerebral ischemia, brain tumors, cardiac arrest, altitude sickness and liver failure. Affecting millions worldwide, research over the past few years has shown that a plethora of complex molecular and cellular mechanisms contribute to this pathological accumulation of water in the brain parenchyma.In parallel, the development of new neuroimaging tools has provided a new way to examine how edema develops longitudinally and in real time, both in pre-clinical models and in patients. Despite intense research over the past few decades, therapeutic options are still limited and sometimes not effective.- Presents a comprehensive understanding of the molecular mechanisms involved in edema formation and resolution- Discusses the specific role of edema development in several pathologies, including traumatic brain injury, stroke, brain tumors, cardiac arrest, and liver failure- Proposes a new classification of edema based on molecular processes- Discusses clinical management of new clinical trials coming from pre-clinical studies- Addresses the possible link between edema formation, other molecular and cellular processes, including inflammation and neuroinflammation

Section IV

Brain Edema Process in Preclinical Models

Outline

Chapter 12 Edema and BBB Breakdown in Stroke

Chapter 13 Brain Edema Formation in Traumatic Brain Injury

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

Chapter 15 Brain Edema in Acute Liver Failure

Chapter 16 Blood–Brain Barrier and Edema in Brain Tumors

Chapter 17 Water Homeostasis Dysfunction in Epilepsy

Chapter 18 Water Homeostasis Dysfunctions and Edema in Neuroinflammatory Disease

Chapter 19 Experimental Therapies for Brain Edema and Intracranial Hypertension

Chapter 12

Edema and BBB Breakdown in Stroke

Kathleen E. Salmeron, Danielle N. Edwards, Justin F. Fraser and Gregory J. Bix, University of Kentucky, Lexington, KY, United States

Abstract

Stroke is a leading cause of death and disability affecting 15 million people worldwide. Although rapid recognition and treatment have dropped mortality rates, many are left with permanent disability. Approximately 87% of all strokes result from the occlusion of cerebrovasculature (ischemic strokes). Current research distinguishes between zones of core infarct and areas of metabolically compromised but potentially viable tissue receiving collateral circulation known as penumbra. Research has long focused on how endogenous mechanisms of neuroprotection and neurorepair affect penumbral expansion. Such therapeutic approaches have included antiinflammatory interventions, reactive oxygen species scavengers, and many other targets with the common goal of mitigating the acute and chronic inflammatory responses typically seen in an ischemic stroke. This chapter will discuss acute and chronic molecular mechanisms underlying edema following ischemic stroke.

Keywords

BBB breakdown; cerebrovasculature; edema; penumbra; stroke

Outline

Introduction 220

Physiologic Structure and Function of the Blood–Brain Barrier 220

The Phases of Edema in Stroke 221

Hyperacute Phase: The First Few Minutes 221

The Acute Phase: The First Hours 222

The Patient in the Clinic: Reperfusion and Edema 223

Edema 226

The Subacute Phase: 24–48 Hours 227

The Chronic Phase: 3 Days–2 Weeks 228

Summary 228

References 229

Further Reading 233

Introduction

Stroke is a leading cause of death and disability affecting 15 million people worldwide. Although rapid recognition and treatment have dropped mortality rates, many are left with permanent disability. Approximately 87% of all strokes result from the occlusion of cerebrovasculature (ischemic strokes).¹ Current research distinguishes between zones of core infarct and areas of metabolically compromised but potentially viable tissue receiving collateral circulation known as penumbra.² Research has long focused on how endogenous mechanisms of neuroprotection and neurorepair affect penumbral expansion. Such therapeutic approaches have included antiinflammatory interventions, reactive oxygen species (ROS) scavengers, and many other targets with the common goal of mitigating the acute and chronic inflammatory responses typically seen in an ischemic stroke. This chapter will discuss acute and chronic molecular mechanisms underlying edema following ischemic stroke.

Despite advancements in reperfusion and recanalization through intravenous tPA and mechanical thrombectomy, stroke still often results in significant disability. Edema and inflammation compound the injury and can turn a disabling infarct into a deadly lesion causing mass effect. Despite advancements in recanalization, the expansion of ischemic injury occurs regardless of the restoration of blood flow. A key component of such injury expansion is the breakdown of the blood–brain barrier (BBB).³ Here, we will examine how this breakdown leads to brain swelling (edema). To do this, we the first need to understand the composition and physiologic function of the BBB.

Physiologic Structure and Function of the Blood–Brain Barrier

Under physiologic conditions, the BBB separates the healthy brain from the systemic blood supply. It is a multilayered unit made up of astrocytic endfeet, extracellular matrix (ECM), microglia, pericytes, and nonfenestrated capillaries, which are tightly interconnected in order to protect the brain parenchyma from noxious substances in blood such as immune cells and cytokines. Moreover, the BBB is also responsible for regulating the flow of nutrients into the brain and metabolic by-products out of the brain, thereby helping to maintain a healthy brain environment.^4,5 Specifically, although the vasculature in the majority of the brain is tightly contained, astrocytes with endfeet in close proximity to the vasculature are tasked with filtering nutrients and water into the brain parenchyma and delivering them to neurons.^5,6 Importantly, astrocytes remain unreactive under normal conditions.⁷ Astrocytic endfeet are anchored to, and separated from the endothelium by, the ECM.^4,5 The same is true with vascular endothelial cells, which are anchored to the matrix. Previously, biochemists believed that the ECM was just a water-based substance that filled the space between cells throughout the body. Today, we know that the matrix provides crucial signal transduction proteins, scaffolding for cell stability and motility, and facilitates homeostasis.⁸

Among the most important cellular signaling receptors that interact with the ECM are integrins. These interactions with ECM components such as collagen, laminin, and fibronectin, aid in cell signaling, activation, and migration.^5,9–13 In addition, brain endothelial cells form intercellular barriers called tight junctions (TJs), made up of TJs proteins including claudin, occludin, and junction adhesion molecules.⁵ TJs are responsible for regulating and maintaining the relative impermeability of the brain parenchyma to cells as well as to large molecules.^4,5 Pericytes, while not as well understood, are thought to aid in this regulation of BBB permeability under normal conditions.^14,15 Taken together, the barrier is essential for protecting the brain parenchyma and, if disturbed, can result in or exacerbate brain injury.

The Phases of Edema in Stroke

Stroke occurs in three main phases: acute (can be further split into hyperacute and acute phases), subacute, and chronic. The hyperacute phase, occurring within the first several minutes of stroke onset, is the phase in which clinical symptoms appear but is not the phase in which most damage occurs. The second phase, the acute phase, occurs within the first few hours of a stroke and is the phase in which most, if not all, clinical intervention must occur for there to be any positive change in patient outcome.² The subacute phase occurs 24–48 hours after onset. This phase is difficult to define because the infarct has not yet reached its maximum volume. It is, however, past the therapeutic window for either IV t-PA or for endovascular thrombectomy.^2,6,16,17 The final or chronic phase can last for 1–2 weeks. This is the phase wherein the brain pathophysiology transitions from neuroprotective to neuroreparative mechanisms.^5,6,16

Hyperacute Phase: The First Few Minutes

The brain’s response to an ischemic event is swift. Because the cells are not receiving the oxygen and energy that they need, ion pumps fail to maintain homeostatic sodium and potassium concentrations, resulting in calcium influx into the cytoplasm. This rapid ion exchange causes excitatory cells (neurons) to depolarize in a process called anoxic depolarization,¹⁸ which releases glutamate into the extracellular space. Astrocytes, in carrying out their physiological function, take up the released glutamate using the glutamate–sodium cotransporter. In addition, the further influx of water through channels, known as aquaporins, causes osmotic swelling of the cell.^2,19 The end result is that neurons and astrocytes within the ischemic core terminally depolarize and will eventually undergo apoptosis. Some studies have shown that blockade or selective knock-down of these aquaporins, particularly aquaporin-4, helps to prevent the formation of metabolic edema after events such as stroke and traumatic brain injury.^6,19

Meanwhile, the cells of the neurovascular unit release Hypoxia Inducible Factors (HIFs) as well as other signaling molecules, which rapidly activate glial cells. HIFs are typically not released in sufficient quantities to initiate widespread effects. Local astrocytes and microglia; however, will release pro- and antiinflammatory cytokines and other inflammatory markers into the core of the infarcted area.¹⁷ This release of inflammatory mediators results in acute, local swelling, which triggers a decrease in diameter of the vasculature.^5,6 In addition, many of the cytokines released by glial cells cause a breech in the integrity of the BBB.¹⁷ Although this process is just beginning within the first few minutes of ischemia, these early initial events set up a ca...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Acknowledgments
• List of Contributors
• Introduction: Brain Edema Formation—Significance for Patient Outcome
• Section I: General Introduction
• Section II: Techniques to Investigate Cerebral Blood
• Section III: Molecular Basis and Concepts in Brain Edema Formation for New Treatment Development
• Section IV: Brain Edema Process in Preclinical Models
• Section V: Clinical Features and Management of Brain Edema
• Index