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M. Oehmichen R. N. Auer H.G. König Forensic Neuropathology and Associated Neurology

M. Oehmichen R. N. Auer H.G. König

Forensic Neuropathology and Associated Neurology With a Foreword by Kurt A. Jellinger With 264 Figures and 69 Tables

123

Manfred Oehmichen Universitätsklinikum Schleswig-Holstein Institut Rechtsmedizin Kahlhorststrasse 31–35 D-24562 Lübeck Germany

Hans Günter König Universität Tübingen, Institut für Gerichtliche Medizin Eberhardtstrasse 4 D-72074 Tübingen Germany

Arnold-Heller-Strasse 12 24105 Kiel Germany Roland N. Auer Dept. of Pathology and Laboratory, University of Calgary 3330 Hospital Drive NW Calgary Alberta, T2N 4N1 Canada

Photo Documentation by Mrs. Dagmar Angermann Institute of Legal Medicine University of Lübeck

ISBN-10 ISBN-13

3-540-23500-0 978-3-540-23500-2

Libary of Congress Control Number: 2005924215 This work is subjekt to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must be obtained from Springer-Verlag. Violations are liable to prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springeronline.com © Springer-Verlag Berlin Heidelberg 2006 Printed in Germany

Basic Translation by James Heywood 142 W. 2nd St. Mesa/AZ 85201 USA

Springer-Verlag Berlin Heidelberg New York The use of general descriptive names, registered names, trademarks, etc. in this publications does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Gabriele Schröder, Heidelberg Desk Editor: Stephanie Benko, Heidelberg Typesetting: Satz-Druck-Service, Leimen Production: Pro Edit GmbH, Heidelberg Cover-Design: Frido Steinen-Broo, EStudio Calamar, Spain Printing and Binding: Stürtz, Würzburg Printed on acid-free paper

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Foreword

Partly as a result of major recent advances in neurobiology and molecular sciences, but also as a consequence of improving methods in clinical neurosciences, general and forensic pathology, forensic neuropathology has become a highly specialized field of modern medicine, which deals with disorders of the nervous system under non-natural, traumatic, exogenous or criminal conditions. Although forensic neuropathology has a long tradition, leading from C.B. Courville (1964) via Leestma (1988), and Unterharnscheidt (1992−94) to Manfred Oehmichen, and is of eminent importance within the field of forensic sciences, this particular and complicated subject has received only little attention within the scientific community. With greater and more precise understanding of the pathological, physical, biochemical, and molecular genetic processes involved in disorders of the nervous system and their relations with causes of death under natural and non-natural circ*mstances, the prospects of new forms of investigation into fatal processes are becoming more practicable. Based on lifelong experience in the field of general forensic medicine and, in particular, forensic pathology and neuropathology, Forensic Neuropathology and Associated Neurology, written by Manfred Oehmichen, Roland N. Auer, and Hans Günter König presents a timely overview of the state-of-the-art of examination and clarification of diseases of the nervous system under general and forensic circ*mstances. Like general pathology and neuropathology, its forensic part serves not only to clarify the causes of death due to nervous system disorders, but it is an important method for quality control excluding natural causes of death. Thus, forensic neuropathology, based on recent results, guidelines and standards of modern pathology and neurosciences, has become an integral part of forensic medicine and practice. The concept and the structure of the book is based on the principles of forensic neuropathology, modern cytology, cell and tissue reactions, modern biophysics, and molecular biology of the nervous system. It is an important and difficult task for the

forensic neuropathologist to differentiate naturally occurring disorders from non-natural and exogenous ones, and he needs extensive experience in order to avoid misinterpretation of cerebral lesions, which becomes more and more difficult with our increasing knowledge of the pathology and pathogenesis of nervous system disorders, the etiology of which remains to be elucidated. On the other hand, basic and clinical neuropathologists not experienced in forensic problems often may not be able to differentiate naturally developing disorders from forensic ones, while many forensic pathologists are not acquainted with the current neuropathological literature. The present book, the first one on forensic neuropathology after almost two decades, and the first written by German scientists after Unterharnscheidt’s handbooks of traumatic lesions of the brain and spinal cord, closes a broad gap between clinical and forensic neuropathology. The coverage of the topics listed in the table of contents is comprehensive and complete. After dealing with general aspects and basic mechanisms of molecular neuroscience, it reviews the major disorders of the central and peripheral nervous system with impact on lesions most frequently observed in forensic medicine, i.e., physical, ischemic/hypoxic, and toxic damage to the nervous system of adults, and especially of infants and children, but also naturally occurring disorders of the nervous system, including vascular, metabolic, toxic, degenerative, and age-related diseases, all handled in a well-written, concise, and didactic way. The book is based on the senior author’s vast experience in his particular profession, and will provide the reader with a state-of-the-art overview of forensic neuropathology. The illustrations, as one would expect in a Springer book, are outstanding, and the reference lists added to each chapter are informative. Speaking as one who has spent much of his lifetime in neuropathology and applied neurosciences and as a close friend to the senior author of this seminal book, I am glad to note that it covers practically the whole field of neuropathology with impact on

VI

Foreword forensic problems. I am happy to recommend this outstanding volume as a first-rate reference book to a wide audience of forensic scientists, general pathologists, clinical neuropathologists as well as to neurologists, neuropediatrists, and psychiatrists, and other health professionals interested and engaged in forensic problems of disorders of the nervous system. Indeed, many physicians and health

professionals will find much information within its pages. I am confident that this outstanding and distinguished textbook is assured of full success. K.A. Jellinger, MD Professor of Neurology and Neuropathology, Medical University of Vienna Senior Editor-in-chief of Acta Neuropathologica

Preface

The present textbook was written with the same intentions as Leestma introduced his excellent monograph (Forensic Neuropathology. Raven, New York, 1988), “to deal with those areas which have the most importance in forensic settings, are typical problem areas, or seem to be poorly understood by most forensic pathologists….” The authors have attempted not only to describe the pathom*orphology of insults of the human nervous system, but also the underlying pathophysiological, molecular, and biomechanical principles that can help forensic pathologists to understand the pathological changes induced by a traumatic event and enable the expert witness to reconstruct the criminal act; they have tried to integrate the forensic and criminalistic problems and questions as well as − to a certain degree − the clinical features and sequelae. The aim of this volume is to bridge the gap between the ways of thinking of the basic neuroscientist, the researcher, the practicing medicolegal neuropathologist, and the clinical phy-

sician. We hope the reader will find this approach unique and useful, as well as intriguingly broadening the horizons of what is usually discussed under medicolegal headings and topics. The clinical aspects are discussed since forensic pathologists are increasingly asked to aid in medicolegal questions in connection with medical lawsuits. On the other hand we have lost sight of the needs of clinical neurologists, neurosurgeons, neuropediatricians, neurotraumatologists, and neuroradiologists, who may also be called to serve as expert witnesses in court. Thus we offer essential information on the pathological processes encountered in survivors of different brain injuries. The present book may therefore be a useful tool for both pathologists and clinicians confronted with forensically relevant injuries and disorders of the human nervous system.

M. Oehmichen, R.N. Auer, H.G. König

Acknowledgements

This volume was made possible by the many years the authors have devoted to traumatology of the nervous system in the fields of clinical neuropathology (R.N. Auer), forensic physics (H.G. König), as well as clinical neuropathology and forensic pathology and neuropathology (M. Oehmichen). We would like to thank Dr. med. Carol Falk for advice on the use of medical English. We cannot let this opportunity pass without expressing our special gratitude to Mrs. Silke Tychsen-Langer, Mrs. Dagmar Angermann and Mrs. Susanne Rath. Mrs. Tychsen-Langer has devoted countless hours to the painstaking task of typing and correcting the manuscript not just once, but many times as the text evolved and grew. Without her help this book would not exist in its present form. Mrs. Angermannn has been responsible for the figures, from the beginning (autopsy) up to the final electronic processing and management; thus her documentation is the basic framework of the textbook. Mrs. Rath was responsible for total the histological and immunohistological techniques. M. Oehmichen owes a great debt of gratitude to his fellow scientists and wishes to express additional acknowledgements, as follows: ▬ Dr. Ivana Gerling/Lübeck, Germany ▬ PD Dr. Christoph Meissner/Lübeck, Germany ▬ Dr. Arthur Reiter/Lübeck, Germany who over many years of joint effort performed autopsies and issued expert opinions from which in

part the present volume’s extensive documentation and work-up of case material was cooperatively derived. ▬ Professor Dr. Rainer Mattern/Heidelberg, Germany ▬ Professor Dr. Ingo Pedal/Heidelberg, Germany ▬ Professor Dr. Klaus-Steffen Saternus/Göttingen, Germany ▬ Professor Dr. Volker Schmidt/Halle, Germany who have provided many years of expert consultation and assistance in clarifying causes of death (neuropathological examinations and reports being entrusted to M.O.) and whose case material has compensated for short falls in our own. ▬ Professor Dr. Hans-Björn Gehl/Lübeck, Germany ▬ Dr. Ulrich van Laak/Kiel, Germany ▬ Professor Dr. Ingo Pedal/Heidelberg, Germany ▬ Professor Dr. Erich Reusche/Lübeck, Germany ▬ Professor Dr. Gisela Skopp/Heidelberg, Germany ▬ Professor Dr. Horst Wiethölter/Stuttgart, Germany who proffered their critical review of parts of the manuscript and constructive comments and valuable suggestions. Their joint contribution and support made it possible to complete this volume in its present form.

Contents

Abbreviations

3.4

XXI

1

Introduction

I

Principles of Forensic Neuropathology 5

2 2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.5.1 2.1.5.2 2.2 2.2.1 2.2.2 2.2.3 2.2.4

Risks, Responsibilities and Liabilities 7 Basic Principles 7 Identity of the Victim 8 Manner of Death 8 Cause of Death 8 Process of Dying 9 Causation 10 German Theories of Causation 10 American Theories of Causation 10 Role of Expertise and Expert Witness 11 Definition: Expert Witness 11 Standards in (the American) Court 11 Function of Expert Witness 12 Probability of Expert Opinion 12 Bibliography 12 References 12

3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.2.3 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.4 3.3 3.3.1 3.3.2 3.3.3

1

Cytology of the CNS 15 Neurons 15 Morphology 15 Function 17 Pathology 19 Astrocytes 20 Morphology, Classification, and Immunoreactivity 20 Function 20 Pathology 23 Reactive Astrogliosis 23 Piloid Gliosis 24 Metabolic (Protoplasmic) Gliosis Regressive Alterations 24 Oligodendrocytes 24 Morphology, Classification, and Immunoreactivity 24 Function 25 Pathology 26

24

Microglia and/or Mononuclear Phagocytes of the CNS 27 3.4.1 Morphology, Classification, and Immunoreactivity 27 3.4.2 Pathology 28 3.4.3 Function 31 3.4.3.1 Resting Microglia 32 3.4.3.2 Perivascular Microglia 32 3.4.3.3 Activated Microglia (Macrophages) 32 3.5 Additional Cell Types and Tissue Components 32 3.5.1 Leptomeningeal and Perivascular Cells 32 3.5.2 Parenchymal Vessels 33 3.5.3 Choroid Plexus and Ependyma 33 3.5.4 Pathology of the CSF and Cells Within the CNS 33 Bibliography 34 References 34 4 4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.1.4.1 4.1.4.2 4.1.4.3 4.1.5 4.1.6 4.1.7 4.1.7.1 4.1.7.2 4.1.7.3 4.1.7.4 4.1.8 4.2 4.2.1 4.2.2 4.2.3 4.3

Cell and Tissue Reactions 41 Increased Brain Volume − Edema 42 Definition 42 Clinical Features 42 Pathogenesis 44 Types of Brain Edema 44 Vasogenic Edema 44 Cytotoxic Edema 47 Conclusion 47 Neuropathology 48 Space-Occupying Effects 49 Herniation 51 Uncal Herniation 51 Cingulate Herniation 53 Central Transtentorial Herniation 53 Upward Tentorial Displacement 54 Forensic Implications 54 Hydrocephalus 54 Classification and Pathogenesis 54 Neuropathology 55 Clinical Features 56 Cell and Tissue Decay 56

XII

Contents 4.3.1 4.3.1.1 4.3.1.2 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.6.1 4.3.6.2 4.3.7 4.4 4.4.1 4.4.2 4.4.2.1 4.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5 4.4.3 4.4.3.1 4.4.3.2 4.4.3.3 4.4.4 4.4.4.1 4.4.4.2 4.4.4.3 4.4.5 4.5 4.5.1 4.5.2

5 5.1 5.1.1 5.1.1.1 5.1.1.2 5.1.1.3 5.1.2 5.1.2.1 5.1.2.2 5.1.2.3

Injury-Induced Cell Death: Necrosis 56 Incomplete Necrosis 57 Tissue Necrosis: Infarction 58 Gene-Regulated Cell Death: Apoptosis 60 Necrosis Versus Apoptosis 62 Penumbra 63 Dendritic Injury 64 Axonal Injury 65 Anterograde (Wallerian) Degeneration 66 Retrograde Degeneration 66 Regenerative Capacity 66 Inflammation 67 Principles of Neuroimmunology 67 Inflammatory Cells 67 Polymorphonuclear Leukocytes 69 Lymphocytes 69 Microglia and Brain Macrophages 69 Astrocytes 70 Endothelial Cells and Collagen Fibers 70 Inflammatory Mediators 71 Cytokines 71 Chemokines 71 Effector Molecules 71 Types of Inflammation 72 Sterile Inflammation 72 Cell-Mediated Inflammation 72 Antibody-Mediated Inflammation 73 Inflammation-Induced Ischemia 73 Misinterpretable Findings 73 Gross Findings 73 Microscopic Findings 74 Bibliography 75 References 76

Methods in Forensic Neuropathology 83 Macroscopic Examination 83 Principles of Brain Autopsy 83 Biosafety 83 Preserved Native Material 83 Documentation 84 Brain 84 Fixation Procedures 84 Examination during Autopsy 85 Sectioning of the Formalin-Fixed Brain 85 5.1.2.4 Block Selection for Microscopy 86 5.1.2.5 Paraffin Embedding 88 5.1.2.6 Special Problems 88 5.1.3 Spinal Cord 89 5.1.4 Peripheral Nerves 89 5.2 Microscopic Examination 90

5.3

Postmortem Imaging Bibliography 92 References 92

II

Physical Trauma 95

6 6.1 6.2

Basic Principles of Mechanical Trauma 97 Classification 97 Epidemiology of Mechanical Brain Injury 98 Forensic Aspects 98 Biomechanical Aspects and Pathom*orphology 99 Physical Quantities 99 Mechanical Forces 99 Types of Mechanical Brain Injury 101 Pathology 102 Secondary Lesions 103 Clinical Features 104 Somatic Symptoms 104 Neuropsychological Impairment 105 Outcome 106 Medicolegal Principles 106 Bibliography 107 References 107

6.3 6.4 6.4.1 6.4.2 6.4.3 6.4.4 6.4.5 6.5 6.5.1 6.5.2 6.6 6.7

7 7.1 7.1.1 7.1.2 7.1.3 7.1.3.1 7.1.3.2 7.1.3.3 7.1.3.4 7.1.3.5 7.2 7.2.1 7.2.2 7.2.2.1 7.2.2.2 7.2.2.3 7.2.2.4 7.2.2.5 7.2.2.6 7.2.3 7.3 7.3.1 7.3.2 7.3.3 7.4 7.4.1 7.4.2

90

Injuries of the Brain’s Coverings 111 The Scalp 113 Anatomy 113 Pathophysiology 113 Pathology 113 Abrasion Injury 114 Contusion Injury 114 Hematoma 114 Laceration Injury 114 Avulsion Injury 114 The Skull 115 Anatomy 115 Biomechanical Aspects 116 Linear Calvarial Fracture 117 Depressed Calvarial Fracture 117 Combined Fractures 117 Basilar Skull Fracture 117 Facial Skull Fracture 120 Growing Skull Fracture 120 Clinical Features 120 Dura Mater 120 Anatomy 120 Pathology 120 Secondary Lesion (Herniation Syndrome) 123 Epidural Hemorrhage 123 Classification 123 Biomechanical Aspects 123

Contents 7.4.3 7.4.4 7.4.4.1 7.5 7.5.1 7.5.2 7.5.3 7.5.3.1 7.5.3.2 7.5.3.3 7.5.4 7.5.4.1 7.5.4.2 7.5.4.3 7.5.4.4

Pathology 125 Clinical Features 125 Prognosis 125 Subdural Hemorrhage 126 Classification 126 Biomechanical Aspects 127 Clinical Features 129 Types and Causes of SDH 129 Prognosis 129 Diagnosis 130 Pathology 130 Acute SDH 130 Subacute SDH 132 Chronic SDH 132 Internal Hemorrhagic Pachymeningitis 135 7.5.4.5 Hygroma 135 7.6 Histology and Microscopic Dating of EDH and SDH 135 7.7 Injuries of Intracranial Vessels 138 7.7.1 Mechanically Induced Subarachnoid Hemorrhage and Intraventricular Hemorrhage 139 7.7.1.1 Biomechanical Aspects 139 7.7.1.2 Clinical Features 141 7.7.1.3 Pathology and Differential Diagnosis 142 7.7.1.4 Delayed Mechanically Induced Apoplexy 143 7.7.2 Mechanically Induced Aneurysm 143 7.7.2.1 “False” Aneurysm 143 7.7.2.2 Dissecting Aneurysm 144 7.7.3 Mechanically Induced Arterial Thrombosis 144 7.7.4 Injury of the Veins 145 7.7.4.1 Injury of the Sinuses (Sinus Thrombosis) 145 7.7.4.2 Carotid Artery − Cavernous Sinus Fistula (Carotid-Cavernous Fistula, CCF) 145 7.8 Injuries of the Extracranial Arteries 146 7.8.1 Injury of the Carotid Artery 146 7.8.2 Injury of the Vertebral Artery 147 Bibliography 147 References 147 8 8.1 8.1.1 8.1.2 8.1.3 8.2 8.3 8.3.1 8.3.2 8.3.3

Open Brain Injuries 151 Basic Principles 151 Classification 151 Biomechanical Aspects 151 Pathology 151 Stabbing and Incision Wounds Gunshot Wounds 154 Clinical Features and Capability to Act 155 Biomechanical Aspects 159 Pathology 161

8.3.3.1 8.3.3.2 8.3.3.3 8.3.4 8.3.5 8.3.6 8.4

Scalp 161 Skull 162 Brain 165 Postmortem Imaging 167 Homicide, Suicide, Accident 168 Dating of Gunshot Wounds 169 Secondary Lesions 171 References 173

9 9.1 9.2

Closed Brain Injuries 177 Classification 177 Concussion Injury and Cortical Hemorrhage 179 Biomechanical Aspects 179 Injury by Fall 183 Injury by Blow 184 Cellular and Molecular Mechanisms 185 Cytological Reaction 185 Necrosis 187 Apoptosis 188 ApoE-Genotype 189 Pathology 189 Concussion Injury 189 Contusion Injury 189 Posterior Fossa Hemorrhage 190 Scar Formation 190 Dating of Cortical Hemorrhages 190 Intracerebral Hemorrhages 194 Classification 194 Pathology and Differentiation 196 Brain Stem Hemorrhages 198 Primary Brain Stem Hemorrhage 199 Secondary Brain Stem Hemorrhage 200 Intraventricular Hemorrhage 201 Diffuse Brain Injuries 202 Edema 202 Ischemia 204 Axonal Injury 205 Vascular Lesion 207 Boxing Brain Injury (Punch Drunk Syndrome) 207 CNS Involvement in Mechanical Injury without Primary Brain Injury 208 Fat Embolism 208 Air Embolism 209 Vascular Injury 210 Coagulation Disorders 210 Ischemic Injury 210 Bibliography 210 References 210

9.2.1 9.2.1.1 9.2.1.2 9.2.2 9.2.2.1 9.2.2.2 9.2.2.3 9.2.2.4 9.2.3 9.2.3.1 9.2.3.2 9.2.3.3 9.2.3.4 9.2.4 9.3 9.3.1 9.3.2 9.3.3 9.3.3.1 9.3.3.2 9.3.4 9.4 9.4.1 9.4.2 9.4.3 9.4.4 9.4.5 9.5 9.5.1 9.5.2 9.5.3 9.5.4 9.5.5

152 10 10.1 10.1.1 10.1.2

Injuries of Spine and Spinal Cord Basic Principles 217 Epidemiology 217 Anatomy 218

217

XIII

XIV

Contents 10.1.3 10.1.4 10.1.5 10.2 10.2.1 10.2.2 10.2.2.1 10.2.2.2 10.2.2.3 10.2.2.4 10.2.3 10.2.3.1 10.2.3.2 10.2.4 10.2.4.1 10.2.4.2 10.2.4.3 10.2.4.4 10.3 10.3.1 10.3.1.1 10.3.1.2 10.3.2 10.3.3

11 11.1 11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.2.5 11.3 11.3.1 11.3.2 11.3.3

12 12.1 12.1.1 12.1.1.1 12.1.1.2 12.1.1.3 12.1.1.4 12.1.2 12.1.2.1

Pathophysiology 219 Clinical Features 219 Biomechanical Aspects 220 Spinal Cord Injury (SCI) 221 Subdural and Epidural Hemorrhage 221 Penetrating SCI 221 Stab Wound 223 Gunshot Wound 223 Disruption of the Craniocervical Junction 223 Pathology of Penetrating Injury 224 Closed Cord Injury 225 Biomechanical Aspects 225 Clinical Features 225 Neuropathology 226 Contusional Injury of the Cord 226 Compression Injury of the Cord 229 Vascular Myelopathy 231 Iatrogenic Cord Injury 231 Injury of the Cervical Spine 233 Biomechanical Features 233 Direct Injury 233 Indirect Injury 234 Indirect (“Whiplash”) Injury 234 Chiropractic Manipulation 235 Bibliography 236 References 236 Injuries of Peripheral Nerves 241 Anatomy 241 Types of Morphological Reactions 242 Wallerian Degeneration 242 Retrograde Reaction (Axonal Degeneration) 242 Remote Effects 242 Edema 243 Regeneration 243 Types of Injury 243 Injuries by Compression and Percussion 243 Injuries by Traction and Elongation 243 Injuries by Transection 244 Bibliography 244 References 244 Special Physical Trauma 245 Thermal Trauma 245 Hypothermia 246 Incidence 246 Pathophysiology 246 Clinical Features 247 Neuropathology 248 Hyperthermia 248 Incidence 248

12.1.2.2 Pathophysiology 249 12.1.2.3 Clinical Features and Neuropathology 249 12.1.2.4 Heat Exhaustion 250 12.1.2.5 Sunstroke (Insolation) 250 12.1.2.6 Heatstroke 250 12.1.3 Trauma by Fire and Burns 251 12.1.3.1 Incidence 251 12.1.3.2 Clinical Features 251 12.1.3.3 Neuropathology 251 12.2 Electrical Trauma 254 12.2.1 Incidence 254 12.2.2 Clinical Features 254 12.2.3 Pathogenesis 255 12.2.4 Neuropathology 255 12.2.5 Electric Shock Devices 256 12.2.6 Electromagnetic Radiation 256 12.3 Lightning Trauma 256 12.3.1 Incidence 256 12.3.2 Clinical Features 256 12.2.3 Neuropathology 257 12.4 Irradiation Trauma 257 12.4.1 Pathogenesis 257 12.4.2 Types of CNS Reaction 258 12.4.3 Acute Radiation Injury 258 12.4.3.1 Radiation Necrosis 258 12.4.3.2 Transitory Radiation Myelopathy 259 12.4.3.3 Radiation Neuropathy 259 12.4.4 Early Delayed Reaction 259 12.4.5 Chronic Radiation Injury 259 12.4.5.1 Acute Onset 259 12.4.5.2 Chronic Progressive Injury 259 12.5 Special Mechanical Trauma 259 12.5.1 Ultrasound Injury 259 12.5.2 Pressure Injury 260 12.5.2.1 Barotrauma 260 12.5.3 Toxicity of Hyperbaric Gases 261 12.5.4 Decompression Sickness (DCS) 261 12.5.4.1 Incidence 261 12.5.4.2 Pathophysiology 261 12.5.4.3 Clinical Features 261 12.5.4.4 Neuropathology 262 12.5.5 Gas Embolism 262 12.5.5.1 Pathophysiology and Clinical Features 262 12.5.5.2 Neuropathology 263 12.5.6 High-Altitude Illness 263 12.5.6.1 Incidence 263 12.5.6.2 Clinical Features and Pathophysiology 263 12.5.6.3 Pathology and Neuropathology 264 Bibliography 264 References 264

Contents

III

Ischemia and Asphyxia 271

13 13.1 13.2 13.3 13.3.1 13.3.2 13.3.3 13.3.4 13.3.5 13.4 13.4.1 13.4.2 13.4.2.1 13.4.2.2 13.4.2.3 13.4.2.4 13.4.2.5 13.4.2.6 13.4.2.7

Hypoxia, Ischemia (Hypoglycemia) 273 Basic Principles 273 Metabolic Disturbances 275 Hypoxia 276 High-Altitude Mountaineering 277 Respiratory Disease 278 Anemic Hypoxia 279 Histotoxic Hypoxia 279 Neuropathology 279 Ischemia 280 Pathophysiology 280 Neuropathology 281 Cerebral Cortex 281 Hippocampus 282 Basal Ganglia 284 Brain Stem 284 Cerebellum 285 Spinal Cord 285 White Matter Lesions (Leukoencephalopathy) 286 Hypoglycemia 286 Neuropathology 287 Bibliography 288 References 288

13.5 13.5.1

14 14.1 14.1.1 14.1.2 14.1.3 14.1.4 14.1.5 14.1.5.1 14.1.5.2 14.2 14.2.1 14.2.2 14.2.3 14.2.4 14.2.4.1 14.2.4.2 14.2.5 14.3 14.3.1 14.3.2 14.3.3

Forensic Types of Ischemia and Asphyxia 293 Suffocation 294 Environmental Suffocation 294 Smothering, Choking, and Gagging 295 Drowning 295 Mechanical Asphyxia 296 Neuropathology of Suffocation 296 Acute Death after Suffocation 296 Delayed Death after Suffocation 296 Strangulation 297 Hanging 297 Ligature Strangulation 298 Manual Strangulation 298 Neuropathology of Strangulation 298 Acute Death after Strangulation 299 Delayed Death after Strangulation 299 Cervical Spine and Strangulation 300 Time Course of Ischemia 301 Macroscopic Findings 301 Edema 301 Microthrombosis and Fibrin Deposition 303 14.3.4 Neurons 303 14.3.5 Neuronal Proteins 305 14.3.6 Astrocytes 306 14.3.7 Polymorphonuclear Leukocytes 307 14.3.8 Mononuclear Phagocytes/Microglia 307 14.3.9 Mesenchymal Reaction 308 14.3.10 Cytokines 308

14.3.11 14.4 14.5 14.6 14.7 14.8

Enzymes 309 Clinical Features of Acute Asphyxia 310 Transient Ischemia 311 Selective Neuronal Necrosis 312 Apallic Syndrome 312 Ethical Implications 312 Bibliography 313 References 313

15 15.1 15.2 15.3 15.4 15.4.1 15.4.2 15.5 15.5.1

Permanent Global Ischemia 319 Classification 319 Pathophysiology 319 Clinical Features 321 Neuropathology 321 Gross Examination 321 Microscopic Examination 322 Forensic Implications 323 Respirator Brain and/or Postmortem Autolysis 323 Declaration of Death 325 Time of Brain Death 326 Time of Causal Event Leading to Brain Death 327 Morphological Statement of Intracranial Circulatory Arrest 328 Bibliography 328 References 328

15.5.2 15.5.3 15.5.4 15.5.5

IV

Intoxication 331

16 16.1 16.2 16.3

Introductory Remarks 333 Biological Principles 333 Toxic Encephalopathy 335 Toxic Neuropathy/Polyneuropathy 336 Bibliography 337 References 337

17 17.1 17.1.1 17.1.2 17.1.2.1 17.1.2.2 17.1.3 17.1.4 17.1.5 17.1.6 17.1.6.1 17.1.6.2 17.1.7 17.1.8 17.1.9 17.1.9.1

Specific Types of Neurotoxins 339 Metals and Metallic Compounds 339 Aluminum (Al) 339 Arsenic (As) 341 Inorganic Arsenicals 341 Organic Arsenicals 341 Bismuth (Bi) 341 Cadmium (Cd) 342 Gold (Au) 342 Lead (Pb) 342 Inorganic Lead Compounds 342 Organic Lead Compounds 343 Lithium (Li) 343 Manganese (Mn) 344 Mercury (Hg) 344 Elementary Mercury and Inorganic Mercury Compounds 344

XV

XVI

Contents 17.1.9.2 Organic Mercury Compounds 344 17.1.10 Platinum (Pt) 345 17.1.11 Thallium (Tl) 346 17.1.12 Tin (Sn) and Tin Compounds 346 17.1.12.1 Triethyltin 346 17.1.12.2 Trimethyltin 346 17.2 Non-Metallic Inorganic Neurotoxins 347 17.2.1 Phosphorus (P) and Phosphorous Compounds 347 17.2.2 Sulfur (S) 347 17.2.2.1 Carbon Disulfide 347 17.2.3 Tellurium (Te) 347 17.3 Gases 347 17.3.1 Carbon Monoxide (CO) 347 17.3.1.1 Acute Intoxication 349 17.3.1.2 Intermittent Exposure 350 17.3.1.3 Chronic Intoxication 351 17.3.2 Cyanides and Cyanide Compounds 351 17.3.3 Hydrogen Sulfide (H2S) 352 17.3.4 Nitrous Gases and Nitrites 352 17.3.5 Oxygen (O2) 352 17.4 Industrial and Environmental Toxins 353 17.4.1 Acrylamide 353 17.4.2 Aliphatic Hydrocarbons 353 17.4.3 Halogenated Hydrocarbons 353 17.4.3.1 Methyl Chloride 353 17.4.3.2 Trichloroethylene 353 17.4.4 Chlorinated Cyclic Hydrocarbons 354 17.4.4.1 Hexachlorophene (HCP) 354 17.4.4.2 Lindane 354 17.4.5 Methyl Alcohol (Methanol) 354 17.4.6 Organophosphorus Compounds 355 17.4.7 Toxic Oil 356 17.5 Nerve Agents 356 17.6 Drugs and Pharmaceutical Products 357 17.6.1 Sedatives, Hypnotics and Analgesics 357 17.6.2 Antiprotozoal Agents 358 17.6.2.1 Chloroquine 358 17.6.2.2 Clioquinol 358 17.6.3 Cytostatics and Antituberculous Agents 359 17.6.3.1 Methotrexate 359 17.6.3.2 Vincristine, Vinblastine 359 17.6.3.3 Isoniacid 360 17.7 Biological Toxins 360 17.7.1 Plants 360 17.7.2 Animals 362 17.7.3 Microorganisms 362 17.7.3.1 Botulinum Toxin 362 17.7.3.2 Tetanospasmin 362 17.7.3.3 Diphtheria Toxin 363 17.7.3.4 Anthrax 363 Bibliography 363 References 363

18 18.1 18.2

Alcohol, Organic Solvents, and Aerosols 371 Epidemiology 371 Metabolism, Kinetics, and Causes of Death 372 18.3 Pharmacology 373 18.4 Clinical Features 374 18.4.1 Acute Intoxication 374 18.4.2 Chronic Intoxication (Alcoholism) 374 18.5 Neuropathology 375 18.5.1 Acute Intoxication 375 18.5.2 Chronic Intoxication 375 18.5.2.1 Diffuse Brain Alterations 376 18.5.2.2 Cerebellar Atrophy 378 18.5.2.3 Wernicke − Korsakoff Syndrome 378 18.5.2.4 Central Pontine Myelinolysis 379 18.5.2.5 Marchiafava − Bignami Syndrome 380 18.5.2.6 Pellagra 380 18.5.2.7 Alcoholic Myelopathy 380 18.5.2.8 Neuropathy of the Autonomic Nervous System 380 18.5.2.9 Neuropathy/Polyneuropathy 380 18.5.2.10 Myopathy 381 18.5.2.11 Secondary Pathologic Alterations 381 18.5.2.12 Disulfiram Treatment 383 18.6 Alcoholic Fetopathy and Embryopathy 383 18.7 Organic Solvents and Aerosol 384 Bibliography 385 References 385 19 19.1 19.2 19.3 19.3.1 19.3.2 19.3.3 19.3.3.1 19.3.3.2 19.3.4 19.4 19.4.1 19.4.1.1 19.4.1.2 19.4.1.3 19.4.2 19.4.3 19.4.4 19.4.5 19.4.6 19.4.7 19.5

Illegal Drugs and Drug Dependence 391 Epidemiological and Social Data 391 Cannabis 392 Hallucinogens and Entactogens 392 Mescaline 393 Lysergic Acid Diethylamide (LSD) 393 Amphetamine Substitutes 393 MDMA (3,4-methylenedioxmethamphetamine) 393 MDEA (3,4-methylenedioxyethamphetamine) 394 Other Agents 394 Narcotics: Opium and Opioids 394 Basic Principles 394 Epidemiology 394 Pathophysiology 395 Neuropathology 395 Morphine 397 Heroin 397 Codeine 397 Dihydrocodeine (DHC) 398 Methadone 398 Other Narcotic Agents 398 Stimulants 398

Contents 19.5.1 19.5.2 19.5.3 19.5.4 19.5.5 19.5.6

Cocaine 398 Cocaine Freebase: Crack 399 Amphetamine and Methamphetamine (Speed) Caffeine 400 Ephedrine 400 Khat 400 Bibliography 401 References 401

399

V

Pediatric Neuropathology 405

20 20.1 20.1.1 20.1.2 20.2 20.2.1 20.2.2 20.3 20.3.1 20.3.2 20.3.3 20.3.4 20.4

Basic Principles 407 Epidemiology 407 Injuries During the Perinatal Period 407 Acquired Postnatal Injury 408 Developmental Neuroanatomy 408 The Coverings 408 The Brain 411 Autopsy Findings 412 Head and Cranial Contents 413 Cervical Spine 413 Ears and Mastoids 414 Eyes 414 Microscopic Examination: Cell Reaction 414 Postmortem Biochemistry 415 Diffuse Cerebral Swelling 415 Hyperemia 416 Edema 416 Hydrocephalus 416 Forensic Aspects (Expert Witness) 417 Medical Malpractice 417 Physical Abuse 419 Ethical Aspects 419 Bibliography 420 References 420

20.5 20.6 20.6.1 20.6.2 20.6.3 20.7 20.7.1 20.7.2 20.7.3

21 21.1 21.2 21.2.1 21.3 21.3.1 21.3.2 21.4

Fetal Neuropathology 425 Malformations 425 Hypoxic − Ischemic Encephalopathy Neuropathology 428 Intoxication 429 Cocaine 431 Heroin 431 Infection 431 Bibliography 432 References 432

22 22.1 22.1.1 22.1.2 22.1.2.1

Perinatal CNS Injury 433 Ischemic−Asphyxiant Injury 434 Causes of Oxygen Depletion 434 Ischemic Cell Injury 435 Pathophysiology 435

427

22.1.2.2 22.1.3 22.1.3.1 22.1.3.2 22.1.4 22.2 22.2.1 22.2.2 22.2.3 22.2.3.1 22.2.3.2 22.2.3.3 22.2.3.4 22.2.3.5 22.2.4 22.2.5 22.3 22.4

Cytopathology 436 Neuropathology 436 Qualitative Differences 437 Topographical Differences 439 Dating of Asphyxiant Injury 441 Mechanical Injury (Birth Injury) 441 Extracranial Hemorrhages 441 Skull Fracture 443 Intracranial Hemorrhages 443 Epidural Hemorrhage (EDH) 443 Subdural Hemorrhage (SDH) 443 Subarachnoid Hemorrhage (SAH) 444 Intraparenchymal Hemorrhage 444 Dating of Intracerebral Hemorrhages in Immature Infants 445 Spinal Cord Injury 445 Peripheral Nerve Injury 445 Venous Sinus Thrombosis 446 Late Sequelae of Perinatal Brain Injury 447 Bibliography 447 References 447

23 23.1 23.1.1 23.1.1.1 23.1.1.2 23.1.2 23.1.2.1 23.1.2.2 23.1.3

Postnatal Natural CNS Death 451 Metabolic Diseases 451 Bilirubin Encephalopathy 452 Pathophysiology 454 Neuropathology 454 Hypoglycemic Encephalopathy 454 Pathophysiology 455 Neuropathology 455 Hemorrhagic Shock and Encephalopathy Syndrome (HSES) 455 23.1.4 Iron Deficiency 456 23.2 Stroke 456 23.3 Infectious Diseases 457 23.3.1 Bacterial Meningitis 457 23.3.2 Abacterial Meningoencephalitis 458 23.4 Tumor 459 23.5 Sudden Infant Death Syndrome (SIDS) 460 23.5.1 Definition and Incidence 460 23.5.2 Neuropathology and Pathophysiology 461 23.5.2.1 Primary CNS Changes 461 23.5.2.2 Perfusion Disturbance or Ischemia 463 23.5.3 Conclusion 465 Bibliography 465 References 465 24 24.1 24.2

Postnatal Mechanical Brain Injury (MBI) Incidence 471 Clinical Features 472

471

XVII

XVIII Contents 24.3

Biomechanical Aspects and Causal Events 472 24.4 Skull Fracture 474 24.4.1 Growing Fracture 478 24.5 Dural Hemorrhages 478 24.5.1 Epidural Hemorrhage (EDH) 478 24.5.2 Subdural Hemorrhage (SDH) 479 24.5.3 Chronic Subdural Hemorrhage (SDH) 479 24.5.4 Subdural Hygroma 479 24.6 Subarachnoid Hemorrhage (SAH) 480 24.7 Cerebral Contusion and Laceration Injury 480 24.7.1 Neuropathology 481 24.7.2 Biomechanics 481 24.7.3 Clinical Features 481 24.8 Mechanical Vessel Injury 481 24.9 Secondary Alterations 481 24.9.1 Edema and Hypoxia 481 24.9.2 Inflammation 482 24.10 Late Sequelae 482 24.10.1 Hydrocephalus 482 24.10.2 Seizures 483 24.11 Spinal Cord Injury 484 Bibliography 484 References 484 25 25.1 25.1.1 25.1.2 25.1.3 25.1.4 25.2 25.3 25.3.1 25.3.2 25.3.2.1 25.3.2.2 25.3.2.3 25.3.2.4 25.3.2.5 25.3.2.6 25.3.2.7 25.3.3 25.3.4 25.3.5 25.3.6 25.3.7 25.3.7.1 25.3.7.2 25.3.7.3

Physical Abuse 489 Basic Principles 489 Sociopsychological/ Forensic Considerations 489 Definition 491 Incidence 492 Types of Brain Injuries 492 Mechanically Caused Brain Injury 493 Shaken Infant Syndrome 493 Clinical Features 493 Autoptic Findings 496 Intracranial Hemorrhage 497 Retinal Hemorrhage 497 Brain Edema 500 Cervical Cord Injury: Dural Hemorrhage and Cord Lesion 500 Skull Fracture 501 Further Morphological Alterations 502 The Repeated Shaking 502 Shaking Impact Syndrome 502 “Tin-Ear” Syndrome 502 Cause of Death 503 Clinical Outcome 503 Differential Diagnosis 504 Wounding by Birth 505 Dehydration 505 Physiotherapy in Premature Infants 506

25.3.7.4 Sudden Infant Death Syndrome (SIDS) 506 25.3.7.5 Resuscitation 506 25.3.7.6 “Rebleed” of Chronic Subdural Hematoma 507 25.3.8 Shaking versus Fall 507 25.3.8.1 Epidemiologic Evaluation 507 25.3.8.2 Biomechanical Aspects 508 25.3.8.3 Conclusion 510 25.4 Asphyxiant Brain Injury 511 25.4.1 Types of Violence 511 25.4.2 Compression of the Chest 511 25.4.3 Drowning 512 25.4.4 Neuropathology 513 25.5 Toxic Brain Injury 513 25.5.1 Incidence 513 25.5.2 Clinical Features and Neuropathology 514 25.6 Obligations of an Expert Witness 514 Bibliography 515 References 515

VI

Clinical Neuropathology 523

26 26.1 26.1.1 26.1.2 26.1.3 26.1.3.1 26.1.3.2

Basic Principles 525 Sudden, Unexpected Death 525 Definition 525 Epidemiology 526 Classification 526 Neuronal-Mediated Death 526 Death Associated with Vascular Diseases 527 26.1.3.3 Death Associated with Inflammatory Diseases 527 26.2 Further Cerebral Diseases of Forensic Significance 527 Bibliography 528 References 528 27 27.1 27.2 27.3 27.4 27.5 27.6 27.7 27.7.1 27.7.2 27.7.3 27.7.4 27.8 27.8.1

Seizures and Epilepsy 529 Classification 529 Clinical Features 531 Etiology of Symptomatic Epilepsy 531 Pathogenesis 532 Pathophysiology 532 Epidemiology 532 Neuropathology 533 Hippocampal Pathology 534 Temporal Lobe Epilepsy 535 Myoclonic Epilepsy 535 Status Epilepticus 535 Cause of Death 535 Sudden Unexpected Death in Epilepsy (SUDEP) 536

Contents 27.8.1.1 27.8.1.2 27.8.1.3 27.9

Risk Factors 536 Pathogenetic Considerations 536 Diagnosis of SUDEP 537 Additional Forensic Implications 537 Bibliography 537 References 537

28 28.1

Vascular Diseases 541 Physiology of the Cerebral Circulation 542 Anatomy of Cerebral Vessels 543 Pathology of Cerebral Arteries 543 Cerebral Atherosclerosis 543 Brain Calcinosis 545 Cerebral Thromboembolism 546 Hypertensive Angiopathy 546 Lacunar Infarcts 548 Amyloid Angiopathy 548 Cystic Medial Necrosis 549 Aneurysms 549 Saccular (Fusiform) Aneurysm 550 Dissecting Aneurysm 552 Infectious (Mycotic) Aneurysm 553 Mechanically Induced Aneurysm 553 Inflammatory Vessel Disease (Vasculitis) 553 Non-Infectious Primary CNS Vasculitis 553 Infectious Vascular Diseases 554 Pathology of Cerebral Veins 555 Cerebral Venous Thrombosis 555 Vascular Malformations 557 Cavernous Angioma 557 Capillary Angioma 557 Venous Angioma 557 Arteriovenous Malformation 558 Von Hippel−Lindau Hemangioblastoma 558 Tumor-Induced Stroke 558 Thrombosis and Embolism 559 Tumor Vessels and Hemorrhage 559 Extracerebral Causes of Stroke 561 Coagulopathy, Hemostatic Disorder, Cerebral Thrombosis 561 Cerebral Embolism 561 Circulatory Disturbance 561 Illegal Drugs 564 Ischemic Stroke: Infarction 564 Classification of Cerebral Ischemia 565 Clinical Features of Transient and Permanent Focal Ischemia 565 Neuropathology 566 Spontaneous Intracerebral Hemorrhage 569

28.2 28.3 28.3.1 28.3.2 28.3.3 28.3.4 28.3.5 28.3.6 28.3.7 28.3.8 28.3.8.1 28.3.8.2 28.3.8.3 28.3.8.4 28.3.9 28.3.9.1 28.3.9.2 28.4 28.4.1 28.5 28.5.1 28.5.2 28.5.3 28.5.4 28.5.5 28.6 28.6.1 28.6.2 28.7 28.7.1 28.7.2 28.7.3 28.7.4 28.8 28.8.1 28.8.2 28.8.3 28.9

28.9.1 28.9.2 28.9.3 28.9.3.1

Incidence 569 Clinical Features 569 Neuropathology 571 Causes of Spontaneous Intracerebral Hemorrhage 572 28.10 Vascular Diseases of the Spinal Cord 573 28.10.1 Anatomy of the Spinal Vessels 573 28.10.2 Pathology of the Spinal Vessels 573 28.11 Forensic Aspects of Stroke 574 Bibliography 574 References 574 29 29.1 29.1.1 29.1.1.1 29.1.1.2 29.1.1.3 29.1.1.4 29.1.1.5 29.1.1.6 29.1.2 29.1.3 29.1.4 29.1.5 29.1.6 29.2 29.2.1 29.2.2 29.2.3 29.2.4 29.3 29.3.1

Inflammatory Diseases 581 Bacterial CNS Diseases 582 Purulent Leptomeningitis 582 Neuropathology 584 Late Complications 585 Neonatal Meningitis 585 Meningococcal Meningitis 585 Haemophilus Influenzae Meningitis 585 Pneumococcal Meningitis 585 Epidural Abscess 585 Subdural Abscess and/or Empyema 586 Brain Abscess 586 Tuberculous Brain Infection 587 Septic Encephalopathy 587 Abacterial CNS Diseases 590 Classification 590 Pathogenesis 591 Clinical Features 591 Neuropathology 591 AIDS and the Nervous System 593 Primary HIV-Associated Nervous System Infection 593 29.3.1.1 HIV Encephalopathy (Subacute Dementia Encephalopathy) 593 29.3.1.2 HIV Myelopathy 593 29.3.1.3 HIV Neuropathy 594 29.3.2 Secondary HIV-Associated NS Infection 594 29.4 Transmissible Spongiform Encephalopathies 595 29.5 Non-Infectious Inflammatory Diseases 596 29.5.1 Acute Hemorrhagic Leukoencephalitis (Hurst’s Disease) 596 29.5.2 Acute Demyelinating Disease 597 29.5.3 Chronic Demyelinating Disease: Multiple Sclerosis 598 Bibliography 601 References 601 30 30.1 30.1.1

Nutritional and Metabolic Insults 605 Starvation and Malnutrition 606 Protein Deficiency 606

XIX

XX

Contents 30.1.2 30.1.3 30.1.3.1 30.1.3.2 30.1.3.3 30.2 30.2.1 30.2.2 30.2.3 30.2.4 30.3 30.3.1 30.3.2 30.3.3 30.3.4 30.4 30.4.1

31 31.1 31.1.1

Vitamin Deficiencies 606 Disturbances of Glucose Metabolism 607 Hypoglycemic Encephalopathy 607 Hyperglycemia 608 Diagnosis 608 Dissociation of Water and Electrolyte Balance 608 Dehydration 608 Hypernatremia 609 Hyponatremia and Water Intoxication 609 Hyponatremia and Central Pontine Myelinolysis 610 Hepatic Encephalopathy 611 Fulminant Hepatic Failure 611 Chronic Liver Disease and Portal-Systemic Bypass 611 Familial Hepatolenticular Degeneration (Wilson’s Disease) 612 Reye’s Syndrome 612 Uremic Encephalopathy 612 Dialysis Encephalopathy 613 Bibliography 614 References 614 Aging and Brain Pathology Basic Principles 619 Biology of Aging 619

619

31.1.2 31.1.3 31.1.4 31.2 31.2.1 31.2.2 31.2.2.1 31.2.2.2 31.3 31.3.1 31.3.1.1 31.3.1.2 31.3.1.3 31.3.2 31.3.3 31.3.4 31.3.5 31.3.6 31.3.7

Neurobiology of Aging 620 Dementia and Delirium 620 Classification of Age-Dependent Dementias 621 Morphology of the Aging Brain 621 Macroscopic Alterations 621 Microscopic Alterations 622 Neurofibrillary Tangles 623 Senile Plaques 625 Pathology of the Aging Brain 625 Alzheimer’s Disease (AD) 626 Clinical Features 626 Neuropathology and Diagnostic Criteria 627 Pathogenesis 629 Neurofibrillary Tangles and Dementia 630 Dementia Pugilistica 630 Dementia in Parkinson’s Disease (PD) 631 Lewy Body Dementia 632 Frontotemporal Dementia (Pick’s Disease) 632 Vascular Dementia 634 Bibliography 636 References 636 Subject Index

641

Abbreviations

AAP AC ACh ACTH AD

American Academy of Pediatrics alcohol concentration acetylcholine adrenocorticotrophic hormone Alzheimer’s disease AD Anno Domini ADC apparent diffusion coefficient ADCC antibody-dependent cell-mediated cytotoxicity ADH alcohol dehydrogenase ADP adenosine diphosphate AI axonal injury AIDS acquired immune deficiency syndrome ALDH aldehyde dehydrogenase AMS acute mountain sickness apoE apolipoprotein E β-APP beta-amyloid precursor protein ATP adenosine triphosphate ATPase adenosine triphosphatase BAC blood alcohol concentration BBB blood − brain barrier BC before Christ BCNU cytostatic agent: carmustine BMT bone marrow transplantation BrdU bromodeoxy uridine BSE bovine spongiforme encephalopathy BZE benzoylecognine C1, 2, etc. vertebral body of the cervical spine CA cornu Ammonis = hippocampus CA1, anatomical subfields of the hippoCA2, etc. campal area CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CAII carbonic anhydrase II CBF cerebral blood flow CCNU cytostatic agent: lomustine CCS children’s coma score CCT cerebral computer tomography CD cytoplasmic dynein CDC Centers for Disease Control and Prevention

CERAD

Consortium to Establish a Registry for Alzheimer’s Disease CHE dichlorvos CJD Creutzfeldt−Jakob disease CMRglc glucose metabolic rate CNS central nervous system CO−Hb carboxyhemoglobin COS children’s outcome scale COX cyclooxygenase CPP cerebral perfusion pressure CRH corticotrophin-releasing hormone CS cervical spine CSF cerebrospinal fluid CT computer tomography CVT cerebral venous thrombosis D-1, 2, etc. vertebral body of the thoracic spine DAE dialysis-associated encephalopathy DAI diffuse axonal injury DCS decompression sickness DFP diisopropyl fluorophosphate DHC dihydrocodeine DIC disseminated intravascular coagulation DNA deoxyribonucleic acid DOM 2,5-dimethoxy-4-methylamphetamine DW-MRI diffusion-weighted MRI kinetic muzzle energy of projectile Eo kinetic energy of projectile at a E5 distance of 5 m from muzzle E-605 parathion EAE experimental autoimmune encephalitis ECPE encephaloclastic porencephaly EDH epidural hemorrhage EEG electroencephalogram EME ecgonine methylester EOM extraocular muscles E-selectin endothelial-leukocyte adhesion molecule-1 Fc fragment crystalline; c-terminal part of both the H-chains of immunoglobulin G fractional inspiratory concentration of fiO2 oxygen FRG Federal Republic of Germany

XXII

Abbreviations GABA GFAP H&E HACE HAPE HBV HCV HDL hGH HIV HSES ICAM ICH ICP IEG IFN-γ IL iNOS IPSP IQ IVF IVH JNK LAMMA LD50 LDL LFA LSD M3G M6G MABP 6-MAM MAO MAP MAPK MBI MBK MBP MDEA MDMA MELAS MEOS MERRF MHC MPTP

gamma-aminobutyric acid glial fibrillary acidic protein hematoxylin and eosin high-altitude cerebral edema high-altitude pulmonary edema hepatitis B virus hepatitis C virus high density lipoprotein human growth hormone human immunodeficiency virus hemorrhagic shock and encephalopathy syndrome intracellular adhesion molecule intracerebral hemorrhage intracranial pressure immediate early gene interferon-gamma interleukin inducible nitric oxide synthase inhibitory postsynaptic potential intelligence quotient in vitro fertilization intraventricular hemorrhage c-jun N-terminal kinase laser microprobe mass analysis dosis letalis media low density lipoprotein lymphocyte function-associated antigen lysergic acid diethylamide morphine-3-glucuronide morphine-6-glucuronide mean arterial blood pressure 6-monoacetylmorphine monoamine oxidase microtubule-associated protein mitogen-activated protein kinase mechanical brain injury methyl-n-butyl ketone myelin basic protein 3,4-methylenedioxyethamphetamine 3,4-methylenedioxymethamphetamine mitochondrial encephalopathy with lactic acidosis and stroke microsomal oxidizing systems mitochondrial encephalopathy with ragged red fibers major histocompatibility complex N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MRI MW NASDClAE NFP NFT NIA NMDA NO NOS NS nvCJD PACNS PAS PCP PD PDGF-β PLP PNS pO2 ppm PrP RNA ROS SAH SAS SCI SCUBA SDH SI SiCH SIDS SMON SOD STAT 3 SUDEP TC,F,K,R TET TGFβ Th THC TIA TNF TPP v5 VCAM vo WBC

magnetic resonance imaging molecular weight naphthol AS-D chloroacetate esterase neurofilament protein neurofibrillary tangle National Institute of Aging N-methyl-D-aspartate nitric oxide nitric oxide synthase nervous system new variant Creutzfeldt−Jakob disease primary angiitis of the CNS periodic acid-Schiff reaction phencyclidine Parkinson’s disease platelet-derived growth factor β proteo-lipid protein peripheral nervous system oxygen pressure ‰ prion protein ribonucleic acid reactive oxygen species subarachnoid hemorrhage subarachnoid space spinal cord injury self containing underwater breathing apparatus subdural hemorrhage International System of Units spontaneous intracranial hemorrhage sudden infant death syndrome subacute myelo-optic neuropathy superoxide dismutase signal transducer and activator of transcription 3 sudden unexpected death in epilepsy temperature measured in °C, °F, K, °R triethyltin transforming growth factor β thoracic spine ∆9-tetrahydrocannabinol transient ischemic attack tumor necrosis factor thiamine pyrophosphate velocity at 5 m from muzzle vascular cell adhesion molecule muzzle velocity of projectile white blood cells

Quantities and Units

In this book physical quantities on principle will be measured in “SI-Units,” laid down in the “Système International d’Unités” (SI) by the “Conférence

Générale des Poids et Mesures” (CGPM), abbreviated according to agreement, and expanded by the following prefixes as decimal magnitude factors.

Prefix

Abbreviation

Decimal

Factor

hecto-

h

102

100

kilo-

k

103

1,000

mega-

M

106

1,000,000

giga-

G

109

1,000,000,000

deci-

d

10 −1

0.1

centi-

c

10 −2

0.01

milli-

m

10 −3

0.001

micro-

µ

10 −6

0.000001

nano-

n

10 −9

0.000000001

Example: 1 kilometer = 1 km = 103 m = 1,000 m 1 micrometer = 1 µm = 10−6 m = 10−3 mm = 0.001 mm

XXIV Quantities and Units Quantity

Conversions

SI-Unit

Name

Abbreviation

Name

Abbreviation

Length

l

Meter

m

1 mm=0.039 in; 1 cm=0.394 in 1 dm=0.328 ft; 1 m=1.094 yd 1 km=0.621 miles 1 in=25.4 mm=2.54 cm 1 ft=30.48 cm; 1 yd=0.914 m 1 mile=1.609 km

Area

A

Square meter

m2

1 m2=104 cm2; 1 cm2=100 mm2 1 in2=6.45 cm2=645.2 mm2 1 ft2=0.0929 m2=929.03 cm2

Volume

V

Cubic meter (Liter)

m3

1 m3 =103 dm3 =106 cm3 1 l=1 dm3 =10 −3 m3

l

1 ml=1 cm3, 1 dl=100 cm3 1 in3 =16.387 cm3 1 ft3 =28.23 dm3 =0.028 m3 1 yd3 =764.53 dm3 =0.765 m3 Mass

m

Kilogram

kg

1 kg=1000 g=2.205 lb 1 g=1000 mg=15.432 gr 1 g=0.0648 gr 1 lb=0.454 kg

Mass density

ρ

3

kg/m

1 kg/m3 =1 g/dm3 =1 g/l=1 mg/ml 1 g/m3 =1 mg/dm3 =1 mg/l 1 mg/m3 =1 µg/l=1 ng/ml 1 lb/ft3=16.019 kg/m3=16.019 g/dm3=16.019 g/l

Time

t

Second

s

(Minute)

min

1 min=60 s

(Hour)

h

1 h=60 min=3600 s

(Day)

d

1 d=24 h

(Year)

1 year=365 d

Quantities and Units XXV Quantity Name Frequency

Conversions

SI-Unit Abbreviation

Name

Abbreviation

f

Hertz

Hz

1 Hz=1/s 1 cycle/s=1 Hz

Angle

Radian

rad

1 degree (1°)=(π/180) rad=0.01745 rad 1 rad=57,296°

Temperature

T

Kelvin

K

1°C=1 K=9/5°R=9/5°F

(Degree Celsius)

°C

TC=(TK−273.15)°C =5/9 (TR−491.67)°C =5/9 (TF−32)°C

Velocity

v

m/s

1 m/s=3.6 km/h=5.793 miles/h=3.281 ft/s 1 km/h=0.278 m/s=0.911 ft/s=0.621 miles/h 1 ft/s=0.305 m/s=1.097 km/h 1 mile/h=1.609 km/h=0.447 m/s

Angular velocity

ω

rad/s

1 rad/s=57.296 °/s 1 °/s=0.0175 rad/s

Acceleration

m/s2

a

1 m/s2=3.281 ft/s2 1 ft/s2=0.3048 m/s2 Gravitational acceleration (g) =9.807 m/s2=32.174 ft/s2

Angular acceleration

α

Force

F

rad/s2

1 rad/s2=57.296 °/s2 1 °/s2=0.0175 rad/s2

Newton

N

1 N=1 kg m/s2 1 N=0.102 kp a; 1 kp a=9.807 N 1 pdl=0.138 N 1 lbf=4.448 N 1 kgf=9.807 N

XXVI Quantities and Units Quantity Name Pressure

Conversions

SI-Unit Abbreviation

Name

Abbreviation

p

Pascal

Pa

1 Pa=1 N/m2 1 bar=100 kPa 1 mbar=100 Pa=1 hPa 1 mmHg=1 torr=133 Pa 1 atm=760 torr=101.325 kPa 1 pdl/ft2=1.488 Pa 1 lbf/in2=0.068 atm=6.895 kPa 1 lbf/ft2=47.88 Pa

Energy

E

Joule

Potential

J Nm

Kinetic

kg m2/s2

Electric

V A s=W s

Radiation

1 Gy kg

Thermal Power

1 J=1 N m=1 kg m2/s2=1 W s=1 Gy kg

P

(Calorie)

cal

1 cal=4.184 J

Watt

W

1 W=1 J/s=1 N m/s=1 V A 1 ft pdl/s=42.14 mW

Electric quantities Voltage

U

Volt

V

Intensity of current

I

Ampere

A

Resistance (impedance)

R

Ohm

1 Ω=1 V/A

Charge

Q

Coulomb

C

1 C=1 A s

Capacity

C

Farad

F

1 F=1 A s/V

Field strength

E

Radiation dose

V/m Gray

Gy

1 Gy=1 J/kg 1 Rad (rd)=10 mGy

Amount of substance

n

Mole

mol

Concentration of amount of substance

mol/m3

Molality

mol/kg

1 mol/m3 =1 mmol/l

CHAPTER 1

Introduction

The information obtained at autopsy is important in clinical and forensic practice at four different levels (Keeling 1993): 1. The light it sheds on the cause of death is of interest to the family of the deceased and the treating clinicians. It can serve as a quality control of the diagnostic and therapeutic measures taken. 2. It is indispensable for adequate audit of a department’s policies and practices. 3. It will contribute to regional or national statistics by classifying data derived from postmortem examination. 4. It is important for students and doctors studying the morphology of disease processes and trauma. Neuropathologists deal with disorders of the nervous system (NS), i.e., the brain, the spinal cord, the peripheral nerves, and, sometimes, the muscles. The NS extends to all other organ systems of the body as a network, connecting, coordinating, and regulating their functions. The pathology of the NS is therefore also an integral part of the pathology of all organ and tissue systems of the body. At autopsy the neuropathologist applies the same criteria that apply to general autopsy. Yet, in contrast to the clinical neuropathologist, the forensic neuropathologist must not only diagnose disease processes of the NS, including tumors, inflammation, and degenerative diseases, but he must also − and predominantly − investigate non-natural, exogenous events leading to injuries and/or death. The forensic neuropathologist is especially confronted with injuries of the head and brain as well as the spine and spinal cord and peripheral nerves, or secondary alterations of the NS which are caused by hypoxia, ischemia, toxic agents, etc. The present volume deals with the problems of neuropathology for both the forensic and clinical neuropathologist, particularly emphasizing the relevance for routine practice. It incorporates recent findings in anatomy, physiology, pathophysiology, molecular biology, nosology, clinical features and sequelae, epidemiology, biomechanics, immunology, and pathology. Part I provides basic information on the tasks of the forensic expert, the cytology of the NS, techniques for dissection of the brain and spinal

1

cord, and on staining methods. Parts II−IV discuss the various types of physical loadings to the head and central nervous system (CNS), asphyxia-related effects on the brain such as hypoxia and ischemia, and toxic effects on the brain. Part V deals with injuries in infants and children caused by prenatal and childhood traumatic events. Part VI is devoted to aspects of clinical neuropathology with cases of NS diseases leading suddenly and unexpectedly to death, that have to be considered in differential diagnosis or that are often additionally observed in cases of unnatural death. Forensic neuropathology does not intend to substitute for clinical neuropathology. In contrast, the knowledge of general and special clinical neuropathology will be a precondition for understanding the present textbook, though the authors have strived to give basic information as well. Incorporating the most recent literature and up-to-date methods, the present textbook covers the main aspects of neuropathology with regard to the needs of forensic pathologists and specialists in associated fields, such as clinical pathology and neuropathology, neurology, neurosurgery, pediatrics, law, and criminology. The authors have attempted to impart basic information that can be fundamental to further scientific investigations. The concise, direct style is intended to provide the reader with succinct and easy-to-find answers to forensic-pathological and forensic-neurological problems. The forensic neuropathologist is expected to provide answers regarding: (1) the cause of death, i.e., whether the neuropathological findings are sufficient to explain why the death occurred; (2) information on whether neuropathological changes could have influenced the fatal mechanism, i.e., whether the death was hastened by NS injury or diseases; (3) the victim’s capacity or incapacity to act at a given time point, i.e., whether he was capable of resistance or flight, or could still perceive anything such as pain or danger; (4) the mode of death, i.e., whether death was caused by accident, disease, or was a suicide or homicide (murder, manslaughter, or due to negligence). These questions can usually be answered by (5) a plausible and detailed reconstruction of the process and/or events leading to the death inclusive

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INTRODUCTION

dating (time course) based on eyewitness accounts, evidence at the scene, analysis of the injuries, medical records, etc. But why should the nervous system be examined by a forensic neuropathologist at all? Is a textbook dealing with the forensic aspects of only one organ system really necessary? More than 50% of all cases of death encountered at forensic autopsy are associated with primary or secondary involvement of the NS, especially of the brain. The forensic pathologist must be able to judge or comment on NS injuries and/or diseases in dead as well as sometimes in living subjects. Often pathological examinations of the NS are sufficient to determine the “mode of death,” sometimes only by ruling out a natural process within the NS as the cause of death. The neuropathological investigation can therefore also serve as a form of quality assessment and quality control, and can help to explain discrepant diagnoses presented at trial. Peiffer (1996) and Black and Graham (2002) have surveyed the types of cases dealt with by forensic neuropathologists and the sort of problems they pose. According to the American Trauma Society (in Trauma Facts 1992) an estimated 500,000 Americans are admitted to hospitals as a result of mechanical brain injuries and more than one million children in the world sustain head injuries each year. Such cases should be assessed to determine whether the injuries could have been avoided in order to enhance prevention in future. The complexity of such cases and the methods used to examine them consequently warrant special, more in-depth consideration, possibly in the form of a monograph or textbook. In-depth coverage can also aid in quality control and accreditation of laboratories. Guidelines and standards for neuropathological examinations must be set, which can be of special value to forensic neuropathologists confronted with questions of their own legal liability (Pounder 2002; Tingle 2002). Equally important are questions of research as they relate to forensic practice. This holds particularly true for cases that are encountered only in legal medical institutions, rather than in clinicopathological or cliniconeuropathological institutes. In this regard it is a much appreciated development that forensic neuropathologists are being increasingly provided with their own distinct forums at congresses. This is happening both at meetings devoted solely to clinical neuropathology (Neuropath Appl Neurobiol 25:27−28, 1999; Kalimo et al. 2004) and at international congresses on forensic pathology and related fields (Oehmichen 2001). One of the prime reasons for publishing a textbook on forensic neuropathology and associated neurology is reflected in the statement by Courville (1964) describing his own: “… unhappy experience to learn that all too often a misinterpretation or an

erroneous evaluation of a cerebral lesion has led to a gross miscarriage of justice.” The present textbook also has its roots in many forensic pathologists‘ practice of dissecting and then disposing of the brain after autopsy, without considering minor, though potentially important, findings. In such cases the brain is treated like a diffuse parenchymatous organ comparable to the liver, specimens being taken at random, fixed in formalin, and examined microscopically. Because the remaining brain tissue is discarded, it is no longer available for further investigations, precluding any retrospective examinations. Conscientious forensic pathologists lacking either the knowledge or experience to deal with a particular problem themselves will fix the brain and spinal cord in formalin and hand them over to a clinical neuropathologist for evaluation. Sometimes though, the clinical neuropathologist may have no particular interest in forensic problems, and thus may find it difficult to unravel the true nature of the problem at hand. Moreover, the clinical neuropathologist is often not acquainted with the current forensic literature, or may not be able to differentiate autolytic changes and putrefaction from pathological findings and, when examining the autolytic material, to detect forensically relevant changes. The authors therefore regard expertise training and education in forensic neuropathology as highly desirable. Even though not every institute will need such special investigative techniques and experience, central research laboratories could be established that would make the neuroscientists, technicians, and methods needed for such investigations readily available. The last comprehensive survey of forensic neuropathology in a textbook format was published by Leestma in 1988. The volume followed the example of Courville (1964), who was the first to write a textbook in this field. In the early 1990s Unterharnscheidt (1992−1994) published a handbook comprised of four monumental volumes in German devoted to mechanical injury of the head and spinal cord giving a review on the investigations, findings, and the literature of the previous 50 years. The numerous important findings that have been published since 1990, especially in the fields of molecular biology and biochemistry of the CNS, make the present volume both justified and necessary.

References American Trauma Society (1992) Trauma facts. Upper Marlboro, Md. Black M, Graham DI (2002) Sudden unexplained death in adults caused by intracranial pathology. J Clin Pathol 55:44−50

CHAPTER 1: Introduction

Courville CB (1964) Forensic neuropathology. Lesions of the brain and spinal cord of medicolegal importance. Callaghan, Mundelein, Ill. Kalimo H, Saukko P, Graham DI (eds) (2004) Special issue: forensic neuropathology. Forensic Sci Int 146:71−147 Keeling JW (1993) The perinatal necropsy. In: Keeling JW (ed) Fetal and neonatal pathology. Springer, Berlin Heidelberg New York, pp 1−46 Leestma JE (1988) Forensic neuropathology. Raven, New York Oehmichen M (ed) (2001) Brain hypoxia and ischemia. In: Research in legal medicine, vol 24. Schmidt-Römhild, Lübeck Peiffer J (1996) 30 Jahre neurologisch-neuropathogische Gutachtertätigkeit − Auftraggeber, Fragestellungen, Problembereiche. Med Sachverst 92:116−120

Pounder D (2002) Forensic pathology services. BMJ 324:1408−1409 Tingle JH (2002) Do guidelines have legal implications? Arch Dis Child 86:387−388 Unterharnscheidt F (1992−1994) Pathologie des Nervensystems von Hirn und Rückenmark: Traumatologie von Hirn und Rückenmark. In: Doerr W, Seifert G (eds) Spezielle pathologische Anatomie, vol 13/VI A,B − 1993; vol 13/VI C − 1994; vol 13/VII − 1992. Springer, Berlin Heidelberg New York

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PART I

Principles of Forensic Neuropathology

Chapter 2 Risks, Responsibilities and Liabilities Chapter 3 Cytology of the CNS

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Chapter 4 Cell and Tissue Reactions

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Chapter 5 Methods in Forensic Neuropathology

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CHAPTER 2

Risks, Responsibilities and Liabilities

2.1 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.5.1 2.1.5.2

Basic Principles 7 Identity of the Victim 8 Manner of Death 8 Cause of Death 8 Process of Dying 9 Causation 10 German Theories of Causation 10 American Theories of Causation 10

2.2 2.2.1 2.2.2 2.2.3 2.2.4

Role of Expertise and Expert Witness 11 Definition: Expert Witness 11 Standards in (the American) Court 11 Function of Expert Witness 12 Probability of Expert Opinion 12 Bibliography 12 References

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The formal tasks that forensic pathologists and neuropathologists are asked to perform in the courts vary from country to country according to convention and statute, and will therefore not be dealt with in detail here. For details on the role of expert forensic witnesses in U.S. courts, the reader is referred to Leestma and Magee (1988), and for the English system to Knight (1996). In all different countries the forensic pathologist/neuropathologist is accountable primarily to legal authorities, i.e., the judiciary, lawyers, and/or public prosecutors. But they cannot avoid an additional, specifically medical/ethical responsibility, which extends to questions of experimental neuropathology and neurology, i.e., the use of certain experimental diagnostic and therapeutic methods, and to civil and political actions such as maltreatment and torture. To our knowledge, no legal system in the world places physicians as physicians under the threat of civil liability. Physicians, therefore, are subject to the general rules of liability, with the effect that modern laws of medical liability are a part of case law created by the courts in most countries. Beyond this formal task, a second justification forms the basis of the forensic physician’s conception of his efforts: the prevention of unnatural death as

well as the prevention of injury as a result of maltreatment and torture. Unnatural deaths are preventable and therefore − of course − of eminent interest in the field of (forensic) medicine. Recognition of violence, maltreatment, and torture is an especially important task of the forensic physician (Oehmichen 1999; Hall 2000; Barnett 2001), who is duty-bound to undertake all measures necessary to prevent these forms of violent injury before they result in death. Even if such a case has ended in death, measures must be taken to prevent others from becoming further victims. The appropriate civil and/or law enforcement agencies must be informed, and, in certain circ*mstances, the public itself. This duty must be fulfilled not only in cases of violence and maltreatment within a family or specific social group, but also in cases of maltreatment on the part of the police, prison guards, and/or the public prosecutor’s office. Such a task is of particular importance − and entails real risks − in countries where torture is still officially tolerated. If violence, maltreatment or torture is observed or suspected, the physician − even the forensic neuropathologist − is obliged to register a protest from the medical point of view.

2.1 Basic Principles The forensic neuropathologist is asked to examine cases classified as “unnatural death.” In the United States and Germany, medically attended patients dying of natural causes can be autopsied only with permission of the next of kin. Official autopsies can be performed at the discretion of a forensic pathologist under the following circ*mstances (cf. Helpern 1977): 1. Sudden and unexpected death of persons in apparently good health 2. Cases involving evidence or suspicion of violent death, especially of accident, suicide or homicide 3. Deaths resulting from suspected medical malpractice and/or negligence 4. Deaths occurring during incarceration or while in police or institutional custody

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PART I: Principles of Forensic Neuropathology

5. Death at the workplace or due to toxic agents 6. Cases of death involving victims of unknown identity 7. Cases in which tissue loss due to decay and animal activity is so extensive that the victim‘s identity is unknown and neither the cause nor type of death can be established without autopsy Many countries allow forensic autopsies if there is reason to believe that violence or poisoning has played a role in the death, or if there is evidence or suspicion of a criminal event. In most countries however autopsies are not allowed even in cases of violent death known to be purely accidental. In autopsies of such cases the forensic pathologist, neuropathologist, toxicologist, molecular biologist or physicist must address the following issues depending on the nature of the case: ▬ Identity of the victim ▬ Manner of death (natural or unnatural death) ▬ Cause of death ▬ Process of dying (reconstruction of the process) ▬ Causality linking an event with death The forensic neuropathologist can be asked to give an opinion on at least some of these issues. The individual points can be commented on as follows.

2.1.1 Identity of the Victim The forensic neuropathologist is not often asked to establish identity, a task usually left to the expertise of the medical examiner or forensic pathologist. The forensic neuropathologist can however be asked to determine whether a mix-up has occurred in surgical or biopsy material from a neurological or neurosurgical clinic or from an institute of pathology. The identity of a biopsy specimen can be established by DNA analysis of the specimen by a molecular biologist. Only rarely must brain tissue be identified, following train accidents for example, or massive explosions with multiple casualties (the result of industrial accidents or terrorist attacks). Sometimes brain tissue can provide evidence that violent injury has indeed occurred (Oehmichen et al. 1984). In all such cases DNA analysis is now the investigative method of choice.

2.1.2 Manner of Death A strict distinction must be made between the manner and the cause of a death. The manner of death differentiates between natural and unnatural death, and will give further information on the mechanisms

of deaths: accident, suicide or homicide. The cause of death also defines the cause of the irreversible cardiac and respiratory arrest or of the respirator brain. As already mentioned, the accused and their legal council (and the civil authorities) are often only interested in an autopsy when an unnatural death has been certified or is suspected. In most cases, however, an autopsy − at least in Germany − is only performed if a criminal act by a third party is suspected or known to have led to the death. Even if the manner of death is usually determined by a pathologist at autopsy, in up to 10% of cases a forensic neuropathologist has to make this determination. A distinction must always be made between the following manners of death: 1. Accidental death. The most common cause of accidental death in affluent Western societies is traffic accidents, the fatality often caused by mechanical brain injury; accidental deaths in the workplace are comparatively rare. Such deaths usually involve the sequelae of traumatic blunt impact, the death sometimes occurring after lengthy hospitalization and resulting from secondary complications. 2. Suicide. Death from suicide can result from brain injury caused by mechanical violence, due to a gunshot or fall for example, intoxication/poisoning (parathion, heroin, arsenic), electric shock, ischemic effects, etc. 3. Homicide. A distinction is made between murder and manslaughter. Depending on the type of weapon and cause of death, the victim can die of primary cerebral functional failure due to a blow to the head for example, of ischemia of the brain, of poisoning by centrally active drugs, or of secondary functional failure, such as acute blood loss, fat embolism, etc. In some cases not even an autopsy can establish with certainty that the death was a suicide, accident, or homicide; this is especially common in drug-related deaths, or deaths associated with autoerotic manipulation.

2.1.3 Cause of Death After performing an autopsy the neuropathologist, in cooperation with the pathologist, must certify the cause of death (for review see Black and Graham 2000). Among the neuropathologically relevant causes of death are intracranial processes such as poisoning that can lead to primary functional failure of the brain. An intracranial process can also be a secondary cause of fatal respiratory and cardiac arrest. Not every intracranial process (bleeding, inflammation, tumor, etc.), of course, is itself sufficient to exp-

CHAPTER 2: Risks, Responsibilities and Liabilities

lain a “central” death. The extent of the changes undoubtedly plays a major role. An irreversible cardiac arrest may be explained by brain edema with disturbances of brain stem function, the disturbances occurring secondary to “herniation” or brain stem hemorrhages, edema-induced generalized hypoxia or ischemia, etc. And lastly, extracranial processes can influence brain function and lead to death (cf. also Leestma 1988). The following is to be added in detail: 1. Primary functional failure of the brain associated with intracranial processes is generally the result of the following mechanisms: − Primary toxic effects (e.g., cyanide‘s effect on the central nervous system). − Primary ischemic effects. − Mass effects (intracranial hemorrhage, edema, etc.). − Primary mechanical effects causing diffuse axonal injury (DAI) and/or injury of multiple blood vessels and/or acute disturbance of the blood−brain barrier (acute edema). 2. Neurally mediated death is associated with the following events: − Brain stem hemorrhage secondary to herniation. − Neural discharges may reach the heart via the hypothalamus and autonomic centers of the brain stem. Parasympathetic impulses may briefly stop the heart while sympathetic discharges increase heart blood volume and blood pressure, with supervening arrhythmia, the most serious type being ventricular fibrillation, which can lead to a fatal outcome. The effect of environmental stress on cardiac dysfunction was reviewed by Natelson (1985). A more recent survey is given by Cechetto (2000) who listed three regions of the forebrain that are intimately involved in central control of the cardiovascular system. These regions are the mediators of the cardiovascular consequences of stroke and stress, and likely play a significant role in pathologies such as sudden cardiac death. The insular cortex, the infralimbic cortex, and the amygdala are the anatomical structures that influence the cardiac function. Moreover, a sudden catecholamine release is obviously able to induce a sudden unexpected cardiac arrest (Pedal et al. 1999; Kernbach-Wighton et al. 2003). − Disruption of respiratory control may induce Cheyne−Stokes breathing (alternating hyperpnea and apnea) and respiratory arrest. Among the possible causes are intoxication (heroin), DAI associated with closed head injury, and disruptive or destructive lesions deep to the cortex as in large basal ganglia or subcortical regions. Finally, total respiratory failure can

result from downregulation of the respiratory centers secondary to brain stem trauma, brain stem herniation or neural shock. − Neurogenic pulmonary edema and congestion are observed especially following head trauma and can develop extremely rapidly. − Patients in a vegetative state often suffer sudden unexpected death. Such deaths can be caused by neural (electric) discharges or secondary diseases such as aspiration pneumonia or sepsis. − A spinal shock can lead to dilation of peripheral vessels and thus to low blood volume, which in turn can result in inadequate blood supply to the brain and heart. This phenomenon is associated with acute spinal trauma for example. 3. Extracranial processes can lead to functional failure of the brain as follows: − Low blood volume and/or blood loss resulting in insufficient oxygen supply to the brain. − Hypoglycemia associated with diabetes mellitus or insulin overdose. − Hyperthermia due to fever or excessive ambient heat can lead to death via brain edema and congestion. − Toxins. Potentiation of the mechanisms described here may occur if the brain is simultaneously assaulted by toxins from, for example, an infection.

2.1.4 Process of Dying If the death is not sudden and readily explained by massive blood loss or brain stem destruction due, for example, to gunshot injury, reconstruction of the lethal process can be difficult. The following questions arise and may require a forensic-neuropathological answer: 1. How long did the victim survive the traumatic event? This can often provide clues regarding the cause − and thus, the course − of the traumatic event. Estimation of the survival time (dating) is therefore of major importance for the forensic neuropathologist. 2. If the survival time is known and if the victim was treated in hospital, the question arises as to how the “lethal” course can be explained despite the medical treatment. If, as often happens, the victim has survived for months or years, it can be difficult to demonstrate an unbroken causal chain connecting the traumatic event with the death (see below) or, conversely, to demonstrate a clear break in the causal chain. The latter eventuality can be assumed if it can be shown, for example, that the death was the result of serious malpractice or neglect on the part of the attending physicians or nursing staff.

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3. If the cerebral injuries are comparatively minor, the same questions arise as discussed under “Cause of Death.” What event led ultimately to death, and what is the pathophysiological explanation of the lethal process? Did the injury induced by the external event contribute to the lethal course at all? 4. In deaths following long survival times, the question always arises as to whether death might have occurred even in the absence of the traumatic event. This question, however, anticipates the next topic, Causation.

2.1.5 Causation The following determinations must be made right at the start (Dawidoff 1977; Leithoff 1992). The assessment of a possible relationship between a particular event and its effect has to begin with a definition of causation. The legal definition of “cause” differs from the scientific definition (factual cause vs. actual cause), the latter encompassing a much broader spectrum not restricted by legal theories of justice and expediency. The medical definition of causation is based on “natural” correlations and is deduced from the knowledge of a physical effect of an external event on the human body and its resulting organic or functional disorders (Zülch 1969). The juridical definition depends upon “artificial” correlations set by people through regulations and laws. In this case, the event must be the “main and essential” cause of the effects. To define one cause as main and essential presupposes that its action must be so prominent that without its effects the lesion ought not to have arisen at all nor else with the same speed of development nor to the same degree. There can be a wide-ranging debate as to whether a particular event produced or contributed to a particular result. Like all legal concepts, the term “causation” is applied with an aim to guiding activity and redressing grievance by representing a consequence of factual activity in terms of a doctrine supporting the law‘s purposes. Even when there is factual and legal cause of action, the other elements of a cause of action − breach of duty and damages − must coexist for the defendant to be liable to the plaintiff. Moreover, the cause must be of the type that has been recognized within the confines of the particular legal theory that forms the basis of the plaintiff‘s complaint. Law, like other disciplines, deals with behavior in accordance with its own purposes and objectives, which are specifically reflected in its theory of causation. The same state of affairs can be subject to the differing standards of proof in civil law or criminal law. Different types of causation can be cited depending on the type of legal proceeding, the theories

underlying German legal practice differing from those of other countries. The expert has to avoid “putative” causes of diseases and injuries. Like the general public, judges and juries learn of the purported facts surrounding a case from broadcast and published news sources, the internet, etc. Such sources also report the results of scientific studies and may highlight public concerns regarding environmental exposure to toxic material from hazardous waste sites, chemical spills, or from electromagnetic fields created by power lines, or reported high cancer rates in specific places (Erdreich 1999). In German law the statement of different degrees of likelihood of causal relation may be “certain” (indubitable), “likely” or “possible” (see below, p. 12). The American as well as the German legal system makes a clear distinction between civil and criminal malfeasance by providing separate legal proceedings and distinct legal responses to the two types of wrongdoing (Finkelstein 2002). In practice, the distinction looks something like this: in civil law, a private party brings a civil action against another party to seek compensation for an unintentional harm caused unlawfully by another party, whereas in criminal law the State brings a criminal action against a person for a deliberate offense against the community. Civil actions are pursued in civil courts and are governed by rules of civil procedure and constitutional provisions relating to civil cases. Criminal actions are tried in criminal courts and are governed by rules of criminal procedure and by a larger number of constitutional provisions. Civil actions seek civil remedies (pecuniary damages or injunctions), whereas criminal actions seek distinctive criminal punishments (imprisonment or the death penalty). 2.1.5.1 German Theories of Causation Theory of necessary condition in criminal law: necessary conditions are those conditions (e.g., a blow) without which a given event (e.g., death or injury) cannot have happened (conditio sine qua non). The standard of evidence demands certainty or “probability bordering on certainty” that the death or injury, for example, was the result of the purported act. Theory of adequate cause in tort law: only that condition which it is reasonable to assume was in itself sufficient to cause a given event is regarded as causal. A person cannot be held liable for an entirely unusual, unpredictable course of events. 2.1.5.2 American Theories of Causation (Moore 2002) The criminal law contains several thousand prohibitions and requirements embodied in statutes that either prohibit citizens from causing certain results

CHAPTER 2: Risks, Responsibilities and Liabilities

or require them to cause certain results. Causation enters into both the prohibitions and the requirements and is thus central to criminal liability. The so-called proximate cause, acting as it may have in combination with many other causes, is in essence something without which the event would not have happened (Palsgraf v. Long Island R.R. 248 N.Y. 339−356. 162 NE 99−105, 1928). Proximate cause refers to nearness in the order of responsible causation. Thus, the law establishes a point of causal proximity to the event in question that reflects legal concepts of responsibility, retribution, and deterrence. Proximate cause favors plaintiffs because it leaves ample room for acts to be causally linked to injury. In establishing proximate cause, the issue of negligence or wrongdoing is decided first, the question of responsible cause is then addressed as a perceptibly separate issue. In qualifying causation, the term “proximate cause” is used alternatively with the term “direct cause.” In essence, tort law has but one injunction: do not act so as to cause harm to another. Such an injunction places greater weight on causation while at the same time leaving open a broader range of questions regarding causality than does criminal law, such as “Do not intentionally hit another [person].”

2.2 Role of Expertise and Expert Witness 2.2.1 Definition: Expert Witness Matson (1999) defines the expert witness as follows: the evidence given by the medical expert should be objective, the independent product of expertise uninfluenced by the exigencies of the litigation. This definition is accepted in both the AngloAmerican tradition and in Germany. The task of the expert witness in Germany is described in detail by Martens (1999), who also briefly describes the differences of definition between Germany and other countries. On the other hand, however, there are distinct differences in the expert witness‘ tasks in court.

2.2.2 Standards in (the American) Court A basic tenet of American legal practice is its insistence that information is sought from the most reliable sources at trial. American law however has also long recognized that many human undertakings involve complex disciplines which the lay person can

scarcely hope to understand without guidance from experts. Courts require that such expert witnesses have sufficient expertise in the field in question that their opinion will help the fact finder to arrive at a decision. While courts may rule that a member of a given profession (such as medicine or pharmacology) should serve as an expert witness, they do not always require a specialist from a particular field, however much such expertise may be desired. Expert opinion regarding mechanical brain injury (MBI) is generally based on postmortem morphology or on intravital computed tomography (CT) scans, x-rays, electroencephalographs (EEG), and magnetic resonance imaging (MRI). Cognitive deficits in a victim of MBI are often revealed by neuropsychological testing where more traditional testing, such as routine neurological examination, x-rays, CT scans, and MRIs, failed to document organic impairment. Neuropathological evidence of impairment can be presented in court to demonstrate the morphological consequences of a lethal traumatic event. If the medical evidence poses apparent difficulties, the pre-trial period is the proper time to clarify and define scientific matters of direct forensic interest (Shepherd 1993). This may prove difficult in practice, however, and the following discusses some of the issues that may arise (Roberts 1999): ▬ Before the case reaches court, undue reliance may be placed on medical evidence that is not in fact as strong as prosecutors or the defense believe (or have been led to believe by experts). ▬ Once in court, these deficiencies in the medical evidence may be exposed; for example, if a physician relies too dogmatically on evidence adduced from an examination while failing to acknowledge other, equally likely, explanations of the findings. ▬ After the court proceedings, problems can arise, not least for the victims. The medical expert‘s main task is to provide guidance and assistance to the court in rendering a scientifically tenable decision (Weinstein 1999). Among the surveys of the tasks of the expert witness in court are those of Myers (2001) and Shevell (2001). In most cases, the candidate expert is put in the witness stand to answer questions about his educational accomplishments, specialized training, and relevant experience. The judge must be convinced that the candidate possesses sufficient expertise to qualify as an expert. If counsel requests, the expert must set out the basis for his opinion in an expert‘s written report. This report must include: 1. Explicit identification of the purposes for which the report has been prepared 2. A statement of the expert‘s own expertise and credentials that warrant expert status

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3. A list of the materials and documents upon which the opinion is based 4. A review and chronology of the facts of the case under question 5. The expert‘s assessment and conclusions regarding the relevant questions at issue in the case Assessment of the expert‘s competence must include the question of whether the expert has paid due regard to all relevant facts in formulating the opinion; whether the expert‘s understanding of pertinent clinical and scientific principles was adequate; whether the expert used appropriate, reliable, and valid methods of inquiry; whether the expert offered reasonable assumptions and conclusions based on the facts; whether the expert was reasonably objective. The main issue is whether the expert‘s reasoning is consistent, logical, and reasonably objective.

2.2.3 Function of Expert Witness Expert testimony fulfils four separate functions, but the expert witness can only testify with regard to areas in which he is qualified (Matson 1999): 1. Factual witness. The expert witness is asked to testify regarding what could be observed at first hand. The witness may, for example, study the documentation in the case and testify as to what portions bear directly on the issue in question. 2. Interpretation of the facts. The expert witness is asked to explain the cause-and-effect relationships tying the data and/or facts of the case together. Correlating an apparent cause and effect link without theoretical justification is not recommended. 3. Comments on the opposing expert‘s facts and opinions. This aspect commonly does not arise in German courts, but is a part of the Anglo-American legal traditions. 4. Definition of the professional standards in the particular area of his expertise. In oral testimony the judge or jury are provided with information on the standards to which professionals in the field of expertise are held. Giving an opinion is the most common form of expert testimony.

2.2.4 Probability of Expert Opinion In American criminal law, expert witnesses must be reasonably confident of the opinions they give. The term lawyers use to describe the requisite degree of confidence is “reasonable certainty.” The degree of

certainty subsumed within this term lies somewhere between guesswork and absolute certainty. Forensic neuropathologists do not need to possess any special legal knowledge. They must, however, be aware of differences in the evidentiary requirements of the various courts. An expert opinion must always explain the degree of probability with which a causal connection can be claimed to link two events and/ or a particular diagnosis made. In German criminal law, the following five degrees of probability have become established in recognition of the fact that a clear “yes” or “no” is not possible in the majority of cases: 1. “Probability bordering on certainty”: this corresponds to a probability of 99.8%; a reasonable doubt does not exist. 2. Probable: the evidence favoring a causal connection between two events is weightier than that against. 3. Undecided: the evidence for a causal connection and that against such a connection are equally plausible (50:50), i.e., the issue cannot be decided one way or the other. 4. Improbability: the evidence against a causal connection between two events is weightier than that for such a connection. 5. Least possibility: if a situation is theoretically possible, but the evidence clearly shows it was not the case, then it can be ruled out with a “probability bordering on certainty.”

Bibliography Bronstein DA (1999) Law for the expert witness. CRC, Boca Raton, Fla. Dressler J (ed) (2002) Encyclopedia of crime and justice, 2nd edn. MacMillan Reference, New York Leestma JE (1988) Forensic neuropathology. Raven, New York Matson JV (1999) Effective expert witnessing. CRC, Boca Raton, Fla.

References Barnett PD (2001) Ethics in forensic science: professional standards for the practice of criminalistics. CRC, Boca Raton, Fla., p 1184 Black M, Graham DI (2002) Sudden unexplained death in adults caused by intracranial pathology. J Clin Pathol 55:44−50 Cechetto DF (2000) Neuropathology and cardiovascular regulation. In: Ter Horst GJ (ed) The nervous system and the heart. Human Press, Totoja, N.J., pp 159−179 Dawidoff DJ (1977) Causation. In: Tedeschi CG, Eckert WG, Tedeschi LG (eds) Forensic medicine, vol III. WB Saunders, Philadelphia, Pa., pp 1660−1664

CHAPTER 2: Risks, Responsibilities and Liabilities

Erdreich LS (1999) Using epidemiology to explain disease causation to judges and juries. In: Meyer C (ed) Expert witnessing. Explaining and understanding science. CRC, Boca Raton, Fla., pp 173−183 Finkelstein C (2002) Civil and criminal divide. In: Dressler J (ed) Encyclopedia of crime and justice, vol 1. MacMillan Reference, New York, pp 160−161 Hall RAS (2000) The ethical foundations of criminal justice. CRC, Boca Raton, Fla Helpern M (1977) The responsibility of the pathologist in workmen’s compensation claims. In: Tedeschi CG, Eckert WG, Tedeschi LG (eds) Forensic medicine, vol III. WB Saunders, Philadelphia, Pa., pp 1675−1680 Kernbach-Wighton G, Sprung R, Kijewski H, Saternus K-S (2003) Höchsterregung und plötzlicher Tod. In: Saternus K-S, Kernbach-Wighton G (eds) Fixierung erregter Personen. Todesfälle in Klinik und Gewahrsam. Research in legal medicine, vol 28. Schmidt-Römhild, Lübeck, pp 55−74 Knight B (1996) Forensic pathology. Arnold, London Leithoff H (1992) Ärztliches Gutachten. In: Schwerd W (ed) Rechtsmedizin. Lehrbuch für Medizin und Juristen. Deutscher Ärzte-Verlag, Cologne, pp 261−269 Martens C-P (1999) The role of experts in German environmental law. CRC, Boca Raton, Fla., pp 89−97 Moore MS (2002) Causation. In: Dressler J (ed) Encyclopedia of crime and justice, vol 1, 2nd edn. MacMillan Reference, New York, pp 150−160 Myers JEB (2001) Medicolegal aspects of child abuse. In: Reece RM, Ludwig S (eds) Child abuse. Medical diagnosis and ma-

nagement. Lippin, Williams and Wilkins, Philadelphia, Pa., pp 545−562 Natelson BH (1985) Neurocardiology. An interdisciplinary area for the 80s. Arch Neurol 42:178−184 Oehmichen M (1999) The forensic physician‘s conception of himself. Documentation and prevention of maltreatment and torture as a special task. Forensic Sci Int 100:77−86 Oehmichen M, König HG, Pedal I (1984) Zytologischer Befund als Indiz: Morphologische und immunhistochemische Identifizierung von menschlichem Hirngewebe an der Täterkleidung. Arch Kriminol 173:129−141 Pedal I, Zimmer G, Mattern R, Mittmeyer HJ, Oehmichen M (1999) Tödliche Zwischenfälle bei der Festnahme höchstgradig erregter Personen. Arch Kriminol 203:1−9 Roberts REJ (1999) Forensic medical evidence in rape and child sexual abuse: controversies and a possible solution. J R Soc Med 92:388−392 Shepherd JP (1993) Presenting expert evidence in criminal proceedings. BMJ 307:317−318 Shevell MJ (2001) The pediatric neurologist as expert witness with particular reference to perinatal asphyxia. Can J Neurol Sci 28:107−112 Weinstein JB (1999) Expert witness testimony − a trial judge‘s perspective. Neurol Clin 17:355−362 Zülch K-J (1969) Medical causation. In: Walker AE, Caveness WF, Critchley M (eds) The late effects of head injury. Charles C Thomas, Springfield, Ill., pp 453−472

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Cytology of the CNS

3.1 3.1.1 3.1.2 3.1.3

Neurons 15 Morphology 15 Function 17 Pathology 19

3.2 3.2.1

Astrocytes 20 Morphology, Classification, and Immunoreactivity 20 Function 20 Pathology 23 Reactive Astrogliosis 23 Piloid Gliosis 24 Metabolic (Protoplasmic) Gliosis Regressive Alterations 24

3.2.2 3.2.3 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.4 3.3 3.3.1 3.3.2 3.3.3 3.4 3.4.1 3.4.2 3.4.3 3.4.3.1 3.4.3.2 3.4.3.3

3.5 3.5.1 3.5.2 3.5.3 3.5.4

Most standard textbooks of neurohistology and neurophysiology (e.g., Brodal 1998) contain both a general survey and detailed description of the morphology and function of the various cell types that make up the nervous system. Here we will only touch briefly on the essential points without attempting to provide a thorough overview. The term ”pathology” will be used here to denote the morphological changes exhibited by cells under pathological conditions and the reactions of various cell types to pathological changes within the nervous system. 24

3.1 Neurons

Oligodendrocytes 24 Morphology, Classification, and Immunoreactivity 24 Function 25 Pathology 26

3.1.1 Morphology

Microglia and/or Mononuclear Phagocytes of the CNS 27 Morphology, Classification, and Immunoreactivity 27 Pathology 28 Function 31 Resting Microglia 32 Perivascular Microglia 32 Activated Microglia (Macrophages) 32 Additional Cell Types and Tissue Components 32 Leptomeningeal and Perivascular Cells 32 Parenchymal Vessels 33 Choroid Plexus and Ependyma Pathology of the CSF and Cells within the CNS 33 Bibliography 34 References

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Neurons are simultaneously genetic, structural, functional, and trophic units. Characteristically large nuclei of neurons are spherical or oval, with clear nucleoplasm containing one or two distinct nucleoli (Fig. 3.1a). The state of neuronal activity is reflected in the structure of its nucleoli. Human brains contain about 1×1012 neurons and each cortical neuron receives up to 30,000 presynaptic terminals (Tanner 1978). With increasing age the lipofuscin content of the neurons increases (Fig. 3.1b). If there is disruption of peripheral axons, the perikaryon will swell and the Nissl substance will disappear centrally, a process termed central chromatolysis (Fig. 3.1c). The cell body of the neuron, the perikaryon, is typically pyramidal in shape (Fig. 3.1a) and has long processes varying in number and length extending outward from it. There are usually several branched dendrites but only a single axon with terminal ramifications. Dendrites often possess spines or spikes that are sites of specialized, adjustable contact with other neurons. Intact dendrites are demonstrable by microtubule-associated protein (MAP) immunohistochemistry (Fig. 3.2a) and may be disrupted and destroyed by mechanical and ischemic influences (Fig. 3.2b). The axons are demonstrable by silver

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Fig. 3.1a−c. Nerve cells. a Normal pyramidal nerve cells in the cerebral cortex; b lipofuscin-containing neurons of an aged man; c central chromatolysis. a, c Nissl stain; b H&E; magnification a−c ×1,000

staining (intact axons: Fig. 3.2c; disrupted axons: Fig. 3.2d). Axonal injury leads to a ball-like swelling of the disrupted axon which is seen in silver staining specimens (Fig. 3.2e) and after β-amyloid precursor protein (β-APP) immunohistochemistry (Fig. 3.2f). The cytoplasm of neurons is rich in organelles for oxidative metabolism and protein synthesis. The numerous mitochondria attest to the intense aerobic adenosine triphosphate (ATP) production using glucose as a substrate. The neuronal cytoplasm contains free ribosomes, lysosomes, Golgi complexes, and rough endoplasmic reticulum − organized in so-called Nissl bodies − for protein synthesis.

The perikaryon also has a special cytoskeleton consisting of fibrillary proteins, especially actin filaments, microtubules, and intermediate filaments (neurofilaments) that manage cytoplasmic transport within the axons and dendrites. Such a system is necessary to transport proteins along the axons and to sustain the synapses. Stains used to demonstrate neurons are the Nissl method (Aniline dye) and silver staining techniques for demonstration of axons, dendrites, and/or spines (Golgi methods). Golgi methods usually stain only about 5% of neurons, which is to great advantage since the sections would be uniformly black, and uninterpretable if the silver precipitated through every neuron in a section. Axons are either myelinated or “unmyelinated.” The myelin sheath of myelinated axons (Fig. 3.3a) reduces the current loss between nodes of Ranvier, from the axons to ambient tissue fluid during impulse conduction, allowing the current to jump faster from node to node (see below). The velocity at which an impulse travels along the axon is proportional to the diameter of the axon and of the myelin sheath: axons with the thickest myelin sheaths conduct at about 120 m/s, while unmyelinated axons conduct at less than 1 m/s. The (pathological) demyelination follows ischemic or inflammatory insults and is marked by a loss of myelinated axons (Fig. 3.3b, c) and phagocytosis of myelin fragments (Fig. 3.3d). Peripheral nerves are surrounded by three layers of connective tissue that protect them from mechanical trauma: an external thick layer, the epineurium, an internal layer, the perineurium, and a layer of thin collagen fibers and fibroblasts, the endoneurium. A nerve impulse is conducted along the axon to its synaptic end, where chemically mediated transfer of signals between neurons takes place. Neurotransmitters (e.g., glutamate, norepinephrine or acetylcholine) reside in synaptic vesicles located near the presynaptic membrane of boutons and are released by exocytosis. From each packet released by the presynaptic bouton, only a few thousand molecules find a receptor before they disperse or are removed enzymatically or by re-uptake. Depolarization of the presynaptic membrane usually precedes transmitter release, which itself requires Ca 2+ to enter the bouton. The number of quanta of transmitters released is directly proportional to the amount of Ca 2+ entering the bouton. Neurons have three major cytoskeletal elements: neurofilaments, which are neuron-specific intermediate filaments that fill most of the axoplasm; microtubules, which are formed in the perikaryon and axon and serve the axonal transport system; and purified microtubuli, which consist mainly of α- and βtubulin plus several polypeptides known collectively as microtubule-associated proteins (MAPs). The chief MAPs, MAP1 (350 kDa) and MAP2 (280 kDa) (see Fig. 3.2a), contribute to the assembly and stabi-

CHAPTER 3: Cytology of the CNS

Fig. 3.2a−f. Neuronal processes. a Intact dendrites and b destroyed dendrites in the cerebral cortex (MAP2; magnification a ×500, b ×1,000); c intact axons and d disrupted axons (silver

lization of microtubules. MAP2 is a dendritic cytoskeletal molecule. Because no protein synthesis occurs in either axons or distal dendrites, the transport system allows anterograde and retrograde transport of proteins within axons and dendrites (Sotelo and Triller 1997). Although neurons are generally regarded as postmitotic cells, recent investigations have demonstrated “adult neurogenesis,” especially in the hippocampal dentate and olfactory bulb (for details, see p. 66).

stain; magnification c, d ×1,000); e axon swelling/balls (silver stain; magnification ×1,000); f axon swelling/balls [β-amyloid precursor protein (β-APP) reactivity; magnification ×500]

3.1.2 Function Neurons are the principal transducing cells of both the central and peripheral nervous systems. Though they exhibit great structural variation, they all serve the same purpose: to receive, process, and transmit information via bioelectric signals (Kreutzberg et al. 1997). Neurons are characterized by their excitability and ability to conduct impulses, i.e., if sufficiently stimulated they release a brief electrical discharge, termed an action potential, which is conducted along the axon. The action potential is a major constituent

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Fig. 3.3a−d. Myelin. a Normal myelin-staining pattern and b focal demyelinated structures in white matter of the cerebrum (Luxol fast blue; magnification a ×1,000; b ×100); c local demyelination in white matter as seen by application of antibodies

against myelin basic protein (= MBP; magnification ×200); d the demyelination is characterized by phagocytosing cells (activated microglia) which contain myelin fragments (Luxol fast blue; magnification ×1,000)

of communication among nerve cells and between nerve cells and the body; it is an indispensable link between the central nervous system (CNS) and the world around us. An action potential is created by the movement of ions through the cell membrane, which requires an electrical potential between the interior and exterior of the cell, the membrane potential. The electrical current is transformed at the synaptic level into a chemical signal: the released transmitters bind briefly to receptors on the postsynaptic membrane. The action potential is based on the presence of voltage-gated Na+ channels that open when the membrane is depolarized. Depolarization can result from electrical stimulation or opening of transmitter-gated Na+ channels. The latter induces a flow of Na+ into the cell driven by the concentration gradient and membrane potential. The inflow of Na+ ions ceases once the membrane depolarizes to +55 mV. The action potential is the result of an invariable all-or-nothing phenomenon. Messages can only be varied by a variation in the rate of action potentials, which in turn depends on the degree of depolarization. Some neurons are capable of a maximum frequency of action potentials exceeding 100 per second (100 Hz).

The velocity at which an impulse is conducted depends on the axon‘s diameter and myelin thickness and in meters per second is roughly 6 times the axonal diameter in microns. An action potential is generated when positive charges penetrate to the proximal part of the axon, which at that point becomes positive relative to more distal parts along its length. A corresponding current of positive charges moves in the opposite direction outside the axon, thus establishing an electrical circuit. The action potential in myelinated axons spreads passively (electronically) to the first node of Ranvier and is regenerated at each further node, where the axon membrane lacks a myelin sheath. The action potential moves by “jumping” from one node of Ranvier to the next. Several authors have studied the role of neurons in the immune response process (Sedgwick and Hickey 1997). It is thought that healthy neurons probably do not respond even to cytokines, such as interferon-γ (IFN-γ), which are associated with the major histocompatibility complex (MHC). On the other hand, following infection, MHC expression has been found in neurons in vivo. In the healthy CNS, MHC class I and II molecules are virtually absent. Under pathological conditions, however, MHC molecules are known to be upregu-

CHAPTER 3: Cytology of the CNS

lated by various cells within the CNS (see below). Under normal circ*mstances neurons are able to prevent and/or limit inflammatory responses (for review see Neumann 2000, 2001). Under pathological conditions such as mechanical brain injury, genes are turned on, inducing a proinflammatory milieu with upregulation of MHC molecules, local production of proinflammatory cytokines, and recruitment of inflammatory cells (Streit et al. 1989; Olsson et al. 1992).

3.1.3 Pathology Two apparently related types of cell death are to be distinguished: necrosis and apoptosis (pp. 62f). In addition to these degenerative changes of the cells themselves, pathological processes can be initiated by non-specific damage to axons and dendrites, as well as by regenerative processes. Since these negative and positive types of reactions affect all nervous tissue, not just neurons, they will be discussed in Chap. 4, “Cell and Tissue Reactions” (pp. 42ff). Ischemic cell necrosis is a specific pathological reaction of the neuron and is described in detail in Chap. 13. For details on the morphology and pathogenesis of the other specific pathological changes of neurons, the reader is referred to the relevant neuropathology textbooks (especially Haymaker and Adams 1982; Graham and Lantos 2002; Peiffer et al. 2002). Let it be noted here, however, that in most cases diagnosis is based not on changes of the neurons alone, but on those changes in relation to all other trauma-induced tissue changes, i.e., in microglial cells, neuroglia, blood vessels, etc. Neurons undergo certain physiological changes, notably the accumulation of lipofuscin in neurons (Fig. 3.1b) of the dentate nucleus of the cerebellum and inferior olive, and in motor neurons in the anterior horn of the spinal cord. Such changes are especially common in brains of the elderly. Neurons also react to axonal injury in the form of retrograde degeneration, i.e., a central chromatolysis or ballooned neurons (Fig. 3.1c). A chronic cell change is characterized by a shrunken, intense, dark staining neuron. Further degeneration processes will be described below. But the following phenomena should be mentioned at the beginning: ▬ Loss of dendrites (and their MAP reactivity − see Li et al. 1995, 1997) by ischemic or mechanical loading (Fig. 3.2b). ▬ Destruction of axonal fibers as demonstrated by silver technique (Fig. 3.2d). ▬ Axonal swelling as a result of an axonal lesion − as demonstrated by the silver technique (Fig. 3.2e) and reactivity to β-amyloid precursor protein (βAPP) (Fig. 3.2f).

Destruction and loss of myelin is demonstrable both by loss of myelin staining and an increase in scavenger cells (macrophages), the latter indicating active demyelination (Fig. 3.3d).

Intracytoplasmic Storage. Neurons can store other

substances besides lipofuscin. A new classification of the storage diseases was recently introduced based on the intracytoplasmic increase in gangliosides or ceroid lipofuscin in neurons (for details: see textbooks on clinical neuropathology). Basophilic Inclusions (Lafora Bodies − In Familial Myoclonic Epilepsy). Basophilic inclusions are globular

bodies located within the cytoplasm. They vary in size from 1 µm to 20 µm, pushing the nucleus and Nissl bodies to the periphery of the perikaryon. The body is hom*ogeneous in places, structured in others, and liable to splintering. If present in large numbers, they are indicative of a familial disease (myoclonic seizures, cerebellar ataxia). In rare cases, solitary Lafora bodies are present in normal postmortem material. Inclusion Bodies in Viral Diseases. Inclusion bodies

associated with viral diseases are usually intranuclear. In rabies, however, cytoplasmic inclusions are seen, termed Negri bodies, virus factories located in the cytoplasm of nerve cells of rabies victims (pyramidal cells of the hippocampus, Purkinje cells, and large motor cells of the brain stem and spinal cord). These are roughly spherical or oval bodies that range from 0.5 to 4.0 µm in diameter. Intranuclear inclusion bodies are the norm in viral illness, and are encountered in neurons and glial cells (oligodendrocytes, ependymal cells) of patients with cytomegalovirus infection, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, or herpes simplex virus encephalitis. They possess an amorphous spherical structure that is hom*ogeneous or granular and surrounded by a small clear zone of nucleoplasm. Neuronal Vacuolation (Bovine Spongiform Encephalopathy = BSE). The large neuronal vacuoles have

thin walls and appear to coalesce. They almost completely displace the perikaryon.

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3.2 Astrocytes Astrocytes are the most common cellular elements of the brain, outnumbering neurons by ten to one and taking up about one-third of the volume of the cerebral cortex (Pope 1978). Astrocytes, like oligodendrocytes, are “neuroglial cells” or “macroglial cells.” The two cell types derive from different precursors. These precursors, however, are the progeny of a common ancestor, the glioblast. Before birth the glioblast resides in the ventricular layer, after birth in the subependymal layer (Levison and Goldman 1993).

3.2.1 Morphology, Classification, and Immunoreactivity A specific cell structure, immunoreactivity, and function characterize “astrocytes” as a distinct cell type. Morphologically they are distinguished by long, sometimes branched processes found in gray and white matter. Astrocytes are interconnected with each other via gap junctions that create a syncytium allowing ionic and metabolic coupling (Norenberg 1997). Endowed with receptors to most neurotransmitters and neuropeptides (Murphy and Pearce 1987), astrocytes possess messenger systems that maintain essential communication between themselves and neurons. Among the chief biological markers of astrocytes, besides glial fibrillary acidic protein (GFAP), are glutamine synthetase, S-100 protein, and pyruvate carboxylase. All those cell types possess 10-µm intermediate filaments. Those in astrocytes express nestin, vimentin, and GFAP (49-kDa protein) (Eng et al. 1971; Galou et al. 1996; Colucci-Guyon et al. 1999). Thus vimentin and GFAP, for example, coexist in immature and in reactive astrocytes (Eng and Lee 1995). As stated above, astrocytes also express glutamine synthetase and S-100 protein. Some astrocytes are GFAP negative (GFAP-negative astrocytes), chiefly in the fetal nervous system and in gray matter of the adult brain (Kitamura et al. 1987). In normal gray matter, these protoplasmic astrocytes contain only sparse GFAP and do not stain for GFAP in routine paraffin material. Astrocytes are of three basic types: fibrous and protoplasmic astrocytes, and radial astrocytes. The former two types are demonstrable in adult CNS; the first type is most frequently found in the white matter (fibrous type), the second in the gray matter (protoplasmic type). Radial astrocytes are found in the walls of cerebral vessels and the neural tube mainly during embryonic development.

The three types of astrocyte can be classified, and exhibit the following features (Privat et al. 1995): 1. Fibrous astrocytes (white matter astrocytes − Fig. 3.4a,b). Markedly fewer in number than radial astrocytes, they are stellate in structure with long, thin, poorly ramified processes that are smoothly surfaced. The nucleus is spherical or oval shaped. Fibrous astrocytes react with GFAP antibody, but the cell body stains incompletely. 2. Protoplasmic astrocytes (gray matter astrocytes − Fig. 3.4c). Protoplasmic astrocytes have ramified processes of variable caliber. Most astrocytes residing in normal gray matter are GFAP negative, and this is the basis for determining reactive gliosis. GFAP-positive astrocytes in the gray matter are small and possess many short processes radiating from the cell body, which is usually poorly marked by GFAP immunoreactivity. 3. Radial astrocytes (white matter astrocytes). These cells, disposed in a plane perpendicular to the axis of the ventricles, are of particular importance during CNS embryology (Rakic 1995; Parnavelas and Nadarajahn 2001). The nucleus and perikaryon of radial astrocytes are located in close proximity to the pia mater, especially in the cerebellum and spinal cord. The processes lack ramification and at least one process touches the pia mater, the others coursing through the gray matter. GFAP-positive fibrous processes are distributed in the white matter of the lateral and ventral fasciculi of the spinal cord.

3.2.2 Function Astrocytes are essential not only for keeping the highly differentiated neurons in their proper place within the brain, but also for maintaining their physiological environment (Lugaro 1907). It is known (Newman 1995) that a highly regulated intercellular environment is required for neuronal function and that astrocytes regulate the crucial environmental homeostasis of electrolytes, water, and pH and which eliminate amino acids and proteins from the extracellular space. Although primarily the role of endothelial tight junctions, astrocytes also uphold the blood−brain barrier (BBB) from extracerebral influences by controlling and regulating the intercellular transport of molecules from the vessel to the neuron. Astrocytes perform the following functions: 1. Developmental function (neurotrophic action). Astrocytes are indispensable for neuronal survival, migration, and neurite outgrowth. GFAP-negative astrocytes constitute a better substrate for such functions than GFAP-positive astrocytes. This phenomenon may explain why astrocytes do

CHAPTER 3: Cytology of the CNS

Fig. 3.4a−h. Astrocytes. a, b White matter astrocytes, i.e., fibrous astrocytes (GFAP; magnification a ×500; b ×1,000); c gray matter astrocytes, i.e., protoplasmic astrocytes (GFAP; magnification ×300); d activated, plump (hypertrophic) astrocytes (GFAP; magnification ×1,000); e isomorphic gliosis (GFAP; magnifica-

tion ×300); f anisomorphic gliosis (GFAP; magnification ×300); g Alzheimer type II astrocytes marked by arrows (H&E; magnification ×1,000); h clasmatodendrosis of GFAP-positive astrocytes (GFAP; magnification ×1,000)

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not express GFAP until relatively late in CNS development after the early phase of neurogenesis has been completed (Menet et al. 2000). Astrocytes also promote myelin synthesis and remyelination (Franklin et al. 1993). 2. Electrolyte and water homeostasis and osmoregulation. Depolarization of neurons is achieved by a cellular efflux of K+ from active neurons with a consequent increase in extracellular K+. Astrocytes possess mechanisms for active and passive accumulation of K+ in the intercellular space and the transfer of K+ by spatial buffer currents to the capillaries and/or cerebrospinal fluid (CSF) space (Newman 1995). As stated above, astrocytes regulate not only K+ homeostasis, but also the homeostasis of Cl− and bicarbonate (Walz 1995), Na+ (Ballanyi 1995), Ca 2+ (Finkbeiner 1995), and the pH (Deitmer 1995). Astrocytic swelling, known as cytotoxic edema (see below, p. 47), occurs almost immediately following the incidence of CNS injury and has been described in experimental allergic encephalitis (Eng et al. 1989). Axonal swelling probably arises from a trauma or disease-induced increase in levels of potassium, glutamate, fatty acids, arachidonic acid, lactic acid, and free radicals. 3. Astrocyte-neuron lactate shuttle. According to a recent published hypothesis (Hertz 2004), neuronal activity-induced uptake of glucose takes place predominantly in astrocytes, which metabolize glucose anaerobically while lacate produced from anaerobic glycolysis in astrocytes is then released from astrocytes and provides the primary metabolic fuel for neurons (Chih and Roberts 2003, Hertz and Dienel 2005). 4. Control of vascular tone. Zonta et al. (2003) suggest that neuron-to-astrocyte signaling in the cerebral cortex is central to the dynamic control of vascular tone, and that astrocytes play a crucial role in this process. This conclusion is based on the fact that following electrode stimulation of neuronal afferents Ca 2+ levels increase in the somata and endfeet of astrocytes linked to arterioles. Thus there is a bridge between the response of astrocytes to neural activity and the observed dilation of arterioles (cf. Reilly 2003). 5. Transmitter inactivation mechanism. Henn and Hamberger (1971) demonstrated the uptake of γ-aminobutyric acid (GABA), norepinephrine, dopamine, and serotonin by a cell fraction rich in glial cells, suggesting that glia can eliminate, i.e., take up and metabolize, transmitters that overflow from the synaptic cleft. It is now known that protoplasmic astrocytes in the gray matter perform this function for the aforementioned amino acids and for the excitatory amino acid glutamate, inhibitory adenosine and adenosine triphos-

phate, histamine and N-acetylaspartylglutamate (Martin 1995). 6. Plasma protein uptake. Astrocytes immunostain for albumin (Klatzo et al. 1980), a phenomenon which has prompted some authors to propose that astroglial ingestion of plasma protein might aid in the resolution of brain edema (Oehmichen et al. 1979a; Tomimoto et al. 1996; Del Bigio et al. 2000). 7. Reactivity in CNS injuries. Following mechanical violence to the CNS, astrocytes undergo specific proliferative, morphological, and biochemical changes termed astrogliosis or reactive gliosis (see below, pp. 23f). 8. Immunological activity (for review see Dietrich et al. 2003). Astrocytes are stimulated by the cytokines interleukin-1 (IL-1), IFN-γ and tumor necrosis factor-α (TNF-α), as well as by multiple other growth factors (Norenberg 1997). Enlarged (reactive) astrocytes harbor an enhanced number of cytoplasmic organelles plus increased levels of GFAP, Ia antigen, IL-1, α-1-anti-chymotrypsin, and acute phase reactive protein (Eddleston and Mucke 1993). Under pathological conditions (infiltration by activated T-cells, blood−brain barrier disruption), the CNS shows an increased expression of the class I/II MHC, the adhesion molecule ICAM-1, the TNF-α receptor and complement component C3 (see Morgan 1999) plus production of TNF-α and IL-6 (Benveniste 1997). Astrocytes release various neuroactive compounds when stimulated by neurotransmitters, compounds such as taurine in response to βadrenergic stimulation or GABA after glutamate receptor stimulation. A survey of the immune factors synthesized and released by astrocytes − and their effects − was published by Norenberg (1997). 9. Regenerative CNS processes. Gliosis clearly has an inhibitory effect on regeneration of the adult mammalian CNS (Fitch et al. 1999). However, there is also evidence that astrocytes play an active role in both embryonic and adult neurogenesis (Reilly 2002; Song et al. 2002; Svendsen 2002; − for details see p. 66). 10. Neuron-like function. Recent evidence suggests that glial cells play more sophisticated, neuronlike roles; they integrate neuronal input, modulate synaptic activity, and process signals related to learning and memory (Kurosinski and Götz 2002).

CHAPTER 3: Cytology of the CNS

3.2.3 Pathology Astrocytes react differently to different neuropathological conditions, including trauma, infection, seizure, infarct, metabolic processes, and tumor infiltration. GFAP upregulation and fibrillogenesis are the principal factors underlying the formation of the glial scar. 3.2.3.1 Reactive Astrogliosis Reactive astrocytes typically undergo enlargement of the (hom*ogeneously stained) cell body and filaments. Cells and processes both increase strikingly in number. The increase of the processes may culminate in sclerosing gliosis. Astrogliosis is primarily characterized by swelling of the cell body and upregulation of glial filament expression (GFAP, vimentin). If cytoplasm is abundant and the cell rounded, such cells are variously termed “plump” astrocytes, “fattened” astrocytes or “gemistocytic” astrocytes (Fig. 3.4d). This cell type exhibits a hom*ogeneous cytoplasm and a slightly enlarged nucleus with angular projections from which the processes arise. The nucleus is lateralized to one side of the cell body and may be irregularly rounded. Astrogliosis is induced by transmembrane signals (e.g., growth factors and neuropeptides) via extracellular signal-regulated kinase and mitogenactivated protein kinase (Mandell 2001). In certain respects, reactive astrocytes resemble neurons undergoing central chromatolysis, which is a basic reaction to axonal transection (Bignami and Dahl 1995 − see below, p. 66). Moreover, at sites of brain tissue destruction, astrocytes form a scar in which they begin to shrink after some time and finally disappear, leaving behind a dense meshwork of glial fibers (Weil 1933). Clean excision of the brain parenchyma will leave a fluid-filled space the surrounding wall of which contains astrocytes that have undergone only a slight reactive change. Laceration as well as hypoxic changes (see below) of the brain parenchyma produce a powerful glial response and also proliferation of connective tissue. Gliosis may be isomorphic or anisomorphic. Isomorphic gliosis (see also piloid gliosis − Fig. 3.4e) typically occurs in cases of selective damage to neurons and their processes in which the glial fibers maintain their normal orientation. Anisomorphic gliosis (Fig. 3.4f) is seen in cases of severe brain damage with major disruption of the brain and glial architectonics with consequent disruption of the blood−brain barrier. Under pathological conditions glial cells form accessory glial limiting membranes. Reactive astro-

cytes, for example, may surround the necrotic tissue created by an infarct with a thick mesh of fibrils, thus demarcating it from viable brain tissue and helping to thwart the spread of edema. This glial scar (Figs. 9.10−9.12) will eventually be covered by a basal lamina and form a new surface of the brain. The cyst produced as macrophages absorb the necrotic tissue becomes part of the subarachnoid space. Astrocytes contribute to the synthesis of chondroitin sulfate proteoglycan (Gallo and Bertolotto 1990) and of the basal membrane proteins laminin and fibronectin (Price and Hynes 1985; Liesi and Risteli 1989). Reactive astrocytes are characterized by a rapid synthesis of GFAP and − to a lesser degree − vimentin and by hypertrophy of the astrocyte cytoplasmic processes. The astrocytes in certain areas of healthy adult brain tissue, including the cerebellum, retina, and large tracts of myelinated fibers and optic nerve, continue to co-express vimentin and GFAP (Pixley and De Vellis 1984; Calvo et al. 1990; Schmidt-Kastner et al. 1990). Numerous studies have shown in a variety of lesions that reactive astrocytes upregulate GFAP (Bignami and Dahl 1976; Tetzlaff et al. 1988). Although normal astrocytes lose their ability to express vimentin during normal development, reactive astrocytes appear to recover this capacity, especially in close proximity to the site of injury (Pixley and De Vellis 1984; Schiffer et al. 1988). Various experimental models [brain wounds in neonatal (Pixley and De Vellis 1984) and adult (Calvo et al. 1991) rats, for example] have demonstrated the co-expression of GFAP and vimentin by reactive astrocytes. Hozumi et al. (1990) used comparative quantitative immunoblots and immunohistochemistry to show the presence of GFAP-positive cells around the wound 3 h after wounding, unaccompanied however by an increase in total GFAP. By 6 h after wounding, GFAP had decreased to 80% of the sham-operated control value, but began to increase again by 24 h. Reactive glia in the vicinity of the wound increased steadily in number and intensity, peaking at about 7 days, then declining significantly by 21 days. A number of experimental models have shown increased immunostaining of GFAP in gliosis, after stab wounding for example (Miyake et al. 1988). Astrocytes proliferate dramatically from day 0.5 to day 3 after experimental stab wounding (Miyake et al. 1992 − see also Janeczko 1989). Maximum numbers of proliferating cells (an increase of GFAP-positive astrocytes) were observed on days 2.5 and 3. The phenomenon of astrocyte proliferation is however relatively limited, being confined mainly to the injury site (Miyake et al. 1992).

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3.2.3.2 Piloid Gliosis Piloid gliosis (also termed pilocytic or isomorphic gliosis) is associated with long-standing degeneration of nerve fibers in, among other sites, the spinal cord. The unusually long fibrils course in pathways parallel to the degenerating nerve fibers. 3.2.3.3 Metabolic (Protoplasmic) Gliosis Metabolic gliosis (Norenberg 1996) develops mainly in the basal ganglia and cerebral cortex of patients in hepatic or uremic coma or in a precoma lasting several days, especially in victims of hyperammonemia. The astrocytes associated with metabolic gliosis are called “Alzheimer‘s type II astrocytes” (Fig. 3.4g). In metabolic diseases (Adams and Foley 1953) they exhibit a tendency to aggregation (giving rise to socalled Gliarasen) with an increase in number and size of their nuclei, which occur in clusters or pairs as a sign of the proliferation process. The nuclei are vesicular and may show a twofold increase in size. They have a prominent nuclear membrane and an optically empty nucleoplasm whose scant chromatin particles resemble nucleoli. Some of the astrocytes are located in close proximity to neurons (neuronal satellitosis) as a sign of neuronal damage. Intranuclear inclusions may be found upon staining for glycogen [e.g., Periodic Acid Schiff (PAS) stain]. Some but not all of the astrocytes express GFAP. Metabolic gliosis does not exhibit glial fiber formation. 3.2.3.4 Regressive Alterations Astrocytes do not undergo progressive alterations alone, but also regressive changes such as atrophy, pyknosis, and clasmatodendrosis (Fig. 3.4h). In the early phase following mechanical loading or ischemic injury, the cell body swells and becomes rounded. Later lipid granules and vacuoles appear in the cell body and the surface becomes irregular. The cytoplasmic processes break off (clasmatodendrosis) and disintegrate into granular debris. Astroglia possessing pseudopodia-like appendages alone are called ameboid glial cells.

3.3 Oligodendrocytes 3.3.1 Morphology, Classification, and Immunoreactivity Oligodendrocytes are small cells with a round or oval, relatively dense nucleus and a small rim of cytoplasm with a cell diameter of 6−8 µm. Oligodendrocytes possess ramified processes that can be demonstrated by silver techniques. They also exhibit a structural polymorphism that reflects differences in function. Three to five types of oligodendrocyte can be distinguished based on localization, which may also be related to differences in function. 1. Perineuronal oligodendrocytes (gray matter oligodendrocytes − Fig. 3.5a, b). This type of oligodendrocyte is commonly located near the larger pyramidal cells of the cerebral cortex and the nerve cells of the basal ganglia. Perineuronal oligodendrocytes are considered to be analogous to capsule cells of the dorsal root ganglia. They constitute 51% of the total perineuronal glial population (Bunge 1968). 2. Perivascular oligodendrocytes (gray matter oligodendrocytes). Fairly numerous, these cells are seen mainly around cerebral cortical vessels. 3. Interfascicular oligodendrocytes (white matter oligodendrocytes − Fig. 3.3c, d). This is by far the most common type of cell in the white matter. These have processes that run parallel to nerve fibers and partly or completely encircle nerve fibers; the cell nuclei are disposed in rows. In the corpus callosum of the rat 69.8% of glial cells in these rows are oligodendrocytes (Mori and Leblond 1970). 4. Szuchet (1995) describes a fourth type of oligodendroglia according to Rio Hortega (1956) which is associated with large axons and located near the entrance of nerve roots into the CNS. 5. An oligodendrocyte precursor cell is described as a fifth type, which comprises 5−8% of the glial cell population in the CNS (Levine et al. 2001). These cells have small cell bodies with multiple branched processes. In gray matter, the processes tend to be oriented radially, in white matter they are more longitudinally arranged and aligned with nerve fibers. Under normal circ*mstances the processes are in contact with synapses and nodes of Ranvier, a possible indication that these structures play a regulatory role in the axonal impulse conduction. 6. Meanwhile the oligodendrocyte has served as a model for lineage development in part due to the identification of specific additional phenotypic

CHAPTER 3: Cytology of the CNS

Fig. 3.5a−d. Oligodendrocytes. a, b Perineuronal oligodendrocytes = gray matter oligodendrocytes (a carbonic anhydrase II = CA II; magnification ×500; b silver stain; magnification ×1,000);

stages during maturation (Grinspan 2002). The result is the identification of numerous signaling molecules inducing oligodendrocyte development. Oligodendrocytes can be demonstrated by the silver technique and by antibodies to myelin basic protein (MBP), myelin oligodendrocyte glycoprotein, platelet-derived growth factor, galactocerebroside, or to proteolipid protein (Levine et al. 2001; for review, see Friedman et al. 1989). Also specific for oligodendrocytes are the monoclonal antibodies Rip (Friedman et al. 1989), Otex 1 (Mori de Moro et al. 1990), and CC-1 (Bath et al. 1996). In addition, oligodendrocytes have been found to selectively express carbonic anhydrase II (CA II) (Cammer et al. 1977; Ghandour et al. 1980), gluthathione-S-transferase, isoenzyme pi (Tansey and Crammer 1991), and cell-surface sphingolipids, such as galactocerebroside (Raff et al. 1978).

c, d interfascicular oligodendrocytes = white matter oligodendrocytes (c CA II; d silver stain; magnification c ×500, d ×1,000)

3.3.2 Function The function of oligodendrocytes is still largely unknown. Different functions have been attributed to the various types of oligodendrocyte. 1. Peters et al. (1991) propose that perineuronal oligodendrocytes may contribute to neuronal nutrition. It has also been suggested that under certain conditions, such as in remyelination, these satellites are able to produce myelin (Ludwin 1978; Polak et al. 1982). The total amount of myelin oligodendrocytes are able to synthesize is thought to remain relatively constant (Blakemore 1981). It is on the basis of these findings that neurons are considered to be the regulators of myelination. 2. Interfascicular oligodendrocytes are known to be involved in the myelination and remyelinating processes (Harrison and McDonald 1977). In the early stages of myelin formation the cytoplasmic processes sequentially ensheathe the axons. Following demyelination, the myelin sheath regenerates chiefly by forming near internodes. Before remyelinated fibers may be recognized (within 3 weeks) demyelinated axons are surrounded by processes from one or more cell types, such as

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3. 4.

5.

6.

7.

astrocytes and debris-laden mononuclear phagocytes. None of these cell types, however, is able to produce a membrane that spirals around the axons or which is compacted in a myelin-like fashion. The regenerated myelin sheaths are formed by oligodendrocytes, which possess microtubules but no filaments (Harrison and McDonald 1977). Little is known about the function of perivascular oligodendrocytes. Oligodendrocyte precursor cells have processes that are in contact with synapses and the nodes of Ranvier, an indication, as mentioned above, that these structures fulfill a regulatory function in transmitting information via bioelectric signals (Levine et al. 2001). Although they divide slowly, these cells constitute about 70% of cells labeled by a pulse injection of bromodeoxyuridine (labeling index: 0.2−0.3%; cf. Horner et al. 2000). Oligodendrocytes as a cell group also play an active role as an antigen-presenting cell type and are thus involved in immunological processes. Though oligodendrocytes are negative for MHC class I and II expression in normal human CNS (Sedgwick and Hickey 1997), under pathological conditions oligodendrocytes may show an increase in class I MHC expression (Benveniste 1997). This is because INF-γ, normally produced by activated T-cells and absent from the intact CNS, becomes a potent modulator of MHC antigen expression under pathological conditions, such as T-cell infiltration or disrupted blood−brain barrier. No systematic studies have yet clarified the influence of neurons or astrocytes on oligodendrocytes. Fulcrand and Privat (1977) thought oligodendrocytes need neuronal input, but they did not examine whether there must be physical contact between the two cell types or whether neurons influence oligodendrocytes via secreted factors. Astrocytes and oligodendrocytes are coupled in situ by gap junctions (Massa and Mugnaini 1982). Oligodendrocytes can perform their myelination repertoire without gap junctions, which suggests that these junctions fulfill a function not necessarily directly related to the formation of myelin. Little is known either about the interactions between oligodendrocytes. Oligodendrocytes are aligned in closely apposed rows, the cells being joined by tight junctions (Massa and Mugnaini 1982). This may indicate intense interaction among these cells, the details of which remain unknown.

3.3.3 Pathology Oligodendrocytes are compromised in many neurological diseases, including demyelinating diseases (e.g., multiple sclerosis), metabolic diseases (e.g., Pelizaeus-Merzbacher‘s disease), infectious diseases (e.g., progressive multifocal leukoencephalopathy), neurodegenerative diseases (e.g., Alzheimer‘s disease), and tumors (e.g., oligodendrogliomas). Under pathological conditions oligodendrocytes assume the various functions described above, the nature of the function partly dependent on the particular cell type. However, this cell type is mainly activated under conditions of myelin degeneration, and their main function is remyelination. Destruction of oligodendrocytes induces unchecked demyelination, with disastrous consequences for brain function. Myelin formation was recently examined by Campagnoni and Skoff (2001) to aid our understanding of oligodendrocyte function. They found that myelin basic protein (MBP) and myelin proteo-lipid protein (PLP/DM20) genes encode classic MBP and PLP isoforms. The products of non-classic MBP isoforms appear to be components of transcriptional complexes in the nucleus of oligodendrocytes. The products of non-classic PLP/DM20 isoforms appear to make up part of the intracellular transport particles within oligodendrocytes. The same authors reported evidence that PLP/DM20 proteins play a role in neuronal death mechanisms, paracrine and autocrine regulation of oligodendrocytes and neurons, oligodendrocyte migration, and intracellular transport. Matsushima and Morell (2001) developed an experimental animal model designed to induce myelin degeneration and remyelination by dietary introduction of the copper chelator bis-cyclohexanone oxaldihydrazone (Cuprizone). After ingestion of the toxin in this model, oligodendrocytes suffer a specific primary insult and undergo apoptosis. Soon thereafter, recruitment of microglia begins and myelin phagocytosis ensues. Next, oligodendrocyte progenitor cells proliferate and invade the demyelinated area. Once the Cuprizone challenge is ended, remyelination commences and is almost completed in a matter of weeks. It can be inferred from their findings that different cell types communicate by soluble factors. Remyelination is to a certain extent accomplished either by surviving oligodendrocytes, or by cells newly differentiated from the adult progenitor pool. The oligodendrocyte precursor cells in injured CNS constitute a reactive glial population that goes through hypertrophy and mitosis under stimulation from an array of cytokines and growth factors. If there is demyelination, these cells divide and differentiate into new oligodendrocytes that replace the ones that were lost. Activation and proliferation of

CHAPTER 3: Cytology of the CNS

these cells also occur in response to other types of CNS damage, including excitotoxicity, mechanical injury, and viral infection. Ischemic oligodendroglial injury was recently described in a neonatal rodent stroke model (Liu et al. 2002). The authors showed that myelin proteins are restored in the brain after moderate, but not after severe, cerebral hypoxia-ischemia. Dewar et al. (2003) gave an excellent review on this topic and demonstrated that oligodendrocytes may be targets of injury in acute ischemia. Alterations of their distinct cytologic features and specific immunocytochemical reaction gave evidence of oligodendrocyte damage in animal models. For example, oligodendrocytes became immunoreactive for the cytoskeletal protein tau (Dewar and Dawson 1995; Irving et al. 1996, 2001; Uchihara et al. 2000). Oligodendrocytes have also been shown to inhibit the regenerative response to axonal injury (Schwab 1993 − see also p. 66).

ningeal macrophage population is slowly replaced by hematogenous macrophages. The population of parenchymal microglia, in contrast, seems to be quite stable in the mature normal brain and may not be replaced by new bone marrow-derived macrophages (Bauer et al. 2001). Additionally we have to point to another cell population within the CNS with similar functional properties as microglia: dendritic cells. Dendritic cells are a subclass of antigen-presenting cells critical in the initiation and regulation of adaptive immunity against pathogens and tumors as well as in the triggering of autoimmunity (for review see Pashenkov et al. 2003). Dendritic cells are present in normal meninges, choroid plexus, and CSF, but absent from the normal brain parenchyma. Inflammation is accompanied by recruitment and/or development of dendritic cells in the affected brain tissue.

3.4.1 Morphology, Classification, and Immunoreactivity

3.4 Microglia and/or Mononuclear Phagocytes of the CNS Microglia make 5−12% of the CNS glia (Lawson et al. 1990). If microglia constitute 10% of the total glial cell pool, and if glial cells are at least 10 times as numerous as neurons in the CNS, then microglia are as numerous as neurons (Streit 1995). The proliferative activity, i.e., the microglial turnover rate, is very low (0.05% − Lawson et al. 1992), which means this cell type has a long life span within the brain tissue. Rio Hortega (1932) ascribed to microglia a mesenchymal origin. Especially during embryonic development, hematopoietic monocytes invade the CNS as well as the CSF and the perivascular spaces, and mature within the brain parenchyma into typical process-bearing resident microglia (Ling and Wong 1993). Only a few authors still question this process (Fedoroff 1995). Research on bone marrow transplantation (BMT) has provided information on the turnover rate of mononuclear CSF cells. When bone marrow cells from male donors are transplanted into female hosts, in situ hybridization with Y-chromosome-specific probes showed that by the time complete donor type hematopoiesis had become established (19−97 days after BMT), all cells within the CSF were donor derived (Hibi et al. 1997). In another study, perivascular cells within the brain contained the donor marker, while parenchymal microglia did not (Unger et al. 1993). These recent findings as former observations (for review see Oehmichen 1978) indicate that mesenchymal cells derived from the bone marrow patrol the CNS continuously and that the perivascular and me-

Microglia can be differentiated by localization or functional stage. The term “mononuclear phagocyte” (Oehmichen 1978) is well chosen and designates all monocyte-derived cells within the CNS. The following cell types are distinguished (Oehmichen 1978; Hickey et al. 1992; Gehrmann and Kreutzberg 1995; Perry and Gordon 1997): 1. Leptomeningeal and choroidal macrophages (Fig. 3.6a, b). These cells are phenotypically macrophages, express macrophage antigens, and are localized within the subarachnoid space and ventricular system. They have a relatively high replacement rate (60% − Hickey et al. 1992). 2. Perivascular macrophages (Fig. 3.6c). These are important immunoregulatory cells to be distinguished from so-called pericytes. They are enclosed by a basal lamina, express macrophage markers, and may act as sensors of CNS perturbations. They are activated by CNS inflammation and are primary targets of human immunodeficiency virus (HIV) infection in the CNS (Williams et al. 2001). Their turnover rate is about 30% (Hickey et al. 1992). Leptomeningeal, choroidal, and perivascular macrophages can all be induced to phagocytosis. Unlike other glial cells, even compared to resting microglia, they are efficient and active antigenpresenting cells (Hickey and Kimura 1988; Ford et al. 1995). 3. Perivascular microglia (Fig. 3.6d). These cells form a subtype of resting parenchymal microglia. Perivascular microglia come in direct contact with the adjacent basal lamina and thus, like pe-

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Fig. 3.6a−d. Mononuclear phagocytes. a Subarachnoid macrophages as seen on microscopic sections (v. Gieson stain); b subarachnoid macrophages as seen in CSF specimens (see Oehmichen 1976; Giemsa stain); c perivascular macrophages

within Virchow-Robin space (CD68 reactivity); d perivascular microglia in the next vicinity of capillaries (CD68 reactivity; magnification a, c ×300, b, d ×1,000)

rivascular astrocytic endfeet, form part of the perivascular glia limitans (Lassmann et al. 1991). 4. Ramified resting microglia in the normal CNS (Fig. 3.7). This cell type has a small heterochromatic nucleus and fine, ramified processes which exhibit a stellate morphology in the gray matter and a bipolar, longitudinal morphology in the white matter. Under pathological conditions they may transform into “activated microglia” (see below).

the intact blood−brain barrier in response to the degeneration of other cell types or to inflammatory substances within the parenchyma. Like activated Tlymphocytes, monocytes are also known to cross the intact blood−brain barrier under non-pathological conditions (Hickey 1999). For a long time, the demonstration of resting and activated microglia only succeeded due to silver techniques. Selective immunohistochemical staining is only possible because of the expression of specific surface proteins in microglia. Visualization in vivo is possible (Banati 2002) using 11C-labeled ligands for the peripheral benzodiazepine binding site (PBBS), which binds to activated but not resting microglia with relatively cellular selectivity.

Leptomeningeal, choroidal, and perivascular macrophages exhibit the same immunoreactive pattern as macrophages and activated microglia and may be termed “mononuclear phagocytes.” Ramified resting microglia are demonstrated by the silver carbonate method (Rio Hortega 1919), by immunohistochemical procedures (for review see Gehrmann and Kreutzberg 1991; Streit 1995), and by histochemical techniques (Oehmichen 1980). As late as the 1990s it was thought that the blood−brain barrier prevented macrophages from invading the CNS. It was observed that a disrupted blood−brain barrier did not invariably result in invasion of the CNS parenchyma by monocytes. In addition it was noted that circulatory monocytes cross

3.4.2 Pathology Under pathological conditions a cell type appears which stains like resting microglia, the so-called activated microglia. Activated resting microglia in animal experiments (mice) express OX-42 and CR3complement receptors (Graeber et al. 1988a) plus F4/80 and Mac-1 antigen (Perry et al. 1985). In pa-

CHAPTER 3: Cytology of the CNS

Fig. 3.7a−f. Ramified resting microglia in normal CNS. a, b Silver stain; c, d UDPase; e, f CD68 reactivity (magnification a, c, e ×500; b, d, f ×1,000)

thological human brain tissue, activated microglia can be detected in routine paraffin material using the monoclonal antibody LN-3 (Sasaki et al. 1991). Activated microglia also express MHC class I and II antigens (Streit et al. 1989) in addition to almost all other macrophage-specific antigens. Activated microglia possess an ability to proliferate locally, to emigrate to the site of injury, to change morphologically, immunophenotypically, as well as functionally (Gehrmann and Kreutzberg 1995). Two types of activated microglia are recognized: ▬ Activated, non-phagocytic microglia (Fig. 3.8a). These cells are hypertrophic and have processes which are more numerous than those of resting microglia. They express vimentin, several ma-

crophage markers, including CR3 complement receptor, MHC class I and II, and CD4 antigen (Streit and Kreutzberg 1987). They are characterized by intense upregulation of CD68 and CD14 (Beschorner et al. 2002). Activated phagocytic microglia (Fig. 3.8b-d). Morphologically these cells are characterized by an ameboid cell structure lacking processes as seen after traumatic (Fig. 9.8) or ischemic events (Fig. 14.12−14.15); functionally they resemble non-phagocytic microglia, but are additionally capable of phagocytosis of neurons (Fig. 3.8e), of fat (Fig. 3.8f), of myelin (Fig. 3.3d), etc. and are capable of releasing immunomodulatory compounds. Microglia may respond to sterile CNS in-

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Fig. 3.8a−f. Activated microglia. A moderate (a) and a distinct cluster-like increase (b, c) of activated microglia demonstrated by CD68-immunohistochemistry as well as by silver stain (d) (magnification a ×500; b ×100; c ×500; d ×1,000); e perineuronal aggregation of microglia (satellitosis or microglial nodule) as an

indication of neuronal phagocytosis (Nissl stain; magnification ×1,000); f lipid-containing phagocytes (Fettkörnchen-Zellen) as an indication of the scavenger function of microglia (oil-red 0; magnification ×1,000)

jury as a consequence of their scavenger function, such injury also stimulating a release of growth factors that participate in the scarring process of gliosis.

hydration, microglial cells proliferate in the posterior pituitary and the supraoptic nucleus (Lawson et al. 1993). It has recently been shown that monocytes aggravate neuronal degeneration, for example in cases of HIV-infected macrophages which produce a neurotoxic substance (Giulian et al. 1990). In other conditions involving rapid recruitment of macrophages, they secrete neurotoxic compounds (Piani et al. 1991) and can damage myelin (Coffey et al. 1990 − for review see Giulian 1995).

Graeber et al. (1997) suggested that microglia are a “sensor” of the pathological status of the human CNS. Under certain physiological and especially pathological conditions of the CNS microglia react very quickly. Microglia are slightly more numerous in elderly brains and they show more phagocytotic activity (Peters et al. 1991). Under conditions of de-

CHAPTER 3: Cytology of the CNS

Two observations have potential practical (forensic) applications: Lassmann (1997) used the detection of myelin degradation products within brain macrophages to estimate the age of trauma-induced demyelination (1−14 days), and thus to stage lesions of CNS white matter (cf. Oehmichen et al. 1986). Meyermann et al. (1997) applied various immunoreactive macrophage markers to show that although MBI may induce upregulation of various antigens, it does not induce macrophage proliferation at the margins of mechanically induced hemorrhages − in contrast to the processes resulting from an ischemic lesion. A sophisticated questioning of the functional potential of microglia was given by Streit (2002). He examined the possible consequences of microglial dysfunction as a result of aging, genetics, or epigenetics. He supposed that microglial senescence was a potential factor in the pathogenesis of Alzheimer‘s disease. His hypothesis is based on observations of microglial abnormalities, especially microglial deramification, spheroid formation, gnarling and fragmentation of processes in Alzheimer‘s disease (Streit et al. 2004), A further question must be answered: the fate of activated microglia. Obviously, a part of activated microglia will leave the CNS by migrating along lymphatic pathways (Oehmichen et al. 1979b). Another portion may disappear by focal cell death induced by interleukin-13 (IL-13) in association with IL-4 in a time-dependent manner (Yang et al. 2002).

3.4.3 Function A cell type‘s immunophenotypical properties are an indication of its phagocytic and immunological functions (Oehmichen 1983; Gehrmann and Kreutzberg 1995). 1. Resting microglia as well as the group of mononuclear phagocytes upregulate Fc and complement receptors (Oehmichen 1978), which could also be demonstrated in resting microglia using a monoclonal F4/80 antibody (Perry et al. 1985). 2. Resting microglia normally lack MHC class I and only a few microglial cells express MHC class II (Perry and Gordon 1997). The immunological situation created by inflammatory processes (neuritis, brain abscess, glioma, viral infection, neurotoxin lesion) leads to the activation of resting microglia and infiltration of the CNS by blood monocytes, which express MHC classes I and II. 3. Recent investigations give evidence of the expression of “scavenger” receptors (class A, Bi and CD36) by microglia, astrocytes, cerebral microvascular endothelial cells, etc. (Husemann et al. 2002). These receptors are cell surface proteins that mediate cell adhesion to, and endocytosis of,

various native and pathologically modified substances, and participate in intracellular signaling, lipid metabolism, and host defense against bacterial pathogens. Neonatal microglia express scavenger receptors, while these receptors are not expressed in normal mouse or human adult brain microglia. 4. Activated microglia synthesize tumor necrosis factor (TNF) in the very early phase (minutes to a few hours) after induction of ischemia (Lambertsen et al. 2002). TNF is a potential neurotoxic cytokine. 5. Activated microglia upregulate vimentin (Graeber et al. 1988b) and both MHC classes I and II, ED-1, etc. (see above). 6. Activated microglia perform all of the immunological functions attributed to macrophages in sterile and non-sterile inflammation: they release immunomodulatory compounds and interact with other immunocompetent cells. Moreover, the functional potential of microglia is not limited to their surface protein expression but it is additionally characterized by their interaction with cytokines (for review see Hanisch 2002). Cytokines constitute a significant portion of the immuno- and neuromodulatory messengers that can be released by activated microglia. By virtue of potent effects of resident and invading cells, microglial cytokines and chemokines regulate innate defense mechanisms, help the initiation and influence the type of immune response, participate in the recruitment of leukocytes to the CNS, and support attempts at tissue repair and recovery. Moreover, microglia can also receive cytokine and chemokine signals as part of their communication with astrocytes, neurons, endothelium, and leukocyte infiltrates. The inflammatory response, therefore, is marked by the appearance of phagocytes, which arise from activated resting microglia as well as from invading monocytes, which bear scavenger receptors within 5−8 h after wounding (Giulian et al. 1993). In the rat brain their numbers were found to peak 2 days after the traumatic event. Meanwhile there is additional evidence of the reciprocal interactions between microglia and neurons and complex signaling systems (Polazzi and Contestabile 2002). The signal relates to the suppression of immunological properties of microglia by neurons in the healthy brain and between damaged neurons and microglia. The authors propose that microglial activation, consequent to neuronal injury, is primarily aimed at neuroprotection (Polazzi and Contestabile 2003). The loss of specific communication between damaged neurons and microglia is viewed as being responsible for the transformation of microglia to a hyperactive state, allowing them to escape neuronal

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control and giving rise to persistent inflammation, resulting in exacerbation of neuropathology. 3.4.3.1 Resting Microglia It is still not known exactly what function resting microglia perform within normal brain parenchyma. They may participate in tissue homeostasis and in the early defense against injury and infection (Gordon et al. 1988; Perry and Gordon 1997). Because resting microglia and mononuclear phagocytes cross react, using different antibodies, resting microglia seem to take up the same functions in the CNS as resting macrophages in the tissue of other parenchymal organs, i.e., both a scavenger function and an immunological function. The most important function appears to be their transformation under pathological conditions into intrinsic phagocytes. Their ability to be activated is expressed above all in their capacity to proliferate, to phagocytose, and to release immunomodulatory compounds. Microglia form a network of antigen-presenting cells whose main function is immune surveillance (Oehmichen 1983; Perry and Gordon 1997). Under pathological conditions resting microglia change into mobile, phagocytic cells that are capable of neuronophagia (Banati et al. 1993) and which release proteases, proinflammatory cytokines (IL-1, TNF-α, IL-6, etc.), anti-inflammatory cytokines (IL-10, TGF-β), cytotoxic molecules (nitric and oxygen radicals), prostanoids (PGD2, PGE2, thromboxane B2), and chemokines (IL-8, etc.) (Aloisi 2001). 3.4.3.2 Perivascular Microglia Perivascular microglia apparently participate in functions of the blood−brain barrier system. Together with leptomeningeal phagocytes, they fulfill a scavenger function within the CSF, especially under pathological conditions such as hemorrhage, stroke or infection (for review of literature up to 1982 see Oehmichen 1982b; 1982−1995: see Gehrmann and Kreutzberg 1995). They are involved in the immunoreactive response as they are antigen-presenting cells. Some data appear to indicate that perivascular microglia return to the spleen and lymph nodes bearing the material they have gathered in the CNS (Oehmichen et al. 1982a, b; Broadwell et al. 1994). Direct labeling of a particulate antigen in the CNS, however, could not show that these cells triggered an immune response to the antigen (Matyszak and Perry 1998, cf. Graeber et al. 1992).

3.4.3.3 Activated Microglia (Macrophages) Activated non-phagocytic microglia is involved in immunological processes as a regulatory cell in the defense against pathogens and tumor. Activated phagocytic microglia phagocytose necrotic cells − especially necrotic neurons (Fig. 3.8e), cell particles, and other debris resulting from, e.g., edema, myelin degradation (Figs. 3.3d, 9.15), necrosis, i.e., lipids (Figs. 3.8f, 9.16), or red blood cells in hemorrhages (Figs. 9.17, 9.18). Activated microglia may ingest extravascular erythrocytes, which can be demonstrated as erythrocyte- or siderin-bearing macrophages (Figs. 9.17, 9.18). They may also contain ingested nuclear material, myelin, and lipids, which are changed by intracellular digestion (Oehmichen et al. 1986; Lassmann 1997). In special cases the ingested substances may enable retrospective diagnosis and timing.

3.5 Additional Cell Types and Tissue Components The cell types and different tissues described in the following protect the CNS parenchyma from extracerebral influences, such as blood constituents and microorganisms, and thus maintain intracerebral homeostasis (for a survey of these cell types see Bargmann et al. 1982).

3.5.1 Leptomeningeal and Perivascular Cells The leptomeninges are composed of the two more delicate components of the meninges, the pia mater and the arachnoid mater, considered together. The pia mater contains the blood vessels that penetrate the brain, while the arachnoid mater is composed of the arachnoid membrane and trabeculae, the latter stretching from the membrane to the pia. Since this situation arises from a progressive enlargement embryologically of the extracellular space of the originally solid leptomeninges, the arachnoid trabeculae are surrounded by the subarachnoid space containing CSF. The term pia mater is applied to the entire brain and spinal cord surface. Moreover, funnel-shaped pia mater accompanies vessels that extend into the brain. The undersurface of the pia mater possesses a well-defined glial basem*nt membrane. The portion of the glial membrane that courses along the penetrating vessels is called the membrana gliae perivascularis.

CHAPTER 3: Cytology of the CNS

The arachnoid membrane constitutes the outer limit of the arachnoid. The membrane spans the sulci of the cerebrum and cerebellum and lies near the brain stem. The arachnoid trabeculae composed of collagen fibrils, fibrocytes, and fibroblasts span the subarachnoid space and attach the arachnoid membrane to the pia mater. The vessels entering the cortex are thin-walled, comprised merely of a basem*nt membrane, endothelium, and a single layer of smooth muscle cells. The Virchow-Robin space (perivascular space) lies between the vessel basem*nt membrane and the glial basem*nt membrane. Both the subarachnoid space (Fig. 3.6a, b) and the Virchow-Robin space (Fig. 3.6c) are filled with CSF, which contains single macrophages and isolated lymphocytes (Oehmichen 1976). Two-thirds of the CSF is produced by the choroid plexus. To reach the subarachnoid space, CSF courses from the lateral to the third ventricles through the interventricular foramina (of Monro), the third ventricle, the cerebral aqueduct of the midbrain, the fourth ventricle, the two lateral foramina of Luschka and the midline foramen of Magendie. It exits the intracranial spaces via arachnoid villi or via lymph channels at the level of the nerve roots (for review: Oehmichen et al. 1982a, b).

3.5.2 Parenchymal Vessels Parenchymal vessel walls of the brain are very similar in construction to those of other organs (for details, see Chap. 28, pp. 542 ff). Normal arteries possess an intimal layer composed of endothelial cells with longitudinally oriented nuclei and perikarya. A basem*nt membrane covers the endothelial cells. The internal elastic lamina separates the intimal layer from the lamina media, which consists of smooth muscle cells. The lamina adventitia is formed of loose connective tissue containing collagenous fibers, pericytes, fibroblasts, and perivascular macrophages, which are typical of the Virchow-Robin space. The normal veins of the brain are characterized by a wide lumina and relatively thin vessel walls. They have no internal elastic lamina. Brain capillaries differ from those of other organs by their complete or almost complete impermeability (blood−brain barrier) and lack of fenestrations. The neighboring endothelial cells are bound together by tight junctions or zonulae occludentes, which prevent the passage of tracer substances. This barrier function is absent in vessels of the choroid plexus, pineal body, pituitary gland, area postrema, tuber cinereum, and median eminence. Under pathological conditions, shrinkage of endothelium can occur and thus leads to the formation

of fenestrations. The tight junctions can also fail, or pinocytotic vesicles may arise within the endothelial cells, all of which are associated with a breakdown in the blood−brain barrier (cf. Chap. 4, pp. 42f). Endothelial cells may proliferate, as seen in glioblastoma, or as a consequence of ischemic and/or toxic damage to the CNS.

3.5.3 Choroid Plexus and Ependyma The cells of the surface of the choroid plexus (choroidal cells) as well as of the ventricular system (ependymal cells) originate from neuroectodermal ependymoblasts of the neural tube. The choroid plexus possesses fronds produced by elaborate infolding of the plexus surface. The fronds exhibit ramified villous processes, each supported by connective tissue. The choroid plexus has clearly defined projections into the third, fourth, and lateral ventricles of the brain. Its surface is covered by a thin epithelium composed of low columnar, cuboidal, or squamous cells mounted on a basem*nt membrane. Choroidal cells secrete two-thirds of the CSF (roughly 500 ml/ day in an adult), the remaining one-third (roughly 250 ml/day in an adult) arising from the interstitial fluid of the brain. The choroidal CSF can be thought of as fresh fluid diluting and rinsing the more stagnant and metabolite-laden extrachoroidal, tissuederived CSF. The ventricular surfaces are lined by cuboidal to columnar cells with cilia and microvilli, the ependymal cells. Adjacent cells are bound to each other by desmosomes. The hypothalamic wall of the third ventricle contains a specialized ependymal cell type called the tanycyte. The functions of ependymal cells are secretion, absorption, transport, receptor tasks, and provision of a barrier between the CSF and brain (Del Bigio 1995).

3.5.4 Pathology of the CSF and Cells Within the CNS Disturbance of CSF turnover can lead to a pathological reaction in the form of hydrocephalus (cf. pp. 54 ff). The turnover can be disturbed by disruption of CSF reabsorption, particularly by diseases of the arachnoid villi. Subarachnoid hemorrhage due to an efflux of red blood cells can cause blockage of the arachnoid villi, and thus a backup of CSF, while the ventricle to CSF pathways for CSF flow remains open (communicating hydrocephalus). Disturbance of the pathways communicating between the ventricular system and subarachnoid space may cause internal hydrocephalus (non-communicating hydrocephalus). The pathways can also be congenitally blocked

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or impeded by an atresia (congenital non-communicating hydrocephalus) or the blockage can result from infection (postmeningitic hydrocephalus) or tumor, giving rise in each instance to an obstructive, i.e., high pressure, hydrocephalus. Disease processes, e.g., following mechanical violence or stroke, can lead to a reduction in the brain parenchyma, producing a so-called hydrocephalus ex vacuo. All of the above mentioned cell types discussed here line the surfaces of the brain and protect it against extracerebral influences (Adams et al. 1982). The vessels of the brain are especially well suited by their barrier function to guarantee hom*oeostasis within the brain parenchyma. The CNS was once thought to be an immunologically privileged organ, exempted from immune reactivity and immune surveillance. This is attested to by the absence of MHC molecules basic to antigen presentation from resident cells of the nervous system, but not from perivascular cells and CSF macrophages. Under normal circ*mstances the aforementioned resting microglia are present in the CNS and subject to activation. Normal CSF contains a few lymphocytes (Oehmichen 1976), and activated (but not resting) T-lymphocytes can cross the blood−brain barrier to carry out immune surveillance of the normal brain parenchyma (Wekerle et al. 1986). A constant surveillance of the intact healthy CNS is performed by activated T-cells. Recent investigations show that B-lymphocytes enter all parts of the normal brain in very low numbers and that the B-lymphocytes within the brain parenchyma display an activated (CD23 positive) phenotype (Anthony et al. 2003). Under pathological conditions, the situation changes considerably, the alterations involving both the endothelial cells and leukocytes (cf. Chap. 29, pp. 582 ff). The CNS is subjected to massive infiltration by immune cells (Flügel and Bradl 2001; Hickey 2001) dependent on antigens (Hickey et al. 1997) and release of various cytokines (Benveniste 1997). When attachment and transendothelial migration of blood-derived immunocompetent cells occur, cell surface glycoproteins called adhesion molecules, expressed on both lymphocytes and endothelial cells, exert extensive control over the leukocytes. When emigration from the vascular compartment into the extravascular compartment is to occur, leukocytes first establish loose contact with endothelial cells via C-type lectins, or selectin molecules, especially the P-selectin (CD62), which appears within minutes after a mechanical or ischemic insult on the surface of endothelial cells. Attachment of the leukocyte to the endothelial cell is mediated by adhesion molecules such as the intercellular adhesion molecules (ICAMs) and the vascular cell adhesion molecule-1 (VCAM-1). Integrins such as the lymphocyte function-associated antigen-1 (LFA-1) may contribute to a cell‘s ability to migrate out of a vessel.

The endothelium of the CNS normally expresses no or only low levels of adhesion molecules. If there is inflammation of the CNS, adhesion molecules are widely expressed. TNF-α, a cytokine released by macrophages, plays an especially crucial role in the induction of adhesion molecules. Once leukocytes have entered, T-cells (and possibly B-cells) recognize their antigen, thus initiating the next step in the induction of inflammation. Antigen-presenting cells other than astrocytes, oligodendrocytes, and endothelial cells include perivascular cells, microglia, and leptomeningeal macrophages. In macrophages, proinflammatory cytokines upregulate the antigenpresenting function. The chief cytokine in this regard is IFN-γ, which is released by activated T-cells (Sedgwick and Hickey 1997). The role of complement in the emigration of leukocytes in inflammation and injury is still not entirely known (Morgan 1999). Administration of the complement inhibitor sCR1 just before brain injury has been shown to greatly inhibit infiltration of neutrophils into the injured area, an indication that local activation of complement contributes to inflammation (Kaczorowski et al. 1995). In aneurysm rupture causing cerebral hemorrhage, complement activation is combined with potentially life-threatening cerebral vasospasm (Ostergard et al. 1987). Complement activation and reperfusion injury may follow transient cerebral ischemia in stroke and transient ischemic attacks, with fatal consequences (Czurko and Nishino 1994).

Bibliography Adams RD, Lee JC (1982) Neurons and neuronal reactions in disease states. In: Haymaker W, Adams RD (eds) Histology and histopathology of the nervous system. Charles C Thomas, Springfield, Ill., pp 174−275 Graeber MB, Blakemore WF, Kreutzberg GW (2002) Cellular pathology of the central nervous system. In: Graham DI, Lantos PL (eds) Greenfield‘s neuropathology, vol 1. Arnold, London, pp 123−191 Kettenmann H, Ransom BR (eds) (1995) Neuroglia. Oxford University Press, New York Lindenberg R (1982) Tissue reactions in the gray matter of the central nervous system. In: Haymaker W, Adams RD (eds) Histology and histopathology of the nervous system, vol 1. Charles C Thomas, Springfield, Ill., pp 973−1275

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Piani D, Frei K, Do KQ et al. (1991) Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 133:159−162 Pixley SK, De Vellis J (1984) Transition between immature radial glia and mature astrocytes studied with a monoclonal antibody to vimentin. Brain Res 317:201−209 Polak M, Haymaker W, Johnson JE, D‘Amelio F (1982) Neuroglia and their reactions. In: Haymaker W, Adams RD (eds) Histology and histopathology of the nervous system. Charles C Thomas, Springfield, Ill., pp 363−480 Polazzi E, Contestabile A (2002) Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev Neurosci 13:221−242 Polazzi E, Contestabile A (2003) Neuron-conditioned media differentially affect the survival of activated or unstimulated microglia: evidence for neuronal control on apoptotic elimination of activated microglia. J Neuropathol Exp Neurol 62:351−362 Pope A (1978) Neuroglia: quantitative aspects. In: Schoffeniels E, Franck G, Hertz L, Tower DB (eds) Dynamic properties of glia cells. Pergamon, London, pp 13−20 Price J, Hynes RO (1985) Astrocytes in culture synthesize and secrete a variant form of fibronectin. J Neurosci 5:2205−2211 Privat A, Gimenez-Ribotta M, Ridet J-L (1995) Morphology of astrocytes. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, New York, pp 3−22 Raff MC, Mirsky R, Fields KL et al (1978) Galactocerebroside is a specific cell-surface antigenic marker for oligodendrocytes in culture. Nature 274:813−816 Rakic P (1995) Radial glial cells: scaffolding for brain construction. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, New York, pp 746−762 Reilly CE (2002) Astrocytes instruct stem cells to differentiate into neurons. J Neurol 249:950−952 Reilly CE (2003) Astrocytes act as signal transducer in neuronal activation and cerebral arteriole vasodilation. J Neurol 250:384−386 Rio Hortega P del (1919) El tercer elemento de los centros nerviosos. I. La microglia en estados normal. II. Intervencio de la microglia en los processos patologicas. III. Naturaleza probable de la microglia. Bol Soc Espanola Biol 9:69−120 Rio Hortega P del (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system, vol 2. Hoeber, New York, pp 481−534 Rio Hortega P del (1956) Tercera aportación al conocimiento morfológico e interpretación funcional de la oligodendroglia. Mem R Soc Esp Hist Nat 14:5−122 Sasaki K, Nakanishi Y, Nakazato Y, Yamaguchi H (1991) Application of lectin and B-lymphocyte-specific monoclonal antibodies for the demonstration of human microglia in formalin-fixed paraffin-embedded brain tissue. Virchows Arch A Pathol Anat 419:291−299 Schiffer D, Giordana MT, Migheli A et al. (1988) Glial fibrillary acidic protein and vimentin in the experimental glial reaction of the rat brain. Brain Res 374:110−118 Schmidt-Kastner R, Szymas J, Hossmann KA (1990) Immunohistochemical study of glial reaction and serum protein extravasa-

CHAPTER 3: Cytology of the CNS

tion in relation to neuronal damage in rat hippocampus after ischemia. Neuroscience 38:527−540 Schwab ME (1993) Experimental aspects of spinal cord regeneration. Curr Opin Neurol Neurosurg 6:549−553 Sedgwick JD, Hickey WF (1997) Antigen presentation in the central nervous system. In: Keane RW, Hickey WF (eds) Immunology of the nervous system. Oxford University Press, New York, pp 364−418 Song H, Stevens CF, Gage FH (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417:39−44 Sotelo C, Triller A (1997) The central neuron. In: Graham DI, Lantos PL (eds) Greenfield‘s neuropathology, vol I. Arnold, London, pp 5−61 Streit WJ (1995) Microglial cells. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, New York, pp 85−96 Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133−139 Streit WJ, Kreutzberg GW (1987) Lectin binding by resting and reactive microglia. J Neurocytol 16:249−260 Streit WJ, Graeber MB, Kreutzberg GW (1989) Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury. Exp Neurol 105:115−126 Streit WJ, Sammons NW, Kuhns AJ, Sparks DL (2004) Dystrophic microglia in the aging human brain. Glia 45:208−212 Svendsen CN (2002) The amazing astrocyte. Nature 417:29−32 Szuchet S (1995) The morphology and ultrastructure of oligodendrocytes and their functional implications. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, New York, pp 23−43 Tanner JM (1978) Growth and development of the brain in foetus into man. Open Books, London, pp 103−116 Tansey FA, Crammer W (1991) A pi form of glutathione S-transferase is a myelin- and oligodendrocyte-associated enzyme in mouse brain. J Neurochem 57:95−102

Tetzlaff W, Graeber M, Bisby MA, Kreutzberg GW (1988) Increased glia fibrillary acidic protein syntheses in astrocytes during retrograde reaction of the rat facial nucleus. Glia 1:90−95 Tomimoto H, Akiguchi I, Wakita H et al (1996) Glial expression of cytokines in the brains of cerebrovascular disease patients. Acta Neuropathol (Berl) 92:281−287 Uchihara T, Tsuchiya K, Nakamura A, Ikeda K (2000) Appearance of tau-2-immunoreactivity in glial cells in human brain with cerebral infarction. Neurosci Lett 286:99−102 Unger ER, Sung JH, Manivel JC et al. (1993) Male donor-derived cells in the brains of female sex mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridisation study. J Neuropathol Exp Neurol 52:460−470 Walz W (1995) Distribution and transport of chloride and bicarbonate ions across membranes. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, New York, pp 221−229 Weil A (1933) A text-book of neuropathology. Lea & Febiger, Philadelphia, Pa. Wekerle H, Linington H, Lassman H et al. (1986) Cellular immune reactivity within the CNS. Trends Neurosci 9:271−277 Williams K, Alvarez X, Lackner AA (2001) Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 36:156−164 Yang M-S, Park EJ, Sohn S et al (2002) Interleukin-13 and -4 induce death of activated microglia. Glia 38:273−280 Zonta M, Angulo MC, Gobbo S et al (2003) Neuron-to astrocyte signalling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43−50

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CHAPTER 4

Cell and Tissue Reactions

4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.1.4.1 4.1.4.2 4.1.4.3 4.1.5 4.1.6 4.1.7 4.1.7.1 4.1.7.2 4.1.7.3 4.1.7.4 4.1.8

Increased Brain Volume − Edema 42 Definition 42 Clinical Features 42 Pathogenesis 44 Types of Brain Edema 44 Vasogenic Edema 44 Cytotoxic Edema 47 Conclusion 47 Neuropathology 48 Space-Occupying Effects 49 Herniation 51 Uncal Herniation 51 Cingulate Herniation 53 Central Transtentorial Herniation 53 Upward Tentorial Displacement 54 Forensic Implications 54

4.2 4.2.1 4.2.2 4.2.3

Hydrocephalus 54 Classification and Pathogenesis Neuropathology 55 Clinical Features 56

4.3 4.3.1

4.3.6.2 4.3.7

Cell and Tissue Decay 56 Injury-Induced Cell Death: Necrosis 56 Incomplete Necrosis 57 Tissue Necrosis: Infarction 58 Gene-Regulated Cell Death: Apoptosis 60 Necrosis Versus Apoptosis 62 Penumbra 63 Dendritic Injury 64 Axonal Injury 65 Anterograde (Wallerian) Degeneration 66 Retrograde Degeneration 66 Regenerative Capacity 66

4.4 4.4.1 4.4.2 4.4.2.1 4.4.2.2

Inflammation 67 Principles of Neuroimmunology 67 Inflammatory Cells 67 Polymorphonuclear Leukocytes 69 Lymphocytes 69

4.3.1.1 4.3.1.2 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.3.6.1

54

4.4.2.3

4

4.4.3 4.4.3.1 4.4.3.2 4.4.3.3 4.4.4 4.4.4.1 4.4.4.2 4.4.4.3 4.4.5

Microglia and Brain Macrophages 69 Astrocytes 70 Endothelial Cells and Collagen Fibers 70 Inflammatory Mediators 71 Cytokines 71 Chemokines 71 Effector Molecules 71 Types of Inflammation 72 Sterile Inflammation 72 Cell-Mediated Inflammation 72 Antibody-Mediated Inflammation 73 Inflammation-Induced Ischemia 73

4.5 4.5.1 4.5.2

Misinterpretable Findings 73 Gross Findings 73 Microscopic Findings 74

4.4.2.4 4.4.2.5

Bibliography 75 References

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Similar types of tissue reaction result as a final common pathway from a wide array of different internal brain pathophysiological states and external insults. Since these cellular and tissue reactions are largely independent of the specific type of insults, they are, therefore, non-specific. The tissue reactions are to be differentiated according to their specific pathogenetic mechanisms, though these mechanisms as well as the phenomena are overlapping as demonstrated in Fig. 4.1; brain ischemia as a type of metabolic disturbance, edema, intracranial pressure, necrosis, herniation and inflammation are influencing themselves and are dependent on each other. Some will be mentioned again in later chapters as viewed from different forensic aspects; therefore, a certain redundancy is unavoidable. Immediately following, we offer a survey of the individual types of reaction and their fundamental pathophysiological principles and morphology.

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4.1 Increased Brain Volume − Edema 4.1.1 Definition If brain volume increases, both blood and CSF are displaced until the intracranial pressure (ICP) increases. The consequent pression of the brain against the inelastic dura mater (Fig. 4.2) and the skull can lead to a lethal series of complications in clinical neurology. The following remarks are based largely on Ironside and Pickard (2002). Brain volume depends on the following factors: 1. Water content (cerebral hydration). The brain has a normal water content of about 75%. A disturbance of the blood−brain barrier (BBB) can lead to an increase in the fluid content, with a consequent increase in brain volume. 2. Intracranial blood volume (Hirai et al. 1986). This can be driven upward by a number of factors: arterial hypertension (Marshall et al. 1969); enhanced cerebral blood flow secondary to elevated cerebral perfusion pressure (Artru et al. 1976); a decline in the cerebrovascular resistance of arterioles, capillaries, and postcapillary vessels (Langfitt et al. 1965) due to hypercapnia, hypoxemia associated with severe elevation of arterial pressure (Marmarou et al. 1997), or due to obstruction of the venous outflow of the brain. Elevated cerebral blood volume, also known as “brain swelling,” is a congestive process. 3. Cerebrospinal fluid (CSF) pressure. The central nervous system (CNS) of the average adult contains a CSF volume of approximately 120−140 ml. Among the causes of a rise in CSF pressure is acute obstructive high pressure hydrocephalus (see pp. 54 f). A number of additional factors may also influence brain volume. The congested brain expands particularly rapidly under high arterial pressure (Leech and Miller 1974). Nawashiro et al. (1995) used experimental closed brain injury in rats to demonstrate a rapid and widespread increase in regional cerebral blood flow and impaired cerebral autoregulation. In humans a variety of factors act in concert after the incidence of severe brain injury. Cerebral computed tomography (CCT) and magnetic resonance imaging (MRI) studies have shown that brain edema is the major fluid component of brain swelling (Marmarou et al. 1997, 2000). A reactive hyperemia is an additional factor and may be the mechanism underlying mechanical/ischemic brain injury (Seida et al. 1989). Moreover, regional cerebral ischemia additionally is

Fig. 4.1. Schematic demonstration of overlapping pathogenetic mechanisms that are associated with different types of tissue reactions by a causal link: metabolic disturbance, i.e., edema, increasing cerebral blood volume, perfusion pressure and herniation, i.e., brain swelling and cortical necrosis

attributed to a compromised, leaky microvasculature rather than to vasospasm of larger vessels (Schröder et al. 1998). The conclusion that brain swelling is due primarily to edema and not congestion of blood appears to be valid also for children (see Chap. 20, pp. 415 f). Cerebral blood flow in children with severe head injuries is not substantially increased over that in uninjured children (Zwienenberg and Muizelaar 1999). This has also been demonstrated following experimental generation of brain trauma in newborn and juvenile pigs (Armstead and Kurth 1994). The experimental findings of Biagas and coworkers (1996), in contrast, demonstrated a delayed rise in cerebral blood flow following experimental contusion in young and adult, but not in elderly, rats.

4.1.2 Clinical Features Normal adult ICP is less than 2 kPa (1 kPa=7.5 mm Hg=7.5 torr), mild elevations in pressure range from 2 kPa to 3 kPa, moderate elevations attain 4 kPa, while major intracranial hypertension exceeds 5 kPa (Miller and Ironside 1997). Normal CSF pressure in adults is 0−1.3 kPa, with an upper limit of 2 kPa. While a short-term rise in ICP pressure of up to 10 kPa may be tolerated so long as it does not cause distortion of the brain (Johnston and Paterson 1974), a MBI-induced rise of more than 8 kPa with distortion of the brain can result in herniation and brain death syndrome. The classic symptoms associated with elevated ICP are vomiting, headache, papilledema, and coma.

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.2a−d. Macroscopic findings in brain swelling. a Tightened dura; b flattened gyri; c compressed ventricles and notches (ar-

rows) which give evidence of a slight herniation; d compressed cerebellar tonsils

Distortion or pressure on the floor of the fourth ventricle are most likely responsible for the vomiting, while stretching and distortion of the dura mater and major intracranial blood vessels, all sensitive to pain, probably account for the headache. The papilledema is not a direct result of the rise in water content, but the consequence of an accumulation of axoplasm in the optic papilla secondary to the blockade of axoplasmic flow from ganglion cells along the optic nerve. Papilledema is a common symptom of chronic intracranial hypertension. It is not, however, a common feature of MBI (Selhorst et al. 1985),

and its absence does not necessarily mean that ICP is normal. A further increase of ICP leads to a loss of consciousness and coma. Elevated ICP affects other organ systems as well. It often induces arterial hypertension and systolic blood pressure may climb to 40 kPa or more. The arterial hypertension is caused by an increase in sympathetic activity. Cases of raised ICP with myocardial involvement often exhibit pathological alterations consisting of subendocardial hemorrhage and widespread focal myocardial necrosis as well as electrocardiographic changes such as T-wave inver-

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sion and elevation of the ST−segment, which point to myocardial ischemia (Connor 1968). Respiratory disturbances associated with elevated ICP often precede apnea. Central neurogenic hyperventilation is observed in connection with the midbrain lesion. In patients with raised ICP, neurogenic pulmonary edema can complicate the clinical course. The mucosa of the digestive and urogenital tracts can become hemorrhagic, eroded, and ulcerated, gastric erosions being particularly common in comatose patients with elevated ICP.

4.1.3 Pathogenesis A fundamental distinction must be made between global and focal cerebral edema. The former follows acute systemic hypoxic events, e.g., transitory cardiac arrest or chronic hypoxia in respiratory diseases. Global cerebral edema may also be associated with metabolic diseases, intoxications, and inflammation. Focal cerebral edema results from focal tissue destruction or alteration of brain tissue that has undergone membrane failure in cells and vessels due to infarction or traumatic hemorrhage or tumor. The tissue surrounding the central lesion has passed only the upper threshold of electrical silence and thus retains the capacity to recover if perfusion is restored in time (Harding and Copp 1997). This zone resembles the penumbra surrounding the moon in full eclipse (Astrup et al. 1981). Because these tissue changes are partly reversible, they are of considerable therapeutic interest (see pp. 63 f). Information on the incidence of intracranial hypertension has been gained mainly from survivors of MBI. Miller and his associates (1977) reported that ICP levels exceeded 2.7 kPa for 5 min or longer in 44% of 160 patients in one series and in 53% of another series of 215 patients (Miller et al. 1981). Raised ICP was found in more than 70% of cases in a more detailed prospective study of elevated ICP in victims with severe head injury by Marmarou and colleagues (1991). Jones and colleagues (1994) found elevated ICP in more than 80% of 74 brain injury patients (54 severe, 17 moderate and 3 minor) undergoing artificial ventilation with ICP monitoring. These findings indicate that intracranial hypertension is a common event, especially in comatose patients. Certain features detected by CCT are consistently associated with elevated ICP. Loss of the images of the third ventricle and perimesencephalic CSF cisterns, and dilatation of the lateral ventricle contralateral to a mass lesion, as well as the absence of these features are no guarantee that ICP will remain normal (Teasdale et al. 1984; O‘Sullivan et al. 1994). Elevated ICP is also common in patients who are comatose from causes other than brain injury (Chan-

dler and Kindt 1976). Among the possible causes are liver failure (hepatic coma), intracranial hemorrhage (subarachnoid and intracerebral), post-hypoxemic states (cardiorespiratory arrest, near drowning), infection (meningitis, abscess, and encephalitis), as well as various other types of inflammation and intoxication. Adams and Graham (1976) published neuropathological criteria for determining at autopsy whether ICP in victims of brain injury was elevated during life. The same team (Graham et al. 1987) compared the nature of the brain damage in patients with and without elevated ICP after suffering a non-missile brain injury who had survived long enough to receive treatment in a neurosurgical unit. Pressure necrosis of the parahippocampal gyrus, an indicator of high supratentorial ICP and tentorial herniation, was present in twothirds of the 434 patients in their most recent study. It was closely associated with skull fracture, brain swelling, diffuse axonal injury, hypoxic brain damage, and extensive supratentorial hematoma. The brain stem was damaged in 68% of victims with pressure necrosis, the anterior lobe of pituitary was necrotic in 45%, and there was hemorrhagic infarction in the distribution of the posterior cerebral artery in 36%.

4.1.4 Types of Brain Edema Klatzo (1967) distinguishes two types of edema: vasogenic edema and cytotoxic edema (Table 4.1). This distinction continues to be of both theoretical and practical value (cf. Kimelberg 1995a, b; Mendelow et al. 2000). 4.1.4.1 Vasogenic Edema Blood vessels in the CNS are uniquely restricted in their permeability. Many substances are exchanged between the blood and brain parenchyma at slower rates and the concentrations in CNS at steady state are lower than in other organs (Lee 1982). Dyes as well as proteins, drugs, and microorganisms introduced into the CSF enter the brain freely, while those introduced into the blood stream do not. This limited permeability is attributed to the BBB, a specialized feature of the CNS that restricts the entry of viruses and bacteria, emigration of immune cells, and diffusion in the CNS of drugs and soluble molecules from the systemic compartment. Intravenously applied Evans blue will bind to serum albumin and permeate the BBB only under pathological conditions. This phenomenon is demonstrated after experimentally induced ischemia of one hemisphere by means of macroscopic observation (Fig. 4.3a) and by means of fluorescence micros-

CHAPTER 4: Cell and Tisue Reactions

Table 4.1. Classification of the two types of edema: vasogenic edema and cytotoxic edema

Vascogenic edema

Cytotoxic edema

Intercellular accumulation of fluid associated with volumetric enlargement of the brain

Intracellular accumulation of fluid and (possibly) secondary increase of the brain volume

Perifocal edema (penumbra) surrounding hemorrhages, tumors, abscesses, etc.

Ischemia (generalized or focal), intoxications, especially by triethyltin and cyanide, metabolic diseases, etc.

Injury of endothelial cells (tight junction)

Injury of brain cell membranes in neurons by metabolic or electrophysiologic mechanisms

Increased vascular permeability with leakage of plasma including plasma proteins

Impairment of the cellular Na-K membrane pump

Involvement of the white matter

Involvement of the gray (and white) matter

Enlargement of the extracellular spaces

Hydropic swelling of astrocytes and (mostly irreversibly injured) neurons

Swelling of the perivascular astrocyte foot processes Light-microscopic demonstration of plasma proteins in the perivascular neuropil and astrocytes

Fig. 4.3a−d. Vasogenic and cytotoxic edema. Experimentally induced ischemia of the right hemisphere in gerbils results in a disruption of the blood−brain barrier (vasogenic edema: a, b) and a potassium loss (cytotoxic edema − see. Oehmichen et al. 2000: c); d human brain expresses extravasated albumin (brown

Light-microscopic demonstration of potassium loss in astrocytes and neurons

color) exclusively during the very early postmortem interval (see Oehmichen and Gencic 1980a) (a, b Evans blue fluorescence; magnification b ×100; c histochemical demonstration of potassium; d albumin reactivity, magnification ×300)

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PART I: Principles of Forensic Neuropathology

Fig. 4.4a, b. Vasogenic perifocal edema in a case of a traffic accident associated with liver failure and elevated bilirubin level. a Massive intracerebral hemorrhages and green-colored edema; b focal hemorrhage; perifocal as well as contralateral greencolored edema

copy (Fig. 4.3b). The demonstration of albumin in human brain using immunohistochemistry will only succeed during the very early postmortem interval (Fig. 4.3d) − before a general diffusion of blood serum occurs within the brain parenchyma − as a morphological marker of the diffuse postmortem BBB disturbance. Under experimental conditions an accumulation of plasma proteins in Purkinje cells (Oehmichen and Gencic 1980a, Ikegaya et al. 2004) takes place. Anatomically the BBB consists of a capillary endothelium containing intercellular tight junctions and specialized enzymes, such as transpeptidases, dehydrogenases, decarboxylases, and monoamine oxidases (Reese and Karnowsky 1967; Brightman and Reese 1969; Lee 1982). The intercellular junctions are most conspicuous near the luminal surface where the cell membranes fuse. A basem*nt membrane in contact with astrocytic foot processes surrounds the endothelial cells. Pericytes are enclosed by an envelope of the perivascular basem*nt membrane, which splits to enclose the pericyte. Brain capillaries are almost totally invested by astrocytic processes. Astrocytes exert inductive actions during development

and are thereby largely responsible for the special attributes exhibited by endothelial cells, such as the presence of tight junctions between the cells (Abbott et al. 1992). Astrocytes and microglia both contribute to the formation of the BBB (Prat et al. 2001). There is an inverse hemodynamic relation between ICP and cerebral blood flow (CBF): the higher the ICP, the lower the CBF. If cerebral circulation and circulatory autoregulation are normal, a drop in ICP will induce only a slight increase in CBF until a threshold level of about 8 kPa is attained. CBF is regulated by mechanisms such as compensatory dilatation of small arteries and arterioles. Patients suffering from acute MBI, intracranial hemorrhage, or hypoxic brain injury need a mean arterial blood pressure above 8 kPa to maintain perfusion. The brain damage in such circ*mstances is associated with a rise in cerebrovascular resistance due to the vessels‘ spastic reactivity. Baseline ICP levels may even need to be higher in order to drive sufficient blood through the brain tissue (Chan et al. 1992). Should CBF drop below 10 (ml/min)/100 g, potassium levels in the intercellular spaces rise, while intracellular sodium and calcium increase. Cellular edema causes the cells to swell and a calcium influx triggers a series of autodestructive processes. The BBB can be compromised by the following three mechanisms (see Miller and Ironside 1997): 1. Enhanced vesicular transport and creation of transendothelial channels by perturbation of endothelial plasmalemma, increased pinocytic activity, the activity of free oxygen radicals, or an increase in superoxides. Subarachnoid application of hemoglobin and hemoglobin degradation are known to cause brain edema (Huang et al. 2002). 2. Disconnection of the interendothelial tight junctions, e.g., by substances of very high osmolarity. 3. Structural or biochemical modification of the endothelial membrane that intensifies its permeability. It has also been known for a long time that the ability of certain substances to pass through the BBB depends on their specific properties: ▬ Their nature regarding the capacity of the BBB for active transport (Broman and Steinwall 1967) ▬ Their affinity for carrier molecules (Lajtha 1968). ▬ Their molecular radius (Thompson 1970). ▬ Their lipid solubility (Oldendorf 1977). As shown in detail later, the permeability of the BBB also depends on age. A good example of this is bilirubin encephalopathy, which is caused by bilirubin crossing the BBB of certain nuclei during the perinatal period − a feat it is incapable of in later life − and inflicting damage on nerve cells and, to a lesser

CHAPTER 4: Cell and Tisue Reactions

degree, on astrocytes (for further information see pp. 452 ff). Thus for bilirubin at least the BBB appears to be less efficient at birth than in children or adults (Haymaker et al. 1961). In MBI with intracerebral hemorrhages and associated elevation of the bilirubin level the perifocal edema can be marked by a green color demonstrating extravascular bilirubin as demonstrated in Fig. 4.4. In senile and mentally disturbed patients, the BBB has been found to have a lower rate of transport, a reduced uptake of glucose and other nutrients, plus a diminished outflow of metabolic wastes (Quadbeck 1967, 1968). 4.1.4.2 Cytotoxic Edema The movement of water from the vascular compartment to intracellular or interstitial spaces is not regulated biochemically by the BBB since hydrostatic and more powerful osmotic gradients enable free water to diffuse passively across capillary membranes. The passage of ions and molecules of various sizes is controlled by lipid-soluble substances in the endothelial wall and by ionic channels and active pumps. The white matter of the brain is 68% water, the gray matter 80% (Adachi and Feigin 1966). A rise in brain water content entails an increase in brain volume, i.e., brain edema. As a result of energy failure (deprivation of oxygen and glucose), which disables the sodium-potassium membrane ATPase pump system, water accumulation within the cells follows an osmotically obliged response to an increase in intracellular sodium and loss of potassium (Fig. 4.3c). The influx of osmotically drawn water causes swelling of the cell. The energy failure is accompanied by an influx of sodium and chloride and an efflux of hydrogen ions, potassium, and bicarbonate. There is a parallel disturbance of the voltage- and ligand-gated mechanisms that regulate the entry of calcium into the cell that initiates a calcium-mediated destructive sequence. Cytotoxic edema is the result of the action of various cytotoxic agents, e.g., of cyanide or triethyl tin (also see Chaps. 16, 17). Brain cells can also swell without a concomitant increase in brain volume if fluid shifts from an extracellular to an intracellular space. Although this does not produce an immediate rise in ICP, cellular edema ultimately draws water from the vasculature into the brain, increasing brain volume and precipitating a rise in ICP. Ischemic edema is a cytotoxic edema whose clinical effects depend on how much and for how long cerebral blood flow is reduced (Bell et al. 1985). Klatzo (1967) showed that the initial cytotoxic edema following permanent occlusion of a major blood vessel causes irreversible ischemic cell damage, resulting in a secondary vasogenic edema when endothelial cells

are damaged. Even temporary ischemia with subsequent reperfusion will induce reactive hyperemia and secondary endothelial damage that produces a secondary vasogenic edema (Greenwood 1991). As a whole, the brain is resistant to pure hypoxia (diminished oxygen supply) (pp. 276 ff, see also Miyamoto and Auer 2000), which causes no or only partial breakdown of the BBB and which may be reversible after recovery (Bakay and Lee 1968; Auer 2000). Anoxia (complete lack of oxygen), by contrast, results in a rapid rise in BBB permeability that becomes irreversible after just a few minutes (pp. 280 ff). If anoxia acts in combination with complete ischemia secondary to ligation of both common carotid and subclavian arteries, the BBB can retain its impermeability for as long as 3 h (Broman 1949; Blank and Kirshner 1977). Incomplete ischemia, however, will rapidly and completely break down the BBB (Bakay and Lee 1965). Kimelberg and colleagues (1997) could demonstrate the potential toxic mechanisms of this type of edema on neurons. They describe a primary cytotoxic effect on astrocytes that induces astrocytic swelling. This swelling in turn leads to the release of excitatory amino acids such as glutamate, whose levels increase in extracellular spaces following the incidence of MBI (Kanthan and Shuaib 1995). A rise in extracellular glutamate levels causes cell death due to an influx of Ca 2+ via the neurons‘ activated ionotropic glutamate receptors (Choi and Rothman 1990). Other authors have offered a somewhat different explanation for the irreversible injury: it may be induced by simultaneously generated free radicals or extravasated plasma components that stimulate the activation of nitric oxide synthase (NOS) in reactive cells. Nitric oxide thus generated may contribute to diffuse degeneration of the white matter (Gotoh et al. 1998). The accumulation of plasma proteins within neurons and microglia in combination with cytochrome-C release by astrocytes can lead to DNA fragmentation and cell death (Matz et al. 2001). 4.1.4.3 Conclusion Klatzo‘s (1967) classification of brain edema has proved to be a useful aid in distinguishing between various pathogenetic mechanisms and their sequelae. In experimental and clinical practice however it must be assumed that brain swelling is caused by a combination and/or a temporal overlapping of a number of processes, as described by Kimelberg et al. (1997). Non-invasive diffusion-weighted (DW) MRI is able of calculating changes in the apparent diffusion coefficient (ADC) of water protons in the brain (Garcia et al. 1995; Chu et al. 2001). A decline in ADC has

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PART I: Principles of Forensic Neuropathology

Fig. 4.5a−d. Microscopic features indicative of a preponderate cytotoxic edema. a, b Cortical spongious alteration as a result of perineuronal (c) and perivascular (d) swelling of astrocytic proc-

esses (a van Gieson stain; b, d H&E; c Nissl stain; magnification a ×100; b ×500; c, d ×1,000)

been attributed mainly to a reduction of the extracellular space and a rise in intracellular volume, although other contributing factors are possible (Pierpaoli et al. 1996). In this manner cellular (cytotoxic) edema can be differentiated from extracellular (vasogenic) edema and a correlation made with the severity of injury and consequent deficit. Because DWMRI (see also Mendelow et al. 2000) enables edema types to be determined intra vitam under clinical conditions, current classifications of edema types could be revised in light of new findings. However, we should remember that all edema ultimately arises from the blood. It is the size of the leak in the brain vasculature that gives rise to the artificial distinction between cytotoxic and vasogenic edema, cytotoxic edema being mainly water and vasogenic edema including proteins also derived from the blood.

and paler than normal. The normal, sharp demarcation between gray and white matter is lost, often with thinning of the cortex overlying the zone of white matter edema. The arcuate fibers are spared. In rare cases of vasogenic edema associated with liver insufficiency combined with elevated bilirubin levels in serum the spread of edema may be characterized by a greenish-yellow color (Fig. 4.4). Under normal conditions bilirubin is not able to permeate the BBB, with one exception: the newborn (see pp. 452 ff). Cytotoxic edema, which predominates in gray matter, is characterized by astrocytic swelling and the enlargement of perineuronal and perivascular spaces indicative of the swelling of astrocytic foot processes around neurons, capillaries, and arterioles (Fig. 4.5). The hallmarks of vasogenic edema include swelling of pericapillary astrocytic processes and of oligodendrocyte cytoplasm, plus the spread of exudate in the extracellular space of white matter (Fig. 4.6). Macroscopically vasogenic edema induces a slight green discoloration of the white matter. Histologically, edema, vasogenic edema in particular, features extensive cytoplasmic vacuolation in the white matter with status spongiosus where a clear space surrounds small vessels and nuclei (Fig. 4.6). Ultrastructurally, few visible changes are evident in

4.1.5 Neuropathology Brain swelling caused by edema, congestion or a rise in CSF pressure can obliterate the subarachnoid space, flatten the gyri, reduce ventricular size (Squier 1993, Fig. 4.2), and cause herniation (see pp. 51 ff). At autopsy the white matter seems softer in consistency

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.6a−d. Microscopic features of a predominantly vasogenic edema. a The beginning of extravasation is marked by a perivascular spongious structure which (b, c) will lead to a widespread

diffuse or (d) a focal, sharp demarcated edema and beginning necrosis (a, c, d H&E, b Luxol fast blue; magnification a, c, d ×200; b ×100)

the cerebral capillaries. The brain parenchyma, in contrast, exhibits swelling of glial processes or dendrites, splits in the myelin laminae and, less often, enlargement of the extracellular space. Vacuolation may be especially prominent in myelinated fiber bundles and constitute the earliest and most consistent elementary edema-induced change. Following immersion fixation, however, these phenomena can often be difficult to distinguish from (postmortem) artifacts. These phenomena may be associated in the beginning with a leukocyte emigration (Fig. 4.7a) and in the last stage with astrocytic hyperplasia and hypertrophy (Fig. 4.7c, d). Astrocytes and macrophages also ingest extravasated plasma proteins. Myelin sheaths undergo increasing fragmentation and macrophages phagocytose lipid breakdown (Figs. 3.8f, 9.15b, 9.16). Oligodendrocytes are much less likely to partake in the alterations of edematous brain tissue. Most cases of brain edema exhibit a combination of cytotoxic and vasogenic edema. Inhibition of ion pumping or secondary retrograde reaction can cause swelling of neurons. The usual reaction is neuronal shrinkage, commonly combined with swelling of neighboring glial cells, especially of astrocytic processes. Irreversible changes in the myelin sheath are unequivocally manifested by the apposition of mac-

rophage reaction in the form of compound granular cells. Involvement of the white matter by edema of this severe degree coincides with a so-called edematous necrosis (Jacob 1947). The final phase of terminal edema can be marked by cystic alteration or glial scaring.

4.1.6 Space-Occupying Effects Brain swelling is one of a wide variety of neurological conditions, among them tumors, hemorrhages, and ischemia/hypoxia, that can induce an increase in ICP. A rise in ICP leads not only to compression of the brain, but to diminished CSF volume, shifting, and herniation, as well as to secondary complications such as ischemia and hemorrhage. If not treated, ICP can rapidly progress to death due to brain stem compression secondary to cerebellar or uncal herniation (Meyer 1920). Focal expanding mass lesions must be distinguished from diffuse space-occupying processes. ▬ Diffuse brain lesions such as inflammation, bilateral intracranial hemorrhage, total brain ischemia (cardiac arrest) or intoxication are macroscopically characterized (Fig. 4.2) by a tension of

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Fig. 4.7a−d. Cell response to edema and beginning edematous necrosis. a The first stage is characterized by a leukocyte infiltration, the second stage (b) by an increase of macrophages ingesting albumin and red cells in the case of a simultaneous hemorrhage; c, d the last stage is marked by an

astrocytic reaction whereby the sessile astrocytes contain albumin (c), and the astrocytes increased in number upregulate GFAP and vimentin (d) (a N-AS-DClAE, b, c albumin reactivity, d GFAP reactivity; magnification a, d ×300, b ×1,000, c ×500)

the dura, gyral flattening, and by narrow ventricles that are symmetrically compressed. No lateral shift of midline structures is seen, but rather central herniation of the diencephalon (centrencephalic herniation) and by cerebellar tonsillar herniation and compression of the medulla oblongata. Bilateral herniation may occur and various types of herniation result from caudal displacement of the brain parenchyma (for types of herniation, see below). Focal intracranial processes such as abscess, tumor, infarction or subdural hemorrhage (Fig. 4.8a, b) are also capable of inducing a life-threatening hom*olateral rise in ICP. Because they allow time for intrinsic compensatory mechanisms to operate, particularly reduced CSF volume, slowly expanding focal lesions are less likely to cause an early increase in ICP and brain shift. However, the distortion and herniation of the brain in such cases can be considerable. Rapidly expanding focal lesions, by contrast, are more likely to produce an immediately elevated ICP. Brain death often supervenes in such cases before much distortion or herniation can occur.

Distortion of the brain results from compressive forces exerted by adjacent structures, which leads to overall expansion of the hemispheres. The dura mater may become so tense as to compress the terminal branches of the cerebral arteries, with consequent ischemic or hemorrhagic necrosis of cortical structures (Lindenberg 1955) or impairment of perfusion (Janzer and Friede 1979) accompanied by perisulcal infarcts. Continued expansion of the mass may provoke contralateral displacement of the midline structures (see Chap. 7 and Fig. 4.8a). If the contralateral foramen of Monro is obliterated, the contralateral lateral ventricle may become enlarged, triggering a further rise in ICP. A lesion that expands in the frontal lobe may displace the free margin of the anterior part of the falx cerebri (Fig. 4.8a, d). If a lesion expands in the temporal lobe, a disproportionately pronounced shift of the third ventricle will occur (Fig. 4.8a), with upward displacement of the Sylvian fissure and neighboring branches of the middle cerebral artery.

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.8a−e. Unilateral intracranial pressures. a Subdural hemorrhage on the left parietal lobe leads to a distinct shift (upper arrow) of the midline structures from left to right, which may be associated with a hemorrhage in the left cingulate gyrus and a left midbrain hemorrhage (lower arrow), b a hippocampal hemorrhage (arrows), as well as (c) a pontine hemorrhage;

4.1.7 Herniation The ultimate result of the space-occupying process is development of lateral and then downward herniation, visible at several loci: 1. Falx cerebri (cingulate, or subfalcine herniation). 2. Tentorium cerebelli (lateral, or uncal herniation). 3. Thalamus/hypothalamus (central, or diencephalic herniation) which may result in downward

d a hemorrhage in the upper frontal lobe may lead to a notch, a hemorrhage or a softening of the corpus callosum; e a rare tentorial displacement caused by an infratentorial space-occupying process is demonstrated by notches on the upper cerebellar surface (arrows)

displacement and hemorrhage in the midbrain and pontine tegmentum. 4. Foramen magnum (tonsillar herniation). 4.1.7.1 Uncal Herniation A bilateral expanding supratentorial mass can cause herniation-induced notches as well as hemorrhages of the uncal area. This in turn exerts downward pressure on the medial part of the parahippocampal gyrus toward and through the tentorial incisura (Figs. 4.8b, 4.9). The clinical and morphological se-

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Fig. 4.10a, b. Supratentorial pressure induced compression of the basal arteries, especially of the posterior cerebral artery, which leads to a hemorrhagic infarct of the occipital lobe (arrows)

Fig. 4.9a, b. Symmetrical (bilateral) supratentorial pressure causes bilateral uncal herniation as demonstrated by notches (a arrows); these notches may be marked by a hemorrhage and tissue necrosis (b arrows)

quelae of uncal herniation depend on the magnitude of the supratentorial pressure and on anatomical variations in the size of the tentorial notch, position of the brain stem within the notch, position of the oculomotor or third nerve, and the inter-oculomotor nerve angle. They also depend on the structure and course of the posterior cerebral artery, known to play a role in herniation syndromes (Adler and Milhorat 2002).

Herniation of the parahippocampal gyrus (Fig. 4.9) creates narrowing of the midbrain along its transverse axis and compression of the aqueduct. This pushes − in the case of a unilateral expanding mass − the contralateral cerebral peduncle against the opposite free tentorial edge (Fig. 4.8b), pinning the ipsilateral oculomotor nerve between the petroclinoid ligament or free edge of the tentorium and the posterior cerebral artery. The lesion of the ipsilateral oculomotor nerve is associated clinically with ptosis and dilatation of the ipsilateral pupil, which becomes unresponsive to light. The elevated ICP produces a wedge of hemorrhagic necrosis along the parahippocampal gyrus groove (so-called pressure necrosis, to be differentiated from “herniation contusion” − see Figs. 4.8b, 4.9b). Pressure necrosis can result from an ICP exceeding 5.4 kPa (see Adams and Graham 1976). It is analogous to necrosis due to brain retractor pressure in neurosurgery. Clinically, uncal herniation is accompanied by an abrupt worsening of the patient‘s neurological status, with loss of consciousness and onset of decerebrate rigidity, both due to midbrain impairment caused by pressure coming from above.

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.11a−c. Herniation-associated pontine hemorrhage as caused by downward axial displacement (a) of the dorsal brain stem; displacement of the cerebellar tonsils (b, c) through the fo-

ramen magnum which is caused by supratentorial and infratentorial displacement (pressure marks − see arrows)

Compression of arteries can also cause secondary necrosis: if the anterior choroidal artery is occluded, the result can be infarction of the medial part of the globus pallidus; posterior cerebral artery occlusion can cause hemorrhagic infarction of the thalamus, of the medial and inferior surfaces of the cortex of the occipital lobe (Figs. 4.10, 9.24), and of the temporal lobe including the hippocampus.

arteries, the parietal parasagittal cortex can become infarcted, which is expressed clinically as weakness or sensory loss in one or both legs.

4.1.7.2 Cingulate Herniation Herniation of the ipsilateral cingulate gyrus under the free edge of the falx results from the unilateral growth of a mass in the frontal or parietal lobe and causes selective displacement of the pericallosal arteries away from the midline (Fig. 4.8a, d). Should this compromise circulation through the pericallosal

4.1.7.3 Central Transtentorial Herniation A frontal or parietal mass lesion can induce downward axial displacement of the diencephalon (Fig. 4.8a) and rostral brain stem (Figs. 4.8c, 4.11a). The consequent symmetrical herniation of both parahippocampal gyri (Fig. 4.9a, b) may be manifested clinically by bilateral ptosis and failure of upward gaze. The final clinical result is loss of consciousness, decerebrate rigidity, and bilateral dilatation of the pupils with loss of the pupillary light reflex. The blood pressure rises due to increased sympathetic activity.

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Hemorrhage or necrosis of the midbrain and/ or pons are the possible sequelae of supratentorial space-occupying processes located adjacent to the midline (Figs. 4.8a, 4.11a, 9.23). These lesions are caused by caudal displacement and anterior-posterior elongation of the rostral brain stem and by sideto-side compression by the tentorial hernia, coupled with relative immobility of the basilar artery. Progressive displacement stretches and narrows the central perforating branches of the basilar artery which supply the rostral brain stem, causing spasm, infarction or hemorrhage. An early complication of expanding masses in the posterior cranial fossa is displacement of the cerebellar tonsils through the foramen magnum (Figs. 4.2d, 4.11b, c). This may also be caused, however, by lesions occupying the supratentorial space. Morphologically, the tips of the tonsils display hemorrhagic necrosis and grooving of the ventral surface of the medulla where it impinges on the anterior border of the foramen magnum. Clinically these changes give rise to apnea, which can occur while the victim is still conscious. Among the other common neurological deficits are decerebrate rigidity and impairment of brain stem reflexes.

4.1.7.4 Upward Tentorial Displacement Upward tentorial displacement (Fig. 4.8e) is produced by enlargement of an infratentorial mass in the posterior cranial fossa. Both the fourth ventricle and aqueduct become compressed and displaced contralaterally. There is upward herniation of the superior surface of the cerebellum, which is distinguished clinically by the abrupt manifestation of bilateral extensor rigidity and loss of pupillary light response.

Pharmacotherapy must not be performed without knowing whether the agent can permeate the BBB and affect the CNS. This is especially true of substances such as antibiotics or cytostatics that are intended to reach and act upon the CNS. Other substances are not intended to reach the CNS because they are toxic there; thus, the contraindication for intrathecal application of vincristine (see p. 359). If CNS edema already exists, the BBB may be (pathologically) permeable to substances not intended to reach the CNS, some of which can then have a toxic effect. A MBI-induced perifocal edema, for example that arises in the context of polytrauma-induced shock, can produce greenish discoloration of the perifocal edema as a consequence of an accompanying hepatic insufficiency, which can have an additional neurotoxicologic effect on the neurons. The status of the BBB may well be age dependent, its postnatal status differing from that of adults. Blood group incompatibility between mother and child during pregnancy or after birth can cause bilirubin encephalopathy (see pp. 452 ff). The BBB appears to be less permeable in the elderly. A cytotoxic effect can be mediated by alcohol in MBIs with consequent loss of neurons. Alcohol lowers cerebral perfusion pressure (CBF) and depresses ventilation. It diminishes respiratory drive in response to elevated PaCO2 levels. Ethanol-induced respiratory depression and hypotension can increase the morbidity and mortality associated with brain injury. The theoretical considerations of Kimelberg et al. (1997) appear to contradict these empirical findings, arguing rather that alcohol inhibits both the excitotoxin receptor function of neurons (Simson et al. 1991) and the influx of Ca 2+ via NMDA receptor ion channels.

4.1.8 Forensic Implications A number of clinical complications associated with brain swelling, brain edema, and BBB can arise during diagnostic and therapeutic interventions in the CNS carried out by physicians or nursing personnel. Since the sequelae are foreseeable − and in most cases avoidable − these complications will be dealt with briefly in the following. ▬ In patients with elevated ICP, a lumbar puncture of the CSF can give rise to herniation. Papilledema, though not always associated with ICP, must be excluded before every CSF puncture. Should other clinical signs of high ICP be present, a CT examination must be carried out prior to puncture.

4.2 Hydrocephalus 4.2.1 Classification and Pathogenesis Hydrocephalus is characterized by abnormal accumulation of fluid within CSF spaces, i.e., within the cerebral ventricles and subarachnoid space. By this time, there is atrophy of the brain parenchyma and additional ventricular enlargement. CSF is formed by the choroid plexus at a rate that remains unchanged within a wide range of ICP values: 15−25 ml/h will avert a long-lasting imbalance between its formation and absorption. Elevated CSF pressure is associated

CHAPTER 4: Cell and Tisue Reactions

Table 4.2. Causes of obstructive hydrocephalus. Source: Garton and Piatt 2004

Prematurity (posthemorrhagic hydrocephalus) Myelomeningocele Other congenital or developmental conditions affecting the brain Dandy−Walker malformation Arachnoid cysts Interhemispheric cysts Aqueductal stenosis Encephalocele Brain tumor Subarachnoid hemorrhage Mechanical brain injury Aneurysmal subarachnoid hemorrhage Congenital or developmental conditions affecting the skull Crouzon’s and Pfeiffer’s syndromes Achondroplasia Meningitis

only with acute or obstructive hydrocephalus (see below). The subarachnoid space and ventricular system are connected via the foramina of Luschka and Magendie in the basal cisterns. CSF is absorbed by the arachnoid villi, which do not fully develop until adolescence or young adulthood (Grassman and Potts 1974). In fetuses and infants, CSF is absorbed mainly through nerve roots and periventricular and arachnoid veins. External hydrocephalus ex vacuo involves diffuse loss of gray matter that gives rise to external atrophy, with dilatation of the subarachnoid space (Fig. 31.6a, b). Diffuse loss of white matter can cause expansion of the ventricular system, the so-called internal hydrocephalus ex vacuo (Fig. 31.6c). The causes of the gray and white tissue damage may vary, but CSF kinetics and anatomic pathways are important considerations (see also pp. 482 f). A distinction is made between normal pressure hydrocephalus of still unknown etiology (Adams et al. 1965; Hurley et al. 1999), low pressure hydrocephalus, and high pressure hydrocephalus. The latter is caused by accumulation of fluid secondary to elevated CSF production (hypersecretory hydrocephalus) or insufficient resorption (malabsorptive hydrocephalus or communicating hydrocephalus). Disten-

sion of the ventricles results from pressure-induced fluid build up in the cerebral ventricles (reversible) or from pressure-induced (irreversible) atrophy as a result of parenchymal loss. Fluid may also enter the periventricular tissue (trans-ependymal resorption of CSF seen on neuroimaging). Normal pressure hydrocephalus can feature repeated brief episodes of elevated ICP, possibly in the form of an intermittent pressure or occult hydrocephalus. Normal pressure hydrocephalus can also result from a hydrocephalus ex vacuo, which is associated with primary ventricular system enlargement and white matter destruction. It is often found in victims of severe brain injury, in alcoholics, and vascular disease patients with multi-infarct dementia or other types of progressive degenerative brain disorders, especially age-dependent dementia (Miller and Ironside 1997). Hydrocephalus ex vacuo can also be caused by long-lasting generalized brain edema with high ICP. The causes of obstructive hydrocephalus are MBI, subarachnoid hemorrhage, meningitis and arachnoid fibrosis, Arnold-Chiari malformation, aqueductal stenosis (for complete list see Table 4.2, for review see Garton and Piatt 2004). The latter can be either congenital due to atresia or acquired due to inflammation, compression or reactive gliosis, hemorrhages or tumor. The responsible congenital abnormalities consist in most cases of replacement of the aqueduct lumen by numerous random, narrow channels or ependymal nests.

4.2.2 Neuropathology External hydrocephalus, whatever the causes are, exhibits dilation of the subarachnoid space, with no increase in collagenous fibers or cellular elements, but an increase in CSF. The causative encephaloclastic disease may be diagnosed on the basis of other phenomena, such as liver cirrhosis in alcoholics, or loss of neurons in the presence of plaques and tangles in senile dementia or Alzheimer‘s disease. Typical macroscopic features of internal hydrocephalus include an enlarged ventricular system (Fig. 4.12a, b) (Weller and Shulman 1972), interstitial edema, disruption of the ependymal cells lining the ventricle, and axonal and myelin destruction in the periventricular white matter (Del Bigio 2004). Secondary changes in neurons reflect compensation to the stress or ultimately the disconnection. Proliferating astrocytes and/or gliosis (Fig. 4.12c) replace in part the interrupted ependymal cell line. These glial nodules appear granular or like small tumors (Fig. 4.12c) upon macroscopic inspection of the inner surface of the ventricles (Fig. 4.12b). There is also a partial reestablishment of flattened ependymal

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4.2.3 Clinical Features In adults, the clinical symptoms of hydrocephalus are non-specific; in infants and children they may be specific (see Chap. 21 − pp. 482 f) and depend on the causes and the time course of the hydrocephalus. The salient symptoms comprise psychopathological alterations such as dementia, memory disturbances, and loss of orientation, culminating in the most severe cases in loss of consciousness. The first step in diagnosing hydrocephalus involves the use of imaging techniques, MRI and CCT, to establish its presence. The second step seeks to determine the underlying cause, and again employs as its methods of choice MRI and CCT, in combination with clinico-chemical (Fishman 1980) and cytological analysis of the CSF itself (Oehmichen 1976a).

4.3 Cell and Tissue Decay

Fig. 4.12a−c. Internal hydrocephalus. a Expanding ventricular system associated with an atrophy of white matter; b the ventricular surface is commonly marked by a granular surface structure, which (c) microscopically is characterized by multiple glial nodules which replace lost segments of the ependymal layer (H&E, magnification ×200)

cells, and a decline in the number of axons with parallel proliferation of glial fibers in the periventricular white matter. In chronic hydrocephalus with high pressure hydrocephalus, a flattening of the gyral crests is seen (Fig. 4.13a); in addition a small reactive glial zone around the ventricular system (Fig. 4.13b) may develop which can be separated from the intact white matter at autopsy (Fig. 4.13c).

“Necrosis” (for review see Lindenberg 1982) is commonly used to designate the death of tissue components, including that of cells and their processes in a defined area of blood and oxygen supply. After a severe episode of ischemia, MBI or epilepsy, it is typical to find necrotic cell death within the injury core. In addition, a substantial number of neurons in regions surrounding the injury core have been observed to die via the programmed cell death pathways due to secondary effects derived from the various types of insults (Liou et al. 2003). “Apoptosis” (for review see Vermes et al. 1998) is applied to the selective (programmed) death of one or more individual cells. Apoptosis is the more active and physiological form of cell death. In necrotic cell death, a stimulus such as ischemia, hemorrhage, mechanical or chemical damage alters cell homeostasis thus causing cell death, whereas in apoptosis an internal death stimulus triggers the innate cellular suicide program, the latter (not the stimulus itself) mediating the cellular demise (Beal 1995). In the following, the various pathogeneses and mechanisms of these types of cell death will be described, along with their different morphologies and underlying molecular factors.

4.3.1 Injury-Induced Cell Death: Necrosis The most common cause of necrosis is ischemia. Other causes include mechanical injury (contusion

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.13a−c. High pressure hydrocephalus. a Increased brain volume and flattened gyral crests; b extreme periventricular glio-

necrosis), toxic agents (formic acid in methyl alcohol), heat (thermocoagulation), freezing (cryosurgery), infections (poliovirus), and overexposure to ultrasound. Each case, however, involves the action of additional factors independent of the type of primary traumatic event. Chief among these factors are free radicals and nitric oxide (NO). Reaction products of NO and O2, including potent oxidizing molecules such as peroxynitrite and nitrogen dioxide, can be more toxic than NO itself. The type of brain necrosis depends in large part on the duration of local circulatory arrest: 1. Transient ischemia only destroys neurons and oligodendrocytes, inducing incomplete necrosis or selective neuronal necrosis (Scholz 1953). 2. Prolonged ischemia, termed “infarction,” gives rise to complete necrosis of all tissue components.

sis with atrophy of the caudate nuclei; c dissociation of the glial surface membrane of the ventricular system

4.3.1.1 Incomplete Necrosis Morphologically cell necrosis, especially neuronal necrosis, features irreversible changes of the cytoplasm (condensation, hydropic swelling, intense eosinophilia, loss of structure, hom*ogenization) (Fig. 4.14) and of the nucleus (pyknosis, karyolysis, karyorrhexis) (Majno and Joris 1995). Time Course. The data vary on how soon after the on-

set of ischemia the first microscopic neuronal changes become evident. Some authors report an interval of 30 min (Jacob and Pyrkosch 1951), others 14/15 h (Müller 1930). The data may differ in part due to prolongation of the necrotic process for as long after death as brain temperature remains favorable (Lindenberg 1982).

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Fig. 4.14a−d. Neuronal necrosis caused by ischemia. a, b Eosinophilic cortical nerve cells characterized by (b) a pyknotic nucleus and an intense eosinophilia of the cytoplasm (arrows); c time-dependent reduction of the nerve cells as seen in the CA1-

segment of the hippocampus; d ischemic neuronal necrosis in the Purkinje cell layer of the cerebellum (ischemic neurons, see arrows) (a−d H&E; magnification a, c ×200, b, d ×300)

Inflammation. Necrotic tissue and cells always at-

and surrounding tissue by way of a vascular network (perifocal edema). Neurons become thorny and severely shrunken within 12−36 h, with darkly staining incrustation of their pericellular structures. A survival time of 12 h leads to hom*ogenization of the cytoplasm and nuclear and cytoplasmic pallor. Between 36 h and 48 h, the neurons disappear except for the nuclei (see Fig. 4.14c). Within 1−2 h the necrotic tissue is characterized by an emigration of neutrophil leukocytes (Fig. 4.15a, b). Within 18 h the necrotic area exhibits proliferation and extensive activation of microglial cells (Fig. 4.15c−f). Along the infarct margin, macrophage numbers increase. Hypertrophic astrocytes appear along the border zone within the brain parenchyma after 4−6 days (Fig. 4.16). The infarct liquefies at its center and macrophages phagocytose the debris. The final stage of cortical liquefactive necrosis is termed “laminar necrosis” (Fig. 4.17a−c) associated with intense gliosis during the final phase (Fig. 4.17d). The final stage of ischemic involvement of the basal ganglia and the thalamic nuclei is a cystic necrosis (Fig. 4.18). Ischemic damage of the hippocampal area is characterized by a segmental loss of neurons in the hippocampal cortex (Fig. 4.19a, b) associated

tract neutrophils, macrophages, and sometimes lymphocytes. The tissue can activate the scavenger function of resting microglia for elimination of myelin as well as cell debris. Hsu et al. (1995) have published an overview of the association between cell-mediated injury and cellular reactions. Lipid inflammatory mediators are crucial for cellular interactions in sterile inflammation. Among the mediators involved in inflammatory processes as a reaction to cell necrosis are thromboxane A 2, leukotrienes, and prostaglandins, collectively termed eicosanoids (Hsu et al. 1995). 4.3.1.2 Tissue Necrosis: Infarction Prolonged ischemia-induced tissue necrosis is termed “infarction” or liquefactive necrosis. The infarcted area displays macroscopically evident pallor on H&E, Nissl, and myelin preparations within 3−5 h as an indication of acidosis. A narrow halo of even greater pallor surrounds the necrotic area (Fig. 4.20a). Around the necrotic area, vessels are distended and release fluid into the infarcted tissue

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.15a−f. Cytologic sequelae of regional necrosis. a, b An early leukocyte reaction is demonstrated by means of NAS-DClAE; c−e CD68 reactive macrophages in the cortex as

well as (f) in the white matter increase (magnification c ×100; a, b, d, f ×500, e ×1,000)

with compensatory (early) microglial activation (Fig. 4.19c) and secondary gliosis (Fig. 4.19d). Another type of brain tissue necrosis is the rare phenomenon “persistent coagulative necrosis” first described by Spielmeyer (1922) (Fig. 4.20), which affects cell tissue elements. Within gray matter the outlines of dead neurons are recognizable, their cytoplasm is intensely eosinophilic and usually contains numerous, often large, vacuoles, and the nucleus stains poorly with hematoxylin. This picture, which is recognizable within the first 4−6 h, is followed by decreasing stainability of nucleus and cytoplasm until a barely recognizable ghost cell is all that re-

mains. Acute and enduring deprivation of blood supply causes necrosis of cells and tissue components, the lesion remaining in a state of “coagulation” for a prolonged period. The cells appear only as shadows and the necrotic tissue persists within the brain as a foreign body and sometimes becomes encapsulated in mesenchymal tissue. The pathogenesis of this rare type of necrosis is still unknown (Escolá and Hager 1963; Cervos-Navarro and Ferszt 1977).

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4.3.2 Gene-Regulated Cell Death: Apoptosis Apoptosis can be differentiated from necrosis based on differences in their pathogenesis, cell reactions, and morphologic features. Apoptosis is the programmed death of a cell as regulated by specific death genes (for review see Clarke 1998). It initiates a delayed secondary death of neurons in response to environmental changes, deficient metabolic and trophic supply, and changed gene transcription. During apoptosis, the integrity of mitochondria is compromised and various pro-apoptotic proteins are released into the cytoplasm. This results in activation of caspases, proteases that orchestrate the death of the cell (Waterhouse 2003). Apoptosis requires active protein synthesis (McIntosh et al. 1998; Raghupathi et al. 2000). A single cell can undergo a switch between the two types of cell death based on several pathways (McConkey 1998; Fiskum et al. 1999; see also Leist et al. 1990) (for further informations, see p. 620). The characteristic morphology of apoptosis exhibits cleavage of the internucleosomal chromatin that can be identified in situ using the terminal Fig. 4.16a, b. Activated astrocytes along the border zone of necrosis. a Astrocytic reaction in the cortex and (b) in the white matter (GFAP reactivity; magnification a ×1,000, b ×500)

Fig. 4.17a−d. Cortical necrosis, i.e., laminated necrosis. a Macroscopy of long-time survival of cortical necrosis which is associated with a complete cortical (cystic) necrosis (b) while in the

cerebellum the necrosis (c) is totally replaced (d) by a distinct gliosis (b−d H&E; magnification b, c ×100; d ×200)

CHAPTER 4: Cell and Tisue Reactions

Fig. 4.18a−d. Global ischemia leads to cystic necrosis of the basal ganglia. Two cases are demonstrated: (a, c) and (b, d) with a

long survival time after cardiac arrest demonstrating necrosis of the pallidum (a, b: MRI)

Fig. 4.19a−d. Neuronal loss in the hippocampal area (CA1 sector) and glial reaction (see also Fig. 14.14, p. 309). a The Ammon‘s horn CA1 sector is characterized by a distinct loss of nerve cells; b by high magnification of the marked sector (see a) intact neurons are seen in the center as well as a bilateral loss of neurons;

c the lost neurons are replaced by CD68 reactive microglia and d in cases of longer survival time, by astrocytes (a, b MAP2 reactivity; c CD68 reactivity; d GFAP reactivity; magnification a ×50; b, c, d ×500)

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(for review Kermer et al. 1999; see also Huppertz et al. 1999): 1. Immediate early gene transcription factors (cjun, jun-B, jun-D, c-fos, AP-1, ATF, NF-κB) 2. Proteases (calpains, caspases) 3. Glutamate-mediated toxicity (free radicals, protein-kinases, Ca 2+ homeostasis, second messenger systems) The death-inducing activity of the Bax, Bad, Bid, Bcl-xs family members is thought by Raghupathi et al. (2000) to be in dynamic equilibrium with their survival-promoting cognates Bcl-2, Bcl-x L . Shifts in the protective intracellular Bcl-2-family-protein levels can tilt the balance toward cell death by activating the death-inducing cysteine proteases, caspases (Thornberry and Lazebnik 1998). The death of single cells releases insufficient quantities of chemoattractants to allow effective concentrations of molecular species to reach the vascular endothelium. For this reason a genuine cell reaction does not occur. Neighboring cells that are not professional phagocytes cannibalize the cell debris in a process specific to apoptosis (Majno and Joris 1995). In inflammatory diseases, an essential factor in the resolution of the inflammatory attack is the clearance of apoptotic leukocytes by tissue-specific phagocytes (Platt et al. 1998). This process has been termed the “safe, phagocytic clearance of dying, yet intact leukocytes undergoing apoptosis” involving rapid recognition, uptake, and degradation. Microglial cells were recently shown to be capable of protecting neurons, cerebellar granule neurons in particular, from apoptosis (Polazzi et al. 2001): molecules are released by apoptotic neurons that enable the anti-apoptotic activity of microglia. In vitro, normal microglia release molecules capable of rescuing neurons from apoptotic death. Fig. 4.20a−c. Coagulation necrosis. a Necrotic area is limited by a spongious border zone (arrows); b, c fragments of intact tissue components are visible and not phagocytosed (a H&E; b, c van Gieson stain; magnification a ×5; b ×100; c ×200)

deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method (Gavrieli et al. 1992). Apoptosis causes pyknosis of the nucleus and condensation and shrinkage of the cell body. As it progresses, budding and karyorrhexis occur, and ultimately a breakup into clusters of apoptotic bodies (Majno and Joris 1995). The time course of apoptosis following a traumatic event is as follows: about 4 h after a traumatic event, apoptosis begins, and remains demonstrable for about 3 days (Yakovlev and Faden 1997). Three major factors are known to participate in the apoptotic cascade of “delayed” neuronal death

4.3.3 Necrosis Versus Apoptosis Microglia, astrocytes, and oligodendroglia may participate in apoptotic or necrotic processes. The reaction of neurons highly sensitive to injuries such as ischemia, hypoglycemia, infection, and mechanical trauma are described above and classified systematically in Table 4.3. A review by Rosenblum (1997) includes a comparison of various hypotheses regarding the underlying causes of “delayed” neuronal death, among them excitotoxicity, calcium, and apoptosis. Rubin (1997) and Abe (1999) review the phenomenon of neuronal apoptosis as it appears in various neurological diseases.

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Table 4.3. Different pathophysiological and phenomenological features of necrosis and apoptosis. Sources: Granville et al. 1998; Abe 1999; König and Rosenberg 2000; Jellinger and Stadelmann 2000

Features

Necrosis

Apoptosis

Causes

Toxic influences

Developmental/programmed degenerative changes

Massive ischemia

Growth factor deprivation

Radiation (high dose)

Mild ischemia, radiation, etc.

Non-coordinated events

Programmed cascade

Cellular processes

Molecular events

Cell membrane rupture

Membrane phospholipid asymmetry

Mitochondrial swelling

Organelles preserved/shrunk

Energy independence

Energy (ATP) dependence

No protein synthesis

Requires protein synthesis

No RNA synthesis

Requires new RNA transcription

ATP depletion

Mitochondrial permeability transition

Enzymatic digestion

Mitochondrial cytochrome c release

Protein denaturation

Caspase activations

Diffuse DNA digestion

Internucleosomal endonucleases Transglutaminase activation Poly(ADP-ribose) polymerase cleavage

Tissue distribution

Group of cells

Single cells

Tissue reaction

Lysis and release of cellular contents resulting in inflammation of surrounding tissues

Phagocytosis of membrane-enclosed vesicles by macrophages or neighboring cells; little or no inflammation

Cell

Swelling

Cell shrinkage, loss of membrane contact with neighboring cells

Plasma membrane

Loss of integrity, enhanced permeability

Blebbing formation of apoptic bodies

Morphology

Organelles

Damaged

Intact

Nucleus

Disintegrated

Condensed and fragmented

Lysosomes

Ruptured

Intact

Mitochondria

Defective, ATP-depleted, swollen, ruptured

Swelling, permeability transition, may rupture

DNA

Non-specific degradation

Internucleosomal DNA cleavage

Protein

Non-specific degradation

Activation of caspases, calpains

Substrates

Non-specific hydrolysis

Specific substrates

Anti-death molecules

Bcl-2 (in some cases) (Kane et al. 1995)

Bcl-2 family, IAPs, FLIPs, crmA, caspase inhibitors

No

Yes

Biochemistry

Adenosine triphosphate requirement

4.3.4 Penumbra Astrup et al. (1981) first defined the ischemic penumbra as brain tissue perfused at a level within the

thresholds of functional impairment and morphologic integrity, which has the capacity to recover if perfusion is improved. Because tolerance of tissue to ischemic damage is dependent on residual flow and duration of flow disturbance (Heiss and Rosner 1983), the ischemic penumbra is a dynamic process;

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Fig. 4.21a−f. Dendritic and axonal injury. a Dendritic processes and neuronal perikarya are reactive with a MAP2 antibody which (b) lose their reactivity within a short time after an ischemic period as well as in cases of (c) MBI-induced hemorrhage; d axonal

injury is demonstrable by axonal bulbs or balls using H&E stain as well as (e, f) by their reactivity to β-APP antibody (magnification a ×50; b ×500, c ×100; d−f ×1,000)

it exists for a short period even in the center of ischemia, from which the conversion into irreversible necrosis propagates over time to the neighboring tissue. Focal ischemia results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Increased expression of caspase-1, -3, -8, and -9, and of cleaved caspase-8 has been observed in the penumbra (for details, see Ferrer and Planas 2003). But for a limited time interval, penumbral tissue has the potential for recovery and, therefore, is the target for

interventional therapy in acute ischemic stroke (time window, Heiss 2000).

4.3.5 Dendritic Injury Relatively little is known about the effects of injury of the dendritic processes of neurons. Axotomy of a motor neuron induces loss of some presynaptic terminals and the retraction of processes (Blinzinger and Kreutzberg 1968; Summer and Watson 1971). Abnormalities in dendritic spines have been report-

CHAPTER 4: Cell and Tisue Reactions

ed during the perinatal period in cases of developmental retardation (Purpura 1975, 1976). Li et al. (1997) showed that expression of microtubule-associated protein 2 (MAP2) in perikaryons and dendrites is a sensitive marker of dendritic lesions in spinal cord trauma (Fig. 3.2b; see also Chap. 10 − pp. 226 f). As early as 4 h after moderate or severe compression of the spinal cord, loss of MAP2 immunoreactivity in dendrites and nerve cell bodies became evident in the injured segment. This phenomenon continued for the duration of the 9-day experimental period. How much MAP2 immunoreactivity is lost depends on how hard the cord is impacted (Li et al. 1995). The loss of immunoreactivity may result from an (impact-induced) influx of calcium, activating calcium-dependent proteolytic enzymes capable of degrading MAP2 (Inuzuka et al. 1990). The same phenomena may be observed as a result of hypoxic lesions in the hippocampal area (Fig. 4.21a, b).

4.3.6 Axonal Injury Axonal injury is characterized by an interruption of axonal fibers (Fig. 3.2b) as demonstrable − for example − as a result of a gunshot: the axons will be fragmented (Figs. 8.13b, 9.19). Moreover, axonal injury induces an anterograde (Wallerian) and retrograde degeneration of the injured axons. The terms “anterograde” and “retrograde” refer to the directions of conduction of the nerve impulse along the axon, i.e., the degeneration following focal damage proceeds in a centrifugal or centripetal direction (for review see Brodal 1982). An interrupted anterograde flow of proteins along the axon can cause the phenomenon of axonal injury. This phenomenon was once demonstrated by H&E stain and by silver staining techniques within 16−24 h after a traumatic event (Strich 1956; Adams et al. 1982). But since the injured axon is selectively characterized by expression of β-amyloid precursor protein (β-APP) (Fig. 4.21d−f; cf. Gentleman et al. 1993; Sherriff et al. 1994), it is now routinely confirmed in 105−180 min (Blumbergs et al. 1995; Oehmichen et al. 1999), in adult brains as well as in infant brains (Reichard et al. 2003). β-APP expression is seen even if the axonal injury is moderate or the axotomy delayed or incomplete (Povlishock 1992). Although axonal injury was long thought to be a morphological correlate of MBI, it is now known to be a non-specific phenomenon also associated with acute intoxication (Nies et al. 2002) or hypoxia/ischemia (Oehmichen et al. 1999). In a recent study Graham et al. (2004) evaluated the pattern of β-APP immunoreactivity. The authors identified three different types:

Fig. 4.22a−c. Demyelination as represented in a case of multiple sclerosis with perivenous lymphocytes. a Structural disintegration of the perivascular white matter using Luxol fast blue stain or (b, c) demonstrating myelin basic protein (= MBP) reactivity (magnification a ×50; b ×300; c ×1,000)

1. A diffuse − multifocal type − in MBI, CO poisoning and hypoglycemia; 2. A type corresponding to the outlines of an infarct or hematoma with evidence of raised intracranical pressure; 3. A mixture of (1) and (2) which was seen in serve MBI. It is still unclear which events trigger axonal degeneration within the CNS and PNS. Kapoor et al. (2003) suggest a link between nitric oxide (NO) and subsequent molecular events that previously have been indicated as contributors to reversible and irrevers-

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ible axonal injury. Waxman (2003) demonstrates the axonal death cascade induced by hypoxia, ischemia, mechanical trauma, inflammation or NO. The molecular events involving sodium channels and the Na+/Ca 2+ exchanger lead to an increase in intracellular calcium, which can provoke axonal degeneration. Axonal injury of myelinated axons is always accompanied by a demyelinating process, i.e., a loss of myelin, which will be eliminated by mononuclear phagocytes (see: Fig. 9.15b). The sequelae will be a glial scar lacking myelin as demonstrable by Luxol fast blue stain (Fig. 4.22a) or by immunohistochemistry using an antibody against myelin basic protein (Fig. 4.22b, c). 4.3.6.1 Anterograde (Wallerian) Degeneration Interrupted axons or injured neurons exhibit disintegration of the distal stump. Breakdown of the distal axonal stump is known as “Wallerian degeneration” and begins several days after a traumatic event. Its salient morphological features are lysis of axons and myelin, Schwann cell proliferation, and phagocytosis by invading macrophages. Axonal and myelin degeneration follow a time course described in detail by Brodal (1982) (see also p. 242). 4.3.6.2 Retrograde Degeneration Axotomy induces a characteristic centripetally directed morphological change of the neuron termed retrograde axonal degeneration. This retrograde alteration is characterized by rounding of the neuronal contours, swelling of the neuronal cytoplasm, and a decline in the number of Nissl bodies at the center of the cytoplasm (central chromatolysis − see Fig. 3.1c). The nucleus becomes slightly deformed and is displaced to the periphery of the perikaryon. These changes correspond to the changed or increased neuronal gene expression after axotomy (Graeber et al. 2002). Axotomy is followed in hours by rapid upregulation of the immediate early genes, such as cfos, c-jun, jun-B (Haas et al. 1993), in association with the upregulation of heat shock proteins (Kalmar et al. 2002). The one constant change associated with acute retrograde changes may be chromatolysis. These changes are sometimes accompanied by local proliferation of satellite glial cells whose time course has also been described by Brodal (1982) (see also pp. 242 and 304 f).

4.3.7 Regenerative Capacity It is accepted as common knowledge that plasticityassociated molecular and structural events occur in the injured brain. These are at least partly responsible for functional recovery. Increases in dendritic arborization, spine density, and synaptogenesis in both peri-injury and intact cortical areas are the potential morphological strategies that enable the brain to reorganize its neuronal circuits (Keyvani and Schallert 2002). On the other hand we have to consider that the scarring process is an ineffective regenerative process which is associated with cell proliferation. The cell proliferation will be − especially within the first 48 h after the traumatic event − non cell-specific, as immunostaining with markers for immature and mature astrocytes, activated microglia, neural precursors, and mature neurons will be negative (Chirumamilla et al. 2002). Nevertheless, it is also accepted that both retrograde degeneration and the axonal injury-induced bulbs and swelling of the proximal axonal stump are markers of a regeneration process. Although the CNS has little innate capacity for repair, this capacity does exist for the peripheral nervous system. It is not known why axons in the adult CNS are not capable of better regeneration; it is known that they do in fact regenerate, as was recently reconfirmed by von Euler et al. (2002). The observations of Schwab and Caroni (1988; Schwab 1993) are of major importance. They show that proteins released by oligodendrocytes inhibit axonal elongation. This inhibitory protein has since been identified and cloned (Chen et al. 2000; GrandPré et al. 2000; Prinjha et al. 2000). These authors also identified the protein (Nogo) of a previously unknown gene that encodes the inhibitory myelin protein in rats and humans. The myelin-derived axon outgrowth inhibitor Nogo protein binds to an axonal Nogo-66 receptor and at least accounts for the lack of CNS repair (Li and Strittmatter 2003; McGee and Strittmatter 2003). It remains unclear, however, what effect other factors may have, whether negative (e.g., the release by neurons of large quantities of glutamate following the incidence of spinal cord injury), or positive [e.g., release of tissue growth factors (Ramer et al. 2000) and cytokines, or induction of the macrophage scavenger function (see also Schwab 2000)]. It is now thought that neurons are renewed throughout life from endogenous stem cells and added to the dentate gyrus. Adult neurogenesis could be demonstrated in the subgranular and subventricular zones of the hippocampus (Kempermann et al. 1998; Cameron and McKay 1999) and the olfactory bulb (Craig et al. 1999). These are the only zones where differentiation of neural stem cells into neurons is

CHAPTER 4: Cell and Tisue Reactions

known to take place in the intact adult CNS (Reilly 2002). Because this process does not occur in the adult spinal cord, Svendsen (2002) postulates that the growth of neurites can only be stimulated by newly regenerated astrocytes. Additional findings suggest that adult neurogenesis is actively regulated in large part by astrocytes (Reilly 2002; Song et al. 2002). Gage (1998) and colleagues (Kempermann et al. 1998) were able to show that exposure to an environmental challenge evokes much greater neurogenesis in old than in young animals. More recent data suggest that the old brain reacts quickly with a neurogenic response to functional challenges, a type of cellular plasticity associated with the continued sensory stimulation and activity of the aging brain (Kempermann et al. 2002; McKhan 2002).

4.4 Inflammation 4.4.1 Principles of Neuroimmunology The CNS was once described as an “immunologically privileged site” (Medawar 1948). This hypothesis was based mainly on the existence of the BBB (Pachter et al. 2003), which restricts diffusion of soluble molecules and the migration of immune cells out of the systemic circulation into the CNS (Oehmichen 1983). Pericytes, endothelial cells, microglia and astrocytes, by contributing to BBB function (see above), participate in CNS immune regulation (Prat et al. 2001). Meanwhile a number of basic processes are known (Bauer et al. 2001) that explain how the CNS responds to inflammatory attack by regulating local antigen presentation, by the different cell types, and by its special cytokine environment. It also eliminates inflammation via emigrating macrophages (Oehmichen et al. 1979 − for review Oehmichen 1982; Cserr and Knopf 1997) and destruction of apoptotic T-cells. In vitro and in vivo studies have elucidated the mechanisms underlying immune-mediated (via cytokines, macrophage/microglial toxins, and antibodies) tissue damage, featuring many different potential pathways. The normal CNS has limited expression of major histocompatibility complex (MHC) class I antigens, primarily on the endothelium and glial cells, and no expression of MHC-II and the various immunoactive adhesion molecules. Fontana et al. (1982) were the first to point out that cytokines such as interferonγ (IFN-γ) are able to stimulate astrocytes to express MHC class II to secrete cytokines (IL-1, IL-3, TNF-α), and to present antigens such as myelin basic protein

(MBP) to specific T-cell lines (Fontana et al. 1982, 1984; Massa et al. 1987). Frei et al. (1987) focused on microglia and found that they too could respond to IFN-γ by upregulating MHC-II. If IFN-γ or IFN-γ and TNF-α are introduced directly into the CNS, there is independent, progressive upregulation of both MHC classes and of adhesion molecules, such as the intercellular adhesion molecule-1 (ICAM-1), which are expressed first by perivascular macrophages (Hickey and Kimura 1988), subsequently by microglia and macrophages throughout the CNS, and finally by astrocytes (Massa et al. 1986). Experimental induction of autoimmune encephalitis (EAE) revealed that perivascular macrophages are the chief presenters of CNS antigens to circulating T-cells (Hickey and Kimura 1988). The role of the endothelium in antigen presentation within the CNS is ambiguous. Astrocytes too are thought (Waksman 1997) to play an ambiguous role. When presenting antigen to specific T-cells in vitro, they are lysed. It is not known whether T-cells are induced to proliferate or to release inflammatory cytokines, or possibly both, or whether they shut down for lack of suitable co-stimulatory signals (so-called clonal anergy). The duality of the inflammatory response is crucial to host repair and defense. It may also however cause loss or impairment of function, i.e., although otherwise beneficial, inflammation may impair neuronal function (Perry et al. 1999).

4.4.2 Inflammatory Cells Instead of the BBB being a limiting factor of the CNS immune response as once believed, today it is thought that the brain itself is an immune system organ (Fabry et al. 1994; Chao et al. 1997). This conclusion is based on the numerous cytological and immunological findings of the past two decades showing that the targets to be protected are neurons, axons, and myelin. In the absence of protection these can become necrotic or succumb to apoptosis, be phagocytosed and disappear. Ultimately all signs of degenerative alteration can be demonstrated. There is no direct correlation however between leukocyte emigration and parenchymal cell death in vivo (Schmid-Schönbein et al. 1999). Glial cells outnumber neurons in the cortex, where there are eight glial cells for every neuron. Among glial cells in the cortex, astrocytes comprise 80%, microglia 15%, and oligodendroglia 5% (Chao et al. 1997). These cells possess many immunological features marking them as important immunoregulatory cells. Hallmarks of CNS inflammation in particular are activated microglia and astrocytes. Inflammation undoubtedly serves primarily as a host

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Fig. 4.23a−d. Hematogenous cells as an early inflammatory response. a Platelets adherent to endothelial surfaces of a venous vessel (arrows); b emigrating leukocytes around a small artery; c leukocytic response to an intracranial hemorrhage; d lym-

phocytic aggregation in a scar caused by mechanical brain injury (a platelet antibody; b H&E, c N-AS-DClAE, d Nissl stain; magnification a ×1,000; b−d ×300)

defense mechanism in peripheral tissue, facilitating essential repair processes by altering local blood flow in the injured tissue, with accumulation of fluid and specialized cells. The brain possesses cellular host defense mechanisms since activated T-cells are capable of crossing the BBB (Hickey et al. 1991). Cellular mediators of CNS inflammation in the brain have been shown to differ with regard to type and number from those of the periphery (see below). These differences are mainly due to the brain‘s tight regulatory environment and the balance between inflammation-induced tissue damage and tissue repair (Parsons and Hunter 1999). The specificity of the immune response appears to be controlled largely by CNS antigen presentation (Sedgwick and Hickey 1997), though the precise nature of the control remains unresolved. CNS antigen presentation according to Hart and Fabry (1995) occurs outside and inside the CNS, with the BBB playing a major role in the regulation of CNS immune function. Parsons and Hunter (1999) showed that the early events leading to T-cell activation by antigenpresenting cells result from MHC binding. Co-stimulatory molecules then bind to the antigen, presenting cell−T-cell complexes for further development of the cascade. MHC is expressed not only on astrocytes

and microglia, but under certain conditions also on neurons and oligodendrocytes (Sedgwick and Hickey 1997). MHC II antigens are also expressed under normal conditions in a population of macrophages inhibiting the perivascular space, subarachnoid space, and choroid plexus. This expression may indicate that these cells perform a modulatory function at the blood/CSF interface (Matyszak et al. 1992). Under highly specific circ*mstances, physiological response mechanisms resembling those at the periphery also appear to take place in the brain. Under pathological conditions, hematogenous cells that are absent or extremely rare under normal circ*mstances appear to accumulate in the brain, i.e., platelets (Fig. 4.23a), neutrophilic leukocytes (Fig. 4.23b,c), lymphocytes (Fig. 4.23d), and macrophages. The number and type of inflammatory cells in the CNS vary widely depending on the attracting stimulus or on their inherent ability to attack a CNS antigen.

CHAPTER 4: Cell and Tisue Reactions

4.4.2.1 Polymorphonuclear Leukocytes The intravascular cells, especially the leukocytes, interact with vessel walls as determined by integrins (Hynes 1992), selectins (Bevilaqua 1993), and immunoglobulins of the supergene family (Springer 1990). Among the heterogeneous supergene family are MHC molecules, T-cell receptors, and ICAM-1. During emigration, i.e., extravasation, leukocytes initially come into loose contact with the walls of vessels of the microcirculation via selectin molecules or lectins, producing a rolling motion along the vessel wall (McEver 1994). They are then expressed on the endothelium. The selectin molecules are E-selectin (ELAM-1), L-selectin (LAM-1, LECCAM-1), and P-selectin (CD62). P-selectin plays a role in recruitment of neutrophils to the brain parenchyma (BernardesSilva et al. 2001), while E-selectin is thought to participate in both neutrophil and CD4+ T-cell adhesion (Harlan and Liu 1992). Endothelial selectins can be rapidly upregulated following wounding, P-selectin within minutes (2−3 h (Oehmichen et al. 1997), most frequently in both the corpus callosum and the rostral portion of the brain stem as an indication of diffuse axonal injury (DAI) (Graham and Gennarelli 1987). Examination of the alcohol concentration (AC) in the dura hematomas in comparison with the peripheral blood will be of special diagnostic value. The AC will give evidence of the time course of the bleeding process and the dying process as demonstrated in Fig. 7.9. In this special case a contact mechanism caused an epidural and subdural hemorrhage. While the blood alcohol concentration (BAC) was 0.05‰ at the time of death, the concentration in the SDH was 0.42‰ and in the epidural hematoma (EDH) 1.00‰. These differences give evidence of the velocity of

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bleeding and some information on the duration of the agony. The outcome in EDH and SDH was found to be predominantly influenced by the preoperative state of consciousness, associated brain lesions, and, in comatose patients, the duration of the time interval between onset of coma and surgical decompression. When this interval exceeded 2 h, mortality from SDH rose from 47 to 80% (good outcomes 32 and 4%, respectively). In acute EDH an interval under 2 h led to 17% mortality and 67% of good recoveries compared to 65% mortality and 13% of good recoveries after an interval of more than 2 h (Haselsberger et al. 1988).

7.3.3 Secondary Lesion (Herniation Syndrome) Supratentorial brain herniation exhibits the following major patterns: subfalcine, central transtentorial, uncal, and tonsillar as demonstrated in Fig. 7.7. If untreated, it can culminate in total intracerebral circulatory arrest (brain death syndrome). In any case, the prognosis depends on the size of the hemorrhage as well as on the speed of the space-occupying bleeding. An expanding mass lesion may cause a compression of one hemisphere (Fig. 7.10a) and a medial shift of the ipsilateral hemisphere, forcing the cingulate gyrus beneath the falx cerebri (subfalcine herniation) (Fig. 7.10b) and causing local hemorrhage in the ipsilateral gyrus cingulus and/or in the center of the corpus callosum. Herniation of this type may lead to compression of the ipsilateral anterior cerebral artery. The result is often cerebral ischemia and possible (hemorrhagic) infarction of the medial posterior frontal and parietal lobes supplied by this artery. Supratentorial hemorrhages, either subdural or epidural, may cause central transtentorial herniation. Such lesions displace the cerebral hemispheres and basal nuclei downward, pushing the diencephalon and adjacent midbrain through the tentorial notch. The clinical symptoms reflect bilateral progressive injury of the diencephalon. They include drowsiness, agitation, and impaired upward gaze, the latter secondary to compression of the quadrigeminal bodies at the level of the superior colliculi. If herniation continues to progress, stupor and coma rapidly follow. Uncal herniation (Fig. 7.10c) results from lesions expanding in the lateral middle fossa or temporal lobe, displacing the medial edge of the uncus and hippocampal gyrus medially and over the ipsilateral edge of the tentorium cerebelli. Compression of the midbrain occurs, as well as compression or stretching of the contralateral or ipsilateral third cranial nerve. In its classic form, uncal herniation syndrome

entails compression of the posterior cerebral artery and ipsilateral cerebral peduncle and stretching of the ipsilateral oculomotor nerve. The resulting symptoms include diminished consciousness, contralateral hemiparesis, and a dilated ipsilateral pupil that is unreactive to light. Compression of the opposite cerebral peduncle against the contralateral edge of the tentorium (Kernohan‘s notch) will induce hemiplegia ipsilateral to the mass lesion. Progression to coma then rapidly follows pupillary dilation. Such secondary changes, which are common to all types of intracranial space-occupying processes, can produce focal hemorrhages in the corpus callosum, cingulate gyri, hippocampal gyrus, and in the brain stem. Tonsillar herniation (Fig. 7.10d) is caused by compression of the cerebellar tonsils into the foramen magnum. The clinical symptoms reflect the brain stem compression with the result of bleeding within the midbrain or pons (Fig. 7.10e) and the clinical features of apnea and bradycardia, respiratory and cardiac arrest.

7.4 Epidural Hemorrhage 7.4.1 Classification Epidural hemorrhage (EDH), bleeding between the skull and the dura mater, is most commonly related to traffic accidents, and much less frequently encountered than SDH. It is especially rare in children under the age of two and in the elderly. EDH usually involves arterial bleeding (>50%). If the mechanical loading does not induce immediate central nervous symptoms, the lucid interval between the generation of injury and appearance of the first symptoms is commonly shorter than for SDH, in most cases lasting not more than a few hours (delayed EDH). In very rare cases, however, the interval can last up to days. The delayed form of EDH has been reported in up to 30% of cases (Poon et al. 1992). The mortality of EDH is markedly higher than that of SDH, even given optimal neurosurgical intervention. Chronic EDH is rare and more likely to result from venous than arterial bleeding (Iwakuma and Brunngraber 1973).

7.4.2 Biomechanical Aspects Unlike SDH, EDH is caused by local impact loading of the head and is, thus, nearly always associated with contact injury. EDH arises from injury of the middle

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meningeal artery and its branches near the impact site. In a typical case, EDH occurs when a fracture crosses the middle meningeal artery, which adheres tightly to the inner surface of the temporal bone. About 24% of all instances of skull fracture are associated with EDH (Edna 1983); only about 1% of EDH are not associated with a fracture (Galbraith 1973). Edges of fractured bone can cause laceration of underlying dural arteries and, less frequently, veins. In rare cases, EDH is caused by lacerations of one or more branches of the venous sinuses or emissary veins. EDH rarely occurs spontaneously. Bilateral EDH is uncommon. Bilateral EDH in the absence of fracture has been reported in a few children under 10 years of age (Cooper 1987). Deformation of the elastic skull in children can strip the dura from the inner table and lacerate the adherent vessels (Mealey 1960; Freytag 1963). Fracturing of the skull absorbs much of the impact energy itself. Consequently, EDH is less likely to produce cerebral contusion injuries than SDH. Only 25% of patients suffering EDH exhibit associated parenchymal lesions of the brain (Bricolo and Pasut 1984; Guillermain 1986). If a parenchymal lesion does occur, it may produce a concomitant SDH.

7.4.3 Pathology EDH is characterized by the presence of a hematoma between the dura and skull. It attaches tightly to the skull and dura mater at the borders of the sutures and has a thick lenticular, convex appearance (Fig. 7.11b, c). The volume of blood varies greatly, but amounts to at least 100 ml in most fatal cases (Lindenberg 1971; Leestma 1988). The EDH is usually located beneath the fracture in the cranial vault (Fig. 7.11a), i.e., on the side of the impact, in most cases in the region of the temporal bone (see Table 7.1). EDH rarely develops contralateral to the impact site. Although a primary, mechanically induced, intracerebral hemorrhage involving the brain parenchyma rarely occurs, disseminated axonal injury is often seen in the brain parenchyma, especially in the corpus callosum and brain stem, sometimes without attendant hemorrhage. A space-

Fig. 7.10a−e. The herniation sequelae of space-occupying intracranial (subdural) hemorrhage. a Compression of one hemisphere (right) and compression of the contralateral hemisphere (left) in a formalin-fixed brain after removing the subdural hemorrhage; b extreme hemispheric shifting as a result of a (right) subdural hemorrhage characterized by a flattening of the lateral parts of

occupying EDH will displace the brain (Fig. 7.11c, d), resulting in compression of the brain stem (herniation syndrome). The cytological and histological features resemble those of SDH and vary according to the survival time (see below).

7.4.4 Clinical Features If there is concomitant injury of the brain parenchyma, clouding of consciousness with neurological deficits will develop either immediately (in approx. 25−30% of cases) or after an interval of minutes or hours (usually within 4−8 h − Auer et al. 1989), typically with focal ipsilateral mydriasis and hemiplegia. As already mentioned, skull fractures may be associated with EDH, the incidence of EDH being 20 times higher in cases with skull fracture than in cases without fracture (Auer et al. 1989). If a skull fracture is suspected, CT should be performed to confirm or exclude an incipient EDH. The typical appearance of EDH in CT is the presence of a biconvex hyperdense mass. 7.4.4.1 Prognosis Prognosis depends on the interval between onset of the space-occupying EDH-induced cerebral compression and the start of surgical decompression; this means that timely diagnosis and treatment are essential to a favorable prognosis. The patient‘s life can only be saved by early surgical decompression. If performed early enough, this can achieve a complete recovery. The mortality of EDH varies between 0% (Paterniti et al. 1994), 5% (Poon et al. 1992) and 43% (Seelig et al. 1984). Early surgical intervention does not guarantee the patient‘s survival or complete recovery. The possibility of mistaken diagnosis is just as likely in EDH as in SDH and is discussed below (see p. 130).

the hemisphere with discrete lesion of the corpus callosum and hemorrhage in the right gyrus cingulus (= subfalcine herniation); c extreme basal brain herniation causing hippocampal hemorrhage (= uncal herniation); d tonsillar herniation; e herniation-induced pontine hemorrhage

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Fig. 7.11a−d. Epidural hemorrhage (EDH). a Fracture of the temporal and latero-parietal bone can be associated with a laceration injury to the medial meningeal artery with the sequelae of an epidural hemorrhage; b EDH compress the right hemisphere

7.5 Subdural Hemorrhage Subdural hemorrhage (SDH), bleeding into the space between the dura and the arachnoid, is commonly associated with mechanical brain injury and has a correspondingly high mortality rate. It is most frequently found in elderly and alcoholics, often in connection with a fall. SDH tends to be initially overlooked in the absence of fractures, intracerebral hemorrhage, or early neurological symptoms.

as the result of a space-occupying process; c EDH leads to an intracranial displacement of the brain parenchyma with d a midline shift from right to left

7.5.1 Classification SDH is 3−5 times as common as EDH. Acute, subacute, and chronic courses can be clinically and morphologically differentiated. Special forms of SDH are hemorrhagic internal pachymeningitis and subdural hygroma. SDH can occur bilaterally or unilaterally, in isolation or in combination with skull fractures, with or without cortical hemorrhage.

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Table 7.1. Localization of epidural hemorrhages (n=23). Source: Guillermain 1986

Location

Percentage

Temporal

70−90

Frontal

5−25

Parietal

1−3

Occipital

3−14

Posterior fossa

3−12

The source of the bleeding may be arterial or venous. According to Krauland‘s (1982) survey of his own cases and cases in the literature, the sources of SDH are, in order of frequency, as follows: ▬ Cortical hemorrhage (contusion injury) (60−70%) ▬ Tear in a bridging vein (2.5−20%) ▬ Arterial injury (cortical part of the middle cerebral artery) (2.5−10%) ▬ Sinusoidal injury (4−9%) In 4−11% of cases the source cannot be found, either because there is no visible, accompanying local SAH or because the traumatic event is too long past and scarring has obliterated clear signs of the source.

7.5.2 Biomechanical Aspects Each of the four different sources of bleeding has its particular underlying mechanism. The different types of SDH are summarized according to their pathogenetic features: 1. Recurrent “spontaneous” SDH undoubtedly exists (Matsuyama et al. 1997), although its pathogenesis has been questioned (Maxeiner 1997). Most spontaneous SDH are arterial in origin caused by a hypertensive peak in blood pressure or preexisting damage to an arterial wall (e.g., arteriosclerosis). A compromised vessel can also tear spontaneously. Spontaneous SDH is also associated with hematological or hepatic coagulation disorders and with anticoagulation therapy. A (secondary) SDH may result from the rupture of a cerebral arterial aneurysm or an intracerebral angioma into the subdural space. Friede‘s (1971) electron microscopic studies of the dura showed that a subdural neomembrane may form even in the absence of a traumatic event due to a proliferation of dural endothelial cells; a secondary spontaneous SDH is possible in such cases

Bridging veins

Fig. 7.12. Acceleration mechanism of the head which causes a tearing and stretching of the (blue colored) parasagittal bridging veins connecting the arachnoid and the dura (source: Wilson 1946; see also Sellier and Unterharnscheidt 1963)

(Friede and Schachenmayr 1978; Schachenmayr and Friede 1978). 2. Contusion-induced SDH arises when intracerebral pressure causes tearing of, e.g., small cortical veins. The cavitation theory (see Chap. 9, pp. 179 ff) does not adequately account for such arterial tearing. Additional distortion of the vessels − such as that caused by an acceleration event − is required for tearing to occur. 3. Cortical lacerations associated with fissures, linear fractures or depressed fractures of the skull can cause SDH when arteries or veins are torn by sharp bone edges. Attendant lesions of the arachnoid will result in bleeding into the subdural space. In most cases, laceration or contusion injuries of the scalp are found at the site of impact. 4. Acceleration/rotational mechanisms (Fig. 7.12): SDH is less likely to be near the impact site than a contusion injury (even in the presence of a fracture). Thus, inertia is probably responsible for some instances of SDH (Ommaya and Gennarelli 1974; Gentleman et al. 1992). Gurdjian (1975) created experimental loading conditions that initiated rapid acceleration without impact to the head to show that acute SDH can be induced without contact. Biomechanical conditions sufficient to cause SDH can also be generated by a blow (assault) or fall. About 30% of all cases of SDH involve isolated SDH without associated skull fracture or cortical hemorrhages (Unterharnscheidt 1993; Graham and Gennarelli 1997; Maxeiner 1998), generally caused by acceleration (Gennarelli and Thibault 1982) or a blow.

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Fig. 7.13a−d. Rupture of bridging veins along the sagittal fissure. a, b Seen at autopsy on the surface of the left brain hemisphere and − a second case − c after formalin fixation demonstrating the bridging veins (arrows) connecting the arachnoid and the inter-

nal lamina of the dura on the left hemisphere; d the vessel‘s rupture (arrows) on the crest of the first frontal gyrus of the right and left hemisphere is demonstrated on the frontal section

CHAPTER 7: Injuries of the Brain’s Coverings

Non-contact mechanisms usually produce no injury of the scalp. A blow to the chin, however, can induce rotational movement sufficient to cause tears of the bridging veins and/or cortical and basal arteries (Krauland 1982; Unterharnscheidt 1993). The resulting SDH may be bilateral or occur on the same or contralateral side of the impact. SDH may be induced in infants by shaking with or without accompanying impact (see Chap. 25, pp. 493 ff). In the elderly, SDH may occur without apparent or negligible head injuries. Most SDH are located over the cerebral convexities, associated with cortical hemorrhages, and result from associated (indirect) tearing and stretching of the parasagittal bridging veins (Krauland 1961; Jamieson and Yelland 1972) that drain the surface of the cerebral hemispheres and the CSF into the dural venous sinuses. Parasagittal bridging veins are highly vulnerable to rupture from brief, high-velocity angular acceleration of the head (Gurdjian 1975). If angular acceleration is low and of long duration, as often happens in traffic accidents, strains are propagated deep within the brain and cause diffuse axonal injury (DAI). Increased acceleration can result in acute SDH combined with DAI and torn-tissue hemorrhages (Gurdjian 1975). Such acceleration can be produced by falls in which the head strikes a hard surface or a blow, with broad impact and induced rotation. Seventy-two percent of acute SDH on file at the University of Pennsylvania Head Injury Center Data Bank had been attributed to a fall or blow, only 24% to motor vehicle accidents (Gurdjian 1975; Maxeiner 1998). Rotation is most likely to cause tearing of the bridging veins along a transverse or diagonal-frontal axis, the greatest displacement of the skull relative to the brain occurring along the midline (Krauland 1982). If there is rotation around a transversal axis, which is often associated with translational acceleration, the brain is rotationally displaced against the skull in the parietal region, injuring the cortical arteries and inducing parietal cortical hemorrhages. The macroscopic picture is dominated by the intracranial shift of brain tissue and edema, usually becoming apparent in the contralateral hemisphere through obliteration of the gyral sulci and flattening of the gyral crests. SDH is often attended by extensive subarachnoid hemorrhage (SAH). A circ*mscribed SAH may indicate the site of the torn bridging veins (Fig. 7.13).

7.5.3 Clinical Features Clinical symptoms of SDH, which commonly involve venous hemorrhage, often arise after a lucid interval, developing more slowly and later than in EDH. A hemorrhage is regarded as subacute if it takes lon-

ger than 48−72 h after the traumatic event to become clinically relevant. The mortality rate of SDH is very high; it is even higher if the SDH is associated with a parenchymal lesion (Becker 1986). 7.5.3.1 Types and Causes of SDH ▬

In the perinatal period, birth trauma can occur mainly in premature babies including SDH associated with a tentorial tear. Clinically there may be a symptom-free interval of 2−3 days followed by symptoms of increased intracranial pressure (p. 504). In infants, SDH is usually the result of a fall or associated with shaken baby syndrome (pp. 493 ff), a consequence of child abuse. Death ensues after cerebral injury results in increased intracranial pressure, edema, secondary hypoxia, and shock caused by the loss of blood (Schiefer et al. 1968 − see pp. 502 f). In adults, the correct diagnosis of SDH is usually easy when there is a clear temporal relationship between the traumatic event and the appearance of clinical symptoms. Early diagnosis can be difficult, however, if no such readily apparent connection exists, when for example a minor head injury in an alcohol-dependent man has given rise to a chronic SDH. If the SDH is bilateral rather than confined to a single hemisphere, diagnosis can be even more difficult (Jacobsen and Farmer 1979). In the elderly, the clinical presentation is often dominated by an organic psychosyndrome rather than by hemiparesis and disturbed consciousness secondary to tissue displacement. A relatively minor head injury can cause SDH in the elderly. This brings with it the danger of incorrect diagnosis with serious consequences, especially when bilateral subdural hematoma is mistaken for a degenerative process intrinsic to the brain. 7.5.3.2 Prognosis

The prognosis for SDH is generally somewhat better than that for EDH. It is largely dependent upon the period of time between onset of the neurological deficits and neurosurgical intervention, i.e., early diagnosis is crucial to a favorable outcome. If decompression surgical treatment is effected within 4 h after the traumatic event and/or at the time of onset of neurological deficits, mortality falls significantly. Decompression surgery, however, is only necessary if clinical symptoms develop. If the victim exhibits the symptoms of herniation with intracranial circulatory arrest, it is already too late for neurosurgical intervention. Therefore, the indications for neurosurgical intervention depend upon clinical criteria.

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7.5.3.3 Diagnosis Diagnosis of SDH and EDH is usually based on cranial computed tomography (CCT). Even discrete neurological symptoms expressing a GCS 37.5°C (for review see Jelkmann 2000). The maximum core temperature compatible with life is 42°C. For every degree Celsius rise in core temperature, the metabolic rate increases by 13% (Holtzclaw 1992). Early rewarming, for example, after cardiac arrest may be detrimental to recovery of the brain. Moreover, mild cerebral hyperthermia worsens brain injury (Dietrich et al. 1990). The increased metabolic demand is especially harmful to ischemic neurons. Heat-related illness includes sunburn, heat cramps, heat rash, heat exhaustion, and heatstroke. The most serious types of these heat-related illnesses are heat exhaustion, sunstroke, and heatstroke. 12.1.2.1 Incidence Hyperthermia-induced disease arises secondary to generalized overheating of the body during physical exertion at high environmental temperatures, in crowded meeting rooms with poor ventilation, during heat waves and in the desert (environmental hyperthermia). In the United States each year approximately 400 deaths are attributed to excessive natural heat (sem*nza et al. 1996). During 1979−1999 in the United States, 8,015 deaths were associated with excessive heat exposure. Of these, 3,829 deaths (48%) were due to weather conditions (National Center for Health Statistics 2002). In July of 1995, at least 700

CHAPTER 12: Special Physical Trauma

heat-related deaths were recorded in Chicago (sem*nza et al. 1996). In Missouri, New Mexico, Oklahoma, and Texas during July−August 2001, 95 deaths were attributed to excessive natural heat (Morbidity and Mortality Weekly Report 2002; 51:567−570). Infants, the elderly, socially isolated people, those who are bedridden, and those with mental and chronic illnesses are at high risk (Kaiser et al. 2001). The elderly are susceptible to heat-related illness because they are less able to adjust to physiologic changes, e.g., vasodilation that occurs with exposure to excessive heat, and are more likely to take medications for chronic illnesses that increase the risk of heatrelated illness (Kilbourne 1997). Infants are known to be sensitive to heat. For example, mild fever can progress quickly to heatstroke if heat stress occurs. Heatstroke can occur in young healthy persons who are exercising (Vassallo and Delaney 1998). Infant and early childhood death caused by environmental hyperthermia (fatal heatstroke) is rare, but typically occurs in vehicles or beds. Ten cases ranging in age from 53 days to 9 years have recently been reported (Krous et al. 2001; see also Wadlington et al. 1976; Bacon and Bellman 1983). Infants and young children left unattended in motor vehicles are at high risk of heatstroke and death because intra-vehicular temperatures can increase quickly to lethal levels, especially when the vehicles are parked in direct sunlight. Hyperthermia is frequently seen in patients following mechanical brain injury which may be due to posttraumatic cerebral inflammation, direct hypothalamic damage, or secondary infection resulting in fever (Thompson et al. 2003). Regardless of the underlying cause, hyperthermia increases metabolic expenditure, glutamate release, and neutrophil activity to levels higher than those occurring in the normothermic brain-injured patient. This synergism may further compromise the injured brain, enhancing the vulnerability to secondary pathogenic events, thereby exacerbating neuronal damage. Moreover, brain hyperthermia is also a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use (Käferstein and Sticht 2000). METH produced dose-dependent hyperthermia, with brain structures showing a more rapid and pronounced temperature increase than the muscle. At the highest dose, brain and body temperatures increased 3.5°C to 4.0°C above basal levels and remained elevated for 3−5 h. Stressful and other high activity situations such as interaction with a conspecific female are also known to induce a significant hyperthermic response in the rat. METH administration during social interaction produced stronger and longer-lasting increases in brain and body temperature than induced by the drug alone, heating the brain in some animals to near its biological limit (41°C) (Brown et al. 2003).

12.1.2.2 Pathophysiology In normothermia, heated venous blood from the deep organ vasculature and cooled venous blood from the periphery mix to result in a stable arterial blood temperature (Brengelmann 2002). Hyperthermia develops when the venous streams from the periphery (from heated skin or active skeletal muscle) supply heat to the mix. Then arterial temperatures rise, followed with little lag by an increase in temperatures of the well-perfused tissues since their blood flow rate is high relative to their mass. Because splanchnic and renal blood flow rates drop drastically in hyperthermic humans (Rowell et al. 1970), the temperature increment of the venous blood draining from these organs will approach the 1°C limit consistent with steady-state aerobic metabolism. Temperatures of the organ parenchyma, therefore, rise relative to arterial temperature. As far as we know, brain blood flow is unaffected in the readjustment of distribution of cardiac output that occurs in hyperthermia (Rowell 1986). The heat that is being delivered to the body arrives via heated blood. At the cellular level, it is known that cells within the CNS exhibit an altered pattern of gene expression and elevated synthesis of heat shock proteins (HSP − Tytell et al. 1993). The 70-kDa protein HSP 70 is one of the major proteins induced by thermal stress. The HSP 70 gene is activated in glial cells within 1 h, in neurons within 5 h. The harmful effect of hyperthermia is caused by several additional factors (Corbett and Thornhill 2000): ▬ High body temperatures escalate the rate of glutamate release (Sternau et al. 1992). ▬ High body temperatures stimulate the production of oxygen radicals following recirculation after global ischemia (Globus et al. 1995). ▬ Hyperthermia compromises the blood−brain barrier, leading to edema (Kil et al. 1996). ▬ Hyperthermia increases cytoskeletal protein degradation, e.g., spectrin, microtubule-associated protein 2 (MAP2), and calpain activity (Morimoto et al. 1997). 12.1.2.3 Clinical Features and Neuropathology In addition to the factors named above, the victim‘s age and preliminary state of health, especially of the cardiovascular system, also play a role, as does the degree of dehydration (Visser and Gallagher 1998). Recent experimental data (pigtail monkeys, cerebral temperature: 42°C) provide evidence that the CNS exhibits functional disturbances, although the brains were found to be macroscopically and microscopically normal in six of eight monkeys (Eshel and

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Safar 2002). The authors concluded that the acute cerebral derangements during and after lethal hyperthermia are reversible. The cause of death is not structural CNS damage but systemic hemodynamic deterioration. Moreover, febrile seizures are known, especially in infants and children, but the mechanisms underlying the generation of febrile seizures are poorly understood. By animal experiments it could be stated (Liebregts et al. 2002) that hyperthermia contributes to seizures in the immature hippocampus by decreasing CA1 inhibition while in adults a decrease in CA1 inhibition requires a high degree of hyperthermia, and hippocampal seizure generation is opposed by an increase in dentate gyrus inhibition. The following clinical and morphological syndromes are to be distinguished. 12.1.2.4 Heat Exhaustion The clinical features are characterized by heavy sweating, muscle cramps, fatigue, weakness, cold or clammy skin, dizziness, headache, nausea or vomiting, and fainting. Untreated heat exhaustion can progress to heatstroke (Knochel 1974). Even with prompt medical care, 15% of heatstroke cases are fatal (Kilbourne 1997). Heat exhaustion can be caused by high ambient temperatures as well as by excessive endogenous heat generation due to, for example, fever or physical exertion. It is characterized by dilatation of the peripheral vessels and a drop in circulating blood volume (hypovolemia). Heat prostration is almost always survived, making acute morphological findings rare. The functional changes are attributable mainly to the state of the victim‘s hemodynamics. 12.1.2.5 Sunstroke (Insolation) So-called sunstroke is heatstroke caused by prolonged exposure of the uncovered head to the sun. It is apparently triggered by a 1.5°C to 2.5°C increase in brain temperature (Koslowski and Krause 1970). The brain is within the head, which comprises 9% of the body surface area, and is subjected to selective heating and cooling. Brain temperature is affected by local cooling (e.g., nasal ventilation) and heating (e.g., the helmeted head) factors (Cabanac 1993). Symptoms in sunstroke develop suddenly on exposure without prodrome and include headache, visual disturbances, nausea, delirium, confusion, and coma. Like heat prostration, sunstroke is usually survived; persistence of symptoms is an indication of brain edema. In cases resulting in death, which are virtually indistinguishable clinically from

heatstroke, the morphological picture is dominated by edema and congestion. 12.1.2.6 Heatstroke Clinical Features. Heatstroke is characterized by high body temperature (core temperature: >41.1°C), red, hot, dry skin, and no sweating; rapid pulse, headache, dizziness, nausea, confusion, disorientation, delirium, and coma. The clinical picture of heatstroke must be regarded as extremely life threatening, ending in death in about 50% of cases (Shibolet et al. 1967; Sherman et al. 1989; Hiss et al. 1994). Pathogenesis. The true pathogenetic process remains

unknown (Brengelmann 2002) in spite of recent experimental data (Eshel and Safar 2002). Heatstroke is caused by a failure of the diencephalic temperature regulation centers. Heat exhaustion also results from dehydration combined with salt deficiency. Only a few experimental studies have dealt specifically with heatstroke. Sharma and Westman (2000) could show that the effects of heat can disrupt the blood−brain barrier, leading to cerebral edema which, combined with secondary ischemic changes, can lead to cerebral functional disturbances. According to these authors, there is a simultaneous upregulation of GFAP and vimentin in astrocytes as well as an increased expression of heat shock proteins, nitric oxide synthase, and heme oxygenase. Neuropathology. The morphology of heatstroke is characterized by hemodynamically induced injury (shock and blood−brain barrier disturbances with plasma and cellular extravasation − see Jacob 1955; Sohal et al. 1968). There is a conspicuous preponderance of neuronal loss in the cerebellar cortex (Shibolet et al. 1967). Petechial hemorrhages (Lahl 1974) and purpura (Schwab 1925), sometimes in the form of hemorrhagic encephalitis (Büchner 1962), are seen; neuronal swelling has been described in a few cases (Schwab 1925). But the signal neuropathologic finding is the brain edema described by several authors (Sharma and Westman 2000; Krous et al. 2001) and explained by a heat-induced disturbance of the blood−brain barrier (Sharma and Westman 2000). Other postmortem findings vary and depend on the duration of survival and hyperthermic exposure (Hiss et al. 1994) and include petechiae, pulmonary edema, visceral cellular degeneration and necrosis as well as disseminated intravascular coagulation (DIC) (Di Maio and Di Maio 2001). Heatstroke results in a wide variety of neurological complications, which are secondary to cerebellar, basal ganglia, anterior horn cell, and peripheral nerve involvement (Kalita and Misra 2001). In a review comprising 29 patients from 13 published re-

CHAPTER 12: Special Physical Trauma

ports, a cerebellar syndrome was the most common (12 patients). The pancerebellar syndrome following heatstroke is attributed to a direct thermal effect on the cerebellum resulting in degeneration of Purkinje cells (Yaqub 1987). Computed tomography and magnetic resonance imaging (MRI) studies have also revealed cerebellar atrophy and white matter involvement (Mehta and Baker 1970). However, in various cases, the cerebellar atrophy was noted on MRI after 10 weeks, being progressive for 1 year (Albukrek et al. 1997), or appeared 1 year later and became more marked at 2 years (Biary et al. 1995).

12.1.3 Trauma by Fire and Burns 12.1.3.1 Incidence Death from fire that results directly or indirectly from the effects of flames and/or heat on the brain is extremely rare. In most cases, acute death is primarily caused by shock or inhalation of poisonous fumes, especially of carbon monoxide, before the brain can be affected by flames or heat. A delayed death, on the other hand, is caused by protein loss, edema, renal failure, and/or secondary infection. The mortality rate from burns depends in large part on three factors: the age of the victim, the severity and extent of the burns, and the intensity and composition of the fumes. Mortality can be depicted by scatter diagrams showing survivors and fatalities plotted against age and the percentage of full-thickness burn. Elderly victims may die of chronic organic diseases in combination with burns, e.g., from stroke. If the victim suffers only burning of the skin of the head, which comprises 9% of the body surface, the aforementioned correlation between age and percentage of full thickness burn would indicate that such an injury is compatible with survival almost regardless of age, provided other aggravating factors are excluded. 12.1.3.2 Clinical Features As mentioned above, injury and acute death result primarily from asphyxia or inhalation of poisonous fumes rather than from the effect of flames on the brain. The relationship between the duration of exposure to noxious gases or oxygen depletion and their effects was summed up by Davies (1991, Table 14.2). The fumes, especially carbon monoxide (CO-intoxication, see pp. 347 ff), induce coma. In most cases, the intoxication itself proves fatal or the coma-induced immobility leads to death from

the flames and heat. If more than 40% of hemoglobin (carboxyhemoglobin level) is bound to CO, the victim may fall into a coma and if more than 60% is bound, the victim will die. In survivors, the heat as well as inhaled poisons can cause inhalation injury of the upper respiratory tract and lungs, with loss of surfactant-associated proteins and injury of type II pneumocytes. A shock phase develops if the victim survives the primary injury of heat, fire, fumes, and inhalation injury. The severity of shock symptoms depends on the extent of skin burned, not the depth of burning. The factors underlying the grave circulatory and metabolic disorders as a result of burn injury are gradually being identified. Distant effects of thermal injury of the skin include intravascular hemolysis, vascular permeability, acute lung injury, renal failure, and impaired liver function. Both primary fume-induced CNS intoxication and indirect sequelae such as hypoxia due to inhalation injury or shock can lead to changes in the brain. 12.1.3.3 Neuropathology In cases of acute death as a consequence of CO intoxication, signs of CO poisoning predominate, with macroscopically evident bright red coloration in formalin-fixed brain sections (Fig. 17.3). Postmortem alterations, such as coagulation of the brain surface or of the entire brain, are also visible (Fig. 12.1c, d), especially if the cranium has lost all of its soft tissue or has burst from the heat (Fig. 12.1a, b). The brain may be shrunken, although the structures of the gray and white matter can still be differentiated. The brain is partially or wholly dehydrated (Dotzauer and Jacob 1952; Klein 1975) and coagulated. These changes, like the accumulation of blood in the epidural space (burn hematoma − Fig. 12.1e, f), occur postmortem (see below). The almost invariably demonstrable high carboxyhemoglobin levels of >50% indicate that the victim had already died of CO poisoning before heat affected the brain (Gerling et al. 2000; Oehmichen 2000a). The morphological differentiation between intravital and postmortem injuries may be difficult as demonstrated in Fig. 12.2. Similarly, proof of epidural and subdural accumulation of blood as well as the demonstration of herniation, of cortical hemorrhages in the frontal base of the brain and the pons give evidence of a vital mechanism, while burn hematoma and brain surface coagulation are postmortem alterations. If burns are survived, secondary phenomena will result from the fire-induced burn wounds and/or the wound healing process. Survival depends on the severity of the burns, i.e., on the extent of skin surface

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Fig. 12.1a−f. Postmortem alterations as a result of fire and burning on scalp, skull and brain. a, b Loss of hairs, cutis, and soft tissue, i.e., loss of total the scalp, as well as fracture and loss of parts

of the external table of the skull; c, d coagulation of the brain surface (arrowheads) e, f accumulation of blood in the epidural space = burn hematoma

CHAPTER 12: Special Physical Trauma

Fig. 12.2a−e. Differentiation between intravital and postmortal alterations. a Postmortem (extradural) burn hematoma; b intravital “subdural” hemorrhage; c intravital white matter and cortical

hemorrhages (circles); d intravital herniation (arrows); e intravital pontine hemorrhage (circles)

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and soft tissue destruction, and on the severity of the CO-induced brain damage. Clinically, burn victims who survive only briefly (early death) develop a clouding of consciousness, often lapsing into coma. The morphological picture is characterized by hyperemia and edema secondary to the altered hemodynamics and toxic vessel damage (Hagedorn et al. 1975). The simultaneous increase in the permeability of the blood−brain barrier to plasma proteins causes inflammation with intravascular thromboses and sometimes also gives rise to intravascular fibrin bodies secondary to shock (Hagedorn et al. 1975). Perivascular spongiform disintegration of myelin, perivascular aggregation of lipid-containing and hemosiderin-containing macrophages, cerebral hemorrhages, nerve cell shrinkage, pallor and astroglial swelling and proliferation have all been described (Jacob 1955). Delayed death from burn injuries is caused mainly by infections of burned skin areas and airways. Extravascular water retention increases throughout the body (including the brain) secondary to a pathologic increase in the permeability of vessel walls and enhanced loss of plasma proteins. The result is both generalized edema and brain edema, which may be potentiated by systemic hypoxia. Common delayed complications of burn injury include CNS infection with sepsis (15% of cases), secondary changes (septic arterial occlusion or DIC), which induce infarction (18% of cases), and intracerebral hemorrhage (Winkelmann and Galloway 1992). In cases with long survival times, the clinical picture is dominated by the ischemic injury. Internal hydrocephalus has the clinical features of an encephalopathy, which is seen mainly in children. The Problem of Vitality. In cases of acute death, it

must always be determined whether the victim was already dead or still alive at the time of the fire. This question can usually be answered at autopsy by demonstration of soot in the airways and elevated CO-Hb levels in the blood. In some cases, signs of vital processes may be lacking, an indication that death did not result from the fire. The neuropathologist must then help to establish the exact cause of death and find signs of whether, for example, the fire was intentionally set to conceal a prior homicide (e.g., by strangulation, asphyxia, MBI, etc.). Two frequent morphological findings are of importance in this respect: 1. Skull fractures and/or skull destruction (Fig. 12.1a, b): biomechanical analysis of the type of fracture can help to establish whether the dome of the skull burst as the result of a heat-induced increase in intracranial gas pressure (bursting fractures) or has broken as a consequence of a blow (bending fractures).

2. Epidural hematoma (Fig. 12.1e, f): a so-called burn hematoma must be differentiated from primary mechanically caused hemorrhage. If there are no signs of external mechanical violence to the head, and no secondary (vital) effects such as shifting of the brain, brain edema, or cell reactivity, then primary mechanically induced hematoma can be ruled out. There are, however, difficulties in the interpretation of findings in cases in which blow and fire injure the head at the same time or at only very brief consecutive intervals. In cases of burn hematomas the head has usually already undergone skeletonization, with incineration of the overlying soft tissues as well as heat-induced deformation of the inner table of the skull. Local thermal changes in the brain are caused almost exclusively by electrically induced burn injuries. The effects of heat can cause considerable destruction of the scalp and skull at the point of contact, which is typical of electrical burns. Heat-induced local tissue necrosis is also seen in the underlying dura mater and brain tissue, especially in high voltage industrial accidents or as induced by lightning.

12.2 Electrical Trauma 12.2.1 Incidence Deaths from electric violence are usually accidental, although occasionally they are associated with suicide or homicide. In the USA, about 1,000 deaths from electrical shock are reported annually (Lee 1997), another 100,000 injuries from electrical shock are survived (Mellen et al. 1992). In 1967, global rates of fatal electrical accidents per 100,000 inhabitants ranged from 0.13 in Northern Ireland to 0.76 in Italy (Wyzga and Lindroos 1999).

12.2.2 Clinical Features The symptoms are determined by the type and the quantity of electrical current, its path through the body as well as its density, frequency, and duration. Even relatively weak intensity can cause acute symptoms such as paresthesias, muscular spasms and muscular pain, numbness of the limbs, somnolence, convulsions, and loss of consciousness (Panse 1955; Posner 1973; IEC 1987, 1994). The latter symptoms in particular, as well as persistent headache, nausea, and

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vomiting, may be associated with cerebral edema and increased intracranial pressure. If the current passing through the heart is strong enough, asystole-induced ventricular fibrillation will occur, resulting in respiratory arrest. Delayed effects of electrical shock include phantom sensations in limbs amputated due to electrical injury, spinal atrophy and spastic spinal paralysis, as well as seizures, which sometimes occur at intervals and usually disappear again (Levine et al. 1975; Petty and Parkin 1986). Long-term cognitive and emotional deficits, apparently the result of posttraumatic stress disorder (Kelley et al. 1999), are also described, as well as total or partial loss of memory, sometimes in the form of retrograde amnesia.

12.2.3 Pathogenesis Electrical violence can cause thermal injuries (cf. “Hyperthermia”) that must be distinguished from electrical shock-induced functional injuries. Thermal injuries from electrical shock can range in severity from local necrosis to complete carbonization. The degree of functional injury depends on the extent of the electrolyte shift at the molecular level (IEC 1987, 1994; Chen et al. 1999; Tsong and Su 1999). Exposure of cells in suspension to direct intense electrical pulses has been shown to damage cell membranes and the supramolecular organization of cells and cause denaturation of macromolecules, producing injuries and tears much like those seen in victims of electrical violence (Tsong and Su 1999). The severity of the injury depends on the source of voltage and the type of electrical current [direct current (DC), alternating current (AC), impulse current (IC)], on the type and medium of conduction (broad surface contact, point contact, spark gap in air, water, etc.), on the anatomic location of the contact site, and on the current path through the body (handhand, right hand-left foot, etc.). The severity also depends on quantitative factors such as the touch voltage, skin impedance, internal body impedance, and the resulting effective intensity of the current (root-mean-square value), duration of current flow, current density, frequency (IEC 1994, 1987) and − of course − on the victim‘s primary state of health (cf. Barnes et al. 1996). Tensions as low as 25 V can be dangerous (Jaffe 1928), and tensions of 46 V can be lethal (Stevenson 1942) if the total body impedance and the contact resistances are very small and if the heart lies in the current path. The brain appears to be relatively resistant to long-term functional disturbances and morphological changes secondary to electrical shock, as evidenced for example by the lack of secondary injuries following electroconvulsive therapy for depressive disorders (stimulus load: 25−50 mC, stimulus

frequency: 30−70 Hz, impulse duration: 0.5−2.0 ms, stimulus duration: 0.5−8 s) (cf. Abrams 1992; Devanand et al. 1994; Folkerts 1995, 2000). The effect on the systems of transmitters as well as the ion shift in the nervous system disturb conduction, impulse formation, and stimulus transport and may cause permeability changes in the vessels due to angiospasm (American Psychiatric Association 2001). Secondary mechanical and toxic injury may also occur, but will not be dealt with here in detail.

12.2.4 Neuropathology Venous hyperemia is observed, sometimes accompanied by hemorrhage in the third ventricle of the brain, the floor of the fourth ventricle, and in the cerebral cortex at the border between the gray and white matter; the hemorrhaging is sometimes massive (Somogyi and Tedeschi 1977; Stanley and Suss 1985). The hemorrhages are caused by angiospasm and by an electric shock-induced rise in blood pressure (Koeppen 1953). Demyelination, fragmentation of axons, degeneration of neurons, and perivascular necrosis are caused by hypoxia (Stevenson 1942) and have been described in persons temporarily surviving an execution in the electric chair (Hassin 1933; Silversides 1964). Cerebral venous thrombi have been described in a few cases (Patel and Lo 1993; Sure and Kleihues 1997). A delayed disease caused by electrical shock is electrotraumatic spinal atrophy (Farrell and Starr 1968; Levine et al. 1975; Panse 1975; Petty and Parkin 1986), which can occur weeks or months after the traumatic event. This is especially common after hand-to-hand contacts, which cause lesions between the fifth and seventh cervical segments (mainly softening with myelin degeneration, slight hemorrhaging, and cavitating lesions) (Alexander 1938). Spastic spinal paralysis with atrophy of the posterior white column and lateral white column has also been described (Koeppen and Panse 1955; Panse 1955; Osypka 1963), in each case with attendant demyelination. A few cases of internal hydrocephalus have been reported (Bach 1950). Recent intense study has failed to explain cases of delayed psychopathological reactions resembling post-traumatic stress syndrome without morphological equivalents (Pliskin et al. 1998, 1999; Kelley et al. 1999). Peripheral nerve injuries are associated with severe burning of adjacent tissues, overextension of the limbs, muscle rupture, and fracture-dislocation of bones and joints, all of which can be caused by electroshock therapy of psychotic patients. Myelin degeneration and axon cylinder injury may result from impaired blood flow (Alexander 1938).

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Eickhorn et al. (1988) studied the effect on the isolated frog nerve of high voltage condenser discharges with a field strength of up to 1,000 V/cm applied for 0.24−8 ms. They noted impaired propagation of action potentials, including a transient total block of conduction. Such conduction disturbances usually disappear within minutes. Electric shock-induced injury of peripheral nerves is often manifested morphologically − in the form of axonal injury and demyelination − only after a long latency period.

12.2.5 Electric Shock Devices The use of electric shock devices has increased in recent decades. Their effect depends largely on the type and magnitude of the electric current they deliver to the body (Osypka 1963). The individual pulses of its high-frequent oscillating impulse current can attain peak values of several amperes with durations of less than a tenth or even a hundredth of 1 ms. Weak devices can deliver impulse energies of several mJ, powerful devices of up to about 1 J. The effective current strengths (root-mean-square current) range from 10 to 100 mA with impulse repetition rates of 10−30 Hz. For the more powerful devices with an impulse repetition rate of 10 Hz or more a shock duration of only a few seconds is sufficient to block the whole motor nervous system completely. The electric current spreads throughout the whole body, following the routes of least resistance such as blood vessels, lymph channels, tissue fluid, muscle, and nerve paths (Robinson et al. 1990). The resulting block of the motor nervous system is due to the intervals between the applied impulses being shorter than the refractory period of the muscle fibers following contraction (~100 ms), but longer than the interval for the relative recovery of the nerve cells after stimulation (~5 ms).

12.2.6 Electromagnetic Radiation In recent years, a number of authors have hypothesized that the electromagnetic radiation of mobile phones (cellular phones) can induce brain tumors (Rothman et al. 1996; Maier et al. 2000). Cellular phones transmit and receive electromagnetic radiation at frequencies of about 1,000 MHz, just above the ultrahigh frequencies of television transmissions and just below the microwave portion of the electromagnetic spectrum. Recent studies were able to allay most of these fears (Inskip et al. 2001; Utteridge et al. 2002).

12.3 Lightning Trauma 12.3.1 Incidence Lightning can strike humans under a variety of circ*mstances and is certainly life threatening, but not always fatal (only 20−30% of victims die) (König and Pedal 1983; Blount 1990; Mackerras 1992). In the United States, the National Oceanic and Atmospheric Administration evaluated the years 1959−1994 (Curran et al. 1997): lightning was responsible for more than 3,000 deaths and nearly 10,000 casualties. Injury and death are due to the effects of electric, thermal, and mechanical violence. Cardiac arrest is the principal cause of death from lightning strikes, but for survivors the most devastating complications are neurologic. Lightning injuries differ significantly from other high voltage electrical injuries because of the high current flow, but extremely short duration of the lightning bolt. Also, mechanical injury from the blast effects of lightning is unlike injury due to common human-generated currents. This includes fractures of the skeleton and the skull (Skan 1949).

12.3.2 Clinical Features Slight clinical symptoms are intact consciousness and reversible neurological deficits with a distribution pattern that cannot be explained based on anatomical structures. Coma can last up to several days and “secondary changes,” especially hypoxia, dominate the clinical picture and may lead to death. If the victim survives, there is the potential for disturbances of cardiac function and peripheral neurovascular complications. Successful resuscitation is common, even among victims with conventional signs of brain death (Lifschultz et al. 1993). According to the review of Cherington (2003; see also Cherington et al. 1992; Muehlberger et al. 2001) we have to differentiate four groups of neurologic complications, which vary from transient benign symptoms to permanent disabilities: 1. Immediate and transient symptoms, i.e., brief loss of consciousness, amnesia, confusion, headache, paresthesia, and weakness. 2. Immediate and prolonged or permanent symptoms, i.e., patients will have structural lesions, for example post-hypoxic/ischemic encephalopathy, intracranial hemorrhages, cerebral infarction or cerebellar syndromes. 3. Possible delayed neurologic syndromes, i.e., motor neuron disease and movement disorders which

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have followed lightning strikes by days, months or years. 4. Lightning-linked secondary injury from falls or blast. Burn-induced necrosis (punctate burns) is usually visible at the sites of entry and exit; only a few cases of lightning injury without burns have been reported (Wetli 1996). Death is apparently caused by a very powerful and rapidly increasing magnetic field in the immediate vicinity of the lightning bolt, which produces brief high voltage currents in the human body. If this happens in the vulnerable period of atrial conduction, it can trigger asystole and produce ventricular fibrillation (Cherington et al. 1998).

12.3.3 Neuropathology A lightning strike to the head causes local burns on the epidermis and subcutaneous connective tissue; it can also produce subarachnoid or even parenchymal cerebral hemorrhages (Andrews et al. 1992; Lifschultz et al. 1993; Wetli 1996). Hypoxia-related changes are also observed. A few reported cases have found hemorrhagic foci beneath the point of lightning strike, with tearing of the white matter of the brain thought to be a direct result of the electrical violence itself. Moreover, some authors attribute basal ganglionic hemorrhage (Andrews et al. 1992; Wetli 1996) as well as skull fracture (Morgan et al. 1958) directly to the lightning stroke with the obvious difficulty of differentiating fracture due to a fall. Lightning has induced fractures in a recumbent, sleeping individual (Skan 1949) and an epidural hemorrhage was described in one case (Morgan et al. 1958). But even fatal lightning injury with severe blasting mechanical injuries and skull fractures leaves the brain intact (Skan 1949).

12.4 Irradiation Trauma Ionizing radiation has become an increasingly important therapeutic tool in medicine. Widely accepted radiation standards have been developed for the protection of patients and clinicians; their implementation has resulted in a dramatic decline in the number of injuries due to manmade sources of radiation (X-ray, nuclear pharmaceutical agents, therapeutic radiation apparatus). The genetically relevant annual dose from medical and dental sources is about 1 mGy (radiation dose 1 Gy=1 J radiation energy per kg body mass).

12.4.1 Pathogenesis The effect of X-ray irradiation to the adult CNS is dose-dependent (Zeman 1963, 1964): ▬ 100 Gy: whole body irradiation causes immediate death. ▬ 70 Gy: local irradiation causes acute necrosis of white and gray matter. ▬ 50−70 Gy: local irradiation causes partial tissue necrosis. ▬ 20−25 Gy: local irradiation causes delayed white matter necrosis because X-rays induce the functional impairment of oligodendrocytes (Blakemore 1978) and endothelial cells (Blakemore and Palmer 1982). According to Schmitt (1983) local application of ionizing radiation to the CNS can have the following effects: ▬ Inactivation of enzymes, generation of free radicals, and/or loss of binding sites on molecules and atoms. ▬ Oxygen free radical damage to DNA (Ravanat et al. 2001) with loss of the ability of DNA to replicate; it can damage chromosomes and cause mutations and abnormal cell growth. ▬ Reduction of brain metabolism, especially cerebral consumption of glucose (d‘Avella et al. 1994). ▬ Death of cells (Chan et al. 1999) and organelles ensuing from destruction of the organic molecular structure. ▬ Changes in the cerebral arterial wall due to the sensitivity of endothelial cells and smooth muscle cells to irradiation (O‘Connor and Mayberg 2000). ▬ The developing brain is highly sensitive to X-ray and CNS malformation may be the consequence of X-ray exposure during pregnancy (Sundaresan et al. 1978). Cell division is blocked by X-rays by three different pathways: 1. Mitosis is irreversibly interrupted and the cell will die by apoptosis when exposed during the G1- and S-phases (Ferrer et al. 1993). 2. X-irradiation induces the production of free radicals and inhibits DNA repair enzymes with the result of cell death by necrotic mechanisms. 3. There are indications of an increase in apoptosis as well as active caspase-3 expression following exposure to radiation (Marshman et al. 2001). These investigations are based on irradiated intestine, but may reflect basic principles of radiation injury.

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Fig. 12.3a−d. Radiation injury. a−c Vasculopathy marked by hyalinization of the vascular wall without fibrinoid necrosis; d ex-

Radiation energy acts through radiolysis of water molecules to trigger the release of OH and H radicals, which react with amino acids and SH groups on the membranes of cells and organelles. With regard to complex molecules, radiation can alter the activity of enzymes, giving rise to an accumulation of enzymedependent substances. The decisive pathogenetic factor is damage to the capacity of cells to reproduce, resulting in acute radiation necrosis and mutations. The most vulnerable cells are those capable of mitosis within the CNS, i.e., glial cells as well as endothelial and muscle cells of vessel walls (Hopewell 1979; Schmitt 1983). The histopathological findings in vessels following irradiation include thickening of vessel walls, thrombosis, luminal occlusion, and occasional telangiectasis (O‘Connor and Mayberg 2000). In the early stages, the combined effect of irradiation on vascular walls and parenchyma causes damage to the oligodendroglia and the remaining parenchyma; in later stages, injury of vascular walls predominates (O‘Connor and Mayberg 2000). The injury is thought to be mediated by cytokines and growth factors (Kureshi et al. 1994) released from hematopoietic and local cells.

treme gliosis; (a, b trichrome stain; c van Gieson stain; d Holzer stain; magnification a, c, d ×300; b ×1,000)

12.4.2 Types of CNS Reaction The following types of CNS reaction may be distinguished: ▬ Acute reaction: impaired blood−brain barrier leads to edema (Rubin et al. 1994). ▬ Early delayed reaction: within weeks, myelin and axons are involved as well as the vessels; hyalinization without fibrinoid necrosis (Jellinger and Sturm 1971). ▬ Late delayed reaction: coagulative tissue necrosis with hyaline and fibrinoid alterations of the vessels, activation of astrocytes and microglia (Chiang et al. 1993).

12.4.3 Acute Radiation Injury 12.4.3.1 Radiation Necrosis In the early phase after irradiation, the first morphological change is vasculopathy (Fig. 12.3a−c), which may be an initiating factor and the cause for subsequent changes. Reactive astrocytes appear later at

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both the target site and in the surrounding regions (Yang et al. 2000). A gliosis develops in addition to tissue necrosis (Fig. 12.3d). Calcium deposits, inflammatory reactions, vessel proliferation, and hyalinization are seen. There is infiltration by T-cells (CD4, CD8) and a proliferation of macrophages; TNF-α and interleukin-6 (Kureshi et al. 1994) are released. Irradiation causes increased vulnerability of myelin sheaths comparable to that found in radiation injury to nerve cells. The nerve cells exhibit central chromatolysis. The irradiation-induced blood−brain barrier disturbance causes a brain edema, which largely accounts for the morphological sequelae. Oligodendroglia are more sensitive to radiation than astroglia, which in turn are more sensitive than nerve cells (Blakemore and Palmer 1982). 12.4.3.2 Transitory Radiation Myelopathy The spinal cord is generally more sensitive than the cerebrum to ionizing radiation (Scholz et al. 1959), apparently due to comparatively less bone absorption (Fröscher 1976). The cervical area is especially susceptible to irradiation of tumors in the oral cavity, pharynx, and larynx. The doses tolerated in these areas range 10−60 Gy (Fröscher 1976). Today, normal therapeutic regimens (55−60 Gy, administered over 5−6 weeks) entail a 1−5% risk of radiation-induced myelopathy. The vulnerability of the oligodendroglia leads in most cases to demyelination, mainly in the posterior white columns, which may induce clinical symptoms, i.e., an unpleasant electric shock-like paresthesia upon tilting of the head. 12.4.3.3 Radiation Neuropathy Delayed X-ray injury to the peripheral nerves (Fritzemeier 1985) is rare. It is mainly seen in the area of the plexus brachialis in patients undergoing, for example, irradiation of breast carcinoma; in most cases it develops 3−4 years after the irradiation. Fibrosis dominates the microscopic picture.

12.4.4 Early Delayed Reaction Development of clinical symptoms occurring weeks after X-irradiation is termed “delayed reaction.” Neuropathologically this type of injury is characterized by distinct hyalinization of the vascular wall without fibrinoid necrosis (Fig. 12.3b) as well as by demyelination and axonal injury (Jellinger and Sturm 1971).

12.4.5 Chronic Radiation Injury The latent period between irradiation and onset of clinical symptoms ranges from a few months to 13 years (an average of 16.4 months) (Fröscher 1976). An acute onset is distinguished from a chronic-progressive form. 12.4.5.1 Acute Onset Symptoms of delayed injury of both the brain and, especially, the spinal cord can appear in an acute form after a period of latency. Partial or complete paraplegia and other central nervous symptoms can develop within days. Morphologically, vascular changes do not predominate, but, in contrast, injury of the glia, with demyelination and white matter necrosis are most apparent. During the latency period, the mitotically damaged glial cells develop functional disturbances after several mitotic cycles similar to those seen in endothelial cells (Hopewell 1979), e.g., edema. 12.4.5.2 Chronic Progressive Injury Clinically, the picture in spinal cord damage is predominated by marked sensory disturbances (54%); less common are combined motor and sensory deficits (21%) and paresis (22%) (Fröscher 1976). In this prognostically unfavorable form of delayed injury, the vascular component predominates, with simultaneous partial or complete demyelination and slight spongiform structural disintegration.

12.5 Special Mechanical Trauma 12.5.1 Ultrasound Injury Occurrence. Accidental exposure to high-dose ultrasound is rare. At frequencies of up to 10 MHz ultrasound is used today in diagnostic sonography. All available evidence suggests that, when properly applied, this modality is safe (Lele 1972). Ultrasound has a mechanical effect on tissue dependent upon its the wavelength or frequency, intensity, and the duration of exposure (Lizzi and Ostromogilsky 1987). Accidental application of highenergy ultrasound has been known to cause thermal injuries. Exposure of brain tissue to 2.7 MHz for 2 s

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at an intensity of 600 W/cm2 can induce brain tissue temperatures as high as 55°C in anaesthetized animals (Davies 1997). Focused high-energy ultrasound applied to the CNS can cause local coagulation necrosis (Fig. 12.4), the extent of which is a function of dosage (Heyck and Höpker 1952; Nelson et al. 1959; Aström et al. 1961), as well as chromosomal damage (Brown and Gordon 1967). Focused high-dose ultrasound has been used to destroy lesions such as Schwannomas and to destroy brain tissue in patients with Parkinson‘s disease (Myers et al. 1959; Nelson et al. 1959; Ballantine and Bell 1960); as the increase in heat at interfaces between different types of tissue can result in cell destruction.

12.5.2 Pressure Injury Natural changes in pressure conditions, e.g., decreased atmospheric pressure at high altitudes, most frequently associated with changes in oxygen tension caused by a reduction in O2 partial pressure (pO2) or under water, with increased environmental and increased partial pressure of the breathing gases acting on divers can injure the human organism. Pressure equipment allowing a controlled release of gases and liquids is frequently used today in various therapeutic and non-therapeutic situations. The use of such equipment can be hazardous and produce injuries with a unique pathophysiology and morphology (for review see Török 1997). 12.5.2.1 Barotrauma Pathophysiology. As the environmental pressure to

which humans are exposed decreases or increases, so does the pressure in the intrathoracic space. The

adult lung has a total lung volume of about 6 l. At increasing depths, associated for example with apnoe diving, external pressure increases on the diver‘s chest and the volume of air in the lungs decreases as the pressure increases. Air breathed at 50 m under the water surface is at a pressure of about 600 kPa (6 atm) and is 6 times denser than at the surface. The gases dissolve in the body fluids and tissues in direct proportion to their environmental pressure. The increase in pressure against the atmospheric conditions at the water surface together with the added resistance of breathing apparatus increase the effort of breathing. The most hazardous period, however, is that of returning to the water surface, as the relative pressure−volume changes are greatest at this time and gas loses its solubility in liquid. When a diver ascends toward the surface, the environmental pressure decreases and gas will be released by the tissues. Furthermore gas in the air-filled body cavities expands according to Boyle‘s law. Lung damage is thus caused by over-distention and stretching rather than by any direct effect of increased pressure. Pulmonary barotrauma manifests itself in pneumothorax, interstitial emphysema, and air embolism, whereby a tearing of tissue may occur. Neuropathology. In instances of barotrauma, changes in brain tissue are characterized by those of systemic hypoxia and extreme edema. In cases of the additional influence of decompression sickness a combination of hypoxia, edema, and extravascular bubbles within the cerebral parenchyma and spinal cord can be observed in histological sections (see below). Obviously, the air bubbles do not cause a breakdown of the blood−brain barrier (Hjelde et al. 2002). The brain edemas may be the result of the hypoxic−ischemic process.

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Neuropathology. The morphological features of ex-

12.5.3 Toxicity of Hyperbaric Gases

posure to hyperbaric gases are characterized by the phenomenon of decompression sickness (see below) as well as by generalized hypoxic alterations.

Pathophysiology. Increases in external pressure lead

to nitrogen build-up and carbon dioxide retention. Increased arterial nitrogen partial pressures of more than 8 kPa lead to nitrogen narcosis. Hypercapnia also leads to an increase in the level of circulating catecholamines, which, in turn, alter tissue blood flow so that, under special circ*mstances, decompression sickness (and possibly hypothermia) becomes more likely (see below). Increased pO2 in diving (eubaric hyperoxemia) as well as the process of reperfusion (Aronowski et al. 1997) may be associated with tissue damage due to increased oxygen free radical production (oxygen intoxication, see Bacon et al. 1996). In contrast to this concept are recent experimental findings by Flynn and Auer (2002) showing that hyperoxia isolated to the reperfusion period reduces cortical necrosis. In diving, effects of O2 on the lungs and CNS are paramount, although a systemic fatigue syndrome has also been described (Sterk and Schrier 1985). At depths exceeding 100 m the diver experiences a state of rapture with euphoria, and impairment of thought processes and coordination caused by N2 intoxication (Strauss and Prockop 1973). However, significant impairment of safe diving due to N2 narcosis may be present from depths of 40 m. There is also a risk of oxygen intoxication − as described below − with seizures and loss of consciousness. CNS toxicity usually presents first at pO2 values of 300 kPa and above while the pulmonary effects predominate at pressures of 200 kPa or less. The CNS manifestation of oxygen poisoning is a grand mal seizure occurring with no predictable warning signs or symptoms. The phenomenon of oxygen toxicity of the brain has been systematically investigated by Donald, and susceptibility to it was found to vary markedly from day to day and between individuals (Donald 1947; see also Flynn and Auer 2002). Donald found that breathing pure oxygen at pressures as low as 190 kPa (1.9 atm, 9 m depth) while working in the water produced convulsions, but exposure to 176 kPa (1.7 atm) did not. Susceptibility to oxygen toxicity is increased by immersion and underwater activity. Hypercapnia also increases susceptibility to oxygen-toxic seizures, which are, therefore, most likely when dense gas is being inhaled under pressure and while a diver is working. The subject of CNS oxygen toxicity has been reviewed (Mayevsky 1984). The incidence of oxygen-toxic seizures associated with routine hyperbaric oxygen therapy was evaluated by Hampson and Atik (2003). Among 20,328 total patient treatments performed from 1992 to 2001, 6 patients experienced an oxygen-toxic seizure for an overall incidence of 1 in 3,388 treatments (0.03%).

12.5.4 Decompression Sickness (DCS) Synonyms for DCS are “Caisson” disease, or “the bends” (Bühlmann 1993; Oehmichen et al. 1994; van Laak 1999). 12.5.4.1 Incidence DCS occurs in professional divers engaged in tasks such as bridge building or construction of drilling platforms at sea, as well as in recreational divers. Two types of DCS are differentiated. Type I is characterized by pain in the joints and muscles and lymph node swelling. Its most common symptom is joint pain. Type II DCS is serious and life threatening. It most commonly includes peripheral nerve and/or CNS compromise; 90% of serious DCS injuries involve the CNS. Most cases of DCS can be successfully treated in a hyperbaric chamber. Permanent injury is uncommon and death extremely rare, usually resulting from drowning due to decompensation. 12.5.4.2 Pathophysiology The clinical findings result from a change in atmospheric pressure from above normal to normal. The hydrostatic pressure on the body increases proportionally to the water depth, producing a proportionally greater capacity for dissolution of inhaled gases, especially nitrogen, in blood and tissues, creating excess saturation. 12.5.4.3 Clinical Features A whole range of changes from bradycardia, muscle, and bone pain to shock, loss of consciousness, and paralysis of disseminated type are encountered (Petropoulos and Timiras 1974). If a diver surfaces too quickly (Hock et al. 1994), decompression results in the release of the excess gas into soft tissues, vessels, and parenchymatous tissue such as that of the brain. It forms embolic gas bubbles that cannot be released into the atmosphere, i.e., expired by the lungs. The number of bubbles is a function of the correlation between the water depth and the speed of ascent to the surface. Permanent neuropsychological changes such as memory disturbances and depression occur even

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Fig. 12.5a, b. Pressure injury. a Venous gas embolism; b gas bubbles and edema within the brain parenchyma as a result of reduced hydrostatic pressure seen after a diving accident caused

by a fast return to the water surface (a, b H&E; magnification ×100)

in professional divers who have never experienced clinical decompression sickness. The spinal cord is also damaged histologically in divers who have never had overt symptoms, showing Marchi-positive myelin degeneration in the white matter (Palmer 1990). The changes are probably the result of intravascular microbubbles insufficient to cause primary clinical symptoms. Recent investigations have found evidence of CNS lesions in amateur divers as well (Reul et al. 1995).

cannot be interpreted as a vital phenomenon, the only valid criterion of vitality is brain edema. In professional divers, the repeated release of gas bubbles has been shown to produce focal injury and scarring of the CNS (cortex, white matter, ependyma), the spinal cord being especially affected (Palmer 1990; Morild and Mørk 1994; Mørk et al. 1994; Tetzlaff et al. 1999). Chronic vascular disease can also develop (Palmer et al. 1992), with hyalinization of vessels walls, necrotic foci in gray matter, and perivascular vacuolization in white matter. The pathological process seems to be that of endothelial injury. Some authors assume that endothelial changes arise from intravascular gas bubble formation (Nossum et al. 1999).

12.5.4.4 Neuropathology The released gases can be demonstrated in tissues and intravascularly (Novomeský 1994). Gas bubble embolism (bubbles within the vessels − Fig. 12.5a) and local generation of gas bubbles within the tissue (Fig. 12.5b) are seen, together with disturbed microcirculation (Wolf et al. 1990), disseminated intravascular coagulation, lipid embolism, and fat embolism (Pedal 1994). The brain exhibits foci of spongiform structural disintegration as well as signs of a breakdown of the blood−brain barrier (Fig. 12.5b). A cohort study of multiple brain lesions in recreational divers showed that all victims had a patent foramen ovale (Knauth et al. 1997). It must be noted that demonstration of the release of gas bubbles in the corpse is not in itself proof of a vital process, and thus cannot be established as the cause of death. The same phenomenon also occurs when a body is recovered from great depths (Oehmichen and van Laak 1994). The demonstration of extravascular and intravascular bubbles in combination with brain edema and in the absence of putrefaction, however, is generally regarded as a marker of air embolism. Demonstration of thrombocytes on the surface of bubbles does not confirm the intra-vital release of the intravascular bubbles either (RitzTimme et al. 1998). Since the gas bubbles themselves

12.5.5 Gas Embolism 12.5.5.1 Pathophysiology and Clinical Features Gas embolism may be produced by bubbles forming in the circulatory system in DCS. Arterial gas embolism is the most dangerous manifestation of type II DCS. Gas emboli can also occur (for differential diagnosis − see Muth and Shank 2000) during diving as a result of barotrauma secondary to changes in gas volume within gas-filled body cavities during compression or, particularly, decompression. There are two categories of gas embolism, venous and arterial, which are distinguished by the mechanism of gas entry and the site at which the emboli ultimately lodge: the pulmonary tissue can be injured if gas flow is impeded (see above: Barotrauma). The resultant gas emboli can lodge in coronary, cerebral, and other systemic arteries and capillaries. In instances of venous gas embolism the gas is transported to the lungs through the pulmonary ar-

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teries, causing interference with gas exchange and cardiac arrhythmias. Rapid entry of large volumes of gas produces pulmonary hypertension by gas bubble obstruction of the pulmonary circulation, resulting in a strain on the right ventricle and eventually cardiac failure. Arterial gas embolism is caused by entry of gas into the pulmonary veins or directly into the arteries of the systemic circulation. As mentioned above, gas may enter the arteries as a result of over-expansion of the lungs by decompression. Besides this type of gas embolism we have to consider iatrogenic cerebral arterial gas embolism (Peirce 1980), which may occur as a complication of central venous catheterization (Heckman et al. 2000), of cardiac operations (Ziser et al. 1999), and other invasive medical procedures (Murphy et al. 1985). Even if only small amounts of gas enter the arterial system, the flow of gas bubbles into functional end arteries occludes these vessels. Obstruction of the nutrient arteries of the brain is especially serious and may be fatal. Bubbles obstructing end-arterial flow cause distal ischemia and development of cytotoxic edema. The surface of the bubble generates a foreign-body response of the cellular and humoral immune mechanisms. The bubble also causes mechanical irritation of the arterial endothelium. Both processes result in vasogenic edema and impairment of perfusion in the adjacent vicinity, so the neuronal injury extends beyond the area of obstruction (Moon 1996; Muth and Shank 2000). The clinical features are dependent on the body region involved. Commonly it is characterized by cramps, headache, anxiety, extremity weakness, syncope, impaired vision, speech disturbances, confusion, dizziness, somnolence, focal neurological deficit, and unresponsiveness, paresis, paraesthesia, hemi- or tetraplegia or generalized seizures (Tovar et al. 1995). Benson et al. (2003) describe the clinical features of 19 patients with iatrogenic cerebral arterial gas embolism after hyperbaric O2 therapy. Immediately after treatment, 5 patients completely resolved all signs and symptoms, 11 had improvements, 1 had no change, and 2 were not assessable. Within 2 months of treatment, 3 additional patients completely resolved and 6 had further improvements. Patients with a venous source all experienced pulmonary signs or symptoms, with 8 of 9 chest radiographs demonstrating pulmonary edema. Patients with an arterial source had no pulmonary edema. 12.5.5.2 Neuropathology The morphologic features of gas embolism are distinguished by ischemic encephalomalacia, ischemic neuronal cell changes (tigrolysis), air-induced vacuolization of vessels and capillaries, as well as micro-

circulatory disturbances. Small areas of hemorrhage are often found in the cortex, the meninges and − less often − in the medulla oblongata (Janssen 1967); these hemorrhages lie in the topographical vicinity of the vessels occluded by the air embolism (Rössle 1948). There is a pericapillary and periarterial accumulation of air or air-plasma mixtures in the perivascular spaces [emphysema around the perivascular sheaths according to Rössle (1944)].

12.5.6 High-Altitude Illness 12.5.6.1 Incidence At roughly 5,500 m (18,000 feet), the atmospheric pressure is half that at sea level, which means that the partial pressure of all atmospheric gases, including O2, is half that at sea level (Arias-Stella 1977; Auer and Sutherland 2002). Altitude sickness can occur at even lower levels, at elevations beginning at 2,500−3,000 m (Sonna 2002), and is characterized by impaired cell function due to reduced oxygen supply (Austin and Sleigh 1995). As reported by Maggiorini et al. (1990), 34% of trekkers develop “acute mountain sickness” when ascending to 3650 m. Klocke et al. (1998) reported that altitude sickness is experienced by approximately 20% of tourists to Colorado ski resorts at an altitude of about 3000 m. A review of the frequency of clinical relevant symptoms in adults on ascent to moderately high altitudes (3600−4600 m) has been presented by Sonna (2002). The symptoms are due to the decrease in pO2 that occurs with the reduction in atmospheric pressure accompanying altitude increase. 12.5.6.2 Clinical Features and Pathophysiology Three manifestations of acute altitude sickness are differentiated (Houston 1976; Hackett and Roach 2001; Sonna 2002; Basnyat and Murdoch 2003): ▬ Acute mountain sickness (AMS) is characterized by headache accompanied by symptoms such as fatigue, dyspnea, gastrointestinal symptoms (anorexia, nausea, even vomiting), dizziness, or sleep disturbance. ▬ High-altitude pulmonary edema (HAPE) is characterized by a non-cardiogenic form of pulmonary infiltrates of patchy distribution as demonstrable on chest radiograph. ▬ High-altitude cerebral edema (HACE) is a potentially fatal encephalopathy, and is a dreaded condition that begins with headache, ataxia, altered mental status (confusion) and may progress to

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stupor, coma, and death from cerebral herniation. As supposed by Roach and Hackett (2001), the symptoms of AMS and HACE are largely neurological in origin and HACE is considered the end-stage of severe AMS, which has recently been identified as a vasogenic edema (Hackett et al. 1998) opening the possibility of blood−brain barrier permeability playing a role in the etiology of AMS. The likely source of the edema is fluid leakage from new microvessels stimulated by hypobaric hypoxia (Mironov et al. 1994), in the face of a hyperdynamic cerebral circulation. Chronic acclimatization does, however, double the tissue pO2 (Dunn et al. 2000). The incidence and severity of the various altitude illnesses are dependent upon factors such as the rapidity of ascent, the final altitude achieved, residence at a low altitude prior to ascent, sleeping at altitude, and a host of individual physiological variables (for further information, see Chap. 13, pp. 277 f). Untreated, HAPE has a reported mortality of 44%, compared with 6% among those who receive supplementary oxygen, descend to a lower altitude, or both; evidence of pulmonary edema has been demonstrated in 40 (15%) of 262 people climbing up to 4559 m (Sonna 2002). The clinical picture of HAPE is dominated by dyspnea, generalized malaise, and a cough that is at first dry and later produces foamy pink sputum. The patient feels anxious, the lips and limbs are cyanotic, and disseminated rales can be heard throughout the lungs. Hemodynamically, there is a marked increase in arterial pressure in the pulmonary circulation with normal left atrial pressure. The risk of HAPE obviously is not confined to a small group of genetically susceptible people but likely exists for most climbers if the rate of ascent and degree of physical effort is great enough, especially if the lung size is normal or low (Cremona et al. 2002). 12.5.6.3 Pathology and Neuropathology Patho-anatomically there is an alveolar edema of the lung, accompanied by hyaline membranes and fresh thrombosis in pulmonary capillaries and arterioles, and marked capillary congestion and dilatation of lung arterioles. Cerebral involvement is clinically characterized by impaired concentration and memory, visual disturbances, apathy, and slurring of speech. The neuropathological findings are non-specific. As mentioned elsewhere (pp. 277 f), high altitude mountaineering as an example of hypoxia, i.e., reduction of pO2 in external atmosphere, commonly does not lead to permanent alterations of mental

functioning or permanent morphological alterations of the CNS. In delayed death due to HACE associated with severe pulmonary injury, the neuropathology is characterized by extensive (vasogenic) edema of the brain.

Bibliography Cooper GJ, Dudley HAE, Gann DS, Little RA, Maynard RL (1997) Scientific foundations of trauma. Butterworth-Heinemann, Oxford IEC (1987) International Electrotechnical Commission. Effects of current passing through the human body. Part 2: Special aspects. Technical Report IEC 479−2, 2nd edn IEC (1994) International Electrotechnical Commission. Effects of current on human beings and livestock. Part 1: General aspects. Technical Report IEC 479−1, 3rd edn Schmitt HP (1983) Die physikalischen Schäden des ZNS und seiner Hüllen. In: Doerr W, Seifert G (eds) Pathologie des Nervensystems II. Springer, Berlin Heidelberg New York, pp 657−902 Tedeschi CG, Eckert WG, Tedeschi LG (eds) (1977) Forensic Medicine: study in trauma und environmental hazards. Saunders, Philadelphia, Pa.

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Rothman KJ, Chou CK, Morgan R et al (1996) Assessment of cellular telephone and other radio frequency exposure for epidemiologic research. Epidemiology 7:291−298 Rowell LB (1986) Human circulation. Regulation during physical stress. Oxford University Press, New York Rowell LB, Brengelmann GL, Blackmon JR, Murray JA (1970) Redistribution of blood flow during sustained high skin temperature in resting man. J Appl Physiol 28:415−420 Rubin P, Gash DH, Hansen JT et al (1994) Disruption of the bloodbrain barrier as the primary effect of CNS irradiation. Radiother Oncol 31:51−60 Safar P (1997) Resuscitation of the ischemic brain. In: Albin MS (ed) Textbook of neuroanesthesia: with neurosurgical and neuroscience perspectives. McGraw-Hill, New York, pp 557−593 Safar PJ, Kochanek PM (2002) Therapeutic hypothermia after cardiac arrest. N Engl J Med 346:612−613 Schaller MD, Fischer AP, Perret CH (1990) Hyperkalemia: a prognostic factor during acute severe hypothermia. J Am Med Assoc 264:1842−1845 Schindelmeiser J, Bergmann M, Lehmenkühler A, Kersting V (1987) Tracer permeability of rat cortical blood vessels during regional hypothermia. Acta Neuropathol 73:349−365 Schmitt HP (1983) Die physikalischen Schäden des ZNS und seiner Hüllen. In: Doerr W, Seifert G (eds) Pathologie des Nervensystems II. Entwicklungsstörungen. Chemische und physikalische Krankheitsursachen. Springer, Berlin Heidelberg New York, pp 720−734 Scholz W, Ducho EG, Breit A (1959) Experimentelle Röntgenschäden am Rückenmark des erwachsenen Kaninchens. Psychiatr Neurol Jpn 61:417−441 Schwab W (1925) Über Hirnveränderungen bei Sonnenstich. Schweiz Med Wochenschr 6:33−38 sem*nza JC, Rubin CH, Falter KH et al (1996) Heat-related deaths during the July 1995 heat wave in Chicago. New Engl J Med 335:84−90 Sharma HS, Westman J (2000) Pathophysiology of hyperthermic brain injury. Current concepts, molecular mechanisms and pharmacological strategies. In: Oehmichen M (ed) Hyperthermie, Brand und Kohlenmonoxid. Research in legal medicine, vol 21, Schmidt-Römhild, Lübeck, pp 79−120 Sherman R, Copes R, Stewart RK et al (1989) Occupational death due to heat stroke: report of two cases. Can Med Assoc J 140:1057−1058 Shibolet S, Coll R, Gilat T, Sohar E (1967) Heat stroke: its clinical picture and mechanism in 36 cases. Q J Med 36:525−548 Silversides J (1964) The neurological sequelae of electrical injury. Can Med Assoc J 91:195−204 Skan DA (1949) Death from lightning-stroke with multiple injuries. Br Med J 1:666 Sohal RS, Sun SC, Colcolough HL, Burch GE (1968) Heat stroke. An electron microscopic study of endothelial cell damage and disseminated vascular coagulation. Arch Intern Med 122:43−47 Somogyi E, Tedeschi CG (1977) Injury by electrical force. In: Tedeschi CG, Eckert WG, Tedescji LG (eds) Forensic medicine: a study in trauma and environmental hazards. Saunders, Philadelphia, Pa., pp 645−676

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Sonna LA (2002) Pulmonary oedema at moderately high altitudes. Lancet 359:276−277 Soukup J, Zauner A, Doppenberg EMR et al (2002) The importance of brain temperature in patients after severe head injury: relationship to intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and outcome. J Neurotrauma 5:559−571 Stanley LD, Suss RA (1985) Intracerebral hematoma secondary to lightning stroke: case report and review of the literature. Neurosurgery 16:686−688 Stepahn H (1991) Zerebrale Effekte der hypothermen extrakorporalen Zirkulation. Springer, Berlin Heidelberg New York Sterk W, Schrier LM (1985) Effects of intermittent exposure to hyperoxia in operational diving. In: Örnhagen H (ed) Diving and hyperbaric medicine. In: Proceeding of the XI Annual Meeting of the Undersea Biomedical Society, National Defense Research Institute, Stockholm, p 123 Sternau LL, Globus MY-T, Dietrich WD et al (1992) Ischemia induced neurotransmitter release: effects of mild intraischemic hyperthermia. In: Globus MY-T, Dietrich WD (eds) The role of neurotransmitters in brain injury. Plenum, New York, pp 33−38 Stevenson LD (1942) Electrical injuries to the nervous system. Arch Neurol Psychiatry 48:179−186 Strauss RH, Prockop LD (1973) Decompression sickness among scuba divers. J Am Med Assoc 223:637−640 Sundaresan N, Guiterrez FA, Larsen MB (1978) Radiation myelopathy in children. Ann Neurol 4:47−50 Sure U, Kleihues P (1997) Intracerebral venous thrombosis and hematoma secondary to high-voltage brain injury. J Trauma 42:1161−1164 Tetzlaff K, Friege L, Hutzelmann A et al (1999) Magnetic resonance signal abnormalities and neuropsychological deficits in elderly compressed-air divers. Eur Neurol 42:194−199 Thompson HJ, Tkacs NC, Saatman KE et al (2003) Hyperthermia following traumatic brain injury: a critical evaluation. Neurobiol Dis 12:163−173 Tipton M, Eglin C, Genser M, Golden F (1999) Immersion deaths and deterioration in swimming performance in cold water. Lancet 354:626−629 Török Z (1997) Barotrauma. In: Cooper GJ, Dudley HAF, Gann DS, Little RA, Maynard RL (eds) Scientific foundations of trauma. Heinemann-Butterworth, London, pp 300−313 Tovar EA, Del Campo C, Borsari A et al (1995) Postoperative management of cerebral air embolism: gas physiology for surgeons. Ann Thorac Surg 60:1138−1142 Tsong TY, Su Z-D (1999) Biological effects of electric shock and heat denaturation and oxidation of molecules, membranes, and cellular functions. Ann NY Acad Sci 888:211−232

Tytell M, Barbe MF, Brown IR (1993) Stress (heat shock) protein accumulation in the central nervous system. Adv Neurol 59:293−303 Utteridge TD, Gebski V, Finnie JW et al (2002) Long-term exposure of E micro-Pim1 transgenic mice to 898.MHz microwaves does not increase lymphoma incidence. Radiat Res 158:357−364 Vassallo SU, Delaney KA (1998) Thermoregulatory principles. In: Goldfrank LR (ed) Goldfrank‘s toxicologic emergencies, 6th edn. Appleton and Lange, Stamford, Conn., pp 295−307 Visser M, Gallagher D (1998). Age-related change in body water and hydration in old age. In: Arnaud MJ (ed) Hydration throughout life. Libbey, Paris, pp 117–25 Wadlington WB, Tucker AL Jr, Fly F, Greene HL (1976) Heat stroke in infancy. Am J Dis Child 130:1250−1251 Walpoth BH (2004) Accidental hypothermia: diagnosis and treatment. In: Oehmichen (ed) Hypothermia. Clinical, pathom*orphological and forensic features. Research in legal medicine, vol 31. Schmidt-Römhild, Lübeck, pp 263–272 Walpoth BH, Walopoth-Aslan BN, Mattle HP et al (1997) Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporeal blood warming. N Engl J Med 337:1500−1505 Wetli CV (1996) Keraunopathology. An analysis of 45 fatalities. Am J Forensic Med Pathol 17:89−98 Weyman AE, Greenbaum DM, Grace WJ (1974) Accidental hyperthermia in an alcoholic population. Am J Med 56:13−21 Winkelmann MD, Galloway PG (1992) Central nervous system complications of thermal burns: a postmortem study of 139 patients. Medicine (Baltimore) 71:271−283 Wolf HK, Moon RE, Mitchell PR, Burger PC (1990) Barotrauma and air embolism in hyperbaric oxygen therapy. Am J Forensic Med Pathol 11:149−153 Wyzga RE, Lindroos W (1999) Health implications of global electrification. In: Chen C-T, Lee RC, Shih J-X, Zhong M-H (eds) Occupational electrical injury: an international symposium. Ann N Y Acad Sci 888:1−7 Yang T, Wu S-L, Liang J-C, Rao Z-R, Ju G (2000) Time-dependent astroglial changes after gamma knife radiosurgery in the rat forebrain. Neurosurgery 47:407−416 Yaqub BA (1987) Neurologic manifestations of the heat stroke at the Mecca pilgrimage. Neurology 37:1004−1005 Zeman W (1963) Disturbance of nucleic acid metabolism preceding delayed radionecrosis of nervous tissue. Proc Natl Acad Sci 50:626−637 Zeman W (1964) Strahlenschäden des Nervensystems. Arch Psychiat Nervenkrh 206:185−209 Ziser A, Adir Y, Lavon H et al (1999) Hyberbaric oxygen therapy for massive arterial air embolism during cardiac operations. J Thorac Cardiovasc Surg 117:818−821

PART III

Ischemia and Asphyxia

Chapter 13 Hypoxia, Ischemia (Hypoglycemia)

273

Chapter 14 Forensic Types of Ischemia and Asphyxia Chapter 15 Permanent Global Ischemia

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Hypoxia, Ischemia(Hypoglycemia)

13.1

Basic Principles 273

13.2

Metabolic Disturbances 275

13.3 13.3.1 13.3.2 13.3.3 13.3.4 13.3.5

Hypoxia 276 High-Altitude Mountaineering Respiratory Disease 278 Anemic Hypoxia 279 Histotoxic Hypoxia 279 Neuropathology 279

13.4 13.4.1 13.4.2 13.4.2.1 13.4.2.2 13.4.2.3 13.4.2.4 13.4.2.5 13.4.2.6 13.4.2.7

Ischemia 280 Pathophysiology 280 Neuropathology 281 Cerebral Cortex 281 Hippocampus 282 Basal Ganglia 284 Brain Stem 284 Cerebellum 285 Spinal Cord 285 White Matter Lesions (Leukoencephalopathy)

13.5 13.5.1

13.1 Basic Principles

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286

Hypoglycemia 286 Neuropathology 287 Bibliography 288 References

288

The following three chapters describe the neuropathological features caused by a reduction of energy supply to the total brain. The morphological phenomena of a metabolic disturbance of single cells and tissue compartments are described in Chap. 4, while the focal disturbances of cerebral blood flow are discussed in Chap. 28. The present chapter describes the global oxygen depletion of the brain and its functional and neuropathological consequences.

The terms “ischemia” and “asphyxia” describe the failure of cells to receive or to utilize oxygen (DiMaio and DiMaio 2001). While ischemia is characterized by an isolated interruption of the oxygen supply, the physiologic definition of asphyxia is associated with carbon dioxide retention, i.e., asphyxia will be associated with acidosis, hypotension, and occasionally hypoglycemia and coagulopathy (Taensch et al. 1991). Each of these additional insults − isolated − may have a deleterious effect on the brain. The combined effect will become the worst case and the neuropathological features will be characterized by mixed morphological alterations. Hypoxia is characterized by a reduction of the partial pressure of oxygen (pO2) below the normal level, i.e., a lack of molecular oxygen. The target organ of ischemia, hypoxia, and asphyxia will be the brain and within the brain the target cells are the neurons which exhibit a different susceptibility to oxygen deficiency. The susceptibility is dependent on the vasculature and the vulnerability of different types of neurons. According to Fig. 13.1 ischemic necrosis of neurons will first be seen in the cleft between the first and second frontal gyrus (watershed zone), in the globus pallidus, in the cornu Ammonis and the cerebellar cortex (Purkinje cells). In the cornu Ammonis (Fig. 13.2) the very early ischemic alterations are seen in the CA1 sector and in the CA4 sector, the hilus. Neurons of the CA1 sector and hilar region of the hippocampus and layers III, V, and VI of the cerebral cortex have been deemed “selectively vulnerable” because of their inordinate sensitivity to transient ischemia. Furthermore, biochemical studies of protein synthesis during reperfusion (Kleihues and Hossmann 1973; Grosse Ophoff et al. 1984; Bodsch et al. 1985; DeGracia et al. 1996) support the contention that its suppression is an early event (Araki et al. 1990) and its restoration may play an important role in neuronal survival after transient ischemia (Thilmann et al. 1986). It is now generally accepted that this suppression of protein synthesis is a result of inhibition of translation initiation (Krause and Tiffany 1993).

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Fig. 13.1. Topography of ischemia-susceptible areas in the cerebrum and cerebellum (blue areas)

Though the target organ of ischemia will be the cerebrum, including the cerebellum and brain stem, we should also point out the sequelae for the spinal cord (see p. 285). On the basis of alterations of reflex activity and morphology, van Harreveld and Schadé (1962) examined the results of asphyxia on spinal cord neurons of cats for periods of 30−50 min, which allowed them to recover within 2 weeks. If the asphyxiation lasted for 30 min reflexes were present, whereas prolongation to 50 min led to a loss of tone and reflex. After asphyxiation for 28 min, marked neuronal destruction − with the total loss of nerve cells in the central cord around the spinal canal − had taken place. Because the brain stores neither glucose nor oxygen, severely reduced or completely blocked cerebral blood flow can lead, within minutes, to irreversible cerebral damage and long-lasting neurological disorders, including memory, motor, and sensory losses. The outcome of the ischemic impact is mainly determined by post-ischemic factors (Hossmann et al. 1973), but it cannot be excluded that differences in the metabolic response of the brain during ischemia are of equal importance (Hossmann et al. 1993). In particular, the roles of the residual level of energy-rich substrates, of the degree of acidosis developing during ischemia as well as the factors responsible for the speed of removal of metabolic waste products from the brain to the blood have not been established. The normal cerebral blood flow (CBF) to the brain in adults is 50-60 ml/100 g per min which is

autonomously regulated, dependent on the consumption (for neonates, see p. 436). In the hypoxic state CBF will increase while the O2 utilization will become normal. The ischemic damage of the CNS involves a cascade of molecular and biochemical mechanisms which are discussed in part in Chap. 4 (pp. 56 ff) and which are reviewed in detail by Siesjö (1992), Pulsinelli (1992), and Choi (1998). Focal cerebral ischemia is associated with the total loss of neurons in the region supplied by the arteries, while transient global ischemia yields progressive damage to selectively vulnerable populations of neurons (Smith et al. 1984). As described by Berger and Garnier (1999), oxidative phosphorylation in the brain comes to a standstill owing to the acute reduction in oxygen supply. The Na+/K+ pump of the cell membrane has no more energy to maintain the ionic gradients. In the absence of a membrane potential, large amounts of calcium ions flow through voltage-dependent channels, down an extreme extra/intracellular concentration gradient, into the cell. Current research suggests that the excessive increase in levels of intracellular calcium, so-called calcium overload, leads to cell damage through the activation of proteases, lipases, and endonucleases. During ischemia, as well as the influx of calcium ions into the cells via voltage-dependent calcium channels, yet more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an excitatory neurotransmitter, is released from presynaptic vesicles during ischemia following anoxic cell depolarization. The acute lack of cellular energy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesis returns to pre-ischemic levels in nonvulnerable regions of the brain, while in more vulnerable areas it remains inhibited. The inhibition of protein syntheses, therefore, appears to be an early indicator of subsequent neuronal death. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the post-ischemic release of oxygen radicals, synthesis of nitric oxide (NO), inflammatory reactions, and an imbalance between the excitatory and inhibitory neurotransmitter systems. A selection of diseases associated with asphyxia are summed up in Table 13.1. The pathophysiological principles and the neuropathological findings are put together in Table 13.2. The pathophysiologic and neuropathologic principles and sequelae in infants and children are discussed elswhere (see Chap. 22, pp. 435 ff). We can distinguish different stages of severity of neuronal loss, which depend on the duration of global brain ischemia, brain temperature, the effects of drugs, etc. According to the morphological sequelae the following neuropathological features are known:

CHAPTER 13: Hypoxia, Ischemia (Hypoglycemia) Fig. 13.2. The anatomical structure of the cornu ammonis demonstrating the different segments

Dentatus Gyrus Stratum radiatum et lacunosum-moleculare

Table 13.1. Diseases associated with asphyxia

Pathophysiology

Causes

Reduction of pO2 in external atmosphere

High-altitude illness

Blockage of the external respiratory openings

Plastic bag, pillow on the mouth/nose

Stenosis/blockage of internal respiratory passages

Asthma bronchiale, aspiration, bolus, external compression of the trachea

Restriction of respiratory movements of the chest

Thorax compression, curare-like drugs, brain-induced respiratory arrest

Lung diseases

Pneumonia, pulmonary edema, adult respiratory distress syndrome

Reduction of cerebral blood flow

Cardiac arrest, arterial hypotension

Reduction of O2-blood transport capacity

Severe anemia, carbon monoxide

Blockage of the cellular O2 metabolism

HCN − intoxication

1. Selective neuronal necrosis associated with disseminated damage of single neurons. 2. Transient ischemia with a distinct focal loss of neurons in vulnerable regions of the brain and their glial and/or cystic replacement. 3. Transient ischemia with pan-necrosis including neurons, glial cells and neuropil of cortical and subcortical brain structures. 4. Persistent vegetative state or apallic syndrome associated with a total loss of cortical neurons and an intact − but reduced − cerebral blood flow. 5. Respirator brain (brain death) characterized by a global brain necrosis as a result of the complete cessation of the intracranial circulation.

To start with, we will evaluate the morphological sequelae of isolated types of metabolic failures within the CNS, i.e., hypoxia, ischemia as well as hypoglycemia; in Chap. 14 we sum up forensic types of asphyxia; in Chap. 15 we describe the characteristics of the global permanent ischemia (or respirator brain).

13.2 Metabolic Disturbances The energy metabolism of the brain depends on the oxygen and glucose supply. The absence or reduction of one of these energetic elements in blood unquestioningly leads to a breakdown of the metabolism in

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Table 13.2. Pathophysiological principles and neuropathological findings in different types of asphyxia

Term

Meaning

Disease/trauma

Neuropathology

Anemic hypoxia

Low blood hemoglobin

Hemorrhagic shock

No alterations

Hypoxemia

Low oxygen in blood

Asthma, pneumonia

Reversible synaptic alterations

Hypobaric hypoxia

Hypoxemia + pO2 athmosphere ↓

High-altitude disease

Transient ischemia

pO2 tissue ↓

Cardiac arrhythmia, heat stroke

Stagnant hypoxia

pO2 tissue ↓

Cardiac arrest

Ischemia

No oxygen in blood

Respiratory arrest

brain cells. As interruptions of the oxygen and glucose supplies lead to the same metabolic disaster, we will describe both their pathologies together in one chapter, though − from the systematic aspect − hypoglycemia is additionally discussed elsewhere (Chap. 30, pp. 607 ff). The normal oxygen consumption of the brain will be 46 ml O2/min associated with a cerebral blood flow of about 750 ml/min. Under normal conditions of hemoglobin concentration, cerebral blood perfusion and pH, the critical O2 saturation will be 68% and the critical arterial concentration 13.8 ml O2/ 100 ml blood while the critical pO2 will be 36 mmHg (Nunn 1993). Under anoxic conditions consciousness will be lost within 15−20 s and irreversible brain lesions will be seen within 2−3 min. Ischemia is associated with a marked elevation in extracellular glutamate concentrations. Hypoxia, without ischemia, is not associated with extracellular glutamate and there are no neuropathologic changes even with pO2 maintained below 20 mmHg for 20 min in rats (Pearigen et al. 1996). Thus, although the terms hypoxia and ischemia are often used interchangeably, the pathophysiologic sequelae are different (see Pappert et al. 1999; Simon 1999). The commonly used term “hypoxic brain damage” has been loosely applied to a number of conditions ranging from global ischemia (cardiac arrest), to high-altitude hypoxia, air embolism after deep sea diving (“the bends”), and even epileptic brain damage or hypoglycemic brain damage. It is one of the purposes of this chapter to clearly distinguish and define each of these influencing entities, their basic pathophysiology, and their potential for producing brain damage. We will outline the regional brain predilections for each of these insults to produce neuronal necrosis, and only then will combinations of these insults be dealt with, as seen in the various forms of asphyxial deaths in the field of forensic pathology. The aim is to provide clarity with respect

Ischemia (neuronal necrosis)

Edema

to mechanism and pathogenesis, which in turn will provide a practical guide for the medicolegal neuropathologist in assessing brains that have been referred for delineation of the degree and nature of a cerebral insult which could comprise ischemia, hypoxia, hypoglycemia, in reference to carbon monoxide poisoning, epilepsy or any of these insults with superimposed hypoxia. These subthemes will partly be dealt with in the present chapter as they are representative of different types of metabolic disturbance. Additional information will be given elsewhere [Chaps. 4 (pp. 56 ff, Cell and Tissue Reactions), 27 (pp. 529 ff, Seizures and Epilepsy), 28 (pp. 542 ff, Vascular Diseases), 30 (pp. 606 ff, Nutritional and Metabolic Insults)]. To start, it would be useful to add some more definitions. Table 13.3 implicitly presents the terms “hypoxia” and “ischemia” and also outlines the changes in cerebral energy state, blood flow, extracellular amino acids, lactate, and the potential of the insult to produce neuronal necrosis. We define ischemia as a reduction of cerebral blood flow, and hypoxemia as a reduction in blood oxygen concentration. We note that arterial hypoxemia immediately leads to an increase in cerebral blood flow (CBF) whereas ischemia, by definition, decreases CBF. Thus, at least one aspect of these two conditions (hypoxia and ischemia) contrasts sharply. We will consider these episodes singly and combine them only later when the pathophysiology of each condition has been given consideration. The various traditional forms of hypoxia will be discussed first.

13.3 Hypoxia Hypoxia is often divided into decreased supply of oxygen to the body, decreased transport of oxygen (anemia), and decreased utilization of oxygen (histotoxic

CHAPTER 13: Hypoxia, Ischemia (Hypoglycemia)

Table 13.3. The different pathophysiologic principles of hypoxia and ischemia. (CMRgl cerebral metabolic rate of glucose, 0 no consistent change, ± change in both directions reported at different time points, locations in relation to ischemia, + increased, − decreased) Ischemia

Hypoglycemia

Epilepsy

Histotoxic Hypoxia (CN−, S−2)

CO poisoning

++

+

+

+

+

CMRgl

±

Lactate

Hypoxemia

Anemia

Energy failure

Cerebral blood flow

++

pH of brain

Extracellular excitatory amino acid overflow

Glutamate

Aspartate

Clinical coma

+

+

+

+

+

+

Brain necrosis (without hypotension)

++++

++

+

+

hypoxia). In its pure form hypoxia differs from ischemia (or stagnant anoxia) in as far as the blood flow is maintained: consequently the oxygen-deficient tissue continues to be supplied with glucose and blood substances other than oxygen, while waste products, such as lactic acid, continue to be removed. Classic reports have suggested that this type of hypoxia preferentially leads to damage of the neostriatum, globus pallidus, and subthalamic nuclei (Scholz 1953). We will first consider exemplary arterial hypoxemia due to a decrease in the fractional inspiratory concentration of oxygen (fiO2) due to hypobaria, a decrease in the general atmospheric pressure without decreasing the actual percentage of oxygen in the air, and then respiratory obstructive disease. Both have equivalent pathophysiologic results in that the effective oxygen concentration in the alveoli is reduced.

13.3.1 High-Altitude Mountaineering (See also Chap. 12, pp. 263 f) We note that halving the atmospheric pressure from sea level to 5,486 m (=18,000 ft) of altitude is tantamount to cutting the

normobaric fiO2 in half − from normal air which has 20.96% O2 to 10.48% O2. Both produce a pO2 in the inspired air of 80 mmHg or approximately half the normal of 160 mmHg. It is now clear that, in an intact animal, pure hypoxia without a decrease in CBF does not by itself cause necrotizing brain damage. The first arena to reveal this startling fact is human high-altitude mountaineering. Beginning with Edmund Hillary and Tenzing Norgay, who ascended to the 8,848 m summit of Mt. Everest in 1953, individuals have returned from the summit with no neurologic deficit (Jason et al. 1989). Articles claiming to find differences from normal in high-altitude mountaineers (Townes et al. 1984) show “abnormalities” in only 2 out of 22 tests, no higher than by chance. Examination of the raw data of the tests that are claimed to show group differences (finger tapping and short-term recall) in fact reveals that there are no significant differences between the controls and the individuals exposed to high altitude. Further attesting to the high level of mental functioning of individuals who have climbed Mt. Everest is the authorship of good literature by individuals who have summited, arguing against high-altitude brain

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Fig. 13.3. Oxygen cascade demonstrating a step-wise decrease in pO2 levels and flattening of the cascade

damage. The book detailing the 1996 Mt. Everest disaster (Krakauer 1997) which killed nine people, entitled Into Thin Air, was written by Jon Krakauer after summiting Mt. Everest, and won a literary award. Such high-level literary composition, performed after protracted periods spent at high altitude, has for years been a tacit element against the very existence of brain damage due to high-altitude mountaineering. One individual who was left for dead and nearly succumbed at high altitude and without oxygen was a pathologist, Dr. S. Beck Weathers. The title of his book, Left for Dead (Weathers 2000) gives another personal account of the Everest tragedy of 1996 and was written after exposure to prolonged hypoxia at altitude including a 16-h coma. Noteworthy with respect to the question of hypoxic brain damage is the fact that Dr. Weathers has returned (after initial hesitation fostered by the widespread belief in hypoxic brain damage) to practicing pathology. Like literary composition, practicing pathology is a highlevel mental function. Dr. Weathers (personal communication) relates that an initial skepticism, critical self-examination, and examination by colleagues of high-level mental functioning eventually gave way over months to the realization that no alteration in pathologic diagnostic competency had taken place according to professional colleagues. The sum of the entire high-altitude mountaineering experience attests to the ability of altitude to cause freezing necrosis of limbs, but there is no good evidence of permanent alteration of mental functioning. There is in fact ample evidence of intact preservation of brain function long after return from high altitude. While on the mountain, several mechanisms account for long-term tolerance to high-altitude hypoxia. These maintain the pO2 even at altitude, and include an increase in the circulating hemoglobin and a proliferation of brain capillaries. The adaptive increase in brain capillary density at altitude reduces

the average distance from capillary to brain mitochondrion, and maintains the tissue pO2 in the range of 16−18 mmHg, similar to that at low altitudes. Unfortunately, one consequence of this new capillarization of the brain at altitude may be high-altitude cerebral edema (HACE), since new capillaries are more leaky. This, combined with the hyperdynamic cerebral circulation caused by the increased CBF at altitude, leads to a propensity to HACE. We note that HACE occurs independently of the level of previous mountaineering expertise, being related to physiological, not psychological, factors. Unless there is a rapid return to lower altitude to reverse the hyperdynamic cerebral circulation leaking through the brain capillaries, death due to progressive and fatal cerebral edema rapidly results.

13.3.2 Respiratory Disease Anesthetists have long known that short periods of hypoxia, unaccompanied by significant hypotension or cardiac arrest, are innocuous. But additional documentation that hypoxia does not cause brain damage comes from the arena of bronchopulmonary and ventilatory diseases, including asthma, anaphylaxis, occlusive bronchitis and bronchiolitis, pneumonia, croup, and epiglottidis. One of the most amazing well-documented cases was that of a two-and-a-half-year-old boy, who had a respiratory arrest due to bronchitis. Rapid clinical action led to tracheotomy and removal of pus with forceps − pus which had formed virtual casts of the bronchi. Although the boy remained in a coma for 14−16 days, subsequent recovery was without neurologic impairment, including school performance (Sadove et al. 1961). Another paper on pure hypoxia (Gray and Horner 1970) presents a collection of profoundly hypoxic patients without vascular disease, with arterial pO2 levels under 20 mmHg and ranging to a low of 8 mmHg (with survival). The outcome of these patients showed that pure hypoxia, without global ischemia, causes no permanent brain damage. The venous pO2 corresponding to the lowest recorded arterial pO2 of 8 mmHg was 2 mmHg! Noticing that hypoxia could not cause brain damage, Rie and Bernad (1980) reported three neuropathologic autopsies of profoundly low arterial pO2 levels which all failed to show necrotizing brain damage. All patients died subsequently of other causes after having had 28−192 h of exposure to profoundly low arterial pO2 levels in the range of 24−38 mmHg that were commonly assumed to cause necrotizing brain damage. That such profound arterial hypoxemia is even survivable is made possible by a flattening of the staircase of the “oxygen cascade” (Fig. 13.3) where

CHAPTER 13: Hypoxia, Ischemia (Hypoglycemia)

there is a progressive, step-wise decrease in pO2 levels. In the case of respiratory obstructive disease, pulmonary venous pO2 levels are greatly reduced in the blood. The principle of flattening of the staircase of the oxygen cascade also applies to high-altitude mountaineering.

13.3.3 Anemic Hypoxia Anemia does not cause brain damage. The high white blood cell (WBC) counts associated with various forms of leukemia give rise to leukostasis with WBC counts >300,000 per mm3 (Freireich et al. 1960), with accompanying ischemia and hemorrhage as seen in leukemia. But anemia itself is not the mechanism of brain damage in leukemia. Anemia actually has a protective effect in cerebral ischemia (Kannel et al. 1972; Tohgi et al. 1978) via the increase in CBF, and the hyperdynamic circulation generally that accompanies anemia, upholding the cerebral metabolic rate for O2 (Borgström et al. 1975). In contrast to pure anemia or isolated hypoxic events the combination of anemia or hypoxia and hypotension will lead to brain damage as described below in the case of CO poisoning (pp. 347 ff) as well as in Chap. 14 (pp. 294 ff). As might be suspected, polycythemia and high hematocrit are a risk factor for cerebral ischemia (Pearson and Wetherley-Mein 1978), even in normal individuals, with stroke risk in the general population increasing with the hemoglobin (Tohgi et al. 1978). When ischemia occurs, the consequences are worse in the face of high hemoglobin. There thus seems to be a linear association between the hemoglobin level and ischemic risk. There also seems to be a negative correlation between ischemic brain damage when it occurs, and the hematocrit, spanning the low, medium and high range of hematocrit, although smoking and high blood pressure may be the underlying causes (Kannel et al. 1972). It is important to remember, however, that although the hemoglobin level influences ischemic brain damage, hypoxic brain damage due to anemia does not exist.

13.3.4 Histotoxic Hypoxia By this it is meant the inability of tissue to utilize oxygen. This may occur due to poisoning of the mitochondrial cytochromes, or it may be due to intrinsic mitochondrial disease as in the MERRF (mitochondrial encephalopathy with ragged red fibers) and MELAS (mitochondrial encephalopathy with lactic acidosis and stroke) syndromes. In such poisonings or in such diseases impairing mitochondrial function, inadequate energy production leads

to a stimulation of glycolysis. Lactate and proton production is increased, but without ischemia brain necrosis should not occur. “Non-vascular infarcts” and parenchymal gliosis have been noted, however, in mitochondrial disease (Ohno et al. 1997; Prayson and Wang 1998; Ohsh*ta et al. 2000; Oppenheim et al. 2000), Leigh‘s disease (Detre et al. 1991), and in the vulnerable brain tissue areas in Wernicke‘s encephalopathy (Hakim 1984, 1986), the likely mechanism being profound focal acidosis in brain tissue causing pan-necrosis (Kraig et al. 1987). We focus here, however, on the exogenous or environmental toxins azide, sulfide, and cyanide. Since azide (pp. 359 f) is no longer used as a cleaning or fumigating agent, the most common agents causing histotoxic hypoxia at present are cyanide and sulfide. Cyanide (pp. 351 f) is encountered as an agent used in accidental and intentional poisoning (MacMillan 1989), while sulfide (pp. 352) is most commonly seen in workers of the sour gas industry, where gas wells contain not only aliphatic and cyclic hydrocarbons but also hydrogen sulfide or H2S (Baldelli et al. 1993). Although cyanide is usually considered the ultimate histotoxic poison in discussions such as this, it is interesting to note that the sulfide anion has a potency to inhibit mitochondrial cytochrome respiration that exceeds even that of cyanide (Smith et al. 1977). Sour gas exposure is the most common occupational setting of histotoxic hypoxia, due to the sulfide anion in the blood, formed in an equilibrium between H2S, NaHS, and Na 2S. Unless the heart stops due to the cardiotoxic effects of sulfide (or cyanide), brain damage in the form of necrosis does not occur (Baldelli et al. 1993). The practical implications in histotoxic hypoxia for the patient are, similar to the situation in hypoxemia, that ventilation and maintenance of cardiac function are of paramount importance in order to obviate brain necrosis. These pure hypoxic insults can only generate brain necrosis through heart stoppage or hypotension (MacMillan 1989; Baldelli et al. 1993).

13.3.5 Neuropathology Recognition of the fact that hypoxia alone does not cause necrotizing brain damage is especially important in view of the fact that acute-onset hypoxia may cause prolonged coma. A pure hypoxic coma of this kind is caused by synaptic alterations, not neuronal cell body necrosis. Such a patient may be mistaken as being brain dead as they would be in the truly hopeless situation of ischemic decortication consequent to cortical necrosis in transient global ischemia. If there has been no ischemia, however, because cardiac function was preserved, patients with purely hypoxic coma invariably wake up after ~2 weeks. Hypoxia,

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while not causing cell body necrosis, clearly causes synaptic alterations. In this regard, it is important to clearly think about the relationship of the pathology to the clinical state: ischemia causes cell body necrosis of neurons (perikaryal necrosis, evident by pathologic examination), whereas hypoxia does not. Synaptic function is tested by clinical neurologic examination (whereas pathology examines cell bodies, not synapses) and synaptic function is profoundly deranged in hypoxic coma without cell body necrosis. The distinction between hypoxia and ischemia is thus of paramount importance in determining the prognosis of coma. If the heart has not stopped, and blood pressure has been well maintained, or if the heart has stopped for only a brief period, and ventilation has been adequate, then widespread pan-cortical necrosis and brain death is unlikely to have occurred. If such patients eventually die, autopsy will reveal no significant necrosis in the brain, whereas brain death will reveal the classical changes in neocortex and pituitary gland (Auer and Sutherland 2002).

13.4 Ischemia 13.4.1 Pathophysiology Ischemia can be divided into focal and global, transient and permanent. Permanent global ischemia constitutes brain death, and is dealt with in Chap. 15 (p. 319). Transient global ischemia constitutes the typical clinical situation of cardiac arrest, where a duration of 2−4 min is known to be critical in the development of irreversible necrotizing cerebral damage (Smith et al. 1984). Of course, the actual duration in any clinical situation will depend on the temperature (Busto et al. 1987), the blood glucose level (Voll and Auer 1988), and any accompanying epileptic activity (Voll and Auer 1991), in addition to the duration of cerebral ischemia. The extreme importance of the temperature is attested to by the fact that 40 min of immersion drowning can be survived without permanent neurologic sequelae if the temperature is very low (Siebke et al. 1975). Or − according to Walpoth (2004) − a 25-year-old man fell into a crevasse to a depth of 42 m where he became wedged in the ice. He was found to have a rectal temperature of 17.5°C and a total arrest time of nearly 4 h. He was immediately re-warmed by cardiopulmonary bypass and regained a sinus heart rate at a temperature of 29°C. After being discharged from the intensive care unit after 11 days he was transferred to a rehabilitation centre which led him to complete normalization of all his functions at late follow-up 5 years later.

Transient global ischemia renders the entire brain ischemic for a limited period of time and because the commonest cause of this entity is heart stoppage, it is virtually synonymous with “cardiac arrest encephalopathy.” It is to be delineated from the condition of the brain after extracorporal circulation, i.e., cardiopulmonary bypass (Nussmeier et al. 1986; Moody et al. 1990; Kol et al. 1993), and is to be distinguished even more clearly from the brain and spinal cord changes after nitrogen embolism following diving (“the bends”) (Palmer et al. 1981, 1987; Palmer 1990). It is important to remember that ischemia is centrally involved in the pathophysiology of these conditions, and is also part of the pathophysiology and morphology of MBI (Graham et al. 1978). Transient focal and permanent focal ischemia constitute a continuum: if the duration of transient focal ischemia is long enough, irreversible necrosis takes place and it becomes irrelevant whether reperfusion takes place at later times, since only dead tissue is perfused and the infarct maturation is completed (Persson et al. 1989). As in transient global ischemia, the duration of ischemia necessary to cause necrosis in transient focal ischemia is variable, depending again on the depth and duration of ischemia, as well as the other factors of temperature, glucose, and epileptiform activity mentioned above. It is clear, however, that transient focal ischemia has a much longer tolerable duration (at least half an hour, depending on temperature, glucose levels, etc.) before necrosis develops than the 2−4 min of transient global ischemia. The implication is that focal ischemic brain damage has a deleterious effect on other parts of the brain. As progressively more of the brain is rendered ischemic, the tolerable duration decreases. Despite the immediate event of ischemia, specific cellular signal transduction pathways in the CNS ultimately influence the extent of cellular injury (White et al. 2000). It is a cascade of mechanisms, rather than a single cellular pathway, which determines cellular survival during toxic insults. These include the pathways of free radical injury, the independent mechanisms of programmed cell death (Chan 2001; Graham and Chen 2001), the role of the complement cascade (D‘Ambrosio et al. 2001), and the downstream signal transduction pathways of endonuclease activation, intracellular pH, cysteine proteases, the cell cycle, and tyrosine phosphatase activity (Malese 2001). Moreover, we have to mention the term “penumbra” again (pp. 63 ff). Ischemic penumbra has been documented as severely hypoperfused, non-functional, but still viable brain tissue surrounding the irreversibly damaged ischemic core (Schaller and Graf 2004). This region is of interest as a potential area for the rescue of neurons from cell death and will provide evidence of the therapeutic window.

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Table 13.4. Cytopathological features of ischemic neuronal damage

Loss of Nissl bodies Basophilia Shrinking of the perikaryon and developing of triangular neurons, containing microvacuoles in the cytoplasm, swelling of dentrites aggregation of Ca2+ in the mitochondria Eosinophilia (Johansen et al. 1986) Acidophila (acid fuchsin − Auer et al. 1984a, b) Argentophilia (Yamamoto et al. 1986)

Early edema, i.e., blood−brain barrier disruption was found in 47 of 144 (33%) patients as demonstrated by MRI (Latour et al. 2004), having a median time from stroke onset to observation of 10.1 h. Reperfusion was found to be the most powerful independent predictor of early blood−brain barrier disruption which may lead to a hemorrhagic transformation and poor outcome in 22 of 47 patients.

13.4.2 Neuropathology The general neuropathological features are summarized in Table 13.4. Moreover, there are topographical differences that are described below. 13.4.2.1 Cerebral Cortex The usual picture of global ischemia is neuronal necrosis in the cerebral cortex, hippocampus, and cerebellar Purkinje cells (Mandel and Berry 1959). Exceptions will be discussed below. The cerebral cortex is the structure most highly sensitive to cardiac arrest, and at the gross level damage usually begins in the triple watershed zone, at the intersection of the territories of the anterior, middle, and posterior cerebral arteries (Fig. 13.1, 13.4a). The microscopic features of cortical ischemia show involvement generally of the middle cortical laminae. Although a specific laminar predilection has been described, most severe cortical damage involves the middle layers (layer III > V, VI). The cytologic features are those of acidophilic neuronal necrosis (Fig. 13.4b), initially consisting of eosinophilic transformation of neuronal cell cytoplasm and nucleus in H&E stains. These “pink neu-

Fig. 13.4a−c. Cortical ischemic lesions. a Ischemic lesions in the watershed zone between the 1st and 2nd frontal gyri (arrows); b distinct acidophilic alterations of cytoplasm and nucleus in H&E stain of neurons (arrows) (magnification ×300); c neuronal microvacuolar degeneration in Nissl stain as a very early indication of ischemic neuronal lesion (magnification ×1,000)

rons” (as opposed to pre-lethal “dark neurons”) are definitively known to be necrotic for two reasons: first, they disappear with uniform regularity from tissue sections in experiments studying differing survival times (Auer et al. 1985a; Lee 1989), and second they show cell membrane breaks and mitochondrial flocculent densities on electron microscopy (Auer et al. 1985b).

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dosis is implicated in the pathogenesis of pan-necrosis (Kraig et al. 1987) whereas excitatory amino acid release, neuronal cell surface receptors, and intrinsic neuronal properties are implicated in selective neuronal necrosis. The histologic features of selective neuronal necrosis and pan-necrosis are contrasted in Fig. 13.5. When both these alterations occur in the brain, these two entities are pathophysiologically as well as morphologically distinct. 13.4.2.2 Hippocampus

Fig. 13.5a−c. Pan-necrosis of the cortex. a, b Involvement of the middle cortical layers as seen on macroscopic sections as well as − after a longer survival time − c in histologic sections with a characteristic sparing of layer I of the cortex (H&E stain; magnification c ×50)

If the degree and/or duration of ischemia is severe enough, possibly with exacerbating factors, then pan-necrosis rather than selective neuronal necrosis will result (see p. 312). Especially high glucose levels in the blood are prone to produce cerebral pan-necrosis, the mechanism being enhanced by lactate and proton (H+) production. Pan-necrosis sweeps away the neuropil and glial cell nuclei, as well as neuronal cell bodies, and likely has a different pathogenesis from selective neuronal necrosis. The morphologic features distinguishing selective neuronal necrosis from pan-necrosis apply in every brain region. Aci-

The hippocampus is extremely sensitive to cardiac arrest, in general, slightly more than even the cerebral cortex, so that changes are often limited to the hippocampus in global ischemia in humans (DeJong et al. 1969; Zola-Morgan et al. 1986) or animals (Auer et al. 1989). It is important to remember, however, that sometimes the hippocampus can be selectively spared (Adams et al. 1966) in global ischemia. In animals, physiologically controlled experiments demonstrate that ischemic periods as short as 2 min are capable of causing hippocampal CA1 pyramidal cell neuronal necrosis (Smith et al. 1984). Like the cerebral cortex, the hippocampus in global ischemic damage can show asymmetric damage, probably due to asymmetries in the human vasculature. These include the size of the carotid arteries and, more importantly, asymmetries in the circle of Willis (Riggs and Rupp 1963; Stehbens 1963). Of all the brain regions, the hippocampus demonstrates within it a most heuristic selective vulnerability, and an order of vulnerability which is quite specific. Whereas some diseases, such as neurolipidoses, affect the CA3 pyramidal cells first, most diseases such as Alzheimer’s disease and ischemia first affect the smaller CA1 pyramidal cells within the hippocampus, which are less rich in RNA and protein synthetic capability. Ischemic CA1 necrosis (Figs. 13.2, 14.9, 14.14) can occur after only 2 min of global ischemia. After 2−4 min of global cerebral ischemia, the CA1 pyramidal cells regularly undergo neuronal necrosis (Smith et al. 1984). However, this does not occur at the time of ischemia or shortly thereafter as was once believed. The seminal experiments of Kirino in the 1980s have conclusively shown that, in gerbils (Kirino 1982) and rats (Kirino et al. 1984), neuronal necrosis after global cerebral ischemia takes place between the second and fourth days. Delayed neuronal death may occur earlier with greater degrees of insult, and even later with insults that are mitigated by hypothermia, or insults that are shorter. But the basic principle in global ischemia is that there is delayed neuronal death, especially in the hippocampus.

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The phenomenon of delayed neuronal death has also been demonstrated in humans, with roughly the same time course of 2−4 days in the hippocampus (Petito et al. 1987; Horn and Schlote 1992). The principles outlined are thus especially important for medicolegal timing of an ischemic insult in relation to the death. In other brain regions such as neocortex and especially striatum, neuronal death occurs more quickly than in hippocampus (Pulsinelli et al. 1982). The hilus cells of the dentate, also known as CA4 (Fig. 13.6a), is phylogenetically the oldest, reticular nervous tissue of the hippocampus. In CA4, cells die after only small global ischemic insults, as they do in CA1, and calcium accumulates there early (Benveniste and Diemer 1988). This is of importance because of the large number of cell types in CA4 (Amaral 1978), many of which are inhibitory (Ribak and Anderson 1980). Loss of such inhibitory cells in the dentate hilus might worsen ischemic damage by removing inhibition through the trisynaptic chain from the dentate granule cells to the CA3 cells, in turn to the CA1 pyramidal cells. The pathologist should examine the dentate hilus if there is suspicion of short periods of global cerebral ischemia, especially in children where microglial activation may be the only change seen (Del Bigio and Becker 1994). After CA1 cells are affected, progressively longer or more severe ischemic insults will cause recruitment of CA3 cells into the necrotic process. Lastly, the dentate gyrus, very resistant to cerebral ischemia, is recruited in the most severe cases of insults. This contrasts with the often seen vulnerability of the dentate gyrus to hypoglycemia, but the latter is based on the massive release of aspartate into the extracellular fluid of the brain (see Sect. 13.5). The above pattern of damage in the hippocampus can be seen unilaterally or bilaterally. This asymmetry has been alluded to above, and its basis may be either vascular or in an asymmetric timing of onset of spreading depression and other prerequisite events which precede and lead to neuronal necrosis in the ischemic process later. In addition to sampling both hemispheres, the hippocampus should ideally be sampled at several points along its septo-temporal axis. The classic section of the hippocampus is seen when a coronal section is taken from the temporal lobe at the level of the lateral geniculate body. This produces a microscope section including the dentate gyrus in its classic C-shape, the hilus or CA4, the CA3 pyramidal cell band, and CA1 cells. CA2, the zone generally ignored, is theoretically a very narrow zone where the zinc-containing mossy fibers do not terminate from dentate granule cells on CA3 cells, yet they have the morphology of CA3 cells. The order of vulnerability within the hippocampus deserves further discussion. CA1 cells are exqui-

Fig. 13.6a, b. Neuronal necrosis in the cornu ammonis and pallidum. a CA4 segment of the cornu ammonis with ischemic neuronal lesion and microglial reaction; b sparing of the lateral pallidal nucleus in a case of generalized ischemia after cardiac arrest (H&E stain; magnification a ×200, b ×5)

sitely sensitive to ischemic insults (as well as hypoglycemic and epileptic insults). This may be related to a combination of cellular features leading to selective vulnerability: small amounts of Nissl substance relative to neuronal size, and high concentration of NMDA receptors (Greenamyre et al. 1985) leading to long-term changes in neuronal excitability that can run down ion gradients of the neuron, without the protein synthetic machinery necessary to ensure a robust cellular response (Bodsch et al. 1986). Since memory formation in the human brain depends on the hippocampus, and the hippocampus can be selectively involved in global brain ischemia or bilateral posterior cerebral artery occlusion (Victor et al. 1961), it is not surprising that selective

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Fig. 13.7a, b. Ischemic lesions in brain stem and medulla oblongata. The lesions are dark-stained as a consequence of focal hemorrhagic infarction symmetrically involving distinct nuclei

in pons (a) and medulla oblongata (b) as a result of hypotension and transient ischemia

amnesia occurs after global ischemia (Woods et al. 1982; Zola-Morgan et al. 1986). However, amnesia of events prior to 15 years before the insult are preserved, as storage and retrieval of distant memories slowly migrate out of the hippocampus into the temporal lobe (Squire et al. 1989).

post-ischemic hypermetabolism in those structures (Diemer and Siemkowicz 1980). The thalamus is affected in some cases of global ischemia, and, together with other extra-hippocampal damage, can contribute to a clinical picture of dementia, rather than merely memory loss (Volpe and Petito 1985).

13.4.2.3 Basal Ganglia Basal ganglia changes in global ischemia (Fig. 13.6b) are interesting in that they can sometimes resemble carbon monoxide poisoning (see below). The globus pallidus has been seen to be selectively affected in global ischemia where no exposure to carbon monoxide has taken place (Garcia 1988). This pattern resembles the true histotoxicity of carbon monoxide poisoning, but without exposure to the gas. It seems that in some cases of cardiac arrest or prolonged hypotension, necrosis of the globus pallidus and pars reticulata of the substantia nigra can occur, similar to that seen in carbon monoxide poisoning. The basis for this is poorly understood, but may relate to focal,

13.4.2.4 Brain Stem The brain stem can show a pattern of hypotensive necrosis that is more commonly seen in younger individuals (Janzer and Friede 1980). Symmetrical necrosis of brain stem nuclei (Fig. 13.7) can affect the inferior colliculi, or various tegmental nuclei of the midbrain or pons (Révész and Geddes 1988). Sometimes, the pars reticulata of the substantia nigra is affected (Brierley et al. 1971b) as seen in rodents (Smith et al. 1984). The basis for the selective vulnerability is likely relative hypermetabolism of brain stem structures following the actual cardiac arrest, leading to lactate accumulation, acidosis, and pannecrosis.

CHAPTER 13: Hypoxia, Ischemia (Hypoglycemia) Fig. 13.8. Ischemic lesion of the cerebellar cortex including a selective necrosis of the Purkinje cell layer: eosinophilic staining of the Purkinje cells and an increase of Bergmann‘s glia in the granule cell layer (H&E stain, magnification ×50)

13.4.2.5 Cerebellum The cerebellum is regularly affected (Fig. 13.8) in global cerebral ischemia, and can be devastated (Cole and Cowie 1987). Purkinje cells are the most vulnerable cell, in spite of the granule cells being laden with the NMDA subtypes of glutamate receptors (Olson et al. 1987) capable of causing long-term alteration in neuronal excitability, run down of ionic cellular transmembrane gradients and other precursors of neuronal death. Thus, the basis of Purkinje cell vulnerability in cerebellar global ischemia is poorly understood. 13.4.2.6 Spinal Cord Spinal cord damage is often seen after global ischemia, provided the spinal cord is examined at autopsy. Two patterns of selective vulnerability at the gross level are noteworthy: a rostro-caudal change in vulnerability along the length of the spinal cord, and vulnerability of the various parts of the spinal cord in any transverse section, especially in the rostral part of the cord. The rostro-caudal distribution of vulnerability is related to watershed zones between the descending supply via the anterior spinal artery, which derives its flow from the vertebral arteries, and the lumbo-sacral enlargement inferiorly, subserved by the artery of Adamkiewicz. The latter is really an extra large fifth lumbar artery, although other arteries can be enlarged and serve the function of the artery of Adamkiewicz. This vascular pattern leaves

the low thoracic and lumbar spinal cord vulnerable (Gilles and Nag 1971; Azzarelli and Roessmann 1977; Cheshire et al. 1996). On transverse section, the spinal cord is subserved in its posterior third (dorsal columns, nucleus proprius and substantia gelatinosa) by the paired dorsal spinal arteries, and in its anterior two-thirds by the anterior spinal artery running in the ventral median fissure (Sliwa and Maclean 1992). Thus, a given cross-section of spinal cord can show demarcated watershed or borderzone necrosis (Garland et al. 1966; Wolf et al. 1990) between the anterior two-thirds and the posterior one-third, effectively the central region of the cord (Blumbergs and Byrne 1980; Imaizumi et al. 1994). To obtain such a section, it is necessary to sample the cord at the level of maximum rostro-caudal ischemia. It is quite common for the spinal cord above and below such a section to be normal, and with reperfusion, the spinal cord ischemia, like brain ischemia, may be morphologically hemorrhagic (Burger and Vogel 1977). Like brain ischemia, spinal ischemia, and the consequent paraplegia, is sensitive to temperature (Marsala et al. 1994) and blood glucose (LeMay et al. 1988; Drummond and Moore 1989). Repeated cardiac arrest may selectively involve the spinal cord (Jennings and Newton 1969). Recovery can occur (Sandson and Friedman 1989), and is more likely with incomplete lesions characterized by spastic paraparesis than flaccid paraplegia (Kim et al. 1988). Asphyxiated infants may also show spinal cord infarction (Sladky and Rorke 1986).

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13.4.2.7 White Matter Lesions (Leukoencephalopathy) In contrast to neuronal damage in acute ischemia rare cases are published demonstrating selective injury of the white matter (Feigin et al. 1973; Ginsberg et al. 1976; Pantoni and Garcia 1997a). In forensic pathology these findings are known as a consequence of chronic drug abuse (see p. 395, Fig. 19.1c). These lesions constitute the core pathology in several dementing disorders, such as Binswanger’s disease, a form of subcortical vascular dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (pp. 634 f) as well as methotrexate intoxication (p. 359), sniffing of organic solvents (pp. 383 f) and granulomatous angitis (p. 554). A positive correlation between white matter lesions and cognitive dysfunction has been demonstrated (Pantoni and Garcia 1997b), although it remains controversial (Hurley et al. 2000). In humans, white matter lesions are accompanied by apoptosis of oligodendroglia and have been thought to be caused by chronic cerebral hypoperfusion, a prolonged period of hypoxemia, hypotension, metabolic imbalance, and elevated venous pressure (Ginsberg et al. 1976; Tomimoto et al. 2003). Meanwhile white matter lesions have been shown to be induced in rats by clipping the bilateral carotid arteries (Wakita et al. 1994). These animals exhibit long-standing cerebral hypoperfusion and behavioral disturbances. A study on this system and human material implicated a dysfunction of the blood−brain barrier (BBB), perivascular edema, and microglial activation in the mechanism underlying the white matter lesion (Wakita et al. 1994). During this process, microglia may play a pivotal role because their activation and the white matter lesions occur concurrently, and both are suppressed by the administration of immunosuppressants such as ciclosporin A or FK 506 (Wakita et al. 1995, 1998). Moreover, reports have suggested that mononuclear phagocytes may play an important role in the pathogenesis of inflammatory demyelination by releasing matrix metalloproteinases (Kieseier et al. 1999). Matrix metalloproteinases influence cell-matrix interactions in the human brain and may also be involved in the disintegration of the basem*nt membranes of microvessels during cerebral ischemia (Hamann et al. 1995). In a more recent study Ihara et al. (2001) could prove the relation between white matter lesions and the expression of matrix metalloproteinases in chronic cerebral hypoperfusion.

13.5 Hypoglycemia For many years (for review, see Auer 1986; 2004), it was believed that hypoglycemia was a form of ischemia (Courville 1957; Brierley et al. 1971a). Part of the reason for this was the belief that low oxygen and low glucose had the same potential to cause neurons to perish. We now know (see above) that hypoxia alone is incapable of causing neuronal necrosis in organisms with an intact beating heart. Rather, ischemia is necessary, not merely hypoxia. Thus, the idea that hypoxia and hypoglycemia have identical consequences within the nervous system was flawed from the beginning. The second flaw in this argument became apparent when the biochemistry of hypoglycemia was worked out by Siesjö and colleagues in Sweden. Salient neurochemical features of hypoglycemic brain damage contrast sharply with those of ischemia (Auer and Siesjö 1993). These include an alkalosis, caused by both increased ammonia production during hypoglycemia and the lack of production of metabolic acids such as lactate, which would normally drive the pH downward. In addition to tissue alkalosis, hypoglycemia is characterized by increased, not decreased cerebral blood flow, again contrasting sharply with ischemia. The amino acid perturbations in the neurochemistry of hypoglycemic brain damage also contrast with ischemia. Excitatory amino acids are known to play a pathophysiologic role in neuronal death in both conditions of hypoglycemia and ischemia. However, in ischemia, the release of synaptic glutamate (Benveniste et al. 1984) has been shown to be the culprit, whereas in hypoglycemia, the predominant excitatory amino acid released seems to be aspartate (Sandberg et al. 1986). It is the lack of glycolytic flux that drives aspartate production in hypoglycemia. The paltry glycolysis in turn leads to a shortage of pyruvate and, because decarboxylation to acetate is slowed, acetate is in short supply. Since oxaloacetate lacks acetate to condense with, to form citrate in normal quantities, oxaloacetate builds up before the block. The increased tissue oxaloacetate, in turn, drives the aspartate-glutamate transaminase reaction towards aspartate and away from glutamate. Thus, tissue amino acid levels of aspartate rise, and glutamate is actually lowered in the tissue during hypoglycemia. The extracellular aspartate increases to 10−20 times the normal concentration. Aspartate is a potent activator of NDMA receptors on neurons. In this fashion, aspartate, not glutamate, kills the neurons in hyperglycemia. The chain of pathophysiologic events leading to neuronal death is thus much longer than would be expected with the cursory thought that glucose deprivation directly starves the neuron

CHAPTER 13: Hypoxia, Ischemia (Hypoglycemia)

Fig. 13.9a, b. Hypoglycemic versus ischemic brain damage. a Hypoglycemic damage of the hippocampal dentate gyrus (arrow

heads), while b in ischemia the dentate gyrus is not involved (H&E stain; magnification a, b ×200)

and kills it. Hypoglycemia is, rather, an excitotoxic death of hyperexcitation. This active neuronal killing contrasts sharply with the old, outmoded concept of neuronal starvation. The idea that neurons can be killed by a negative phenomenon of oxygen or glucose deprivation is an obsolete one. Indeed, even the neuropathology of hypoglycemia can, on occasion, show differences that can be clearly delineated from ischemia.

es (Auer et al. 1989) there is disseminated neuronal death throughout all laminae of the cerebral cortex. In hippocampus, hypoglycemia, like ischemia, selectively affects the CA1 pyramidal neurons. However, often a distinguishing feature from ischemia is seen: neuronal necrosis in the dentate gyrus. In ischemia, the dentate is the last structure within the hippocampus to be affected, but if dentate necrosis is prominent with relative sparing of CA3, and not all the CA1 is necrotic, hypoglycemic brain damage should be suspected. If it is ischemia causing dentate necrosis, this ischemia would have to be very severe indeed, and one should therefore expect widespread cystic necrosis of the cerebral cortex. Hypoglycemia does not cause pan-necrosis of the cortex, due to lack of acidosis and the maintenance of cerebral blood flow in hypoglycemia. Of course, the neuropathologic findings must be seen in an integrative analysis including the circ*mstances of death, insulin overdose or other causes of hypoglycemic brain damage being likely or present. We must remember that in hypoglycemic brain damage, the heart continues to beat while the brain is damaged. Cardiac function can be maintained by oxidation of substrates other than glucose. Another distinguishing feature of hypoglycemic brain damage is the absence of brain stem or cerebellar necrosis. This is made possible by the upheld energy state in these structures. In fact, protein synthesis, a high-level function that is quite sensitive to energy failure, continues unabated in the brain stem during hypoglycemic coma, while telencephalic

13.5.1 Neuropathology Both ischemia and hypoglycemia affect neurons in the cerebral cortex and hippocampus. This is another basis for the previous notion that these two insults are identical. Indeed, it is common in neuropathologic material not to be able to tell the difference definitively. Nevertheless, if certain distinguishing features are seen, it is sometimes possible to distinguish hypoglycemic brain damage and rule out ischemia (Auer et al. 1984a, b). In the cerebral cortex, hypoglycemia occasionally shows a superficial distribution of neuronal necrosis (Fig. 13.9). This can be attributed to extracellular production of aspartate which accumulates in the cerebrospinal fluid above the cerebral cortex. However, since cortical tissue itself is the source of the metabolically derived aspartate (see above), one cannot always expect a superficial distribution in hypoglycemic brain damage. Indeed, in several cas-

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structures show no protein synthesis (Kiessling et al. 1986). The cerebellum, including the Purkinje cells, is spared in hypoglycemic brain damage, contrasting sharply with ischemia. Neurochemical perturbations in the cerebellum (Agardh and Siesjö 1981) are minimal compared to the cerebrum (Agardh et al. 1978). The above neurochemical and neuropathological contrasting features between hypoglycemic brain damage and ischemic brain damage should allow a more complete understanding of the different neurochemistry and pathophysiology of neuronal death and tissue necrosis in hypoglycemia and ischemia.

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Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57−69 Kirino T, Tamura A, Sano K (1984) Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol (Berl) 64:139−147 Kleihues P, Hossmann K-A (1973) Regional incorporation of L-[33H] tyrosine into cat brain proteins after 1 hour of complete ischemia. Acta Neuropath (Berl) 25:313−324 Kol S, Ammar R, Weisz G, Melamed Y (1993) Hyperbaric oxygenation for arterial air embolism during cardiopulmonary bypass. Ann Thorac Surg 55:401−403 Kraig RP, Petito CK, Plum F, Pulsinelli WA (1987) Hydrogen ions kill brain at concentrations reached in ischemia. J Cereb Blood Flow Metab 7:379−386 Krakauer J (1997) Into thin air: a personal account of the Mount Everest disaster. MacMillan London Krause GS, Tiffany BR (1993) Suppression of protein synthesis in the reperfused brain. Stroke 24:747−755 Latour LL, Kang DW, Ezzeddine MA et al (2004) Early blood−brain barrier disruption in human focal brain ischemia. Ann Neurol 56:468−477 Lee GJ (1989) In vivo and in vitro staining of acidophilic neurons as indicative of cell death following kainic acid-induced lesions in rat brain. Acta Neuropathol (Berl) 77:519−524 LeMay DR, Gehua L, Zelenock GB, D‘Alecy G (1988) Insulin administration protects neurologic function in cerebral ischemia in rats. Stroke 19:1411−1419 MacMillan VH (1989) Cerebral energy metabolism in cyanide encephalopathy. J Cereb Blood Flow Metab 9:156−162 Malese K (2001) The dynamics of cellular injury: transformation into neuronal and vascular protection. Histol Histopathol 16:633−644 Mandel MM, Berry RG (1959) Human brain changes in cardiac arrest. Surg Gynecol Obstet 108:692−696 Marsala M, Vanicky I, Yaksh TL (1994) Effect of graded hypothermia (27°C to 34 °C) on behavioral function, histopathology, and spinal blood flow after spinal ischemia in rat. Stroke 25:2038−2046 Moody DM, Bell MA, Challa VR et al (1990) Brain microemboli during cardiac surgery or aortography. Ann Neurol 28:477−486 Nunn J (1993) Nunn‘s applied respiratory physiology. Butterworth-Heinemann, Oxford Nussmeier NA, Arlund C, Slogoff S (1986) Neuropsychiatric complications after cardiopulmonary bypass: cerebral protection by a barbiturate. Anesthesiology 64:165−170 Ohno K, Isotani E, Hirakawa K (1997) MELAS presenting as migraine complicated by stroke: case report. Neuroradiology 39:781−784 Ohsh*ta T, Oka M, Imon Y et al (2000) Serial diffusion-weighted imaging in MELAS. Neuroradiology 42:651−656 Olson JM, Greenamyre JT, Penney JB, Young AB (1987) Autoradiographic localization of cerebellar excitatory amino acid binding sites in the mouse. Neuroscience 22:913−923 Oppenheim C, Galanaud D, Samson Y et al (2000) Can diffusion weighted magnetic resonance imaging help differentiate stroke from stroke-like events in MELAS? J Neurol Neurosurg Psychiatry 69:248−250

Palmer AC (1990) Target organs in decompression sickness. Prog Underwater Sci 15:15−23 Palmer AC, Calder IM, McCallum RI, Mastaglia FL (1981) Spinal cord degeneration in a case of “recovered” spinal decompression sickness. Br Med J 283:888 Palmer AC, Calder IM, Hughes JT (1987) Spinal cord degeneration in divers. Lancet 2:1365−1366 Pantoni L, Garcia JH (1997a) Pathogenesis of leukoaraiosis: a review. Stroke 28:652−659 Pantoni L, Garcia JH (1997b) Cognitive impairment and cellular/ vascular changes in the cerebral white matter. Ann N Y Acad Sci 826:92−102 Pappert EJ, Goetz CG, Vu TQ et al (1999) Animal model of posthypoxic myoclonus. Effects of serotonergic antagonists. Neurology 52:16−21 Pearigen P, Ryder G, Simon RP (1996) The effects in vivo of hypoxia on brain injury (research report). Brain Res 725:184−191 Pearson TC, Wetherley-Mein G (1978) Vascular occlusive episodes and venous hematocrit in primary proliferative polycythemia. Lancet 2:1219−1222 Persson L, Hardemark HG, Bolander HG et al (1989) Neurologic and neuropathologic outcome after middle cerebral artery occlusion in rats. Stroke 20:641−645 Petito CK, Feldmann E, Pulsinelli WA, Plum F (1987) Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37:1281−1286 Prayson RA, Wang N (1998) Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. Arch Pathol Lab Med 122:978−981 Pulsinelli W (1992) Pathophysiology and treatment of focal cerebral ischemia. Part II: mechanisms of damage and treatment. J Neurosurg 77:337−354 Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491−498 Révész T, Geddes JF (1988) Symmetrical columnar necrosis of the basal ganglia and brain stem in an adult following cardiac arrest. Clin Neuropathol 7:294−298 Ribak CE, Anderson L (1980) Ultrastructure of the pyramidal basket cells in the dentate gyrus of the rat. J Comp Neurol 192:903−916 Rie MA, Bernad PG (1980) Prolonged hypoxia in man without circulatory compromise fails to demonstrate cerebral pathology (abstract). Neurology 30:443 Riggs HE, Rupp C (1963) Variations in form of Circle of Willis. Arch Neurol 8:24−30 Sadove MS, Yon MK, Hollinger PH et al (1961) Severe prolonged cerebral hypoxic episode with complete recovery. J Am Med Assoc 175:1102−1104 Sandberg M, Butcher SP, Hagberg H (1986) Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus. J Neurochem 47:178−184 Sandson TA, Friedman JH (1989) Spinal cord infarction. Report of 8 cases and review of the literature. Medicine (Baltimore) 68:282—292

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Schaller B, Graf R (2004) Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab 24:351−371 Scholz W (1953) Die nicht zur Erweichung führenden unvollständigen Gewebsnekrosen. In: Lubarsch O, Henke F, Rössle R (eds) Handbuch der speziellen pathologischen Anatomie und Histologie, vol 13, Nervensystem, part 1, B: Erkrankungen des zentralen Nervensystems I. Springer, Berlin Heidelberg New York, pp 1285−1325 Siebke H, Breivik H, Rod T, Lind B (1975) Survival after 40 minutes‘ submersion without cerebral sequelae. Lancet i:1275−1277 Siesjö BK (1992) Pathophysiology and treatment of focal cerebral ischemia. Part II: mechanisms of damage and treatment. J Neurosurg 77:337−354 Simon RP (1999) Hypoxia versus ischemia. Neurology 52:7−8 Sladky JT, Rorke LB (1986) Perinatal hypoxic/ischemic spinal cord injury. Pediatr Pathol 6:87−101 Sliwa JA, Maclean IC (1992) Ischemic myelopathy: a review of spinal vasculature and related clinical syndromes. Arch Phys Med Rehabil 73:365−372 Smith L, Kruszyna H, Smith RP (1977) The effect of methemoglobin on the inhibition of cytochrome c oxidase by cyanide, sulfide or azide. Biochem Pharmacol 26:2247−2250 Smith M-L, Auer RN, Siesjö BK (1984) The density and distribution of ischemic brain injury in the rat after 2−10 minutes of forebrain ischemia. Acta Neuropathol (Berl) 64:319−332 Squire LR, Haist F, Shimamura AP (1989) The neurology of memory: quantitative assessment of retrograde amnesia in two groups of amnesic patients. J Neurosci 9:828−839 Stehbens WE (1963) Aneurysms and anatomical variation of the cerebral arteries. Arch Pathol 75:45−64 Taensch HW, Ballard RA, Avera MA (eds) (1991) Schaffer and Avery‘s disease of the newborn. WB Saunders, Philadelphia, Pa. Thilmann R, Xie Y, Kleihues P, Kiessling M (1986) Persistent inhibition of protein synthesis precedes delayed neuronal death in postischemic gerbil hippocampus. Acta Neuropathol (Berl) 71:88−93 Tohgi H, Yamanouchi H, Murakami M, Kameyama M (1978) Importance of the hematocrit as a risk factor in cerebral infarction. Stroke 9:369−374 Tomimoto H, Ihara M, Wakita H et al (2003) Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol (Berl) 106:527−534 Townes BD, Hornbein TF, Schoene RB et al (1984) Human cerebral function at extreme high altitude. In: West JB, Lahiri S

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14.1 14.1.1 14.1.2 14.1.3 14.1.4 14.1.5 14.1.5.1 14.1.5.2

Suffocation 294 Environmental Suffocation 294 Smothering, Choking, and Gagging 295 Drowning 295 Mechanical Asphyxia 296 Neuropathology of Suffocation 296 Acute Death after Suffocation 296 Delayed Death after Suffocation 296

14.2 14.2.1 14.2.2 14.2.3 14.2.4 14.2.4.1 14.2.4.2 14.2.5

Strangulation 297 Hanging 297 Ligature Strangulation 298 Manual Strangulation 298 Neuropathology of Strangulation 298 Acute Death after Strangulation 299 Delayed Death after Strangulation 299 Cervical Spine and Strangulation 300

14.3 14.3.1 14.3.2 14.3.3 14.3.4 14.3.5 14.3.6 14.3.7 14.3.8 14.3.9 14.3.10 14.3.11

Time Course of Ischemia 301 Macroscopic Findings 301 Edema 301 Microthrombosis and Fibrin Deposition 303 Neurons 303 Neuronal Proteins 305 Astrocytes 306 Polymorphonuclear Leukocytes 307 Mononuclear Phagocytes/Microglia 307 Mesenchymal Reaction 308 Cytokines 308 Enzymes 309

14.4

Clinical Features of Acute Asphyxia

14.5

Transient Ischemia 311

14.6

Selective Neuronal Necrosis

14.7

Apallic Syndrome

14.8

Ethical Implications Bibliography 313 References

313

312 312

312

310

In Chap. 13 we described the sequelae of disturbances of the pure primary insults of hypoxia, ischemia, and hypoglycemia. Under common pathologic conditions, a combination of different types of metabolic disturbances regularly occurs. The clinical and morphological features, therefore, may partly overlap. This overlapping of processes is especially important in surviving victims, especially in cases of ischemia (or stagnant anoxia) as well as in cases of prolonged hypoxia. In this part we will describe the primary forensic types of ischemia and asphyxia, but we are also aware of natural types of asphyxia, i.e., diseases of the lungs (prevention/reduction of the gaseous interchange by pneumonia, edema, etc.) and the heart (prevention/reduction of the circulation of oxygenated blood). From the forensic point of view we have to distinguish three types of ischemia/asphyxia: ▬ Type 1: Suffocation ▬ Type 2: Strangulation ▬ Type 3: Chemical asphyxiation This classification is according to DiMaio and DiMaio (2001). The last type is described elsewhere, i.e., hydrogen cyanide, hydrogen sulfide (Chap. 17, pp. 351 f); types 1 and 2 are discussed in the present chapter. However, to start with we should state that, in spite of innumerable experiments demonstrating morphological, immunohistochemical, biochemical or molecular alterations, no early neuronal changes are detected, even in experimental circ*mstances (Oehmichen and Meissner 2000; Oehmichen et al. 2003), if an extremely short period of ischemia leads to early death before cellular alteration can mature and appear morphologically. Especially in human autopsy material the ever-present postmortem and agonal changes will interfere with the subtle early signs of ischemic changes (Knight 1996).

14

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Table 14.1. Types of suffocation and strangulation

Term

Meaning

Spontaneous brain perfusion or reperfusion

Suffocation

Deprivation of oxygen

+

Environmental suffocation

Lack of oxygen in breathable environment

+

Smothering, gagging

Blockage of the external air passage

+

Choking

Blockage of the upper airways by foreign body (bolus, aspiration),

+

Manual strangulation: external compression of trachea Immersion-induced blockade of the external air passage and upper airways (aspiration)

+

Mechanical asphyxia

Restriction of respiratory movement of the chest by pressure outside the chest or upper abdomen

+

External pressure to the neck

+/−

Ligature strangulation

The band is tightened by a force other than the body weight

+/−

Manual strangulation

Occlusion of the vessels is produced by pressure of hands, forearm or other limb against the neck

+/−

Mugging

Pressure to the neck by means of an arm crocked around from the rear

+/−

Constricting band is tightened by the weight of the victim‘s body

Ligature strangulation (Spanish method of judicial execution)

Hanging

Garroting

14.1 Suffocation Death by suffocation is caused by a reduction of the oxygen concentration in the respired atmosphere. The different types of suffocation are listed in Table 14.1. The passing neurologic deficits depend on the oxygen concentrations and are described in Table 14.2, while the relationship between carbon dioxide concentration and clinical symptoms is demonstrated in Table 14.3.

Hypoxia

+

Drowning

Strangulation

Ischemia/hypoxia

Intermittent ischemia

Ischemia

14.1.1 Environmental Suffocation The scene is partly described in Chapters 12 and 13 (altitude mountaineering), which is associated with a hypoxic state. An identical lack of atmospheric oxygen concentration may be observed by a physical displacement of oxygen, e.g., by gases such as carbon dioxide, nitrogen or methane, or by chemical changes such as combustion. Each of these will reduce the partial pressure of inspired O2.

CHAPTER 14: Forensic Types of Ischemia and Asphyxia

Table 14.2. The relationship between the time of exposure to oxygen depletion and the clinical effect. Source: Davies 1991

Atmospheric oxygen (%)

21

Clinical symptoms of O2 depletion

Normal concentration in air

12−15

Shortness of breath, headache, dizziness, quick pulse, fatigue on exertion, loss of muscular co-ordination for skilled movements

10−12

Nausea and vomiting, exertion impossible, paralysis of motion

6−8

Collapse and unconsciousness − rapid treatment can prevent death

24 months

hemorrhages in the neck, epidural hemorrhages at the occipito-cervical junction (41%), and hemorrhages in the intervertebral discs in about 70% of 107 examined cases after hanging, mainly at the C5−C6 level. As demonstrated in Fig. 14.1, a laceration and hemorrhage of the anterior or dorsal part of the intervertebral disc is seen in suicidal hanging as well as in homicidal ligature or manual strangulation (Fig. 14.2). These lacerations within the intervertebral discs are an indication of a sudden hyperextension (anterior hemorrhage) or hyperflexion (posterior hemorrhage) of the head and cervical spine − in combination with death agony and/or strangulating forces by the perpetrator. Moreover any type of strangulation may also be accompanied by lesions of the large neck vessels, especially the carotid arteries. A mechanically induced endothelial lesion may become the source of a delayed thrombotic occlusion of the carotid artery in surviving cases. Hartshorne and Reay (1995) reported two cases of bilateral vertebral artery lacerations associated with a basilar subarachnoid hemorrhage after judicial hanging. In one of the cases there was also a separation at C2 and C3 with complete dissection of the cord, bilateral carotid intimal tears, and subdural hemorrhage. The fall of the victim was about 165 cm with the knot slipping to the subaural area.

text sums up more recent investigations, especially Schröder‘s (1983) review which evaluates a great deal of case material involving prolonged ischemia (see Table 14.5).

14.3.1 Macroscopic Findings Between 10 and 12 h after an ischemic event, the first gross alterations are seen, characterized by a diffuse loss of demarcation between white and gray matter, a gelatinous tissue appearance, and a tissue softening (encephalomalacia). A gray or dark staining (edema, congestion, and hemorrhages) will be seen in the cortical structures of the sulci, especially between the 1st and 2nd frontal gyri (Fig. 14.3a), within the thalamic nuclei, hippocampal area (Fig. 14.3b), and the pallidum (Fig. 14.3a), partly associated with hemorrhages. After a survival time of some days the pallidum will be softened and cystically transformed (Fig. 14.4). A survival time of more than 1 week leads to a cortical atrophy of the cerebrum and cerebellum and to cystic alterations of the basal ganglia (Fig. 14.5). The combination of ischemia and arterial hypotension may be associated with involvement of the brain stem and the medulla (Fig. 14.6).

14.3.2 Edema

14.3 Time Course of Ischemia The time dependency of brain tissue alterations in ischemia are comprehensively described by Müller (1930), Baggenstoss et al. (1943), Környey (1955), Peters (1955), and Schröder (1983). The following

The very early microscopic features are marked by a spongious alteration caused by edema involving gray and white matter, which is demonstrable at 2 h up to 8 h of survival time (Peters 1955). The cortical edema (cytotoxic edema) will be extremely expressed; for example, in the depth of the sulcus between the 1st

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Fig. 14.4a, b. Global brain ischemia (pan-necrosis) caused by hanging survived for 4 days. a Ligature mark; b delayed symmetrical necrosis and cystic transformation of the pallidum (circles)

Fig. 14.3a, b. Global brain ischemia (pan-necrosis) with reperfusion (24 h after reperfusion). Ischemia causes dark discoloration of the cortex in the sulci between the 1st and 2nd frontal lobe gyri (a vertical arrows), the globus pallidus (a horizontal arrows), the median thalamic nuclei (b arrows) and hippocampus (b circles), which are microscopically characterized by edema, congestion, and perivascular hemorrhages

and 2nd frontal and parietal gyri (Fig. 14.7a) as well as along the cortical subpial vessels (Fig. 14.7b). A reduction of myelin staining pattern (Luxol fast blue staining) is demonstrable within 2−14 h. An irregular map-like demarcation of edema, especially in the cortex, is first seen after 14 h (Fig. 4.6c, d). Shinnou et al. (1998) could experimentally demonstrate that, in gerbils after ischemia of 30 min duration and a reperfusion time of 90 min, the blood−brain barrier in some vessels along the hippocampal fissure in the medial parts of the hippocampus is more vulnerable to ischemic insults than those in other brain areas: it was clearly demonstrated that intravascular macromolecules display a transendothelial leakage (see also Fig. 14.9a). In contrast, monkeys subjected to 3 or 9 min of global cerebral ischemia were neurologically normal and had normal CA1 histology (Scheller et al. 1992). Monkeys subjected to 15 min of ischemia showed moderate to severe CA1 damage and signi-

Fig. 14.5a, b. Global brain ischemia (pan-necrosis) survived for about 3 weeks. a Cortical atrophy of the cerebrum and b cerebellum (arrowheads) associated with cystic alteration of the basal ganglia (a circles)

CHAPTER 14: Forensic Types of Ischemia and Asphyxia

Fig. 14.6a, b. Global brain ischemia (pan-necrosis) with a gray staining pattern in brain stem and medulla. Periventricular alte-

rations, i.e., edema, congestion, and perivascular hemorrhages, in the pons (a) and medulla (b)

ficant quantifiable neurobehavioral deficits compared with historical control animals (McSweeny et al. 1985).

a perivascular tissue factor is partially responsible for occlusion formation. During ischemia the large plasma protein fibrinogen extravasates and interacts with parenchymal tissue factor, forming significant extravascular fibrin by 24 h of reperfusion.

14.3.3 Microthrombosis and Fibrin Deposition In ischemia the microcirculation is impaired by hemorrheological failure: the microthrombosis (Petito 1979; Obrenovitsch and Hallenbeck 1985). The thrombi are composed of platelets, and a network of fibrin. In some vessels there is only a thick layer of fibrin coating the endothelium and surrounding the platelets. The number of microthrombi increases in humans as the necrotic process ages, and peaks in such stages in which acute ischemic changes coexist with the beginning of phagocytosis: between 7 and 15 days (Figols et al. 1987). Extravascular fibrin deposition was significantly increased by 24 h of reperfusion in adolescent male baboons (Okada et al. 1994) after 2 h or 3 h of middle artery occlusion. These results suggest that microvascular fibrin deposition accumulates in a time-dependent manner during focal cerebral ischemia/reperfusion and that exposure of plasma to

14.3.4 Neurons In the reperfusion type of ischemia ischemic nerve cell alterations in Nissl stain are characterized by tigrolysis (loss of Nissl bodies) and/or microvacuolation (Fig. 13.4c) within 1−3 h (Steegmann 1968). In H&E stain ischemic cortical nerve cell necrosis in layers III, V, and VI is seen within 4 h (Schröder 1983) or 5 h (Horn and Schlote 1992) marked by a hom*ogenizing cell change consisting of eosinophilic or dark Luxol fast blue cytoplasm, a hyperchromatic, pyknotic nucleus, and a pericellular space as described in Chapter 4 (Figs. 4.5c, d, 13.4). After 5 min of ischemia and 1−2 days of recirculation, numerous calcium-containing neurons appeared in the CA4 sector, but only a few were present in the CA1 sector (Bonnekoh et al. 1992).

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Fig. 14.7a, b. Ischemia induced edema in the cerebral cortex. a Edema in the sulcus between the 1st and 2nd frontal gyri (wa-

tershed edema) as well as b along the subpial cortical vessels (H&E; magnification a, b ×50)

Two relevant clinicopathologic investigations of ischemic neuronal death in human autopsy material (Petito et al. 1987; Horn and Schlote 1992) gave evidence of an early and delayed neuronal death, as had already been demonstrated by animal experiments (Ito et al. 1975). In 1982, Kirino demonstrated that the CA1 damage in the gerbil hippocampus takes place with a delay of about 48 h after brief forebrain ischemia, and is completed by the fourth day following an ischemic insult. Horn and Schlote (1992) evaluated 26 human brains and observed the earliest manifestations of ischemic neuronal necrosis by 5 h following cardiac arrest in cortical layers III, V, and VI, whereas hippocampal CA1 and Purkinje cell layers did not yet reveal any definite ischemic cell damage. CA1 pyramidal cell death does not occur until 4 days following global ischemia (cardiac arrest) but afterwards develops rapidly, exceeding the extent of neocortical neuronal injury by about 5 days post arrest. Finally, it seems to be completed no earlier than 7 days after the ischemic insult. These findings allow the conclusion to be drawn that two types of neuronal damage, an early and a delayed one, exist in human brain too. Additional-

ly it is known that the current data substantiate that the cell process determining the fate of CA1 neurons − delayed death or recovery − is related to the first 40 min of post-ischemic reperfusion, thus underlining the particular clinical importance of delayed neuronal death as a therapeutic window of post-ischemia treatment (Kuroiwa et al. 1990). Within the Purkinje cell layers neuronal death takes place significantly earlier and more gradually than in CA1 of the hippocampus. A retrograde reaction of neuronal perikaryon, i.e., a neuronal swelling, a central chromatolysis, and an eccentric localization of the nucleus (Fig. 3.1b), is seen within 35 h and 15 months after ischemia (Schröder 1983; see also Schlote 1970; Torvik and Skjörten 1971); Jacob and Pyrkosch (1951) described “neuronal necrosis” in 3 of 20 cases of hanging. We agree with Schröder (1983) that these alterations may be supravital or postmortem phenomena. Though ischemic changes are mainly consistent with necrosis of neurons we have to accept that DNA fragmentation (apoptosis) occurs after the development of neuronal death in CA1 neurons subjected to 10 min of global ischemia (Petito et al. 1997; Love et al. 2000).

CHAPTER 14: Forensic Types of Ischemia and Asphyxia

Fig. 14.8a−c. Astrocytic reaction in ischemic cornu Ammonis and cerebral cortex. a Intact, non-injured cornu Ammonis; b activation, i.e., astrocytic proliferation and upregulation of GFAP, in the CA4 sector; c upregulation of GFAP in the cerebral cortex (GFAP immunoreactivity; magnification a ×10; b, c ×500)

The temporal profile of neuronal, astrocytic, and microglial cells was studied in rats (Lin et al. 1998). In the striatum, normal neuron counts were first decreased significantly at 2 weeks after the ischemic event. In the CA1 hippocampus, a decreased number of normal neurons was seen at 1 week post ischemia, together with a significant increase in immunoreactive microglia at that time; the latter normalized after 2 weeks. Reactive astrocytes in the CA1 hippocampus and cerebral cortex were significantly increased at 1−2 weeks after ischemia (see also Figs. 14.8, 14.9c).

Fig. 14.9a−c. Selective neuronal injury in the cornu Ammonis (CA1 sector) and reactive astrocytes. a Edema with selective neuronal loss; b neuronal loss without visible edema; c astrocytic reaction (a, c H&E, b Nissl stain; magnification a−c ×300)

14.3.5 Neuronal Proteins The intracytoplasmic proteins of neurons give information on neuronal function. Tomimoto and Yanagihara (2000; see also Tomimoto et al. 1996) could demonstrate that microtubule-associated proteins (MAPs) are more vulnerable than tubulin to ischemic insults. Using immunohistochemistry for MAPs, the earliest ischemic lesion in gerbils occurred in the CA1 and CA2 sector of the hippocampus after transient global ischemia for 3 min (see also Fig. 14.14).

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Fig. 14.10a−d. Astrocytic reactivity in brain ischemia. a Astrocytic hyperplasia in white matter; b increase of astrocytic fibers; c loss of Purkinje cells which are during the

final stage of reactivity d partly replaced by astrocytic fibers (a, b, d GFAP immunoreactivity; c H&E; magnification a, b ×200, c, d ×300)

These lesions were reversible but became irreversible when the duration of ischemia was extended to 4 min. The immunoreactivity of so-called motor proteins, such as cytoplasmic dynein (CD) and kinesin, begins to decrease at 1 h in CA1 neurons (Abe et al. 1995); the decrease becomes more evident at 3 h after ischemia, whereas the immunoreactivity of other neurons remains at a normal level. The motor proteins are linear motors that convert the energy of ATP hydrolysis into mechanical work and move cellular organelles such as mitochondria along microtubules. CD, also referred to as MAP-1C (Paschal et al. 1987), translocates organelles to the proximal end of microtubules. Kinesin is thought to mediate axonal transport to the peripheral end of microtubules. Moreover, we also know that one consequence of ischemia will be a non-disruptive axonal injury (AI), i.e., axonal swellings, and axonal bulbs as described by Maxwell et al. (1997 − see also: Oehmichen et al. 1998, 1999; Kaur et al. 1999) will be demonstrable 1.5−3.0 h after the incidence of the ischemic insult by application of an antibody to β-amyloid precursor protein (β-APP). Martí et al. (2001) described the temporal pattern of expression of proteins of the chromogranin/ secretogranin family by immunohistochemistry. In

gerbils, these authors could demonstrate a strong increase in reactivity of chromogranin A and secretoneurin in the CA3 sector, starting at 12 h with a peak at 24 h and a decrease at 48 h after transient ischemia.

14.3.6 Astrocytes It is generally accepted that astrocytes are highly resistant to ischemic insults. But a specific loss of glial fibrillary acidic protein (GFAP) and immunolabeling in protoplasmic astrocytes occurred within minutes in the area with total depletion of regional blood flow, whereas “classic” gliosis was observed in areas with remaining cerebral blood flow (Lukaszevicz et al. 2002; Zhao et al. 2003). Severe disturbance of cell function, as suggested by decreased GFAP content and increased permeability of the blood−brain barrier to macromolecules, was rapidly followed by necrotic cell death. Astrocytic alterations as demonstrated by cytoplasmic swelling (ameboid glia) are demonstrable within 2−5 h (Müller 1930; Rand and Courville 1932; Blakemore 1971). Hypertrophic astrocytes with eccentric nuclei are first seen 6 days after ischemia

CHAPTER 14: Forensic Types of Ischemia and Asphyxia

14.3.7 Polymorphonuclear Leukocytes The early blood cell reaction is characterized by a neutrophilic emigration within the first 2 h of survival time (Fig. 14.11), especially in the cortex, where focal perivascular aggregation is seen. The peak occurs 12−48 h after ischemia (Baggenstoss et al. 1943; Chelnikov 1979). The infiltration is more distinct in hemorrhagic infarcts than in pale infarcts. The number of leukocytes commonly decreases after 5 days, to vanish by 7 days. This is useful in timing or dating infarcts.

14.3.8 Mononuclear Phagocytes/Microglia

Fig. 14.11a, b. Leukocytic emigration in ischemic injured brain. a Perivascular aggregated leukocytes; b thrombotic occluded vessel associated with emigrating leukocytes (magnification a ×100, b ×300)

(Link and Schleussing 1955; Schröder 1983), in the cornu Ammonis (Figs. 14.8a, 9), cerebral cortex (Fig. 14.8c), the cerebral white matter (Fig. 14.10a, b), and cerebellar cortex (Fig. 14.10c, d). Moreover, in the cerebellar cortex an increase of glial fibers is demonstrable replacing lost Purkinje cells (Fig. 14.10b, c). The astrocytic activation is extensively described by Archer and Walz (2000), who could demonstrate upregulation of GFAP as a first expression of reactivity associated with an increase of GFAP-reactive astrocytic mitosis. The astrocytic activation obviously is protective to neurons subjected to an ischemic insult (Louw et al. 1998). Moreover, a local gliotic response could be distinguished from a remote gliotic response. Schwab et al. (2000) could demonstrate that the number of astrocytes expressing connective tissue growth factors was significantly higher in border zones adjacent to the core, corresponding to the penumbra. These numbers were significantly increased in the first and third days and remained persistently elevated up to several months post infarction.

Mononuclear phagocytes were first seen 7 h after ischemia by Schröder (1983; see also Wisniewski 1961) in a perivascular position (Fig. 14.12a, b), diffusely distributed (Fig. 14.12c), focally aggregated or perineuronal (Fig. 14.12d). Mononuclear phagocytes − in the first stage − are seen in a perineuronal location (Fig. 14.12d, 14.13), and later after a neuronal loss − in the second stage − these phagocytes replace the neurons (Figs. 14.14, 14.15). These cell types will be transformed into an ameboid cell type after 14 h, and into a gitter cell after 32−48 h (Escourolle and Poirier 1973; Schröder 1983). They are accumulated perineuronally in the central cortex and/or basal ganglia and are obviously of hematogenous origin (Schroeter et al. 2001). The earliest microglial response was observed in the rat hippocampal formation after 20 min of reperfusion following global cerebral ischemia in the four-vessel occlusion model (Morioka et al. 1991). In another study, a biphasic microglial reaction was detected in the hippocampus evoked by cerebral ischemia or kainic acid administration (Jørgensen et al. 1993). An early, widespread activation of microglial cells could be seen in all hippocampal regions on the first day after ischemia. This reaction subsided during the next few days in the areas devoid of neuronal degeneration, while it progressed into a protracted, lesion-specific reaction in the areas where neuronal degeneration occurred (Freund and Maglóczky 1993; Jørgensen et al. 1993). Ábrahám and Lázár (2000) could demonstrate an activation of resting microglia within 20 min after ischemia, but no increase of the number of cells. Beschorner et al. (2002) could show an upregulation of CD14 antigen in mononuclear phagocytes in cases of focal cerebral infarction within 1−2.5 days that remained elevated until late stages. This early CD14 expression is suggested to be an essential part of CD14 in the acute inflammatory response following stroke. As mentioned above, Lin et al. (1998) induced

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Fig. 14.12a−d. Increase of activated mononuclear phagocytes in an ischemic injured brain. CD68-positive macrophages are seen a in a perivascular position and b diffusely distributed in the

global ischemia in rats and observed reactive microglia in the striatum which peaked at 1 week, as in the CA1 hippocampus. Single hemosiderin-containing macrophages may be demonstrated after 3 days of survival time (Hammes 1944; Oehmichen and Raff 1980). Lipid-containing foam cells are demonstrable after 3−8 days (Baggenstoss et al. 1943; Strassmann 1945), while myelin-containing macrophages are described after a survival period of 44 h (Schröder 1983).

14.3.9 Mesenchymal Reaction The reactivity of endothelial cells as well as the release of collagenous fibers by fibroblasts will characterize the mesenchymal reaction. The endothelial cells will increase by proliferation with the consequence of an intense vascularization which is evident at the 6th to 10th day after the ischemic event (Garcia and Kamijyo 1974). The increase of collagenous fibers will accompany the endothelial cell proliferation and will peak 1 week after ischemia has occurred (Baggenstoss et al. 1943). The time course of fibroblast proliferation and increase of collagenous fibers in brain wounds remain unknown.

white matter as well as c, d in the cornu Ammonis (a−d CD68 reactivity; magnification a, b ×200, c, d ×500)

14.3.10 Cytokines According to recent investigations cytokines play an important role in ischemia, functioning partly as neurotoxic and partly as neuroprotective (for review see Garcia et al. 1997; Stoll et al. 2000). Feuerstein et al. (1994) could demonstrate tumor necrosis factor-α (TNF-α) mRNA within 1 h after ischemia and upregulation of interleukin-(IL-)6 mRNA or protein preceding the emigration of neutrophils. Microglia may be the source of TNF-α (Gregersen et al. 2000). Kita et al. (1997) measured the level of TNF-α protein in rat cerebrospinal fluid and found a gradual increase during the first hour to a maximal elevation at 3 h and 6 h. The cerebral ischemia caused by permanent occlusion of the middle cerebral artery produces a dramatic increase in IL-6 bioactivity in the ischemic hemisphere within 2 h with further increases at 8 h and 24 h (Loddick et al. 1998). An increased expression of the various isoforms and their receptors of the transforming growth factor-β (TGF-β) by means of immunohistochemistry has been observed as early as 6 h in neurons, endothelial cells, astrocytes, and inflammatory cells (Ata et al. 1997; Ata 2000).

CHAPTER 14: Forensic Types of Ischemia and Asphyxia

Fig. 14.13a, b. Selective neuronal necrosis of the inferior olivary nucleus of the medulla and reactive mononuclear phagocytes. Perineuronal aggregation of CD68-reactive mononuclear phagocytes indicating their scavenger function (a, b CD68 immunoreactivity; magnification a ×50; b ×300)

A dramatic upregulation of surface expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial-leukocyte adhesion molecule-1 (E-selectin) occurred in human endothelial cell culture of cerebral vessels by 4−24 h of exposure (Stanimirovic et al. 1997; Stanimirovic and Satoh 2000) and in rat brain up to 24 h after reperfusion (beginning between 1 and 3 h after reperfusion − see Matsuo et al. 1994a). Acarin et al. (2000) could observe expression of the signal transducer and activator of transcription 3 (STAT 3) in astrocytes as early as 2−4 h after ischemia. The platelet-derived growth factor-β chain (PDGF-β) is distinctly expressed in human neurons (CA1 sector) 6 h after ischemic insult (Kaneko et al. 1998). TGF-β was demonstrable in human autopsy material 1−3 days after insult in perifocal neurons, reactive astroglial cells, endothelial cells, and macrophages (Ata et al. 1999). Immunohistochemistry revealed enhanced reactivity of PDGF-β in neurons in the infarct and in the peri-infarct area from 16 h to 4−7 days, with a peak at 24 h (Iihara et al. 1994).

Fig. 14.14a, b. Selective neuronal necrosis in the cornu Ammonis and reactive mononuclear phagocytes (see also Fig. 4.19). a Intact neurons as demonstrated by MAP immunoreactivity; b the same area (CA1 sector) demonstrates CD68-reactive mononuclear cells which replace the lost neurons of the hippocampal cortex (magnification a, b ×500)

14.3.11 Enzymes An ischemic insult leads to a significant expression of nitric oxide synthase-2 (Loihl and Murphy 1998), which was demonstrated to occur in permanent vessel occlusion in rats on the second to third day post ischemia returning to baseline within 7 days. Recently Tomimoto et al. (2002) demonstrated by means of immunohistochemistry that cyclooxygenase 2 (COX2) was induced robustly in neuronal cell bodies and dendrites during the acute stages of focal ischemic damage and was also upregulated in microglial cells.

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Fig. 14.15a−c. Selective neuronal injury to Purkinje cells and reactive mononuclear phagocytes. a The lost Purkinje cells were replaced, b by an increase in GFAP-reactive astrocytes and c increase of CD68-reactive mononuclear phagocytes (a H&E; b GFAP immunoreactivity; c CD68 immunoreactivity; magnification a, b ×200; c ×400)

14.4 Clinical Features of Acute Asphyxia If the carotid circulation is totally occluded for an unremitting period of 4 min or more, then irreversible cerebral damage may occur. Permanent brain damage is very unlikely if the supply has been cut off continuously for less than 4−5 min. Total recovery has often been recorded after total ischemia of considerably longer than this, even in normothermic con-

ditions, with 9−14 min being quoted. When the body has been exposed under hypothermic conditions, a longer time has been recorded, e.g., 2 h (p. 247). Experimental data cited by DiMaio and DiMaio (2001) give evidence of additional features. Rossen et al. (1943) conducted experiments on 126 normal male volunteers by using an inflatable pressure cuff placed on the lower third of the neck that produced 80 kPa (600 mmHg) within one-eighth of a second of inflation. Acute occlusion of the arterial circulation resulted in blurring of vision, constriction of the visual fields, loss of consciousness, and convulsions. Half of the volunteers lost consciousness in 6−6.5 s; the overall range was approximately 5−11 s. The pressure cuff was released upon loss of consciousness with complete recovery within 1−2 min after the procedure and no subsequent neurologic sequelae. The electroencephalogram showed large, slow waves correlating with the loss of consciousness. The same team studied the effects of prolonged occlusion of cerebral circulation in 11 volunteers. Cervical pressure was maintained for as long as 100 s in some tests. The subjects regained consciousness in 30−40 s and were able to leave the room in 2 min. Convulsions, cyanosis, involuntary urination and defecation in some subjects, bradycardia, and dilatation of the pupils followed loss of consciousness. Bradycardia developed, with the heart rate dropping as much as 50%. Respiration continued throughout the test, increasing in rate. The hemodynamics as well as the respiratory regulation were also documented in children surviving a strangulation. Hanigan et al. (1996) could record a dissociative vasoparalysis with loss of autoregulation and preservation of CO2 reactivity in two cases. Ashwal et al. (1991) observed four cases and noticed that although cerebral blood flow (CBF) was normal in these four children, the hyperventilation response was depressed, variable, and even paradoxical which may be important in the evolution of further brain injury and is a critical factor in deciding whether hyperventilation may be of clinical benefit. Three factors correlated with poor outcome and ultimately death in two patients: an initial blood glucose >300 mg/dl and a CBF/pCO2 response of 12%) Extensive brain swelling Herniation (hippocampal, tonsillar) Brown discoloration Pink centrum semiovale due to poor fixation Poorly defined demarcation of gray and white matter Microscopic examination Structural effacement/washed out tissue picture due to poor staining

law: a car leaves the highway without any explanation and hits a tree at high speed, killing the driver. The diagnosis at autopsy: myocardial infarction; while the postmortem reveals crushing of the skull and brain. The lawyer contends that myocardial infarction − also cardiac arrest − does not meet the criteria for determining death under the brain death classification, and that the death, in fact, resulted from the crushing of the brain in the accident. A claim on the accident insurance was therefore made. Berg and Helwig (1990) have shown that the time of brain death can also have a bearing on certain aspects of criminal law.

Eosinophilia without tissue reaction

Example 2. A doctor refuses to come to the aid of a

Regressive neuronal changes

child severely injured in an accident, who continues to exhibit gasping for breath. The question here is whether brain death had already occurred within 30 min after the accident, that is at a time when the doctor could have come to the aid of the child.

Congestion Borderzone alterations (hemorrhages, cell reactions) Anterior pituitary lobe C1/C3 cervical segments of the cord Displacement of cerebellar tissue of the subarachnoid space of the spinal column Infarction of the optic tract

16−21 h. Single eosinophilic neurons are seen >48 h after cessation of intracranial blood flow in nearly all cases within the cerebral cortex and, especially, within the medulla oblongata. This late eosinophilic expression allows the supposition that the stagnant blood flow prevents the eosinophilic transformation of neurons. Inflammatory reactions within the subarachnoid space do not correlate with the survival time. Reduction of Luxol fast blue stain in the optic nerve and cervical cord are still observed after 8 h of survival time. Spongious demarcation develops after 12−16 h. Demarcating hemorrhages are observed after 30 h of survival time, especially in the cervical cord, and only in one-third of cases (Schneider et al. 1969). Demarcating emigration of leukocytes is seen as early as 24 h; especially in the leptomeninges. A demarcating macrophage reaction is observed 38 h after cessation of intracranial blood flow in the spinal cord (but not in the optic nerve), while an astrocytic reaction is absent. A number of forensic practitioners have dealt with the forensic implications of determining the time of

15.5.4 Time of Causal Event Leading to Brain Death If brain death occurs as a result of ischemic (→ edema) or mechanical (→ hemorrhage) violence, the time of the causal event must be determined, especially in cases involving more than one causal event. Example. A 30-year-old man suffers occult craniocerebral trauma in a fight; the injury, however, does not require immediate medical treatment. Twentyfour days later the man collapses under unknown circ*mstances and is found unconscious. A subdural hematoma is diagnosed and drained. A secondary hemorrhage develops, leading to intracranial circulatory arrest. The question of concern for criminal law is whether death was a result of the fight or of injury sustained from the collapse. In this case, demonstration of reactive cells, i.e., of siderophages, proved that death was a result of the fight. Particular importance attaches to the difference in the case of crimes of violence creating conditions that predispose to brain death when the significance of a further violent act, e.g., stabbing with resultant hemorrhage, has to be assessed. The simple vital reaction of bleeding does not in itself constitute proof in such a situation, unless it is possible to say with a good degree of certainty that brain death did not occur at the moment when the victim was stabbed. It may, however, be possible to state that brain death

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that could have been caused by violence has not yet occurred if complex vital reactions, such as inflammation of a wound, are seen (Adebahr 1986). Adebahr (1986) discussed another point of view in forensic pathology: the diagnosis of poisoning as the cause of brain death can be checked by toxicological examination of brain tissue and of blood in the sinus of the dura mater, since the metabolism in the brain and sinus blood is markedly reduced while drugs and toxic substances continue to be broken down in other organs. 15.5.5 Morphological Statement of Intracranial Circulatory Arrest Brain death is characterized by morphological changes without accompanying glial or hematogenous cell reactions, with one exception: the demarcation reaction (see above). In contrast, if reperfusion occurs, reactive cells will be present, as pointed out by Pearson et al. (1977, 1978). Thus, the near-complete lack of reactive changes must be regarded as a definitive indicator of total intracranial circulatory arrest. Schröder (1978, 1983a), by contrast, observed inflammatory alterations beginning in the posterior cranial fossa as a consequence of a partial recirculation 2 days after intracranial circulatory arrest. Hemorrhagic inflammatory phenomena can even be the consequence of reperfusion due to a diminution of the high intracranial pressure, first in the posterior cranial fossa and then also in the supratentorial region. These findings were confirmed, although to a much lesser extent, by Ito and Kimura (1992). Usually there are no difficulties in declaring morphological proof of brain death on the basis of necrosis of the whole brain. In case reactive cells appear, this should not be proof of a (at least partly) successful reperfusion. Otherwise, the reactive changes at the border zones of the optic nerve, hypophysis, and the cervical cord may provide some evidence of the survival time of the intracranial circulatory arrest.

Bibliography Auer RN, Sutherland G (2002) Hypoxia and related conditions. In: Graham D, Lantos P (eds) Greenfield‘s neuropathology, 7th edn., vol 1. Edward Arnold, London, pp 233−280 Lindenberg R (1955) Compression of brain arteries as a pathogenic factor for tissue necrosis and their areas of predilection. J Neuropathol Exp Neurol 14:233−243 Walker AE (1985) Cerebral death, 3rd edn. Urban and Schwarzenberg, Baltimore, Md.

References Ad Hoc Committee on Brain Death (1987) Determination of brain death. J Pediatr 110:15−19 Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death (1968) A definition of irreversible coma. J Am Med Assoc 205:337−340 Adebahr G (1986) Aspekte des Hirntodes. Z Rechtsmed 97:207−212 Ames A III, Nesbett FB (1983) Pathophysiology of ischemic cell death. I. Time of onset of irreversible damage; importance of the different components of the ischemic insult. Stroke 14:219−226 Backlund E-O (1999) Brain death in practice − a retrospective view. Acta Neurochir Suppl 74:65−68 Beresford HR (1977) The Quinlan decision. Problems and legislatives. Ann Neurol 2:74−81 Berg S, Helwig A (1990) Die Bedeutung einer antezipierten Hirntodvermutung für den Vorwurf unterlassener Hilfeleistung gem. Section 323c StGB. Z Rechtsmed 103:279−290 Bernat JL, Culver CM, Gert B (1981) On the definition and criterion of death. Ann Intern Med 94:389−394 Black PM (1978) Brain death. N Engl J Med 299:338−344, 393−401 Bodsch W, Barbier A, Oehmichen M et al (1986) Recovery of monkey brain after prolonged ischemia. II. Protein synthesis and morphological alterations. J Cereb Blood Flow Metab 6:22−23 Capron AM (2001) Brain death − well settled yet still unresolved. N Engl J Med 344:1244−1246 Deutsch E (1997) Extremsituationen: Notfall, Intensivmedizin, Sterbehilfe, Todeszeitpunkt, Sektion. In: Deutsch E (ed) Arztrecht und Arzneimittelrecht. Springer, Berlin Heidelberg New York Fischer EG (1973) Impaired perfusion following cerebrovascular stasis. A review. Arch Neurol 29:361−366 Gerber E (1984) Brain death, murder and the law. Med J Aust 140:536−537 Grassberger R (1973) Juristische Aspekte des dissoziierten Hirntodes. In: Krösl W, Scherzer E (eds) Die Bestimmung des Todeszeitpunktes. Maudrich, Vienna, pp 295−298 Guidelines for the determination of death (1981) J Am Med Assoc 246:2184−2186 Hamburger J (1988) A propos de “mort cérébrale.” Bull Acad Natl Med 172:703 Hirsch H (1982) Recovery of the electrocorticogram after incomplete and complete ischaemia of the brain. Acta Neurochir 66:147−158 Hirsch H, Müller HA (1962) Funktionelle und histologische Veränderungen des Kaninchengehirns nach kompletter Gehirnischämie. Pflügers Arch 275:277−291 Holczabek W (1973) Gerichtsmedizinische Aspekte des dissoziierten Hirntodes. In: Krösl W, Scherzer E (eds) Die Bestimmung des Todeszeitpunktes. Maudrich, Vienna, pp 267−270 Hossmann K-A (1988) Resuscitation potentials after prolonged global cerebral ischemia in cats. Crit Care Med 16:964−971 Hossmann K-A, Kleihues P (1973) Reversibility of ischemic brain damage. Arch Neurol 29:375−384

CHAPTER 15: Permanent Global Ischemia

Ito Y, Kimura H (1992) Early and late meningeal reaction to trauma after long-term brain death. Forensic Sci Int 56:189−194 Jabre A, Bao Y, Spatz EL (2000) Brain pH monitoring during ischemia. Surg Neurol 54:55−58 Kleihues P, Hossmann K-A (1973) Regional incorporation of L-[33H] tyrosine into cat brain proteins after 1 hour of complete ischemia. Acta Neuropathol (Berl) 25:313−324 Korein J (1978) Terminology, definition, and usage. Ann NY Acad Sci 315:6−10 Kramer W (1966) Extensive necrosis of the brain development during reanimation. Proceedings of the 5th International Congress on Neuropathology. Excerpta Med Int Congr Ser 100:33−45 Kramer W (1973) Neuropathologische Befunde nach intravitalem Hirntod. In: Krösl W, Scherzer E (eds) Die Bestimmung des Todeszeitpunktes. Maudrich, Vienna, pp 223−231 Lindenberg R (1972) Systemic oxygen deficiencies: the respirator brain. In: Minckler J (ed) Pathology of the nervous system, vol 2. McGraw-Hill, New York, pp 1583−1617 Negovsky VA, Gurvitsch AM, Zolotokrylina ES (1983) Postresuscitation disease. Elsevier, Amsterdam Oehmichen M (1994) Brain death: neuropathological findings and forensic implications. Forensic Sci Int 69:205—219 Oehmichen M (1996) Serientötung, Tötung und Lebensverkürzung. In: Oehmichen M (ed) Lebensverkürzung, Tötung und Serientötung – eine interdisziplinäre Analyse der ”Euthanasie”. Research in legal medicine, vol 15. Schmidt-Römhild, Lübeck, pp 229−248 Ogata J, Yutani C, Imakita M et al (1986) Autolysis of the granular layer of the cerebellar cortex in brain death. Acta Neuropathol (Berl) 70:75−78 Pearson J, Korein J, Harris JH et al (1977) Brain death: II. Neuropathological correlation with the radioisotopic bolus technique for evaluation of critical deficit of cerebral blood flow. Ann Neurol 2:206−210 Pearson J, Korein J, Braunstein P (1978) Morphology of defectively perfused brains in patients with persistent extracranial circulation. Ann NY Acad Sci 315:265−271 Pendl G (1986) Der Hirntod. Springer, Berlin Heidelberg New York Roxin C (1973) Zur rechtlichen Problematik des Todeszeitpunktes. In: Krösl W, Scherzer E (eds) Die Bestimmung des Todeszeitpunktes. Maudrich, Vienna, pp 299—302 Plesnila N, Haberstok J, Peters J et al (1999) Effect of lactacidosis on cell volume and intracellular pH of astrocytes. J Neurotrauma 16:831−841 Safar P (1986) Cerebral resuscitation after cardiac arrest. A review. Circulation 74 (Suppl IV):138−153 Safar P (1988) Resuscitation from clinical death: pathophysiologic limits and therapeutic potentials. Crit Care Med 16:923−941 Safar P, Gisvold SE, Vaagenes P et al (1982) Long-term animal models for the study of global ischemia. In: Wauquier A, Borgers M, Amery WK (eds) Protection of tissues against hypoxia. Elsevier, Amsterdam, pp 147−170 Safar P, Breivik H, Abramson N, Detre K (1987) Brain resuscitation clinical trial (BRCT). I. Study group reversibility of clinical death in patients: the myth of the 5-min limit (abstract). Ann Emerg Med 16:496

Safar P, Sterz F, Leonov Y et al (1993) Systematic development of cerebral resuscitation after cardiac arrest. Three promising treatments: cardiopulmonary bypass, hypertensive hemodilution, and mild hypothermia. Acta Neurochir Suppl (Wien) 57:110−121 Sayer H, Wiethölter H, Oehmichen M, Zentner J (1981) Diagnostic significance of nerve cells in human CSF with particular reference to CSF cytology in brain death syndrome. J Neurol 225:109−117 Schneider H (1970) Der Hirntod. Begriffsgeschichte und Pathogenese. Nervenarzt 41:381−397 Schneider H, Masshoff W, Neuhaus GA (1969) Klinische und morphologische Aspekte des Hirntodes. Klin Wschr 47:844−859 Schneider M, Matakas F (1973) Zur Morphologie des Hirntodes. In: Krösl W, Scherzer E (eds) Die Bestimmung des Todeszeitpunktes. Maudrich, Vienna, pp 213−221 Schröder R (1978) Chronomorphology of brain death. Adv Neurosurg 5:346−348 Schröder R (1983a) Later changes in brain death. Signs of partial recirculation. Acta Neuropath (Berl) 62:15−23 Schröder R (1983b) Chronomorphologie der zerebralen Durchblutungsstörung. Springer, Berlin Heidelberg New York Schröder R, Richard KE (1980) Time-interval between a brain lesion and the onset of brain death. A contribution to the inherent dynamics of malignant brain swelling. Neurosurg Rev 3:183−188 Schwerd W (1969) Todeszeit und Leichenschau heute und morgen. Arztrecht 11:163−166 Siesjö BK (1981) Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab 1:155−185 Siesjö BK (1988) Historical overview. Calcium ischemia, and death of brain cells. Ann NY Acad Sci 522:638−661 Spann W (1973) Die Bestimmung des Todeszeitpunktes aus gerichtsärztlicher Sicht. In: Krösl W, Scherzer E (eds) Die Bestimmung des Todeszeitpunktes. Maudrich, Vienna, pp 263−266 Swash M, Beresford R (2002) Brain death. Still-unresolved issues worldwide. Neurology 58:9−10 Symon L (1993) Recovery of brain function following ischemia. Acta Neurochir 57:102−109 Towbin A (1973) The respirator brain death syndrome. Hum Pathol 4:583−594 Vaagenes P, Cantadore R, Safar P et al (1984) Amelioration of brain damage by lidoflazine after prolonged ventricular fibrillation cardiac arrest in dogs. Crit Care Med 12:846−855 Walker AE (1985) Cerebral death, 3rd edn. Urban and Schwarzenberg, Baltimore, Md. Walpoth BH (2004) Accidental hypothermia: diagnosis and treatment. In: Oehmichen M (ed) Hypothermia. Clinical, pathom*orphological and forensic features. In: Research in legal medicine, vol 3. Schmidt-Römhild, Lübeck, pp 269−278 Wijdicks EFM (2001) The diagnosis of brain death. N Engl J Med 344:1215−1221 Wijdicks EFM (2002) Brain death worldwide. Accepted fact but no global consensus in diagnostic criteria. Neurology 58:20−25 Youngner SJ (1992) Defining death. A superficial and fragile consensus. Arch Neurol 49:570−572

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Intoxication

Chapter 16 Introductory Remarks

IV

333

Chapter 17 Specific Types of Neurotoxins

339

Chapter 18 Alcohol, Organic Solvents, and Aerosols Chapter 19 Illegal Drugs and Drug Dependence

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371

CHAPTER 16

Introductory Remarks

16.1

Biological Principles 333

16.2

Toxic Encephalopathy

16.3

Toxic Neuropathy/Polyneuropathy

335 336

Bibliography 337 References

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16.1 Biological Principles Poisoning refers to the damaging physiologic effects of ingestion of, inhalation of, or other exposure to, a range of pharmaceuticals, illicit drugs, and chemicals, including pesticides, heavy metals, and gases/ vapors. Poisoning can be caused by common household substances, such as bleach and ammonia, as well as by animals and plants. In the United States the death rate from poisoning increased from 5.0 per 100,000 population in 1990 to 7.8 in 2001, i.e., 56%. In 2001, of 22,242 poisoning deaths, 14,078 (63%) were unintentional (Morbidity and Mortality Weekly Report 2004, 53:233−238). Intoxication involving the central and peripheral nervous systems (CNS and PNS) can be classified in several ways. The present Part presents, in alphabetical order, neurotoxic poisonings based on groups of substances ingested, injected or otherwise absorbed. Intoxication due to alcohol or the use of illicit drugs will be treated separately as the effects of these substances are encountered with incomparable frequency in forensic pathology and neuropathology. Poisoning occurs intentionally (suicide, addiction, homicide) or unintentionally (occupational, environmental or iatrogenic poisoning). Poisoning with homicidal intent rarely occurs today and its consequences are seldom seen in institutes of forensic pathology. When deliberate poisoning does occur, it usually affects elderly, helpless patients and is often done to shorten the dying process (active euthanasia). Sometimes, from the criminological point

16

of view, it occurs for financial reasons (Oehmichen 1996; Oehmichen and Meissner 2000) or in the spectrum of deranged physician behavior, as in the recent Shipman murders, in the United Kingdom. Meanwhile the risk of biological and chemical terrorism is in discussion, especially by cyanide poisons, organophosphate poisons, botulinum toxin, and anthrax, which affect the nervous system (Martin and Adams 2003). However, the majority of poisonings today are accidental and affect children (Ashton 1981; Proudfoot 1989; Kruse and Oehmichen 1994; Bays and Feldman 2001). Many are also due to pollution of the environment or workplace, and accidental or iatrogenic medication overdose. Nevertheless, the current public discussion is predominantly focused on the problems associated with chronic alcoholism and drug abuse. The severity of any given case of poisoning depends on the solubility, dosage, route of administration (oral or parenteral), as well as the degree of absorption, the distribution and elimination, which finally determine the effective concentration of the toxic substance within the CNS or PNS or the body. As a rule, poisoning can only be verified by chemicaltoxicological analysis. This is true not only for acute poisoning, which can be demonstrated by determination of the levels of foreign substances and/or their metabolites in the blood, but also for poisoning that is chronic, intermittent or occurred in the distant past, which can be confirmed qualitatively (and within certain limits also quantitatively) by the demonstration of the presence of the toxic substance in urine, hair (Frisch et al. 1997; Sachs 1997) or − even in long-dead cadavers − in the bone (Rochholz et al. 1999). A suspicion of poisoning should be raised in cases for which no other plausible explanation for an illness or death is forthcoming, whenever the clinical symptoms and/or morphological changes detected by the pathologist/neuropathologist are generally consistent with a state of poisoning, or when specific characteristic symptoms or morphological alterations are present. Morphological changes are especially helpful in establishing the occurrence of poisoning in cases with long subsequent periods of survival.

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The nervous system is the primary target organ for many toxic substances or it may suffer secondary damage mainly affecting the neurons and their processes. It is well known that not all areas of the brain and not all neuronal systems react to toxins in an identical manner. The term “pathoclisis” introduced by Cecile and Oskar Vogt (1937) indicates a specific affinity of certain toxins for certain systems of organs, but this term of the Vogts was applied broadly, to include ischemia as well. It includes the selective vulnerability of specific neurons to respective toxins in specific topographic areas of the brain. As is known from cases of status epilepticus, cardiac arrest and hypoglycemia, a loss of neurons may be observed in various combinations involving or sparing anatomical structures in neocortex, hippocampus, thalamus, and brain stem (Auer and Siesjö 1988). The same general phenomenon of selective vulnerability is observed in poisonings (Whetsell 2002). Abnormalities in energy homeostasis as the triggering or causative mechanism have been suggested as an explanation for this phenomenon, but this explanation does not hold up, since epilepsy, for example, does not even involve energy failure. It has been discovered that when endogenous glutamate reaches high concentrations in the synaptic cleft, it binds at specific sites, initiating a series of receptor, ionic, and metabolic events that can lead to neuronal destruction (Collins 1987). The phenomenon of pathoclisis, or selective vulnerability, also enables the experimental simulation of pathological processes associated with topographically circ*mscribed foci of neuronal or axonal degeneration (Ceccarelli and Clementi 1979; Baumgarten and Zimmermann 1992). It is known that insecticides, methanol, heavy metals, and organic solvents are sources of striatal injury (Whetsell 2002). As reviewed by Whetsell (1996, 2002) the selective vulnerability of neurons is partly caused by the differing receptor binding capacity of the neurons. Heptachlor, for example, has demonstrated its toxicity to γ-aminobutyric acid (GABA-ergic) neurons. More recently it was found that heptachlor alters dopamine transporter functions such that dopamine uptake at dopamine terminals in the striatum is decreased at higher levels of exposure (Kirby et al. 2001). In contrast, chloropyrifox is shown to cause persistent impairment of cholinergic synaptic function (Slotkin et al. 2001). Moreover, the selective vulnerability is explained by the different expression of glutamate receptors. Those receptors are the basis of disastrous excitotoxicity when excessively stimulated by glutamate or its structural analogs. Endogenous glutamate analogs of particular importance are aspartate and quinolinic acid, since these are not the natural ligands, yet have high affinity for the receptor, with the ability to activate it. The phenomenon of excitotoxicity is described as “axon-sparing,

postsynaptic degeneration” based on its electron microscopic appearance, occurring specifically at glutamatergic synapses which are, of course, the prototypic excitatory synapses (Whetsell 1996). Astrocytes may also suffer structural and/or functional injury, e.g., after water or lead poisoning. Proper CNS function involves interactive signaling between astrocytes and neurons (Aschner et al. 2002). For example, an alcohol-induced decrease in glial cell proliferation and increased cell death in response to cytokines has been suggested as an important mechanism involved in the neurological and neurobehavioral dysfunction associated with prenatal alcohol exposure (De Vito et al. 2000). Abnormalities in glutamate metabolism and glutamatergic neurotransmission appear to play an important role in the pathogenesis of hyperammonemia and hepatic encephalopathy (Norenberg 1995). Both conditions result in excessive ammonia accumulation within the CNS due to liver failure. The exclusive site for the detoxification of glutamate to glutamine is within astrocytes. This process requires ATP-dependent amination of glutamate to glutamine, a process mediated by the astrocyte-specific enzyme glutamine synthetase. In vivo chronic exposure to ammonia leads to decreased glutamine metabolism within the astrocytes and impairment of astrocytic energy metabolism (Norenberg 1995). Oligodendrocytes in the CNS may suffer selective damage, e.g., from diphtheria toxin or ethidium bromide. The possibility of poisoning and its severity also depends − among other factors − on the biological age of the victim (Auer 1991). The fetus for example passes through phases of particular vulnerability to toxic effects, the sequelae of which include malformations (dysmelia) and long-term functional impairment (Ashton 1981). In children, even small doses can have a toxic effect not seen in adults, and there is an unknown consistent correlation between dosage and body mass (Bays and Feldman 2001). The elderly, too, are especially vulnerable because of agerelated changes in vascular walls, fluctuations in blood pressure, changes in the immune system, and functional impairment of single organ systems such as liver or kidney. Regardless of age, however, the chronic application of small doses of many substances during gestation may have teratogenic effects. For interpretation of chemical analytical findings the following experiences are to be considered: it is known that − for example − cardioactive drugs such as digoxin accumulate in the heart during an individual‘s life time and are released into the cardiac blood after death. Therefore, it is basically advisable to use peripheral blood or vitreous humor when screening for cardiac drugs to avoid obtaining spuriously high levels in blood from the heart.

CHAPTER 16: Introductory Remarks

The clinical and morphological effects of poisoning by different neurotoxic agents can be roughly differentiated according to their principal target site, i.e., toxic encephalopathy or toxic neuropathy.

16.2 Toxic Encephalopathy ▬

The suspicion of poisoning must always be raised in cases exhibiting clinically conspicuous psychophysical changes not attributable to illness or known disturbances in CNS function. This is also true in diagnosis in the field of anatomical pathology: if a morphological finding is not characteristic of any known disease of the CNS, then poisoning must be considered. Circ*mstances (environment, heavy drinking, drugs) or external markings (changes in the mouth, needle marks on the arms, constricted or dilated pupils, known or unknown smell, etc.) can also suggest a possible poisoning. Among the general clinical symptoms of poisoning are changes in global cognitive function, level of consciousness and vigilance. Dementia, seizures, headache, hydrocephalus, cerebellar syndromes, tremor, and disturbances of the visual, auditory, vestibular, or olfactory systems may also be observed. Morphologically, the following changes are almost universally present: ▬ Cerebral edema (Klatzo 1977), which is dependent upon the relative lipophilia of the toxic agent, its molecular weight, carrier-mediated transport mechanisms (e.g., cationization or glycolysation) and transport capacity. Cytotoxic edema resulting from membrane damage (heavy metals, triethyltin) and/or injury of the membrane enzyme system (heavy metals, cyanide) must be differentiated from vascular edema caused by, for example, alcohol, although the two types of edema may occur simultaneously or sequentially (for review see Oehmichen et al. 2001, see also p. 47). ▬ Neuronal and axonal injury, which is due to impaired axoplasmic transport (Müller and Jeschke 1970) resulting in isolated neuropathy or polyneuropathy (cf. toxic neuropathy), characteristic of, for example, aluminum, acrylamide, colchicine, organophosphate or alcohol poisoning. ▬ Neuronal injury, which is due to faulty energy metabolism (Krieglstein and Kuglisch 1992), the chief cause being carbon monoxide, but including also ethanol and organophosphates. Without ischemia due to heart failure, neither cyanide(MacMillan 1989) nor sulfide-induced (Baldelli et al. 1993) inhibition of energy metabolism causes necrosis.

Injury of the white matter, i.e., leukoencephalopathy, which is a structural alteration of cerebral white matter in which myelin suffers the most damage (Shields et al. 1998; Filley 1999; Filley and Kleinschmidt-DeMasters 2001). Toxic leukoencephalopathy may be caused by exposure to a wide variety of agents, including therapeutic agents, the misuse of drugs, environmental toxins, and cranial irradiation (see Table 16.1). Focal necrosis, which is caused by, for example, hyperbaric oxygen or carbon monoxide, methanol, heavy metals, and methotrexate. Injury of and functional impairment of cholinergic transmission (Dolly 1992; Hörtnagel and Hanin 1992), which is caused by, for example, phosphate esters, clostridium, botulinum and tetanus toxins, colchicine, alcohol, and aluminum. Damage to and functional impairment of the noradrenergic system, which is caused by, for example, alcohol, amphetamines, cocaine, and cannabinoids. Effects on a neurotransmitter system (Dolly 1992), in particular the receptors, with the excitatory receptors being most affected (GABA and acetylcholine receptors) in the absence of an obvious morphological equivalent. Effects on the visual system (Merigan and Weiss 1980), for example due to methanol, carbon disulfide, methyl mercury, and organophosphate poisoning. Teratogenic effects on the fetal nervous system caused by, for example, ethanol, methyl mercury, or carcinogenic effects, e.g., caused by cadmium.

At the cellular level, the following additional functional distinction can be made (Haschek and Rousseaux 1998): ▬ Neuronal oxidative metabolism: this may be impaired by ischemia or hypoxia secondary to poisoning. Toxic agents can also disturb the homeostasis of the electrolyte balance by: ▬ Inhibition of protein synthesis (e.g., adriamycin). ▬ Damage to the cytoskeletal structure (e.g., platinum). ▬ Triggering of a glial reaction (astrocytic changes in liver disease, oligodendroglial changes caused by triethyltin poisoning). ▬ Injury of capillaries, caused for example by heavy metals such as arsenic or inhalation of methyl bromide.

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Table 16.1. Causes of toxic leukoencephalopathy. Source: Filley and Kleinschmidt-DeMasters 2001

Anti-neoplastic agents Cranial irradiation

Fluorouracil

Methotrexate

Levamisole

Carmustine

Fludarabine

Cisplatin

Thiotepa

Cytarabine

Interleukin-2 Interferon-α

Antimicrobial agents Amphotericin B

Hexachlorophene

Drugs of abuse Toluene

Intravenous heroin

Ethanol

Inhaled “heroin” pyrolysate

Cocaine

Psilocybin

3,4-Methylenedioxymethamphetamine Environmental toxins Carbon monoxide

Carbon tetrachloride

Arsenic

16.3 Toxic Neuropathy/Polyneuropathy Excellent reviews are published by Dyck et al. (1975) and by Schröder (1999). The clinical features of toxic neuropathy are dependent upon the specific target site of the toxin in the PNS. A predominantly motor neuropathy can usually be distinguished from a predominantly sensory neuropathy. A distinction may also be made between primary involvement of the autonomic nervous system (vegetative neuropathy), cranial neuropathy, and changes in neuromuscular transmission and toxic myopathy. A causal distinction must be made between nutritionally produced neuropathy (e.g., vitamin B deficiency, alcohol) and endotoxic neuropathy secondary to a systemic metabolic disorder (e.g., diabetes mellitus, uremia, etc.). Neuropathy caused by poisoning must be suspected in the presence of the following clinical features (Schaumburg 2000): 1. Gradual insidious onset 2. Initial findings in the lower extremities 3. Stocking glove sensory and motor loss 4. Early and symmetrical loss of ankle jerk reflexes

5. Normal to mildly retarded motor nerve conduction 6. Normal protein level in the cerebrospinal fluid (CSF) 7. Slow recovery 8. Coasting 9. Signs of CNS disease 10. Pain (Schröder 1999) Pathogenetically, different systems can suffer damage, including the neuronal and axonal systems, the myelin sheath and oligodendrocytes, and/or the macrophage system. Various types of neuropathy must be differentiated (Thomas 1980) depending upon the primary localization of the respective functional impairment or morphological changes. The distal axonopathy denotes a selective distal degeneration of axons, progressing in a centripetal fashion: Cavanagh (1964) attributed this to a “dying-back” process, which he was able to produce experimentally in cats by administration of organophosphates. The process begins with degeneration of the large diameter sensory fibers, known also to be caused for example by acrylamide, organic hydrocarbons, or by carbon disulfide-induced poisoning.

CHAPTER 16: Introductory Remarks

The axons display focal enlargements due to aggregations of neurofilaments. In contrast to distal axonopathy, proximal and focal axonopathies are mainly of theoretical and experimental interest. Demyelination and Schwann cell alteration occur secondary to axonopathy. Some substances inflict primary injury of myelin, e.g., lead, diphtheria toxin or triethyltin and hexachlorophene (intramyelinic edema). Selective injury of Schwann cells is caused by 6-aminonicotinamide, for example. The pathological features are attributable mainly to primary or secondary degenerative changes and may also vary according to the target site. Axons, myelin, and/or Schwann cells may exhibit extensive disintegration. In the majority of cases, neuropathy produces macroscopically apparent neurogenic muscular atrophy (see Chaps. 2−5). Microscopy of a cross section of muscle reveals a neurogenic, i.e., panellike, atrophy of the muscle fibers (see Chaps. 6−12).

Bibliography Ashton HE (1981) Disorders of the foetus and infant. In: Davies DM (ed) Textbook of adverse drug reactions, 2nd edn. Oxford University Press, Oxford, pp 64−80 Bays J, Feldman KW (2001) Child abuse by poisoning. In: Reece RM, Ludwig S (eds) Child abuse: medical diagnosis and management, 2nd edn. Lippincott, Williams and Wilkins, Philadelphia, Pa., pp 405−441 Schaumburg HH (2000) Human neurotoxic disease. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Oxford University Press, Oxford, pp 55−82 Schröder JM (1999) Pathologie peripherer Nerven. In: Doerr W, Seifert G (eds) Spezielle pathologische Anatomie, vol 13/VIII. Springer, Berlin Heidelberg New York

References Aschner M, Sonnewald U, Tan KH (2002) Astrocyte modulation of neurotoxic injury. Brain Pathol 12:475−481 Ashton HE (1981) Disorders of the foetus and infant. In: Davies DM (ed) Textbook of adverse drug reactions, 2nd edn. Oxford University Press, Oxford, pp 64−80 Auer RN (1991) Excitotoxic mechanisms, and age-related susceptibility to brain damage in ischemia, hypoglycemia and toxic mussel poisoning. Neurotoxicity 12:541−546 Auer RN, Siesjö BK (1988) Biological differences between ischemia, hypoglycemia and epilepsy. Ann Neurol 24:699−707 Baldelli RJ, Green FHY, Auer RN (1993) Sulfide toxicity: the role of mechanical ventilation and hypotension in determining survival rate and brain necrosis. J Appl Physiol 75:1348−1353 Baumgarten HG, Zimmermann B (1992) Cellular and subcellular targets of neurotoxins: the concept of selective vulnerability.

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Müller HA, Jeschke R (1970) Cytologische Befunde an den motorischen Vorderhornganglienzellen beim Tetanus. Verh Dtsch Path Ges 54:650 Norenberg MD (1995) Hepatic encephalopathy. In: Kettenmann H, Ransom BR (eds) Neuroglia. Oxford University Press, New York, pp 950−953 Oehmichen M (ed) (1996) Lebensverkürzung, Tötung und Serientötung − eine interdisziplinäre Analyse der “Euthanasie”. Schmidt-Römhild, Lübeck Oehmichen M, Meissner C (2000) Life shortening and physician assistance in dying. Euthanasia from the viewpoint of German Legal Medicine. Gerontology 46:212−218 Oehmichen M, Ochs U, Meissner C (2001) Regional potassium distribution in the brain in forensically relevant types of intoxication. Neurotoxicology 22:99−107 Proudfoot AT (1989) Poisoning in children. In: Mason K (ed) Paediatric forensic medicine and pathology. Chapman and Hall Medical, London, pp 256−268 Rochholz G, Fischer F, Schütz T, Ritz-Timme S, Kaatsch H-J (1999) Nachweis von Drogen und Medikamenten in humanem Knochengewebe. Rechtsmedizin 9:A84 Sachs H (1997) Drogennachweis in Haaren. In: Kijewski H (ed) Das Haar als Spur. In: Research in legal medicine, vol 16, SchmidtRömhild, Lübeck, pp 119−133

Schaumburg HH (2000) Human neurotoxic disease. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Oxford University Press, Oxford, pp 55−82 Schröder JM (1999) Pathologie peripherer Nerven. In: Doerr W, Seifert G (eds) Spezielle pathologische Anatomie, vol 13/VIII. Springer, Berlin Heidelberg New York Shields LBE, Corey Handy T, Parker JC, Burns C (1998) Postmortem diagnosis of leukodystrophies. J Forensic Sci 43:1068−1071 Slotkin TA, Cousins MM, Tate CA, Seidler FJ, (2001) Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure. Brain Res 902:229−234 Thomas PK (1980) The peripheral nervous system as a target for toxic substances. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Williams and Wilkins, Baltimore, Md., pp 35−47 Vogt C, Vogt O (1937) Sitz und Wesen der Krankheit im Lichte der topistischen Hirnforschung und des Variierens der Tiere. J Psychol Neurol 47:237−457 Whetsell WO (1996) Current concepts of excitotoxicity. J Neuropathol Exp Neurol 55:1−13 Whetsell WO (2002) The mammalian striatum and neurotoxic injury. Brain Pathol 12:482−487

CHAPTER 17

Specific Types of Neurotoxins

17.1 17.1.1 17.1.2 17.1.2.1 17.1.2.2 17.1.3 17.1.4 17.1.5 17.1.6 17.1.6.1 17.1.6.2 17.1.7 17.1.8 17.1.9 17.1.9.1 17.1.9.2 17.1.10 17.1.11 17.1.12 17.1.12.1 17.1.12.2

Metals and Metallic Compounds 339 Aluminum (Al) 339 Arsenic (As) 341 Inorganic Arsenicals 341 Organic Arsenicals 341 Bismuth (Bi) 341 Cadmium (Cd) 342 Gold (Au) 342 Lead (Pb) 342 Inorganic Lead Compounds 342 Organic Lead Compounds 343 Lithium (Li) 343 Manganese (Mn) 344 Mercury (Hg) 344 Elementary Mercury and Inorganic Mercury Compounds 344 Organic Mercury Compounds 344 Platinum (Pt) 345 Thallium (Tl) 346 Tin (Sn) and Tin Compounds 346 Triethyltin 346 Trimethyltin 346

17.2.2 17.2.2.1 17.2.3

Non-Metallic Inorganic Neurotoxins 347 Phosphorus (P) and Phosphorous Compounds 347 Sulfur (S) 347 Carbon Disulfide 347 Tellurium (Te) 347

17.3 17.3.1 17.3.1.1 17.3.1.2 17.3.1.3 17.3.2 17.3.3 17.3.4 17.3.5

Gases 347 Carbon Monoxide (CO) 347 Acute Intoxication 349 Intermittent Exposure 350 Chronic Intoxication 351 Cyanides and Cyanide Compounds Hydrogen Sulfide (H2S) 352 Nitrous Gases and Nitrites 352 Oxygen (O2) 352

17.4 17.4.1 17.4.2 17.4.3 17.4.3.1 17.4.3.2

Industrial and Environmental Toxins Acrylamide 353 Aliphatic Hydrocarbons 353 Halogenated Hydrocarbons 353 Methyl Chloride 353 Trichloroethylene 353

17.2 17.2.1

17.4.4 17.4.4.1 17.4.4.2 17.4.5 17.4.6 17.4.7

Chlorinated Cyclic Hydrocarbons 354 Hexachlorophene (HCP) 354 Lindane 354 Methyl Alcohol (Methanol) 354 Organophosphorus Compounds 355 Toxic Oil 356

17.5

Nerve Agents

17.6 17.6.1 17.6.2 17.6.2.1 17.6.2.2 17.6.3 17.6.3.1 17.6.3.2 17.6.3.3

Drugs and Pharmaceutical Products 357 Sedatives, Hypnotics and Analgesics 357 Antiprotozoal Agents 358 Chloroquine 358 Clioquinol 358 Cytostatics and Antituberculous Agents 359 Methotrexate 359 Vincristine, Vinblastine 359 Isoniacid 360

17.7 17.7.1 17.7.2 17.7.3 17.7.3.1 17.7.3.2 17.7.3.3 17.7.3.4

Biological Toxins Plants 360 Animals 362 Microorganisms Botulinum Toxin Tetanospasmin Diphtheria Toxin Anthrax 363

356

360

362 362 362 363

Bibliography 363 References

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363

17.1 Metals and Metallic Compounds 17.1.1 Aluminum (Al)

353

Source. Aluminum (Al) is ubiquitous in its oxidized form, present in air, food, and water. Its main industrial use is in the metal working industries. Aluminum hydroxide is frequently used as an antacid without producing clinical symptoms. However,

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clinical features attributed to aluminum intoxication have been described after chronic dialysis (see also p. 613 f) with dialysis fluid containing aluminum as well as following oral administration of phosphatebinding agents containing aluminum (McLaughlin et al. 1962; Alfrey et al. 1976; Elliott et al. 1978; Martyn et al. 1989). A relationship has been hypothesized between exposure to aluminum in food and water and Alzheimer’s disease (Wisniewski et al. 1979). The normal concentration of aluminum in the brain is ≤10 µg/l, which increases with age. Pathogenesis. If the blood contains elevated levels

of aluminum in association with a compromised blood−brain barrier (McDermott et al. 1978), the brain will also have elevated levels of aluminum (Crapper McLachlan et al. 1983). Plasma levels above 100 µg/l are potentially toxic; levels exceeding 500 µg/l are indicative of acute aluminum poisoning. At the cellular level, aluminum is known to disrupt the slow transport of neurofilament proteins (NFP), which leads to an accumulation of NFP at the proximal end of the axon (Bizzi et al. 1984; Bin and Garfinkel 1994) and a proliferation of microfilaments in the perikaryon (Klatzo et al. 1965; Weinstein 1974). The similarity of clinical symptoms in association with elevated levels of aluminum demonstrated in the brains of victims of dementia of Alzheimer type (Crapper McLachlan et al. 1983) has given rise to a theory that Alzheimer’s disease may be caused by an accumulation of aluminum in the brain (Martyn et al. 1989). This hypothesis has fallen out of favor. Clinical Features. Aluminum poisoning is character-

ized by progressive dementia with speech impairment, myoclonus, focal and/or generalized epileptic seizures, focal neurological symptoms, and loss of consciousness. An aluminum-induced degeneration of motor neurons must be distinguished from a dialysis encephalopathy. The disease can end in death. The differential diagnosis must include Alzheimer’s disease. Desferrioxamine is the specific chelating antidote.

Fig. 17.1a−d. Dialysis-associated encephalopathy. a Hypoglossal neuron with pathognomonic deeply black, fine-granular cytoplasmic inclusions in dialysis-associated encephalopathy in comparison with the brownish neuronal lipofuscin in neurons of the inferior olivary nucleus (b − silver staining; ×2000). c Laser microprobe mass analysis with aluminum peak at m/z 27, confirming the high aluminum content of silver-stained inclusions (peaks at m/z 104 and 106 result from silver staining). d Electron microscopy with partly electron-dense, partly bizarre electron-lucent material of (aluminum-containing) inclusions (×40,000). The figure was kindly provided by Professor Dr. E. Reusche, Lübeck

Morphology. The morphological changes caused by aluminum intoxication are non-characteristic in H&E preparations (McLaughlin et al. 1962). Ganglion cells are shrunken, but usually there is no clear decline in their numbers. Some differences can be demonstrated immunohistochemically: in aluminum poisoning, neurons do not react to microtubule-associated protein 2 (MAP-2), β-tubulin or ubiquitin, while in Alzheimer's disease they do (Strong et al. 1991). Aluminum poisoning is also associated with proliferation of microglia and astrocytes as well as a spongiform disintegration of the neuropil in the second and third cortical layer.

CHAPTER 17: Specific Types of Neurotoxins

Using new variants of silver staining, Reusche described in 1991 a new effective method for the demonstration of Alzheimer changes by light- and electron microscopy (Reusche et al. 1992). The same methods allowed for the first time the demonstration in ten long-term hemodialyzed patients of characteristic and pathognomonic aluminum-containing inclusions in the cytoplasm of choroid plexus epithelia, glia, and neurons of the CNS (Reusche and Seydel 1993). Argyrophilic proteinaceous deposits of this “dialysis-associated encephalopathy” (DAE) were shown by light- and electron microscopy. They obviously result from long-standing and futile cytoplasmic lysosomal degradation of aluminum. Similar deposits could be demonstrated in peripheral organs as well (Reusche et al. 1996). Laser microprobe mass analysis confirmed high cellular levels of aluminum (Fig. 17.1). The morphology is completely different from neuronal changes in Alzheimer‘s disease (Reusche and Seydel 1993; Reusche 1997). The evaluation of 50 long-term hemodialyzed patients − with ingestion of aluminum-containing drugs, up to 2.5 kg “pure” aluminum − presented no increase in the incidence of Alzheimer‘s disease (Reusche et al. 2001).

17.1.2 Arsenic (As) 17.1.2.1 Inorganic Arsenicals Source. Inorganic arsenicals are used in the manu-

facture of glass (smelting industry), in the preservation of wool, and as a pesticide. Intentional acute or chronic arsenic (As) poisoning often occurs in criminal cases (Geldmacher von Mallinckrodt 1975).

The toxicity of arsenic is based on its capacity to uncouple mitochondrial oxidative phosphorylation. Arsenic binds in the place of inorganic phosphate, forming arsenic analogs of high-energy phosphates, which are unstable and break down to regenerate inorganic arsenic (Vahter 1999). The pentavalent form, arsenate, is much less toxic than the trivalent form, known as arsenite. Morphologically, the effects of arsenic poisoning are characterized by axonal degeneration of the peripheral, large fibers (Hörtnagel and Hanin 1992), sometimes combined with segmental demyelination (Crapper McLachlan and De Boni 1980), occasionally presenting as a Guillain−Barré-like syndrome (Donofrio et al. 1987). No changes are apparent in the CNS. 17.1.2.2 Organic Arsenicals Source. Organic arsenicals are used mainly in the

treatment of syphilis and trypanosomiasis. Clinically, poisoning by organic arsenicals produces symptoms of encephalopathy and exfoliative dermatitis as well as peripheral neuropathy. Treatment with British anti lewisite (BAL, =2,3-dimercaptopropanol; dimercaprol) has proven effective. It is assumed that the clinical symptoms are caused less by the direct toxic effect than by an allergic reaction (Adams et al. 1986). Morphologically, arsenic encephalopathy is characterized by pericapillary bleeding, mainly in the midbrain (hemorrhagic encephalopathy) (Hurst 1959). Sometimes the disease manifests as an acute hemorrhagic leukoencephalitis (Adams et al. 1986), which suggests an allergic pathogenesis. Finally, a Guillain−Barré-like syndrome has been attributed to treatment with melarsoprol (Gherardi et al. 1990).

Clinical Features. Acute arsenic poisoning is char-

acterized by gastrointestinal symptoms including nausea, vomiting, and diarrhea, accompanied by confusion, delirium, coma, circulatory collapse, and death. Arsenite is a strong inhibitor of the pyruvate dehydrogenase system (glycolysis) forming a stable complex with the thiol groups of the enzyme complex (Devlin 1997). Victims who survive develop symptoms of peripheral neuropathy with sensory defects (Le Quesne and McLeod 1977; Heaven et al. 1994). Victims of chronic arsenic poisoning exhibit symptoms of peripheral neuropathy with loss of motor function, but gastrointestinal disturbances are sometimes lacking. At the same time, hyperkeratosis of the hands and feet is observed in most cases (plus so-called Mees’ lines on the fingernails). Progression of an arsenic-induced polyneuropathy can be halted by administration of water-soluble 2,3-dimercaptopropanesulfonate (DMPS).

17.1.3 Bismuth (Bi) Source. Bismuth (Bi) is used to treat constipation,

gastric ulcers, and indigestion following removal of the large bowel. It is also used in dental procedures and as a radiographic contrast medium. Clinical Features. The predominant clinical features

of bismuth intoxication are functional disturbances, osseous changes as well as gastrointestinal disturbances with diarrhea and bleeding. Insoluble inorganic compounds are particularly neurotoxic. Brain involvement is usually characterized by mental and/ or neurological symptoms, such as anxiety, depression, ataxia, tremor, dementia, memory loss, confusion, delirium, psychosis, and irritability. The disease process may lead to coma and end in death.

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Pathogenesis. The pathogenesis of bismuth poison-

ing is not yet clear and sensitivity to its effects varies from individual to individual. Morphology. Morphological changes in the nervous

system typical of bismuth poisoning include a predominant loss of Purkinje cells in the cerebellum and of neurons in the neocortex (laminar necrosis) and hippocampus (Liessens et al. 1978). There is also a loss of neurons and proliferation of microglia in the basal ganglia, especially the putamen (Jungreis and Schaumburg 1993). Elevated bismuth levels have been observed in the frontal cortex, basal ganglia, and cerebellar cortex (Drenckhahn and LüllmannRauch 1979).

17.1.4. Cadmium (Cd) Source. Exposure to cadmium (Cd) is always in com-

bination with zinc and − occasionally − with lead. Today it is almost impossible to avoid exposure to cadmium since this metal is ubiquitous in the environment. Cadmium is highly toxic and has an extremely long biological half-life (15−20 years), so that it accumulates within tissue. It can cause sterility and is teratogenic, carcinogenic, and may also play a role in aging (Bin and Garfinkel 1994). Cadmium does not penetrate the blood−brain barrier and thus it may be assumed that its neurotoxic effects derive secondarily from its interference with zinc metabolism (Jin et al. 1998). Pathogenesis. Cadmium is thought to bind competi-

tively at Ca 2+ -rich binding sites on the cell surface as well as to intracellular receptors (Gabbiani et al. 1967). This hypothesis is supported by the observation that cadmium inhibits endothelin-binding activity (Wada et al. 1991). In nerve cells, cadmium blocks NMDA-gated channels (Reynolds and Miller 1988) as well as N-, L- and T-type Ca 2+ channels on neurons (Gadbut et al. 1991) and glia (MacVicar 1984, 1987).

Morphology. (For review see Schröder 2000.) Cad-

mium affects mainly the lung (acute intoxication: pneumonia; chronic intoxication: emphysema). In Japan, a series of cadmium poisonings occurring between 1939 and 1945 produced a clinical syndrome called “itai-itai disease,” which caused bone pain among other symptoms, apparently due to involvement of the spinal ganglia (Murata 1971). Cadmiumrelated encephalopathy has been described in a male adolescent in East India (Provias et al. 1994) with brain swelling, herniation, and perivascular edema indicating a disturbance of the blood−brain barrier.

17.1.5 Gold (Au) Gold (Au) solutions, aurothioglucose and sodium aurothiomalate, are used to treat rheumatoid arthritis today (chrysotherapy). The side-effects are dermatitis, renal damage with hematuria and impaired hematopoiesis. Neurological deficits are uncommon and include encephalopathy, cranial neuropathy, myokymia and peripheral neuropathy, possibly Guillain−Barré syndrome. Psychiatric symptoms have been described in a few instances (Fam et al. 1984; Pery and Jacobsen 1984). It is unclear as to whether the neurotoxic mechanism involves a hypersensitivity reaction, a direct toxic effect, or both. Morphological changes in the NS have not been described.

17.1.6 Lead (Pb) 17.1.6.1 Inorganic Lead Compounds Source. Lead accumulates in the body and reaches

especially high levels in the blood, bone marrow, and soft tissues as well as in skin, muscle, and bone. Sources of exposure are manufacturing processes releasing lead or lead compounds in the form of dust, smoke or steam. At one time, lead paint, lead pottery glazes, and lead pipes in water systems were major sources of lead poisoning. Today, automobile emissions and exposure to tetraethyl lead are the principal sources of lead poisoning. Pathogenesis. In the United States, there are

12,000−16,000 new cases and 200 deaths from lead poisoning annually. Children are particularly at risk. Pathological lead values have been found in 10−25% of children in slum areas (Ludwig 1977a). Lead is taken into the body through the lungs and gastrointestinal tract. In the form of dust or vapor, metallic lead oxidizes to lead oxide. Lead concentrations in the brain are a function of blood lead levels. The effects of lead at the cellular level are largely unknown. Absorbed lead is not metabolized and is excreted via the kidneys. An adult member of the general population will excrete lead at the rate of 25%. Incapacitation − which obviously increases the danger of continued exposure leading to death − usually occurs acutely at CO-Hb levels of 30−40%. Death is due to central respiratory and circulatory arrest (Geldmacher von Mallinckrodt 1975). The recommended treatment for acute CO poisoning is 100% normobaric oxygen, but meanwhile Weaver et al. (2002) have demonstrated that hyperbaric-oxygen therapy at 304 kPa (3 atm) absolute is superior to normobaric-oxygen therapy in reducing the incidence of delayed cognitive dysfunction at 6 weeks and 12 months after acute CO poisoning (see Hampson et al. 2001). The diagnosis is confirmed by measurement of blood CO-Hb. A delayed neurologic deterioration is usually termed “talk and die” in the consideration of death after incidence of cerebral trauma (p. 472). However, a

similar phenomenon of delayed death can occur after cardiac arrest, and especially after CO poisoning (Plum et al. 1962; Maxeiner 1987; Opeskin and Drummer 1994). The cause, as has long been known, is delayed white matter deterioration (Grinker 1925; Lapresle and Fardeau 1967; Salama et al. 1986). Obviously CO poisoning in these cases also causes adduct formation between myelin basic protein (MBP) and malonylaldehyde, a reactive product of lipid peroxidation, resulting in an immunological cascade (Thom et al. 2004). MBP loses its normal cationic characteristics, and antibody recognition of MBP is altered. Immunohistochemical evidence of degraded MBP occurs in brain over days, along with influx of macrophages and CD4 lymphocytes. Lymphocytes from CO-poisoned rats subsequently exhibit an autoreactive proliferative response to MBP, and there is a significant increase in the number of activated microglia in the brain. These results demonstrate that delayed CO-mediated neuropathology is linked to an adaptive immunological response to chemically modified MBP. Morphology. If death is sudden, the sole macroscopi-

cally conspicuous feature is a bright redness of the blood and of brain sections at autopsy (Fig. 17.3a) − even after fixation in formalin (Fig. 17.3b, c). In rare cases with massive congestion, extravasation can also occur. If the acute poisoning is survived, changes occur which resemble those seen in global ischemia: laminar cortical necroses, nerve cell loss in the hippocampal formation, Purkinje cell loss, and white matter necrosis. A bilateral necrosis of the globus pallidus (Fig. 17.3d) and the pars reticulata of the substantia nigra are known as non-specific alterations. [For further details of the pallidal necrosis see Pankratz et al. (1988).] White matter deterioration in

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Fig. 17.3a−d. Carbon monoxide poisoning. Acute intoxication: bright redness of the dura (a) at autopsy and of the brain surface after formalin fixation (b) associated with brain swelling and (c)

redness of the frontal section. Chronic intoxication: bilateral pallidal necrosis as demonstrated by circles (d)

the sensed multifocal leukoencephalopathy (see also Sect. 17.3.1.2) are the morphological sequelae of a delayed feature of CO poisoning.

Morphology. The morphologic picture is characterized by confluent foci of demyelination with swelling of oligodendrocytes and proliferation of astrocytes. The demyelination with its patchy distribution and indistinct borders resembles the pattern of multifocal leukoencephalopathy; there is a continuous spectrum up to complete demyelination (“Grinkers’ disease” or “Grinker’s myelinopathy”). White matter edema is accompanied by a drop in blood pressure and increased acidosis (Brucher 1966).

17.3.1.2 Intermittent Exposure Clinical Features. A coma lasting days or weeks in the

first phase of illness may be followed by increasing clarity of consciousness. The second phase begins after 10−30 days with signs of progressive encephalopathy including dementia, akinesia and rigidity, and finally coma.

CHAPTER 17: Specific Types of Neurotoxins

Table 17.2. The relationship between atmospheric concentration of hydrogen cyanide and clinical effect. Source: Davies 1991

Hydrogen cyanide (%)

Clinical feature

0.004−0.005

Tolerated for 0.5−1 h

0.011−0.013

Death after 0.5−1 h

0.018

Death after 10 min

0.028

Immediate death

17.3.1.3 Chronic Intoxication

cyanide (HCN) and its salts are characterized by the smell of bitter almonds.

Clinical Features. Low levels of CO exposure can

cause headache and nausea. The marked affinity of CO for Hb plus the resultant reduced expiration of CO results in an accumulation of CO-Hb in the blood, which over a period of days or weeks can produce all of the symptoms of acute intoxication and, if unchecked, lead to death. Morphology. The aforementioned hypotensive hypoxic and ischemic necrosis and white matter injuries predominate.

17.3.2 Cyanides and Cyanide Compounds Source. Deaths due to acute cyanide poisoning are

relatively rare, largely owing to the restricted availability of cyanide. Nevertheless, cyanide is one of the most rapidly acting poisons known and is encountered today in cases of suicide or intentional killing (e.g., euthanasia/assisted suicide − Fernando and Busuttil 1991; Cina et al. 1994; for review see Musshoff et al. 2002). Chronic poisoning from ingestion of fruit seeds or plants containing cyanide, e.g., almonds, is rare. Of major importance is the occurrence of prussic acid in gas produced by the combustion of nitrogen-containing plastics (polyurethane, polyacrylnitrite, synthetic fibers, e.g., artificial wool or silk), which can cause mixed poisonings with CO. A few victims of acute poisoning have survived due to intensive medical measures. The lethal cyanide dose is relatively small and, because death is usually immediate, attempts at medical intervention are nearly always futile. The minimal lethal dose of hydrogen cyanide is 100 mg; for sodium cyanide 150 mg and potassium cyanide 200 mg (Baselt and Cravey 1995); bitter almonds: 70 nuts for adults, 6−7 nuts for children. Hydrogen

Pathogenesis. Cyanide is readily soluble in lipids

and diffuses rapidly. It binds to the Fe3+ in the heme group of cytochrome oxidase and thereby inhibits cellular utilization of oxygen. This results in histotoxic anoxia at the cellular level; i.e.,“internal” suffocation and energy failure associated with lactate production and severe metabolic acidosis (Hall and Rumack 1986; Borron and Baud 1996; Musshoff et al. 2002). Central suppression of respiration is thought to result from changes in neuronal excitability (Greer and Carter 1995). However, hypotension due to heart pump failure is a critical and necessary determinant of brain necrosis, since structural brain damage is absent without ischemia, and direct necrotizing CNS histotoxicity seems not to occur (MacMillan 1989).

Clinical Features. Cyanide intoxication is characterized by dose-dependent impairment of neurologic function, beginning with non-specific symptoms such as headache or dizziness at one end of the spectrum and convulsions and coma at the other. Coma and convulsions may develop within seconds. The reconstructive analysis of 27 cases of lethal poisoning with cyanide by Vock et al. (1999) revealed that some victims had the capacity to act, especially for 5−10 min, though most victims lost consciousness within a few seconds to 1−2 min. Cardiac arrest follows, depending on the concentration, almost immediately with all the discrete signs of suffocation (Table 17.2). The diagnosis commonly is made by toxicological examination. Cyanide levels in serum >2.5 mg/l are associated with coma and are fatal without treatment. However, cyanide is unstable in blood and therefore cyanide levels may drop as a result of degradation into less toxic components if the postmortem interval before autopsy (and the storage time of blood until examination) is too long (Ballantyne et al. 1974; Musshoff et al. 2002).

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Morphology. The morphology of acute lethal cyanide

poisoning (see also p. 279) is similar to CO poisoning, but generally without the marked pallidal vulnerability due to CO binding of Fe. It cannot be distinguished from global ischemia, and is characterized by massive congestion, sometimes with perivascular and subarachnoid bleeding. Instances of long survival times, which are very rare, exhibit Purkinje cell loss, gliosis of the cerebral cortex, disseminated petechial bleeding, circ*mscribed white matter necrosis, and as can be seen in cardiac hypotension associated with critical illness (Burger and Vogel 1977) bilateral necrosis of the globus pallidus (Ule and Pribilla 1962; Kim et al. 1982). Prolonged cyanide poisoning is accompanied by striatal degeneration with Parkinsonism and dystonia, which might also result from a glutamate-mediated neurotoxic effect comparable to that associated with CO (Spencer 1999).

17.3.3 Hydrogen Sulfide (H2S) Source. Hydrogen sulfide (see p. 279) is a colorless,

combustible, heavier than air gas, which smells like rotten eggs. It is potentially explosive if mixed with oxygen. It can be encountered in volcanic areas, in “sour gas” wells, and artificially in the manufacture of hydrochloric and sulfuric acids. It is also emitted by furnaces. Being a by-product of decomposition of human, animal or plant organic matter, it is found in sewers (Adelson and Sunshine 1966). Hydrogen sulfide gas is usually inhaled, although experimentally Na 2S intravenous injection gives rise to a similar picture, without the pulmonary histotoxicity (Baldelli et al. 1993). Pathogenesis. The mechanism underlying the tox-

icity of H2S is similar to cyanide, with even tighter binding of the sulfide anion to cytochromes. This explains how it inhibits intracellular respiration (Geldmacher von Mallinckrodt 1975).

Morphology. Morphologically, acute cases (Osetowska 1971) of hydrogen sulfide poisoning exhibit congestion and edema; in cases with longer periods of survival, the morphological picture includes signs of generalized hypoxic ischemia (Tvedt et al. 1991) and changes associated with intravital brain death (Bersch et al. 1974; Snyder et al. 1995). Physiologically controlled experiments in animals show that, as in cyanide poisoning, inhibition of heart pumping action and severe hypotension are critical, necessary prerequisites of brain necrosis (Baldelli et al. 1993).

17.3.4 Nitrous Gases and Nitrites Source and Clinical Features. Nitrous gases are pro-

duced by heating nitric acid or by the combination of nitric acid with metals or organic substances, during welding, for example. NO2 and N2O4 chiefly affect the respiratory passages and can cause pulmonary edema leading to death. Inhalation, for example of nitrous oxide (N2O) as an anesthetic, can cause methemoglobin, respiratory distress, cyanosis, vomiting, dizziness, and falling blood pressure resembling the symptoms induced by nitrite poisoning. Nitrite, especially sodium nitrite, is used in the dye industry. Sodium nitrite gives color to stored meat. Spinach contains nitrate, which can transform into nitrite. Children are especially at risk. Pathogenesis. Oxidation of the Fe2+ in hemoglobin

to Fe3+ (methemoglobin) results in an inadequate oxygen transport capacity of the blood that causes central cyanosis. Morphology. Morphologically, both nitrifying gas and nitrite intoxication produce the sequelae of oxygen deficiency. In a few instances, purpura cerebri has been described.

17.3.5 Oxygen (O2)

Clinical Features. The first clinical symptoms are re-

actions of the mucous membranes, followed by headache, dizziness, ataxia, respiratory distress, a drop in blood pressure, convulsions, loss of consciousness, and respiratory and cardiac arrest (Smith 1997). If the dose is very high, paralysis of olfactory nerves impedes smell and the ability to detect the telltale rotten egg smell. The associated sudden respiratory arrest that occurs within seconds or minutes, so called knockdown, thus results in continued, lethal exposure. Often, those attempting rescue and removal of the poisoned individual become overcome themselves, starting a chain reaction of victims.

Source. Pulmonary changes caused by high oxygen

pressure have long been known, and nervous system effects were first described in the late 1800s by Paul Bert. Changes are seen in neonates, deep-sea divers, with decompression sickness and in the treatment of Clostridium infection. They have also been described within the context of the US space program (Balentine 1982). Clinically, the syndrome of oxygen toxicity is dominated by convulsions, which can sometimes be fatal. Morphologically, the picture is non-specific. Necrosis has not been found in humans, although in animal studies it has been shown to result from

CHAPTER 17: Specific Types of Neurotoxins

a toxic effect on enzymes of cellular respiration in various organelles as well as cell membranes (Balentine 1982).

17.4 Industrial and Environmental Toxins 17.4.1 Acrylamide Source. Acrylamide is used industrially in the manufacture of paper, fibers, and dyes. It is a cumulative neurotoxin; i.e., symptoms only occur when threshold values have been exceeded. The clinical symptoms correspond to peripheral neuropathy (acrylamide neuropathy), which begins with reversible paresthesia, followed by motor weakness and, possibly, ataxia (Spencer and Schaumburg 1974; Kesson et al. 1977). Morphology. Axons in the peripheral nervous system are the most affected, but axons in the CNS may be involved as well: there is axonal degeneration in the gracile nucleus (Schaumburg et al. 1989) as well as progressive degeneration of Purkinje cell dendrites in cerebellar cortex (Lehning et al. 2002). Distal swelling and eventual degeneration of axons in the CNS and PNS are the characteristic morphological features. Based on accumulating evidence, LoPachin and his team (2003b) have demonstrated that nerve terminals, and not axons, are the primary site of acrylamide action and that compromise of corresponding function is responsible for the autonomic, sensory, and motor defects that accompany acrylamide intoxication. Substantial evidence, therefore, indicates that axon degeneration is a secondary effect (LoPachin et al. 2003a, b).

17.4.2 Aliphatic Hydrocarbons Source. Aliphatic hydrocarbons are used as solvents

in the glue and mineral oil industries. N-Hexane and methyl-n-butyl ketone (MBK) are especially neurotoxic. Poisonings occur by oral ingestion (children) and glue sniffing. In the latter, the liquid glue or solvent is typically poured into a plastic bag and inhaled to achieve a psychotropic effect. Acute exposure is associated with dizziness, signs of sedation and irritation, narcosis, and euphoria. During inhalation, death can occur from suffocation and acute cardiac arrhythmia.

Pathogenesis. The solvent can cause axonal injury,

which via a “dying back” mechanism gives rise to symptoms primarily of the peripheral nervous system (McLean et al. 1980). Morphologically ascending axonopathies have been described.

17.4.3 Halogenated Hydrocarbons Source. Halogenated hydrocarbons are used as sol-

vents and cooling agents, chiefly in the plastics industry. They are incorporated via the respiratory tract and because they are lipid soluble, they also can cross the blood−brain barrier. 17.4.3.1 Methyl Chloride Source. Methyl chloride (chloromethane) is a color-

less gas used mainly as a coolant for domestic and commercial refrigeration units. Clinically, acute poisoning begins with headache, nausea, vomiting, dizziness, tremors, and weakness followed by convulsions, coma, and death (Thomas 1960). Chronic intoxication leads to somnolence and signs of extrapyramidal system defects and to polyneuropathies. Morphology. Necrosis is seen in the inner granule

cell layer of the cerebellum, as well as axon torpedoes in the same layer and in the Purkinje cell layer. The nerve cells of the dorsal horns of the spinal cord are characterized by marked chromatolysis and vacuolation. The nerve cells of both the posterior and anterior horns of the spinal cord contain argentophilic deposits. Signs of neuroaxonal dystrophy are invariably present (Thomas 1960; Kolkmann and Volk 1976). 17.4.3.2 Trichloroethylene Trichloroethylene is used as an industrial solvent and degreasing agent as well as a narcotic by sniffers, which is also true of toluene. Clinically, a cranial neuropathy develops with impaired coordination in the form of ataxia and dysarthria (Baker 1958; Malm and Lying-Tunell 1980) as well as dysphagia and trigeminal anesthesia (Lawrence and Partyka 1981). Vasomotor and gastrointestinal disturbances develop in some cases. Morphological findings have been shown only with neuroimaging techniques described as cerebral atrophy (Juntunen et al. 1980).

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cephalopathy (Powell et al. 1973; Marinez et al. 1974; Shuman et al. 1974) with extensive vacuolar degeneration in the white matter of the cerebrum and cerebellum (Mullick 1973). Severe granule cell necrosis also occurs in the cerebellum with proliferation of Bergmann glia and degeneration of dendritic spines (Diemer 1976). The changes caused by thiophene intoxication are similar (Herndon 1968). There is a splitting of the myelin sheaths and spongy changes in the cerebral white matter, chiefly subependymally, and in the cerebellar white matter. A spongy alteration has been described in the white matter of the pons and medulla oblongata as well (Tripier et al. 1981). Differential diagnosis must include triethyltin poisoning. Premature and newborn infants with desquamative skin changes are especially affected. It is unclear whether hexachlorophene itself can cause death, since infants so treated are already at particular risk due to their immaturity (Powell and Lampert 1977). 17.4.4.2 Lindane Lindane (γ-hexachlorocyclohexane = HCH) is primarily an insecticide. In medicine, it is applied externally to treat scabies and pediculosis. Overdose − both by massive cutaneous resorption and oral ingestion − can cause acute intoxication with mydriasis, hyperglycemia, cyanosis, respiratory distress as well as clouding of consciousness, generalized seizures, and cardiac arrest. Chronic intoxication leads to neuropsychiatric deficits. Morphologically, the picture includes among other things extensive necrosis of the small blood vessels in the lungs, kidneys, and brain (Velvart and Moeschlin 1980).

Fig. 17.4a−c. Methanol intoxication. a Symmetrical putamen necrosis and intense demyelination with cystic changes (b) are characteristic due to direct neuronal toxicity and secondary demyelination (c). (b, c Luxol fast blue; magnification b ×100, c ×300)

17.4.4 Chlorinated Cyclic Hydrocarbons 17.4.4.1 Hexachlorophene (HCP) Hexachlorophene is used because of its bactericidal effect (antimicrobial agent) as a preservative in cosmetics and soaps. Hexachlorophene has a toxic effect on the myelin sheaths and leads to a vacuolar en-

17.4.5 Methyl Alcohol (Methanol) Source. Methyl alcohol is a colorless, combustible

liquid that smells somewhat like spirit of wine and has a not unpleasant taste. It is used as antifreeze in the cooling systems of gasoline engines, and as a solvent for paints, glues, cleaning agents, etc. Methyl alcohol is ingested because it is mistaken for ethanol or as an additive to home-distilled spirits. During the prohibition era in the United States, methyl alcohol was used as an alcohol substitute. Inhalation and percutaneous application have also been described. Doses as low as 10 ml can cause severe intoxication, 30−100 ml can be lethal. Morphology. The morphology of the affected brain is characterized by two kinds of changes, symmetrical necroses characteristic of methanol, and nonspecific diffuse or disseminated findings. The latter

CHAPTER 17: Specific Types of Neurotoxins

include hyperemia and edema (Schmidt 1946; Orthner 1949), with perivascular hemorrhagic necrosis, and (hemorrhagic) leukoencephalopathy (Fig. 17.4) (Menne 1938; Henze et al. 1986; Phang et al. 1988). Although selective vulnerability exists in almost all neuropathological conditions, methanol is a striking example of the principle that a generalized insult, in this case a circulating toxin that reaches all CNS tissue via the blood, nevertheless causes damage in highly specific regions. Intriguingly specific to methanol, if death occurs slowly, the bilateral necroses are seen in three regions of the CNS. First, there is necrosis of the putamen (Fig. 17.4a) with late cystic changes (Erlanson et al. 1965); and second, there is visual damage and retinal ganglion cell necrosis, which was long thought to be due to direct ganglion cell toxicity in the retina (McLean et al. 1980). But methanol blindness is now known to be due to symmetrical areas of softening in the retro-orbital portion of the optic nerve. The nerve cell destruction in the retinal ganglion cell layer is thus merely secondary to the axonal destruction in the optic nerve (Sharpe et al. 1982), as are changes in the lateral geniculate body, the white matter, and spinal cord (Kolkmann and Volk 1976). A third area of symmetrical necrosis in addition to the optic nerves and putamena is the pontine tegmentum, visible on MR imaging as well as neuropathologically (Gaul et al. 1995). Why methanol should cause symmetrical necrosis in these three regions of the CNS remains a mystery, but its NMDA antagonist properties (Lovinger et al. 1989) seem not to correlate and thus cannot explain the remarkable regional localization of brain damage due to methanol.

17.4.6 Organophosphorus Compounds

Fig. 17.5a, b. Parathion intoxication. The clinical feature and autopsy findings are commonly characterized by an extreme myosis (a) and/or blue-colored stain around the mouth on the clothes (b)

confusion, tremor, ataxia, coma, convulsions, muscular weakness, fasciculation, and respiratory depression. Further symptoms are miosis, salivation, abdominal cramps, and diarrhea. The symptoms occur within 10 min to 2 h; death is caused by central respiratory arrest. Small doses and less toxic agents cause an axonal neuropathy.

Source. Phosphate esters are used as pesticides. Poi-

sonings are generally either accidental or suicidal, and are rarely associated with homicide. This large family of compounds have also been used militarily as nerve agents. Pathogenesis. Phosphate esters of different types

are potent inhibitors of cholinesterase and acetyl cholinesterase, some acting directly (dichlorvos), others indirectly. Parathion (E 605), for example, is metabolized in the body to paraoxon (E 600), which is toxic, whereas parathion itself is not (Reiner and Lotti 1993). Organophosphate insecticide has been shown to cause persistent impairment of cholinergic synaptic function (Slotkin et al. 2001), especially in the mammalian striatum. Clinical Features. (For review see Murphy 1986; Lotti

2000.) Acute poisoning is characterized by anxiety,

Morphology. At autopsy commonly an extreme

miosis is conspicuous (Fig. 17.5a), and often a bluecolored stain − a warning color in parathion solutions − is visible around the mouth and/or on the clothes (Fig. 17.5b). In the brain, only hyperemia and edema are seen (Oehmichen et al. 1983). Histochemical detection of acetylcholinesterase allows demonstration of this enzyme’s inhibition in the putamen (Fig. 17.6a, b), in muscles and in the myenteric plexus of the intestines (Fig. 17.6c, d; cf. Table 17.3) as could be demonstrated by Oehmichen and Besserer (1982). An inhibitory effect was dose-dependent (Table 17.3). An inhibition of non-specific esterase is also demonstrable in monocytes of the peripheral blood (Oehmichen et al. 1984). If intoxication is survived due, for example, to intensive medical therapy, the brain may exhibit signs of systemic circulatory collapse in the form of changes seen in global ischemia.

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Morphology. The early phase of intoxication is characterized by endomyseal inflammation of the skeletal musculature, and the infiltrates gradually but continually diminish. This is followed by severe fascicular neurogenic muscular atrophy with round cell infiltrates surrounding venules and capillaries. Biopsy samples of the sural nerve consistently show perineurial fibrosis. Focal loss or degeneration of individual axons is observed, as is an occasional myelin breakdown (Ricoy et al. 1983).

17.5 Nerve Agents

Fig. 17.6a−d. Parathion intoxication. In animal experiments (Oehmichen and Besserer 1982) reduced acetylcholinesterase activity is demonstrable in the putamen (a normal staining; b state after poisoning) and the myenteric plexus of the intestine (c normal activity, d state after poisoning) [a−d acetylcholine esterase histochemistry according to El-Badawi and Schenk (1967); magnification a−d ×100]

17.4.7 Toxic Oil In the spring of 1981, Spain experienced an epidemic attributed to the consumption of rapeseed oil containing oleyl-anilide (Philen and Posada 1993). Symptoms included atypical pneumonia, myalgias, and eosinophilia. The clinical picture was dominated by neurological symptoms, mainly muscle weakness, peripheral neuropathy, and respiratory insufficiency. Soldiers in France suffered poisoning when machine gun cooling oil was mistakenly used as cooking oil. The toxic agent was the extremely poisonous tricresyl-phosphate. Shortly after ingestion nausea, vomiting, diarrhea, and convulsions occurred. After 15−20 days, paralytic symptoms were noted, which subsequently increased before finally receding (Neue Züricher Zeitung 2000, July 29/30, p. 29).

A number of chemical warfare agents were developed during the Second World War: in England diisopropyl fluorophosphate (DFP), in Germany, tabun, which is 10 times as toxic. Since 1945, sarin, which is 5−10 times as toxic as tabun, has been developed (for review see Lee 2003) and more recently pinacolyl ester (soman), which is itself 5−10 times as toxic as sarin. All of these agents belong to the family of organophosphorus compounds (Schrader 1963). Absorption occurs via the skin and respiratory tract. Clinically, the first conspicuous symptoms are respiratory distress and miosis; these are followed by convulsions, which can transform into status epilepticus. These agents of chemical warfare are at present very difficult or even impossible to detect by chemical analytical techniques due to the extremely small concentrations in the body. But inhibition of cholinesterase is demonstrable, which explains the pathophysiological effect. Sarin recently made world headlines when it was used in an attack by the Aum sect (1995) on the Tokyo subway, leaving 12 people dead. A gas attack in Matsumoto in 1994, which killed 4 people, was apparently carried out by the same sect (Okudera et al. 1997; Okumura et al. 1998; Yokoyama et al. 1998). Sarin was first used in war during the Iran−Iraq conflict in the 1980s (Brown and Brix 1998). Animal studies on the effectivity of sarin have recently been reported (Spencer et al. 2000). After intravenous application of sarin-like organophosphorus agents, the brain showed an increase in tyrosine phosphorylation of several proteins in the cytosol fraction as well as an activation of c-jun N-terminal kinase (JNK) and slight activation of mitogen-activated protein kinase (MAPK). The activation of these enzymes may be related to the high toxicity of these nerve agents.

CHAPTER 17: Specific Types of Neurotoxins

Table 17.3. Dose dependence of the inhibitory effect of paraoxone and parathion on acetylcholinesterase activity in intestines, muscles, and brain. Experimental study in mice and semiquantitative analysis. Source: Oehmichen and Besserer 1982

Dose: mouse

Survival time (min)

AChE activity in: Intestine

Muscle

Brain

15a

+++

++

++

30a

+++

++

++

Paraoxone 0.2 mg/kg 0.7 mg/kg

15

a

+

+

+

+/−

++

+

a

+

+

1.4 mg/kg

15b

2.1 mg/kg

b

+/−

+

30a 60

13

Parathion

a b

1 g/kg

43b

++

+/−

5 g/kg

50

a

+

10 g/kg

30a

+

20 g/kg

b

+

20

Result checked in two decapitated mice Died spontaneously

17.6 Drugs and Pharmaceutical Products 17.6.1 Sedatives, Hypnotics and Analgesics The medications in this group (barbiturates, benzodiazepines, bromine, methaqualone, pyrazolon derivatives, salicylic acid derivatives, etc.) all affect the CNS, but they do not have a primary neurotoxic effect that causes morphological changes. They all, however, can induce secondary systemic hypoxia via a central respiratory paralysis, which, in turn, triggers morphological destruction of parts of the brain as a consequence of generalized cardiorespiratory failure. The detailed description of each of these neurotoxic agents is beyond the scope of this text, and, therefore, comments will be limited to a few representative substances. The synthetic drug MPTP (N-methyl-4-phenyl1,2,3,6,-tetrahydropyridine) was developed in the 1970s. It is illegally combined with heroin for use as a narcotic. This drug can lead to a Parkinson-like syndrome, caused by drug-induced neuronal loss in the substantia nigra and in the striatum. MPTP

is involved in the metabolism of catecholaminergic neurons. Inhibition of the monoamine oxidase B enzyme leads to the accumulation of a toxic metabolite, which is stored in the cell. Phenytoin (diphenylhydantoin) is used today after decades as a successful anti-epileptic. Clinically chronic overdose induces tremor, ataxia, diplopia as well as dizziness and vomiting. These symptoms are reversible. Morphologically an overdose can lead to atrophy of the cerebellar cortex (Dam 1972) with depletion of Purkinje and granule cells plus gliosis in the molecular layer. Pathogenetically it was discussed for a long time whether the injury is caused by hypoxia-induced convulsions alone. Nowadays it is thought that diphenylhydantoin has a primary neurotoxic effect (Volk et al. 1986). Tryptophan (Eosinophilic Myalgia). L-Tryptophan is

applied to treat depression, sleep disorders, premenstrual syndrome, and in drug-withdrawal therapy. In 1989, it was reported to induce severe myalgia and eosinophilia together with numerous other symptoms (facial edema/swelling, sclerodermatitis-like skin changes, myopathy, pulmonary manifestations, etc. − Bulpitt et al. 1990). The predominant adverse effect however is a polyneuropathy.

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matory effect in treatment of rheumatoid arthritis and for their antiprotozoal effect as antimalarials. Chloroquine’s amphophilic nature gives it a membrane stabilizing effect. Chronic use however is associated with numerous side-effects − which chloroquine shares with other amphophilic substances, such as tricyclic neuroleptics (phenothiazines), cholesterol synthesis inhibitors, the appetite suppressant chlorphentermine, and the cardiovascular agent perhexiline (Klinghard 1976; Drenckhahn and Lüllmann-Rauch 1979) − such as skin changes, muscle degeneration, muscular dystrophy, and epileptiform convulsions. Clinical Features. Retinopathy and polyneuropathy are sometimes seen. In acute intoxication, exogenous psychosis with the psychogenic symptoms − paranoia, aggressiveness, depression, confusion − are observed together with compulsive behavior and phobias. No deaths have been reported. Morphology. The morphology is characterized by neurolipidosis. The nerve cells − mainly the spinal ganglia − contain membranous multilamellar bodies or lamellar or hexagonally arranged crystalloid inclusions (Klinghard 1976). The picture resembles GM2 gangliosidosis and/or neurovisceral ceroid lipofuscinosis.

17.6.2.2 Clioquinol Source. Clioquinol is used to treat diarrhea caused by

amoebae, lambliae, and shigellosae. In Japan, chronic use in the treatment of diarrhea induced signs of a subacute myelo-optic neuropathy syndrome (SMON) (Mamoli et al. 1975; Shigematsu and Yanagawa 1978). This disease occurred in epidemic proportions. Fig. 17.7a−c. Clioquinol intoxication called subacute myelooptic neuropathy (SMON). Chronic treatment of diarrhea by clioquinol leads to demyelination of the posterior white columns (a), the anterior and lateral funiculi of the spinal cord (b) and the optic nerve (c). (a, b Luxol fast blue; c: silver stain; magnification a, b ×50; c ×500). The figures were kindly provided by Professor Dr. Yoshio Narita, Tokyo

17.6.2 Antiprotozoal Agents 17.6.2.1 Chloroquine Source. Drugs containing chloroquine (sulfate)

are lysosomotropic and used for their anti-inflam-

Clinical Features. The most salient symptoms are

reduced vision, spinal ataxia, signs of a pyramidal tract lesion and sensorimotor deficits, together with bladder insufficiency. Pathogenesis. There is a distal axonopathy confined

to the CNS (Schaumburg and Spencer 1980) thought to be caused by impaired axonal transport (Thomas et al. 1984). Morphology. The morphological picture is dominated by edematous alterations in the cerebrum and cerebellum with gliosis. Foci of demyelination are evident in the optic nerve, the posterior white columns as well as in the anterior and lateral funiculi of the spinal cord (Fig. 17.7).

CHAPTER 17: Specific Types of Neurotoxins

Clinical Features. The following clinical features have

been described: acute myelopathy, subacute myelopathy and chronic leukoencephalopathy. Acute signs of transient confusion, lethargy, and headache have also been reported. Chronic administration may induce fatigue, irritability, ataxia, and confusion. Spasticity has also been occasionally observed. Morphology. Intrathecal or intraventricular metho-

trexate treatment is known to cause a necrotizing leukoencephalopathy located mainly periventricularly, but which also occurs multifocally with coagulation necrosis (Shapiro et al. 1973) and axon swelling (Fig. 17.8). Intrathecal application combined with radiotherapy is associated with demyelination alone or in combination with disseminated necrosis, especially in the centrum semiovale (Rubinstein et al. 1975; Robain et al. 1984). It is striking that there is no significant cellular reaction. The neurotoxic effect is especially conspicuous under the conditions of pregnancy which may cause a cytostatic embryopathy. The characteristic morphologic feature is systemic hypoxia-like damage of the entire brain (microcephaly, hydrocephalus, hypoxic changes of the cortex) associated with malformation of the skull (Fig. 17.9).

Fig. 17.8a, b. Necrotizing leukoencephalopathy, as a morphologic marker of an intrathecal methotrexate application

17.6.3 Cytostatics and Antituberculous Agents Many cytostatic agents, such as cyclohexyl-1-nitrosourea (CCNU) or bischloroethyl nitrosourea (BCNU) as well as selected antituberculous agents, for example isoniazid, can cause CNS injury by a vascular mechanism (Omojola et al. 1982) but we concentrate here on agents damaging the brain by a mechanism directly acting on the nervous parenchyma.

17.6.3.2 Vincristine, Vinblastine The intrathecal or intraventricular application of vincristine or vinblastine is not allowed. In single reported cases, accidental injection into these compartments has occurred and leads to death (Slyter et al. 1980). Both vincristine and vinblastine inhibit mitosis by causing metaphase arrest. Their ability to simultaneously bind tubulin and block its polymerization into microtubules (Prakash and Timasheff 1992) inhibits axoplasmic transport (Chan et al. 1980), which in turn leads to aggregation of the microtubules within the axon. Clinical Features. The clinically dominant feature is

a sensorimotor peripheral neuropathy, especially associated with vincristine. Morphology. The predominant signs are axonal

17.6.3.1 Methotrexate Source. Methotrexate is a folic acid antagonist used as

a cytostatic, especially in the treatment of leukemias. For this purpose, methotrexate is applied intrathecally in combination with cranial and craniospinal radiotherapy. This combined treatment can cause neuronal injury. Intravenous application of methotrexate alone has a neurotoxic effect in sufficiently high doses.

degeneration with proliferation of neurotubules and neurofilaments. Only intrathecal application is known to produce primary cell irritation with marked aggregation of neurofilaments (Slyter et al. 1980). There is rapid onset of fatal encephalomyelopathy with diffuse necrosis of CNS tissue (Fig. 17.10) in contact with cerebrospinal fluid (Wisniewski et al. 1968; Williams et al. 1983).

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Fig. 17.9a−d. Cytostatic embryopathy. a Malformation of the base of the skull; b extreme hydrocephalus and cortical atrophy with lamellated structure; c, d loss of neurons, glial reaction

17.6.3.3 Isoniazid During the treatment of tuberculosis isoniazid, i.e. isonicotinic acid hydracide (=INH), produce peripheral neuropathies. PNS demyelination obviously is secondary to axonal degeneration. In experimental animals the CNS may be additionally effected. The morphology is characterized by spongy changes in the white matter and resemble those in TET intoxication.

and widening of the perivascular spaces in a 7-year-old child (c, d H&E; c magnification ×50; d magnification ×200)

17.7 Biological Toxins 17.7.1 Plants Among poisonous plants, mushrooms are the most important. Clinically, mushroom poisoning sometimes produces gastrointestinal, sometimes CNS symptoms, although morphological findings in the CNS are as yet unknown. The differential diagnosis

CHAPTER 17: Specific Types of Neurotoxins

Fig. 17.10a−d. Vincristine intoxication. a Macroscopically cortical atrophy is visible; b microscopically the neurons and dendrites of the cortex, the basal ganglia and thalamic nuclei are lost, associated with a conspicuous glial reaction (b H&E, magnifica-

tion ×500); c a loss of dendrites in the cortical structures (MAP reactivity) and d an increase of axonal balls (β-APP reactivity) are demonstrable (magnification c, d ×500)

is discussed by Flammer (1980). Reference is made to three different types of mushroom: Amanita muscaria is capable of inducing a pantherina syndrome within only a few minutes to 2 h after consumption. The symptoms include fatigue, giddiness, dizziness, clouding of consciousness or even unconsciousness. Victims appear to be slowed down; they sometimes feel euphoric, indifferent and relaxed as though in a narcotic state. Death can occur within 15−24 h from circulatory collapse. Amanita phalloides (Death Cup) initially (within 6−24 h) causes gastrointestinal disturbances with

considerable loss of water and oliguria, followed by symptoms of acute liver dystrophy. The biological effect is characterized by a reduction of the contractility of structural proteins, as evidenced by, for example, the inhibition of mitosis. Inocybes or cl*tocybes induce a muscarinic syndrome with marked perspiration, hypersalivation and lacrimation, hyperthermia, slow pulse, miotic pupils and impaired vision appearing within a few minutes to 1 h following ingestion. The differential diagnosis must include phosphate ester-induced intoxication.

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In 1987, many inhabitants of Canada became ill after eating commercially grown shellfish. The acute symptoms were headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. Chronically, neuropsychological testing several months later revealed that 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy was found in 11 patients. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. A few victims exhibited temporal lobe epilepsy (Cendes et al. 1995). The illness was caused by domoic acid, a potently excitotoxic amino acid released by the single-cell alga Nitzschia pungens and which was found to be present in large amounts in the shellfish (Perl et al. 1990; Teitelbaum et al. 1990). Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the CA3 and CA1 hippocampus and amygdala (Carpenter 1990; Teitelbaum et al. 1990).

17.7.2 Animals Poisoning can also be caused by animal toxins, which can induce CNS symptoms (Mebs 2002) for which, however, no neuropathological equivalents have yet been found. Among snakes (snake venom) in Germany, the most important are the European viper and the aspis viper, whose poison contains toxalbumins; i.e., hemolysins, neurotoxins, coagulins, proteases, and other enzymes. The clinical sequelae are severe pain at the site of penetration and rapid spread of edema and discoloration. This is followed by symptoms of shock and progressive signs of a hemorrhagic tendency with bloody vomiting, bloody diarrhea, sinking blood pressure, and hemolysis. Other snake venoms may cause necrotizing myopathy and neuromuscular transmission syndrome. Poisonous fishes include the puffer and the blowfish (for review see Schaper et al. 2002). The puffer‘s poison (tetrodotoxin) is found mainly in its bile and liver, that of the blowfish in the ovaries. The poison affects the sodium−potassium pump in the cell membrane and leads to an acute disruption of neuronal function with paralysis, coma, and death. Specific morphological changes have not been described. The Black widow (Latrodectus mactans) is the only dangerous spider native to both Central Europe and North America. Its bite releases a neurotoxin, the so-called α-latrotoxin, which binds to the presynaptic membrane, which then becomes permeable

to Ca 2+ ions. The influx of calcium leads to a release of transmitters (Lazdunski et al. 1986) from cholinergic as well as adrenergic peripheral nerve endings. The blood−brain barrier is not breached. Clinical symptoms appear 10−15 min following a bite and disappear spontaneously after 12−24 h. The most predominant symptom is exquisite pain resulting from generalized muscle spasms. In addition, autonomic as well as psychological symptoms appear (Rehm et al. 1988). Members of the order Hymenoptera (bees, wasps, hornets and fire ants) are also potentially dangerous. Their toxins often cause anaphylactic reactions. Primary neurotoxic effects are rare, bee venom apparently representing an exception in being capable of causing a peripheral neuropathy in some victims (Saida et al. 1977).

17.7.3 Microorganisms Chief among toxin-producing microorganisms are the anaerobic spore-forming bacilli (Clostridium botulinum, Clostridium tetani), which produce potentially life-threatening neurotoxins. While the diphtheria toxin is, of course, of general significant importance, anthrax has recently become known as a potent biological toxin being a specific weapon of terrorism. 17.7.3.1 Botulinum Toxin Source. Clostridium botulinum synthesizes a toxin

which is inactivated at 80°C. It is incorporated with food or through skin wounds. The botulinus toxin binds to the peripheral cholinergic, presynaptic nerve ending and blocks the release of acetylcholine (neuromuscular blockade) (Ochs 1992). Clinically, the toxin has a delayed onset of action. The main symptoms are headache, dizziness, prominent cranial nerve palsies, and descending paralysis. Morphological changes have not been described. 17.7.3.2 Tetanospasmin Under anaerobic conditions, Clostridium tetani produces the toxin tetanospasmin, which becomes inert at 65°C. If the toxin reaches the blood, it induces toxemia. The clinical picture is characterized by nausea, irritability, headache, and spasms of the facial muscles (risus sardonicus). Death occurs from shock or respiratory insufficiency. Pathogenetically the toxin attaches to presynaptic terminals of cholinergic synapses (Price et al. 1975a, b), from which the toxin travels in a retrograde man-

CHAPTER 17: Specific Types of Neurotoxins

ner as far as the anterior horns of the spinal cord (Walsh et al. 1982). Morphologically all changes are non-specific. The cytoplasmic vacuoles in the motor cells of the anterior horn are regarded as characteristic (Müller and Jeschke 1970). 17.7.3.3 Diphtheria Toxin The non-sporulating Corynebacterium diphtheriae generates a toxin that binds stereospecifically to membrane receptors and is transported by endocytosis into the interior of the cell (Walsh et al. 1982). Clinically the picture is that of a peripheral neuropathy, in some cases with progressive paralysis of the Guillain−Barré type. Morphologically there is destruction of myelin mainly of the peripheral nerves with relatively well preserved axons and no signs of inflammation − chiefly in the spinal ganglia of the posterior roots (Fisher and Adams 1956; Kaplan 1980; MacGregor 1995). 17.7.3.4 Anthrax Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Anthrax can occur in humans when they are exposed to infected animals or tissue from infected animals. Anthrax lethal toxin is the principal virulence factor associated with lethal pathologies following infection with Bacillus anthracis (McAllister et al. 2003). Recently, anthrax is best known as a biological weapon (Inglesby et al. 1999). There are three types of anthrax transmission and clinical features (Dixon et al. 1999): 1. Cutaneous transmission, with bacterium entering through a cut or abrasion on the skin. Skin infection begins as a raised itchy bump that resembles an insect bite, which develops into a painless ulcer with a characteristic black necrotic area in the center. 2. Several days after inhalational transmission, victims develop symptoms that may progress to severe breathing problems and shock. Inhalation anthrax is usually fatal. 3. Intestinal transmission may follow the consumption of contaminated meat (food poisoning) and is characterized by an acute inflammation of the intestinal tract. Intestinal anthrax results in death in 25 − 60% of cases. Clinical and Neuropathological Manifestation. An-

thrax bacillus has been implicated in a wide range of infections including abscesses, bacteremia/septicemia, wound and burn infections, ear infections, endocarditis, ophthalmitis, osteomyelitis, peritonitis, and respiratory and urinary tract infections. Most

of these occur as secondary or mixed infections or in immunodeficient or otherwise immunocompromised hosts, such as alcoholics and diabetics. CNS involvement is characterized by a fulminant and rapidly fatal hemorrhagic meningoencephalitis (Meyer 2003). According to Dixon et al. (1999) the most common portal of entry to the leptomeninges is the skin (and inhalation route), from which the organisms can spread to the central nervous system by hematogenous or lymphatic routes. Anthrax meningitis is almost always fatal, with death occurring 1−6 days after the onset of illness. Gross examination at autopsy reveals extensive hemorrhage of the leptomeninges, which gives them a dark red appearance described as “cardinal’s cap” (Abramova et al. 1993). The microscopic findings are consistent with a hemorrhagic meningitis (Tahernia and Hashemi 1972; Martin and Adams 2003), with extensive edema, inflammatory infiltrates, and numerous Gram-positive bacilli in the leptomeninges (Dutz and Kohout 1971; Rangel and Gonzalez 1975).

Bibliography Ammon HPT (1991) Arzneimittelneben- und -wechselwirkungen. Wissenschaftliche Verlagsgesellschaft, Stuttgart Ellenhorn MJ, Barceloux DG (1988) Medical toxicology. Elsevier, New York Gilman AG, Rall TW, Nies AS, Taylor P (2000) The pharmacological basis of therapeutics. Pergamon, New York Haschek WM, Rousseaux CG (1997) Fundamentals of toxicologic pathology. Academic Press, San Diego, Calif. Herken H, Hucho F (1992) Selective neurotoxicity. Springer, Berlin Heidelberg New York Marquardt H, Schäfer SG, eds (1997) Lehrbuch der Toxikologie. Spektrum Akademischer Verlag, Heidelberg Berlin Schröder JM (1999) Pathologie peripherer Nerven. In: Doerr W, Seifert G (eds) Spezielle pathologische Anatomie, vol 13/VIII. Springer, Berlin Heidelberg New York Spencer PS, Schaumburg HH (eds) (2000) Experimental and chemical neurotoxicology. Oxford University Press, New York Stötzer H, Stötzer H (1999) Erkrankungen durch Arzneimittel. Gustav Fischer, Stuttgart

References Abramova FA, Grinberg LM, Yampolskaya OV, Walkter DH (1993) Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci USA 90:2291−2294 Adams JH, Haller L, Boa FY et al (1986) Human African trypanosomiasis (T. b. gambiense): a study of 16 fatal cases of sleeping sickness with some observations on acute reactive arsenical encephalopathy. Neuropathol Appl Neurobiol 12:81−94

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Plum F, Posner JB, Hain RF (1962) Delayed neurological deterioration after anoxia. Arch Int Med 110:56−63 Powell HC, Lampert PW (1977) Hexachlorophene neurotoxicity. In: Roizen L, Shiraki H, Grèeviæ N (eds) Neurotoxicology. Raven, New York, pp 381−389 Powell H, Swarner O, Gluck L, Lampert P (1973) Hexachlorophene myelinopathy in premature infants. J Pediatr 82:976−981 Prakash V, Timasheff SN (1992) Aging of tubulin at neutral pH: the destabilizing effect of vinca alkaloids. Arch Biochem Biophys 295:137−145 Price DL, Griffin J, Peck K (1975a) Tetanus toxin: evidence for binding at presynaptic nerve endings. Brain Res 121:379−384 Price DL, Griffin J, Young A et al (1975b) Tetanus toxin: direct evidence for retrograde axonal transport. Science 188:945−947 Provias JP, Ackerley CA, Smith C, Becker LE (1994) Cadmium encephalopathy: a report with elemental analysis and pathological findings. Acta Neuropathol (Berl) 88:583−586 Rangel RA, Gonzalez DA (1975) Bacillus anthracic meningitis. Neurology 25:525−530 Rehm H, Bidard JN, Schweitz H, Lazdunski M (1988) The receptor site for the bee venom mast cell degranulating peptide. Affinity labeling and evidence for a common molecular target for mast cell degranulating peptide and dendrotoxin I, a snake toxin active on K+ channels. Biochemistry 27:1827−1832 Reiner E, Lotti M (eds) (1993) Enzymes interacting with organophosphorus compounds. Chem Biol Interact (Special Issue) 87 Reusche E (1991) Silver staining of senile plaques and neurofibrillary tangles in paraffin sections- a simple and effective method. Pathol Res Pract 187:1045−1048 Reusche E (1997) Argyrophilic inclusions distinct from Alzheimer neurofibrillary changes in one case of dialysis-associated encephalopathy. Acta Neuropathol (Berl) 94:612−616 Reusche E, Seydel U (1993) Dialysis associated encephalopathy. Light and electron microscopic morphology and topography with evidence of aluminium by laser microprobe mass analysis. Acta Neuropathol (Berl) 86:249−258 Reusche E, Ogomori K, Diebold J, Johannisson R (1992) Electron microscopic study of paired helical filaments and cerebral amyloid using a novel en bloc silver staining method. Virchows Arch A 420:519−525 Reusche E, Koch V, Friedrich HJ et al (1996) Correlation of drugrelated aluminum intake and dialysis treatment with deposition of argyrophilic aluminium-containing inclusions in CNS and organ systems of patients with dialysis-associated encephalopathy. Clin Neuropathol 15:342−347 Reusche E, Koch V, Lindner B et al (2001) Alzheimer morphology is not increased in dialysis-associated encephalopathy and long-term hemodialysis. Acta Neuropathol (Berl) 101:211−216 Reynolds IJ, Miller RJ (1988) Multiple sites for the regulation of the N-methyl- D-aspartate receptor. Mol Pharmacol 33:581−584 Ricoy JR, Cabello A, Rodriguez J, Tellez I (1983) Neuropathological studies on the tox syndrome related to adulterated rapeseed oil in Spain. Brain 106:817−835 Robain O, Dulac O, Dommergues JP et al (1984) Necrotising leukoencephalopathy complicating treatment of childhood leukemia. J Neurol Neurosurg Psychiatry 47:65−72

CHAPTER 17: Specific Types of Neurotoxins

Rodier J (1955) Manganese poisoning in Moroccan miners. Br J Indust Med 12:21−35 Rogan WJ, Ware JH (2003) Exposure to lead in children − how low is low enough? N Engl J Med 348:1515−1516 Ross WD, Emmett EA, Steiner J, Tureen R (1981) Neurotoxic effects of occupational exposure to organotins. Am J Psychiatry 138:1092−1095 Rubinstein LJ, Herman MM, Long TF, Wilbur JR (1975) Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 35:291−305 Saida K, Mendell JR, Sahenk Z (1977) Peripheral nerve changes induced by local application of bee venom. J Neuropathol Exp Neurol 36:783−796 Salama J, Gherardi R, Amiel H et al (1986) Post-anoxic delayed encephalopathy with leukoencephalopathy and non-hemorrhagic cerebral amyloid angiopathy. Clin Neuropathol 5:153−156 Sarafian T, Verity MA (1986) Mechanism of apparent transcription inhibition by methylmercury in cerebellar neurons. J Neurochem 47:625−631 Schaper A, Ebbecke M, Rosenbusch J, Desel H (2002) Fischvergiftung. Dtsch Ärztebl 99:A1151−A1158 Schaumburg HH, Spencer PS (1980) Clioquinol. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical pathology. Williams and Wilkins, Baltimore, Md., pp 395−406 Schaumburg HH, Arezzo JC, Spencer PS (1989) Delayed onset of distal axonal neuropathy in primates after prolonged lowlevel administration of a neurotoxin. Ann Neurol 26:576−579 Schmidt G (1946) Zur Klinik der akuten Methylalkoholvergiftung. Dtsch Med Wochenschr 71:61−64 Schrader G (1963) Die Entwicklung neuer insektizider Phosphorsäure-Ester. Verlag Chemie, Weinheim Schröder JM (2000) Cadmium. In: Spencer PS, Schaumburg HH (eds) Experimental and chemical neurotoxicology. Williams and Wilkins, Baltimore, Md., pp 276−280 Schwedenberg TH (1959) Leukoencephalopathy following carbon monoxide asphyxia. J Neuropathol Exp Neurol 18:597−608 Shapiro WR, Chernik NL, Posner JB (1973) Necrotizing encephalopathy following intraventricular instillation of methotrexate. Arch Neurol 28:96−102 Sharpe JA, Hostovsky M, Bilbao JM, Rewcastle NB (1982) Methanol optic neuropathy: a histopathological study. Neurology 32:1093−1100 Shigematsu I, Yanagawa H (1978) Data on clioquinol and S.M.O.N. Lancet 11:945 Shuman RM, Leech RW, Alvord EC (1974) Neurotoxicity of hexachlorophene in human infants: a histopathologic study of 250 infants. Am J Pathol 70:19a−20a Silbergeld EK (1983) Localization of metals: issues of importance to neurotoxicology of lead. Neurotoxicology 4:193−200 Slotkin TA, Cousins MM, Tate CA, Seidler FJ (2001) Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure. Brain Res 902:229−243 Slyter H, Liwnicz B, Herrick MK, Mason R (1980) Fatal myelo-encephalopathy caused by intrathecal vincristine. Neurology 30:867−871

Smith RP (1997) Editorial commentary − sulfide poisoning. Clin Toxicol 35:305−306 Snyder JW, Safir EF, Summerville GP, Middleberg RA (1995) Occupational fatality and persistent neurological sequelae after mass exposure to hydrogen sulfide. Am J Emerg Med 13:199−203 Song SY, Okeda R, Funata N, Higoshino F (1983) An experimental study of the pathogenesis of the selective lesion of the globus pallidus in acute carbon monoxide poisoning in cats. Acta Neuropathol (Berl) 61:232−238 Spencer PS (1999) Food toxins, AMPA receptors, and motor neuron diseases. Drug Metab Rev 31:561−587 Spencer PS, Schaumburg HH (1974) A review of acrylamide neurotoxicity. Part I. Properties, uses and human exposure. Can J Neurol Sci 1:151−169 Spencer PS, Wilson BW, Albuquerque EX (2000) Sarin, other “nerve agents”, and their antidotes. In: Spencer PS, Schaumburg HH, Ludolph AC (eds) Experimental and clinical neurotoxicology, 2nd edn. Oxford University Press, New York, pp 1073−1093 Strong MJ, Wolff AB, Wakayama I, Garruto RM (1991) Aluminiuminduced chronic myelopathy in rabbits. Neurotoxicology 12:9−21 Takeuchi T, Eto N, Eto K (1979) Neuropathology of childhood cases of methylmercury poisoning (Minamata disease) with prolonged symptoms, with particular reference to the decortication syndrome. Neurotoxicology 1:1−20 Teitelbaum JS, Zatorre RJ, Carpenter S, Gendron D, Evans AC, Gjedde A, Cashman NR (1990) Neurologic sequelae of domoic acid intoxication due to ingestion of contaminated mussels. N Engl J Med 322:1781−1787 Thom SR (1990) Carbon monoxide-mediated brain lipid peroxidation in the rat. J Appl Physiol 68:997−1003 Thom SR (1992) Dehydrogenase conversion to oxidase and lipid peroxidation in brain after carbon monoxide poisoning. J Appl Physiol 73:1584—1589 Thom SR, Taber RL, Mendiguren II et al (1995) Delayed neuropsychologic sequelae after carbon monoxide poisoning prevention by treatment with hyperbaric oxygen. Ann Emerg Med 25:474—480 Thom SR, Bhopale VM, Fisher D et al (2004) Delayed neuropathology after carbon monoxide poisoning is immune-mediated. Proc Natl Acad Sci USA 101:13660−13665 Thomas E (1960) Veränderungen des Nervensystems bei Vergiftungen mit niedrigen Halogenkohlenwasserstoffen. Dtsch Z Nervenheilk 180:530−561 Thomas PK, Schaumburg HH, Spencer PS et al (1984) Central distal axonopathy syndromes: newly recognized models of naturally occurring human degenerative disease. Ann Neurol 15:313−315 Tonge JI, Burry AF, Saal JR (1977) Cerebellar calcification: a possible marker of lead poisoning. Pathology 9:289−300 Tripier MF, Bérard M, Toga M et al (1981) Hexachlorophene and the central nervous system. Acta Neuropathol (Berl) 53:65−74 Tvedt B, Skyberg K, Aaserud O et al (1991) Brain damage caused by hydrogen sulfide: a follow-up study of six patients. Am J Indust Med 20:91−101

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Ule G, Pribilla O (1962) Hirnveränderungen nach Cyankalivergiftung mit protrahiertem (intervallärem) klinischen Verlauf. Acta Neuropathol (Berl) 1:406−412 Vahter M (1999) Methylation of inorganic arsenic in different mammalian species and population groups. Sci Prog 82:69 Valpey R, Sumi M, Copass MK, Goble GJ (1978) Acute and chronic progressive encephalopathy due to gasoline sniffing. Neurology 28:507−510 Velvart J, Moeschlin S (1980) Insektizide. In: Moeschlin S (ed) Klinik und Therapie der Vergiftungen. Thieme, Stuttgart, pp S422−S444 Verity MA, Brown WJ, Cheung M (1975) Organic mercurial encephalopathy: in vivo and in vitro effects of methyl mercury on synaptosomal respiration. J Neurochem 25:759−766 Villeda-Hernandez J, Barroso-Moguel R, Mendez-Armenta M et al (2001) Enhanced brain regional lipid peroxidation in developing rats exposed to low level lead acetate. Brain Res Bull 55:247−251 Vock R, Magerl H, Lange O et al (1999) Handlungsfähigkeit bei tödlichen oralen Intoxikationen mit Cyan-Verbindungen. Rechtsmed 9:56−61 Volk B, Kirchgässner N, Detmar M (1986) Degeneration of granule cells following chronic phenytoin administration and electron microscopic investigation of the mouse cerebellum. Exp Neurol 91:60−70 Wada K, Fujii Y, Watanabe H, Satoh M, Furuichi Y (1991) Cadmium directly acts on endothelin receptor and inhibits endothelin binding activity. FEBS Lett 285:71−74 Walsh TJ, Clark AW, Parhad IM, Green WR (1982) Neurotoxic effects of cisplatin therapy. Arch Neurol 39:719−720 Weaver LK (1999) Carbon monoxide poisoning. Crit Care Clin 15:297−317

Weaver LK, Hopkins RO, Chan KJ et al (2002) Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 347:1057−1067 Weinstein L (1974) Diphtheria. In: Wintrobe MM, Thorn GW, Adams RD, Braunwald E, Isselbacher KJ, Petersdorf RG (eds) Harrison‘s principles of internal medicine, 7th edn. McGraw-Hill, New York, pp 841−845 Whetsell WO Jr (2002) The mammalian striatum and neurotoxic injury. Brain Pathol 12:482−487 Williams ME, Walker AN, Bracikowski JP et al (1983) Ascending myeloencephalopathy due to intrathecal vincristine sulfate. Cancer 51:2041−2047 Wisniewski H, Shelanski ML, Terry RD (1968) Effects of mitotic spindle inhibitors on neurotubules and neurofilaments in anterior horn cells. J Cell Biol 38:224−229 Wisniewski HM, Sturman JA, Shek JW (1979) Aluminium chloride induced neurofibrillary changes in the developing rabbit: a chronic animal model. Ann Neurol 8:479−490 Yamada M, Ohno S, Okayasu I et al (1986) Chronic manganese poisoning: a neuropathological study with determination of manganese distribution in the brain. Acta Neuropathol (Berl) 70:273−278 Yokoyama K, Arak S, Murata K et al (1998) A preliminary study on delayed vestibulo-cerebellar effects of Tokyo Subway sarin poisoning in relation to gender difference: frequency analysis of postural sway. J Occup Environ Med 40:17−21 Zhang J, Piantadosi CA (1992) Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 90:1193−1199 Zheng W, Ren S, Graziano JH (1998) Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity. Brain Res 799:334−342

CHAPTER 18

Alcohol, Organic Solvents, and Aerosols

371

18.1

Epidemiology

18.2

Metabolism, Kinetics, and Causes of Death 372

18.3

Pharmacology

18.4 18.4.1 18.4.2

Clinical Features 374 Acute Intoxication 374 Chronic Intoxication (Alcoholism)

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Neuropathology 375 Acute Intoxication 375 Chronic Intoxication 375 Diffuse Brain Alterations 376 Cerebellar Atrophy 378 Wernicke−Korsakoff Syndrome 378 Central Pontine Myelinolysis 379 Marchiafava−Bignami Syndrome 380 Pellagra 380 Alcoholic Myelopathy 380 Neuropathy of the Autonomic Nervous System 380 18.5.2.9 Neuropathy/Polyneuropathy 380 18.5.2.10 Myopathy 381 18.5.2.11 Secondary Pathologic Alterations 381 18.5.2.12 Disulfiram Treatment 383 18.5 18.5.1 18.5.2 18.5.2.1 18.5.2.2 18.5.2.3 18.5.2.4 18.5.2.5 18.5.2.6 18.5.2.7 18.5.2.8

18.6

Alcoholic Fetopathy and Embryopathy

18.7

Organic Solvents and Aerosol

383

384

Bibliography 385 References

385

18.1 Epidemiology In the Federal Republic of Germany, 4.5 million people are estimated to be alcohol dependent and about 40,000 alcohol-related deaths occur annually (Trojan 1980; Petersson et al. 1982). Among individuals

≥16 years of age, 2−7% of the population are alcoholics, 16−47% are heavy consumers of alcohol, whereas only 6−14% abstain entirely or “almost” entirely from alcohol (Trojan 1980). The heaviest consumers of alcohol are males aged 30−49 years (Feuerlein and Küfner 1977). Mortality studies in Norway have demonstrated an excess mortality of 113% for alcohol-dependent persons relative to the general population of Norway (Sundby 1967). The principal causes of alcohol-related death were determined by Schmidt and de Lint (1972): these include cirrhosis of the liver, cancer of the stomach and the upper digestive tract, apoplexy, suicide, and accidents. The following statistics also apply: 1. The mortality rate of alcoholics is 2.5−4 times greater than that of the general population (Garfield 1981; Taylor et al. 1983; Lithell et al. 1987). 2. The total annual mortality per 1,000 alcoholics was 25.9, but was only 8.8 for drug users (Barr et al. 1984). 3. Prospective studies by Petersson and colleagues (1982) showed that 3 years after examination of 10,000 males aged 46−48 years, 199 had died, 61 (30.7%) of alcohol-related causes. 4. The relative proportion of alcohol deaths documented in Institutes of Forensic Pathology is 0.6−22% (Kringsholm 1976; Wiese et al. 1990). 5. The percentage of deaths whose cause could not be determined is twice as high for alcoholics as for control cases (Hansen and Simonsen 1991). Alcoholism usually occurs sporadically. But family, twin, and adoption studies have convincingly demonstrated that genes play an important role in the development of alcohol dependence (for review see Dick and Foroud 2003), accounting for approximately 50−60%. Furthermore, there is evidence of genetic effects on patterns of alcohol use as early as in adolescence, and these effects seem to increase during the course of time (Rose et al. 2001). In spite of these findings the complexity of alcohol-related traits has made the path to specific gene identification arduous. Alcohol dehydrogenase (ADH) genes − in particular ADH class I isoenzyme ADH1B, which is closely linked on chromosome 4q23 (Edenberg and

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Bosron 1997), as well as the acetaldehyde dehydrogenase (ALDH) gene, especially the ALDH class II isoenzyme ALDH2 (Harada et al. 1982) − remain the only genes with definitely established contributions to alcohol dependence. The effects of these genes seem to be additive, with ALDH2 having a stronger effect. Subsequent studies have reported reduced rates of the ADH1B and/or ALDH2 allele among alcoholics in Asian populations (Chen et al. 2001).

18.2 Metabolism, Kinetics, and Causes of Death Alcohol is absorbed through the gastrointestinal tract and diffuses into the circulatory system (for review see Goodman et al. 2001). There are three pathways of alcohol metabolism (for review see Matsumoto and f*ckui 2002): 1. Alcohol dehydrogenase (ADH: EC 1.1.1.1): oxidizes alcohol to acetaldehyde, which in turn is oxidized by acetaldehyde dehydrogenase to acetic acid. The ADH family consists of numerous isoenzymes (von Wartburg et al. 1964; Hines et al. 2001). The rate of alcohol metabolism is determined by the type and activities of the enzymes present in a given individual. In the Mongoloid race − compared to the Caucasian race − up to 90% of the population possesses an atypical ADH associated with a low tolerance for alcohol (Agarwal and Goedde 1995). ADH is located mainly in the liver, but it is also present in other organs, such as the central nervous system (CNS). Whereas ADH can be induced (Raskin and Sokoloff 1968; so-called adaptive acceleration of catabolic metabolism − cf. Topel 1984), acetaldehyde dehydrogenase is limited in its adaptability. An increase in the alcohol dose, therefore, leads to an accumulation of acetaldehyde in the blood, which is much more toxic than alcohol. 2. The microsomal oxidizing systems (MEOS; Ohnischi and Lieber 1977) or microsomal mixedfunction oxidases (Gilman and Abraham 2001): the activity of this oxidative system is stimulated not only by alcohol but also by some medications, e.g., barbiturates. 3. Catalase (Keilin and Hartree 1936). 4. Conjugation with glucuronic acid (Besserer and Schmidt 1983): items 3 and 4 account for a negligible percentage of alcohol metabolism when compared to ADH and MEOS. The elimination of alcohol from the body (mainly via the liver) is largely a function of time (zero-order kinetics) and not exponential. The mean rate is 15 (mg/

dl)/h (Mallach 1987; Schmidt 1988). Alcohol diffuses throughout the brain, where its levels are proportional to the blood alcohol concentration (BAC); in total the cerebrum: Agapejev et al. (1992); in the occipital lobe and cerebellum: Moore et al. (1997). Acetaldehyde is the main toxic factor (Pratt et al. 1990). Since this metabolite can penetrate the blood−brain barrier only at very high blood concentrations (Hunt 1996), the question arises as to how elevated acetaldehyde levels come to be present in brain tissue even in cases with low blood alcohol levels. A particular isoform of ADH has been demonstrated in the brain, the activity of which is inducible − only in the hemispheres, and not in the brain stem − (Raskin and Sokoloff 1974 − cf. Rout 1992); moreover, in the brain, further catalase activity (Cohen et al. 1980; Zimatkin and Lindros 1996) generates acetaldehyde as a metabolite (Smith et al. 1997). A similar situation holds true for MEOS, which can also be demonstrated in brain tissue (Zimatkin and Dietrich 1997). The accumulation of locally produced acetaldehyde can, therefore, be explained by the presence of local dehydrogenase (Spivak et al. 1987; Zimatkin et al. 1998). Besides ethanol, alcoholic beverages (wine, beer, cognac, whiskey, etc.) contain alcoholic congeners, so-called fusel alcohols, in concentrations that are characteristic for each type of beverage. Fusel alcohols are byproducts of the fermentation process and include methanol, 1- and 2-propanol, 1- and 2-butanol, isobutanol, and amylalcohol (Bonte 1987). Most of them are toxic and account for the post-intoxication “hangover” effect. Detection and quantification of fusel alcohol is used in forensic practice to demonstrate the type of alcoholic beverage consumed, especially if “after drinks” are claimed. Alcohol, acetaldehyde, and fusel alcohols have a toxic effect on numerous organ systems, the chief target organs being the liver and cardiovascular system (Altura and Altura 1987). They simultaneously target organs of the gastrointestinal tract and the pancreas (for review see Oehmichen et al. 1992; Singer and Teyssen 2001). Recent investigations give evidence of a genderdependent difference in brain metabolism of alcohol (Wang et al. 2003). Since alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABA-ergic neurotransmission, the differences could be demonstrated with positron emission tomography. The magnitude of the alcohol-induced decrease of the whole-brain metabolism was significantly larger in male than in female subjects. This phenomenon correlates with studies which documented a greater behavioral effect of alcohol in female subjects than in male subjects. Death can occur with alcohol without evident organic disease, however. The following types of cases can be differentiated:

CHAPTER 18: Alcohols, Organic Solvents, and Aerosols

1. Alcohol can be an additional, possibly contributing factor, in an acute lethal event involving physical or chemical trauma (blow, fall, stab, traffic accident, hypothermia) and/or reflex mechanisms (bolus, drowning) and/or disease-induced processes (coronary thrombosis, rupture of an aneurysm at the base of the brain, etc. − Weston 1980). This class of events includes combined drug and/or pharmacological and alcohol intoxication (Geldmacher von Mallinckrodt et al. 1976; King 1982). 2. Acute death of an alcoholic can occur without acute alcohol intoxication, but in conjunction with chronic organic changes which explain the death sufficiently (e.g., hemorrhage of esophageal varices, hepatic coma, etc.). 3. Acute death may be due to acute alcohol intoxication in individuals with no known history of alcohol abuse. 4. Acute death may be due to acute alcohol intoxication in individuals with a history of alcohol abuse. 5. Acute death of an alcoholic may occur during alcohol intoxication with observable chronic organic changes, but of a type that would not explain the death. The possible causes of death in these cases include asystole caused by bradyarrhythmia secondary to alcoholic cardiomyopathy or organic brain paroxysm. 6. Acute death may be a result of chronic alcohol consumption and stroke. The relative risk of stroke of chronic alcoholics was recently evaluated by Reynolds et al. (2003): compared to abstainers, consumption of more than 60 g alcohol per day was associated with an increased relative risk of total stroke, while consumption of less than 12 g/day was associated with a reduced relative risk of total stroke, and consumption of 12−24 g/ day was associated with a reduced relative risk of ischemic stroke (not hemorrhagic stroke). Acute alcohol poisoning is lethal at a BAC of between 180 mg/dl (1.8‰) and 670 mg/dl (6.7‰) (Kaye and Haag 1957; cf. Mallach et al. 1980). BACs of this magnitude cause (central) respiratory arrest and consecutive cardiac arrest secondary to hypoxemia and diminished venous reflux (Polaczek-Kornecki et al. 1972). Alcoholics are often discovered dead, however for no discernible reason without highly toxic BACs (Copeland 1985).

18.3 Pharmacology The effects of alcohol can be divided into three phases: stimulation, disinhibition, and inhibition. At the

cellular level, ethanol‘s lipophilic and hydrophobic properties affect neuronal membranes, changing the composition of the membranous lipids by, for example, membrane liquefaction (Kurella and Genkina 1989; Gustavsson 1990); membrane liquefaction is accompanied by a hypnotic effect. The pharmacological effect of ethanol is highly complex and cannot be explained by a simple model. Alcohol influences not only membranes, but also membrane-bound proteins, i.e., both neurotransmitters and receptors (Eue and Kemper 1992). Low alcohol levels increase the turnover of noradrenaline, higher levels reduce it, and they also inhibit the cholinergic and GABA-ergic transmitter systems (Hörtnagl and Hanin 1992). The functional changes are apparently caused by glutamate receptors in the hippocampus, cortex, striatum, and thalamus (Foster and Wong 1987), the N-methyl-D-aspartate (NMDA) receptor being the most important. Acute exposure to alcohol inhibits the NMDA receptor response, chronic exposure leads to an adaptive hypersensitivity in the sense of dependence and tolerance (Rudolph et al. 1997). Simultaneously, receptors of various transmitters influence the transmission of neurotransmitters by cyclic AMP and cyclic GMP. In the brain, nitric oxide (NO) metabolites are released; they are present in elevated levels in the cerebrospinal fluid of alcoholics (Neiman and Benthin 1997). Nitric oxide itself is released by excessive glutamate stimulation of the NMDA receptors (Lancaster 1992). Alcohol is also known (Riley and Walker 1978) to influence the synthesis, release, and metabolism of endogenous opiates. In rats, met-enkephalin and β-endorphin levels increase following acute alcohol consumption, whereas chronic alcohol consumption reduces their levels; alcohol influences the binding of opiates to their receptors (overview see Feuerlein 1989). Application of the opioid antagonist naltrexone can significantly reduce the alcohol uptake of rats (Franck et al. 1988), suggesting that the central δ-opioid receptor modifies voluntary alcohol consumption in rats. The effects of ethanol are mediated by an activation of γ-aminobutyric acid (GABA A) receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems (Anton 1996). The depressant actions of ethanol in the brain are related to its interaction with NMDA and the benzodiazepine/GABA receptor complex (Weight et al. 1992). The hypothermic effects of ethanol have complex interactions with other drugs, which differ in their interaction from those affecting motor behavior (Maickel and Nash 1986).

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18.4 Clinical Features 18.4.1 Acute Intoxication Acute alcohol poisoning is psychopathologically characterized by simple “drunkenness,” which can be divided into three stages (Witter 1972): 1. Mild inebriation (BAC = 0.5−1.5‰ = 10.8− 32.5 mmol/l = 50−150 mg/dl): general psychopathological disinhibition, decrease in psychom*otor performance, impaired coordination, impaired driving ability − caused by involvement of polysynaptic neuronal connections in the reticular formation of the brain stem, the cerebral cortex, and the cerebellum (Klemm 1979). 2. Moderate inebriation (BAC: 1.5−2.5‰ = 32.5− 54.2 mmol/l = 150−250 mg/dl): euphoria or aggressive irritability, diminished capacity for selfcriticism, satisfying of instinctual drives. 3. Severe inebriation (BAC: >2.5‰ = 54.2 mmol/l = 250 mg/dl): impaired consciousness, poor judgment, disorientation, visual and/or auditory and/ or tactile, and/or olfactory hallucinations (illusionary misinterpretation in a given situation), inexplicable fear, agitation, signs of functional impairment of the vestibular organ(s) and cerebellum such as nystagmus, double vision, speech disturbances, ataxia, hypotension, hypothermia, etc. As mentioned above, lethal intoxication can occur at BAC of about 180−670 mg/dl, with a peak at values of 450−500 mg/dl (Poikolainen 1984; Johnson 1985; Kubo et al. 1991). Extremely rare by contrast are observations of BAC exceeding 500 mg/dl, for example of 800 mg/dl (Hammond et al. 1973; Lindblad and Olsson 1976; Püschel et al. 1978). How can the phenomenon of tolerance be explained at the molecular level? If alcohol does indeed lead to an acute increase in the permeability of the membrane lipids, then it may be possible for the neuronal membranes to become resistant to this effect (Chin and Goldstein 1977; Harris et al. 1984). Of at least equal importance is alcohol‘s affect on the receptor system regulating the ion canals, especially the Cl− and Ca 2+ channels. Alcohol reduces depolarization-induced Ca 2+ flow into neuronal cells. Adaptation to this effect would mean that the number of Ca 2+ channels in the cell membrane would increase (Hudspith et al. 1987; Rubin 1987). Withdrawal from alcohol itself leads to impairment of neuronal function, above all to overshooting neuronal activity.

18.4.2 Chronic Intoxication (Alcoholism) Chronic alcohol abuse can be defined by the following criteria (Feuerlein 1989): 1. Abnormal drinking behavior 2. Alcohol-induced somatic damage 3. Alcohol-induced psychosocial damage 4. Development of tolerance and withdrawal syndrome (physical dependence) 5. Withdrawal syndrome at the subjective level (psychic dependence) Chronic alcoholics have long been characterized exclusively − and essentially − by drinking behavior and associated changes in social behavior. Clinical symptoms usually occur later. Even in the preclinical stages, however, reduced cerebral metabolism (Volkow et al. 1992) and EMG changes are often evident as precursors of polyneuropathy (D‘Amour and Butterworth 1994). Clinical data imply that relapse and craving for alcohol can be induced through different mechanisms (Spanagel 2002, 2003): ▬ A first pathway may induce alcohol craving and relapse through the mood-enhancing, positive reinforcing effects of alcohol consumption. This pathway seems to involve opioidergic systems in the ventral striatum. The role of the dopaminergic system may lie in the direction of attention towards reward-indicating stimuli, while the induction of euphoria and positive mood states may be mediated by opioidergic systems (Spanagel and Weiss 1999; Olive et al. 2001). Associative learning may, in turn, transform positive mood states and previously neutral environmental stimuli into alcohol-associated ones that acquire positive motivational salience and induce reward craving. ▬ A second pathway may induce alcohol craving and relapse by negative motivational states, including conditional withdrawal and stress. This pathway seems to involve the glutamatergic system and the corticotrophin-releasing hormone (CRH) system (Spanagel 2002). Chronic alcohol intake leads to compensatory neurotransmission, and increased CRH release leads to a state of hyperexcitability, which becomes manifest as craving, anxiety, seizures, and autonomic dysregulation (Spanagel and Bienkowski 2002). The neurological deficits are characterized by the following clinical picture: 1. Alcoholic encephalopathy: this picture is associated with dementia and inner and outer brain atrophy (mainly of the frontal and temporal lobes), cerebellar atrophy, and alcoholic epilepsy. There

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2.

3.

4.

5.

is evidence that light-to-moderate alcohol consumption is associated with a reduced risk of dementia in individuals aged 55 years or older (Ruitenberg et al. 2002). Wernicke−Korsakoff syndrome: a small proportion of alcoholics suffer from this disease, which progressively develops − in variable order − with the following symptoms: − Oculomotor paralysis with pupillary disturbances and uncertain gait − Slight symptoms of delirium − Korsakoff‘s psychosis with loss of long-term memory, decrease in spontaneity, confabulation and poor concentration. Delirium and hallucinosis: in combination with − but also independently of − the aforementioned disturbances, delirious states can also occur (Böning and Holzbach 1987), including hallucinosis (Glass 1989a, b) with paresthesias and/or tactile hallucinations. Finally, schizophrenia-like psychoses can also develop. Convulsive disorders: organic brain seizures (grand mal) have been seen in 7.8% (Wilkinson et al. 1971) and 5−35% of alcoholics (Meyer and Forst 1977). They can occur after episodes of excessive alcohol intake or during withdrawal (Bartolomei et al. 1997). In some cases, however the convulsive disorder is associated with the cerebral sequelae of cranio-cerebral trauma incidental to alcoholism. Withdrawal symptoms: studies of the cellular and molecular actions of acute ethanol exposure suggest effects that reduce synaptic excitation (Aguayo 1990). Removal of ethanol after chronic exposure leads to “hyperexcitability” (Walker and Zornetzer 1974) of the CNS. In the most extreme cases tonic/clonic seizures of pre-convulsive states are observed during withdrawal from chronic ethanol abuse (for review see Crabbe et al. 1990; Lovinger 1993).

Acute alcohol withdrawal can produce the following symptoms (Gross et al. 1972): ▬ Disturbances of perception/cognition (attributable to cortical structures): nausea, tinnitus, visual impairment, paresthesias, optic, acoustic or tactile hallucinations, motor restlessness. ▬ Autonomic disturbances (attributable to the limbic system): tremor, profuse sweating, depression, anxiety. ▬ Disturbances attributable to the brain stem: disturbed consciousness, gait disorders, etc. ▬ Seizures (see above). ▬ Delirium tremens (Taylor and Lewis 1993): this clinical picture is defined (ICD 10) as an acute, temporary, generalized organic disease of the central nervous system with impairment of consciousness and vigilance. It is associated with

increased mortality, especially in older patients (Trzepacz et al. 1985). The pathogenesis has not yet been satisfactorily explained. It may well be caused by a generalized metabolic disturbance combined with cardiovascular disorders. Contributing factors may include magnesium deficiency and respiratory alkalosis (secondary to hyperventilation; Victor 1977) and/or an increase in acetylcholine and/or the activity of the entire cholinergic system (Ital and Fink 1966; Taylor and Lewis 1993). Only a few pathological−anatomical studies are available: they show non-specific changes and/or lesions typical of alcoholism in general (cf. Ikeda et al. 1993).

18.5 Neuropathology 18.5.1 Acute Intoxication The neuropathology following acute alcohol intake is non-specific and characterized by brain edema and congestion. The pathomechanical course is explained by a primary toxic central respiratory paralysis or arrest, which leads to acute right heart failure (Oehmichen et al. 1992). The congestion of the brain can additionally be explained by a vasomotor paralysis, which may be caused by an accumulation of acetate in the brain (Schwartz et al. 1993). The sequelae in addition to the congestion include perivascular extravasation, especially periventricularly. Neuronal changes are usually absent. Although a recent experimental study (Phillips et al. 1997) could not demonstrate a disturbance of the blood−brain barrier, empirical measurements demonstrated an increase in brain volume (Powell et al. 1980; Harper 1982). Of paramount importance in this regard is the consistent observation of massive perifocal edema secondary to combined brain trauma and acute alcohol intoxication (Persson and Rosengren 1977; Jurkovich et al. 1993; Zink et al. 1993). The prognosis in such cases however does not appear to be noticeably worsened, as has been shown in clinical (Kelly et al. 1995) and experimental (Kelly et al. 2000) studies.

18.5.2 Chronic Intoxication Neuropathological investigations carried out in a comprehensive study (Skullerud et al. 1991; cf. Torvik 1987) of 127 cases of chronic alcoholism found

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alcohol-related findings in 50% of cases: 14% Wernicke encephalopathy; 37% cerebellar atrophy; two cases of central pontine myelinolysis; one case of hepatic encephalopathy. These changes were evenly distributed between males and females (Harper et al. 1990; Mann et al. 1992). Moreover, there is clear evidence today that the central nervous system of females may be more susceptible than that of males to neuronal damage during alcohol intoxication and during withdrawal from long-term ethanol exposure (Prendergast et al. 2000; Hommer et al. 2001; Pfefferbaum et al. 2001). An analysis of alcohol-specific brain damage was recently published by Harper (1998; see also Gass and Hennerici 1999), who describes the following primary alcohol-toxic sequelae: 1. Injury to the cerebral white matter with interior and exterior brain atrophy. 2. Nerve cell loss in the cerebral cortex, the hypothalamus, and cerebellum [but not in the hippocampus − cf. Harding et al. (1997); in contrast to Bengochea and Gonzalo (1990) and Franke et al. (1996)]. 3. Dendritic and synaptic damage together with receptor and transmitter-induced changes as the early equivalents of functional and cognitive deficits. Cell death as well as astrocytic death may be enhanced by inflammatory mediators (Valles et al. 2004). Chronic ethanol treatment of rats stimulates glial cells, upregulating the production and expression of inflammatory mediators (iNOS, COX-2, IL-1β) in the brain, and activating signalling pathways and transcription factors involved in inflammatory damage and cell death. These changes occur to varying degrees, and are usually observed in combination, with the combinations observed differing from patient to patient. The clinical result can be a dementia and ataxic-motor disturbances. The symptoms are not always identical. Apparently, the pattern of neuropathological findings is aggravated by an associated thiamine deficit (vitamin B1 − comp. pp. 606 f), including for example neuronal changes in the cerebral cortex (Kril and Homewood 1993) with widespread sparing of the noradrenergic neurons (Baker et al. 1994) and injury of the cerebral white matter (Langlais and Zhang 1997). Animal studies have demonstrated damage to synapses in the stratum lucidum of the CA3 region (Lundqvist et al. 1994), and loss of the hippocampal granule cell layer and pyramidal cell layer, primarily in the CA3 region, as well as an astrocytic reaction (Franke et al. 1996). The described Hirano bodies, which occur in the CA1 region of the hippocampus, must be regarded as non-specific (Laas and Hagel 1994).

It should be noted that some of the functional and morphological deficits are reversible with withdrawal treatment. This is especially true of the socalled atrophy, which is thought to be caused by alcohol-toxic dehydration. Rehydration, regeneration or elevated corticoid levels during withdrawal treatment − in some cases − have been reported to have produced “normalization.” Detailed studies taking into account the literature have excluded phenomena such as dehydration (Harper et al. 1988) and changes in the corticoid levels as influencing factors (Mann 1992). Moreover, functional reversibility can additionally be explained by a partial regeneration in the sense of fresh dendritic arborization, rearborization and the formation of new synapses (Riley and Walker 1978), which can apparently occur within 2 weeks (Mann 1992). Referring to the different patterns of injury, Peiffer (1989) distinguishes neuronotropic, gliovasotropic, and myelinotropic damage to the brain from polyneuropathy and myopathy. This morphological classification can include non-specific alcohol-induced changes and particular clinical syndromes in combination with localized and tissue-specific structural changes. 18.5.2.1 Diffuse Brain Alterations Cortical and subcortical white matter damage is due to thiamine deficiency as well as to direct toxic effects of alcohol (Langlais and Zhang 1997). Atrophy of the cortex and white matter (Fig. 18.1) can be observed by CT, macroscopically as well as microscopically. This results in a mean loss in brain mass of 1.43−1.35 kg in males (Harper and Kril 1993). The extent of atrophy has been shown (Harding et al. 1996) to be dependent upon the amount of alcohol consumed and the duration of alcohol dependence. Atrophy is based on a reduction of cortical neurons (Fig. 18.1a, b) and of the prefrontal cerebral white matter (Kril et al. 1997) (Fig. 18.1c−e), as well as − especially − the corpus callosum (Fig. 18.1c) (Harper and Kril 1988). The cerebral white matter is usually more vulnerable than the gray matter (Hansen et al. 1991), especially the subcortical white matter. The atrophic process partly is reversible, however (see above) (Pfefferbaum et al. 1995; Trabert et al. 1995). A recent study (Pfefferbaum et al. 2002) on the effect of alcohol abuse on white matter brain macrostructure provided evidence of a correlation between a higher life-time level of alcohol consumption and smaller volumes and prolonged transverse relaxation time in the pons; an overall deficit in white matter macrostructural size is observed in alcoholic women. A loss of neuronal elements in the cerebral cortex is seen mostly in patients with Wernicke−Korsakoff syndrome (see below) (Kril et al. 1997). Harper et al.

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Fig. 18.1a−e. Chronic alcohol intoxication. a Cortical atrophy; b the atrophy is caused by a decline in nerve cell density and secondary gliosis (H&E, magnification ×200); c atrophic mammillary bodies are seen associated with an extreme hydrocephalus inter-

nus and a reduction of the corpus callosum; d subcortical white matter atrophy, which results in an interior atrophy, e rarely associated with macroscopic visible bilateral cystic white matter involvement

(1987) observed a loss of neurons in the frontal cortex (Moselhy et al. 2001) chiefly involving the large pyramidal cells (Harper and Kril 1989). There is also a reduction in the number of dendritic branches in the third cortical nerve cell layer (Harper and Corbett 1990) and a decrease in the number of dendritic spines in the fifth cortical nerve cell layer (Ferrer et al. 1986). A decline in nerve cell density is seen, especially a loss of vasopressin-immunoreactive neurons in the magnocellular hypothalamus, supraoptic nucleus,

and paraventricular nucleus (Harding et al. 1996; Harper et al. 1997). On the other hand, secondary gliosis has only been observed in a few cases (Harper et al. 1997). The Alzheimer’s type I and II astrocytes observed in the thalamus and striatum are less a direct indication of chronic alcoholism than of the accompanying impairment of liver function with subsequent brain involvement in the sense of hepato-cerebral degeneration (p. 611).

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Fig. 18.2a, b. Chronic alcohol intoxication. An early alteration is the cortical atrophy of the superior cerebellar vermis, which is macroscopically (a) and microscopically (b) visible, associated with an atrophy of the molecular layer and a decline of Purkinje cells

Fig. 18.3a, b. Wernicke−Korsakoff syndrome. Brownish-colored siderin-positive mammillary bodies (old hemorrhages) are seen as well as acute periventricular hemorrhages

ciated with the development of cerebellar shrinkage (Nicolás et al. 2000). 18.5.2.2 Cerebellar Atrophy Cerebral computer tomography (CCT) confirmed cerebellar atrophy in about 40% of chronic alcoholics (Haan 1986). Pathological-anatomical atrophy was found in 26.8% of alcoholics (Torvik et al. 1982), with shrinking mainly of the anterior superior cerebellar vermis. The atrophy was caused by a reduction in cerebellar white matter (Harding et al. 1998) and of the molecular layer (stratum moleculare) of the cerebellar vermis and a drop in Purkinje cell density (Karhunen et al. 1994) as well as reactive proliferation of astrocytes, the Bergmann glia (Fig. 18.2). The total number and density of Purkinje cells declines, apparently a dose-dependent phenomenon (Karhunen et al. 1994). A decrease in dendritic arborization has also been shown (Ferrer et al. 1984). Cerebellar atrophy is expressed clinically in ataxia and impaired coordination, mainly of the lower extremities. Thiamine deficiency is thought to be the chief cause of the cerebellar atrophy (cf. Adams 1976), resulting from malnutrition and a daily ethanol intake of more than 140 g over 10 years, which were independently asso-

18.5.2.3 Wernicke−Korsakoff Syndrome Whereas the clinical symptoms of somnolence, ataxia, and ophthalmoplegia can be attributed to the Wernicke syndrome, the Korsakoff psychosis is characterized mainly by amnesia, disorientation, and suggestibility with confabulation. Neither of the two syndromes is a distinct entity since the transitions between them are fluid both clinically and pathologically. Both types of changes must be attributed to alcohol intoxication in combination with a thiamine deficiency (Butterworth 1989; Laforenza et al. 1990), as well as activation of microglia and astroglia (Todd and Butterworth 1999). An acute course must be distinguished from a more chronic course. The acute course is characterized by disorientation, confusion, and autonomic deficits and has a poor prognosis. Both macroscopically and microscopically new, sometimes non-reactive capillary hemorrhages can be demonstrated; they are located mainly in the mammillary bodies, but also in the paraventricular nuclei, especially the supraoptic nu-

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Fig. 18.4a−d. Wernicke−Korsakoff Syndrome. Microscopically the mammillary bodies are characterized by hemorrhages of different age, a spongy desintegration (a), an intense vascularization and astrogliosis (b, c), as well as fibrinoid degeneration of

arterioles and capillaries with morphologically intact neurons (d) (a, c van Gieson stain; b Prussian blue reaction; c trichrome stain; magnification a ×100, b ×500, c ×50, d ×1000)

cleus and quadrigeminal plate (Colmant 1965). The acute course is rare. The chronic course exhibits both of the aforementioned clinical pictures (Wernicke‘s syndrome, Korsakoff psychosis). Morphologically the following changes are encountered. The gross appearance is dominated by atrophic, brownish mammillary bodies (Fig. 18.3) and periventricular hemorrhages (Fig. 18.4a) of varying age at the level of the third and fourth ventricles and the aqueduct. Histology reveals astrogliosis and capillary proliferation (Fig. 18.4c) plus siderophages (Fig. 18.4a) and spongy disintegration of the neuropil and demyelination as well. The vascular changes include angiectasis, looping, and swelling of endothelium as well as fibrinoid degeneration (Fig. 18.4d) selectively affecting arterioles and capillaries (Okeda et al. 1995). The neuronal elements remain largely intact and only occasionally exhibit swelling with chromatolysis. A large proportion of cases also have neuronal changes in the thalamic nucleus (53−100%, Harper and Butterworth 1997, especially in the mediodorsal and anterior principal nuclei), including perineuronal vacuoles and degenerating neurons, some with eosinophilic cell change and cytoplasmic vacuolization (Olney 1990; Meldrum and Garthwaite

1991). All of these morphological phenomena have been reproduced experimentally by reductions in thiamine intake. In chronic alcoholics, they are explained by impaired intestinal absorption caused by alcoholic gastroenteritis. 18.5.2.4 Central Pontine Myelinolysis The primary cause of this disorder does not appear to be specifically alcohol induced but caused by a secondary electrolyte disturbance (pp. 610 f) in the sense of hyponatremia (Endo et al. 1981), and especially the rapid clinical correction of an existing hyponatremia (Kleinschmidt-DeMasters and Norenberg 1981; Illowski and Laureno 1993). A combination with other factors has also been discussed (Bratzke and Neumann 1989; Mundle et al. 1999). The main morphological feature of central pontine myelinosis is a glial-myelinolytic process, seen mainly in the rostral central cerebellar peduncle. Macroscopically it is characterized by clearly demarcated symmetrical demyelination of the central pontine segments, mainly in the raphe (Fig. 18.5). Microscopically there is a selective demyelination process involving neurons and axons with oligodendrocyte

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alcohol-caused malnutrition, can cause dementia. Primarily there is a degeneration of cortical motoneurons (and basal ganglia), cerebellar nuclei, and anterior horn cells of the spinal cord (see below). The clinical features are marked by depression, fatigue, loss of concentration, confusion, hallucination, and optic nerve atrophy (Harper and Butterworth 1997; Gass and Hennerici 1999). 18.5.2.7 Alcoholic Myelopathy

Fig. 18.5. Central pontine myelinolysis. Demyelination in the center of the pons, characterized by a spongiform degeneration, axonal swelling, and increase of macrophages

loss. Macrophage proliferation is combined with the spongy disintegration. The clinical picture is dominated by pseudobulbar paralytic symptoms such as dysphagia, dysarthria, and paralysis of deglutition. The picture can progress to decerebrate rigidity (Berlet et al. 1983). With increased awareness, the causal diagnosis is now made more often clinically, and with computed tomography and magnetic resonance imaging. 18.5.2.5 Marchiafava−Bignami Syndrome This is an exceptionally rare disease seen nearly exclusively in male alcoholics, especially Italian red wine drinkers but also in Japanese drinkers of rice wine (sake) (Brion 1976; Kohler et al. 2000). Macroscopically there is a gray discoloration of the corpus callosum caused by local demyelination, with disintegration of the white matter resembling that encountered in central pontine myelinolysis. Microscopically there is demyelination of the corpus callosum with spread to the deep frontoparietal cerebral white matter (see Fig. 18.1c−e). 18.5.2.6 Pellagra A deficiency of nicotinic acid (vitamin B6) or of its precursor tryptophan, which may be the result of

Only isolated case reports have been published (Wieser 1965; Sage et al. 1984). The clinical picture is characterized by spastic paralysis and cystoplegia. Liver damage is almost universal and could, in itself, be etiologic. Sage et al. (1984), however, describe cases without liver damage or vitamin deficiency, so that a primary alcoholic effect can be assumed. In addition to chronic alcoholic intoxication, the main cause is a vitamin B12 and niacin deficiency. Degeneration of the anterior horn cells appears, which could also − or additionally − represent the sequelae of progressive Wallerian degeneration in primary peripheral neuropathy (Victor et al. 1989). 18.5.2.8 Neuropathy of the Autonomic Nervous System Detailed studies have found that 5 of 30 chronic alcoholics suffer from an isolated parasympathetic neuropathy and, in 6 cases, a combined parasympath etic−sympathetic neuropathy was found (Barter and Tanner 1987; cf. also Johnson and Robinson 1988). Morphologically, there was a significant decline in the density of myelinated nerve fibers in the distal portion of the vagal nerve, together with axonal degeneration and changes associated with “dying-back” (Walsh and McLeod 1970). Sudden unexpected death in alcoholics with known symptoms of Wernicke−Korsakoff has been observed in combination with an autonomic neuropathy (Johnson and Robinson 1988). 18.5.2.9 Neuropathy/Polyneuropathy The morphology characterized by widespread symmetric axonal involvement in conjunction with sensory and motor symptoms. The disorder corresponds to the pattern of distal axonopathy, where axonal changes primarily involve the distal tract of the longest fibers with the largest diameter of the lower limbs, and, to a lesser degree, the upper limbs (Fig. 18.6a, b − Pinelli 1985). Alcoholic neuropathy is one of the most common consequences of chronic alcoholism. Although only 9% of 1030 hospitalized alcoholics had clinical

CHAPTER 18: Alcohols, Organic Solvents, and Aerosols

Fig. 18.6a−d. Alcoholic neuropathy and myopathy. a Macroscopically chronic alcohol intoxication often is characterized by a muscle atrophy of the distal type; b microscopically, in comparison with the normal density of axons in the sural nerve, c a decline of axons is demonstrable; d moreover, a typical distribu-

tion of atrophic muscle fibers is seen, which is associated with a neurogenic muscle atrophy (symmetric atrophy of small groups of fibers of the lower leg muscles). (b−d Semithin sections; magnification ×1000). The figures b−d were kindly provided by Professor Dr. H. Wiethölter, Stuttgart

symptoms of polyneuropathy (Victor et al. 1971), 93% of them exhibited electromyographic changes (D’Amour et al. 1991; D’Amour and Butterworth 1994). This phenomenon was recently stated by Vittadini et al. (2001) who found polyneuropathies especially in wine-drinkers.

fibers. The muscle weakness and atrophy predominate (Fig. 18.6a, d) (Haller and Knochel 1984; Martin et al. 1985). Pathologic change is not uniformly distributed throughout the muscle, but is more marked in some areas than in others. Atrophic fibers may be seen in some specimens as a group of smaller fibers surrounded by relatively normal-sized fibers. The small group atrophy is characteristic of denervation. Large group atrophy is caused by the direct toxic effect of alcohol. Perturbations in protein metabolism are central to the effects on muscle and account for the reductions in muscle mass and fiber diameter. Further biochemical mechanisms, including carbohydrate as well as lipid metabolism, ethanol-mediated insulin resistance, metabolic disturbances due to alcoholic cirrhosis, etc., are discussed by Preedy et al. (2001).

18.5.2.10 Myopathy Alcoholic myopathy is found in about 46% of outpatients (Urbano-Marquez et al. 1989) and 60% of hospitalized patients (Martin et al. 1985). It is apparently partly caused by the direct toxic effect of alcohol, and, in part, by neuropathic atrophy. Acute muscle fiber necrosis can arise in the form of rhabdomyolysis (Haller and Knochel 1984), which chiefly affects the proximal muscles of the extremities (symmetric, asymmetric or focal − for review see Charness et al. 1989). Type I fibers appear to be selectively vulnerable. Subjectively, patients complain of pain in addition to impaired motor function. Chronic intoxication can lead above all to atrophy of type II

18.5.2.11 Secondary Pathologic Alterations Specific alcohol-induced changes of the brain are discussed below; the following secondary pathologi-

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Fig. 18.7a−d. Secondary cerebral involvement in chronic alcohol intoxication. Intracranial bleeding caused by associated coag-

ulation involvement and minor MBI: a, b subdural hemorrhage; c, d multiple intracranial hemorrhages

CHAPTER 18: Alcohols, Organic Solvents, and Aerosols

cal processes pose an increased risk to chronic alcoholics: 1. Mechanically induced brain damage can be caused by alcohol-induced motor impairment and/or by the milieu (Rönty et al. 1993). 2. Vascular injury, especially stroke, is more common in alcoholics. They usually involve ischemic necrosis, not hemorrhagic infarction (Gorelick 1989; Hansagi et al. 1995). 3. Intracranial bleeding, especially subdural hemorrhages (Fig. 18.7a, b) and intracerebral hemorrhages (Fig. 18.7c, d) is seen secondary to elevated blood pressure and impaired liver function with coagulation disorders (Monforte et al. 1990). 4. Thiamine (vitamin B1) deficiency is caused by poor nutrition, insufficient absorption, and/or diminished phosphorylation of the coenzyme thiamine pyrophosphate (TPP). The activity of the TPP-dependent pyruvate dehydrogenase is significantly depressed in the cerebellar vermis of alcoholic patients (Butterworth et al. 1993). 5. A proliferation of Alzheimer type II astrocytes is induced by liver cirrhosis (hepatic encephalopathy) in the putamen: this type of astrocyte is characterized by PAS and glycogen granules inside a large, pale, vacuolated nucleus and a dense nuclear membrane. In severe cases, there can also be a proliferation of Alzheimer type I astrocytes with large, lobulated nuclei and distinct nucleoli (Diemer 1978). Because treatment usually interrupts the disease, nowadays mostly type II astrocytes are characteristically seen in hepatic encephalopathy. Both Alzheimer type II and type I astrocytes result from elevated levels of ammonia in the blood (Haschek and Rousseaux 1998). The astrocytes also contain elevated levels of glutamine synthetase, which converts glutamate to glutamine by incorporation of ammonia. 18.5.2.12 Disulfiram Treatment Disulfiram is an inhibitor of aldehyde dehydrogenase (ALDH), which is used as an active agent in the management of maintaining abstinence. Administration of oral tablets (250 or 500 mg) induces a five- to tenfold increase in blood acetaldehyde concentrations. Disulfiram induces facial flushing, throbbing headache, anxiety, abdominal pain, nausea, vomiting, sweating, thirst, chest pain, tachycardia, etc. This response, of course, does not depend solely on disulfiram‘s inhibition of ALDH and the consequent accumulation of high levels of acetaldehyde (Hald and Jacobsen 1948). It is also in large part due to an additional neurotoxic effect of disulfiram itself. Among other symptoms described are fatigue, restlessness, tremor, as well as psychosis and Parkinsonism. Moreover, a neuropathy of the distal axonopa-

thy type, which begins within a few months after initiation of therapy, has been described, and a few instances of extrapyramidal symptoms associated with bilateral lesions of lentiform nuclei have been reported (Vaccari et al. 1998). Disulfiram appears to be a primary Schwann cell toxicant (Tonkin et al. 2000). Specific morphological alterations in intoxicated patients are not described.

18.6 Alcoholic Fetopathy and Embryopathy Alcohol can also be especially cytotoxic and neurotoxic to embryos and fetuses, since alcohol penetrates the blood−placental barrier and because the enzyme system of the fetus or embryo is still undeveloped (West et al. 1990). The impact is multifarious. Moreover, physical dependence begins from the time of intrauterine intoxication. Among the reported sequelae are intrauterine hypotrophy, craniofacial dysmorphy, and extracranial skeletal malformation (Clarren and Smith 1978; Majewski 1979; Streissguth et al. 1980; Rosett and Weiner 1984). The brain is subject to neuronal migration inhibition with neuroglial heterotopia and internal hydrocephalus. Extensive experimental studies describe, above all, migration inhibition in the cerebellum (Volk 1980). Wisniewski et al. (1983) (see also Archibald et al. 2001) list the following neuropathological changes caused by alcoholic fetopathy and embryopathy (Fig. 18.8): ▬ Microcephaly ▬ Hydrocephalus ▬ Cerebellar malformations, especially of the cerebellar vermis ▬ Abnormalities (agenesis) of the corpus callosum and the anterior commissure ▬ Disproportionality and reduced basal ganglia volume ▬ Hypoplasia of the optic nerve and globe of the eye (microphthalmia) ▬ Loss or deficiency of retinal ganglion cells ▬ Meningeal glioneuronal heterotopia ▬ Neuronal microdysplasia It is now known that alcohol − at least in animals − can cause massive intrauterine cell death; this nerve cell death is apparently caused by the blockade of the NMDA receptors on the one hand and activation of the GABA receptor on the other (Ikonomidou et al. 2000).

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Fig. 18.8a−c. Fetal alcohol syndrome, which is characterized by craniofacial dysmorphy (a), microcephaly and hydrocephalus as well as retarded migration of Purkinje cells in the cerebellar

18.7 Organic Solvents and Aerosol A wide variety of lipophilic solvents are used for socalled sniffing, including spot removers, nail polish remover, gasoline (benzene), hair sprays, deodorants, etc. Table 18.1 offers a list of these substances (Karch 2001). Inhalation of these organic solvents and aerosols, possibly using a plastic bag placed over the head, produces a ”high” similar to that engendered by narcotics. They are also sexually stimulating, which accounts for death due to asphyxia during autoerotic manipulation. Inhalation of solvents can induce a psycho-organic syndrome followed by encephaloneuropathy with personality changes, and dementia with impaired memory and intelligence and emotional disturbances (Rosenberg et al. 1988; Pryor 1990). A few cases of accidental poisoning and its consequences have been reported after accidental inhalation at the workplace. Neuropathology. The literature contains only a few

autopsy reports describing the neuropathological

cortex = heterotopia (b) and microdysgenesis of the pallidum (b, c Nissl stain; magnification b ×1,000; c ×300)

changes of such poisoning. The main finding in cases of chronic abuse is extensive demyelination (Escobar and Aruffo 1980; Rosenberg et al. 1988). Kornfeld et al. (1994) describe three cases with severe, but spotty loss of myelin, but with relatively mild axonal loss and gliosis. PAS-positive macrophages were present in all three cases. Moreover, toxic neuropathies with demyelination have been described. Further pathologic-anatomic findings include glomerulonephritis and acute cardiac death. The forensic neuropathologist must always bear in mind that death in these cases can result from systemic and cerebral ischemia as a consequence of cardiac toxicity.

CHAPTER 18: Alcohols, Organic Solvents, and Aerosols

Table 18.1. List of lipophilic solvents for “sniffing.” Source: Karch 2001

Aerosol propellants (air fresheners, deodorant spray, hair spray) Dimethyl ether Butane

Harper Cl (1998) The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? J Neuropathol Exp Neurol 57:101−110 Jansson B, Jornvall M, Rydberg K, Terenius L, Vallee BL (eds) (1994) Toward a molecular basis of alcohol use and abuse. Birkhäuser, Basel Karch SB (2001) The pathology of drug abuse, 3rd edn. CRC, New York Soyka M (1997) Alkoholismus. Eine Krankheit und ihre Therapie. Wissenschaftl Verlagsgesellschaft, Stuttgart

Halogenated fluorocarbons Bromochlorodifluoromethane (in fire extinguishers) Carbon tetrachloride

References

Ethyl chloride Perchloroethylene Trichloroethylene Gas fuels (disposable cigarette lighters) Propane Butane Liquid petroleum gas Chlorinated solvents (commercial dry cleaning/degreasing agents) Carbon tetrachloride Dichloromethane Methanol Tetrachloroethylene Toluene Solvents from adhesives (also paints, nail polish, varnish remover) Acetone Butane Cyclohexanone Toluene Xylene

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Streissguth AP, Landesmann-Dwyer S, Martin JC, Smith DW (1980) Teratogenic effects of alcohol in humans and laboratory animals. Science 209:353−361 Sundby P (1967) Alcohol and mortality. Publication Division, Rutgers Center of Alcoholic Studies, New Brunswick, New York Taylor D, Lewis S (1993) Delirium. J Neurol Neurosurg Psychiatry 56:742−751 Taylor JR, Combs-Orme T, Taylor DA (1983) Alcohol and mortality. Diagnostic considerations. J Stud Alcohol 44:17−25 Todd KG, Butterworth RF (1999) Early microglial response in experimental thiamine deficiency: an immunohistochemical analysis. Glia 25:190−198 Tonkin EG, Erve JCL, Valentine WM (2000) Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat. J Neuropathol Exp Neurol 59:786−797 Topel H (1984) Biochemische Grundlagen des Alkoholismus. Hochschulverlag, Zurich Torvik A (1987) Brain lesions in alcoholics: neuropathological observations. Acta Med Scand Suppl 717:47−54 Torvik A, Lindboe CF, Rodge S (1982) Brain lesions in alcoholics. A neuropathological study with clinical correlations. J Neurol Sci 56:233−48 Trabert W, Betz T, Niewald M, Huber G (1995) Significant reversibility of alcoholic brain shrinkage within 3 weeks of abstinence. Acta Psychiatr Scand 92:87−90 Trojan A (1980) Epidemiologie des Alkoholkonsums und der Alkoholkrankheit in der Bundesrepublik Deutschland. Suchtgefahren 26:1 Trzepacz PT, Teague GB, Lipowski ZJ (1985) Delirium and other organic mental disorders in a general hospital. Gen Hosp Psychiatry 7:101−106 Urbano-Marquez A, Estruch R, Navarro-Lopez F et al (1989) The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 320:409−415 Vaccari A, Ferraro L, Saba P et al (1998) Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate. J Pharmacol Exp Ther 285:961 Valles SL, Blanco AM, Pascual M, Guerri C (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14:365−371 Victor M (1977) Some observations on the neurological effects of alcohol intoxication and withdrawal. In: Roizin L, Shiraki M, Grèeviæ N (eds) Neurotoxicology. Raven, New York, pp 517−531 Victor M, Adams RD, Collins GH (1971) The Wernicke-Korsakoff syndrome. A clinical and pathological study in 245 patients, 82 with post-mortem examinations. Contemp Neurol Ser 7:1−206 Victor M, Adams RD, Collins GH (1989) The Wernicke-Korsakoff syndrome, 2nd edn. Davis, Philadelphia, Pa. Vittadini G, Buonocore M, Golli G et al (2001) Alcoholic polyneuropathy: a clinical and epidemiological study. Alcohol Alcoholism 36:393−400

Volk B (1980) Paired helical filaments in rat spinal ganglia following chronic alcohol administration: an electron microscopic investigation. Neuropathol Appl Neurobiol 6:143−153 Volkow ND, Hitzemann R, Wang G-J et al (1992) Decreased brain metabolism in neurologically intact healthy alcoholics. Am J Psychiatry 149:1016−1022 Walker DW, Zornetzer SF (1974) Alcohol withdrawal in mice: electroencephalographic and behavioral correlates. Electroencephalogr Clin Neurophysiol 36:233−244 Walsh JC, McLeod JG (1970) Alcoholic neuropathy. An electrophysiological and histological study. J Neurol Sci 10:457−469 Wang G-J, Volkow ND, Fowler JS et al (2003) Alcohol intoxication induces greater reductions in brain metabolism in male than in female subjects. Alcohol Clin Exp Res 27:909−917 Wartburg JP von, Bethune JL von, Vallee BL (1964) Human liver alcohol dehydrogenase. Kinetic and physicochemical properties. Biochemistry 3:1775−1782 Weight FF, Aguayo LG, White G et al (1992) GABA- and glutamategated ion channels as molecular sites of alcohol and anesthetic action. Adv Biochem Psychopharmacol 47:335−347 West JR, Goodlett CR, Bonthius DJ et al (1990) Cell population depletion associated with fetal alcohol brain damage: mechanisms of BAC-dependent cell loss. Alcohol Clin Exp Res 14:813−818 Weston JT (1980) Alcohol’s impact on man’s activities. Am J Clin Pathol 74:755−758 Wiese J, Maxeiner H, Stiebler M (1990) ”Alkoholassoziierte” Todesfälle im rechtsmedizinischen Obduktionsgut der Freien Universität Berlin. Beitr Gerichtl Med 48:535−541 Wieser S (1965) Alkoholismus II. Psychiatrische u. neurologische Komplikationen. Fortschr Neurol Psychiatr 33:349−409 Wilkinson P, Kornaczewski A, Rankin JG, Santamaria JN (1971) Physical disease in alcoholism. Initial survey of 1,000 patients. Med J Aust 1:1217−1223 Wisniewski K, Dambska W, Sher JH, Qazi Q (1983) A clinical neuropathology study of the fetal alcohol syndrome. Neuropediatrics 14:197−201 Witter H (1972) Die Beurteilung Erwachsener im Strafrecht. In: Göppinger H, Witter H (eds) Handbuch der forensischen Psychiatrie. Springer, Berlin Heidelberg New York Zimatkin SM, Dietrich RA (1997) Ethanol metabolism in the brain. Addict Biol 2:387−399 Zimatkin SM, Lindros KO (1996) Distribution of catalase in rat brain: aminergic neurons as possible targets for ethanol effects. Alcohol Alcoholism 31:167−174 Zimatkin SM, Liopo AV, Dietrich RA (1998) Distribution and kinetics of ethanol metabolism in rat brain. Alcohol Clin Exp Res 22:1623−1627 Zink BJ, Walsh RF, Feustel PJ (1993) Effects of ethanol in traumatic brain injury. J Neurotrauma 10:275−283

CHAPTER 19

Illegal Drugs and Drug Dependence

391

19.1

Epidemiological and Social Data

19.2

Cannabis

19.3 19.3.1 19.3.2 19.3.3 19.3.3.1

19.3.4

Hallucinogens and Entactogens 392 Mescaline 393 Lysergic Acid Diethylamide (LSD) 393 Amphetamine Substitutes 393 MDMA (3,4-methylenedioxmethamphetamine) 393 MDEA (3,4-methylenedioxyethamphetamine) 394 Other Agents 394

19.4 19.4.1 19.4.1.1 19.4.1.2 19.4.1.3 19.4.2 19.4.3 19.4.4 19.4.5 19.4.6 19.4.7

Narcotics: Opium and Opioids 394 Basic Principles 394 Epidemiology 394 Pathophysiology 395 Neuropathology 395 Morphine 397 Heroin 397 Codeine 397 Dihydrocodeine (DHC) 398 Methadone 398 Other Narcotic Agents 398

19.5 19.5.1 19.5.2 19.5.3

Stimulants 398 Cocaine 398 Cocaine Freebase: Crack 399 Amphetamine and Methamphetamine (Speed) Caffeine 400 Ephedrine 400 Khat 400

19.3.3.2

19.5.4 19.5.5 19.5.6

Bibliography 401 References

19.1 Epidemiological and Social Data

392

401

399

Alcoholism and the dependency on drugs are “diseases” as any others. In addition to acute and chronic alcohol intoxication, the most common form of lethal poisoning encountered in the forensic laboratory is acute intoxication caused by illicit drugs. Consumption of these drugs is increasing and poses major social, psychological, medical, and forensic problems both in the United States and in Western Europe. The increasing number of deaths among young and chronic addicts is of particular concern and has caused much public debate. Associated with the rise in consumption is an increase in prostitution and in the number of crimes against property and violent crimes committed by addicts to obtain money to finance their habits. Drugs of abuse are able to elicit compulsive drugseeking behaviors upon repeated administration, which ultimately leads to the phenomenon of addiction. Evidence indicates that the susceptibility to develop addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. Addiction is hypothesized to be a cycle of progressive dysregulation of the brain reward system that results in compulsive use and loss of control over drug taking and the initiation of behaviors associated with drug seeking (Koob et al. 1998; Koob and Le Moal 2001). The view that addiction represents a pathological state of reward provides an approach to identifying the factors that contribute to vulnerability, addiction, and relapse in genetic animal models (Laakso et al. 2002). Although each type of drug will be described individually below, most drug addicts today consume more than one type of drug, i.e., they will take any drug that has an effect on the central nervous system (CNS): stimulants such as cocaine, amphetamines; sedatives such as alcohol, codeine, morphine, barbiturates, benzodiazepines, etc.; and hallucinogens such as lysergic acid diethylamide (LSD), mescaline and numerous other substances (Geschwinde 1998;

19

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PART IV: Intoxication

Karch 2001). Substances used in substitution therapy such as methadone and dihydrocodeine (DHC) also have considerable toxic potential and drug addicts consume these substances in highly toxic doses. Particularly the combination of these substances with other drugs − including alcohol − can be fatal. Since in neuropathology only the final condition is assessed, in the individual case it is hardly possible to differentiate which toxic substance caused which morphological changes. Animal studies are of little help in this regard since chronic abuse with such high dosages of toxic substances cannot be created even experimentally, as a rule. In addition the drug scene itself has an influence on the health of street users and can create secondary effects: intravenous injection of suspensions containing insoluble particulate substances, for example, or infections caused by needle sharing, malnutrition, and/or the antisocial milieu together with immunodeficiencies secondary to drug consumption. HIV infection is an ever-present possibility. In forensic-neuropathological practice, therefore, the morphological feature is usually a mixed sequela produced by numerous factors. Nevertheless, we will attempt to present the functional and pathological changes regarded as typical for each toxic agent.

19.2 Cannabis Preparations from cannabis species have been used since antiquity, not only as psychotropic drugs but also in the treatment of a number of ailments. Over 60 cannabinoid compounds are present in hemp. “Marijuana” is made from the tops and leaves of the hemp plant; “hash” from resins covering the flowers and leaves of female plants (Brust 1999). The main active component ∆9-tetrahydrocannabinol (THC) produces most of its effects on the CNS by interacting with specific cannabinoid receptors on neurons (CB1-receptors). Under normal circ*mstances, these receptors are thought to be one element of a neurotransmitter system that controls neuronal excitability. Other components of this putative signaling system include cannabinoids that are found naturally in the body, as well as cellular mechanisms by which these “endocannabinoids” are synthesized, transported, and metabolized (Piomelli et al. 2000 − for review see Christie and Vaughan 2001). Cannabis has been considered an entry drug on the path to “hard” drugs and for this reason is prohibited by law in most Western countries. An inhaled dose of at least 2 mg and an oral dose of at least 10 mg THC is assumed to be the normal dosage. The target organ is the CNS.

Effect. Marijuana and hash are smoked or consumed

orally. After a few “hits,” the smoker feels relaxed and euphoric, his conscious processes and orientation remaining largely unaffected. After even low or medium doses however a mild stupor can occur. Among the psychophysical effects are impaired temporal and spatial orientation, cognitive abilities, vision, motor function (ataxia), and circulation. In acute intoxication, e.g., driving ability is impaired. At the same time, there is a reduction in spontaneity and a certain apathy. At high doses, some individuals experience illusions or hallucinations. The “high” peaks after about 15−40 min (smoking) or 30−120 min (oral application), and lasts for up to 2−6 h. The half-life of THC in blood plasma is 1−4 days; in extreme cases, metabolites of THC can be demonstrated in blood for more than 10−20 days. The urine of chronic users contains traces of cannabinoids (mainly the glucuronide of THC-COOH) for as long as 1−2 months. After prolonged use, a certain psychic tolerance to THC can develop. It is still controversial whether chronic THC consumption can lead to mental abnormalities (Weinrieb and O‘Brien 1993). The most often discussed abnormality is an “anti-motivated syndrome” characterized by apathy and flat affect, decreased attentiveness, and impaired short-term memory (Hollister 1967). Frequent cannabis use in teenage girls predicts later depression and anxiety, with daily users carrying the highest risk (Patton et al. 2002). Given recent increasing levels of cannabis use, measured reduction of frequent and heavy recreational use seems warranted. Moreover, evidence establishes a clear link between the use of cannabis and psychiatric illness, i.e., psychosis (Arseneault et al. 2002; Zammit et al. 2002). Recent studies have also found links between the use of marijuana and depression (Hall and Degenhardt 2000; McKay and Tennant 2000; Bovasso 2001; Rey et al. 2002). Morphologically evident permanent injury of the CNS has not been described (Ray et al. 1979). THC may be powerfully neuroprotective, reducing ischemic neuronal necrosis (Louw et al. 2000) in spite of an increase in brain temperature (Perron et al. 2001).

19.3 Hallucinogens and Entactogens Hallucinogens are substances which are commonly associated with hallucinosis. Entactogens are substances which generate a sense of “the touch within,” i.e., a substance that affects individual physical sensations of touch. Hallucinogens and entactogens not only affect a person‘s emotional state − they can also induce deep psychological changes. These com-

CHAPTER 19: Illegal Drugs and Drug Dependence

pounds include substances that can alter sensory impressions and/or lead partly to sensory hallucinations. Hollister (1967) describes the following common features: 1. Changes in mood and perception dominate 2. Minimal memory or intellectual impairment 3. No association with stupor or excessive agitation 4. Minimal side-effects on the autonomic nervous system 5. Craving and addiction do not occur Chemically the following three groups of hallucinogens can be differentiated: 1. Phenylalkylamines (mescaline) 2. Indole alkylamines (LSD) 3. Substituted amphetamines [3,4-methylenedioxmethamphetamine (MDMA), 3,4-methylenedioxyethamphetamine (MDEA) − without hallucinogenic, but entactogenic effects − cf. Thomasius 2000]. Deaths relating to these compounds are extremely rare compared to heroin-induced deaths. However, the danger exists that the number will increase in the foreseeable future due to the increasing use of these substances. In central Europe meanwhile the preferred drugs are synthetic agents such as MDMA and MDEA.

19.3.1 Mescaline Mescaline is obtained from cacti native from southwestern North America and from the peyote plant. Mescaline was already being produced synthetically at the turn of the last century (1900). However, the main source of mescaline today is the peyote plant. An oral dose exceeding 700 mg has a toxic effect on the liver. The hallucinatory effect occurs after metabolism, i.e., after the mescaline has bound to endogenous proteins. The half-life of mescaline is about 6 h. The highest concentrations occur in the liver and kidneys, the lowest in the brain, where after 30 min mescaline can no longer be detected. About 2% of the ingested mescaline penetrates the blood−brain barrier. The hallucinatory effect begins within 1−2 h and lasts for 8−12 h. In an accidental death attributed to a mescaline-induced state of confusion, the following concentrations were found: blood 9.7 µg/l, urine 1,163 µg/l (Reynolds and Jindrich 1985). Morphological alterations of the brain are not known.

19.3.2 Lysergic Acid Diethylamide (LSD) LSD was first synthesized in 1938 by Albert Hoffmann. Today LSD is taken at “rave” parties as an alternative to MDMA, almost exclusively in small − non-toxic − doses. The resulting levels in urine range over 2−3 µg/l; i.e., near the limit of detection. However, the metabolite’s levels (2-oxo-3-hydroxy-LSD) are comparably high. A single standard street dose today is 20−80 µg (Nelson and Foltz 1992). LSD has an estimated half-life of 2.5 h. Clinical symptoms are similar to those produced by mescaline. From 1960 to 1980, numerous cases of acute panic reactions, flashbacks, and homicides were described (Klepfisz and Racy 1973), but today these phenomena are no longer observed. Only a few deaths from LSD toxicity have been reported. No specific neuropathological features are known.

19.3.3 Amphetamine Substitutes Amphetamine substitutes are summed up by the term “designer drugs” and are generally taken in tablet form (e.g., “ecstasy”), and are often used to enhance performance. The drugs have both amphetamine-like and entactogenic properties. The main consumers of designer drugs are young people who want to make social contacts and dance through the night in discos. Eighty-one deaths related to taking ecstasy in people aged 15−24 years during the period 1997−2000 in England and Wales were evaluated (Schifano et al. 2003). Results of toxicological examination were made available in 75 cases; MDMA was present in 68 (91%), MDEA in 7 (9%), and opiates or opioids in 44 (59%) of these cases. In 26 (38%) cases, one or more drugs had been prescribed to the deceased patient. Those substances are neurotoxic by selective inhibition of monoamine oxidase A (MAOA; Scorza et al. 1997), and by the induction of acute hypertension. 19.3.3.1 MDMA (3,4-methylenedioxmethamphetamine) The half-life of MDMA (synonyms: MDM, Eve, Ecstasy) is about 8 h. In dogs, the LD50 is 8−23 mg/kg, in Rhesus monkeys 17−28 mg/kg, after intravenous administration. Following oral intake of 50 mg, a concentration of 105 µg/l could be detected in the blood of an adult man after 2 h. Blood levels had declined to 5.1 µg/l at 24 h. MDMA can still be detected in the blood after 3 days (Verebey et al. 1988). In cases of lethal intoxication, blood levels of up to 1,260 µg/l have

393

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PART IV: Intoxication

been observed (Bedford et al. 1992). The blood levels of living and dead users overlap. The clinical picture is characterized by hyperpyrexia, seizures, disseminated intravascular coagulation, rhabdomyolysis, and renal failure. In isolated cases (for review see Balmelli et al. 2001) the intake of fluids after MDMA ingestion may lead to potentially fatal hypervolemic hypotonic hyponatremia with cerebral edema. MDMA acts on the CNS by increasing the release of serotonin and catecholamines and preventing reuptake (Abbott and Concar 1992). Clinically, chronic users are liable to develop paranoid psychoses (McGuire et al. 1994; McCann et al. 2000; Ricaurte et al. 2002), seizures, stroke, and various neurocognitive deficits as a result of neurotoxic lesions (Thomasius 2000). In animal experiments using non-human primates the cerebral serotonin terminals were selectively destroyed in neocortex, striatum and hippocampus, and axonal injury could be demonstrated (Insel et al. 1989; Ricaurte et al. 1992, 2000). As demonstrated in mice by Colado et al. (2001), production of specific radicals might be possible by MDMA metabolites reacting in turn with nitric ions. Neuropathological findings in human beings, in contrast, have not been published. A recent study gives evidence of the immunohistochemical reactivity of nearly all neurons and axons of the cerebrum and cerebellum with antibodies to MDMA and MDEA − in two cases (DeLetter et al. 2003). The pathophysiological significance of this reaction pattern is still unknown and the diagnostic relevance has to be reexamined. MDMA seems to have a selective neurotoxic effect on the serotonergic system (Battaglia et al. 1988). Neurochemical investigations and functional neuroimaging studies in humans suggest alterations of central nervous functions after ecstasy use lasting weeks to months (Obrocki et al. 2001). Moreover, pathologic-anatomic evidence of hyperthermia, rhabdomyolysis, renal failure, and disseminated intravascular coagulation as well as hepatopathy including acute yellow hepatic dystrophy have been described (Campkin and Davies 1992). 19.3.3.2 MDEA (3,4-methylenedioxyethamphetamine) This drug is a close relative of MDMA (Synonym: Eve, Ecstasy) with similar psychophysical and pathological effects, kinetics, and concentrations. It is a true “designer drug” synthesized when MDMA was prohibited.

19.3.4 Other Agents A large number of natural and synthetic hallucinogens are known, e.g., psilocybin, 2,5-dimethoxy-4methylamphetamine (DOM), and phencyclidine. Neither acute nor chronic intoxication by most of these substances causes neuropathological changes. Clinically and pathologically they are comparable in their effects to the aforementioned hallucinogens. Phencyclidine (PCP), a dissociative anesthetic and widely abused psychotomimetic drug, and related agents (MK-801, tiletamine, and ketamine) have an apparent neurotoxic effect, which has heretofore been overlooked: these drugs induce acute pathom*orphological changes in specific populations of brain neurons when administered subcutaneously to adult rats in relatively low doses (Olney et al. 1989). It is unlikely, however, that similar lesions appear in the human brain.

19.4 Narcotics: Opium and Opioids 19.4.1 Basic Principles 19.4.1.1 Epidemiology Most deaths due to chronic illicit drug abuse involve the consumption of opiates. The increase in the number of drug deaths in Europe and the USA is due mainly to the increase in the number of intravenous drug addicts. At present, the annual number of drugrelated deaths is approximately 2,000 in Germany (Deutsches Bundeskriminalamt − cf. Oehmichen 1997) and 5,000 in the USA (Drug Abuse Warning Network). As there is no international agreement on the definition of a drug-induced death, the epidemiological data of different countries are not comparable. The German statistics include deaths classified according to the following criteria (Oehmichen and Staak 1988): 1. Direct toxic effect of the drug or its metabolites (accidental or suicidal overdose). 2. Direct toxic effect of adulterants or extraneous substances injected along with the drug. 3. Infections as a complication of the drug culture life-style including needle sharing or depressed immune function (Novick et al. 1989). 4. Death of a drug addict due to causes having no direct connection with drug consumption.

CHAPTER 19: Illegal Drugs and Drug Dependence

Fig. 19.1a−d. Ischemic encephalopathy in chronic drug addicts. a Cerebral cortical atrophy in a 20-year-old man who survived an acute drug intoxication for

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