Forensic Pathology Reviews, Volume 1

Forensic Pathology Reviews Volume 1 Edited by Michael Tsokos, MD Forensic Pathology Reviews FORENSIC PATHOLOGY REVI...

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Forensic Pathology Reviews Volume 1 Edited by

Michael Tsokos, MD

Forensic Pathology Reviews

FORENSIC PATHOLOGY REVIEWS Michael Tsokos, MD, SERIES EDITOR

FORENSIC PATHOLOGY REVIEWS, VOLUME 1, edited by Michael Tsokos, 2004

FORENSIC PATHOLOGY REVIEWS Volume 1 Edited by

Michael Tsokos, MD Institute of Legal Medicine, University of Hamburg, Hamburg, Germany

HUMANA PRESS TOTOWA, NEW JERSEY

© 2004 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected]; website at humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. This publication is printed on acid-free paper. ' ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Production Editor: Robin B. Weisberg. Cover design by Patricia F. Cleary.

Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients is granted by Humana Press, provided that the base fee of US $25.00 per copy is paid directly to the Copyright Clearance Center (CCC), 222 Rosewood Dr., Danvers MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to the Humana Press. The fee code for users of the Transactional Reporting Service is 1-58829-414-5/04 $25.00. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 1-59259-786-6 (e-book) Library of Congress Cataloging-in-Publication Data Forensic pathology reviews, Volume 1 / edited by Michael Tsokos. p. cm. Includes bibliographical references and index. ISBN 1-58829-414-5 (alk. paper) 1. Forensic pathology. I. Tsokos, Michael. RA1063.4.F675 2004 614.1--dc22 2003027503

Series Introduction Over the last decade, the field of forensic science has expanded enormously. The critical subfield of forensic pathology is essentially based on a transverse, multiorgan approach that includes autopsy, histology (comprising neuropathological examination), immunohistochemistry, bacteriology, DNA techniques, and toxicology to resolve obscure fatalities. The expansion of the field has not only contributed to the understanding and interpretation of many pathological findings, the recognition of injury causality, and the availability of new techniques in both autopsy room and laboratories, but also has produced specific new markers for many pathological conditions within the wide variety of traumatic and nontraumatic deaths with which the forensic pathologist deals. The Forensic Pathology Reviews series is designed to reflect this expansion and to provide up-to-date knowledge on special topics in the field, focusing closely on the dynamic and rapidly growing evolution of medical science and law. Individual chapters present a problem-oriented approach to a central issue of forensic pathology. A comprehensive review of the international literature that is otherwise difficult to assimilate is given in each chapter. Insights into new diagnostic techniques and their application, at a high level of evidential proof, to the investigation of death will surely provide helpful guidance and stimulus to all those involved with death investigation. It is hoped that this series will succeed in serving as a practical guide to daily forensic pathological and medicolegal routine, as well as in providing encouragement and inspiration for future research projects. I wish to express my gratitude to Humana Press for the realization of Forensic Pathology Reviews. Michael Tsokos, MD

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Preface The development of specialized areas of expertise within the field of forensic science places heavy demands on the forensic pathologist, as well as the medical examiner and the coroner, to provide satisfactory answers to the investigating authorities in specific cases. Forensic Pathology Reviews, Vol. 1 concentrates on common forensic pathological topics likely to be encountered in the daily routine, as well as on specific pathological conditions rarely seen in the autopsy room. Chapter 1 provides a fundamental and detailed look at what the forensic pathologist, as well as the medical examiner and the coroner, can expect when dealing with burn victims and offers expert guidance on how best to accurately interpret both gross pathology and histological changes. Chapters 2 and 3 focus on trauma deaths and provide an interesting insights into the reconstruction of events in fatalities resulting from kicking and trampling, as well as an up-to-date overview of new immunohistochemical markers applicable to the investigation of traumatic brain injury. Chapter 4 provides an exhaustive overview of the pathology of the central nervous system in drug abuse and points out clinical as well as toxicological implications relevant to the forensic pathologist. Chapter 5 takes a comprehensive look at the pathological examination of the heart in cases of sudden cardiac death and provides details of appropriate dissection techniques and the interpretation of histopathological findings. Chapters 6 and 7 present medicolegal problems in cases of neonaticide and sudden infant death, pointing to possible pitfalls associated with the forensic expertise in such cases. Chapters 8 and 9 cover the pathological features of Mycoplasma pneumoniae and Waterhouse-Friderichsen syndrome, two infectious diseases that have been generally overlooked in the textbooks and manuals of forensic pathology. Chapters 10 and 11 are of special interest to police officers and other members of investigative agencies. These chapters cover the whole spectrum of odd scenarios, such as accidental autoerotic deaths and hypothermia fatalities, that can present at the death scene and hence may lead the inexperienced investigator to the false conclusion about the occurrence of a crime. Chapter 12 describes the pathological features of maternal death from hemolysis, elevated liver enzymes, and a low platelet count (HELLP), showing the relevant aspects

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every forensic pathologist should know when giving a medicolegal expertise in a suspected case of medical malpractice related to this syndrome. Chapter 13 addresses the pathology of injuries resulting from resuscitation procedures and how to distinguish these artifacts from the sequels of a natural disease process or trauma that occurred prior to resuscitation. Chapter 14 deals with the interpretation of alcohol levels in different specimens from deceased and living persons, including the presentation and usage of formulae for the estimation of alcohol concentrations, as well as the observance of the legal chain of custody in such cases. Chapter 15 devotes attention to a rare, but nonetheless important, pathological finding, iliopsoas muscle hemorrhage, and the potential forensic differential diagnoses and interpretation of this finding in the light of autopsy. I owe great thanks to my contributors who are well-recognized national and international researchers and pioneers in their particular scientific fields. Each of them deserves my deepest loyalty for making their practical and scientific knowledge available. Michael Tsokos, MD

Contents Series Introduction ............................................................................................. v Preface ............................................................................................................ vii Contributors ...................................................................................................... xi DEATH FROM ENVIRONMENTAL CONDITIONS 1 Morphological Findings in Burned Bodies Michael Bohnert......................................................................................... 3 TRAUMA 2 Kicking and Trampling to Death: Pathological Features, Biomechanical Mechanisms, and Aspects of Victims and Perpetrators Véronique Henn and Eberhard Lignitz ................................................... 31 NEUROTRAUMATOLOGY 3 Timing of Cortical Contusions in Human Brain Injury: Morphological Parameters for a Forensic Wound-Age Estimation Roland Hausmann ................................................................................... 53 FORENSIC NEUROPATHOLOGY 4 Central Nervous System Alterations in Drug Abuse Andreas Büttner and Serge Weis ............................................................. 79 SUDDEN DEATH FROM NATURAL CAUSES 5 A Forensic Pathological Approach to Sudden Cardiac Death Vittorio Fineschi and Cristoforo Pomara .............................................. 139 CHILD ABUSE, NEGLECT, AND INFANTICIDE 6 Medicolegal Problems With Neonaticide Roger W. Byard ....................................................................................... 171 SIDS 7 Diagnostic and Medicolegal Problems With Sudden Infant Death Syndrome Roger W. Byard and Henry F. Krous ..................................................... 189

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INFECTIOUS DISEASES 8 Fatal Respiratory Tract Infections With Mycoplasma pneumoniae: Histopathological Features, Aspects of Postmortem Diagnosis, and Medicolegal Implications Michael Tsokos ....................................................................................... 201 9 Pathological Features of Waterhouse–Friderichsen Syndrome in Infancy and Childhood Jan P. Sperhake and Michael Tsokos .................................................... 219 DEATH SCENE INVESTIGATION 10 Accidental Autoerotic Death: A Review on the Lethal Paraphiliac Syndrome Stephan Seidl ......................................................................................... 235 11 Lethal Hypothermia: Paradoxical Undressing and Hide-and-Die-Syndrome Can Produce Very Obscure Death Scenes Markus A. Rothschild ............................................................................ 263 MATERNAL DEATH IN PREGNANCY 12 Pathological Features of Maternal Death From HELLP Syndrome Michael Tsokos ....................................................................................... 275 IATROGENIC INJURY 13 Injuries Resulting From Resuscitation Procedures Mario Darok ........................................................................................... 293 TOXICOLOGY 14 Postmortem Alcohol Interpretation: Medicolegal Considerations Affecting Living and Deceased Persons Donna M. Hunsaker and John C. Hunsaker III .................................. 307 FORENSIC DIFFERENTIAL DIAGNOSIS 15 Iliopsoas Muscle Hemorrhage Presenting at Autopsy Elisabeth E. Türk ................................................................................... 341 Index .............................................................................................................. 355

Contributors MICHAEL BOHNERT, MD • Institute of Forensic Medicine, University Hospital of Freiburg, Freiburg, Germany ANDREAS BÜTTNER, MD • Institute of Legal Medicine, University of Munich, Munich, Germany ROGER W. BYARD, MBBS, MD • Forensic Science Centre, Adelaide, Australia MARIO DAROK, MD • Institute of Forensic Medicine, University of Graz, Graz, Austria VITTORIO FINESCHI, MD, PhD • Institute of Forensic Pathology, University of Foggia, Foggia, Italy ROLAND HAUSMANN, MD • Institute of Legal Medicine, Friedrich-AlexanderUniversity Erlangen-Nürnberg, Erlangen, Germany VÉRONIQUE HENN, MD • Institute of Legal Medicine, University of Halle, Halle, Germany DONNA M. HUNSAKER, MD • Office of the Chief Medical Examiner, Louisville, KY JOHN C. HUNSAKER III, MD, JD • Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY HENRY F. KROUS, MD • Department of Pathology, Children’s Hospital-San Diego, University of California, San Diego School of Medicine, San Diego, CA EBERHARD LIGNITZ, MD • Institute of Legal Medicine, University of Greifswald, Greifswald, Germany CRISTOFORO POMARA, MD • Institute of Forensic Pathology, University of Foggia, Foggia, Italy MARKUS A. ROTHSCHILD, MD • Institute of Legal Medicine, University of Cologne, Cologne, Germany STEPHAN SEIDL, MD • Institute of Legal Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany JAN P. SPERHAKE, MD • Institute of Legal Medicine, University of Hamburg, Hamburg, Germany

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MICHAEL TSOKOS, MD • Institute of Legal Medicine, University of Hamburg, Hamburg, Germany ELISABETH E. TÜRK MD • Institute of Legal Medicine, University of Hamburg, Hamburg, Germany SERGE WEIS, MD • Neuropathology Laboratory, The Stanley Medical Research Institute, Bethesda, MD

Burns

Death From Environmental Conditions

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Bohnert

Burns

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1 Morphological Findings in Burned Bodies Michael Bohnert, MD CONTENTS INTRODUCTION EXTERNAL FINDINGS INTERNAL FINDINGS REFERENCES

SUMMARY Morphological findings in burned bodies may cover a broad spectrum. They can range from minor, local, superficial burns of the skin to calcined skeletal remains without any soft tissue left. The external as well as the internal findings in burned bodies depend on the temperature actually applied to the body, the time for which it is applied, the kind of transmission of the heat to the body, and other prevailing conditions. The consequences are burns of the exposed tissue, changes in the content and distribution of tissue fluid, fixation of the tissue, and shrinking processes. In case of direct contact with the flames, the organic matter is consumed as fuel. Only in very rare cases do the effects of the heat cease with the time of death. Consequently, many findings seen at autopsy may be of postmortem origin with fluent transitions between intravital, perimortal, and postmortem changes. Apart from burns (first- to fourthdegree), the external findings may include leathery consolidation and tightening of the skin and the presence of partly long splits. The so-called pugilistic attitude is the result of the shrinkage of muscles and tendons. The internal organs may be considerably reduced in size because of fluid loss and consumption by the fire (so-called “puppet organs”). Heat-related fluid shifts may cause vesicular detachment of the epidermis (false burn blisters) on the skin and pseudo-hemorrhages in From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 3

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the form of heat hematomas inside the body. The latter are most frequently seen in the skull but can also occur in the hollow organs of the abdomen. In the same way, accumulations of large droplets of fat may occur in the vessels, the blood of the right ventricle, or the epidural space. The respiratory tract is the most important organ system for the diagnosis of vitality. Where fire fumes were inhaled, deposits of soot particles will be found. Edema or bleeding of mucous membranes and patchy or vesicular detachment of the mucosa may be indicative of an inhalation of hot gases. Consumption by the fire causes a progressive loss of soft tissue, exposure of the body cavities, and amputation of extremities. Complete cremation of an adult body is reached only under extreme circumstances. Even if high temperatures are applied for several hours, there will usually still be enough skeletal remains to allow successful determination of the species, the body measurements, and the sex as well as to identify skeletal anomalies and the presence of possible injuries. Key Words: Burns; charring; shrinkage of tissue; consumption by fire; heat-related fluid shift; spurious wounds; heat hematoma; skin splitting.

1. INTRODUCTION The rate of annual deaths related to fire is about 13 per million inhabitants in the United States and Canada, and 6 per million inhabitants in Germany. These are mostly accidents (1–8) followed by suicides (9–16). Homicides with subsequent burning of the victim (17–24) or killings by burning (25,26) are comparatively rare in Europe just as in the United States and Japan and are reported more often from India (27–30) or South Africa (31,32). The morphological findings in burned bodies may cover a broad spectrum. They can range from minor, local, superficial burns of the skin to calcined skeletal remains without any soft tissue left and total incineration. The external just as the internal findings depend (a) on the temperature actually applied to the body, (b) the time for which it is applied, (c) the kind of transmission of heat to the body, and (d) other prevailing conditions. In most cases, the effects of heat on the body continue beyond death. Consequently, the changes found are largely of postmortem origin. The effects of heat on the body are (a) burns of the exposed tissue, (b) changes in the content and distribution of tissue fluids, (c) fixation of the tissue, and (d) shrinking processes (Table 1). The kind of heat influences the distribution and extent of the consequences just mentioned: under the direct effect of a fire, the loss of body mass is more pronounced than under radiant heat, because in the first case the organic matter of the body acts as fuel, whereas in the second case the loss of body mass results from the loss of tissue fluid.

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Table 1 Effects of Heat on the Body and Related External and Internal Findings Effects of Heat

External findings

Internal findings

Burns

Burns of skin Singeing of hair Consumption by fire

Burns and consumption of internal organs and bones Edema, mucosal bleeding, and detachment of the mucosa of airways

Changes of content Skin blisters and distribution of tissue fluid

Vaporization of body fluids Rupture of abdominal wall with prolapse of intestinal loops Leakage of fluid from mouth and nose Heat hematoma Accumulations of fat in body cavities, vessels, or heart

Heat fixation

Leatherlike, brownish fixation of skin

Induration of internal organs and muscles Fragmentation of erythrocytes

Shrinking of tissue

Tightening of skin Splitting of skin Protrusion of tongue Petechial hemorrhages of neck and head Pugilistic attitude

Shrinking of organs “Puppet organs”

The forensic investigation of deaths related to fire is important in order to determine the manner and cause of death, the vitality of the findings, and the identity of the victim. The basis of the assessment is a careful evaluation of the autopsy findings. Additional investigations, such as outcome of toxicology (determination of carbon monoxide-hemoglobin [CO-Hb] concentration and cyanide concentration) or histology (particularly of the airways), may help to complete the assessment of the case. The present review deals with the morphological consequences of the effects of heat with the main emphasis being placed on the findings of postmortem origin. The problems associated with the diagnosis of vitality and the determination of the cause of death were recently described in a review (33). Therefore, they are mentioned on the fringe here only. The possibilities to determine the identity of a charred body are not dealt with in this review. The methods available for that purpose do not differ from those used for other deaths.

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2. EXTERNAL FINDINGS 2.1. General Aspects Among the externally discernible changes, the dominant features are the various stages of skin burns, the results of tissue shrinkage, and the consumption by the fire. Destruction can be so extensive that the less experienced tend to consider an autopsy pointless because, in their opinion, it will not produce any findings anyway. But this opinion is definitely wrong: even in charred torsos with general incineration, exposure of the body cavities, and partial amputation of the extremities as a result of the fire, the organs of the thorax and abdomen can usually still be assessed quite well. Moreover, sufficient amounts of body fluids and tissue samples can be obtained for further investigations.

2.2. Burns Skin burns are categorized into four degrees, with each degree characterizing a certain depth of the skin lesion. The categories are: degree 1— superficial burns, degree 2a—superficial partial-thickness burns associated with necrosis of the upper layers of the epidermis, degree 2b—deep partialthickness burns associated with necrosis of the entire thickness of the epidermis, degree 3—full-thickness burns with necrosis involving the dermis as well, and degree 4—charring in which the heat lesion reaches deeper soft-tissue layers. Skin burns are the result of temperature and duration of exposure: the higher the temperature, the lower the duration of exposure necessary to achieve a certain degree of burn. The lowest temperature considered necessary for causing damage is an actual skin temperature of 44°C, although under this condition no less than 6 hours are required to reach a second- to third-degree burn (34–36). Between 44°C and 51°C, a rise in temperature by 1°C halves the duration of exposure necessary to cause a certain degree of damage to the skin. Above 51°C, the excess heat is no longer conducted away by convection via the capillaries of the skin. The heat penetrates into the deeper layers of the tissue. For the actual skin temperature the kind of transmitting of the heat to the body is of major importance: the penetrating power of moist heat is considerably higher than that of dry heat (34–37). The usual staging of skin burns according to clinical symptoms is of minor importance in the forensic evaluation of findings, because no conclusions can be drawn from the degree of the burns to the intravital effects of the heat. The question of whether skin burns occurred while the victim was still alive is difficult to answer. Erythemas (first-degree burns) are characterized

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by dilated skin vessels. After circulation ceases, these empty so that postmortem reddening of the skin is usually no longer recognizable. As a postmortem residue of a first-degree burn, a red margin may occasionally be observed after the reddening of the skin has faded because of hypostasis (38). This phenomenon, which is difficult to detect even histologically, may, however, also be the result of postmortem effects of heat on the skin (39–41). The principle sign of second-degree burns are fluid-filled skin blisters. However, these can be regarded as a vital sign only if cellular reactions, such as the accumulation of leukocytes in the blister content, can be demonstrated (39,42,43). Fluidfilled blisters of the skin can also form postmortem. Then they are a result of a purely mechanical shift of fluid in the skin as owing to the effects of the heat. In most fire deaths, the body is exposed postmortem to temperatures of several hundred degrees celsius for at least several minutes, often by direct contact with the flames. Consequently, burned corpses most often show signs of charring on the outside of the body (4,8). In the rather rare cases of prolonged exposure to comparatively low temperatures, for example, in a smoldering fire, the skin is leathery, firm, and discolored brown (44). DiMaio and DiMaio described this aspect as “such as one sees in a well-done turkey” (44). A special form of skin changes caused by heat can be seen on the palms of the hands and the soles of the feet (45). A whitish discoloration of the epidermis associated with swelling, wrinkling, and vesicular detachment up to glovelike peeling can be observed (Fig. 1). The findings are reminiscent of the so-called washerwoman’s skin, as it is seen after prolonged exposure to a moist environment or in drowning deaths. Histological examination shows fluid-filled blisters in the stratum germinativum, hyperchromasia, and palisade arrangement of the nuclei as well as clumping of the erythrocytes corresponding to second-degree burns of the skin (39,46). Consequently, this is a morphological variation of a second-degree burn owing to the special anatomy of friction skin. Skin burns as well as the extent of burn injuries to human remains are never distributed evenly. Areas of the body pressed against the supporting surface or covered by clothing are often burned less than unclothed skin areas (44). Especially tight-fitting clothes can protect the underlying skin from burns for a long time. In the same way, it may be possible to prove a homicide by manual strangulation in a fire victim with the ligature still in place (47–49). In cases of suicidal self-incineration using fire accelerants, burns may be absent from the feet and lower legs if the incineration took place while the body was in an upright position (50,51). In burns caused by low heat, deep, anatomically circumscribed signs of consumption by the fire may occur. These are

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Bohnert

Fig. 1. Second-degree burns of the hand: whitish discoloration, swelling, and wrinkling of the epidermis of the palmar skin mimicking washerwoman’s skin.

formed when the fire is maintained according to the wick principle: in those parts of the body where the skin has burned away, liquefied subcutaneous fatty tissue leaks out and maintains the fire (47,52,53). This process can go on for several hours (53). The often bizarre distribution of the burn lesions in such cases has given rise to the myth of spontaneous human combustion (54,55). Heat changes of the hair occur at temperatures above 150°C. This can be used to differentiate between burns and scalds or to indicate the approximate temperature reached in smoldering fires. The hair gets frizzy and brittle and assumes a fox-red or dark brown to black color. Temperatures of about 200°C lead to the formation of gas bubbles in the shaft, at 240°C the hair becomes frizzy owing to the melting of the hair keratins, and above 300°C charring occurs (56–58). Singeing of the head hair is usually not associated with high flames, but with a characteristic smell. In contrast to this, frizzy hair burns with high, open, and sustained flames causing severe damage to the neighboring skin or mucosa (59). The explanation for this phenomenon is the larger distance between the individual hairs, which allows better access of oxygen.

2.3. Shrinkage of Tissue The reason why the tissue shrinks is the loss of fluid caused by the heat. Externally, it is characterized by tightening of the skin, splitting of the skin,

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protrusion of the tongue from the open mouth, petechial hemorrhages in the region of the neck and head, and the so-called pugilistic attitude. After prolonged exposure to high temperatures the skin is generally consolidated, of leathery, hard consistency. The surface is reduced because of tightening of the skin. Fire victims often show a very similar facial expression, which makes identification by inspection more difficult. The mouth is usually open with shrunken lips. In most cases the eyes are closed, and the shrunken lids can be opened only with difficulty and incompletely. In some cases, in which no or only a minor degree of postmortem burning occurred, there may be areas without burns and/or soot deposits in the angles of the eyes (Fig. 2) (47,60). These so-called “crow’s feet” are usually regarded as a sign of vitality and clue to a flash fire. However, this opinion is not undisputed. For instance, Bschor pointed out that “crow’s feet” may also occur in fire deaths without a flashover (60); therefore, squinting of the eyes as a reflex to the smoke was also considered a possibility. But one could also imagine a different mechanism of formation, namely shrinkage of the skin because of heat, resulting in a smoothing of the wrinkles of the face. Then the unsooted base of the wrinkles would become visible, which would manifest itself as “crow’s feet” around the eyes. Because of the shrinkage of the skin, pre-existing lesions become smaller and change in shape (47). For example, originally slitlike skin lacerations (e.g., stabs) may assume a circular shape. Moreover, lesions may migrate toward the center of the thermal damage (61). Because of the shrinkage of the perianal tissue, the anus gapes, which may be misinterpreted as the result of anal penetration (41). Splitting of the skin is a frequently observed phenomenon, particularly in charred bodies (Fig. 3). It is very rare in burns of minor severity. In these cases, prolonged exposure to the heat has to be assumed. The splits have sharp edges that can be brought into apposition, are often linear, but occasionally are also angled. In most cases, they reach the subcutaneous fatty tissue and, sometimes the outer muscle layers. This may be explained by the shrinkage of the skin caused by the heat (40,41,62). In this context, little attention is paid to the fact that the tissue exposed in the depth of the splits is usually unburned and often not even sooted. Possibly the splits form only during the cooling of the body or at least become wider in this process. They could also form as a consequence of manipulating the body while recovering and putting it into the coffin, when the skin, which is brittle owing to the heat, may tear easily. The appearance of heat splits in the skin may lead the inexperienced to interpret them as vital injuries. For the diagnosis of a genuine, penetrating wound, corresponding hemorrhages and wound tracks in the deeper tissue layers must be present.

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Fig. 2. “Crows feet” and protrusion of the tongue as a result of the heatmediated shrinkage of skin and soft tissue.

Protrusion of the tongue from the open mouth is a result of the heatrelated shrinkage of the soft tissue of the neck (Fig. 2). In the presence of severe burns on the neck and/or thorax, petechial hemorrhages may occasionally be found in the lids and conjunctivae (60,63–65). The mechanisms involved in their formation are congestion in the upper parts resulting from the shrinkage of the soft tissue of the neck by heat or heat rigidity of the thorax while the circulation is still intact (60,64,65). So petechial hemorrhages in the region of the neck and head would have to be regarded as a vital sign. The typical posture of charred bodies is called pugilistic or boxer’s attitude, with the arms being abducted in the shoulder joint and flexed in the

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Fig. 3. Heat splits of the skin of the right leg and pseudo-washerwoman’s skin of the sole of the foot.

elbow joint and the legs being abducted in the hip joint and flexed in the hip and knee joint (Fig. 4). The reason for this phenomenon is the shrinkage of muscles and tendons caused by the heat (60,63,66). The flexion in the joints of the extremities is because of the predominance of the flexor muscles. This flexion is particularly recognizable on the hands, which are clenched into fists in most cases. This may even result in the dislocation of the wrist. In the same way, contracted feet may be observed, especially after advanced consumption of the legs. In female corpses found faceup, the pugilistic attitude may be mistaken for the result of rape (60). However, the position of a charred body cannot always be explained by the effects of the heat alone. For example, mechanical obstacles, such as rubble from the fire lying on the legs of the deceased, may prevent flexion of the hip and knee joint. Also, in a side-lying

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Bohnert

Fig. 4. Pugilistic attitude of a burn victim.

position (sleeping position), the pugilistic attitude is only vaguely discernible, if at all (60). When the body lies in prone position, the pugilistic attitude is not as pronounced as when it lies on its back.

2.4. Consumption by the Fire The destruction of a body results from the direct exposure to flames. It causes loss of soft tissue, exposure of the body cavities, amputation of the extremities, and finally, consumption of the internal organs. Although the skeleton is also damaged by the fire, it is not consumed completely. Even if it is exposed to a fire with high temperatures over a long period of time, there will usually still be remains to allow macroscopic assessment and successful determination of the species, the body measurements, and

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Table 2 Classification of the Destruction by Burns According to Eckert et al. (69) Level 1 Level 2 Level 3

Complete consumption by the fire—only ashes left Incomplete consumption by the fire—bone fragments without soft tissue left Partial consumption by the fire—soft tissue still present

Level 4

Charring without loss of internal organs

Table 3 Classification of the Destruction by Burns According to Maxeiner (4) Level 1 Level II Level III Level IV Level V Level VI Level VII

Burns up to third degree, <50% of the body surface Burns up to third degree, >50% of the body surface Burns up to fourth degree, <75% of the body surface Burns up to fourth degree, >75% of the body surface Partial destruction of the body by charring, <100% of the body surface Charring, 100% of the body surface Burned torso, extensive destruction

the sex as well as to identify skeletal anomalies and the presence of possible injuries (47,67–75). Some authors have proposed classifications as a tool to describe the extent and distribution of consumption by a fire (4,7,69,76) (Tables 2–5). However, these classifications apply different standardizations and are not compatible with each other (8). The Crow–Glassman Scale (CGS) (76), for example, has been developed to assess the chances of identification by means of the degree of destruction already at the scene of a fire. The classifications according to Eckert et al. (69), Gerling et al. (7), or Maxeiner (4) are purely descriptive tools to quantify the changes caused by a fire. According to our experience, the CGS is the clearest and best usable classification system for forensic purposes. Normally the bodies on which forensic autopsies are performed exhibit only minor or moderately severe burns. According to our own investigations, more than three quarters of the cases can be categorized as CGS level 1–3. There is a clear relation to the scene of the fire. Lower degrees of destruction are found more often in fire victims recovered from buildings, whereas in car fires the extent of consumption by the fire is usually higher because of the

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Bohnert Table 4 Crow–Glassman Scale (CGS) of Burn-Related Destruction of Corpses (76)

Level 1

Level 4

Second-degree burns, sometimes singeing of the hair; visual identification possible Burns of varying severity, sometimes with thermal destruction/amputation of ears, genitals, hands, or feet; visual identification may still be possible Consumption by the fire with partial amputation of arms and/or legs; cerebral cranium intact Bony lesions of the cerebral cranium; residual extremities still present

Level 5

Fragmented skeletal remains without soft tissue

Level 2 Level 3

Table 5 Classification of the Destruction by Burns According to Gerling et al. (7) Level A Minor loss of soft tissue, sometimes with rupture of the abdominal wall Level B Moderate loss of soft tissue, especially of the legs, with opening of the thoracic and/or abdominal cavity but sparing the head Level C Loss of soft tissue of the extremities and exposure of the skull; sometimes in combination with exposure of the thoracic and/or abdominal cavity

higher temperatures produced by these fires. Massive destruction not only requires higher temperatures but especially a longer duration of exposure (8,77). The question as to what extent the level of charring in a burned body allows one to draw conclusions regarding the duration of the fire is rarely asked (21,38). In the literature there are few reports on this topic, most of which refer to observations made during cremations (23,77–80). Apart from these, there is a small number of case reports on fire deaths in which the duration of the fire is known (21,38,79,81). Systematic studies showed that the course of events follows a fixed chronological order: 30 minutes after the fire has been in full progress all body cavities are exposed and the distal portions of the extremities are amputated. The exposed bones show signs of calcination. After a minimum of 50 minutes and a maximum of 80 minutes, the internal organs are largely incinerated and the burned torso breaks apart (77). However, when applying these findings to real fire deaths one should take into consideration that the bodies in those cases are usually not exposed to a constant temperature level for a long period of time, but that a fire develops in several stages, and it will often not be possible to reconstruct the temperatures reached in the individual stages (79,82,83).

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3. INTERNAL FINDINGS 3.1. General Aspects The internal findings in fire deaths are the result of a fixation of the tissue by the heat, processes of shrinking, thermal changes of the content and distribution of tissue fluids, and a rising gas pressure in hollow spaces. After the body cavities have been exposed by the effects of the fire, direct burns occur also on the internal surfaces, and the organs are consumed by the fire. Before death, direct exposure of internal organs to the fire is possible in the respiratory tract. The inhalation of hot gases causes damage to the mucosa. The characteristic findings produced by this constellation are used especially in the diagnosis of vitality (33). The prolonged effect of high temperatures on the body results in the vaporization of body fluids. In closed cavities, such as the body cavities but also in hollow organs, high pressure may build up causing the wall to rupture. A frequently observed finding is the prolapse of intestinal loops following exposure of the abdominal wall due to the fire. Moreover, fluid can be pressed from the openings of the body, resembling changes resulting from putrefaction (38). The loss of fluid and, after exposure of the body cavities, the direct effect of the heat cause shrinking of the internal organs, which become firm, hardened, and cooked by the heat, the so-called “puppet organs” (Fig. 5) (84). Systematic observations of cremations showed that these changes occur between the 30th and 50th minute (77). If the fire continues, the surface of the organs becomes increasingly bosselated and is reduced to a spongelike residual structure in the end. The tissue is meanwhile completely desiccated and disintegrates into ash at the slightest touch. This condition was described as “Zermürbungspunkt” (crumbling point) by Gräff in his investigations of victims of the firestorm resulting from the air raid of Hamburg, Germany, during World War II (84).

3.2. Respiratory Tract The respiratory tract is the most important organ system for the diagnosis of vitality. Where fire fumes were inhaled, deposits of soot particles will be found. On the other hand, the presence of soot aspiration does not necessarily prove that the victim was still alive when exposed to the fire, although this distinction is rarely made (4,33,40). Edema, mucosal bleeding, and patchy or vesicular detachment of the mucosa in the nose, mouth, pharynx, larynx, trachea, and bronchi may be indicative of an inhalation of hot gases. In the same

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Fig. 5. Comparison of a normal kidney (above) and a shrunken kidney (below) after heat exposure of the body (“puppet organ”).

way, the upper portion of the esophagus may also be damaged. Often, increased secretion of mucus is observed in the air passages. This may be interpreted as an attempt to cool the surfaces of the air passages and thus as a sign of vitality, if other causes for the secretion of mucus (bronchial asthma, catarrhal bronchitis) have been ruled out (33,39). Damage caused to the respiratory tract by dry heat is limited more to the upper portions (85). The inhaled hot air is sufficiently cooled down by the mucosa of the airways, so that after exposition to a “normal fire” hardly any changes are found in the medium and small bronchi (33,39,85). But if hot steam is inhaled, the temperature hardly declines in the course of the air passages so that direct thermal damage may occur even in the peripheral parts of the respiratory tract (85). For differentiation between hot steam and dry air, the so-called “pleura sign” can be used at autopsy. If hot

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Fig. 6. Large droplet of fat in the right ventricle of the heart.

steam was inhaled, the parietal pleura is reddened, whereas the costodiaphragmatic angles are pale (86). In deaths caused by the effects of dry heat, this sign is absent even if the circumstances suggest a fire with high temperatures.

3.3. Vessels When performing an autopsy on fire victims, intensive red discoloration of the intima of the vessels, similar to that seen in changes resulting from putrefaction, is very often observed even in cases in which there are no other signs of putrefaction. This finding is the result of hemolysis (87) occurring at temperatures above 52°C (88). Already, at 48°C erythrocytes begin to dissolve, with the hemoglobin-containing fragments behaving like intact erythrocytes in serological tests (89). If the circulation is still intact, the erythrocyte fragments (“fragmentocytes”) can also be demonstrated microscopically in other organs, which has to be interpreted as a sign of vitality (86). The effect of heat on the body leads to shifts of the fluid content in the tissue, which may result in blood extravasates in cavities or organs. Another consequence may be accumulations of large droplets of fat in the epidural space, in greater vessels, or in the blood of the right ventricle (Fig. 6) (90,91). The intravasal spread of fat is no sign of vitality, but a result of postmortem thermal damage with mobilization and displacement of depot fat away from

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the center of the heat (92,93). The accumulation of fat in the veins of the greater circulation or the blood vessels of the lungs must not be confused with vital fat embolism, occuring after mechanical trauma.

3.4. Gastrointestinal Tract The abdominal organs are protected by the abdominal wall from direct damage by the flames for a relatively long period of time. As a result of the heating of the body, the tissue fluids boil away and the pressure inside the hollow organs and the abdominal cavity builds up, which often leads to the rupture of the abdominal wall and the prolapse of intestinal loops. Consumption of the abdominal wall by the fire further promotes the rupture. In rare cases, heatrelated ruptures of the gastrointestinal organs are found, before they were directly exposed to the fire. Schneider reported on the rupture of the stomach in a 2-year-old child and a rupture of the colon in a 3-year-old child (94). In both cases, the abdominal wall was charred without exposing the abdominal cavity. In a case from our own autopsy material, in which the victim had remained in a sauna for several hours after death, there were ruptures of the large intestine with several liters of fluid in the abdominal cavity. Berg and Schumann described a heat hematoma of the stomach (63). In that case, in which the gastric wall was actually charred, a layer of blood had been found on the chyme. The swallowing of blood could be ruled out. The authors assumed that the heat hematoma could have been promoted by strong congestion of the blood vessels in the gastric wall owing to hyperemia during digestion.

3.5. Bones Bones are highly resistant to heat in their gross structure and usually allow macroscopic assessment even after the body was exposed to high temperatures for several hours (69,70,74). At temperatures above 700°C, complete combustion of the organic substances with incineration and recrystallization of the inorganic matter occurs, which is called “calcination” (95,96). The bones are grayish-whitish, desiccated, and disintegrate easily. The surface shows characteristic tears, partly reflecting the course of the trabeculae but often also being irregular in structure (41,68,69,77). As all other organs, bones can also shrink in the heat. In long bones, the reduction in length can be up to 10% (68). Both von Hofmann (97) and Merkel (47) described the problems of differentiating between vital and postmortem fractures. On the one hand, fractures may be caused by the direct effect of the fire. On the other hand, they

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may have occurred after death, for example, when walls or timber collapsed. Especially in charred or calcined bones, a minor mechanical strain may be enough to cause fractures. Therefore, in fractures localized within charred bone areas, the possibility of artifacts should be considered. On the other hand, several authors have stressed expressly that injuries sustained during life can be demonstrated even on charred or calcined bones (47,68,69,74). Eckert et al. (69) found a fracture of the iliac bone caused by blunt force on the pelvis of a female body largely consumed by fire. Merkel (47) and also Herrmann (68) pointed out that traces of sharp force especially can be demonstrated quite well on the skeleton of burned bodies. Fractures away from areas of burned bone are in all probability not a result of thermal effects (23,24). In the assessment of burned bones, special attention must be paid to the bony skull cap. In about one-third of all fire deaths, the skull cap is partially destroyed and the interior of the skull is exposed (8), which makes assessment even more difficult. Isolated fractures of the external table are seen, especially in those cases where a defined area of the skull cap was in direct contact with the flames (23,41). Prolonged exposure to heat causes fractures of the entire thickness of the skull cap with occasional bursting of the sutures of the skull (23). The tears in the skull cap caused by heat may radiate from a center, but can sometimes also be elliptic or circular in shape or resemble a spider’s web fracture (41,68). In rare cases, round or oval bone fragments may burst outward (Fig. 7). Distinction of this finding from a gunshot injury may be difficult (98). Careful examination and consideration of the other findings and the circumstances of the case allow differentiation of mechanical trauma sustained during life from postmortem trauma or heat artifacts, even when consumption by the fire is far advanced (24,47,74,97).

3.6. Cranial Cavity and Brain A frequent finding is the epidural hematoma caused by heat. This is a postmortem effect resulting from the shift of fluid from the diploe (99) and the venous sinuses (100) when the skull cap is in direct contact with the flames. Accordingly, charring of the bony skull is usually found above the site of the heat hematoma. Less often the heat hematoma is localized on the side opposite to the site where the fire had its maximum effect. It is dry, crumbly, and of brick-red color. Occasionally it may be surrounded by fat, and in rare cases accumulations of fat without extravasations of blood can also be found in the epidural space. Apart from that, the hematoma is sometimes found to be interspersed with brain tissue when the dura mater is torn owing to shrinkage by heat (99–103). The shift of brain tissue into the epidural space is caused by the

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Fig. 7. Burn defect of the skull cap resembling a gunshot wound.

elevated steam pressure in the cranial cavity resulting in an enlargement of the brain (99,103). Dotzauer pointed out that postmortem extravasates of blood can occur in all cavities of the skull including the ventricles of the brain (99). But hemorrhages can also be found in the brain tissue itself. In these cases, distinction between postmortem and vital hemorrhages can be particularly difficult (102,104,105). Generally, intracerebral bleeding could be a result of the shrinkage of tissue with laceration of small blood vessels (102,105). One case with postmortem hemorrhages in the pons and the basal ganglia as a result of an injury caused during recovery was described by Dirnhofer and Ranner (104). When the skull cap is intact, the brain of fire victims is often shrunken and of a hardened consistency with filled sulci on the surface (Fig. 8). Dotzauer and Jacob described the finding as “a reduction of the brain volume associated

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Fig. 8. Smoothing of the brain surface in combination with reduction of the brain volume in a burn victim.

with swelling of the internal matter” (106). Histologically, condensation of the vessels and widening of the Virchow–Robinson spaces have been described (39,106). Again, this finding may be explained as the result of a loss of fluid and does not prove a vital thermal damage to the tissue. Evidence of a vital heat trauma may possibly be obtained by examining the ultrastructure of the brain (blood–brain barrier) and/or the expression pattern of various neurochemical mediators (107–109). According to animal experiments, hyperthermic brain damage manifests itself by changes in the shape of nerve and glia cells, edema, disturbances of the blood–brain barrier, and an increased expression of glial fibrillary acidic protein, vimentin, heat shock protein, nitric oxide synthase, and heme oxygenase (107). Quan et al. showed that intranuclear ubiquitin immunoreactivity of the pigmented substantia nigra neurons in the

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midbrain was induced by severe stress in fires (108). Iskhizova and Tumanov examined the ultrasound and histological changes in the central nervous system in cases of thermal trauma. These authors found that derangements of interneuronic bonds and of interrelations between the neurons and capillaries are typical vital changes in the brain (109).

REFERENCES 1. Anderson RA, Watson AA, Harland WA (1981) Fire deaths in the Glasgow area: I. General considerations and pathology. Med Sci Law 21, 175–190. 2. Gormsen H, Jeppesen N, Lund A (1984) The causes of death in fire victims. Forensic Sci Int 24, 107–111. 3. Copeland AR (1985) Accidental fire deaths. The 5-year Metropolitan Dade County experience from 1979 until 1983. Z Rechtsmed 94, 71–79. 4. Maxeiner H (1988) Umstände und Befunde bei 202 Brandtodesfällen. Beitr Gerichtl Med 46, 313–325. 5. Rogde S, Olving JH (1996) Characteristics of fire victims in different sorts of fire. Forensic Sci Int 77, 93–99. 6. Fieguth A, Kistenmacher L, Tröger HD, Kleemann WJ (1997) Todesfälle bei Hitzeeinwirkung. Arch Kriminol 200, 79–86. 7. Gerling I, Meissner C, Reiter A, Oehmichen M (2000) Death from thermal effects and burns. Forensic Sci Int 115, 33–41. 8. Bohnert M, Schmidt U, Große Perdekamp M, Pollak S (2001) Zum Ausmaß der Brandzehrung—eine Analyse von 68 Brandleichen. Arch Kriminol 207, 104–113. 9. Copeland AR (1985) Suicidal fire deaths revisited. Z Rechtsmed 95, 51–57. 10. Shkrum M, Johnston K (1992) Fire and suicide: a three-year study of self-immolation deaths. J Forensic Sci 37, 208–221. 11. Castellani G, Beghini D, Barisoni D, Marigo M (1995) Suicide attempted by burning: a 10-year study of self-immolation deaths. Burns 21, 607–609. 12. Hadjiiski O, Todorov P (1996) Suicide by self-inflicted burns. Burns 22, 381–383. 13. Leth P, Hart-Madsen M (1997) Suicide by self-incineration. Am J Forens Med Pathol 18, 113–118. 14. Schmidt V, Sannemüller U, Pedal I (2000) Suizidale Selbstverbrennung. In Oehmichen M, ed., Hyperthermie, Brand und Kohlenmonoxid. Schmidt-Römhild, Lübeck, pp. 121–134. 15. Rothschild MA, Raatschen H-J, Schneider V (2002) Suicide by self-immolation in Berlin from 1990 to 2000. Forensic Sci Int 124, 163–166. 16. Bohnert M, Rothschild MA (2003) Complex suicides by self-incineration. Forensic Sci Int 131, 197–201. 17. Copeland AR (1985) Homicide by fire. Z Rechtsmed 95, 59–65. 18. Kojima T, Yashiki M, Chikasue F, Miyazaki T (1990) Analysis of inflammable substances to determine whether death has occured before or after burning. Z Rechtsmed 103, 613–619.

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19. Maxeiner H (1990) Vitale, agonale oder postmortale Einwirkung des Feuers bei Fällen von Mordbrand. In Klose W, Oehmichen M, ed., Rechtsmedizinische Forschungsergebnisse. Festschrift zum 70. Lebensjahr für Prof. Dr. med. Otto Pribilla. Schmidt-Römhild, Lübeck, pp. 422–433. 20. Karhunen PJ, Lukkari I, Vuori E (1991) High cyanide level in a homicide victim burned after death: evidence of post-mortem diffusion. Forensic Sci Int 49, 179–183. 21. Madea B (1992) Branddauer und Verkohlungsgrad einer Brandleiche. Arch Kriminol 189, 39–47. 22. Tsaroom S (1996) Investigation of a murder case involving arson. J Forensic Sci 41, 1064–1067. 23. Bohnert M, Rost T, Faller-Marquardt M, Ropohl D, Pollak S (1997) Fractures of the base of the skull in charred bodies—post-mortem heat injuries or signs of mechanical traumatisation. Forensic Sci Int 87, 55–62. 24. Iwase H, Yamada Y, Ootani S, Sasaki Y, Nagao M, Iwadate K, et al. (1998) Evidence for an antemortem injury of a burned head dissected from a burned body. Forensic Sci Int 94, 9–14. 25. Frazier HC (1987) “She went up in flames”: evidence of a burn homicide. Med Sci Law 6, 69–78. 26. Madea B, Schmidt P, Banaschak S, Schyma C (2001) Tötung durch Verbrennen. Arch Kriminol 208, 1–9. 27. Gupta RK, Srivastava AK (1988) Study of fatal burns cases in Kanpur (India). Forensic Sci Int 37, 81–89. 28. Gaur JR, Sangwan SK, Singh I, Thukral K (1993) Evaluation of physical evidence in a burn case. Med Sci Law 33, 75–78. 29. Gaur JR (1993) Forensic examinations in two cases of alleged dowry deaths. Med Sci Law 33, 269–272. 30. Kumar V (2002) Epidemiology of burns among married women in India. J Postgrad Med 48, 331. 31. Lang IR (1994) “Necklace murders”: a review of a series of cases examined in a Port Elizabeth mortuary. Med Law 13, 501–509. 32. Lerer LB (1994) Homicide-associated burning in Cape Town, South Africa. Am J Forens Med Pathol 15, 233–347. 33. Bohnert M, Werner CR, Pollak S (2003) Problems associated with the diagnosis of vitality in burned bodies. Forensic Sci Int 135, 197–205 34. Moritz AR (1947) Studies of thermal injury III. The pathology and pathogenesis of cutaneous burns. An experimental study. Am J Pathol 23, 915–941. 35. Moritz AR, Henriques FC (1947) Studies of thermal injury II. The relative importance of time and surface temperatur in the causation of cutaneous burns. Am J Pathol 23, 695–720. 36. Moritz AR, Henriques FC, Dutra FR, Weisiger JR (1947) Studies of thermal injury IV. An exploration of the casualty-producing attributes of conflagrations; local and systemic effects of general cutaneous exposure to excessive circumambient (air) and circumradiant heat of varying duration and intensity. Am J Pathol 43, 466-488. 37. Price PH, Call DE, Hansen FL, Zerwick CJ (1953) Penetration of heat in thermal burns. Surg Forum 4, 433–438.

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38. Madea B, Schmidt P (2000) Vitale-supravitale-postmortale Befunde bei Verbrennungen. In Oehmichen M, ed., Hyperthermie, Brand und Kohlenmonoxid. Schmidt-Römhild, Lübeck, pp. 305–340. 39. Janssen W (ed.) (1984) Injuries caused by heat and cold. In Forensic Histopathology. Springer, Berlin. 40. Knight B (ed.) (1996) Burns and scalds. In Forensic pathology, 2nd ed. Arnold, London, pp. 305–317. 41. Spitz WU (1993) Thermal injuries. In Spitz WU, ed., Medicolegal investigation of death, 3rd ed. Thomas, Springfield, pp. 413–443. 42. Pioch W (1966) Die histochemische Untersuchung thermischer Hautschäden und ihre Bedeutung für die forensische Praxis. Schmidt-Römhild, Lübeck. 43. Schollmeyer W (1961) Zur histologischen Differentialdiagnose der Hautblasen nach Hitzeeinwirkung und nach Barbituratvergiftung. Dtsch Z ges Gerichtl Med 51, 180–189. 44. DiMaio VJM, DiMaio DJ (2001) Forensic pathology, 2nd ed. CRC, Boca Raton. 45. Bohnert M, Pollak S (2003) Heat-mediated changes to the hands and feet mimicking washerwoman’s skin. Int J Legal Med 117, 102–105. 46. Takamiya M, Saigusa K, Nakayashiki N, Aoki Y (2001) A histological study on the mechanism of epidermal nuclear elongation in electrical and burn injuries. Int J Legal Med 115, 152–157. 47. Merkel H (1932) Diagnostische Feststellungsmöglichkeiten bei verbrannten und verkohlten menschlichen Leichen. Dtsch Z ges Gerichtl Med 18, 232–249. 48. Weimann W (1932) Kriminalistisch wichtige Leichenbefunde auf Brandstätten. Arch Kriminol 91, 19. 49. Suarez-Penaranda JM, Munoz JI, Lopez de Abajo B, Vieira DN, Rico R, Alvarez T, et al. (1999) Concealed homicidal strangulation by burning. Am J Forens Med Pathol 20, 141–144. 50. DeHaan JD (1996) The dynamics of flash fires involving flammable hydrocarbon liquids. Am J Forens Med Pathol 17, 24–31. 51. Grimm U, Sigrist T (1998) Verbrennen im Freien. Arch Kriminol 201, 137–145. 52. DeHaan JD, Campbell SJ, Nurbakhsh S (1999) Combustion of animal fat and its implications for the consumption of human bodies in fires. Sci Justice 39, 27–38. 53. DeHaan JD, Nurbakhsh S (2001) Sustained combustion of an animal carcass and its implications for the consumption of human bodies in fires. J Forensic Sci 46, 1076–1081. 54. Benecke M (1998) Spontaneous human combustion. Skeptical Inquirer 22, 47–51. 55. Gromb S, Lavigne X, Kerautret G, Grosleron-Gros N, Dabadie P (2000) Spontaneous human combustion: a sometimes incomprehensible phenomenon. J Clin Forensic Med 7, 29–31. 56. Berg S (1967) Forensische Spurenkunde: Haare. In Ponsold A, ed., Lehrbuch der Gerichtlichen Medizin, 3rd ed. Thieme, Stuttgart, pp. 495–501. 57. Schaidt G (1975) Haare. In Mueller B, ed., Gerichtliche Medizin, 2nd ed. Springer, Berlin, pp. 122–132. 58. Pabst H (2000) Kurzzeitige Hitzeeinwirkung auf Haare. In Oehmichen M, ed., Hyperthermie, Brand und Kohlenmonoxid. Schmidt-Römhild, Lübeck, pp. 297–303.

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59. Bohnert M, Faller-Marquardt M, Pollak S (2001) Zum unterschiedlichen Brandverhalten von Kopf- und Schamhaaren. Arch Kriminol 207, 42–48. 60. Bschor F (1965) Befunde bei Brandleichen und deren Bewertung. Arch Kriminol 136, 30–38, 93–105. 61. Gubelt A (1972) Eine Gegenüberstellung vitaler und postmortaler Verbrennungsphänomene an der Haut. Med. Thesis, University of Aachen, Germany. 62. Madea B, Schmidt P (2003) Hitze: lokale Hitzeschäden, Verbrennungen und Verbrühungen. In Madea B, ed., Praxis Rechtsmedizin. Springer, Berlin, Heidelberg, New York, pp. 170–181. 63. Berg S, Schumann W (1985) Die Differentialdiganose vitaler und postmortaler Vorgänge bei Brandleichen. Arch Kriminol 175, 65–75. 64. Maxeiner H (1988) Blutaustritte im Kopf-und Halsbereich beim Verbrennungstod. Z Rechtsmed 101, 61–80. 65. Scharschmidt A, Bratzke H (1988) “Stauungsblutungen” als Brandfolge? Arch Kriminol 182, 94–100. 66. Klapproth HJ (1954) Zur Theorie der fixierten Extremitätenversetzung bei Hitzeschrumpfleichen. Dtsch Z gerichtl Med 43, 426–438. 67. Weber W, Schweitzer H (1973) Versuchte Beseitigung einer Kindsleiche durch Verbrennen. Z Rechtsmed 73, 65–69. 68. Herrmann B (1976) Neuere Ergebnisse zur Beurteilung menschlicher Brandknochen. Z Rechtsmed 77, 191–200. 69. Eckert WG, James S, Katchis S (1988) Investigation of cremations and severely burned bodies. Am J Forens Med Pathol 9, 188–200. 70. Hunger H, Rother P, Weigel B, Dalitz B (1988) Weitere Erfahrungen bei der Untersuchung von Leichenbränden. In Bauer G, ed., Gerichtsmedizin. Festschrift für W. Holczabek. Deuticke, Wien, pp. 93–101. 71. Murray KA, Rose JC (1993) The analysis of cremains: a case study involving the inappropriate disposal of mortuary remains. J Forensic Sci 38, 98–103. 72. Grevin G, Bailet P, Quatrehomme G, Ollier A (1998) Anatomical reconstruction of fragments of burned human bones: a necessary means for forensic identification. Forensic Sci Int 96, 129–134. 73. Cattaneo C, DiMartino S, Scali S, Craig OE, Grandi M, Sokol RJ (1999) Determining the human origin of fragments of burnt bone: a comparative study of histological, immunological and DNA techniques. Forensic Sci Int 102, 181–191. 74. Bohnert M, Schmidt U, Große Perdekamp M, Pollak S (2002) Diagnosis of a captive-bolt injury in a skull extremely destroyed by fire. Forensic Sci Int 127, 192–197. 75. de Gruchy S, Rogers TL (2002) Identifying chop marks on cremated bone: a preliminary study. J Forensic Sci 47, 933–936. 76. Glassman DN, Crow RM (1996) Standardization model for describing the extent of burn injury to human remains. J Forensic Sci 41, 152–154. 77. Bohnert M, Rost T, Pollak S (1998) The degree of destruction of human bodies in relation to the duration of the fire. Forensic Sci Int 95, 11–21. 78. Günther H, Schmidt O (1953) Die Zerstörung des menschlichen Gebisses im Verlauf der Einwirkung hoher Temperaturen. Dtsch Z ges Gerichtl Med 42, 180–188.

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79. Richards NF (1977) Fire investigation—destruction of corpses. Med Sci Law 17, 79–82. 80. Eichenhofer W (1980) Temperaturen in der Mundhöhle bei Verbrennungen mit hohen Temperaturen (thermoelektrische Messungen). Med. Thesis, University of Düsseldorf. 81. Westenhoeffer M (1910) Der Fall Beckert (Mord und Brand in der deutschen Gesandschaft zu Santiago de Chile). Vjschr Gerichtl Med 39, 236–305. 82. Redsicker DR, O’Connor JJ (1997) Practical fire and arson investigation, 2nd ed. CRC Press, London. 83. DeHaan JD (1997) Kirk’s fire investigation, 4th ed. Prentice-Hall, London. 84. Gräff S (1948) Tod im Luftangriff. Nölke, Hamburg. 85. Moritz AR, Henriques FC, McLean R (1945) The effects of inhaled heat on the air passages and lungs. Am J Pathol 21, 311–331. 86. Brinkmann B, Kleiber M, Koops E, Püschel K (1979) Vitale Reaktionen bei akutem Verbrühungstod. Z Rechtsmed 83, 1–16. 87. Hagedorn M, Pfrieme B, Mittermayer C, Sandritter W (1975) Intravitale und pathologisch-anatomische Beobachtungen beim Verbrennungsschock des Kaninchens. Beitr Pathol 155, 398–409. 88. Schubothe H, Gross F (1953) Wärmeveränderung roter Blutkörperchen. Schweiz Med Wschr 43, 1048–1050. 89. Prokop O, Göhler W (1976) Die Einwirkung hoher Temperaturen. In Prokop O, Göhler W, eds., Forensische Medizin, 3rd ed. Fischer, Stuttgart, New York, pp. 141–151. 90. Pollak S, Vycudilik W (1981) Über das Verhalten der Lungenfette nach vitalen Verbrennungen. Wien kl Wschr 93, 111–117. 91. Pollak S, Vycudilik W, Reiter C, Remberg G, Denk W (1987) Großtropfiges Fett im Blut des rechten Ventrikels. Z Rechtsmed 99, 109–119. 92. Strassmann G (1933) Über Fettembolie nach Verletzungen durch stumpfe Gewalt und nach Verbrennungen. Dtsch Z ges Gerichtl Med 22, 272–298. 93. Schollmeyer W (1962) Zur Frage der Fettembolie des Lungengewebes bei postmortal Verbrannten. Acta Med Leg Soc (Liège) 15, 77–79. 94. Schneider V, Pietrzak T, Klöppel I (1986) Postmortale Magen-Darm-Rupturen bei Brandleichen. Arch Kriminol 177, 29–33. 95. Herrmann B (1977) On histological investigations of cremated human remains. J Hum Evol 6, 101–103. 96. Bradtmiller B, Buikstra JE (1984) Effects of burning on human bone microstructure: a preliminary study. J Forensic Sci 29, 535–540. 97. von Hofmann E (1875) Beobachtungen an verbrannten Leichenteilen. Wien Med Wschr 25, 395–396, 420–424. 98. Hausmann R, Betz P (2002) Thermally induced entrance wound-like defect of the skull. Forensic Sci Int 128, 159–161. 99. Dotzauer G (1974) Zum Problem des sogenannten Brandhämatoms. Z Rechtsmed 75, 21–24. 100. Reuter F (1919) Kasuistische, experimentelle und kritische Beiträge zur Lehre von der Entstehung der epiduralen Blutextravasate in verkohlten Leichen. Beitr Gerichtl Med 3, 123–144.

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101. Harbitz F (1913) Eigentümliche Funde bei Verbrennungen (Mordbrand). Vjschr Gerichtl Med 45, 34–51. 102. Schneider V (1982) Bemerkenswerte intracranielle Befunde bei einer Brandleiche. Arch Kriminol 169, 129–139. 103. Kondo T, Ohshima T (1994) Epidural herniation of the cerebral tissue in a burned body: a case report. Forensic Sci Int 66, 197–202. 104. Dirnhofer R, Ranner G (1982) Intracerebrale Blutungen bei einer Brandleiche— Brandhämatom, Bergungsverletzung oder intravitale Entstehung. Arch Kriminol 170, 165–172. 105. Schulz F, Petri S, Koops E, Matschke J (1996) Zur Frage der Vitalität und möglichen Ursachen von punktförmigen Blutungen im unteren Hirnstamm bei einer Brandleiche. Arch Kriminol 198, 160–166. 106. Dotzauer G, Jacob H (1952) Über Hirnschäden unter akutem Verbrennungstod. Dtsch Z gerichtl Med 41, 129–146. 107. 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. Schmidt-Römhild, Lübeck, pp. 79–120. 108. Quan L, Zhu BL, Oritani S, Ishida K, Fujita MQ, Maeda H (2001) Intranuclear ubiquitin immunoreactivity in the pigmented neurons of the substantia nigra in fire fatalities. Int J Legal Med 114, 310–315. 109. Iskhizova LN, Tumanov VP (2003) Dinamika morfologicheskikh izmenenii v tsentral’noi nervnoi sisteme kak kriterii prizhiznennosti termicheskoi travmy. Sud Med Ekspert 46, 7–9

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Trauma

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2 Kicking and Trampling to Death Pathological Features, Biomechanical Mechanisms, and Aspects of Victims and Perpetrators Véronique Henn, MD and Eberhard Lignitz, MD CONTENTS INTRODUCTION PATHOLOGICAL FEATURES BIOMECHANICAL MECHANISMS ASPECTS OF VICTIMS AND PERPETRATORS EPIDEMIOLOGY REFERENCES

SUMMARY Kicking and trampling to death is an entity of violence that increased considerably in the northeastern parts of Germany over the final years of the last century. Most of the injuries are located at the head followed by injuries of inner organs and thoracic bones. More than 50% of victims of kicking and trampling deaths have fractures of the calvaria, skull base, or facial bones. In such cases, subdural and subarachnoidal bleeding, brain contusion, and intracerebral hemorrhage is a frequent cause of death. The frequency of injuries deriving from defensive action is associated with the blood alcohol content (BAC) of the victim. These kinds of injuries are rare when the BAC of the victim is higher than 200 mg/dL, and injuries deriving from defensive action can be found in approximately 52% of the cases where the BAC is lower than 200 mg/dL. The injury pattern deriving from kicking and trampling is highly From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 31

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dependent on the location of the impact. Between the skin of the head and the skull there is only little adipose tissue so that the injury pattern often points out to the used underlying mechanism of violence. On occasion, a sole imprint pattern deriving from the shoe used as a “weapon” can be identified, whereas kicking and trampling to the abdomen can occur without leaving any characteristic morphological signs. Special computerized classification systems may enable the identification of a particular shoe by analyzing sole imprints on the victim’s skin. Kicking as well as punching can be performed with the same energy (350–1200) without dependence on gender. Even kicking with bare feet can lead to fatal injuries. When the head of a victim is kicked, the head can experience a maximum acceleration comparable to that in a frontal car crash at 50 km/h. Many of the victims and perpetrators belong to lower social classes of society. Many of the victims have been repeatedly maltreated in the past and have been used to an environment where violence occurred frequently. In most cases, the offender acts alone. Perpetrators acting in a group are generally younger than offenders acting alone. In many cases with elder offenders, the existence of an intimate relationship between victim and perpetrator can be established. Group dynamics especially can have negative influence on social behavior patterns in these fatalities. In former East Germany, the frequency of killing by kicking and trampling has increased with the frequency of unemployment in specific regions. Key Words: Kicking; trampling; blunt-force injuries; injury pattern; victims; perpetrators.

1. INTRODUCTION In a considerable number of homicide cases, it is difficult to interpret underlying biomechanical mechanisms of blunt force because of the variety of injury patterns. On the one hand, injuries can be so unambiguous that the underlying killing mechanisms of blunt force and the cause of death are obvious. On the other hand, there may be different simultaneous signs of violence that make it hard to determine the exact chronology and significance of injuries and to identify the lethal injury. Detailed analyses of the underlying blunt force mechanisms and the resulting cause of death as well as professional experience are the most important basics for a profound interpretation and reconstruction of such cases. It is necessary to examine the victim and the crime scene as well as the perpetrator, if possible (1). If the history of the case and the circumstances are unknown at the time of autopsy, they have to be elucidated by a thorough analysis of the victim’s injury pattern and the crime scene so that a profile of the perpetrator can be

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created. One should keep in mind that in some instances the kind of violence and injury pattern can be the same in homicides and suicides, respectively. Since the 1900s, we could observe an increase of an unkind and extremely brutal type of external violence leading to death—kicking and trampling. In Germany, this kind of violence as cause of death was described in some case reports as early as in the 1930s. Now the large number of cases makes it possible to present an overview of frequent locations of injuries, injury patterns, causes of death, biomechanical mechanisms, epidemiological aspects as well as scene circumstances, and aspects of victims and perpetrators.

2. PATHOLOGICAL FEATURES 2.1. General Aspects In 1933, Schrader described a case of “kicking to death” (2), which is presented here because of its relevance to the present. The case involved a 25-year-old man who was attacked by political enemies on his way home. Twenty-four hours after being taken to the hospital, the man died from the severe injuries he had sustained. The autopsy revealed the following injuries: . . . numerous lacerations at the back of the head, the bone was uninjured. . . . The findings of considerable importance were detected at the skull. On the right side comminuted fractures of the parietal and temporal bone as well as the lateral parts of the frontal bone were found. Some fracture lines showed a particular ovalshaped arched pattern of 6 to 10 cm in diameter. Other fracture lines reached from this oval-shaped area to the frontal bone. At the base of the skull, fractures of the orbital roof, ethmoidal and right side of the sphenoidal bone were detected. Outcome of autopsy: The injury of the head was caused by kicking with the foot. The ovalshaped fracture lines possibly show the contour of a heel . . . . .

A witness as well as one of the perpetrators declared: “. . . was beaten with a stick and broke down when he tried to run away and received several hits against the back of his head. One of the perpetrators kicked the side of his head when he was lying on the floor.” The quoted findings were described in 1933 and fit exactly the skull fracture shown in Fig. 1, which was seen by the authors in a case of kicking to death that took place in November 2000. Over the last few decades, the frequency of kicking and trampling to death has significantly increased in Germany (3,4). The high number of such cases in the northeastern parts of Germany that we as well as others from different Institutes of Legal Medicine in Germany have studied (Table 1) makes it possible to give an overview of the characteristic findings in such cases.

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Fig. 1. Arched fracture lines on the skull as a result of kicking.

Because most of the victims were in a state of inebriation that alone could have been fatal, only such cases were included where injuries resulting from kicking and trampling were undoubtedly the cause of death (3–7). In all studies, most of the victims were maltreated by kicking and other kinds of violence. In 4.5% (Rostock, former East Germany) and in 17.1% (Hamburg, former West Germany), respectively, sole signs of kicking were present. In some of these cases, the victim fell down after an initial punch and was then kicked by the perpetrator while lying on the ground. The majority of the victims were also punched multiple times or received blows with different kinds of objects. Strangulation and asphyxia caused by the perpetrator sitting or kneeling on the victim’s thorax, stab wounds, and/or cuts were rare in these cases (3,4,8–10).

2.2. Location of Injuries Out of 127 victims of kicking and trampling deaths who were autopsied in Hamburg and Greifswald (former East Germany), 81 (64%)—as well as 11 (50%) out of 22 victims examined in Rostock—showed fractures of the calvaria, skull base, or facial bones. In Hamburg, 63% (22 out of 35), in Greifswald 47% (43 out of 92), and in Rostock 55% (12 out of 22) of the maltreated individuals had injuries of inner organs (including diaphragm and vena cava). Fractures of the thoracic bones were found in 54% of all cases analyzed (Hamburg 54%, Greifswald 53%, and Rostock 59%).

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Table 1 Examined Cases of Kicking and Trampling to Death in Northeastern Parts of Germany That Served as the Database for the Current Review Institute of Legal Medicine

Investigation period

Number of cases studied

1982–1995 1982–2000 1980–1997 1958–2000

35 92 152 143

Hamburg (4,5) Greifswald (4,5,8) Berlin (7,26) Rostock (3)

Note. Reference numbers are given in parentheses.

Trauma to the neck, including fractures of the hyoid bone, laryngeal skeleton, and vertebra, was found in one-third of the cases. Lesions of the genital region could be established in two cases. The distribution of injuries is shown in Fig. 2. Missliwetz and Denk analyzed the autopsy protocols of the Institute of Forensic Medicine in Vienna, Austria over a 10-year period during which 5500 autopsies were carried out. Seventy-six individuals died after being maltreated by punching and/or kicking (10); 60.5% of the victims showed head injuries including subdural bleeding and arteriorrhexis; injuries of thoracic and abdominal organs were registered in 46% of the cases.

2.3. Injury Patterns 2.3.1. Injuries to the Head Injury patterns depend on the location and force applied by kicking or punching (1,11,12). The fact that the head is relatively small when compared to the body makes it impossible to believe the statement of perpetrators at court that they just kicked a person’s body without looking where they hit it. One can consider the head as a preferred “target of choice.” Apart from abrasions and lacerations of the skin, most of the head injuries were fractures of the facial bones as well as of the upper and lower jaw bones. Complications following head trauma were epidural and subdural hemorrhage, subarachnoid bleeding, brain contusion, and/or cerebral hemorrhage (Table 2). Very often, injury patterns of the head can be the conclusive proof of the applied type of violence. Because there is only little fatty tissue and muscles between the skin of the head and the skull, blunt-force trauma often leads to characteristic abrasions of the skin and lacerations (1). After a kick or stomp with a shoe, the skin and subcutis may show contusions that mirror the pattern

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Fig. 2. Distribution of injuries (data based on studies in Hamburg, Greifswald and Rostock, Germany, n = 149).

of the sole of the shoe as well as the contour of the heel (Figs. 3–5). The mechanism that leads to this injury pattern is the same as is known to result from impacts with a baseball bat or a belt (13,14).

2.3.2. Injuries to the Neck Neck injuries can be seen in up to 40.9% of cases (Table 3) and can give important information about the applied violence. Nevertheless, one should not confuse these lesions with those found in homicidal asphyxia and suicidal or accidental hanging. Fractures of the throat skeleton (detected in 19 victims [29%] of the cases investigated in Greifswald) were more frequent in victims of kicking and trampling to death than in victims of ligature strangulation in homicidal asphyxia, where this kind of injury was detected in 12.5% of the cases (15) but less than in victims of suicidal or accidental hanging. In the latter, skeleton fractures were seen by Betz and Eisenmenger in 73 out of 109 autopsy cases (67%) (16). In some cases, injury patterns of the thorax or neck can indicate the type of weapon or in single cases even the kind of shoe used to maltreat the victim. The causative mechanism of the injury pattern can be easily explained by the

Number of cases examined Injuries of the skull Orbita Nasal bone Cheek bone Maxilla Mandible Calvaria Base of the skull Intracranial findings Epidural hemorrhage Subdural hemorrhage Subarachnoidal bleeding Contusion, cerebral hemorrhage

Hamburg 1982–1995

Greifswald 1996–2000

Berlin 1980–1997

Rostock 1982–1995

Rostock (kick + punch) 1958–2000

35

92

152

22

136

2 (5.7%) 4 (11.4%) 3 (8.6%) 8 (22.9%) 7 (20.0%) 5 (14.3%) 6 (17.1%)

14 (15.2%) 23 (25.0%) 11 (12.0%) 9 (9.8%) 8 (8.7%) 8 (8.7%) 10 (10.9%)

39 (25.7%) 14 (9.2%) 14 (9.2%)

3 (13.6%) 5 (22.7%) 3 (13.6%) 2 (9.1%) 2 (9.1%) 3 (13.6%) 6 (27.3%)

14 (10.3%) 29 (21.3%) 19 (14.0%) 11 (8.1%) 13 (9.6%) 43 (31.6%) 51 (37.5%)

13 37.1%) 14 (40.0%)

21 (22.8%) 27 (29.3%) 4 (4.3%) 17 (18.5%)

40 (28.3%) 27 (17.8%) 33 (21.7%)

* * * 10 (45.5%)

13 (9.6%) 63 (46.7%) 69 (51.1%) 73 (54.1%)

8 (22.9%)

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Table 2 Injuries of the Skull and Intracranial Findings in Victims Killed by Kicking, Trampling, and Punching

Note. = these data cannot be compared with those of the other studies; Taymoorian (7) described multiple fractures of facial bones in 10 cases (6.6%). * = 50% of the cases analyzed by Brandt (3) showed epidural and/or subdural hemorrhage.

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Fig. 3. Lacerations of the skin. Injury pattern mirroring a part of the sole of a shoe.

Fig. 4. Laceration of the left eyebrow caused by a kick with a shoe and hematoma on the left part of the forehead outlining the heel of a shoe.

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Fig. 5. Pattern of a shoe on the forehead of a victim.

following case (Figs. 6 and 7): the imprint of the sole of a shoe is visible as a negative mark on the skin. The prominent parts of the sole are seen as pale areas that are surrounded by sharp-edged abrasions and bleedings of the skin. Blood has been forced out of blood vessels and extravasated to neighboring tissue. According to Bodziak, the injury pattern depends on the power of the kick, a fact that should be kept in mind when interpreting the imprint pattern. In case of very powerful kicking, confluence of bleedings can occur so that sole prints are not recognizable (17).

2.3.3. Injuries to the Thorax and Inner Organs Dependent on an individual’s age, the thoracic organs are normally well protected by the ribs. With the increase of age, ribs are more vulnerable because of the decrease of elasticity and possible manifestation of osteoporosis. In Greifswald, only 25% of the victims younger than 21 years who were killed by kicking and/or trampling had fractures of ribs or sternum compared to 46.9% in individuals who were between 21 and 40 years of age and 58.9% in the age group between 41 and 60 years.

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Table 3 Injuries to the Neck in Victims Killed by Kicking, Trampling, and Punching

Number of cases examined Hyoid bone Laryngeal cartilage/bone Fracture of the cervical spine Only soft tissue injuries At least one of the injuries mentioned above

Hamburg 1982–1995

Greifswald 1996–2000

Berlin 1980–1997

Rostock 1982–1995

Rostock (kick + punch) 1958–2000

35

92

152

22

136

9 (25.7%) 7 (20.0%) 0 2 (5.7%) 13 (37.1%)

13 (14.1%) 14 (15.2%) 2 (2.2%) 8 (8.7%) 27 (29.3%)

21 (13.8%) 6 (3.9%)

16 (11.8%) 24 (17.7%) 4 (3.0%) 46 (33.8%)

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Note. = these data cannot be compared with those of the other studies.

2 (9.1%) 5 (22.7%) 3 (13.6%) 2 (9.1%) 9 (40.9%)

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Fig. 6. Injury pattern (sole imprint) on the neck and upper thorax.

Fig. 7. The “weapon”: a sneaker (same case as Fig. 6).

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Kicking and trampling led to multiple rib fractures in one-third of the cases examined in Greifswald. Fractures of ribs in combination with fractures of the sternum were seen in 8.7%. Taking a look at the injuries of inner organs, it is not astonishing that more than 25% of the victims showed ruptures of the liver. Because of its location, this organ is very easily injured. Kicking against the abdomen and especially trampling on a victim who is lying on the ground leads to severe injuries of inner organs (Table 4). In the case of blunt force against the abdomen, characteristic signs can be weak or totally missing (Fig. 8). The external lack of signs of a preceding trauma does not have to lead to the conclusion that there are no severe injuries of inner organs (Fig. 9). Findings from the external examination of the body and autopsy findings have to be documented in detail starting with the description of the victim’s clothing. Multiple layers of clothing as well as thick adipose tissue and muscles can function as a crumple zone so that kicking and/or trampling can be without any external morphological correlate (12), and therefore the clothing may be the only objects to give the death investigator important informations. To document a sole imprint to a scale of 1:1, it can easily be drawn on a transparent film. Another simple method is the photo documentation with a scale next to the lesion. For a more specialized three-dimensional documentation of the injury pattern, serial photographs must be taken of all dimensions with a constant distance between camera and object. The same measurements must be taken of the weapon (e.g., shoe) used. The photographs of injury pattern and weapon can be analyzed by a computer program and matching figures can be established (18). In several countries, computerized footwear classification systems are available. In Switzerland, this system is especially designed for partial footwear impressions (19–22). Though these systems were originally developed for crime scene footwear classification, they may help to identify shoes worn by the perpetrator while kicking a victim by describing the sole pattern using special classification codes. In some cases, overlapping injury patterns caused by kicking can occur. On the one hand, an imprint of the weapon is visible, and on the other hand, the structure of the clothing can be mirrored. Not only injuries of the skin and soft tissue, but also (imprint) fractures of the skull can point to the type of weapon used by the perpetrator.

2.3.4. Injuries Caused by Defensive Action Less than 50% of the victims examined in Greifswald showed injuries caused by defensive action like hematomas at the ulnar region of the forearms

Hamburg 1982–1995

Greifswald 1996–2000

Berlin 1980–1997

Rostock 1982–1995

Rostock (kick + punch) 1958–2000

Number of cases examined

35

92

152

22

136

Injuries of the lungs Rupture of heart Rupture of diaphragm Injury of vena cava Rupture of liver Rupture of spleen Contusion/rupture of kidney Rupture of intestine/bowl Injuries of mesentery

5 (14.3%) 5 (14.3%) 0 0 9 (25.7%) 6 (17.1%) 7 (20.0%) 3 (8.6%) 6 (17.1%)

15 (16.3%) 3 (3.3%) 1 (1.1%) 0 17 (18.5%) 7 (7.6%) 6 (6.5%) 3 (3.3%) 15 (16.3%)

21 (13.8%) 11 (7.2%) 30 (19.7%) 7 (4.6%)

6 (27.3%) 1 (4.5%) 2 (9.1%) 1 (4.5%) 3 (13.6%) 1 (4.5%) 6 (27.3%) 3 (13.6%) 6 (27.3%)

20 (14.7%) 9 (6.6%) 8 (5.9%) 16 (11.8%) 5 (3.7%) 16 (11.8%) 11 (8.1%) 21 (15.4%)

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Table 4 Frequency of Injuries to Inner Organs in Victims Killed by Kicking, Trampling, and Punching

Note. = these data cannot be compared with those of the other studies.

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Fig. 8. Without the knowledge of the details from the witness report, it would have been hard to realize that the small abrasions of the skin were a result of jumping on the victim.

Fig. 9. Rupture of the liver caused by jumping on the victim’s abdomen (same case as Fig. 8).

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Fig. 10. Frequency of injuries deriving from defensive action in dependence on blood alcohol content (BAC).

and hematomas of the upper arms. It is noticeable that only 18% of the victims with a blood alcohol content (BAC) >200 mg/dL showed such injuries, whereas in 52% of the victims with a BAC <200 mg/dL injuries deriving from defensive action were present (Fig. 10).

2.4. Causes of Death As a consequence of the injuries sustained, 42.5% of the victims of kicking and trampling to death examined in Greifswald and Hamburg died of severe external or internal blood loss, in some cases in combination with blood aspiration. Sole blood aspiration as the cause of death was diagnosed in 12.6% of the victims, most of them with trauma to the lungs or skull base fractures. Almost one-third of the victims were transferred to a hospital before they died. Victims with a survival time of several days showed typical late complications like pneumonia and/or malignant cerebral edema. In contrast to the analysis of Hiss et al., who found fatal fat embolisms in 60.4% of victims who had been beaten to death (23), fat embolisms contributing to fatal outcome was detected neither by Brandt or Taymoorian (3,7) nor in our series (6).

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3. BIOMECHANICAL MECHANISMS In cases of tangential violence, the findings depend on the tissue layers above and underneath the skin. The weapon (e.g., shoe) as well as the clothing can cause scale-like excoriations. The shreds of the epidermis can show the direction of violence (24). Bleeding of subcutaneous wounds can occur when the dermis is sheared off the subcutaneous fatty tissue. Depending on the direction of violence, shearing of the skin off the subcutaneous tissue may be seen in different ways, and different wrinkles of the skin may develop if the same area was kicked or punched repeatedly. In 1987, Böhm and Schmidt (25) analyzed the biomechanical mechanism of wrinkling by pressing an acrylic sole against skin that was marked with a set pattern. Because of the transparency of the sole, it was demonstrable that the set pattern was contorted in different ways. Kicking the gluteal region from the side caused a clearly recognizable shift of the set pattern, whereas it was not visible when kicking from above. In cases of kicking in combination with sharp-force violence, it is relatively easy to relate the injury pattern to the type of violence, whereas this can be hard and sometimes impossible when kicking is combined with punching and no sole imprint pattern is visible. In experimental studies, Böhm and Schmidt showed that one can achieve similar power by kicking and punching, respectively (25). They recorded the energy of women and men kicking and punching a “punch-ball” that was connected to a special registration unit. The energy of the most powerful punching by women was between 350 and 550 N, and when men punched, energy between 500 and 850 N was registered. The women reached 500–750 N when kicking. Men kicking the “punch-ball” reached energy between 750 and 1200 N. The results of this experiment were summarized by Böhm and Schmidt in one sentence: “The lowest registered power by kicking and the highest power by punching are overlapping without dependence on gender.” It is suggested that these measured values are surpassed when the offenders are in a state of excitement so that involuntary energy is set free (25). Glißmann (8) used a special registration unit to analyze the acceleration of a dummy’s head that was kicked (the dummy was lying on the ground). The maximum acceleration of the head was 103 Gy, which is comparable to the acceleration of the head in a frontal car crash at 50 km/h. These findings and the study of Taymoorian (7) in which a case of kicking to death bare-footed is described confirm the assumption that kicking, without dependence on the shoe worn by the perpetrator or even when bare-footed, as well as punching, can easily lead to fatal injuries.

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4. ASPECTS OF VICTIMS AND PERPETRATORS 4.1. Victims Most of the victims (68–80%) were male with an average age of 43 years. The female victims were 2–5 years older (3,6,7). In the cases examined in Greifswald and Rostock, all victims were Germans, whereas 11% of the victims investigated in Berlin came from other countries. Half of the victims examined in Greifswald and Hamburg knew their perpetrator prior to the offense. They were integrated in a circle of acquaintances where most of the individuals had severe alcohol problems. Some of them had been in a relationship with each other. These circumstances explain why most of the individuals were maltreated in the apartments of either the victims or the offenders (6,9,26). In most cases, the involved persons, victims as well as perpetrators, were under the influence of alcohol when starting a trivial discussion that led to a severe struggle that ended fatally. In blood samples of the victims, an alcohol content of more than 200 mg/dL was regularly found (3,6,26) and registered in 34.8% of the victims examined in Greifswald; in 9% of the cases, the victims had a BAC below 200 mg/dL but a urine alcohol content (UAC) of more than 200 mg/dL. Many of the victims belonged to the so-called lower social class. They were unemployed and depended on social welfare. They often originated from broken homes where parents were unemployed alcoholics. Many of them had been repeatedly maltreated in the past and could be considered to be used to an environment where violence occurred frequently. The advanced age of the victims, when compared to offenders, and the weakening of the body by alcohol abuse for many years as well as the acute inebriation give reasons for their vulnerability.

4.2. Perpetrators In most cases, the offender acted alone. According to our own studies, the average age of solitary perpetrators is about 30 years and perpetrators who acted in a group are about 22 years old. In many cases with elder offenders, there existed an intimate relationship between victim and perpetrator and both lived under plain or even primitive conditions (5,26). The difference in age between solitary and in-group acting offenders points out that group dynamics can have negative influence on social behavior patterns. On the one hand, the group can encourage a member, e.g., to kick or trample, and on the other hand a group member may act brutal because he or she does not want to be excluded from the group (5).

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In Greifswald and Hamburg, women acted only in groups and never solitarily (4,6), whereas 3.1% of single offenders in Rostock and 9.7% (15 out of 155) of those in Berlin were women (3,26). Strauch et al. reported that 14 of 15 female single offenders had cultivated a friendship or deeper relationship with their victims in the past (26). Many of the offenders had only a poor education and no vocational training, were unemployed, and commonly abused alcohol. In many cases, the perpetrators pointed out during police interrogation that they had been severely drunk at the time of the offense and were unable to control their action. They testified in court their consumption of alcohol during the respective day. According to those statements, they must have had BACs of more than 200 mg/dL at the time of the fight. The inebriation may be the main reason why the perpetrators did not use any weapons. Kicking and punching the victim points toward a spontaneous reaction following a prior verbal argument and “weapons” like fists and feet are always available. In comparison with the cases before 1996 where the main reason for the fight was trivial, it was remarkable that from 1996 to 2000 offenders who acted in groups in Greifswald and environment admitted at court that they maltreated the victim “just for fun” or because “[they] were bored and didn’t know what else to do” or that “[they] thought homeless live off other people, so they deserve this treatment.” The behavioral pattern of the perpetrators is illustrated by the following case report: in summer 2000, a homeless alcoholic came to a village (in former East Germany) close to the Baltic Sea and took a rest behind a church when he was seen by a 24-year-old man who was known to be a Nazi and some juveniles. They hit and kicked the homeless man without prior warning and for no apparent reason and then went to a youth club. There, one of the juveniles bragged about this action and demonstrated blood of the victim on his shoes. A few hours later, after having some beer, they came back and saw that the maltreated man was still alive, smoking a cigarette. Immediately, they started kicking him again, so that the victim didn’t even have the time to shout for help. Later, one of the perpetrators jumped on his thorax. After some time, they left and went home without thinking about the possibility of fatal injuries. The victim died the same night of the severe injuries he had sustained. He was found the next morning. After a short period of investigation the perpetrators were caught. The one known to be a Nazi confessed that he kicked and trampled the man because “homeless people do not fit into our society.” He was already known to the authorities from multiple prior criminal offenses and previous convictions. He lived on social welfare in a municipal housing unit. His criminal career dated back 7 years and

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consisted of nine cases including theft, receiving stolen goods, extortion under threat of force, and grievous bodily harm (kicking and punching someone else’s face).

5. EPIDEMIOLOGY Concerning killing mechanisms, one can see regional special features. In the United States, killing by shooting and in Germany and Austria killing by blunt force occur most frequently (27–29). In the former East Germany, killing by kicking occurs more frequently in regions with a high percentage of unemployment (3). The reason may be the offenders’ inability to socially integrate, their alcohol abuse, and their dissatisfaction with their private conditions. However, recent systematic studies are missing in the literature.

REFERENCES 1. Rao VJ (1986) Patterned injury and its evidentiary value. J Forensic Sci 3, 768–772. 2. Schrader S (1933) Wunde und Werkzeug. Tödliche Schädelverletzung durch Fußtritte. Arch Kriminol 92, 229–231. 3. Brandt AK (2003) Morphologie und Phänomenologie des Totschlagens und Tottretens. Eine Auswertung der Kasuistiken im Einzugsgebiet des Rechtsmedizinischen Instituts der Universität Rostock 1958–1989 versus 1990–2000 sowie vergleichende Darstellung von Kasuistiken des Tottretens im Einzugsbereich des Rostocker und Hamburger/Greifswalder Institutes für Rechtsmedizin 1982–1995. Med. Thesis, University of Rostock, Germany. 4. Henn V, Lignitz E, Philipp KP, Püschel K (2000) Zur Morphologie und Phänomenologie des Tottretens (Teil I). Arch Kriminol 205, 15–24. 5. Henn V, Lignitz E, Philipp KP, Püschel K (2000) Zur Morphologie und Phänomenologie des Tottretens (Teil II). Arch Krimonol 205, 65–74. 6. Henn V, Lignitz E (2003) Tötungsdelikte durch Tritte—Biomechanik, Morphologie, Motivation und Wahl der Opfer. In Häßler F, Rebernig E, Schnoor K, Schläfke D, Fegert JM, eds., Forensische Kinder-, Jugend- und Erwachsenenpsychiatrie. Schattauer, Stuttgart, New York, pp. 112–124. 7. Taymoorian U (2000) Rechtsmedizinische Analyse von Todesfällen durch Treten. Med. Thesis, University Hospital Berlin Charité, Germany. 8. Glißmann C (2002) Wirkung von Fußtritten gegen Kopf und Thorax. Med. Thesis, University of Greifswald, Germany. 9. Graß H, Madea B, Schmidt P, Glenewinkel F (1996) Zur Phänomenologie des Tretens und Tottretens. Arch Kriminol 98, 73–78. 10. Missliwetz J, Denk W (1992) Tod infolge Mißhandlung (durch Faustschläge und Tritte). Rechtsmedizin 3, 19–23. 11. Böhm E (1987) Zur Morphologie und Biomechanik von Trittverletzungen. Beitr Gerichtl Med 45, 319–329.

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12. Taere D (1960/61) Blows with the shod foot. Med Sci Law 1, 429–436. 13. Reh H, Weiler G (1995) Zur Traumatologie des Tottretens. Beitr Gerichtl Med 33, 148–153. 14. Smock WS (2000) Recognition of pattern injuries in domestic violence. In Siegel JA, Saukko PJ, Knupfer GC, eds., Encyclopedia of forensic sciences. Academic Press, San Diego, San Francisco, New York, Boston, London, Sydney, Tokyo, pp. 384–391. 15. DiMaio VJ (2000) Homicidal asphyxia. Am J Forensic Med Pathol 21, 1–4. 16. Betz P, Eisenmenger W (1996) Frequency of throat skeleton fractures in hanging. Am J Forensic Med Pathol 17, 191–193. 17. Bodziak WJ (1990) Footwear impression evidence. Elsevier, New York, Amsterdam, London. 18. Brüschweiler W, Braun M, Fuchser HJ, Dirnhofer R (1997) Photogrammetrische Auswertung von Haut- und Weichteilwunden sowie Knochenverletzungen zur Bestimmung des Tatwerkzeuges - grundlegende Aspekte. Rechtsmedizin 7, 76–83. 19. Alexandre G (1996) Computerized classification of the shoeprints of burglar’s soles. Forensic Sci Int 82, 59–65. 20. Ashley W (1996) What shoe was that? The use of computerized image database to assist in identification. Forensic Sci Int 82, 7–20. 21. Geradts Z, Keijzer J (1996) The image-database REBEZO for shoeprints with developments on automatic classification of shoe outsole designs. Forensic Sci Int 82, 21–31. 22. Mikkonen S, Suominen V, Heinonen P (1996) Use of footwear impressions in crime scene investigations assisted by computerized footwear collection system. Forensic Sci Int 82, 67–79. 23. Hiss J, Kahana T, Kugel Ch (1996) Beaten to death: Why do they die? J Trauma 40, 27–30. 24. Pollak S, Saukko PJ (2000) Blunt injury. In Siegel JA, Saukko PJ, Knupfer GC, eds., Encyclopedia of forensic sciences. Academic Press, San Diego, San Francisco, New York, Boston, London, Sydney, Tokyo, pp. 316–325. 25. Böhm E, Schmidt BU (1987) Kriminelle und kinetische Energie bei Tötungshandlungen durch stumpfe Gewalt. Beitr Gerichtl Med 45, 331–338. 26. Strauch H, Wirth I, Taymoorian U, Geserick G (2001) Kicking to death—forensic and criminological aspects. Forensic Sci Int 123, 165–171. 27. Fischer J, Kleemann WJ, Tröger HD (1994) Types of trauma in cases of homicides. Forensic Sci Int 68, 161–167. 28. Missliwetz J (1990) Tatumstand und Verletzungsbild bei vorsätzlicher Körperverletzung (unter besonderer Berücksichtigung des Waffengebrauchs). Beitr Gerichtl Med 8, 299–307. 29. Murphy GK (1991) “Beaten to death.” An autopsy series of homicidal blunt force injuries. Am J Forensic Med Pathol 12, 98–101.

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3 Timing of Cortical Contusions in Human Brain Injury Morphological Parameters for a Forensic Wound-Age Estimation Roland Hausmann, MD CONTENTS INTRODUCTION MORPHOLOGICAL CHANGES AFTER TRAUMATIC BRAIN INJURY MEDICOLEGAL SIGNIFICANCE REFERENCES

SUMMARY Information on the course of destructive and reactive morphological changes following traumatic brain injury (TBI) is the basis used in forensic wound-age estimation. Several studies have already examined the temporal course of the wound-healing process in the central nervous system (CNS) by use of conventional histological and by enzyme histochemical or immunohistological techniques. The earliest appearance of a parameter is of particular interest as it determines the minimum age of a lesion showing a positive reaction for it. If morphological changes occur regularly during a particular postinfliction interval, the absence of this parameter in an unknown lesion indicates a wound age of less or more than the corresponding time interval established in published series. Cortical contusions are characterized by early morphological changes such as hemorrhages or microscopically visible signs of neuronal degeneration, followed by the phase of local cellular reactions. From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 53

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Immunohistochemical studies on the time-dependent course of the inflammatory response revealed evidence of neutrophil accumulations (CD15) at the lesion site as early as 10 minutes after the injury, whereas different leukocyte subtypes (LCA, UCHL-1, CD3) could be detected first about 1–4 days after the injury. Clearing processes are induced by phagocytic mononuclear cells (macrophages, microglia cells) as early as a few hours but peak during the first week after the trauma. The phase of reactive gliosis is characterized by hypertrophy and proliferation of astroglial cells accompanied by neovascularization and deposition of a dense fibrous glial scar at the lesion site. In addition to the findings of several histological studies using conventional stainings, the demonstration of time-related changes in the astroglial immunoreactivity can provide further information on the age of a cortical contusion. It could be demonstrated that a significantly increased number of glial fibrillary acidic protein-positive astrocytes adjacent to the damaged area indicates a wound age of at least 1 day. Injury-induced glial staining reactions could be observed, at the earliest, after a postinfliction interval of 22 hours for vimentin, 3 hours for _1-antichymotrypsin, and 7 days for tenascin. Regarding the vascular response to brain injury, a significantly increased immunoreactivity could be detected in human cortical contusions after a postinfliction interval of at least 3 hours for factor VIII, after 1.6 days for tenascin, and after 6.8 days for thrombomodulin. Key Words: Human brain injury; cortical contusions; morphological findings; wound-age estimation; forensic histopathology.

1. INTRODUCTION Forensic wound-age estimation is based on the temporal classification of traumatically induced morphological changes, which occur during a certain time after the injury. Each phase of the healing process is characterized by chronological events that tend to overlap but that are sufficiently distinct and can be demonstrated by conventional histological and by enzyme histochemical or immunohistological techniques. The earliest appearance of a particular parameter, as established in systematic investigations, determines the minimum age of the lesion showing a positive reaction for it. If a parameter occurs regularly and consistently within a certain period of time, failure to demonstrate it points to a wound age of less or more than the corresponding time interval already established in published series. The latest known appearance of a particular parameter can be useful for the estimation of advanced wound age, but this criterion is considerably influenced by the initial extent of the wound area and is, therefore, of limited diagnostic value.

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Regarding morphological findings, the following states of the woundhealing process can be differentiated in the central nervous system (CNS): tissue destruction, inflammatory cellular response, macrophage-/microglial reactions, and reactive gliosis/glial scar. The phase of tissue destruction is determined by the mechanical disruption of tissue continuity. This tearing can lead to the local disruption of structures or to vessel lesions resulting in ischemia and/or hemorrhage as well as in neuronal damage. These alterations are followed by an acute inflammatory response owing blood cell reactions (platelets, neutrophils, lymphocytes) as well as by clearing processes, which are performed in general by cerebral macrophages and microglial cells. After clearing necrotic nerve cells and damaged axon material, the phase of reactive gliosis follows next. This is a common phenomenon in the CNS characterized by astrocytic proliferation and extensive hypertrophy of the cell body and cytoplasm, accompanied by angiogenesis and deposition of intermediate filaments, finally forming a glial scar. After briefly reviewing the regular temporal sequence of the woundhealing process in the CNS, the findings of systematic studies dealing with time-dependent changes of morphological parameters after traumatic brain injury (TBI), which can be suitable for a forensic wound age estimation, are presented (1).

2. MORPHOLOGICAL CHANGES AFTER TRAUMATIC BRAIN INJURY 2.1. Cortical Hemorrhages Cortical hemorrhages are the earliest morphological changes in TBI (2). Erythrocytes appear almost immediately in perivascular areas (3–6) and extend into adjacent brain tissue during the next several hours to a maximal accumulation about 24 hours after the injury (3). However, intact red blood cells can be observed up to 5 months postinjury as a result of repeated diapedetic hemorrhages (4,5). Blood plasma is leaking into regions of the brain some distance away, where it gives the appearance of edema. The surrounding nerve cells are damaged by the traumatic event and/or by secondary disturbances (e.g., edema).

2.2. Neuronal Degeneration An early histological sign of neuronal degeneration is “cloudy” swelling of neuronal cells followed by shrinkage, eosinophilia, and nuclear pyknosis (“red neurons”). Because neuronal damage may occur in waves, such morphological changes can be observed at the periphery of lesions for as long as

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5 or 6 months after the initial event. Red neurons may remain in tissue for many years and become mineralized in situ (“ferruginated neurons”). Phagocytosis (neuronophagy) can be observed in some cases between 12 and 24 hours and up to 5 days after the injury (3,4). Laboratory studies have determined that TBI produces loss of cytoskeletal proteins including neurofilaments such as NF68 (7), NF200 (7,8), spectrin (9), or microtubule associated protein 2 (MAP2) (10–13). Furthermore, there is evidence of alterations in NF68, NF300, and MAP2 immunolabeling 3 hours following unilateral cortical injury in rats (7). A review of the literature revealed no data of time-related cytoskeletal changes in human neuronal tissue after brain injury that could be considered for a forensic wound-age estimation. Axonal injury is a consistent feature of traumatic brain lesions in both animal and man (3,14). The first histologically appreciable alteration is the development of swollen axons, “spheroids,” which appear as round to ovoid eosinophilic masses that are argyrophilic. Ultrastructurally, the spheroids represent compactions of organelles, such as neurofilaments, mitochondria, endoplasmatic reticulum, and lysosomes (15). Swollen and ballooned axons can be found in and around the contusion but also at great distances from it (diffuse axonal injury). Such histological changes have been observed between 24 and 48 hours after the injury. They may persist, wherever found, for many years in the neuronal tissue (3). Oehmichen et al. (16,17) investigated a forensic-neuropathological case material in order to determine the significance of diffuse axonal injury (DAI), which was demonstrated by immunohistochemical detection of the expression of `-amyloid precursor protein (`-APP). This method has proved to be both sensitive and highly specific (18,19) since `-amyloid is a neuronal glycoprotein conveyed by rapid anterograde transport (20), that accumulates at the lesion site as a result of traumatically induced alterations in the axoplasmic transport. DAI could be detected in the majority of cases with TBI surviving for 3 hours or more, whereas experimental studies in animals revealed evidence of `-APP as early as 105 minutes (21) or 120 minutes (16,22) after the injury. Recently, the `-APP binding protein FE65 was identified (23), and it could be demonstrated by use of a real-time polymerase chain reaction (PCR) in a rat model that FE65 expression increases dramatically as early as 30 minutes after injury and decreases after peaking 1 hour after the injury (24).

2.3. Inflammatory Cellular Response Comparatively few reports exist on the course of the inflammatory cellular response to cortical contusions in human brain tissue and in animals. In

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contrast to peripheral tissue, the cellular reaction in the CNS was found to be characterized by a minimal neutrophil exudation and a delayed increase in mononuclear cell numbers (25–27). Protective mechanisms of the CNS parenchyma, such as the presence of the blood–brain barrier and the specialized nature of the cerebral endothelium or the downregulated microglial activity might be responsible for this comparably late inflammatory response in the brain (25). Concerning the velocity of leukodiapedesis, varying results have been reported in the literature. According to the findings of experimental studies in rats, early neutrophil accumulation within the first 24 hours after TBI, as measured by myeloperoxidase activity, was thought to indicate the beginning of the inflammatory reaction (28-31). Histological investigations of experimental brain injuries, however, revealed no relevant granulocytic recruitment (25,26,32), whereas in other morphological studies some polymorphonuclear (PMN) neutrophils were detectable in damaged cortex 4 hours after the trauma (33). PMN neutrophil infiltrations adjacent to the necrotic neuronal parenchyma of rats were present earliest at Day 2 and decreased further with time (33). In human brain tissue PMN neutrophils have been found within a few hours after the injury (3,4,34,35). In contrast, a rather early leukocytic reaction adjacent to the damaged cortex could be found by immunohistochemical staining (36): CD15-labeled granulocytes (Fig. 1A) were found earliest in a cortical lesion with a postinfliction interval of 10 minutes. Maximal cell numbers occurred within the first 2 days after human brain injury and according to other studies infiltrations were visible up to a postinfliction interval of 4 weeks (3,32). With regard to the mononuclear cellular response in human brain injury, a diffuse lymphoid reaction could be detected 3 or 4 days at the earliest (3,4) and up to a postinfliction interval of 44 years (4). In experimental brain contusions, an inflammatory mononuclear cell response was evident on Day 2 with a maximum on Days 5 and 6, and signs still remained 16 days after the trauma. The majority of these inflammatory cells has immunohistochemically proved to be activated T cells that may have receptormediated cytotoxic or modulating effects on cells in the CNS (26,37). In accordance to these experimental findings, mononuclear cell reactions could also be demonstrated in human cortical contusions (36): significantly increased numbers of T cells labeled by CD 3 (Fig. 1B) were detectable adjacent to cortical lesions after a posttraumatic interval of at least 2 days. UCHL-1 positive lymphocytes (Fig. 1C) occurred 3.7 days after the trauma at the earliest and the leukocyte common antigen showed a positive reaction in traumatically injured brain lesions with a wound age of at least 1.1 day.

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Fig. 1. Inflammatory cellular response to human brain injury. (A) CD15 positively stained polymorphonuclear neutrophils adjacent to damaged neuronal parenchyma in a cortical contusion with a postinfliction interval of 1.3 days. (B) Mononuclear leukocytes showing a positive reaction with the CD3 antibody in a cortical lesion 10 days after the injury. (C) UCHL-1 positive lymphocytes in a cortical contusion with a wound age of 12 days.

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2.4. Macrophage–Microglial Reactions In recent years, it has been recognized that the major component of the response to nerve injury derives from microglia cells and macrophages (32). Cerebral macrophages were first described by Nissl (38) and extensively evaluated by Rio-Hortega (39). Today it is widely accepted that this cell type is ontogenetically related to the monocytic lineage (40,41) and invades the CNS during fetal development. Microglia, the resident macrophages of the CNS, take on an activated phenotype: the typical ramified microglial cells adopt an amoeboid form, thus they cannot be discriminated from infiltrating monocytes (42,43). Furthermore, there is evidence that activated microglia upregulates its expression via cell surface antigen molecules, such as the leukocyte common antigen vimentin (44), CD4 (32,45,46), and the major histocompatibility (MHC) antigens class I and class II (47,48). Because the distribution as well as the number and functional state of cerebral macrophages depends on the survival period, information on the course of morphological and immunological features after tissue destruction can contribute to a forensic wound-age estimation. Conventional histological studies revealed varying results concerning the temporal appearance of brain macrophages in cortical lesions: some authors observed cerebral macrophages as early as a few hours after the injury (3,49,50). On the other hand, a significant macrophage reaction has been reported 12–14 hours (4,34) or 1–2 days (51–53) after the injury at the earliest. A further classification of cerebral macrophages according to the different kind of incorporated material can also be useful for estimating the age of a traumatic brain lesion. Macrophages containing hemosiderin (siderophages) have been found in cortical lesions in cases with survival periods of at least 2–5 days (3,54–60) whereas the non-iron-containing pigment hematoidin was detectable 1–2 weeks after the injury at the earliest (3,55,60). Macrophages showing fatty granules could be observed 3 days after the trauma (55). The macrophage activity in traumatically injured human brain was extensively investigated by Oehmichen et al. (34). The authors described intracellular lipid deposits as early as 24 hours and regularly 5–6 days after the trauma. The minimal survival period was 10 days for the appearance of anisotropic lipids (cholesterol), 16 days for erythrophages, 71 hours for siderophages, 13 days for hematoidin, and 101 hours for ceroid. Regarding the time-dependent immunoreactivity of cerebral macrophages some experimental studies in animals demonstrated elevated numbers of acetylated low-density lipoprotein expressing microglia cells at the earliest 5–8 hours after TBI in rats (61). Two days after trauma, a positive immunoreactivity could

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be observed for MHC I (62,63) as well as for MHC II and ED1 and ED2 (26). In damaged rat brain with a wound age of at least 3 days, microglia cells were positive for OX42 (64). However, the data of such experimental studies cannot easily be used for a wound-age estimation under forensic aspects. But there are only few reports concerning the immunoreactivity of cerebral macrophages in human brain: Meyermann et al. (42) investigated neuronal tissue from 17 patients with a wound age ranging between 6 hours and 6 months. According to the results of this study, microglia cells express HAM-56, MRP-8, and MRP-14 after a delay of more than 72 hours after trauma. The authors noted that the expression of these antigens did not correlate with proliferation, as they could not find a nuclear MIB-1 labeling. In contrast to these findings, a study of this author including 104 individuals with blunt head injuries revealed evidence of MIB-1-positive macrophages in a certain phase of the woundhealing process (65). The earliest nuclear MIB-1 staining reaction could be observed in a cortical contusion with a wound age of about 3 days and in the posttraumatic interval between 7 and 11 days all cases showed MIB-1-positive cells adjacent to the damaged area (Fig. 2A). Furthermore, numerous large round-shaped glial cells that showed a positive immunoreactivity for vimentin could be detected regularly in cortical lesions 1–4 weeks after the injury (Fig. 2B).

2.5. Reactive Gliosis and Glial Scar Reactive gliosis is a common phenomenon in the CNS following tissue destruction, characterized by hypertrophy and proliferation of astroglial cells accompanied by neovascularization and deposition of a dense fibrous glial/ meningeal scar at the lesion site (66). Time-dependent histological changes of glial cells after traumatic injury to human brain have been investigated by Eisenmenger (55). A diminished stainability of oliogodendro and astroglia cells as a result of tissue edema could be observed within 10 minutes after the injury and 12–14 hours after the injury a swelling of the cell nuclei was obvious. Furthermore, the author reported a proliferative activity of glial cells in cortical lesions with a wound age of at least 3–4 days. After a postinfliction interval of 9 days, large round-shaped glial cells appeared at the lesion site. Colmant (67) observed protoplasmic astrocytes for the first time 24 hours after brain damage. Fibrillary astrocytes as well as progressive alterations (e.g., increase in capillaries, fibroblasts, and collagenous fibers) could be detected in damaged brain tissue with a wound age of at least 4–6 days (5,58) or 1 week (3). Further information on the course of reactive gliosis following brain injury was obtained by immunohistological staining of astrocytes, which have been demonstrated to play an important role in the healing phase after tissue

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Fig. 2. Macrophage–microglial reactions 10 days after traumatic brain injury. (A) Macrophages showing a positive nuclear staining for MIB-1 adjacent to the damaged cortical tissue. (B) Numerous large round-shaped glial cells positive for vimentin at the lesion site.

destruction by actively monitoring and controlling the molecular and ionic contents of the extracellular space of the CNS (69). Astrogliosis is characterized by a rapid synthesis of intermediate filaments, finally forming a glial scar (70). As the glial fibrillary acidic protein (GFAP) was found to be the major component of glial filaments (70,71), reactive astrocytes have been most commonly demonstrated by immunohistochemistry using specific antibodies to this protein. Increasing numbers of GFAP-positive astroglial cells following TBI have been described in several experimental studies in animals. Li et al.

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(72) found elevated numbers of GFAP-positive astrocytes at the earliest 4 hours after injury at the impact site in a fluid-percussion model in cats. Other authors observed an astroglial immunocytochemical response in cortical lesions after a postinfliction interval of at least 1 (73,74), 2 (75-77), 3 (78,79), or 5 days (80). These data correlate with an elevation in GFAP gene expression (mRNA) which could be detected in response to mild cortical contusions in animals (80). The increase in GFAP staining can result either from dissociation of glial filament bundles owing to edema or as a result of increase in GFAP synthesis (71) or by fibrous astrocytes which are thought to derive from protoplasmatic astrocytes of the gray matter (II–VI layers) without cell division (80). On the other hand, it could be demonstrated that GFAP-containing astrocytes located in the molecular layer (I) of the cortex and the white matter have the capacity to proliferate after trauma (77). In addition to these experimental models, our own studies examined the course of GFAP expression during the wound-healing process in human brain tissue under forensic aspects (81). The material investigated was brain tissue with macroscopically visible cortical contusions from 104 individuals who had sustained closed head injury. The survival periods ranged between a few minutes and 30 weeks. With regard to the presence of GFAP-positive astrocytes in normal brain tissue, a morphometrical analysis has been performed to obtain reliable information on chronological changes in absolute cell numbers following the brain injury. Compared to the average cell numbers in uninjured brain regions, the GFAP immunoreactivity was significantly increased 1 day after the injury at the earliest and remained elevated up to 4 weeks in all cases (Fig. 3A). As various other molecules have been shown to be modulated in glial cells after injury in experimental studies, time-related changes in astroglial immunoreactivity for vimentin, tenascin, and _1-antichymotrypsin (_1-ACT) were investigated in the above-mentioned human material (82). Vimentin is a major cytoskeletal component in the immature glia. It is considered to be expressed by radial glia and immature astrocytes in the early phase of the development of the CNS and is replaced by GFAP during maturation (76). Adult astrocytes appear to recover the capacity to express vimentin. Furthermore, the coexpression of GFAP and vimentin by reactive astrocytes has been described in experimental models during the first two postlesional weeks (83). Other authors found vimentin-positive astrocytes 5 (80) or 7 days (84) after injury at the earliest. In accordance with these data, our study demonstrated elevated astroglial vimentin expression in cortical lesions with a wound age of at least 6 days and up to 4 weeks after trauma (Fig. 3B).

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Fig. 3. Reactive gliosis. (A) Increased numbers of GFAP-labeled astrocytes adjacent to a cortical contusion with a postinfliction interval of 11 days. (B) Elevated astroglial vimentin expression surrounding the damaged area of a cortical lesion with a wound age of 13 days. (C) Intensive tenascin reactivity of proliferating blood vessels at the edge of a cortical contusion spreading into the damaged tissue 2 weeks after blunt brain injury.

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Tenascin is an extracellular matrix protein that is synthesized and released by immature astrocytes during embryonic and early postnatal development of the CNS (33,85–89). Whereas in the adult nervous system, tenascin can be detected only at very low levels, it has been shown that stab wounds to adult mouse cerebellar and cerebral cortices resulted in an enhanced expression of tenascin in a discrete region around the lesion site that is associated with subsets of GFAP-positive astrocytes (90,91). In the human brain, localized upregulation of tenascin was demonstrated by Brodkey et al. (90). The authors described a dense tenascin immunostaining in extracellular areas as well as some cellular staining (presumably astrocytes), which was located around a gunshot wound with a survival time of 96 hours. In accordance with these findings, tenascin could not be detected in uninjured human brain tissue in our study (82). Increased tenascin expression was, however, evident following brain injury, and about 75% of cases with cortical lesions aged between 7 and 14 days showed a distinct staining of glial cells exclusively located around the damaged area. As described in the literature, the tenascin-positive glial cells were associated with GFAP-positive astrocytes at the lesion site. The findings suggested that tenascin upregulation in the injured adult brain may be directly involved in failed regeneration or indirectly involved through interaction with other glycoconjugates that either inhibit or facilitate neurite growth, as discussed by Laywell et al. (91). The serine protease inhibitor _1-ACT is an acute phase protein that is present in the amyloid plaques that form the pathologic hallmark of Alzheimer’s disease (AD) (92–94). Studies using in situ hybridization indicated that _1ACT found in AD plaques is produced primarily by astrocytes (20,95). Reactive astrocytes expressing _1-ACT have also been found in other neurologic diseases, including Huntington’s chorea, Parkinson’s disease, and ischemic infarction of the brain (96). Recently, it was demonstrated that the expression of _1-ACT by reactive astrocytes can also be induced acutely in mice by focal injury (92). This finding was confirmed by the immunohistological investigations of our human material, where _1-ACT-positive glial cells were observed 3 hours after the trauma at the earliest (82). In the postinfliction interval, ranging between 1 and 13 days, the majority of cases (about 69%) were positive for _1-ACT. These results support the assumption that increased _1-ACT expression may represent a consistent component of the astroglial response to neural injury (92). Some further antibodies have been employed in order to investigate early posttraumatic reactions of astrocytes after experimental brain trauma in animals: Li et al. reported a decrease of the neuron-specific enolase 1–2 hours

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after the injury using a fluid-percussion model in cats, whereas significant changes in the S-100 protein-staining reaction could not be observed (72). Other studies revealed that S-100-positive reactive astrocytes proliferated in mouse cerebral cortex at 3–4 days after stabbing (97-99). Recently it has been reported that a rapid alteration in the cellular distribution of apoliprotein E (apoE) is induced in astrocytes and neurons 2 hours after human brain injury. These findings were thought to reflect a role for apoE in neuronal restoration and reorganization (100). The new formation of blood vessels is a common but not specific phenomenon following TBI. Proliferating capillaries at the lesion site, partly spreading into damaged areas, can be observed histologically during the first week after the trauma (4,35,55,68). Further data on the time course of the vascular response to human brain trauma could be obtained by investigating the immunoreactivity of blood vessels for laminin, type IV collagen, tenascin, thrombomodulin, and factor VIII in cortical contusions from 104 individuals who had sustained blunt head injury (101). Compared to the immunoreactivity in unaltered control tissue, a significantly increased vascular expression could be detected in cortical contusions after a postinfliction interval of at least 3 hours for factor VIII, after 1.6 days for tenascin (Fig. 3C), and after 6.8 days for thrombomodulin, respectively, whereas the immunostaining for laminin and type IV collagene was regularly positive even in the vascular endothelium of uninjured brain tissue. Proliferative processes in the CNS have shown to be regulated by different types of growth factors such as fibroblast growth factor (102), plateletderived growth factor (103), nerve growth factor (104) or transforming growth factor ` (105). The expression of these factors was temporarily induced after experimental TBI in animals (106–109). However, a review of the literature revealed no data deriving from human brain tissue that could be suitable for a forensic wound-age estimation.

3. MEDICOLEGAL SIGNIFICANCE The value of a morphological parameter for forensic wound age estimation essentially depends on its unambiguous and consistent evidence during a certain phase of the healing process as well as on the absence of artificial changes (e.g., background staining in immunohistochemical slides). Positive findings are of particular diagnostic value and the earliest appearance of this parameter determines the minimal age of a traumatic lesion. Negative staining results can provide information if the regular appearance of the parameter has been well established by the systematic evaluation of a sufficient number of

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Hausmann Table 1 Earliest Appearance/Observation Period of Parameters for the Age Estimation of Cortical Lesions Detectable in Routine Histology

Cellular response Erythrocytes Neutrophils (PMN)

Lymphocytes Macrophages

Hemosiderophages

Hematoidin

Lipophages

Earliest appearance/ Observation period

References

0–5 months >2 hours 130 minutes–28 days >4 hours >12 hours >3/4 days 3/4 days 71 hours–44 years few hours >4 hours >6 hours >12 hours 14 hours–58 years >24 hours >48 hours >48 hours 71 hours–44 years >3 days 3/4 days >4 days >4–5 days >5 days >6 days >11 days 10–12 days 12 days–12 months 24 hours >3 days

4–6 5 4 33 27 55 3 4 3 50 49 39 4 52,53 51 58,60 4 56 3 59 55 57 60 55 3 4 34 55

Traumatic Brain Injury Neuronal changes Degeneration, shrinkage

Vacuols Incrustation Axonal swelling

Neuronophagy

Glial changes Edematous swelling Diminished stainability Nuclear swelling Glial proliferation Protoplasmic astrocytes Siderin-containing astrocytes Fibrillary astrocytes

Mesenchymal changes Edema Vascular proliferation

Fibroblasts/fibrocytes

Collagen fibers Note. Modified from ref. 1.

67 Earliest appearance/ Observation period Immediately after the injury Immediately after the injury up to 5–6 months Immediately after the injury 1–3 hours 10–20 hours 24–48 hours 31 hours–28 years 12–24 hours–5 days 14 hours–5 days Earliest appearance/ Observation period Immediately after the injury >10 minutes 12–24 hours 3–4 days >24 hours 101 hours >5–6 days 8 days 6 days 7–10 days >26 days

References 4,5 3 55 55 67 3 4 3 4

References 55 55 55 55 67 4 55 4 4 3 55

Earliest appearance/ Observation period

References

0–9 days >12–24 hours 94 hours–31 years 4–6 days 5–7 days 4–6 days 6 days–8 months 1 week 4–6 days 9 days–58 years

4 55 4 35,58,68 3 35,55,58,68 4 3 35,55,58,68 4

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Hausmann Table 2 Earliest and Frequent Appearance of Immunohiostochemically Detectable Parameters Useful for the Timing of Cortical Contusions

Antigen

Earliest appearance

Routine appearance

Cellular reaction CD15 LCA CD3 UCHL-1

10 minutes 1.1 days 2 days 3.7 days

14 hours–1.6 days 9–21 days 13.3–19 days 10–19 days

Reactive gliosis _1-ACT Vimentin GFAP MIB-1 Tenascin

3.1 hours 22 hours 1 day 3.1 days 7 days

— 5.5 days–4 weeks 1–4 weeks 7–11 days —

Vascular reactions F VIII Tenascin Thrombomodulin MIB-1

3 hours 1.6 days 6.8 days 1 week

6 days–4 weeks 1–4 weeks 1–2 weeks 1–2 weeks

cases with well-known wound ages. Some of the morphological parameters such as GFAP have been demonstrated also in uninjured brain tissue. Thus, a quantitative (morphometrical) analysis is required in order to get reliable information on trauma-induced changes in immunoreactivity. Furthermore, it should be noted that the majority of the presented parameters is not specific for brain trauma but may also occur under pathological conditions such as ischemia, toxic lesions, encephalomyelitis, or brain tumors. Finally, the data obtained in experimental studies using different animal models of TBI cannot easily be transferred to the human brain response. Taking these aspects into consideration, the data in Tables 1 and 2 can be used for estimating the age of cortical contusions in forensic autopsy cases.

REFERENCES 1. Hausmann R (2002) Die Altersbestimmung von Hirnkontusionen bei gedecktem Schädel-Hirn-Trauma des Menschen. Arbeitsmethoden der medizinischen und naturwissenschaftlichen Kriminalistik. Schmidt-Römhild, Lübeck.

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2. Spatz H (1951) Von der Morphologie der Gehirnkontusionen (besonders der Rindenprellungsherde). Münch Med Wschr 93, 1. 3. Cervós-Navarro J, Lafuente JV (1991) Traumatic brain injuries: structural changes. J Neurol Sci 103, 3–14. 4. Oehmichen M, Raff G (1980) Timing of cortical contusion. Correlation between histomorphological alterations and post-traumatic interval. Z Rechtsmed 84, 79–94. 5. Peters G (1943) Über gedeckte Gehirnverletzungen (Rindenkontusionen) im Tierversuch. Zentralbl Neurochir 8, 172–208. 6. Unterharnscheidt F (1963) Die gedeckten Schäden des Gehirns. Experimentelle Untersuchungen mit einmaliger, wiederholter und gehäufter Gewalteinwirkung auf den Schädel. Monographien aus dem Gesamtgebiet der Neurologie und Psychiatrie, Heft 103. Springer, Berlin, Göttingen, Heidelberg. 7. Postmantur RM, Hayes RL, Dixon CE, Taft WC (1994) Neurofilament 68 and neurofilament 200 decrease after traumatic brain injury (TBI). J Neurotrauma 11, 533–545. 8. Huh JW, Laurer HL, Raghupathi R, Helfaer MA, Saatman KE (2002) Rapid loss and partial recovery of neurofilament immunostaining following focal brain injury in mice. Exp Neurol 175, 198–208. 9. Saatman KE, Bozyczko-Coyne D, Marcy V, Siman R, McIntosh TK (1996) Prolonged calpain-mediated spectrin breakdown occurs regionally following experimental brain injury in the rat. J Neuropathol Exp Neurol 55, 850–860. 10. Hicks RR, Smith DH, McIntosh TK (1995) Temporal response and effects of excitatory amino acid antagonism on microtubule-associated protein 2 immunoreactivity following experimental brain injury in rats. Brain Res 678, 151–160. 11. Taft WC, Yang K, Dixon CE, Clifton GL, Hayes RL (1993) Hypothermia attenuates the loss of hippocampal microtubule-associated protein 2 (MAP2) following traumatic brain injury. J Cereb Blood Flow Metab 13, 796–802. 12. Taft WC, Yang K, Dixon CE, Hayes RL (1992) Microtubule-associated protein 2 levels decrease in hippocampus following traumatic brain injury. J Neurotrauma 9, 281–290. 13. Postmantur RM, Kampfl A, Liu SJ, Heck K, Taft WC, Clifton GL, et al. (1996) Cytoskeletal derangements of cortical neuronal processes three hours after traumatic brain injury in rats: an immunofluorescence study. J Neuropath Experimental Neurol 55, 68–80. 14. Povlishock JT (1997) The pathogenesis and implications of axonal injury in traumatically injured animal and human brain. In Oehmichen M, König HG, eds., Neurotraumatology: Biomechanic aspects, cytologic and molecular mechanisms. Schmidt-Römhild, Lübeck, pp. 175–185. 15. Bresnahan, JC (1978) An electron microscopic analysis of axonal alterations following blunt contusion of the spinal cord of the rhesus monkey (Macaca mulatta). J Neurol Sci 37, 59–812. 16. Oehmichen M, Meißner C, Schmidt V, Pedal I, König HG (1997) Axonal injury (AI) in a forensic-neuropathological material. In Oehmichen M, König HG, eds., Neurotraumatology: Biomechanic aspects, cytologic and molecular mechanisms. Schmidt-Römhild, Lübeck, pp. 203–224.

70

Hausmann

17. Oehmichen M, Meißner C, Schmidt V, Pedal I, König HG, Saternus KS (1998) Axonal injury - A diagnostic tool in forensic neuropathology? A Review. Forensic Sci Int 95, 67–83. 18. Gentleman SM, Nash AJ, Sweeting CJ, Graham DI, Roberts GW (1993) `-Amyloid precursor protein (`-APP) as a marker of axonal injury in traumatic brain injury. Neuroscience Letters 160, 139–144. 19. Sheriff FE, Bridges LR, Sivaloganatham S (1994) Early detection of axonal injury after human head trauma using immunocytochemistry for `-amyloid protein. Acta Neuropathol 87, 55–62. 20. Koo EH, Sisoda SS, Archer DR (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A 87, 1561–1565. 21. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ (1995) Topography of axonal injury as defined by amyloid precursor protein and the sector scoring method in mild and severe closed head injury. J Neurotrauma 12, 656–571. 22. McKenzie KJ, McLellan DR, Gentleman SM, Maxwell WL, Gennarelli TA, Graham DI (1996) Is `-APP a marker of axonal damage in short-surviving head injury? Acta Neuropathol 92, 608–613. 23. Russo T, Faraonio R, Minopoli G, De Candia P, Renzis SD, Zambrano N (1998) FE65 and the protein network centered around the cytosolic domain of the Alzheimer’s `-amyloid precursor protein. FEBS Lett 434, 1–7. 24. Iino M, Nakatome M, Ogura Y, Fujimura H, Kuroki H, Inoue H, et al. (2003) Realtime PCR quantitation of FE65 a `-amyloid precursor protein-binding protein after traumatic brain injury in rats. Int J Legal Med 117, 153–159. 25. Andersson PB, Perry VH, Gordon S (1992) The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues. Neuroscience 48, 169–186. 26. Holmin S, Mathiesen T, Shetye J, Biberfeld P (1995) Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir Wien 132, 110–119. 27. Persson L (1976) Cellular reaction to small cerebral stab wounds in the rat frontal lobe. An ultrastructural study. Virch Arch B Cell Pathol Mol Pathol 22, 21–37. 28. Biagas KV, Uhl MW, Schiding JK, Nemoto EM, Kochanek PM (1992) Assessment of posttraumatic polymorphonuclear leucocyte accumulation in rat brain using tissue myeloperoxidase assay and vinblastin treatment. J Neurotrauma 4, 363–371. 29. Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM (1994) Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact model. J Neurotrauma 11, 499–506. 30. Horner HC, Setler PE, Fritz LC, Hines D (1992) Characterization of leucocyte infiltration in traumatic brain injury in the rat. Soc Neurosci Abstr 18, 173. 31. Schoettler RJ, Kochanek PM, Magargee MJ, Uhl MW, Nemoto EM (1990) Early polymorphonuclear leucocyte accumulation correlates with development of posttraumatic cerebral edema in rats. J Neurotrauma 7, 207–217.

Traumatic Brain Injury

71

32. Perry VH, Andersson PB, Gordon S (1993) Macrophages and inflammation in the central nervous system. Trends Neurosci 16, 268–273. 33. Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F (1993) Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of preand post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. J Neuroimmunol 42, 177–186. 34. Oehmichen M, Eisenmenger W, Raff G, Berghaus G (1986) Brain macrophages in human cortical contusions as an indicator of survival period. Forensic Sci Int 30, 281–301. 35. Peters (1955) Die gedeckten Gehirn- und Rückenmarkverletzungen. In Lubarsch O, Henke F, Rössle R, eds., Handbuch der speziellen pathologischen Anatomie und Histologie, vol. XIII/3. In Scholz W, ed., Nervensystem. Springer, Berlin Göttingen Heidelberg, pp. 84–94. 36. Hausmann R, Kaiser A, Lang C, Bohnert M, Betz P (1999) A quantitative immunohistochemical study on the time-dependent course of acute inflammatory cellular response to human brain injury. Int J Legal Med 112, 227–232. 37. Wekerle H, Linington C, Lassman H (1986) Cellular immune reactivity within the CNS. Trends Neurosci 9, 271–277. 38. Nissl F (1899) Über einige Beziehungen zwischen Nervenzellerkrankungen und gliösen Erscheinungen bei verschiedenen Psychosen. Arch Psych 32, 1–21. 39. Rio-Hortega P (1932) Microglia. In Penfield W, ed., Cytology and cellular pathology of the nervous system. Paul P Hocker, New York, pp. 481–584. 40. Oehmichen M (1974) Cytokinetic studies on the origin of the cells of the cerebrospinal fluid. J Neurol Sci 22, 165–176. 41. Oehmichen M (1982) Functional properties of microglia. In Smith WT, Cavanagh JB, eds., Recent advances in neuropathology, vol. 2. Churchill Livingstone, Edinburgh, London, New York, pp. 83–107. 42. Meyermann R, Engel S, Wehner HD, Schlüsener HJ (1997) Microglial reactions in severe closed head injury. In Oehmichen M, König HG, eds., Neurotraumatology: biomechanic aspects, cytologic and molecular mechanisms. Schmidt-Römhild, Lübeck, pp. 261–278. 43. Suzumura A, Marunouchi T, Yamamoto H (1991) Morphological transformation of microglia in vitro. Brain Res 545, 301–306. 44. Graeber MB, von Eitzen U, Grasbon-Frodl E, Egensperger R, Kösel S (1997) Microglia: a sensor of pathology in the human CNS. In Oehmichen M, König HG, eds., Neurotraumatology: biomechanic aspects, cytologic and molecular mechanisms. Schmidt-Römhild, Lübeck, pp. 239–259. 45. Akiyama H, McGeer PL (1990) Brain microglia constitutively express `-2 integrins. J Neuroimmunol 30, 81–93. 46. Perry VH, Brown MC, Gordon S (1987) The macrophage response to central and peripheral nerve injury. J Exp Med 165, 1218–1223. 47. Hayes GM, Woodroofe MN, Cuzner ML (1987) Microglia are the major cell type expression MHC II in human white matter. J Neurol Sci 80, 25–37.

72

Hausmann

48. Steininger B, van de Meide PH (1988) Rat ependyma and microglia cells express class II MHC antigens after intravenous infusion of recombinant gamma interferon. J Neuroimmunol 19, 111–118. 49. Carmichael AE (1929) Microglia: an experimental study in rabbits after intracerebral injection of blood. J Neurol Psychopathol 9, 209–216. 50. Hammes EM (1944) Reaction of the meninges to blood. Arch Neurol Psychiat 52, 505–514. 51. Macklin CC, Macklin MT (1920) A study of brain repair in the rat by use of trypan blue, with special reference to the vital staining of the macrophages. Arch Neurol Psychiat (Chic) 3, 353–393. 52. Masuda Y (1969) Histological and histochemical study of cortical lesion of brain with special reference to the alteration in compressed area. Jap J Leg Med 23, 139–169. 53. Nevin NC (1967) Neuropathological changes in white matter following head injury. J Neuropath Exp Neurol 26, 77–84. 54. Baggenstoss AH, Kernohan JW, Drapiewski JF (1943) The healing process in wounds of the brain. Am J Clin Pathol 13, 333–348. 55. Eisenmenger W (1977) Zur histologischen und histochemischen Altersbestimmung gedeckter Hirnrindenverletzungen. Med. Habil., München. 56. Hallermann W, Illchmann-Christ D (1943) Über eigenartige Strangulationsbefunde. Z Ges Gerichtl Med 38, 97–128. 57. Krauland W (1973) Über die Zeitbestimmung von Schädelhirnverletzungen. Beitr Gerichtl Med 30, 226–251. 58. Lindenberg R, Freytag E (1957) Morphology of cortical contusions. Arch Pathol 63, 23–42. 59. Rautenbach M (1968) Der diagnostische Wert liquorzytologischer Untersuchungen bei perinatalen Hirnblutungen. Wiss Z Humboldt-Univers Math Nat R 17, 552–553. 60. Strassmann G (1949) Formation of hemosiderin after traumatic and spontaneous cerebral hemorrhages. Arch Pathol (Chic) 47, 205–210. 61. Giulian D, Chen J, Ingeman JE, George JK, Noponen M (1989) The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J Neurosci 9, 4416–4429. 62. Hogan B (1981) Laminin and epithelial cell attachement. Nature 290, 737–738. 63. Moffett CW, Paden CM (1994) Microglia in the rat neurohypophysis increase expression of class I major histocompatibility antigens following central nervous system injury. J Neuroimmunol 50, 139–151. 64. Aihara N, Hall JJ, Pitts LH, Fukuda K, Noble LJ (1995) Altered immunoexpression of microglia and macrophages after mild head injury. J Neurotrauma 12, 53–63. 65. Hausmann R, Betz P (2002) The course of MIB-1 expression by cerebral macrophages following human brain injury. Legal Med 4, 79–83. 66. Eisenmenger W, Nerlich A, Glück G (1988) Die Bedeutung des Kollagens bei der Wundaltersbestimmung. Z Rechtsmed 100, 79–100. 67. Colmant HJ (1962) Enzymhistochemische Befunde an der elektiven Parenchymnekrose des Rattengehirns. In Jakob H, ed., IV. Int Kongr Neuropathol, München, Vol. 1. Thieme, Stuttgart, pp. 89–95.

Traumatic Brain Injury

73

68. Sellier K, Unterharnscheidt F (1963) Mechanik und Pathomorphologie der Hirnschäden nach stumpfer Gewalteinwirkung auf den Schädel. Hefte Unfallheilkd, Heft 76. Springer, Berlin, Göttingen, Heidelberg. 69. Eddlestone M, Mucke L (1993) Molecular profile of reactive astrocytes; implications for their role in neurologic diseases. Neuroscience 54, 15–36. 70. Eng LF, Ghirnikar RS (1994) GFAP and astrogliosis. Brain Pathol 4, 229–237. 71. Eng LF (1988) Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes. J Neuroimmunol 8, 203–214. 72. Li R, Fujitani N, Jing-Tao J, Kimura H (1998) Immunohistochemical indicators of early brain injury: an experimental study using the fluid-percussion model in cats. Am J Forensic Med Pathol 19, 129–136. 73. Herrera DG, Cuello AC (1992) Glial fibrillary acidic protein immunoreactivity following cortical devascularizing lesion. Neuroscience 49, 781–791. 74. Hozumi I, Chiu FC, Norton WT (1990) Biochemical and immunocytochemical changes in glial fibrillary acid protein after stab wounds. Brain Res 524, 64–71. 75. Bignami A, Dahl D (1976) The astroglial response to stabbing. Immunofluorescense studies with antibodies to astrocyte-specific protein (GFA) in mammalian and submammalian vertebrates. Neuropathol Appl Neurobiol 2, 99–110. 76. Oblinger MM, Singh LD (1993) Reactive astrocytes in neonate brain upregulate intermediate filament gene expression in response to axonal injury. Int J Dev Neurosci 11, 149–156. 77. Takamiya Y, Kohsaka S, Toya S, Otani M, Tsukada Y (1988) Immunohistochemical studies on the proliferation of reactive astrocytes and the expression of cytoskeletal proteins following brain injury in rats. Dev Brain Res 466, 201–210. 78. Cheng HW, Jiang T, Brown SA, Pasinetti GM, Finch CE, McNeill TH (1994) Response of striatal astrocytes to neuronal deafferentation: an immunocytochemical and ultrastructural study. Neuroscience 62, 425–439. 79. Kinoshita A, Yamada K, Hayakawa T (1991) Wound healing following stab injury on rat cerebral cortex. Neurol Res 13, 184–188. 80. Calvo JL, Carbonell AL, Boya J (1991) Co-expression of glial fibrillary acidic protein and vimentin in reactive astrocytes following brain injury in rats. Brain Res 566, 333–336. 81. Hausmann R, Rieß R, Fieguth A, Betz P (2000) Immunohistochemical investigations on the course of astroglial GFAP expression following human brain injury. Int J Legal Med 113, 70–75. 82. Hausmann R, Betz P (2001) Course of glial immunoreactivity for vimentin, tenascin and _1-antichymotrypsin after traumatic injury to human brain. Int J Legal Med 114, 338–342. 83. Schiffer D, Giordana MT, Cavalla P, Vigliani MC, Attanasio A (1993) Immunohistochemistry of glial reaction after injury in the rat: double staining and markers of cell proliferation. Int J Devl Neurosci 11, 269–280. 84. Yamamoto C, Kawana E (1990) Immunohistochemical detection of laminin and vimentin in the thalamic VB nucleus after ablation of somatosensory cortex in the rat. Okajimas Folia Anat Jpn 67, 21–29.

74

Hausmann

85 Aufderheide E, Eklom P (1988) Tenascin during gut development: appearance in the mesenchyme, shift in molecular forms and dependence on epithelialmesenchymal interactions. J Cell Biol 107, 2341–2349. 86. Chiquet-Ehrismann R, Mackie EJ, Pearson CA, Sakakura T (1986) Tenascin: an extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 98, 131–139. 87. Inaguma Y, Kusakabe M, Mackie EJ, Pearson CA, Chiquet-Ehrismann R, Sakakura T (1988) Epithelial induction of stromal tenascin in the mouse mammary gland: from embryogenesis to carcinogenesis. Dev Biol 128, 245–255. 88. Mackie EJ, Thesleff I, Chiquet-Ehrismann R (1987) Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro. J Cell Biol 105, 2569–2579. 89. Maier A, Mayne R (1987) Distribution of connective tissue proteins in chick muscle spindles as revealed by monoclonal antibodies: a unique distribution of brachionectin/tenascin. Am J Anat 180, 226–236. 90. Brodkey JA, Laywell ED, O’Brien TF, Faissner A, Stefansson K, Dorries HU, et al. (1995) Focal brain injury and upregulation of a developmentally regulated extracellular matrix protein. J Neurosurg 82, 106–112. 91. Laywell ED, Dörries U, Bartsch U, Faissner A, Schachner M, Steindler DA (1992) Enhanced expression of the developmentally regulated extracellular matrix molecule tenascin following adult brain injury. Proc Natl Acad Sci U S A 89, 2634–2638. 92. Abraham CR, Selkoe DJ, Potter H (1988) Immunochemical identification of the serine protease inhibitor alpha1-antichymotrypsin in the brain amyloid deposits of Alzheimer’s disease. Cell 52, 487–501. 93. Abraham CR, Kanemaru K, Mucke L (1993) Expression of cathepsin G-like and (1-antichymotrypsin-like proteins in reactive astrocytes. Brain Res 621, 222–232. 94. Shoji M, Hirai S, Yamaguchi H, Harigaya Y, Ishiguro K, Matsubara E (1991) A comparative study of beta-protein and alpha1-antichymotrypsin immunostaining in the Alzheimer brain. Am J Pathol 138, 247–257. 95. Pasternack JM, Abraham CR, Van Dyke BJ, Potter H, Younkin SG (1989) Astrocytes in Alzheimer’s disease gray matter express alpha1-antichymotrypsin mRNA. Am J Pathol 135, 827–833. 96. Abraham CR, Shirahama T, Potter H (1990) Alpha1-antichymotrypsin is associated soley with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha1-antichymotrypsin. Neurobiol Aging 11, 123–129. 97. Miyake T, Okada M, Kitamura T (1992) Reactive proliferation of astrocytes studied by immunohistochemistry for proliferating cell nuclear antigen. Brain Res 590, 300–302. 98. Hattori T, Fukuda M, Kitamura T, Fujita S (1988) Quantitative studies on proliferative changes of reactive astrocytes in mouse cerebral cortex. Brain Res 451, 133–138. 99. Miyake T, Hattori T, Fukuda M, Kitamura T (1989) Reactions of S-100-positive glia after injury of mouse cerebral cortex. Brain Res 489, 31–40.

Traumatic Brain Injury

75

100. Orihara Y, Nakasono I (2002) Induction of apolipoprotein E after traumatic brain injury in forensic autopsy cases. Int J Legal Med 116, 92–98. 101. Hausmann R, Betz P (2000) The time course of the vascular response to human brain injury—an immunohistochemical study. Int J Legal Med 113, 288–292. 102. Finklestein SP, Apostolides PJ, Caday CG, Prosser J, Philips MF, Klagsbrun M (1988) Increased basic fibroblast growth factor (bFGF) immunoreactivity at the site of focal brain wounds. Brain Res 460, 253–259. 103. Smits A, Kato M, Westermark B, Nister M, Heldin CH, Funa K (1991) Neurotrophic activity of platelet-derived growth factor (PDGF): rat neuronal cells possess functional PDGF beta-type receptor and respond to PDGF. Proc Natl Acad Sci U S A 88, 8159–8163. 104. DeKosky ST, Goss JR, Miller PD, Styren SC, Kochanek PM, Marions D (1994) Upregulation of nerve growth factor following cortical trauma. Exp Neurol 130, 173–177. 105. Nichols NR, Laping NJ, Day JR, Finch CE (1991) Increases in transforming growth factor-` mRNA in hippocampus during response to entorhinal cortex lesions in intact and adrenalectomized rats. J Neurosci Res 28, 134–139. 106. Frautschy SA, Walicke PA, Baird A (1991) Localization of basic fibroblast growth factor and its mRNA after CNS injury. Brain Res 553, 291–299. 107. Reilly JF, Kumari VG (1996) Alterations in fibroblast growth factor receptor expression following brain injury. Exp Neurol 140, 139–150. 108. Takayama S, Sasahara M, Iihara K, Handa J, Hazama F (1994) Platelet-derived growth factor B-chain-like immunoreactivity in injured rat brain. Brain Res 653, 131–140. 109. Davis GE, Varon S, Engvall E, Manthorpe M (1985) Substratum-binding neuritepromoting factors: relationship to laminin. Trends Neurosci 8, 528–532.

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4 Central Nervous System Alterations in Drug Abuse Andreas Büttner, MD and Serge Weis, MD CONTENTS INTRODUCTION OPIATES COCAINE CANNABIS AMPHETAMINE AND METHAMPHETAMINE AMPHETAMINE AND METHAMPHETAMINE DERIVATIVES REFERENCES

SUMMARY Drug abuse represents a significant forensic issue worldwide. The major substances abused include cannabis, opiates, cocaine, amphetamine, methamphetamine, and “ecstasy.” Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of drug toxicity. A broad spectrum of changes affecting the central nervous system is seen in drug abusers. The major findings result from the consequences of cerebral ischemia and cerebrovascular diseases. Especially persons with underlying arteriovenous malformation or aneurysm are at higher risk for such events. So far, except for a few instances of vasculitis, the etiology of these cerebrovascular events is not completely understood. Besides pharmacologically induced vasospasm, impaired hemostasis, platelet dysfunction, and decreased cerebral blood flow have been proposed. Based on animal experiments, the abuse of amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) has been related to neurotoxicity in human long-term abusers and to From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 79

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the risk of developing Parkinson’s disease. However, whether such neurotoxicity occurs remains to be established. A major focus of research in the neurobiology of addiction has been put on the drug-induced adaptations within the brain reward system. Alterations of the intracellular messenger pathways, transcription factors, and immediate early genes in these reward circuits seem to be fundamentally important for the development of addiction and chronic drug abuse. Key Words: Amphetamine; drug abuse; cannabis; central nervous system (CNS); cocaine; ecstasy; forensic pathology; heroin; methamphetamine; opiates.

1. INTRODUCTION Although no brain lesion specific for drug abuse exists, a broad spectrum of changes affecting the central nervous system (CNS) is seen in drug abusers (1–3). Despite the neuroradiological observations of subtle changes in cerebral blood flow (CBF), glucose metabolism, receptor densities, or metabolite profiles (4–11), no morphological correlates of these changes are usually apparent on gross or microscopic examination. Furthermore, the CNS alterations may not only be caused by the abused drug itself but may also be a result of adulterants. Considering the various changes found in the CNS of drug abusers, another problem consists of distinguishing between substancespecific effects related to the properties of the drug itself and secondary effects related to lifestyle of the affected individual, for example, malnutrition, infections, and peripheral diseases. In addition, the possibility that a preexisting condition may have contributed to the CNS alterations cannot be excluded. Because polysubstance abuse is seen in the majority of cases (12–15), it is difficult to relate the observed CNS findings to a single substance. Little is known about the long-term adverse CNS effects of “designer” or “club” drugs, such as “ecstasy,” a-hydroxybutyrate (GHB), ketamine, and herbal substances that constitute the major trend in illicit drug use since the early 1990s in younger people (16–23). Therefore, in many cases the exact etiology of the various CNS alterations is unclear. The rewarding (reinforcing) properties of a number of commonly abused drugs are mediated by activation of the mesolimbic dopaminergic system, the orbitofrontal cortex, and the system of the extended amygdala (24–35). A major focus of research in the neurobiology of addiction has been put on the drug-induced adaptations within these neural systems. Alterations of the intracellular messenger pathways, transcription factors, and immediate early genes in these reward circuits seem to be fundamentally important for the development of addiction and the consequences of chronic drug abuse (26,30,31,36–38). Nitric oxide (NO), which acts as a neuromodulator, might also be involved in drug dependence (39).

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Drug abuse and dependence are neurobehavioral disorders of complex origin. Although environmental factors contribute to drug abuse and addiction, genetic factors also play a significant role. Despite the discovery of certain genes that are thought to be involved in drug abuse, the precise genetic risk factors for drug addiction and the changes in gene expression that are associated with drug abuse remain mostly unknown (40–46). Furthermore, most of our knowledge has been derived from animal models, whereby detailed human studies are lacking. It should be remembered, therefore, that findings in one species (e.g., rat) may not correspond well with what is found in another (e.g., mouse, monkey, human) possibly because of differences in pharmacokinetics. In the following, an overview is given describing the different types of human CNS lesions found in commonly abused drugs including a brief survey of the neuroradiological alterations and the numerous data derived from animal studies.

2. OPIATES Fatalities in opioid abusers are a major public health issue worldwide. Significant risk factors include loss of tolerance after a period of abstinence and concomitant use of alcohol and other CNS depressants. Moreover, systemic disease, for example, pulmonary and hepatic disease as well as HIV infection, may increase susceptibility to a fatal overdose (12–15,47–55).

2.1. Neuroimaging On computed tomography (CT) scans, cerebral atrophy has been shown in chronic heroin abusers (56–59); however, other studies were not able to show any gross abnormalities (60). Using magnetic resonance imaging (MRI), areas of demyelination in the deep white matter have been described (61), but other studies could not detect specific differences between drug abusers and controls (61–63). Single photon emission computed tomographic (SPECT) and positron emission tomographic (PET) studies demonstrated perfusion deficits in chronic opiate abusers without corresponding morphological CNS abnormalities (60,64–66). In longterm heroin abusers, a reduction of N-acetylaspartate in the frontal cortex was demonstrated on magnetic resonance spectroscopy (MRS); this finding was interpreted to be indicative of neuronal cell damage (67).

2.2. Autopsy Findings Rapid death after heroin injection will not always lead to any morphological evidence of cellular injury. In cases of delayed death, hypoxic nerve

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Fig. 1. Vascular congestion (thalamus, hematoxylin and eosin, original magnification × 200).

cell damage will be apparent. In up to 90% of all deaths resulting from opiate intoxication, cerebral edema, and vascular congestion (Fig. 1) with increased brain weight are seen at autopsy (68–72). On histological examination, ischemic nerve cell damage (Figs. 2A,B), characterized by cytoplasmic eosinophilia, loss of Nissl substance, and nuclear shrinkage, is seen in almost all cases after a survival period of 5 hours or longer (70,71). In an immunohistochemical study of the hippocampus, morphine has been selectively demonstrated in neurons, axons, and dendrites (73). In the globus pallidus, neuronal loss has been described (74). Bilateral, symmetrical ischemic lesions/necrosis of the globus pallidus can be found in 5–10% of heroin addicts, which corresponds to hypodensities seen on CT scans (72,75–79). These alterations are believed to be caused by recurrent episodes of hypoxia during opiate intoxication rather than to be related to direct neurotoxic effects of the drugs (72,75,78,80). Similar lesions are found after carbon monoxide (CO) intoxication (80).

2.3. Cerebrovascular Complications Stroke in heroin addicts occurring in the absence of endocarditis or mycotic aneurysms has rarely been observed (53,81–91). The pathogenetic mechanisms proposed by different authors include: (a) global cerebral hypoxia due to hypoventilation and/or hypotension during heroin intoxication

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Fig. 2. Hypoxic-ischemic nerve cell damage with cytoplasmic eosinophilia, loss of Nissl substance, and nuclear shrinkage. (A) Frontal cortex (hematoxylin and eosin, original magnification × 100). (B) Hippocampal formation (hematoxylin and eosin, original magnification × 200).

(81,84,87,88,91), or a focal decrease of the perfusion pressure (89) leading to borderzone infarcts, (b) vascular hypersensitivity reaction to heroin in persons who where re-exposed to the drug after a period of abstinence (85,88,92,93),

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Fig. 3. Nerve cell loss in long-term heroin addiction (olivary nucleus, LuxolFast-Blue stain, original magnification × 200).

(c) cerebral arteritis, necrotizing angiitis (88,93,94,95), or vasculitis (83,84,89,92) as shown by cerebral angiography, (d) embolism from adulterants (81,82,88,90,91), or (e) positional vascular compression (3). Recently, µ-opioid receptors were discovered on human erythrocytes that were significantly elevated in chronic opiate abusers and showed high deformability (96). Necrosis in the arterial boundary zones between the major arteries are owing to a marked sudden hypotension (3,81,89).

2.4. Hypoxic-Ischemic Leukoencephalopathy Hypoxic-ischemic leukoencephalopathy results from hypoxia secondary to respiratory depression and affects the cerebral white matter (79,80,97). In addition, loss of neurons in the hippocampal formation, Purkinje cell layer, and/or olivary nucleus (Fig. 3) is frequently seen and is attributable to primary respiratory failure (70). In nearly 80% of these cases, enhanced expression of glial fibrillary acidic protein by astrocytes and/or a proliferation of microglia have been found in the hippocampus (70). Because such reactive processes are the result of primary neuronal damage, it can be assumed that chronic intravenous drug abuse obviously results in ischemic nerve cell loss. Perivascular pigment laden macrophages are sometimes observed and are attributed to repeated intravenous injections of impure heroin (98).

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Fig. 4. Cerebral mucormycosis, large branching hyphae invading the brain tissue (periodic acid-Schiff reaction, original magnification × 85).

2.5. Infections Infections in heroin abusers mainly result from unsterile injection techniques and from the immunosuppression caused by chronic opiate abuse (3). Brain abscess, meningitis, or ventriculitis resulting from bacteria (72,99) as well as fungal infections (100–105) (Fig. 4) have occasionally been reported. Endocarditis might lead to septic foci in the brain (Fig. 5A,B) (3,72,99,100,106–109) or to intracranial mycotic aneurysms with subsequent rupture and development of subarachnoidal hemorrhage (72,99,100,110). The occurrence of lymphocytic meningitis is indicative of an early stage of HIV-1 infection (98,112,113).

2.6. Transverse Myelitis/Myelopathy Transverse myelitis/myelopathy is an exceptionally rare pathological condition that has been reported in recurrent heroin abusers after a period of abstinence (3,72,113–119) as well as during the course of heroin addiction (114). The affected persons present with a sudden paraparesis or paraplegia of the thoracolumbar region leading to death in some cases (72,113–119). The etiology is still unclear and neither the clinical picture nor the pathological changes conform to any particular pattern.

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Fig. 5. Metastatic meningoencephalitis in a heroin abuser with endocarditis. (A) Macroscopical view. (B) Intracerebral perivascular exsudate of leukocytes (hematoxylin and eosin, original magnification × 200).

2.7. Spongiform Leukoencephalopathy A distinct entity, spongiform leukoencephalopathy (nonspecific toxic demyelination), has been described to occur worldwide almost exclusively after inhalation of preheated heroin (“chasing the dragon,” “Chinese blow-

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ing”) (3,120–140). The clinical features progress from motor restlessness and cerebellar signs to pyramidal and pseudobulbar signs and, in some patients, to a terminal stage with spasms, paraparesis, and death (129,130,139). A lipophilic toxin related to contaminants in conjunction with cerebral hypoxia is considered to be the cause, but a definite toxin has not yet been identified (123,130,133,139). Others postulated that spongiform leukoencephalopathy may be the outcome of a complex mechanism directly triggered by heroin that causes mitochondrial as well as hypoxic injury in specific and limited areas of the cerebral white matter (137). However, the mitochondrial respiratory chain complexes IV, III, and V are unchanged (131). On neuropathological examination there is a diffuse spongiosis of the white matter with loss of oligodendrocytes, axonal reduction, and astrogliosis. The gray matter is usually unremarkable and the brainstem, spinal cord, and peripheral nerves are spared (3,129,131–133,135). The presence of spongiosis with astrogliosis and the absence of typical hypoxic lesions distinguish these cases from those with delayed leukoencephalopathy following severe hypoxia (131). Toxic leukoencephalopathy has also been observed after exposure to alcohol, toluene, cocaine, and hallucinogens (141).

2.8. Alterations of Neurotransmitters, Receptors, and Second Messengers All opiate effects are mediated via several specific types of opioid receptors. Of these, the µ-receptors mediate analgesia, euphoria, respiratory depression, hypothermia, bradycardia, and miosis (31,142–146). Long-term opiate abuse seems not to be associated with a reduced density of CNS µ- and b-opioid receptors because the density and affinity of these receptors were similar to those in controls in the frontal cortex, thalamus, and caudate nucleus (147–152). However, in an immunohistochemical study, an increased density of µ-opioid receptor-immunoreactive neurons has been demonstrated in Brodmann Area 11 of the human cerebral cortex (153). The authors hypothesized, that this receptor upregulation might be associated with a state of functional hypersensitivity in acute heroin intoxication. In investigating the acute and chronic effects of opiates on the CNS and the molecular mechanisms underlying opiate addiction, the second messenger-signaling system seems to play a crucial role (141,154–158). The coupling of opioid receptors to their effectors is mediated by guanosine triphosphate-binding (G) proteins that transmit extracellular, receptor-detected signals across the cell membrane to intracellular effectors (31,153). Opiates acutely inhibit adenylyl cyclase activity (which converts ATP to cAMP [cyclic adenosine monophosphate]) via G proteins

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resulting in decreased cellular cAMP levels. Chronic opiate exposure induces an upregulation in this adenylyl cyclase-cAMP system, which is interpreted to be a compensatory response to the sustained inhibition of the opioid receptor system in order to maintain homeostasis (31,154,156–158). This long-term effect of opiates on the cAMP pathway is mediated via the transcription factor CREB (cAMP response element-binding protein), with the locus coeruleus, the mesolimbic dopaminergic system, and the extended amygdala being the major target areas (150,159). This activation of the reward system in human opiate addiction could be demonstrated by functional neuroimaging (160). Autopsy studies revealed that long-term heroin abuse causes an increase in certain G proteins in different regions of the brain of heroin addicts (154,157). This has been demonstrated for the Gß subunit in the temporal cortex (154) and for the subunits G_·i1/2, G_o, G_s, and Gß in the frontal cortex (157). From these studies it is concluded that opiate addiction is associated with abnormalities in second messenger and signal transduction systems involving G proteins (149,154,157). Other studies have shown a decreased level of Ca2+dependent protein kinase C (PKC)-_ in the frontal cortex of opiate addicts (148) and an increased level of a membrane-associated G protein-coupled receptor kinase (161). It is assumed that the downregulation of the PKC-_ would enhance the upregulation of G_·i1/2 proteins for compensating the opiateinduced desensitization of the µ-opioid receptor system (148). Further findings in the brains of heroin addicts include a significant downregulation of the adenylyl-cyclase subtype I in the temporal cortex, which may play an important role in the molecular mechanism of chronic opiate addiction (156,158), a significant decrease in the density of _2-adrenoreceptors in the frontal cortex, hypothalamus, and caudate nucleus without changes in affinity values (147), and a marked decrease in the immunoreactivity of PKC-_ß in the frontal cortex (162). The observation of markedly decreased levels of immunoreactive neurofilament proteins in the frontal cortex of chronic opiate addicts may represent a specific long-term effect indicating neuronal damage after chronic abuse (163). In a postmortem study of chronic heroin abusers, the density of dopaminergic nerve terminals was not reduced in the striatum (164). In the nucleus accumbens, the levels of tyrosine hydroxylase protein and those of the dopamine (DA) metabolite homovanillic acid were significantly reduced associated with a trend for decreased DA concentration. These changes could reflect either a compensatory downregulation of DA biosynthesis in response to prolonged dopaminergic stimulation caused by heroin, or reduced axoplasmic transport of tyrosine hydroxylase (164). Striatal levels of serotonin (5-hydroxytryptamine

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[5-HT]) were either normal or elevated whereas the concentration of the 5-HT metabolite 5-hydroxyindoleacetic acid was decreased (164). According to the authors, chronic heroin exposure might produce a modest reduction in dopaminergic and serotonergic activity that could affect motivational state and impulse control, respectively. The density of I2-imidazoline receptors and the immunoreactivity of the related receptor protein were decreased in astrocytes of the frontal cortex, indicating that chronic opiate abuse induces downregulation of I2-imidazoline receptors in astrocytes, and presumably downregulates the functions associated with these receptors, for example, reduced growth of astrocytes (165).

2.9. Heroin Maintenance Treatment Codeine, dihydrocodeine, methadone, and buprenorphine are increasingly important in the context of deaths associated with maintenance treatment for heroin addiction (166–181). Monointoxication with one of these substances is the exception and, in the majority of cases, additional CNS depressant drugs, mainly alcohol and benzodiazepines, can be detected. The neuropathological findings are similar to those encountered in heroin deaths and consist of edema and hypoxic nerve cell changes.

3. COCAINE Cocaine abuse represents the third most common addiction disorder next to alcohol and cannabis and is of increasing social and medical concern (3,182–185). Cocaine crosses the blood–brain barrier (BBB) rapidly due to its high lipophilic properties (186,187). In the absence of alcohol, cocaine is mainly metabolized to form the inactive metabolites ecgonine methyl ester (EME) and benzoylecgonine (BE), which do not significantly cross the BBB (3,146,186). Although the uptake of BE into the brain is very low, the enzyme butyrylcholine esterase, which catalyzes the metabolism of cocaine to BE, is abundantly present in the cerebral white matter (188). In the presence of alcohol, cocaine is metabolized to cocaethylene (CE), which crosses the BBB rapidly. With a longer half-life time, CE accumulates to a four times higher concentration and possesses a similar pharmacologic profile to cocaine (146,189–191). Throughout the brain, cocaine and its major metabolites are widely distributed and receptors with varying affinities for cocaine are found (192–195). The region with the highest density of cocaine receptors, which is also the

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region containing the receptors with the greatest affinity for cocaine, is the striatum (192,194). Lower levels of activity are found in the frontal and occipital cortex (195). Most of the CNS effects of cocaine are mediated through alterations of the neurotransmitters DA, norepinephrine (NE), 5-HT, acetylcholine, and a-aminobutyric acid (GABA). Cocaine blocks the presynaptic reuptake of neurotransmitters resulting in their accumulation in the synaptic cleft, thus producing a sustained action on the receptor system followed by neurotransmitter depletion (3,146,184,196). Furthermore, cocaine enhances DA neurotransmission by interacting with the dopamine transporter (DAT), inhibiting the clearance of DA and stimulating the enzyme tyrosine hydroxylase (3,146,185). The interactions of cocaine in the mesolimbic dopaminergic system constitute the basis for its reinforcing properties (30–35,197). The abuse potential of cocaine is mainly based on the rapid development of tolerance to the euphoric effects, which requires the user to increase either dose or frequency of abuse or both to sustain the effects (146,185,198).

3.1. Neuroimaging In chronic cocaine abusers, CT scans revealed significant diffuse cerebral atrophy, which was positively correlated with the duration of cocaine abuse (199). Age-related hyperintense areas in the white matter have been described on MRI in cocaine-dependent persons, which were attributed to ischemic lesions (61,188). Evidence of caudate nucleus and putamen enlargement has been shown on MRI (200). However, other studies could not find significant differences in the total brain volume or the presence of white matter lesions in cocaine abusers (201,202). A global reduction in cerebral glucose metabolism and CBF alterations have been demonstrated in PET and SPECT, studies (203–210). Focal perfusion deficits in different brain regions, could be observed using PET and SPECT, which were partially reversible after abstinence (203–205,208,210,211).

3.2. Cerebrovascular Complications Although different complications have been described in cocaine abuse, most persons experience cerebrovascular events. Cocaine is the most common drug of abuse associated with cerebrovascular events (88,212,213). Intracerebral and subarachnoidal hemorrhages as well as stroke have been reported, manifesting minutes to hours after cocaine abuse (83,90,186,214–237). After alkaloidal cocaine consumption, ischemic and hemorrhagic strokes are equally likely, whereas after cocaine hydrochloride, hemorrhagic stroke occurred twice

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Fig. 6. Cocaine-induced ischemic infarction in the region of the middle cerebral artery.

as often as ischemic stroke (213). In contrast to the non-drug-using population, cocaine-associated stroke occurs primarily in young adults with a peak in the early 30s (3,182,183,213,215,221). Other studies could not detect a relationship between cocaine abuse, either infrequent or frequent, and nonfatal stroke in persons aged 18–45 years (232). In an autopsy study of 72 cocaine-associated deaths, cerebrovascular events were not mentioned (238). Others reported intracerebral hemorrhage as the cause of death in about 2–20% of the cases (227,235). Cocaine-associated ischemic infarctions (Fig. 6) can be found in every brain region, and nearly half of the patients presented with neurological deficits within the first 3 hours after cocaine intake (3,213,217,219,236). The underlying cause is attributed to cerebral vasospasm as a result of the vasoconstrictive and local anesthetic effects of cocaine (88,204,208,213,216,222,240–242). Using MR angiography, a dose-dependent cerebral vasoconstriction after cocaine

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Fig. 7. Cocaine-induced intracerebral hemorrhage with intraventricular extension.

administration in healthy human volunteers has been observed (242). Furthermore, a reduction of global CBF and cerebral perfusion deficits has been shown in human cocaine abusers receiving a single intravenous cocaine dose (204,243). The cerebrovascular symptoms that occur hours to days after cocaine abuse cannot readily be explained by the vasoconstrictive properties of cocaine because of its short plasma half-life of 60–80 minutes (213,219,222,244). Therefore, the longer half-life metabolites BE or CE have been considered to be responsible, as they induced significant vasoconstriction on cerebral arteries in animal experiments (187,189,244–246). Cardiac arrhythmia is another pathogenetic mechanism that can lead to secondary cerebral ischemia on embolic or hemodynamic basis (83,213,216,222,231). A cocaine-induced impairment of hemostasis, platelet dysfunction, and endothelium-dependent vasorelaxation have been described by other authors, but the studies have yielded conflicting results (247–250). In cocaine-associated intracerebral (Fig. 7) and subarachnoidal hemorrhage (Figs. 8A,B), underlying arteriovenous malformations or aneurysms are often observed, but in about half of the affected persons, there was no demonstrable lesion (90,182,186,213,216,218,219,221,223,225,227,229,230,235).

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Fig. 8. Subarachnoidal hemorrhage due to rupture of an aneurysm of the middle cerebral artery in association with cocaine abuse. (A) Computed tomography scan. (B) Macroscopical view.

Compared to non-drug-using persons, cocaine abuse has been shown to predispose to aneurysmal rupture at a significantly earlier age and in much smaller aneurysms (182,186,251). A sudden elevation of blood pressure is believed to be the likely cause, since the majority of cases become symptomatic within a few hours after cocaine abuse (88,186,213,215,217–221,225,229,235). Based on the angiographic observation of segmental stenoses and dilatations, a cocaine-induced cerebral vasculitis (Fig. 9) is considered to be the cause of the ischemic and hemorrhagic lesions (215,220,221,223,230,252–254). However, a vasculitis could be demonstrated by biopsy or autopsy only in rare cases (226,252,255–257). Experimentally, cocaine enhances leukocyte migration across the cerebral vessel wall and opens the BBB to HIV-1 invasion by a direct effect on brain endothelial cells and by the induction of pro-inflammatory cytokines and chemokines (258–260). Furthermore, brain capillary lesions were seen in rats after chronic administration of cocaine (261).

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Fig. 9. Cocaine-induced vasculitis with destruction of the vessel wall and perivascular lymphocytic infiltration (hematoxylin and eosin, original magnification × 120).

3.3. Seizures Cocaine-associated seizures have been reported in 2–10% of cocaine abusers (262–264). The majority of the cases show self-limiting generalized tonic-clonic seizures. However, status epilepticus and consecutive death have been reported in single cases (265). The pathogenetic mechanims are believed be due to a reduction of the seizure threshold or by induction of cardiac arrhythmia (265).

3.4. Movement Disorders Movement disorders, for example, akathisia, choreoathetosis, dystonia, and Parkinsonism, are frequently observed in cocaine abusers, especially in “crack” abusers (“crack dancing”). The symptoms are explained by disturbances in the dopaminergic transmission in the nigrostriatal motor system (266–268).

3.5. Alterations of Neurotransmitters, Receptors, and Gene Expression Marked reductions in the levels of enkephalin mRNA, µ-opioid receptor binding, and DA uptake site binding, concomitant with elevation in levels of

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dynorphin mRNA and g-opioid receptor binding have been described in the striatum of human cocaine-related deaths (269). In chronic cocaine abusers, a decrease in the levels of DA was seen in the caudate nucleus and frontal cortex, but not in the putamen, nucleus accumbens, and cerebral cortex (270–274). This decrease was not paralleled by an increase of DA D1 and D2 gene expression in the nucleus accumbens, caudate nucleus, putamen, or substantia nigra (275). Simultaneously, there was an increase of cocaine binding sites on the DAT with a decrease of the DA D1-receptor density in the striatum and of D1 and D3 receptor density in the nucleus accumbens (271–273,276–278). A marked reduction in vesicular monoamine transporter-2 (VMAT-2) immunoreactivity (270) and of the transcription factor NURR1 (279) in autopsy samples of human cocaine abusers might reflect damage to the dopaminergic system. An overexpression of _-synuclein in midbrain DA neurons in chronic cocaine abusers may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse (280). According to the authors, this accumulation of _-synuclein protein in long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson’s disease. Furthermore, an upregulation of g2-opioid receptors in the limbic system (281) and of CREB in the ventral tegmental area (282) has been described. In the serotonergic system, an increase of the 5-HT transporter in the striatum, substantia nigra, and limbic system has been demonstrated (283). The activity of phospholipase A 2 and phosphocholine cytidylyltransferase was selectively decreased in the putamen, a DA-rich brain area (284,285).

4. CANNABIS Cannabis abuse represents a significant clinical forensic issue worldwide because it is the most common illicit drug in use today. 69-Tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has a high abuse potential and leads to psychological dependency (286–292). Cannabis is thought to underlie its reinforcing and abuse potential by a still unknown mechanism that is most probably similar to that of other drugs of abuse that increase the activity of dopaminergic neurons in the mesolimbic dopaminergic system (293–297).

4.1. Cannabinoid Receptors and Endocannabinoids Within the brain, THC is distributed heterogeneously, with its highest concentrations in neocortical, limbic, sensory, and motor areas (288). THC and other cannabinoids exert their effects by the interaction with specific

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cannabinoid (CB) receptors (293,298–300). Two cannabinoid receptors, CB1 and CB2, have been pharmacologically characterized and anatomically localized (298,301,302). CB1 receptors are found predominantly in the central and peripheral nervous system, where they have been implicated in presynaptic inhibition of neurotransmitter release. CB2 receptors are present on immune cells, where they may be involved in cytokine release (293,301,303). Both receptors are coupled through G proteins to signal transduction mechanisms that include inhibition of adenylyl cyclase, activation of mitogen-activated protein kinase, regulation of calcium and potassium channels (CB1 only), and other signal transduction pathways (293,298,301,303,304). The identification of specific receptors mediating the effects of cannabinoids soon led to the discovery of endogenous cannabinoid agonists (“endocannabinoids”). These lipid mediators of the eicosanoid class, notably arachidonoylethanolamide (anandamide), 2-arachidonoylglycerol and 2-arachidonylglyceryl, ether (noladin ether), bind to both cannabinoid receptor types. They have been implicated in various physiological functions, for example pain reduction, motor regulation, learning, memory, appetite stimulation, and reward (301,304,305). The CB1 receptors are distributed heterogeneously within the brain with the highest density in the substantia nigra, basal ganglia, hippocampus, and cerebellum (302,306–309). In the neocortex they are present with the highest density in the frontal cortex, dentate gyrus, mesolimbic dopaminergic system, and temporal lobe (302,307–309). This specific distribution of CB1 receptors correlates well with the effects of cannabinoids on memory, perception, and the control of movement. However, chronic exposure to THC fails to irreversibly alter brain cannabinoid receptors (310). The very low density of CB1 receptors in the brain stem and medulla oblongata explains the low acute toxicity and lack of lethality of cannabis (286,293,308). Nevertheless, the CNS toxicity of cannabis has been underestimated for a long time (311), since recent findings revealed THC-induced neuronal death (312–314). These studies demonstrated that THC has a time- and concentration-dependent toxic effect on cultured hippocampal, cortical, and neonatal neurons. The THC-induced generation of free radicals has been assumed to be the primary event that could lead to lipid peroxidation and subsequent neuronal apoptosis (312–314). These mechanisms are believed to be responsible for the cognitive deficits seen in chronic cannabis abusers (315).

4.2. CNS Complications Besides cardiovascular complications, CNS complaints are the most common manifestations of acute cannabis toxicity (290). The latter include psychiatric symptoms such as panic attacks, anxiety, depression, or psychosis

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(290,316,317). Furthermore, THC has been shown to affect cognition and impair verbal and memory skills (288,318–320). However, there is little evidence that such impairments in humans are irreversible, or that they are accompanied by cannabis-induced neuropathology (289). THC increases the depressive effects of alcohol, sedatives, and opiates, whereas its interactions with stimulants, for example, amphetamines or cocaine, are complex and can be either additive or antagonistic (291,321).

4.3. Neuroimaging Neuroradiological studies of the consequences after acute or chronic cannabis abuse demonstrated subtle CNS alterations. MRI studies failed to detect morphological brain changes in long-term cannabis abusers (322). However, PET and SPECT studies showed a transient vasodilatation with an increase of CBF and metabolism after acute cannabis abuse (323,324). In contrast, in chronic cannabis abusers a decreased cerebral metabolism and CBF has been described in the frontal lobe and cerebellum (325–329). The age at which exposure to cannabis begins seems to be important for the existence of CBF changes, with the early adolescence as a critical period (329). The cessation of chronic cannabis abuse is believed to lead to a decrease in the functional level of the frontal lobes (327).

4.4. Cerebrovascular Complications Neurological complications after cannabis consumption are rare and mainly consist of cerebrovascular events, for example, cerebral infarction (330,331) or transitory ischemic attacks (332). In all of these cases, cannabis was smoked in high doses over years and the abuse of other drugs has been denied or they were not detected in the acute phase of abuse. A cannabis-induced vasospasm or a cannabis-induced hypotension has been hypothesized to be the cause.

4.5. Alterations of Neurotransmitters, Receptors, and Transcription Factors At the cellular level, abnormalities in the expression of transcription factors, NO formation and alterations in the brain dopaminergic system have been reported in animal experiments (333). The exact etiology of the different CNS alterations associated with cannabis abuse is still unclear.

5. AMPHETAMINE AND METHAMPHETAMINE Over the past years, the illicit use of amphetamine and methamphetamine has significantly risen worldwide (3,20,334–341). Furthermore, in the context

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of 3,4-methylenedioxymethamphetamine (MDMA) abuse, tablets sold as “ecstasy” often contain not only MDMA but other compounds such as amphetamine and methamphetamine (342). Amphetamine, methamphetamine, and cocaine comprise a subclass of psychostimulants that share a molecular site of action at monoamine transporters, in particular the DAT (3,146). Although they bind to the three major monoamine transporters, DA, 5-HT, and NE, it is the actions at DATs that are most central to both the motor-activating and reinforcing (rewarding) properties of these substances, but there are differences in the molecular mechanisms by which these drugs interact with DATs (343). Acute administration of psychostimulants enhance synaptic concentrations of DA and other monoamines. The potent sympathomimetic effects of amphetamine and methamphetamine include an elevation of pulse rate and blood pressure, an increased level of alertness, decreased fatigue, and suppression of appetite (146). The euphoric action and the reinforcing effect are related to their ability to release DA in the mesolimbic dopaminergic system and acetylcholine in the cerebral cortex (343–345). Adverse CNS events include seizures, agitation, and psychosis, often accompanied by aggressive behavior and suicidality (336,341,346–348).

5.1. Cerebrovascular Complications Amphetamines are the second most common cause (after cocaine) of ischemic or hemorrhagic stroke (Fig. 10) occurring largely in persons younger than 45 years (212). Besides stroke, subarachnoidal and intracerebral hemorrhages (Fig. 11) have been described after acute amphetamine and methamphetamine abuse (85,88,182,183,218,335,341,349–365). In the majority of cases there was no underlying brain lesion detectable. Only in single instances could an arteriovenous malformation (Fig. 12) be detected (357,362,364). The pathophysiology of cerebrovascular complications related to amphetamine and methamphetamine abuse may involve several mechanisms (88). A sudden elevation in blood pressure (336,354) or a cerebral vasculitis (341,349,358,365–369) are postulated as major underlying mechanisms. Amphetamine-induced cerebral vasculitis (Fig. 13) is described as a necrotizing angiitis closely resembling periarteritis nodosa, consisting of hemorrhages, infarctions, microaneurysms, and perivascular cuffing occurring in small- to medium-size arteries (88). Interestingly, a recent study indicated that methamphetamine might induce inflammatory genes in human brain endothelial cells (370). The vasoconstrictive effect of both substances may also lead to the development of ischemic stroke (360).

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Fig. 10. Hemorrhagic stroke associated with amphetamine abuse. (A) Macroscopical view. (B) Microscopical view (hematoxylin and eosin, original magnification × 100).

5.2. Neurotoxicity Throughout the brain, methamphetamine is heterogeneously distributed (371). The neurotoxic effects of amphetamine and methamphetamine on the dopaminergic system have been described in various animal species and in

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Fig. 11. Amphetamine-induced intracerebral hemorrhage.

humans by both neuroimaging and postmortem studies. These effects were characterized by desensitization of DA receptor function, and marked reduction of DA levels as well as other levels of dopaminergic axonal markers, for example, tyrosine hydroxylase, DATs, and VMAT-2 (372–410). Similar alterations have been reported in the serotonergic system (380,411-413). However, for most of these studies, the irreversibility of the neuronal deficits has not been established and it is still unclear whether the neurochemical alterations reflect neuroadaptation or neurotoxicity (414). Although these persistent deficits have been attributed to neurodegeneration, direct evidence for the loss of nerve terminals and/or their corresponding substantia nigra cell bodies has not been provided unequivocally (414), with the exception of a few studies in mice suggesting a methamphetamineinduced loss of dopaminergic cell bodies in the substantia nigra (415). Furthermore, a recovery phenomenon for the striatal DA system has also been reported (379,388,389,416). Based on animal studies, there is concern that the alterations in the dopaminergic system may predispose methamphetamine abusers to develop Parkinsonism as they age, at least the ones that survive their abuse (414,417,418). Neuroimaging and autopsy studies of human

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Fig. 12. Intracerebellar hemorrhage associated with amphetamine abuse with an underlying arteriovenous malformation.

Fig. 13. Cerebral vasculitis with perivascular lymphocytic infiltration (hematoxylin and eosin, original magnification × 120).

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methamphetamine abusers, although much more limited, suggest changes in some but not all of the dopaminergic system markers (385,405,406,419). Therefore, the evidence from this human study is inconclusive regarding dopaminergic system degeneration. To define methamphetamine abuse as a risk factor in Parkinson’s disease, it is important to know whether these alterations in the dopaminergic system represent neurodegenerative changes or a drug-induced compensatory response to the disruption of neurochemical homeostasis. It should be noted that symptoms are expressed only when about 90% of DA neurons are lost. Thus, methamphetamine could destroy many dopaminergic neurons without leading to clinical symptoms (417). The mechanisms of methamphetamine-induced neurotoxicity are thought to be mediated by multiple mechanisms including the generation of free radicals and NO, excitotoxicity, disruption of mitochondria, and the induction of immediate early genes as well as transcription factors (380,419–430). Hyperthermia may be an additional mechanism (431,432). However, whether such neurotoxicity occurs in human methamphetamine and amphetamine abusers and is restricted to striatal DA neurons remains to be established.

6. AMPHETAMINE AND METHAMPHETAMINE DERIVATIVES The abuse of amphetamine and methamphetamine derivatives is an emerging issue in current forensic medicine. Common substances include 4-methyl2,5-dimethoxyamphetamine (DOM), 4-bromo-2,5-dimethoxyamphetamine (DOB), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine, “ecstasy,” “Eve” (MDE), 3,4-methylenedioxymethamphetamine, “Adam,” “XTC” (PMA), 4-methylthioamphetamine, “Flatliners,” 4-MTA, and 4-para-methoxyamphetamine (PMA) (3,20,433–436). The street name “ecstasy” subsumizes different hallucinogenic amphetamine derivatives with MDMA and MDE being the main components (342,437). The most important difference between the European and the American experience of “ecstasy” is that whereas it tends to be taken alone or at parties, often combined with cocaine and opiates in the United States, it is used in Europe almost exclusively as a “dance drug” (438,439). Under the latter condition, the pharmacological effects of the drug may be compounded by physical exertion in overheated environments with scarce water supply (438,439). Tablets sold as “ecstasy” may contain not only MDMA but other compounds well known to cause neurotoxicity, such as methamphetamine and amphetamine (342,437). Furthermore, the consumption of “ecstasy” is often combined with the abuse of other drugs. Therefore, little is known about the effects of “ecstasy” abuse or the combination of “ecstasy” and amphetamine

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abuse on neurons in the human brain. As MDMA is the most widely abused substance, this review will focus on CNS alterations associated with this drug.

6.1. Receptor Interactions MDMA affects the peripheral and CNS by acting mainly on the serotonergic system. The drug has sympathomimetic properties and modulates psychomotor and neuroendocrine functions (18,433,440–444). The unique effect of MDMA is the feeling of intimacy and closeness, designated as “entactogenic” (445). MDMA acts as an indirect monoaminergic agonist and displays relatively high, similar affinities for _-adrenoceptors, 5-HT2 receptors, M-1 muscarinic receptors, and H-1 histamine receptors. With less affinity MDMA binds to DA and NE uptake sites, M-2 muscarinic receptors, _1-adrenoceptors, ß-adrenoceptors, 5-HT1 receptors, and D1 and D2 DA receptors. MDMA blocks 5-HT reuptake and induces 5-HT release and, to a lesser extent, also causes DA and NE release (444,446–451). The 5-HT release appears to be related to MDMA action on the 5-HT transporter (452). In addition to its inhibition of monoamine reuptake, MDMA might also increase extracellular levels of monoamines by inhibiting brain monoamine oxidase activity (451). In human postmortem tissue, a distinct immunopositive reaction of MDMA and MDA was observed in the white matter, in all cortical brain regions and the neurons of the basal ganglia, in the hypothalamus, the hippocampus, and the cerebellar vermis, but in the brainstem relatively weak staining of neurons was seen (453).

6.2. Neurotoxicity Exposure to MDMA can cause acute and long-term neurotoxic effects in animals and nonhuman primates (446,450,454–475). Nonhuman primates have been shown to be more sensitive to the neurotoxic effects of MDMA than rats. The serotonergic system seems to be mostly affected. Histological and immunohistochemical studies have also provided evidence for serotonergic neurodegeneration and axonal loss (455,457,462,463,468–472,476,477). Despite extensive studies, the mechanisms underlying MDMA neurotoxicity still remain to be fully elucidated (478–480). Current hypotheses of its damaging mechanisms include the formation of toxic MDMA metabolites with generation of free radicals as well as disturbances in the serotonergic, dopaminergic, GABAergic, glutamatergic, and NO system (481–483). Furthermore, hyperthermia seems to have an influence (484,485). Based on neuroimaging, clinical, and cell culture studies, there is a growing consensus that MDMA might also have acute and long-term neurotoxic

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effects (465,467,486–517). Especially, impaired cognitive performance and an increased incidence of neuropsychiatric disorders have been reported (494,511,512,518,519). Nevertheless, it is still unclear how to extrapolate animal and nonhuman primate data to the human condition (479,481,504,520–522).

6.3. Fatalities Besides serious long-term CNS effects, there is a risk of a fatal outcome after “ecstasy” consumption. Although death rates following MDMA abuse are low compared to the number of abusers, fatalities associated with MDMA have been reported worldwide (438,439,523–538). The cause of death may be a result of cardiovascular arrest, hyponatremia, or hepatic failure, whereas exertional hyperthermia or serotonin syndrome may lead to disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Other victims sustained traumatic injuries, for example, traffic accidents (438,439,539). In these studies, detailed neuropathological examinations have not been performed.

6.4. CNS Complications CNS complications after “ecstasy” consumption have been described occasionally and include ischemic as well as hemorrhagic cerebral infarction of unknown etiology (540–542). Further findings included intracranial hemorrhage (543,544), subarachnoidal hemorrhage (545), sinus vein thrombosis (546), hypersensitivity vasculitis (547), and leukoencephalopathy (548). In the globus pallidus, bilateral hyperintense lesions have been found (549,550). On neuropathological examination, necrosis of the globus pallidus and diffuse astrogliosis and spongiform changes of the white matter have been described (550). The authors pointed out that the globus pallidus is rich in serotonin-releasing neurons and that a local release of serotonin might have led to prolonged vasospasm and necrosis. This hypothesis has been substantiated by a SPECT study that demonstrated the vasoconstrictive properties of acute MDMA consumption via the excessive release of serotonin (413). Other neuropathological findings in deaths after “ecstasy” consumption were mainly owing to the complications of hyperthermia with DIC and consisted of cerebral edema, focal hemorrhages, and nerve cell loss, the latter being evident in the locus coeruleus (533).

ACKNOWLEDGMENTS The help of Ida C. Llenos, MD, and Hans Sachs, PhD, in correcting the manuscript is highly appreciated. We thank Ms. Susanne Ring for her skillful technical assistance.

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REFERENCES 1. Büttner A, Mall G, Penning R, Sachs H, Weis S (2003) The neuropathology of cocaine abuse. Legal Med 5, Suppl 1:S240–S242. 2. Büttner A, Mall G, Penning R, Weis S (2000) The neuropathology of heroin abuse. Forensic Sci Int 113, 435–442. 3. Karch SB (2002) Karch’s pathology of drug abuse, 3rd ed. CRC Press, Boca Raton. 4. Ernst M, London ED (1997) Brain imaging studies of drug abuse: therapeutic implications. Semin Neurosci 9, 120–130. 5. Kaufman MJ, Levin JM (2001) Magnetic resonance findings in substance abuse. In Kaufman MJ, ed., Brain imaging in substance abuse: research, clinical, and forensic applications. Humana Press, Totowa, NJ, pp. 155–198. 6. Kaufman MJ, Pollack MH, Villafuerte RA, Kukes TJ, Rose SL, Mendelson JH, et al. (1999) Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance. Psychiatry Res 90, 143–152. 7. Levin JM (2001) Emission tomographic studies in substance abuse. In Kaufman MJ, ed., Brain imaging in substance abuse: research, clinical, and forensic applications. Humana Press, Totowa, NJ, pp. 113–154. 8. London ED, Ernst M, Grant S, Bonson KR, Weinstein A (2000) Orbitofrontal cortex and human drug abuse: functional imaging. Cereb Cortex 10, 334–342. 9. Neiman J, Haapaniemi HM, Hilbom M (2000) Neurological complications of drug abuse: pathophysiological mechanisms. Eur J Neurol 7, 595–606. 10. Netrakom P, Krasuki JS, Miller NS, O’Tuama LA (1999) Structural and functional neuroimaging findings in substance-related disorders. Psychiatr Clin North Am 22, 313–329. 11. Stapleton JM, Morgan MJ, Phillips RL, Wong DF, Yung BCK, Shaya EK, et al. (1995) Cerebral glucose utilization in polysubstance abuse. Neuropsychopharmacology 13, 21–31. 12. Below E, Lignitz E (2003) Cases of fatal poisoning in post-mortem examination at the Institute of Forensic Medicine in Greifswald—analysis of five decades of post-mortems. Forensic Sci Int 133, 125–131. 13. Coffin PO, Galea S, Ahern J, Leon AC, Vlahov D, Tardiff K (2003) Opiates, cocaine and alcohol combinations in accidental drug overdose deaths in New York City, 1990–1998. Addiction 98, 739–747. 14. Preti A, Miotto P, De Coppi M (2002) Deaths by unintentional illicit drug overdose in Italy, 1984–2000. Drug Alcohol Depend 66, 275–282. 15. Steentoft A, Teige B, Ceder G, Vuori E, Kristinsson J, Simonsen KW, et al. (2001) Fatal poisoning in drug addicts in the Nordic countries. Forensic Sci Int 123, 63–69. 16. Bosman IJ, Lusthof KJ (2003) Forensic cases involving the use of GHB in The Netherlands. Forensic Sci Int 133, 17–21. 17. Dillon P, Copeland J, Jansen K (2003) Patterns of use and harms associated with non-medical ketamine use. Drug Alcohol Depend 69, 23–28. 18. Freese TE, Miotto K, Reback CJ (2002) The effects and consequences of selected club drugs. J Subst Abuse Treat 23, 151–156.

106

Büttner and Weis

19. Gill JR, Stajic M (2000) Ketamine in non-hospital and hospital deaths in New York City. J Forensic Sci 45, 655–658. 20. Koesters SC, Rogers PD, Rajasingham CR (2002) MDMA (“ecstasy”) and other “club drugs”: the new epidemic. Pediatr Clin North Am 49, 415–433. 21. Nicholson KL, Balster RL (2001) GHB: a new and novel drug of abuse. Drug Alcohol Depend 2001 63, 1–22. 22. Rome ES (2001) It’s a rave new world: rave culture and illicit drug use in the young. Cleve Clin J Med 68, 541–550. 23. Smith KM, Larive LL, Romanelli F (2002) Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and a-hydroxybutyrate. Am J Health Syst Pharm 59, 1067–1076. 24. Akil H, Meng F, Devine DP, Watson SJ (1997) Molecular and neuroanatomical properties of the endogenous opioid system: implications for treatment of opiate addiction. Semin Neurosci 9, 70–83. 25. Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159, 1642–1652. 26. Hyman SE, Malenka RC (2001) Addiction and the brain: the neurobiology of compulsion and its persistence. Nature Rev Neurosci 2, 695–703. 27. Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13, 177–184. 28. Leshner AI, Koob GF (1999) Drugs of abuse and the brain. Proc Assoc Am Phys 111, 99–108. 29. Martin-Soelch C, Chevalley A-F, Künig G, Missimer J, Magyar S, Mino A, et al. (2001) Changes in reward-induced brain activation in opiate addicts. Eur J Neurosci 14, 1360–1368. 30. Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nature Rev Neurosci 2,119–128. 31. Nestler EJ (1993) Cellular responses to chronic treatment with drugs of abuse. Crit Rev Neurobiol 7, 23–39. 32. Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54, 1–42. 33. Stewart J (2000) Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatr Neurosci 25, 125–136. 34. Volkow ND, Fowler JS (2000) Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex 10, 318–325. 35. Weiss F, Koob GF (2000) Drug addiction: functional neurotoxicity of the brain reward systems. Neurotox Res 3, 145–156. 36. Harlan RE, Garcia MM (1998) Drugs of abuse and immediate-early genes in the forebrain. Mol Neurobiol 16, 221–267. 37. Kelz MB, Nestler EJ (2000) DeltaFosB: a molecular switch underlying long-term neural plasticity. Curr Opin Neurol 13, 715–720. 38. Marie-Claire C, Laurendeau I, Canestrelli C, Courtin C, Vidaud M, Roques B, et al. (2003) Fos but not Cart (cocaine and amphetamine regulated transcript) is

CNS Alterations in Drug Abuse

39. 40.

41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.

107

overexpressed by several drugs of abuse: a comparative study using real-time quantitative polymerase chain reaction in the rat brain. Neurosci Lett 345, 77–80. Uzbay IT, Oglesby MW (2001) Nitric oxide and substance dependence. Neurosci Biobehav Rev 25, 43–52. Kendler KS, Jacobson KC, Prescott CA, Neale MC (2003) Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am J Psychiatry 160, 687–695. Kuhar MJ, Joyce A, Dominguez G (2001) Genes in drug abuse. Drug Alcohol Depend 62, 157–162. Lichtermann D, Franke P, Maier W, Rao ML (2000) Pharmacogenomics and addiction to opiates. Eur J Pharmacol 410, 269–279. Nestler EJ, Landsman D (2001) Learning about addiction from the genome. Nature 409, 834–835. Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci U S A 99, 8394–8399. Stallings MC, Corley RP, Hewitt JK, Krauter KS, Lessem JM, Mikulich SK, et al. (2003) A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence. Drug Alcohol Depend 70, 295–307. Torres G, Horowitz JM (1999) Drugs of abuse and brain gene expression. Psychosom Med 61, 630–650. Darke S (2003) Polydrug use and overdose: overthrowing old myths. Addiction 98, 711. Darke S, Zador D (1996) Fatal heroin “overdose”: a review. Addiction 91, 1765– 1772. Gerostamoulos J, Staikos V, Drummer OH (2001) Heroin-related deaths in Victoria: a review of cases for 1997 and 1998. Drug Alcohol Depend 61, 123–127. Manzanares J, Corchero J, Romero J, Fernández-Ruiz JJ, Ramos JA, Fuentes JA (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 20, 287–294. Polettini A, Groppi A, Montagna M (1999) The role of alcohol abuse in the etiology of heroin-related deaths. Evidence for pharmacokinetic interactions between heroin and alcohol. J Anal Toxicol 23, 570–576. Püschel K, Teschke F, Castrup U (1993) Etiology of accidental/unexpected overdose in drug-induced deaths. Forensic Sci Int 62, 129–134. Quaglio G, Talamini G, Lechi A, Venturini L, Lugoboni F, Mezzelani P (2001) Study of 2708 heroin-related deaths in north-eastern Italy 1985–98 to establish the main causes of death. Addiction 96, 1127–1137. Sporer KA (1999) Acute heroin overdose. Ann Intern Med 130, 584–590. Warner-Smith M, Darke S, Lynskey M, Hall W (2001) Heroin overdose: causes and consequences. Addiction 96, 1113–1125. Cala LA, Mastaglia FL (1980) Computerized axial tomography in the detection of brain damage: 1. Alcohol, nutritional deficiency and drugs of addiction. Med J Aust 2, 193–198.

108

Büttner and Weis

57. Pezawas L, Fischer G, Diamant K, Schneider C, Schindler SD, Thurnher M, et al. (1998) Cerebral CT findings in male opioid-dependent patients: stereological, planimetric and linear measurements. Psychiatry Res 83, 139–147. 58. Strang J, Gurling H (1989) Computerized tomography and neuropsychological assessment in long-term high-dose heroin addicts. Br J Addiction 84, 1011–1019. 59. Wolf SL, Mikhael MA (1979) Computerized transaxial tomographic and neuropsychologic evaluations in chronic alcoholics and heroin abusers. Am J Psychiatry 136, 598–602. 60. Rose JS, Branchey M, Buydens-Branchey L, Stapleton JM, Chasten K, Werrell A, et al. (1996) Cerebral perfusion in early and late opiate withdrawal: a technetium99m-HMPAO SPECT study. Psychiatry Res 67, 39–47. 61. Volkow ND, Valentine A, Kulkarni M (1988) Modifications radiologiques et neurologiques chez les toxicomanes: études par résonance magnétique. J Neuroradiol 15, 288–293. 62. Aasly J, Storsaeter O, Nilsen G, Smevik O, Rinck P (1993) Minor structural brain changes in young drug abusers. A magnetic resonance study. Acta Neurol Scand 87, 210–214. 63. Amass L, Nardin R, Mendelson JH, Teoh SK, Woods BT (1992) Quantitative magnetic resonance imaging in heroin- and cocaine-dependent men: a preliminary study. Psychiatr Res 45, 15–23. 64. Danos P, Kasper S, Grünwald F, Klemm E, Krappel C, Broich K, et al. (1998) Pathological regional cerebral blood flow in opiate-dependent patients during withdrawal: a HMPAO-SPECT study. Neuropsychobiology 37, 194–199. 65. Galynker II, Watras-Ganz S, Miner C, Rosenthal RN, Des Jarlais DC, Richman BL, et al. (2000) Cerebral metabolism in opiate-dependent subjects: effects of methadone maintenance. Mt Sinai J Med 67, 381–387. 66. Gerra G, Calbiani B, Zaimovic A, Sartori R, Ugolotti G, Ippolito L, et al. (1998) Regional cerebral blood flow and comorbid diagnosis in abstinent opioid addicts. Psychiatry Res 1998 83, 117–126. 67. Haselhorst R, Dürsteler KM, Scheffler K, Ladewig D, Müller-Spahn F, Stohler R, et al. (2002) Frontocortical N-acetylaspartate reduction associated with long-term IV heroin use. Neurology 58, 305–307. 68. Gosztonyi G, Schmidt V, Nickel R, Rothschild MA, Camacho S, Siegel G, et al (1993) Neuropathologic analysis of postmortal brain samples of HIV-seropositive and-seronegative i.v. drug addicts. Forensic Sci Int 62, 101–105. 69. Metter D (1978) Pathologisch-anatomische Befunde bei Heroinvergiftung. Beitr Gerichtl Med 36, 433–437. 70. Oehmichen M, Meißner C, Reiter A, Birkholz M (1996) Neuropathology in nonhuman immunodeficiency virus-infected drug addicts: hypoxic brain damage after chronic intravenous drug abuse. Acta Neuropathol (Berl) 91, 642–646. 71. Pearson J, Challenor YB, Baden MM, Richter RW (1972) The neuropathology of heroin addiction. J Neuropathol Exp Neurol 31, 165–166. 72. Richter RW, Pearson J, Bruun B (1973) Neurological complications of addiction to heroin. Bull N Y Acad Med 49, 3–21.

CNS Alterations in Drug Abuse

109

73. Wehner F, Wehner HD, Subke J, Meyermann R, Fritz P (2000) Demonstration of morphine in ganglion cells of the hippocampus from victims of heroin overdose by means of anti-morphine antiserum. Int J Legal Med 113, 117–120. 74. Pearson J, Baden MB, Richter RW (1975) Neuronal depletion in the globus pallidus of heroin addicts. Drug Alcohol Depend 1, 349–356. 75. Andersen SN, Skullerud K (1999) Hypoxic/ischaemic brain damage, especially pallidal lesions, in heroin addicts. Forensic Sci Int 102, 51–59. 76. Daras MD, Orrego JJ, Akfirat GL, Samkoff LM, Koppel BS (2001) Bilateral symmetrical basal ganglia infarction after intravenous use of cocaine and heroin. Clin Imaging 25, 12–14. 77. Riße M, Weiler G (1984) Heroinsucht als seltene Ursache einer symmetrischen Pallidumnekrose. Z Rechtsmed 93, 227–235. 78. Yee T, Gronner A, Knight RT (1994) CT findings in hypoxic basal ganglia damage. Southern Med J 87, 624–626. 79. Zuckerman GB, Ruiz, DC Keller IA, Brooks J (1996) Neurologic complications following intranasal administration of heroin in an adolescent. Ann Pharmacother 30, 778–781. 80. Ginsberg MD, Hedley-Whyte ET, Richardson EPJ (1976) Hypoxic-ischemic leukoencephalopathy in man. Arch Neurol 33, 5–14. 81. Adle-Biassette H, Marc B, Benhaiem-Sigaux N, Durigon M, Gray F (1996) Infarctus cérébraux chez un toxicomane inhalant l’héroine. Arch Anat Cytol Pathol 44, 12–17. 82. Bartolomei F, Nicoli F, Swiader L, Gastaut JL (1992) Accident vasculaire cérébral ischémique après prise nasale d’héroine. Une nouvelle observation. Presse Med 21, 983–986. 83. Brust JCM (1993) Clinical, radiological, and pathological aspects of cerebrovascular disease associated with drug abuse. Stroke 24, 129–133. 84. Brust JCM, Richter RW (1976) Stroke associated with addiction to heroin. J Neurol Neurosurg Psychiatry 39, 194–199. 85. Caplan LR, Hier DB, Banks G (1982) Current concepts of cerebrovascular disease-stroke: stroke and drug abuse. Stroke 13, 869–872. 86. Herskowitz A, Gross E (1973) Cerebral infarction associated with heroin sniffing. Southern Med J 66, 778–784. 87. Jensen R, Olsen TS, Winther BB (1990) Severe non-occlusive ischemic stroke in young heroin addicts. Acta Neurol Scand 81, 354–357. 88. Kelly MA, Gorelick PB, Mirza D (1992) The role of drugs in the etiology of stroke. Clin Neuropharmacol 15, 249–275. 89. Niehaus L, Meyer BU (1998) Bilateral borderzone brain infarctions in association with heroin abuse. J Neurol Sci 160, 180–182. 90. Sloan MA, Kittner SJ, Rigamonti D, Price TR (1991) Occurence of stroke associated with use/abuse of drugs. Neurology 41, 1358–1364. 91. Vila N, Chamorro A (1997) Ballistic movements due to ischemic infarcts after intravenous heroin overdose: report of two cases. Clin Neurol Neurosurg 99, 259–262.

110

Büttner and Weis

92. Rumbaugh CL, Bergeron T, Fang HCH, McCormick R (1971) Cerebral angiographic changes in the drug abuse patient. Radiology 101, 335–344. 93. Woods BT, Strewler GJ (1972) Hemiparesis occuring six hours after intravenous heroin injection. Neurology 22, 863–866. 94. Halpern M, Citron BP (1971) Necrotizing angiitis associated with drug abuse. AJR Am J Roentgenol 111, 663–671. 95. King J, Richards M, Tress B (1978) Cerebral arteritis associated with heroin abuse. Med J Aust 2, 444–445. 96. Zeiger AR, Patkar AA, Fitzgerald R, Lundy A, Ballas SK, Weinstein SP (2002) Changes in mu opioid receptors and rheological properties of erythrocytes among opioid abusers. Addict Biol 7, 207–217. 97. Protass LM (1971) Delayed postanoxic encephalopathy after heroin use. Ann Intern Med 74, 738–739. 98. Gray F, Lescs MC, Keohane C, Paraire F, Marc B, Durigon M, et al. (1992) Early brain changes in HIV infection: neuropathological study of 11 HIV seropositive, non-AIDS cases. J Neuropathol Exp Neurol 51, 177–185. 99. Amine ARC (1997) Neurosurgical complications of heroin addiction: brain abscess and mycotic aneurysm. Surg Neurol 7, 385–386. 100. Adelman LS, Aronson SM (1969) The neuropathologic complications of narcotic drug addiction. Bull N Y Acad Med 45, 225–234. 101. Hershewe GL, Davis LE, Bicknell JM (1988) Primary cerebellar brain abscess from nocardiosis in a heroin addict. Neurology 38, 1655–1656. 102. Kasantikul V, Shuangshoti S, Taecholarn C (1987) Primary phycomycosis of the brain in heroin addicts. Surg Neurol 28, 468–472. 103. Kasantikul V, Shuangshoti S, Sampatanukul P (1988) Primary chromoblastomycosis of the medulla oblongata: complication of heroin addiction. Surg Neurol 29, 319–321. 104. Masucci EF, Fabara JA, Saini N, Kurtzke JF (1982) Cerebral mucormycosis, (phycomycosis) in a heroin addict. Arch Neurol 39, 304–306. 105. Morrow R, Wong B, Finkelstein WE, Sternberg SS, Armstrong D (1983) Aspergillosis of the cerebral ventricles in a heroin abuser. Case report and review of the literature. Arch Intern Med 143, 161–164. 106. Dreyer NP, Fields BN (1973) Heroin-associated infective endocarditis. A report of 28 cases. Ann Intern Med 78, 699–702. 107. Light JT Jr, Hendrickson M, Sholes WM, Portnoy DA, Bell WH 3rd, Kerstein MD (1991) Acute aortic occlusion secondary to Aspergillus endocarditis in an intravenous drug abuser. Ann Vasc Surg 5, 271–275. 108. Louria DB, Hensle T, Rose J (1967) The major medical complications of heroin addiction. Ann Intern Med 67, 1–22. 109. Verani DA, Carretto E, Bono L, Moggio G, Marone P (1993) Lactobacillus casei endocarditis in an intravenous heroin drug addict: a case report. Funct Neurol 8, 355–357. 110. Gilroy J, Andaya L, Thomas VJ (1973) Intracranial mycotic aneurysms and subacute bacterial endocarditis in heroin addiction. Neurology 23, 1193–1198.

CNS Alterations in Drug Abuse

111

111. Makrigeorgi-Butera M, Hagel C, Laas R, Püschel K, Stavrou D (1996) Comparative brain pathology of HIV-seronegative and HIV-infected drug addicts. Clin Neuropathol 15, 324–329. 112. Weis S, Bise K, Llenos IC, Mehraein P (1992) Neuropathologic features of the brain in HIV-1 infection. In Weis S, Hippius H, eds., HIV-1 infection of the central nervous system. Clinical, pathological, and molecular aspects. Hogrefe & Huber Publishers, Seattle, pp. 159–190. 113. Bernasconi A, Kuntzer T, Ladbon N, Janzer RC, Yersin B, Regli F (1996) Complications neurologiques périphériques et médullaires de la toxicomanie intraveneuse à l’héroine. Rev Neurol 152, 688–694. 114. Ell JJ, Uttley D, Silver JR (1981) Acute myelopathy in association with heroin addiction. J Neurol Neurosurg Psychiatry 44, 448–450. 115. Goodhart LC, Loizou LA, Anderson M (1982) Heroin myelopathy. J Neurol Neurosurg Psychiatry 45, 562–563. 116. Hall JHI, Karp HR (1973) Acute progressive ventral pontine disease in heroin brains. Neurology 23, 6–7. 117. McCreary M, Emerman C, Hanna J, Simon J (2000) Acute myelopathy following intranasal insufflation of heroin: a case report. Neurology 55, 316–317. 118. Nyffeler T, Stabba A, Sturzenegger (2003) Progressive myelopathy with selective involvement of the lateral and posterior columns after inhalation of heroin vapour. J Neurol 250, 496–498. 119. Pearson J, Richter RW, Baden M, Challenor YB, Bruun B (1972) Transverse myelopathy as an illustration of the neurologic features of heroin addiction. Hum Pathol 3, 107–113. 120. Au-Yeung K, Lai C (2002) Toxic leucoencephalopathy after heroin inhalation. Australas Radiol 46, 306–308. 121. Barnett MH, Miller LA, Reddel SW, Davies L (2001) Reversible delayed leukoencephalopathy following intravenous heroin overdose. J Clin Neurosci 8, 165–167. 122. Celius EG, Andersson S (1996) Leucoencephalopathy after inhalation of heroin: a case report. J Neurol Neurosurg Psychiatry 60, 694–695. 123. Chang YJ, Tsai CH, Chen CJ (1997) Leukoencephalopathy after inhalation of heroin vapor. J Formos Med Assoc 96, 758–760. 124. Gacouin A, Lavoue S, Signouret T, Person A, Dinard MD, Shpak N, et al. (2003) Reversible spongiform leucoencephalopathy after inhalation of heated heroin. Intensive Care Med 29, 1012–1015. 125. Hedley-Whyte ET (2000) Leukoencephalopathy and raised brain lactate from heroin vapor inhalation. Neurology 54, 2027–2028. 126. Hill MD, Cooper PW, Perry JR (2000) Chasing the dragon—neurological toxicity associated with inhalation of heroin vapour: case report. Can Med Assoc J 162, 236–238. 127. Keogh CF, Andrews GT, Spacey SD, Forkheim KE, Graeb DA (2003) Neuroimaging features of heroin inhalation toxicity: “chasing the dragon.” AJR Am J Roentgenol 180, 847–850. 128. Koussa S, Tamraz J, Nasnas R (2001) Leucoencephalopathy after heroin inhalation. A case with partial regression of MRI lesions. J Neuroradiol 28, 268–271.

112

Büttner and Weis

129. Kriegstein AR, Armitage BA, Kim PY (1997) Heron inhalation and progressive spongiform leukoencephalopathy. N Engl J Med 336, 589–590. 130. Nuytten D, Wyffels E, Michiels K, Ferrante M, Verbraeken H, Daelemans R, et al. (1998) Drug-induced spongiform leucoencephalopathy, a case report with review of the literature. Acta Neurol Belg 98, 32–35. 131. Rizzuto N, Morbin M, Ferrari S, Cavallaro T, Sparaco M, Boso G, et al. (1997) Delayed spongiform leukoencephalopathy after heroin abuse. Acta Neuropathol (Berl) 94, 87–90. 132. Robertson AS, Jain S, O’Neil RA (2001) Spongiform leukoencephalopathy following intravenous heroin abuse: radiological and histopathological findings. Austral Radiol 45, 390–392. 133. Schiffer D, Brignolio F, Giordana MT, Mongini T, Migheli A, Palmucci L (1985) Spongiform encephalopathy in addicts inhaling pre-heated heroin. Clin Neuropathol 4, 174–480. 134. Sempere AP, Posada I, Ramo C, Cabello A (1991) Spongiform leucoencephalopathy after inhaling heroin. Lancet 338, 320. 135. Stoltenburg-Didinger G, Wiese J, Finck A (1995) Diffuse progressive multifokale spongiöse Leukenzephalopathie nach Inhalation von Heroin—Ein Fallbericht. Akt Neurol 22, 107–110. 136. Tan TP, Algra PR, Valk J, Wolters EC (1994) Toxic leukoencephalopathy after inhalation of poisoned heroin: MR findings. Am J Neuroradiol 15, 175–178. 137. Vella S, Kreis R, Loveblad KO, Steinlin M (2003) Acute leukoencephalopathy after inhalation of a single dose of heroin. Neuropediatrics 34, 100–104. 138. Weber W, Henkes H, Möller P, Bade K, Kühne D (1998) Toxic spongiform leukoencephalopathy after inhaling heroin vapor. Eur Radiol 8, 749–755. 139. Wolters EC, Stam FC, Lousberg RJ, van Wijngaarden GK, Rengelink H, I Schipper ME, et al. (1982) Leucoencephalopathy after inhalating “heroin” pyrolysate. Lancet 2, 1233–1237. 140. Zheng W, Zhang X (2001) Characteristics of spongiform leukoencephalopathy induced by heroin: MRI detection. Chin Med J (Engl) 114, 1193–1195. 141. Filley CM, Kleinschmidt-DeMasters BK (2001) Toxic leukoencephalopathy. N Engl J Med 345, 425–432. 142. Akil H, Owens C, Gutstein H, Taylor L, Curran E, Watson S (1998) Endogenous opioids: overview and current issues. Drug Alcohol Depend 51, 127–140. 143. Gold MS (1993) Opiate addiction and the locus coeruleus. The clinical utility of clonidine, naltrexone, methadone, and buprenorphine. Psychiatr Clin North Am 16, 61–73. 144. Ling W, Wesson DR (1990) Drugs of abuse—opiates. West J Med 152, 565–572. 145. Miotto K, Kaufman D, Anton B, Keith DE Jr, Evans CJ (1996) Human opioid receptors: chromosomal mapping and mRNA localization. NIDA Res Monogr 161, 72–82. 146. Quinn DI, Wodak A, Day RO (1997) Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users. Clin Pharmacokinet 33, 344–400.

CNS Alterations in Drug Abuse

113

147. Gabilondo AM, Meana JJ, Barturen F, Sastre M, García-Sevilla JA (1994) µ-Opioid receptor and _2-adrenoreceptor agonist binding sites in the postmortem brain of heroin addicts. Psychopharmacology (Berl) 115, 135–140. 148. García-Sevilla JA, Ventayol P, Busquets X, La-Harpe R, Walzer C, Guimón J (1997) Regulation of immunolabelled µ-opioid receptors and protein kinase C-_ and c isoforms in the frontal cortex of human opiate addicts. Neurosci Lett 226, 29–32. 149. Meana JJ, González-Maeso J, García-Sevilla JA, Guimón J (2000) µ-Opioid receptor and _2-adrenoreceptor agonist stimulation of [35S]GTPaS binding to G-proteins in postmortem brains of opioid addicts. Mol Psychiatry 5, 308–315. 150. Nestler EJ (1997) Molecular mechanisms underlying opiate addiction: implications for medications development. Semin Neurosci 9, 84–93. 151. Schmidt P, Schmolke C, Mußhoff F, Prohaska C, Menzen M, Madea B (2001) Numerical density of µ opioidreceptor expressing neurons in the frontal cortex of drug related fatalities. Forensic Sci Int 115, 219–229. 152. Schmidt P, Schmolke C, Mußhoff F, Menzen M, Prohaska C, Madea B (2000) Numerical density of b-opioid receptor expressing neurons in the frontal cortex of drug-related fatalities. Forensic Sci Int 113, 423–433. 153. Schmidt P, Schmolke C, Musshoff F, Menzen M, Prohaska C, Madea B (2003) Area-specific increased density of µ-opioid receptor immunoreactive neurons in the cerebral cortex of drug-related fatalities. Forensic Sci Int 133, 204–211. 154. Hashimoto E, Frölich L, Ozawa H, Saito T, Shichinohe S, Takahata N, et al. (1996) Alteration of guanosine triphosphate binding proteins in postmortem brains of heroin addicts. Alcohol Clin Exp Res 20, 301A–304A. 155. Law PY, Wong YH, Loh HH (2000) Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 40, 389–430. 156. Shichinohe S, Ozawa H, Hashimoto E, Tatschner T, Riederer P, Saito T (2001) Changes in the cAMP-related signal transduction mechanism in postmortem human brains of heroin addicts. J Neural Transm 108, 335–347. 157. Escriba PV, Sastre M, García-Sevilla JA (1994) Increased density of guanine nucleotide-binding proteins in the postmortem brains of heroin addicts. Arch Gen Psychiatry 51, 494–501. 158. Shichinohe S, Ozawa H, Saito T, Hashimoto E, Lang C, Riederer P, et al. (1998) Differential alteration of adenyl cyclase subtypes I, II, and V/VI in postmortem human brains of heroin addicts. Alcohol Clin Exp Res 22, 84S–87S. 159. Lane-Ladd SB, Pineda J, Boundy VA, Pfeuffer T, Krupinski J, Aghajanian GK, et al. (1997) CREB (cAMP response element-binding protein) in the locus coeruleus: biochemical, physiological, and behavioral evidence for a role in opiate dependence. J Neurosci 17, 7890–7901. 160. Sell LA, Morris J, Bearn J, Frackowiak RSJ, Friston KJ, Dolan RJ (1999) Activation of reward circuitry in human opiate addicts. Eur J Neurosci 11, 1042–1048. 161. Ozaita A, Escriba PV, Ventayol P, Murga C, Mayor F Jr, García-Sevilla JA (1998) Regulation of G protein-coupled receptor kinase 2 in brains of opiate-treated rats and human opiate addicts. J Neurochem 70, 1249–1257.

114

Büttner and Weis

162. Busquets X, Escriba PV, Sastre M, García-Sevilla JA (1995) Loss of protein kinase C_`‚ in brain of heroin addicts and morphine-dependent rats. J Neurochem 64, 247–252. 163. García-Sevilla JA, Ventayol P, Busquets X, La Harpe R, Walzer C, Guimón J (1997) Marked decrease of immunolabelled 68 kDa neurofilament (NF-L) proteins in brains of opiate addicts. Neuroreport 8, 1561–1570. 164. Kish SJ, Kalasinsky KS, Derkach P, Schmunk GA, Guttman M, Ang L, et al. (2001) Striatal dopaminergic and serotonergic markers in human heroin users. Neuropsychopharmacology 24, 561–567. 165. Sastre M, Ventayol P, García-Sevilla JA (1996) Decreased density of I2-imidazoline receptors in the postmortem brains of heroin addicts. Neuroreport 7, 509–512. 166. Auriacombe M, Franques P, Tignol J (2001) Deaths attributable to methadone vs buprenorphine in France. JAMA 285, 45. 167. Barrett DH, Luk AJ, Parrish RG, Jones TS (1996) An investigation of medical examiner cases in which methadone was detected, Harris County, Texas, 1987– 1992. J Forensic Sci 41, 442–448. 168. Cooper GAA, Seymour A, Cassidy MT, Oliver JS (1999) A study of methadone fatalities in the Strathclyde region, 1991–1996. Med Sci Law 39, 233–241. 169. Drummer OH, Opeskin K, Syrjanen M, Cordner SM (1992) Methadone toxicity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathol 13, 346–350. 170. Gaulier JM, Marquet P, Lacassie E, Dupuy JL, Lachatre G (2000) Fatal intoxication following self-administration of a massive dose of buprenorphin. J Forensic Sci 45, 226–228. 171. Gerostamoulos J, Burke MP, Drummer OH (1996) Involvement of codeine in drug-related deaths. Am J Forensic Med Pathol 17, 327–335. 172. Graß H, Behnsen S, Kimont H-G, Staak M, Käferstein H (2003) Methadone and its role in drug-related fatalities in Cologne 1989–2000. Forensic Sci Int 132, 195–200. 173. Harding-Pink D (1993) Methadone: one person’s maintenance dose is another’s poison. Lancet 341, 665–666. 174. Heinemann A, Iwersen-Bergmann S, Stein S, Schmoldt A, Püschel K (2000) Methadone-related fatalities in Hamburg 1990–1999: implications for quality standards in maintenance treatment? Forensic Sci Int 113, 449–455. 175. Hickman M, Madden P, Henry J, Baker A, Wallace C, Wakefield J, et al. (2003) Trends in drug overdose deaths in England and Wales 1993–98: methadone does not kill more people than heroin. Addiction 98, 419–425. 176. Karch SB, Stephens BG (2000) Toxicology and pathology of deaths related to methadone: retrospective review. West J Med 172, 11–14. 177. Kintz P (2001) Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int 121, 65–69. 178. Kreek MJ (1997) Clinical update of opioid agonist and partial agonist medications for the maintenance treatment of opioid addiction. Semin Neurosci 9, 140–157.

CNS Alterations in Drug Abuse

115

179. Milroy CM, Forrest ARW (2000) Methadone deaths: a toxicological analysis. J Clin Pathol 53, 277–281. 180. Seymour A, Black M, Jay J, Cooper G, Weir C, Oliver J (2003) The role of methadone in drug-related deaths in the west of Scotland. Addiction 98, 995–1002. 181. Worm K, Steentoft A, Kringsholm B (1993) Methadone and drug addicts. Int J Legal Med 106, 119–123. 182. McEvoy AW, Kitchen ND, Thomas DGT (2000) Intracerebral haemorrhage in young adults: the emerging importance of drug misuse. BMJ 320, 1322–1324. 183. Petitti DB, Sidney S, Quesenberry C, Bernstein A (1998) Stroke and cocaine or amphetamine use. Epidemiology 9, 596–600. 184. Prakash A, Das G (1993) Cocaine and the nervous system. Int J Clin Pharmacol Ther Toxicol 31, 575–581. 185. Strang J, Johns A, Caan W (1993) Cocaine in the UK—1991. Br J Psychiatry 162, 1–13. 186. Oyesiku NM, Colohan ART, Barrow DL, Reisner A (1993) Cocaine-induced aneurysmal rupture: an emergent negative factor in the natural history of intracranial aneurysms? Neurosurgery 32, 518–526. 187. Spiehler VR, Reed D (1985) Brain concentrations of cocaine and benzoylecgonine in fatal cases. J Forensic Sci 30, 1003–1011. 188. Bartzokis G, Goldstein IB, Hance DB, Beckson M, Shapiro D, Lu PH, et al. (1999) The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific. AJNR Am J Neuroradiol 20, 1628–1635. 189. Andrews P (1997) Cocaethylene toxicity. J Addict Dis 16, 75–84. 190. Hearn WL, Flynn DD, Hime GW, Rose S, Cofino JC, Mantero-Atienza E, et al. (1991) Cocaethylene: a unique cocaine metabolite displays high affinity for the dopamine transporter. J Neurochem 56, 698–701. 191. Horowitz JM, Torres G (1999) Cocaethylene: effects on brain systems and behavior. Addiction Biol 4, 127–140. 192. Biegon A, Dillon K, Volkow ND, Hitzemann RJ, Fowler JS, Wolf AP (1992) Quantitative autoradiography of cocaine binding sites in human brain postmortem. Synapse 10, 126–130. 193. Kalasinsky KS, Bosy TZ, Schmunk GA, Ang L, Adams V, Gore SB, et al. (2000) Regional distribution of cocaine in postmortem brain of chronic human cocaine users. J Forensic Sci 45, 1041–1048. 194. Volkow ND, Fowler JS, Logan J, Gatley SJ, Dewey SL, MacGregor RR, et al. (1995) Carbon-11-cocaine binding compared at subpharmacological and pharmacological doses: a PET study. J Nucl Med 36, 1289–1297. 195. Calligaro DO, Eldefrawi ME (1987) Central and peripheral cocaine receptors. J Pharmacol Exp Ther 243, 61–68. 196. White SM, Lambe CJT (2003) The pathophysiology of cocaine abuse. J Clin Forensic Med 10, 27–39. 197. Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaineseeking behavior. Psychopharmacology (Berl) 168, 55–56.

116

Büttner and Weis

198. Lowenstein DH, Massa SM, Rowbotham MC, Collins SD, McKinney HE, Simon RP (1987) Acute neurologic and psychiatric complications associated with cocaine abuse. Am J Med 83, 841–846. 199. Pascual-Leone A, Dhuna A, Anderson DC (1991) Cerebral atrophy in habitual cocaine users. A planimetric CT study. Neurology 41, 34–38. 200. Jacobsen LK, Giedd JN, Gottschalk C, Kosten TR, Krystal JH (2001) Quantitative morphology of the caudate and putamen in patients with cocaine dependence. Am J Psychiatry 158, 486–489. 201. Chang L, Mehringer CM, Ernst T, Melchor R, Myers H, Forney D, et al. (1997) Neurochemical alterations in asymptomatic abstinent cocaine users: a proton magnetic resonance spectroscopy study. Biol Psychiatry 42, 1105–1114. 202. Jacobsen LK, Giedd JN, Kreek MJ, Gottschalk C, Kosten TR (2001) Quantitative medial temporal lobe brain morphology and hypothalamic-pituitary-adrenal axis function in cocaine dependence: a preliminary report. Drug Alcohol Depend 62, 49–56. 203. Ernst T, Chang L, Oropilla G, Gustavson A, Speck O (2000) Cerebral perfusion abnormalities in abstinent cocaine abusers: a perfusion MRI and SPECT study. Psychiatry Res 99, 63–74. 204. Gottschalk PC, Kosten TR (2002) Cerebral perfusion defects in combined cocaine and alcohol dependence. Drug Alcohol Depend 68, 95–104. 205. Holman BL, Mendelson J, Garada B, Teoh SK, Hallgring E, Johnson KA, et al. (1993) Regional cerebral blood flow improves with treatment in chronic cocaine polydrug users. J Nucl Med 34, 723–727. 206. Kosten TR, Cheeves C, Palumbo J, Seibyl JP, Price LH, Woods SW (1998) Regional cerebral blood flow during acute and chronic abstinence from combined cocaine-alcohol abuse. Drug Alcohol Depend 50, 187–195. 207. London ED, Cascella NG, Wong DF, Phillips RL, Dannals RF, Links JM, et al. (1990) Cocaine-induced reduction of glucose utilization in human brain. Arch Gen Psychiatry 47, 567–574. 208. Strickland TL, Mena I, Villanueva-Meyer J, Miller BL, Cummings J, Mehringer CM, et al. (1993) Cerebral perfusion and neuropsychological consequences of chronic cocaine use. J Neuropsychiatry Clin Neurosci 5, 419–427. 209. Volkow ND, Fowler JS, Wolf AP, Hitzemann R, Dewey S, Bendriem B, et al. (1991) Changes in brain glucose metabolism in cocaine dependence and withdrawal. Am J Psychiatry 148, 621–626. 210. Volkow ND, Mullani N, Gould KL, Adler S, Krajewski K (1988) Cerebral blood flow in chronic cocaine users: a study with positron emission tomography. Br J Psychiatry 152, 641–648. 211. Tumeh SS, Nagel JS, English RJ, Moore M, Holman BL (1990) Cerebral abnormalities in cocaine abusers: demonstration by SPECT perfusion brain scintigraphy. Radiology 176, 821–824. 212. Kaku DA, Lowenstein DH (1990) Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 113, 821–827.

CNS Alterations in Drug Abuse

117

213. Levine SR, Brust JCM, Futrell N, Brass LM, Blake D, Fayad P, et al. (1991) A comparative study of the cerebrovascular complications of cocaine: alkaloidal versus hydrochloride—a review. Neurology 41, 1173–1177. 214. Aggarwal SK, Williams V, Levine SR, Cassin BJ, Garcia JH (1996) Cocaine-associated intracranial hemorrhage: absence of vasculitis in 14 cases. Neurology 46, 1741–1743. 215. Brown E, Prager J, Lee H-Y, Ramsey RG (1992) CNS complications of cocaine abuse: prevalence, pathophysiology, and neuroradiology. AJR Am J Roentgenol 159, 137–147. 216. Cregler LL, Mark H (1986) Medical complications of cocaine abuse. N Engl J Med 315, 1495–1500. 217. Daras M, Tuchman AJ, Koppel BS, Samkoff LM, Weitzner I, Marc J (1994) Neurovascular complications of cocaine. Acta Neurol Scand 90, 124–129. 218. Davis GD, Swalwell CI (1996) The incidence of acute cocaine or methamphetamine intoxication in deaths due to ruptured cerebral (berry) aneurysms. J Forensic Sci 41, 626–628. 219. Fessler RD, Esshaki CM, Stankewitz RC, Johnson RR, Diaz FG (1997) The neurovascular complications of cocaine. Surg Neurol 47, 339–345. 220. Jacobs IG, Roszler MH, Kelly JK, Klein MA, Kling GA (1989) Cocaine abuse: neurovascular complications. Radiology 170, 223–227. 221. Klonoff DC, Andrews BT, Obana WG (1989) Stroke associated with cocaine use. Arch Neurol 46, 989–993. 222. Konzen JP, Levine SR, Garcia JH (1995) Vasospasm and thrombus formation as possible mechanism of stroke related to alkaloidal cocaine. Stroke 26, 1114–1118. 223. Levine SR, Welch KMA (1988) Cocaine and stroke. Stroke 19, 779–783. 224. Lundberg GD, Garriott JC, Reynolds PC, Cravey RH, Shaw RF (1977) Cocainerelated death. J Forensic Sci 22, 402–408. 225. Mangiardi JR, Daras M, Geller ME, Weitzner I, Tuchman AJ (1988) Cocainerelated intracranial hemorrhage. Report of nine cases and review. Acta Neurol Scand 77, 177–180. 226. Merkel PA, Koroshetz WJ, Irizarry MC, Cudkowicz ME (1995) Cocaine-associated cerebral vasculitis. Semin Arthritis Rheum 25, 172–183. 227. Mittleman RE, Wetli CV (1987) Cocaine and sudden “natural” death. J Forensic Sci 32, 11–19. 228. Mody CK, Miller BL, McIntyre HB, Cobb SK, Goldberg MA (1988) Neurologic complications of cocaine abuse. Neurology 38, 1189–1193. 229. Nolte KB, Brass LM, Fletterick CF (1996) Intracranial hemorrhage associated with cocaine abuse: a prospective autopsy study. Neurology 46, 1291–1296. 230. Peterson PL, Roszler M, Jacobs I, Wilner HI (1991) Neurovascular complications of cocaine abuse. J Neuropsychiatry Clin Neurosci 3, 143–149. 231. Petty GW, Brust JCM, Tatemichi TK, Barr ML (1990) Embolic stroke after smoking “crack” cocaine. Stroke 21, 1632–1635. 232. Qureshi AI, Suri MFK, Guterman LR, Hopkins LN (2001) Cocaine use and the likelihood of nonfatal myocardial infarction and stroke. Data from the Third National Health and Nutrition Examination Survey. Circulation 103, 502–506.

118

Büttner and Weis

233. Qureshi AI, Akbar MS, Czander E, Safdar K, Janssen RS, Frankel MR (1997) Crack cocaine use and stroke in young patients. Neurology 48, 341–345. 234. Sen S, Silliman SL, Braitman LE (1999) Vascular risk factors in cocaine users with stroke. J Stroke Cerebrovasc Dis 8, 254–258. 235. Tardiff K, Gross E, Wu J, Stajic M, Millman R (1989) Analysis of cocaine-positive fatalities. J Forensic Sci 34, 53–63. 236. Van Stavern GP, Gorman M (2002) Orbital infarction after cocaine use. Neurology 59, 642–643. 237. Wojak JC, Flamm ES (1987) Intracranial hemorrhage and cocaine use. Stroke 18, 712–715. 238. Rogers JN, Henry TE, Jones AM, Froede RC, Byers JMI (1986) Cocaine-related deaths in Pima County, Arizona, 1982–1984. J Forensic Sci 31, 1404–1408. 239. Albuquerque ML, Kurth CD (1993) Cocaine constricts immature cerebral arterioles by a local anesthetic mechanism. Eur J Pharmacol 249, 215–220. 240. He GQ, Zhang A, Altura BT, Altura BM (1994) Cocaine-induced cerebrovasospasm and its possible mechanism of action. J Pharmacol Exp Ther 268, 1532–1539. 241. Herning RI, King DE, Better WE, Cadet JL (1999) Neurovascular deficits in cocaine abusers. Neuropsychopharmacology 21, 110–118. 242. Kaufman MJ, Levin JM, Ross MH, Lange N, Rose SL, Kukes TJ, et al. (1988) Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 279, 376–380. 243. Wallace EA, Wisniewski G, Zubal G, vanDyck CH, Pfau SE, Smith EO, et al. (1996) Acute cocaine effects on cerebral blood flow. Psychopharmacology (Berl) 128, 17–20. 244. Madden JA, Konkol RJ, Keller PA, Alvarez TA (1995) Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms. Life Sci 56, 679–686. 245. Covert RF, Schreiber MD, Tebbett IR, Torgerson, LJ (1994) Hemodynamic and cerebral blood flow effects of cocaine, cocaethylene and benzoylecgonine in conscious and anesthetized fetal lambs. J Pharmacol Exp Ther 270, 118–126. 246. Schreiber MD, Madden JA, Covert RF, Torgerson LJ (1994) Effects of cocaine, benzoylecgonine, and cocaine metabolites in cannulated pressurized fetal sheep cerebral arteries. J Appl Physiol 77, 834–839. 247. Havranek EP, Nademanee K, Grayburn PA, Eichhorn EJ (1996) Endotheliumdependent vasorelaxation is impaired in cocaine arteriopathy. J Am Coll Cardiol 28, 1168–1174. 248. Jennings LK, White MM, Sauer CM, Mauer AM, Robertson JT (1993) Cocaineinduced platelets defects. Stroke 24, 1352–1359. 249. Kugelmass AD, Oda A, Monahan K, Cabral C, Ware JA (1993) Activation of human platelets by cocaine. Circulation 88, 876–883. 250. Rinder HM, Ault KA, Jatlow PI, Kosten TR, Smith BR (1994) Platelet alphagranule release in cocaine users. Circulation 90, 1162–1167. 251. Nanda A, Vannemreddy PSSV, Polin RS, Willis BK (2000) Intracranial aneurysms and cocaine abuse: analysis of prognostic indicators. Neurosurgery 46, 1063–1069.

CNS Alterations in Drug Abuse

119

252. Fredericks RK, Lefkowitz DS, Challa VR, Troost BT (1991) Cerebral vasculitis associated with cocaine abuse. Stroke 22, 1437–1439. 253. Kaye BR, Fainstat M (1987) Cerebral vasculitis associated with cocaine abuse. JAMA 258, 2104–2106. 254. Martin K, Rogers T, Kavanaugh A (1995) Central nervous system angiopathy associated with cocaine abuse. J Rheumatol 22, 780–782. 255. Diez-Tejedor E, Frank A, Gutierrez M, Barreiro P (1998) Encephalopathy and biopsy-proven cerebrovascular inflammatory changes in a cocaine abuser. Eur J Neurol 5, 103–107. 256. Krendel DA, Ditter SM, Frankel MR, Ross WK (1990) Biopsy-proven cerebral vasculitis associated with cocaine abuse. Neurology 40, 1092–1094. 257. Morrow PL, McQuillen JB (1993) Cerebral vasculitis associated with cocaine abuse. J Forensic Sci 38, 732–738. 258. Fiala M, Gan XH, Zhang L, House SD, Newton T, Graves MC, et al. (1998) Cocaine enhances monocyte migration across the blood–brain barrier. Cocaine’s connection to AIDS dementia and vasculitis? Adv Exp Med Biol 437, 199–205. 259. Gan X, Zhang L, Berger O, Stins MF, Way D, Taub DD, et al. (1999) Cocaine enhances brain endothelial adhesion molecules and leukocyte migration. Clin Immunol 91, 68–76. 260. Zhang L, Looney D, Taub D, Chang SL, Way D, Witte MH, et al. (1998) Cocaine opens the blood–brain barrier to HIV-1 invasion. J Neurovirol 4, 619–626. 261. Barroso-Moguel R, Villeda-Hernández J, Méndez-Armenta M, Ríos C. Brain capillary lesions produced by cocaine in rats. Toxicol Lett (1997) 92, 9–14. 262. Alldredge BK, Lowenstein DH, Simon RP (1989) Seizures associated with recreational drug abuse. Neurology 39, 1037–1039. 263. Choy-Kwong M, Lipton RB (1989) Seizures in hospitalized cocaine users. Neurology 39, 425–427. 264. Pascual-Leone A, Dhuna A, Altafullah I, Anderson DC (1990) Cocaine-induced seizures. Neurology 40, 404–407. 265. Lathers CM, Tyau LSY, Spino MM, Agarwal I (1988) Cocaine-induced seizures, arrhythmias and sudden death. J Clin Pharmacol 28, 584–593. 266. Bartzokis G, Beckson M, Wirshing DA, Lu PH, Foster JA, Mintz J (1999) Choreoathetoid movements in cocaine dependence. Biol Psychiatry 45, 1630–1635. 267. Cardoso FEC, Jankovic J (1993) Cocaine-related movement disorders. Mov Disord 8, 175–178. 268. Daras M, Koppel BS, Atos-Radzion E (1994) Cocaine-induced choreoathetoid movements (“crack dancing”). Neurology 44, 751–752. 269. Hurd YL, Herkenham M (1993) Molecular alterations in the neostriatum of human cocaine addicts. Synapse 13, 357–369. 270. Little KY, Krolewski DM, Zhang L, Cassin BJ (2003) Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users. Am J Psychiatry 160, 47–55. 271. Little KY, McLaughlin DP, Zhang L, McFinton PR, Dalack GW, Cook EH Jr, et al. (1998) Brain dopamine transporter messenger RNA and binding sites in cocaine users: a postmortem study. Arch Gen Psychiatry 55, 793–799.

120

Büttner and Weis

272. Little KY, Patel UN, Clark TB, Butts JD (1996) Alterations of brain dopamine and serotonin levels in cocaine users: a preliminary report. Am J Psychiatry 153, 1216–1218. 273. Little KY, Kirkman JA, Carroll FI, Clark TB, Duncan GE (1993) Cocaine use increases [3H]WIN 35428 binding sites in human striatum. Brain Res 628, 17–25. 274. Wilson JM, Levey AI, Bergeron C, Kalasinsky K, Ang L, Peretti F, et al. (1996) Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users. Ann Neurol 40, 428–439. 275. Meador-Woodruff JH, Little KY, Damask SP, Mansour A, Watson SJ (1993) Effects of cocaine on dopamine receptor gene expression: a study in the postmortem human brain. Biol Psychiatry 34, 348–355. 276. Mash DC, Pablo J, Ouyang Q, Hearn WL, Itzenwasser S (2002) Dopamine transport function is elevated in cocaine users. J Neurochem 81, 292–300. 277. Segal DM, Moraes CT, Mash DC (1997) Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Mol Brain Res 45, 335–339. 278. Staley JK, Hearn WL, Ruttenber AJ, Wetli CV, Mash DC (1994) High affinity cocaine recognition sites on dopamine transporter are elevated in fatal cocaine overdose victims. J Pharmacol Exp Ther 271, 1678–1685. 279. Bannon MJ, Pruetz B, Manning-Bog AB, Whitty CJ, Michelhaugh SK, Sacchetti P, et al. (2002) Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers. Proc Natl Acad Sci U S A 99, 6382–6385. 280. Mash DC, Ouyang Q, Pablo J, Basile M, Izenwasser S, Lieberman A, et al. (2003) Cocaine abusers have an overexpression of _-synuclein in dopamine neurons. J Neurosci 23, 2564–2571. 281. Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC (1997) g2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. J Neurosci 17, 8225–8233. 282. Tang W-X, Fasulo WH, Mash DC, Hemby SE (2003) Molecular profiling of midbrain dopamine regions in cocaine overdose victims. J Neurochem 85, 911–924. 283. Mash DC, Staley JK, Itzenwasser S, Basile M, Ruttenber AJ (2000) Serotonin transporters upregulate with chronic cocaine use. J Chem Neuroanat 20, 271–280. 284. Ross BM, Moszczynska A, Kalasinsky K, Kish SJ (1996) Phospholipase A2 activity is selectively decreased in the striatum of chronic cocaine users. J Neurochem 67, 2620–2623. 285. Ross BM, Moszczynska A, Peretti FJ, Adams V, Schmunk GA, Kalasinsky K, et al. (2002) Decreased activity of brain phospholipid metabolic enzymes in human users of cocaine and methamphetamine. Drug Alcohol Depend 67, 73–79. 286. Abood MA, Martin BR (1992) Neurobiology of marijuana abuse. Trends Pharmacol Sci 13, 301–306. 287. Ambrosio E, Martin S, García-Lecumberri C, Osta A, Crespo JA (1999) The neurobiology of cannabinoid dependence: sex differences and potential interactions between cannabinoid and opioid systems. Life Sci 65, 687–694.

CNS Alterations in Drug Abuse

121

288. Ashton CH (2001) Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 178, 101–106. 289. Iversen L (2003) Cannabis and the brain. Brain 126, 1252–1270. 290. Johns A (2001) Psychiatric effects of cannabis. Br J Psychiatry 178, 116–122. 291. Nahas GG (2001) The pharmacokinetics of THC in fat and brain: resulting functional responses to marihuana smoking. Hum Psychopharmacol 16, 247–255. 292. Smith NT (2002) A review of the published literature into cannabis withdrawal symptoms in human users. Addiction 97, 621–632. 293. Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58, 315–348. 294. Diana M, Melis M, Muntoni AL, Gessa GL (1998) Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proc Natl Acad Sci U S A 95, 10269– 10273. 295. French ED, Dillon K, Wu X (1997) Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8, 649–652. 296. Hoffman AF, Lupica CR (2001) Direct actions of cannabinoids on synaptic transmission in the nucleus accumbens: a comparison with opioids. J Neurophysiol 85, 72–83. 297. Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common µ1 opioid receptor mechanism. Science 276, 2048–2050. 298. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. (2002) Classification of cannabinoid receptors. Pharmacol Rev 54, 161–202. 299. Onaivi ES, Chakrabarti A, Chaudhuri G (1996) Cannabinoid receptor genes. Prog Neurobiol 48, 275–305. 300. Pertwee RG (1997) Pharmacology of cannabinoid CB 1 and CB2 receptors. Pharmacol Ther 74, 129–180. 301. Fride E (2002) Endocannabinoids in the central nervous system - an overview. Prostaglandins Leukot Essent Fat Acids 66, 221–233. 302. Glass M, Dragunow M, Faull RLM (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal neonatal and adult human brain. Neuroscience 77, 299–318. 303. Childers SR, Breivogel CS (1998) Cannabis and endogenous cannabinoid systems. Drug Alcohol Depend 51, 173–187. 304. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296, 678–682. 305. Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 21, 521–528. 306. Devane WA, Dysarz FA III, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34, 605–613. 307. Herkenham M (1992) Cannabinoid receptor localization in brain: relationship to motor and reward systems. Ann N Y Acad Sci 654, 19–32.

122

Büttner and Weis

308. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 87, 1932–1936. 309. Mailleux P, Parmentier M, Vanderhaeghen JJ (1992) Distribution of cannabinoid receptor messenger RNA in the human brain: An in situ hybridization histochemistry with oligonucleotides. Neurosci Lett 143, 200–204. 310. Westlake TM, Howlett AC, Ali SF, Paule MG, Scallet AC, Slikker WJ (1991) Chronic exposure to 69-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptors. Brain Res 544, 145–149. 311. Scallet AC (1991) Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals. Pharmacol Biochem Behav 40, 671–676. 312. Campbell VA (2001) Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacology 40, 702–709. 313. Chan GCK, Hinds TR, Impey S, Storm DR (1998) Hippocampal neurotoxicity of 69-tetrahydrocannabinol. J Neurosci 18, 5322–5332. 314. Guzmán M, Sánchez C, Galve-Roperh I (2001) Control of the cell survival/death decision by cannabinoids. J Mol Med 78, 613–625. 315. Hampson RE, Deadwyler SA (1999) Cannabinoids, hippocampal function and memory. Life Sci 65, 715–723. 316. Hollister LE (1986) Health aspects of cannabis. Pharmacol Rev 38, 1–20. 317. Maykut MO (1985) Health consequences of acute and chronic marihuana use. Prog Neuropsychopharmacol Biol Psychiatry 9, 209–238. 318. Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL (2002) Dose-related neurocognitive effects of marijuana use. Neurology 59, 1337–1343. 319. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D (2001) Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry 58, 909–915. 320. Schwartz RH (2002) Marijuana: a decade and a half later, still a crude drug with underappreciated toxicology. Pediatrics 109, 284–289. 321. Reid MJ, Bornheim LM (2001) Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol 61, 1357–1367. 322. Block RI, O’Leary DS, Ehrhardt JC, Augustinack JC, Ghoneim MM, Arndt S, et al. (2000) Effects of frequent marijuana use on brain tissue volume and composition. Neuroreport 11, 491–496. 323. Mathew RJ, Wilson WH, Coleman RE, Turkington TG, DeGrado TR (1997) Marijuana intoxication and brain activation in marijuana smokers. Life Sci 60, 2075–2089. 324. Volkow ND, Gillespie H, Mullani N, Tancredi L, Grant C, Valentine A, et al. (1996) Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication. Psychiatry Res 67, 29–38. 325. Amen DG, Waugh M (1998) High resolution SPECT imaging of marijuana smokers with AD/HD. J Psychoactive Drugs 30, 209–214. 326. Block RI, O’Leary DS, Hichwa RD, Augustinack JC, Boles Ponto LL, Ghoneim MM, et al. (2000) Cerebellar hypoactivity in frequent marijuana users. Neuroreport 11, 749–753.

CNS Alterations in Drug Abuse

123

327. Lundqvist T, Jönsson S, Warkentin S (2001) Frontal lobe dysfunction in long-term cannabis users. Neurotoxicol Teratol 23, 437–443. 328. O’Leary DS, Block RI, Koeppel JA, Flaum M, Schultz SK, Andreasen NC, et al. (2002) Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology 26, 802–816. 329. Wilson W, Mathew R, Turkington T, Hawk T, Coleman RE, Provenzale J (2000) Brain morphological changes and early marijuana use: a magnetic resonance and positron emission tomography study. J Addict Dis 19, 1–22. 330. Barnes D, Palace J, O’Brien MD (1991) Stroke following marijuana smoking. Stroke 22, 1381. 331. Zachariah SB (1991) Stroke after heavy marijuana smoking. Stroke 22, 406–409. 332. Mouzak A, Agathos P, Kerezoudi E, Mantas A, Vourdeli-Yiannakoura E (2000) Transient ischemic attack in heavy cannabis smokers–how “safe” is it? Eur Neurol 44, 42–44. 333. Mailleux P, Verslype M, Preud’homme X, Vanderhaeghen JJ (1994) Activation of multiple transcription factor genes by tetrahydrocannabinol in rat forebrain. Neuroreport 5, 1265–1268. 334. Albertson TE, Derlet RW, van Hoozen BE (1999) Methamphetamine and the expanding complications of amphetamines. West J Med 170, 214–219. 335. Karch SB, Stephens BG, Ho CH (1999) Methamphetamine-related deaths in San Francisco: demographic, pathologic, and toxicologic profiles. J Forensic Sci 44, 359–368. 336. Logan BK, Fligner CL, Haddix T (1998) Cause and manner of death in fatalities involving methamphetamine. J Forensic Sci 43, 28–34. 337. Lora-Tamayo C, Tena T, Rodríguez A (1997) Amphetamine derivative related deaths. Forensic Sci Int 85, 149–157. 338. National Institute on Drug Abuse (1999) Methamphetamine abuse alert: NIDA Notes 13 (1). Washington, DC, NIDA. 339. Raikos N, Tsoukali H, Psaroulis D, Vassiliadis N, Tsoungas M, Njau SN (2002) Amphetamine derivative deaths in northern Greece. Forensic Sci Int 128, 31–34. 340. Shaw KP (1999) Human methamphetamine-related fatalities in Taiwan during 1991–1996. J Forensic Sci 44, 27–31. 341. Zhu BL, Oritani S, Shimotouge K, Ishida K, Quan L, Fujita MQ, et al. (2000) Methamphetamine-related fatalities in forensic autopsy during 5 years in southern half of Osaka city and surrounding areas. Forensic Sci Int 113, 443–447. 342. Wolff K, Hay AWM, Sherlock K, Conner M (1995) Contents of “ecstasy.” Lancet 346, 1100–1101. 343. White FJ, Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51, 141–153. 344. Arnold HM, Fadel J, Sarter M, Bruno JP (2001) Amphetamine-stimulated cortical acetylcholine release: role of the basal forebrain. Brain Res 894, 74–87. 345. Di Chiara G (1995) The role of dopamine in drug abuse viewed from the perspective of its role in motivation. Drug Alcohol Depend 38, 95–137. 346. Chan P, Chen JH, Lee MH, Deng JF (1994) Fatal and nonfatal methamphetamine intoxication in the intensive care unit. Clin Toxicol 32, 147–155.

124

Büttner and Weis

347. Derlet RW, Rice P, Horowitz BZ, Lord RV (1989) Amphetamine toxicity: experience with 127 cases. J Emerg Med 7, 157–161. 348. Hart JB, Wallace J (1975) The adverse effects of amphetamines. Clin Toxicol 8, 179–190. 349. Bostwick DG (1981) Amphetamine induced cerebral vasculitis. Hum Pathol 12,1031–1033. 350. Delaney P, Estes M (1980) Intracranial hemorrhage with amphetamine abuse. Neurology 30, 1125–1128. 351. D’Souza T, Shraberg D (1981) Intracranial hemorrhage associated with amphetamine use. Neurology 31, 922–923. 352. Goodman SJ, Becker DP (1970) Intracranial hemorrhage associated with amphetamine abuse. JAMA 212, 480. 353. Harrington H, Heller HA, Dawson D, Caplan L, Rumbaugh C (1983) Intracerebral hemorrhage and oral amphetamine. Arch Neurol 40, 503–507. 354. Heye N, Hankey GJ (1996) Amphetamine-associated stroke. Cerebrovasc Dis 6, 149–155. 355. Imanse J, Vanneste J (1990) Intraventricular hemorrhage following amphetamine abuse. Neurology 40, 1318–1319. 356. Lessing MPA, Hyman NM (1989) Intracranial hemorrhage caused by amphetamine abuse. J Royal Soc Med 82, 766–767. 357. Lukes SA (1983) Intracerebral hemorrhage from an arteriovenous malformation after amphetamine injection. Arch Neurol 40, 60–61. 358. Matick H, Anderson D, Brumlik J (1983) Cerebral vasculitis associated with oral amphetamine overdose. Arch Neurol 40, 253–254. 359. Moriya F, Hashimoto Y (2002) A case of fatal hemorrhage in the cerebral ventricles following intravenous use of methamphetamine. Forensic Sci Int 129, 104–109. 360. Perez JA Jr, Arsura EL, Strategos S (1999) Methamphetamine-related stroke: four cases. J Emerg Med 17, 469–471. 361. Rothrock JF, Rubenstein R, Lyden PD (1988) Ischemic stroke associated with methamphetamine inhalation. Neurology 38, 589–592. 362. Selmi F, Davies KG, Sharma RR, Neal JW (1995) Intracerebral haemorrhage due to amphetamine abuse: report of two cases with underlying arteriovenous malformations. Br J Neurosurg 9, 93–96. 363. Shibata S, Mori K, Sekine I, Suyama H (1991) Subarachnoid and intracerebral hemorrhage associated with necrotizing angiitis due to methamphetamine abuse. An autopsy case. Neurol Med Chir (Tokyo) 31, 49–52. 364. Yen DJ, Wang SJ, Ju TH, Chen CC, Liao KK, Fuh JL, et al. (1994) Stroke associated with methamphetamine inhalation. Eur Neurol 34, 16–22. 365. Yu YJ, Cooper DR, Wellenstein DE, Block B (1983) Cerebral angiitis and intracerebral hemorrhage associated with methamphetamine abuse. Case report. J Neurosurg 58, 109–111. 366. Brust JCM (1997) Vasculitis owing to substance abuse. Neurol Clin 15, 945–957.

CNS Alterations in Drug Abuse

125

367. Citron BP, Halpern M, McCarron M, Lundberg GD, McCormick R, Pincus IJ, et al. (1970) Necrotizing angiitis associated with drug abuse. N Engl J Med 283, 1004–1011. 368. Imbesi SG (1999) Diffuse cerebral vasculitis with normal results on brain MR imaging. AJR Am J Roentgenol 173, 1494–1496. 369. Margolis MT, Newton TH (1971) Methamphetamine (“speed”) arteritis. Neuroradiology 2, 179–182. 370. Lee YW, Hennig B, Yao J, Toborek M (2001) Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells. J Neurosci Res 66, 583–591. 371. Kalasinsky KS, Bosy TZ, Schmunk GA, Reiber G, Anthony RM, Furukawa Y, et al. (2001) Regional distribution of methamphetamine in autopsied brain of chronic methamphetamine users. Forensic Sci Int 116, 163–169. 372. Ali SF, Newport GD, Slikker W Jr (1996) Methamphetamine-induced dopaminergic toxicity in mice. Ann N Y Acad Sci 801, 187–198. 373. Bennett BA, Hollingsworth CK, Martin RS, Harp JJ (1997) Methamphetamineinduced alterations in dopamine transporter function. Brain Res 782, 219–227. 374. Broening HW, Pu C, Vorhees CV (1997) Methamphetamine selectively damages dopaminergic innervation to the nucleus accumbens core while sparing the shell. Synapse 27, 153–160. 375. Brown JM, Hanson GR, Fleckenstein AE (2000) Methamphetamine rapidly decreases vesicular dopamine uptake. J Neurochem 74, 2221–2223. 376. Eisch AJ, Gaffney M, Weihmuller FB, O’Dell SJ, Marshall JF (1992) Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine. Brain Res 598, 321–326. 377. Ernst T, Chang L, Leonido-Yee M, Speck O (2000) Evidence for long-term neurotoxicity associated with methamphetamine abuse. A 1H MRS study. Neurology 54, 1344–1349. 378. Frey K, Kilbourn M, Robinson T (1997) Reduced striatal vesicular monoamine transporters after neurotoxic but not after behaviorally-sensitizing doses of methamphetamine. Eur J Pharmacol 334, 273–279. 379. Friedman SD, Castañeda E, Hodge GK (1998) Long-term monoamine depletion, differential recovery, and subtle behavioral impairment following methamphetamine-induced neurotoxicity. Pharmacol Biochem Behav 61, 35–44. 380. Frost DO, Cadet JL (2000) Effects of methamphetamine-induced neurotoxicity on the development of neural circuits: a hypothesis. Brain Res Rev 34, 103–118. 381. Fumagalli F, Gainetdinov RR, Valenzano KJ, Caron MG (1998) Role of dopamine transporter in methamphetamine-induced neurotoxicity: evidence from mice lacking the transporter. J Neurosci 18, 4861–4869. 382. Hanson GR, Gibb JW, Metzger RR, Kokoshka JM, Fleckenstein AE (1998) Methamphetamine-induced rapid and reversible reduction in the activities of tryptophan hydroxylase and dopamine transporters: oxidative consequences? Ann N Y Acad Sci 844, 103–107.

126

Büttner and Weis

383. Kuperman DI, Freyaldenhoven TE, Schmued LC, Ali SF (1997) Methamphetamine-induced hyperthermia in mice: examination of dopamine depletion and heat-shock protein induction. Brain Res 771, 221–227. 384. Laruelle M, Iyer RJ, Al-Tikriti MS, Zea-Ponce Y, Malison R, Zoghbi SS, et al. (1997) Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates. Synapse 25, 1–14. 385. McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci 18, 8417–8422. 386. Melega WP, Lacan G, DeSalles AAF, Phelps ME (2000) Long term methamphetamine-induced decreases of [11C]WIN 35,428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey. Synapse 35, 243–249. 387. Melega W, Lacan G, Harvey D, Huang S, Phelps M (1998) Dizocilpine and reduced body temperature do not prevent methamphetamine-induced neurotoxicity in the vervet monkey: [11C]WIN-35,428-positron emission tomography studies. Neurosci Lett 258, 17–20. 388. Melega WP, Raleigh MJ, Stout DB, Lacan G, Huang SC, Phelps ME (1997) Recovery of striatal dopamine function after acute amphetamine- and methamphetamine-induced neurotoxicity in the vervet monkey. Brain Res 766, 113–120. 389. Melega WP, Quintana J, Raleigh MJ, Stout DB, Yu DC, Lin KP, et al. (1996) 6-[18F]-fluoro-L-DOPA-PET studies show partial reversibility of long-term effects of chronic amphetamine in monkeys. Synapse 22, 63–69. 390. Metzger RR, Haughey HM, Wilkins DG, Gibb JW, Hanson GR, Fleckenstein AE (2000) Methamphetamine-induced rapid decrease in dopamine transporter function: role of dopamine and hyperthermia. J Pharmacol Exp Ther 295, 1077–1085. 391. O’Dell SJ, Weihmuller FB, Marshall JF (1991) Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity. Brain Res 564, 256–260. 392. Ricaurte GA, McCann UD (1992) Neurotoxic amphetamine analogues: effects in monkeys and implications for humans. Ann N Y Acad Sci 654, 371–382. 393. Ricaurte GA, Seiden LS, Schuster CR (1984) Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers. Brain Res 303, 359–364. 394. Ricaurte GA, Guillery RW, Seiden LS, Schuster CR, Moore RY (1982) Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain. Brain Res 235, 93–103. 395. Ricaurte GA, Schuster CR, Seiden LS (1980) Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study. Brain Res 193, 153–163. 396. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res Rev 11, 157–198.

CNS Alterations in Drug Abuse

127

397. Robinson TE, Yew J, Paulson PE, Camp DM (1990) The long-term effects of neurotoxic doses of methamphetamine on the extracellular concentration of dopamine measured with microdialysis in striatum. Neurosci Lett 110, 193–198. 398. Ryan LJ, Linder JC, Martone ME, Groves PM (1990) Histological and ultrastructural evidence that d-amphetamine causes degeneration in neostriatum and frontal cortex of rats. Brain Res 518, 67–77. 399. Seiden LS, Sabol KE (1996) Methamphetamine and methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell destruction. NIDA Res Monogr 163, 251–276. 400. Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H, et al. (2001) Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry 158, 1206–1214. 401. Steranka LR, Sanders-Bush ES (1980) Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice. Eur J Pharmacol 65, 439–442. 402. Tong J, Ross BM, Schmunk GA, Peretti FJ, Kalasinsky K, Furukawa Y, et al. (2003) Decreased striatal dopamine D1 receptor-stimulated adenylyl cyclase activity in human methamphetamine users. Am J Psychiatry 160, 896–903. 403. Trulson ME, Cannon MS, Faegg TS, Raese JD (1985) Effects of chronic methamphetamine on the nigral-striatal dopamine system in rat brain: tyrosine hydroxylase immunochemistry and quantitative light microscopic studies. Brain Res Bull 15, 569–577. 404. Villemagne V, Yuan J, Wong DF, Dannals RF, Hatzidimitriou G, Mathews WB, et al. (1998) Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C]-WIN-35,428 positron emission tomography studies and direct in vitro determinations. J Neurosci 18, 419–427. 405. Volkow ND, Chang L, Wang G-J, Fowler JS, Ding Y-S, Sedler M, et al. (2001) Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 158, 2015–2021. 406. Volkow ND, Chang L, Wang G-J, Fowler JS, Leonido-Yee M, Franceschi D, et al. (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158, 377–382. 407. Volkow ND, Chang L, Wang GJ, Fowler JS, Franceschi D, Sedler MJ, et al. (2001) Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers. Am J Psychiatry 158, 383–389. 408. Wagner GC, Ricaurte GA, Johanson CE, Schuster CR, Seiden LS (1980) Amphetamine induces depletion of dopamine and loss of dopamine uptake sites in caudate. Neurology 30, 547–550. 409. Wagner GC, Ricaurte GA, Seiden LS, Schuster CR, Miller RJ, Westley J (1980) Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine. Brain Res 181, 151–160. 410. Woolverton WL, Ricaurte GA, Forno LS, Seiden LS (1989) Long-term effects of chronic methamphetamine administration in rhesus monkeys. Brain Res 486, 73–78.

128

Büttner and Weis

411. Axt KJ, Molliver ME (1991) Immunocytochemical evidence for methamphetamine-induced serotonergic axon loss in the rat brain. Synapse 9, 302–313. 412. Fukui K, Nakajima T, Kariyama H, Kashiba A, Kato N, Tohyama I, et al. (1989) Selective reduction of serotonin immunoreactivity in some forebrain regions of rats induced by acute methamphetamine treatment; quantitative morphometric analysis by serotonin immunocytochemistry. Brain Res 482, 198–203. 413. Haughey HM, Fleckenstein AE, Metzger RR, Hanson GR (2000) The effects of methamphetamine on serotonin transporter activity: role of dopamine and hyperthermia. J Neurochem 75, 1608–1617. 414. Harvey DC, Lacan G, Tanious SP, Melega WP (2000) Recovery from methamphetamine induced long-term nigrostriatal dopaminergic deficits without substantia nigra cell loss. Brain Res 871, 259–270. 415. Sonsalla PK, Jochnowitz ND, Zeevalk GD, Oostveen JA, Hall ED (1996) Treatment of mice with methamphetamine produces cell loss in the substantia nigra. Brain Res 738, 172–175. 416. Cass WA, Manning MW (1999) Recovery of presynaptic dopaminergic functioning in rats treated with neurotoxic doses of methamphetamine. J Neurosci 19, 7653–7660. 417. Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Rev 36, 1–22. 418. Guilarte TR (2001) Is methamphetamine abuse a risk factor in parkinsonism? Neurotoxicology 22, 725–731. 419. Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, et al. (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2, 699–703. 420. Bowyer JF, Clausing P, Gough B, Slikker WJr, Holson RR (1995) Nitric oxide regulation of methamphetamine-induced dopamine release in caudate/putamen. Brain Res 699, 62–70. 421. Cadet JL, Brannock C (1998) Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 32, 117–131. 422. Iwasa H (1996) Alterations of g protein subclass mRNA’s in methemphetamineinduced behavioral sensitization. Ann N Y Acad Sci 801, 110–115. 423. Jayanthi S, Ladenheim B, Cadet JL (1998) Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidase in copper/zinc-superoxide dismutase transgenic mice. Ann N Y Acad Sci 844, 92–102. 424. Lee YW, Son KW, Flora G, Hennig B, Nath A, Toborek M (2002) Methamphetamine activates DNA binding of specific redox-responsive transcription factors in mouse brain. J Neurosci Res 70, 82–89. 425. Sheng P, Cerruti C, Ali SF, Cadet JL (1996) Nitric oxide is a mediator of methamphetamine (METH)-induced neurotoxicity. In vitro evidence from primary cell cultures of mesencephalic cells. Ann N Y Acad Sci 801, 174–186. 426. Stumm G, Schlegel J, Schäfer T, Würz C, Mennel HD, Krieg JC, et al. (1999) Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 13, 1065–1072.

CNS Alterations in Drug Abuse

129

427. Umino A, Nishikawa T, Takahashi K (1995) Methamphetamine-induced nuclear c-fos in rat brain regions. Neurochem Int 26, 85–90. 428. Uslaner JM, Norton CS, Watson SJ, Akil H, Robinson TE (2003) Amphetamineinduced c-fos mRNA expression in the caudate-putamen and subthalamic nucleus: interactions between dose, environment, and neuronal phenotype. J Neurochem 85, 105–114. 429. Yamagata K, Suzuki K, Sugiura H, Kawashima N, Okuyama S (2000) Activation of an effector immediate-early gene arc by methamphetamine. Ann N Y Acad Sci 914, 22–32. 430. Yamamoto BK, Zhu W (1998) The effects of methamphetamine on the production of free radicals and oxidative stress. J Pharmacol Exp Ther 287, 107–114. 431. Bowyer JF, Davies DL, Schmued L, Broening HW, Newport GD, Slikker W Jr, et al. (1994) Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther 268, 1571–1580. 432. Cappon GD, Morford LL, Vorhees CV (1997) Ontogeny of methamphetamineinduced neurotoxicity and associated hyperthermic response. Dev Brain Res 103, 155–162. 433. Christophersen AS (2000) Amphetamine designer drugs—an overview and epidemiology. Toxicol Lett 112, 127–131. 434. Felgate HE, Felgate PD, James RA, Sims DN, Vozzo DC (1998) Recent paramethoxymethamphetamine deaths. J Anal Toxicol 22, 169–172. 435. James RA, Dinan A (1998) Hyperpyrexia associated with fatal paramethoxyamphetamine (PMA) abuse. Med Sci Law 38, 83–85. 436. Winstock AR, Wolff K, Ramsey J (2002) 4-MTA: a new synthetic drug on the dance scene. Drug Alcohol Depend 67, 111–115. 437. Cole JC, Bailey M, Sumnall HR, Wagstaff GF, King LA (2002) The content of ecstasy tablets: implications for the study of their long-term effects. Addiction 97, 1531–1536. 438. Gill JR, Hayes JA, deSouza IS, Marker E, Stajic M (2002) Ecstasy (MDMA) deaths in New York City: a case series and review of the literature. J Forensic Sci 47, 121–126. 439. Henry JA, Jeffreys KJ, Dawling S (1992) Toxicity and deaths from 3,4methylenedioxymethamphetamine (“ecstasy”). Lancet 340, 384–387. 440. De la Torre R, Farré M, Roset PN, Hernandez Lopez C, Mas M, Ortuno J, et al. (2000) Pharmacology of MDMA in humans. Ann N Y Acad Sci 914, 225–237. 441. Downing J (1986) The psychological and physiological effects of MDMA on normal volunteers. J Psychoactive Drugs 18, 335–340. 442. Kalant H (2001) The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ 165, 917–928. 443. Liester MB, Grob CS, Bravo GL, Walsh RN (1992) Phenomenology and sequelae of 3,4-methylenedioxymethamphetamine use. J Nerv Ment Dis 180, 345–352. 444. Liechti ME, Vollenweider FX (2001) Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Hum Psychopharmacol Clin Exp 16, 589–598.

130

Büttner and Weis

445. Nichols DE (1986) Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J Psychoactive Drugs 18, 305–313. 446. Battaglia G, Brooks BP, Kulsakdinun C, De Souza EB (1988) Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. Eur J Pharmacol 149, 159–163. 447. Finnegan KT, Ricaurte GA, Ritchie LD, Irwin I, Peroutka SJ, Langston JW (1988) Orally administered MDMA causes a long-term depletion of serotonin in rat brain. Brain Res 447, 141–144. 448. Green AR, Cross AJ, Goodwin GM (1995) Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”). Psychopharmacology (Berl) 119, 247–260. 449. Rochester JA, Kirchner JT (1999) Ecstasy (3,4-methylenedioxymethamphetamine): history, neurochemistry, and toxicology. J Am Board Fam Pract 12, 137–142. 450. Schmidt CJ, Kehne JH (1990) Neurotoxicity of MDMA: neurochemical effects. Ann N Y Acad Sci 600, 665–680. 451. White SR, Obradovic T, Imel KM, Wheaton MJ (1996) The effects of methylenedioxymethamphetamine (MDMA, “Ecstasy”) on monoaminergic neurotransmission in the central nervous system. Prog Neurobiol 49, 455–479. 452. Azmitia EC, Murphy RB, Whitaker-Azmitia PM (1990) MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for Ca2+-dependent toxicity linked to release. Brain Res 510, 97–103. 453. De Letter EA, Espeel M, Craeymeersch M, Lambert WE, Clauwaert K, Dams R, et al. (2003) Immunohistochemical demonstration of the amphetamine derivatives 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) in human post-mortem brain tissues and the pituitary gland. Int J Legal Med 117, 2–9. 454. Ali SF, Newport GD, Scallet AC, Binienda Z, Ferguson SA, Bailey JR, et al. (1993) Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate. Neurotoxicol Teratol 15, 91–96. 455. Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS (1987) Biochemical and histological evidence that methylenedioxymethamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241, 338–345. 456. Frederick DL, Ali SF, Slikker W Jr, Gillam MP, Allen RR, Paule MG (1995) Behavioral and neurochemical effects of chronic methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys. Neurotoxicol Teratol 17, 531–543. 457. Hatzidimitriou G, McCann UD, Ricaurte GA (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (±)3,4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. J Neurosci 19, 5096–5107. 458. Huether G, Zhou D, Rüther E (1997) Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymeth-

CNS Alterations in Drug Abuse

459.

460. 461. 462.

463.

464.

465.

466.

467. 468.

469.

470.

471.

472.

473.

131

amphetamine (MDMA, “ecstasy”) and its congeners. J Neural Transm 104, 771–794. Insel TR, Battaglia G, Johannessen JN, Marra S, De Souza EB (1989) 3,4methylenedioxymethamphetamine (“ecstasy”) selectively destroys brain serotonin terminals in rhesus monkeys. J Pharmacol Exp Ther 249, 713–720. Kleven MS, Seiden LS (1992) Methamphetamine-induced neurotoxicity: structure activity relationships. Ann N Y Acad Sci 654, 292–301. McKenna DJ, Peroutka SJ (1990) Neurochemistry and neurotoxicity of 3,4methylenedioxymethamphetamine (MDMA, “Ecstasy”). J Neurochem 54, 14–22. Molliver ME, Berger UV, Mamounas LA, Molliver DC, O’Hearn E, Wilson MA (1990) Neurotoxicity of MDMA and related compounds: anatomic studies. Ann N Y Acad Sci 600, 640–664. O’Hearn E, Battaglia G, De Souza EB, Kuhar MJ, Molliver ME (1988) Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J Neurosci 8, 2788–2803. Ricaurte GA, Yuan J, Hatzidimitriou G, Cord BJ, McCann DU (2002) Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (“ecstasy”). Science 297, 2260–2263. Ricaurte GA, McCann UD, Szabo Z, Scheffel U (2000) Toxicodynamics and longterm toxicity of the recreational drug, 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Toxicol Lett 112, 143–146. Ricaurte GA, Yuan J, McCann DU (2000) (±)3,4-Methylenedioxymethamphetamine (“ecstasy”)-induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 42, 5–10. Ricaurte GA, McCann DU (1992) Neurotoxic amphetamine analogues: effects in monkeys and implications for humans. Ann N Y Acad Sci 654, 371–382. Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of (±)3,4methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 261, 616–622. Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, et al. (1988) (±)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA 260, 51–55. Ricaurte GA, DeLanney LE, Irwin I, Langston JW (1988) Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration. Brain Res 446, 165–168. Ricaurte GA, Bryan G, Strauss L, Seiden L, Schuster C (1985) Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science 229, 986–988. Scheffel U, Szabo Z, Mathews WB, Finley PA, Dannals RF, Ravert HT, et al. (1998) In vivo detection of short- and long-term MDMA neurotoxicity—a positron emission tomography study in the living baboon brain. Synapse 29, 183–192. Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240, 1–7.

132

Büttner and Weis

474. Stone DM, Merchant KM, Hanson GR, Gibb JW (1987) Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat. Neuropharmacology 26, 1677–1683. 475. Stone DM, Stahl DC, Hanson GR, Gibb JW (1986) The effects of 3,4methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 128, 41–48. 476. Callahan BT, Cord BJ, Ricaurte GA (2001) Long-term impairment of anterograde axonal transport along fiber projections originating in the rostral raphe nuclei after treatment with fenfluramine of methylenedioxymethamphetamine. Synapse 40, 113–121. 477. Scallet AC, Lipe GW, Ali SF, Holson RR, Frith CH, Slikker W Jr (1988) Neuropathological evaluation by combined immunohistochemistry and degenerationspecific methods: application to methylenedioxymethamphetamine. Neurotoxicology 9, 529–538. 478. Cadet JL (1998) Neurotoxicity of drugs of abuse. In Koliatsos VE, Ratan R, eds., Cell death and diseases of the nervous system. Humana Press, Totowa, NJ, pp. 521–526. 479. Curran HV (2000) Is MDMA (“ecstasy”) neurotoxic in humans? An overview of evidence and of methodological problems in research. Neuropsychobiology 42, 34–41. 480. Turner JJD, Parrott AC (2000) “Is MDMA a human neurotoxin?” Diverse views from the discussions. Neuropsychobiology 42, 42–48. 481. Lyles J, Cadet JL (2003) Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity: cellular and molecular mechanisms. Brain Res Rev 42, 155–168. 482. Seiden LS, Sabol KE (1996) Methamphetamine and methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell destruction. NIDA Res Monogr 163, 251–276. 483. Sprague JE, Everman SL, Nichols DE (1998) An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine. Neurotoxicology 19, 427–442. 484. Colado MI, Granados R, O’Shea E, Esteban B, Green AR (1999) The acute effects in rats of 3,4-methylene-dioxymethamphetamine (MDEA, “Eve”) on body temperature and long term degeneration of 5-HT neurones in brain: a comparison with MDMA (“ecstasy”). Pharmacol Toxicol 84, 261–266. 485. Mechan AO, Esteban B, O’Shea E, Elliott JM, Colado MI, Green AR (2002) The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) to rats. Br J Pharmacol 135, 170–180. 486. Bolla KI, McCann UD, Ricaurte GA (1998) Memory impairment in abstinent MDMA (“ecstasy”) users. Neurology 51, 1532–1537. 487. Buchert R, Obrocki J, Thomasius R, Väterlein O, Petersen K, Jenicke L, et al. (2001) Long-term effects of “ecstasy” abuse on the human brain studied by FDG PET. Nucl Med Commun 22, 889–897.

CNS Alterations in Drug Abuse

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488. Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke L, et al. (2003) Long-term effects of “ecstasy” use on serotonin transporters of the human brain investigated by PET. J Nucl Med 44, 375–384. 489. Chang L, Ernst T, Grob CS, Poland RE (1999) Cerebral 1H MRS alterations in recreational 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) users. J MRI 10, 521–526. 490. Chang L, Grob CS, Ernst T, Itti L, Mishkin FS, Jose-Melchor R, et al. (2000) Effect of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study. Psychiatry Res 98, 15–28. 491. Cohen S, Cocores J (1997) Neuropsychiatric manifestations following the use of 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”). Prog Neuropsychopharmacol Biol Psychiatry 21, 727–734. 492. Gerra G, Zaimovic A, Giucastro G, Maestri D, Monica C, Sartori R, et al. (1998) Serotonergic function after (±)3,4-methylene-dioxymethamphetamine (“ecstasy”) in humans. Int Clin Psychopharmacol 13, 1–9. 493. Gerra G, Zaimovic A, Ferri M, Zambelli U, Timpano M, Neri E, et al. (2000) Longlasting effects of (±)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin system functions in humans. Biol Psychiatry 47, 127–136. 494. Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F, Pelz S, Becker S, Kunert HJ, et al. (2000) Impaired cognitive performance in drug free users of recreational ecstasy (MDMA). J Neurol Neurosurg Psychiatry 68, 719–725. 495. Green AR, Goodwin GM (1996) Ecstasy and neurodegeneration. BMJ 312, 1493–1494. 496. Hegadoren KM, Baker GB, Bourin M (1999) 3,4-Methylenedioxy analogues of amphetamine: defining the risks to humans. Neurosci Biobehav Rev 23, 539–553. 497. Kish SJ, Furukawa Y, Ang L, Vorce SP, Kalasinsky KS (2000) Striatal serotonin is depleted in brain of a human MDMA (ecstasy) user. Neurology 55, 294–296. 498. McCann UD, Eligulashvili V, Ricaurte GA (2000) (±)3,4-Methylenedioxymethamphetamine (“ecstasy”)-induced serotonin neurotoxicity: clinical studies. Neuropsychobiology 42, 11–16. 499. McCann UD, Mertl M, Eligulashvili V, Ricaurte GA (1999) Cognitive performance in (±)3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) users: a controlled study. Psychopharmacology (Berl) 143, 417–425. 500. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission computed tomographic evidence of toxic effect of MDMA (“ecstasy”) on brain serotonin neurons in human beings. Lancet 352, 1433–1437. 501. McCann UD, Wong DF, Yokoi F, Villemagne VL, Dannals RF, Ricaurte G (1998) Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathione users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci 18, 8417–8422. 502. McCann UD, Ridenour A, Shaham Y, Ricaurte GA (1994) Serotonin neurotoxicity after (±)3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”), a controlled study in humans. Neuropsychopharmacology 10, 129–138.

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503. McCann UD, Ricaurte GA (1991) Lasting neuropsychiatric sequelae of (±)methylenedioxymethamphetamine (“ecstasy”) in recreational users. J Clin Psychopharmacol 11, 302–305. 504. McGuire P (2000) Long term psychiatric and cognitive effects of MDMA use. Toxicol Lett 112–113, 153–156. 505. Obrocki J, Schmoldt A, Buchert R, Andresen B, Petersen K, Thomasius R (2002) Specific neurotoxicity of chronic use of ecstasy. Toxicol Lett 127, 285–297. 506. Parrott AC (2001) Human psychopharmacology of ecstasy (MDMA): a review of 15 years of empirical research. Hum Psychopharmacol Clin Exp 16, 557–577. 507. Parrott AC (2002) Recreational ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav 71, 837–844. 508. Reneman L, Endert E, de Bruin K, Lavalaye J, Feenstra MG, de Wolff FA, et al. (2002) The acute and chronic effects of MDMA (“ecstasy”) on cortical 5-HT2A receptors in rat and human brain. Neuropsychopharmacology 26, 387–396. 509. Reneman L, Majoie CBL, Flick H, den Heeten GJ (2002) Reduced N-acetylaspartate levels in the frontal cortex of 3,4-methylenedioxymethamphetamine (ecstasy) users: preliminary results. AJNR Am J Neuroradiol 23, 231–237. 510. Reneman L, Booij J, Majoie CBL, van den Brink W, den Heeten GJ (2001) Investigating the potential neurotoxicity of ecstasy (MDMA): an imaging approach. Hum Psychopharmacol Clin Exp 16, 579–588. 511. Reneman L, Lavalaye J, Schmand B, de Wolff FA, van den Brink W, den Heeten GJ, et al. (2001) Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”). Arch Gen Psychiatry 58, 901–906. 512. Reneman L, Booij J, Schmand B, van den Brink W, Gunning B (2000) Memory disturbances in “ecstasy” users are correlated with an altered brain serotonin neurotransmission. Psychopharmacology (Berl) 148, 322–324. 513. Reneman L, Habraken JBA, Majoie CBL, Booij J, den Heeten GJ (2000) MDMA (“ecstasy”) and its association with cerebrovascular accidents: preliminary findings. AJNR Am J Neuroradiol 21, 1001–1007. 514. Schreckenberger M, Gouzoulis-Mayfrank E, Sabri O, Arning C, Zimny M, Zeggel T, et al. (1999) “Ecstasy”-induced changes of cerebral glucose metabolism and their correlation to acute psychopathology. An 18-FDG PET study. Eur J Nucl Med 26, 1572–1579. 515. Semple DM, Ebmeier KP, Glabus MF, O’Carroll RE, Johnstone EC (1999) Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA (“ecstasy”) users. Br J Psychiatry 175, 63–69. 516. Simantov R, Tauber M (1997) The abused drug MDMA (ecstasy) induces programmed cell death of human serotonergic cells. FASEB J 11, 141–146. 517. Zhou JF, Chen P, Zhou YH, Zhang L, Chen HH (2003) 3,4-methylenedioxymethamphetamine (MDMA) abuse may cause oxidative stress and potential free radical damage. Free Radical Res 37, 491–497. 518. Soar K, Turner JJD, Parrott AC (2001) Psychiatric disorders in ecstasy (MDMA) users: a literature review focusing on personal predisposition and drug history. Hum Psychopharmacol Clin Exp 16, 641–645.

CNS Alterations in Drug Abuse

135

519. Zakzanis KK, Young DA (2001) Memory impairment in abstinent MDMA (“ecstasy”) users: a longitudinal investigation. Neurology 56, 966–969. 520. Kish SJ (2002) How strong is the evidence that brain serotonin neurons are damaged in human users of ecstasy? Pharmacol Biochem Behav 71, 845–855. 521. McCann UD, Ricaurte GA, Molliver ME (2001) “Ecstasy” and serotonin neurotoxicity. New findings raise more questions. Arch Gen Psychiatry 58, 907–908. 522. Verbaten MN (2003) Specific memory deficits in ecstasy users? The results of a meta-analysis. Hum Psychopharmacol Clin Exp 18, 281–290. 523. Arimany J, Medallo J, Pujol A, Vingut A, Borondo JC, Valverde JL (1998) Intentional overdose and death with 3,4-methylenedioxyamphetamine (MDEA; “Eve”). Am J Forensic Med Pathol 19, 148–151. 524. Byard RW, Gilbert J, James R, Lokan RJ (1998) Amphetamine derivative fatalities in South Australia—is “ecstasy” the culprit? Am J Forensic Med Pathol 19, 261–265. 525. Chadwick IS, Linsley A, Freemont AJ, Doran B (1991) Ecstasy, 3,4-methylenedioxymethamphetamine (MDMA), a fatality associated with coagulopathy and hyperthermia. J Royal Soc Med 84, 371. 526. Dar KJ, McBrien ME (1996) MDMA induced hyperthermia: report of a fatality and review of current therapy. Intensive Care Med 22, 995–996. 527. De Letter EA, Clauwaert K, Lambert WE, van Bocxlaer JF, De Leenheer AP, Piette MHA (2002) Distribution study of 3,4-methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine in a fatal overdose. J Anal Toxicol 26, 113–118. 528. Dowling GP, McDonough ETI, Bost RO (1987). “Eve” and “ecstasy”: A report of five deaths associated with the use of MDEA and MDMA. JAMA 257, 1615–1617. 529. Duflou J, Mark A (2000) Aortic dissection after ingestion of “ecstasy” (MDMA). Am J Forensic Med Pathol 21, 261–263. 530. Fineschi V, Masti A (1996) Fatal poisoning by MDMA (ecstasy) and MDEA: a case report. Int J Legal Med 108, 272–275. 531. Fineschi V, Centini F, Mazzeo E, Turillazzi E (1999) Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases. Forensic Sci Int 104, 65–74. 532. Forrest ARW, Galloway JH, Marsh ID, Strachan GA, Clark JC (1994) A fatal overdose with 3,4-methylenedioxyamphetamine derivatives. Forensic Sci Int 64, 57–59. 533. Milroy CM, Clark JC, Forrest ARW (1996) Pathology of deaths associated with “ecstasy” and “eve” misuse. J Clin Pathol 49, 149–153. 534. Rohrig TP, Prouty RW (1992) Tissue distribution of methylenedioxymethamphetamine. J Anal Toxicol 16, 52–53. 535. Screaton GR, Cairns HS, Sarner M, Singer M, Thrasher A, Cohen SL (1992) Hyperpyrexia and rhabdomyolysis after MDMA (“ecstasy”) abuse. Lancet 339, 677–678. 536. Suarez RV, Riemersma R (1988) “Ecstasy” and sudden cardiac death. Am J Forensic Med Pathol 9, 339–341. 537. Verebey K, Alrazi J, Jaffe JH (1988) The complications of “ecstasy” (MDMA) JAMA 259, 1649–1650.

136

Büttner and Weis

538. Walubo A, Seger D (1999) Fatal multi-organ failure after suicidal overdose with MDMA, “ecstasy”: case report and review of the literature. Hum Exp Toxicol 18, 119–125. 539. Hooft PJ, van der Voorde HP (1994) Reckless behaviour related to the use of 3,4methylenedioxymethamphetamine (ecstasy): apropos of a fatal accident during car-surfing. Int J Legal Med 106, 328–329. 540. Hanyu S, Ikeguchi K, Imai H, Imai N, Yoshida M (1995) Cerebral infarction associated with 3,4-methylenedioxymethamphetamine (“ecstasy”) abuse. Eur Neurol 35, 173. 541. Manchanda S, Connolly MJ (1993) Cerebral infarction in association with ecstasy abuse. Postgrad Med J 69, 874–875. 542. Schlaeppi M, Prica A, de Torrenté A (1999) Hémorragie cérébrale et “ecstasy.” Praxis 88, 568–572. 543. Harries DP, De Silva R (1992) “Ecstasy” and intracerebral haemorrhage. Scot Med J 37, 150–152. 544. Hughes JC, McCabe M, Evans RJ (1993) Intracranial haemorrhage associated with ingestion of “ecstasy.” Arch Emerg Med 10, 372–374. 545. Gledhill JA, Moore DF, Bell D, Henry JA (1993) Subarachnoid haemorrhage associated with MDMA abuse. J Neurol Neurosurg Psychiatry 56, 1036–1037. 546. Rothwell PM, Grant R (1993) Cerebral venous sinus thrombosis induced by “ecstasy.” J Neurol Neurosurg Psychiatry 56, 1035. 547. Bitsch A, Thiel A, Rieckmann P, Prange H (1996) Acute inflammatory CNS disease after MDMA (“ecstasy”). Eur Neurol 36, 328–329. 548. Bertram M, Egelhoff T, Schwarz S, Schwab S (1999) Toxic leukoencephalopathy following “ecstasy” ingestion. J Neurol 246, 617–618. 549. Spatt J, Glawar B, Mamoli B (1997) A pure amnestic syndrome after MDMA (“ecstasy”) ingestion. J Neurol Neurosurg Psychiatry 62, 418–419. 550. Squier MV, Jalloh S, Hilton-Jones D, Series H (1995) Death after ecstasy ingestion: neuropathological findings. J Neurol Neurosurg Psychiatry 58, 756.

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5 A Forensic Pathological Approach to Sudden Cardiac Death Vittorio Fineschi, MD, PhD and Cristoforo Pomara, MD But O heart! heart! heart! O the bleeding drops of red, Where on the deck my Captain lies, Fallen cold and dead —Walt Whitman, “O Captain! My Captain!”

CONTENTS INTRODUCTION DEFINITION A METHODOLOGICAL APPROACH TO THE DISSECTION AND PREPARATION OF THE HEART CORONARY ANOMALIES AND STENOSIS THE MYOCARDIAL ALTERATION CONCLUSION APPENDIX: HEART MORPHOLOGY STUDY REFERENCES

SUMMARY Sudden cardiac death is reported to occur in 70,000–100,000 individuals per year in Italy and is most prevalent in people between 40 and 65 years of age. In 1998, there were 719,456 cardiac disease deaths among U.S. residents aged 35 years or older, of which 456,076 (63.3%) were defined as sudden cardiac deaths. Sudden cardiac death is a death that is rapid (without any specific chronological limit) and unexpected or unforeseen, both subjectively and objectively, that occurs without prior clinical examination in apparently healthy From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 139

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people (“primary or unexpected or not foreseeable sudden death”) or in patients during an apparent benign phase in the course of a disease (“secondary or expected or foreseeable sudden death”). In children, adolescents, and young adults (21 years of age or younger) myocarditis, cardiomyopathies, and coronary artery anomalies are the most common causes of sudden cardiac death. Coronary atherosclerosis is the most common finding in sudden death in people older than 21 years. Almost all sudden cardiac death investigations require correlation of circumstantial data with autopsy and laboratory data. Relatively few causes of natural death are self-evident at autopsy. A complete autopsy, including detailed neuropathological and cardiovascular examination with toxicological studies, must be performed in the context of all available clinical information and of the circumstances of death, thus excluding noncardiac causes and discovering those that are cardiovascular in origin but not related to coronary causes. A detailed protocol is presented for a practical use in suspected cases of sudden cardiac death. Histology may offer structural details of the cardiac wall and coronary intraluminal changes, particularly when serial section studies are performed. Although some techniques have considerable merit in the research setting, many factors limit their application in daily forensic autopsy practice, particularly when autolysis is present. The possibility that immunohistochemical and biochemical methods, quantitative morphometry, and demonstration of apoptosis in the myocardium might enhance the detection of the early cardiac changes in sudden cardiac death is an exciting field of research. Key Words: Sudden cardiac death; coronary anomalies; coronary atherosclerosis; coronary plaque morphology; atonic death; myocardial contraction bands; colliquative myocytolysis.

1. INTRODUCTION The forensic pathologist has a unique opportunity to study a wide range of sudden cardiac deaths resulting from all types of cardiac diseases (1). Usually, the forensic pathologist is the first professional to investigate these deaths as they are, by definition, sudden and often unexpected, and, therefore, fall under the jurisdiction of the medical examiner or coroner (2). As early as 1707, in De Subitaneis Mortibus, prompted by an “epidemic” of sudden death in 1705, Lancisi clearly defined different types of death: Indeed, this absolutely complete cessation of animal movements and this departure of the soul from the body, even though it happens at all times more swiftly than thought itself, is nevertheless divided for the sake of common parlance and for greater clarity of teaching,

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into natural, untimely and violent death, and those again individually into slow and sudden death, into those that are foreseen and forefelt and finally into such as are unforeseen, imperceptible and unexpected.

Two basic notions pertain to sudden death: (a) its mystery from the clinical standpoint, and (b) its occurrence in apparently healthy people as well as in those in various phases of clinically recognized diseases, a distinction that any study of sudden death should consider to gain more precise knowledge of this phenomenon. In term of expectancy, sudden death in a healthy marathon runner during a race may be quite different from sudden death in a patient with chronic ischemic heart disease. In other words, a correct approach would distinguish between a first episode and a secondary event in which complications and/or iatrogenic effects may change the natural history of the disease process.

2. DEFINITION On the basis that we as forensic pathologists prefer, the definition of sudden death is that of a death that is rapid (without any specific chronological limit) and unexpected or unforeseen, both subjectively and objectively, occurring without any prior clinical evaluation in apparently healthy people (“primary or unexpected or not foreseeable sudden death”) or in patients during an apparent benign phase in the course of a disease (“secondary or expected or foreseeable sudden death”). One should bear in mind that in the present etiologic and pathogenic uncertainty, any definition is only a working one that helps determine a better selection of case material to study. Sudden cardiac death is reported to occur in 70,000–100,000 individuals per year in Italy and is most prevalent in people between 40 and 65 years of age. In 1998, there were 719,456 cardiac disease deaths among U.S. residents aged 35 years or older, of which 456,076 (63.3%) were defined as sudden cardiac deaths (3). A variety of pathological conditions may lead to sudden cardiac death. In children, adolescents, and young adults (21 years of age or younger) myocarditis, cardiomyopathies, and coronary artery anomalies are the most common causes of sudden cardiac death. Coronary atherosclerosis is the most common finding in sudden cardiac death in people older than 21 years (Table 1) (4). At present, unique objective data are postmortem findings and, in a selected group, changes detectable by electrocardiography in monitored patients or clinical follow-ups from resuscitated patients. Almost all sudden cardiac death investigations require a careful correlation of circumstantial data with autopsy and laboratory findings. Relatively few natural death causes are selfevident by themselves at autopsy.

Immediate cause

Underlying cause

Mechanisms

Acute ischemia

Coronary atherosclerosis, nonatherosclerotic coronary diseases, aortic stenosis

Infiltrative diseases

Inflammatory (myocarditis), scars (healed infarcts, cardiomyopathy) Hypertrophic cardiomyopathy, systemic hypertension, idiopathic concentric left ventricular hypertrophy, aortic stenosis Dilated cardiomyopathy, chronic ischemia, systemic hypertension, aortic insufficiency, mitral insufficiency Rupture myocardial infarct, aortic rupture Pulmonary embolism, mitral stenosis, left atrial myxoma Severe ischemic heart disease, aortic stenosis

Ventricular fibrillation, bradycardia, electromechanical dissociation (usually end stage or postresuscitation) Ventricular fibrillation, bradyarrhythmias (uncommona) Ventricular fibrillation, bradyarrhythmias (uncommon)

Cardiac hypertrophy

Cardiac dilatation (congestive failure) Cardiac tamponade Mechanical disruption of cardiac blood flow Global myocardial hypoxia Acute heart failure

Bradyarrhythmias Baroreflex stimulation with bradycardia Atrial fibrillation A ventricular fibrillation Ventricular fibrillation (torsades de pointes) Bradycardia A ventricular fibrillation

EMD, electromechanical dissociation; AV, atrioventricular; MVP, mitral valve prolapse. in the presence of infiltrative processes involving the conduction system. From ref. 6.

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Generalized hypoxia Vasovagal stimulation Preexcitation syndrome Long QT syndrome Heart block

Massive myocardial infarct, rupture papillary muscle, acute endocarditis with chordal or leaflet rupture, MVP with chordal rupture Pulmonary stenosis, pulmonary hypertension Neuromuscular diseases Accessory pathways Congenital and acquired states AV nodal scarring, inflammation, tumor

Ventricular fibrillation, bradyarrhythmias (uncommon) Electromechanical dissociation Electromechanical dissociation, ventricular fibrillation Baroreflex stimulation with bradyarrhythmias, ventricular tachyarrhythmias Electromechanical dissociation, ventricular fibrillation

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Table 1 Causes and Mechanisms of Sudden Cardiac Death

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Davis has developed the following philosophical concepts concerning the investigation of sudden death (1): • Sudden death investigative opinions are dependent on circumstances as well as autopsy findings. • Circumstantial data is usually more important than autopsy findings. • What we call the “cause” of death does not answer the question why the affected individual died. • Autopsy findings of disease or injury may or may not be relevant to the cause of death.

From this philosophical approach toward the investigation of sudden unexpected death derives the correct way as proposed by Cohle and Sampson in 2001 using four steps in sudden cardiac death investigation (5): 1. 2. 3. 4.

Medical history and scene examination. Autopsy (gross examination and histology). Laboratory tests. Establishing the diagnosis.

3. A METHODOLOGICAL APPROACH TO THE DISSECTION AND PREPARATION OF THE HEART A complete autopsy, including detailed neuropathological and cardiovascular examination with toxicological studies, must be performed in the context of all available clinical information and on the circumstances of death, thus excluding noncardiac causes such as subarachnoid hemorrhage or pulmonary embolism, and discovering those that are cardiovascular in origin but not related to coronary atherosclerosis (6). A properly performed examination of the heart is the basis of every forensic autopsy. When the heart is examined, it is very important that the method adopted is compatible between the exhausting and very often overwhelming work requested in an autopsy room and the time one can devote to it. The dissection of the heart can be practiced in different ways (7,8). The most common of all is the one proposed by Virchow and modified by Prausnitz: the cut follows the direction of the blood flow from the caval veins on the right side of the heart to the conum and pulmonary artery (inflow–outflow method). On the left side, the atrium is opened by cutting the pulmonary veins and the cut is continued with the dissection of the left side of the infundibulum and of the aorta. To examine the coronary arteries, different methods that are more or less complicated have been introduced, such as the postmortem chalk injection, injections of colored or transparent radiopaque fluids into opened or

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undissected hearts, or plastic substances with the corrosion of the heart tissue and the resection of the tissue for a histological control before the corrosion (9). In the end, specific dissection plans have to be made to be compared with the echocardiographic images, if available. Each method has advantages and disadvantages because it is impossible to scrutinize simultaneously all possible changes. A long-standing method exists that (10) permits physicians to study groups of patients with quantitative and morphological changes of the heart structures that can be correlated with the previous medical history. This method can be adopted without waste of time and material, offering excellent diagnostic and scientific results. The heart is removed from the pericardium by cutting all the big vessels, all cavities are cleaned, and the heart is weighed and examined on the surface. The heart is left in a large container, containing a 10% formalin solution for 24 hours. Coronary arteries and each segment (main branches on the surface of the heart; extramural or epicardial coronary arteries or branches) are cross-sectioned at 3-mm-thick intervals along their whole course by carefully avoiding any damage. The lumen reduction of coronary arteries must be expressed as a percentage of the lumen diameter calculated from plastic casts of normal vessels (11). Then, the whole heart is dissected into 1-cm-thick slices parallel to the posterior atrioventricular sulcus, taking care to proceed from the apex to the base. The last upper slice is cut on the plane of the left ventricular papillary muscles. The heart slices, the atrio-valve section, and the coronary segments are disposed in their anatomic sequence and color-photographed with a scale. In this way it is possible to obtain information on the thickness of the walls and the volumes of the cavities and to measure planimetrically the extension of a lesion in percentage of the body heart mass. After that, the end auricles, valves, and any other structures can be easily examined. Systematic sampling for histological and immunohistochemical investigations has to be undertaken from the specific parts. A histological examination of the entire ventricular wall (2 cm × wholewall thickness) at the apex and at the anterior, lateral, and posterior walls of left ventricle, anterior and posterior right ventricle, interventricular septum, and in each area with a macroscopically detectable lesion must be performed. When a more careful examination is necessary, instead of one slice, histological sections are made from the upper and lower parts of the slices. After further fixation in 10% formalin solution, the remaining tissue should be stored completely in hermetically sealed plastic bags. Each histological myocardial section (excluding epicardium and endocardium) should be measured by an image analysis system (e.g., Quantimet Leica, Cambridge, UK). Both the numbers of foci and myocardial cells with pathological alterations must be normalized to 100 mm2.

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Fig. 1. Coronary congenital anomalies.

A detailed protocol for practical usage in sudden cardiac death cases is presented in the appendix.

4. CORONARY ANOMALIES AND STENOSIS Congenital coronary anomalies constitute a statistical incidence of 0.3–0.8% and represent 0.1–2% of all congenital cardiac conditions worldwide. Congenital anomalies of the coronary arteries can present great difficulties in their diagnosis because these diseases can, at times, be absolutely asymptomatic and, although rarely, can manifest themselves with syncopal episodes or with a fading symptomatology leading to heart failure (9). However, the more serious the anomaly is, the more precocious is death (Fig. 1). Sudden cardiac death is most common when the origin of the left coronary artery is located in the right sinus of Valsalva. In such cases, several pathogenetic mechanisms have been proposed. These include compression by the pulmonary trunk, kinking, coronary artery spasm, or an acute ostial outlet resulting in a slitlike intramural course that allows diastolic compression, especially during exercise. Origin of both right and left coronary ostia in the left sinus is a less common and significant anomaly, even though a similar acutely angled outlet may be present. Another anomaly is the origin of the left main coronary artery from the pulmonary trunk (6).

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The anomalous origin of the right coronary artery from the left Valsalva sinus has long been considered a mostly benign disease. In an earlier study, 10 cases of sudden cardiac death were described that were attributed to this type of congenital anomaly (12). The origin of the right coronary artery from the left sinus may be an incidental observation during autopsy. Ischemia is usually precipitated by strenuous, prolonged effort, and this explains why a basal electrocardiogram (ECG) or even a stress test ECG may be negative. Syncopal episodes are the only prodromal symptoms. Repetitive ischemic episodes may cause patchy myocardial necrosis and fibrosis as well as ventricular hypertrophy, which eventually can elicit arrhythmias because of the malignant combination of acute and chronic substrates. This may explain why sudden cardiac death, associated with an anomalous origin of a coronary artery from the wrong sinus, may occur in adults even though the anomaly has been present since birth. An anomalous origin of the left circumflex artery from the left coronary sinus itself with a separate ostium has also been described in victims of unexpected arrhythmic sudden death. This anomaly was considered a benign condition until cases were reported, both clinically and pathologically, with evidence of myocardial ischemia in the absence of obstructive coronary atherosclerosis or causes other than the malformation itself. It should be noted that in children and young adults with coronary anomalies, sudden death often occurs during or following physical exertion (13–20). Coronary aneurysms are typical complications of Kawasaki disease in the healed phase. Coronarography studies found coronary artery aneurysms in more than 23% of Kawasaki patients that occurred in the initial tract of the coronary arteries, the right coronary artery being more frequently involved and occluded (21). Deaths from myocardial infarction in Takayasu disease are also described; a stenosing coronary arteritis is observed in such cases (22). The term “sudden coronary death” is in harmony with the classic pathogenetic viewpoint that any coronary arterial obstructive lesion leads to myocardial ischemia with consequent structural and functional damage to the cardiac pump. Any attempt to interpret the functional significance of coronary atherosclerotic plaques demands knowledge of their frequency and the degree of luminal reduction they cause in a healthy population. Pathologists are regularly consulted to assess coronary atherosclerosis at autopsy despite the difficulties inherent in the methods used to quantify stenosis. The preferred method is to cut multiple cross-sections at 2- to 3-mm-thick intervals along all the three major coronary arteries. Visual assessment can be made by the degree of stenosis seen at different sites. This method has very serious limitations when

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used for correlation with angiography that was carried out during life or when used to indicate clinical significance. Pathologists will tend to overestimate the degree of narrowing. The explanation for this is the remodeling of the vessel wall. When comparing the lumen to the size of the vessel, the pathologist has to bear in mind the remodeling that occurs. The external size of the vessel at this time is larger than normal and the degree of stenosis will be overestimated. A second factor is that pathologists are examining collapsed and empty coronary arteries in which the lumen is often slitlike. In coronary arteries with eccentric plaques that are distended by blood flow, the lumen becomes round to oval, but when the lumen is bloodless it appears slitlike, thus causing a spurious impression of stenosis. The final factor is that calcification will hinder the cutting of cross-sections without completely distorting the lumen. A more sophisticated technique consists in decalcifying the coronary arteries before making the cross-sections. Segments of the major coronary arteries of several centimeters long can be removed from the heart and decalcified for 24 hours. In such segments, the degree of stenosis can be accurately assessed by comparing the vessel lumen at the narrowest point compared with the lumen at an area of the artery in which the wall appears relatively normal, thus giving an impression of the extent of stenosis that comes close to angiographic pictures in life (23). Histology may offer structural details of the wall and intraluminal changes, particularly when serial section studies are performed (Fig. 2). However, findings include aspects of events that occurred during the whole life of a plaque. We constructed a history of the coronary atherosclerotic plaque by studying many coronary sections and verifying the trend of morphological changes in relation to intimal thickening and lumen reduction in ischemic and clinically normal subjects (9). From the significant associations of first and second order of variables and the highest chi-square values obtained according to sensitive and specific codes, it was possible to outline a three-dimensional (radial, circumferential, and longitudinal) progression of the atherosclerotic plaque in patients with ischemic heart disease and in controls (Table 2). It is as follows: initially, a plaque is a nodular fibrous intimal thickening likely due to smooth muscle cell hyperplasia with subsequent fibrous tissue replacement. This early fibrous plaque is the only pattern occasionally seen in young people less than 20 years of age (24). The second stage is proteoglycan accumulation (basophilia) deep to the fibrous cap. Both fibrosis and basophilia are recurrent phenomena, being two basic elements in plaque progression. Subsequently, foam cells and cholesterol clefts and/or calcification appear in the proteoglygan pool, in keeping with the chemical

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Fig. 2. Physiologic intimal thickening. (A) Smooth myocellular and (B) elastic fibre hyperplasia. (C,D) With increasing age this intimal thickening progressively loses myocellular and elastic components becoming (E,F) a fibrous intimal layer (hematoxylin and eosin and Gomori, original magnification × 50).

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Table 2 Schematic Presentation of the Progression of Atherosclerotic Plaques in Relation to Increasing Intimal Thickening and Lumen Reduction Intimal thickness (µ)

Morphologic variables

Lumen reduction (%)

>300

Nodular smooth myocyte hyperplasia ? Fibrosis

<50

600

Fibrosis + basophilia early adventitial/intimal inflammatory reaction

50–69

1000

Basophilia Atheroma B Calcification B

70–79 ?

2000

Inflammatory reaction

90

affinity of glycosaminoglycans for lipoproteins and calcium salts (25). Therefore, a basophilic pool may evolve into either a calcified area or atheroma. The final plaque pattern is a result of the extension in three directions of these repetitive phenomena plus further complications such as hemorrhage and thrombosis (11) (Fig. 3). A critically narrowed atherosclerotic plaque means that a functioning collateral system formed by satellite, homocoronary, and/or intercoronary anastomosis and by a network of communicating channels around and within the plaque bypasses the stenosed lumen. This hemodynamic background may act, per se, with stasis of blood around and within the greatly vascularized plaque, or may be associated with (a) a mechanical action of the contracting myocardium on the coronary wall especially in exertion, (b) coronary spasm, and (c) extravascular compression of nonfunctioning myocardium with increased peripheral resistance and further blockage of blood flow in the related coronary artery both in the residual lumen and in connected intimal/ adventitial vessels. All these mechanisms can explain the sequence of events in a dynamic or active plaque causing fissuring or rupture, hemorrhage, and thrombosis. In acute coronary syndromes, the atherosclerotic plaque is the site of several events, which may explain luminal and intimal changes secondary to hemodynamic or medial or nerve impairment. In our definition, an active plaque (Fig. 4) is related to an inflammatory process that may derange

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Fig. 3. Typical atherosclerotic plaque without allograft vasculopathy changes showing lymphocytic perimedial infiltration (hematoxylin and eosin, original magnification × 50).

regional contractility via nerve involvement, release of active substances resulting in coronary spasm, or myocardial asynergy (11).

5. THE MYOCARDIAL ALTERATION In sudden cardiac death, the myocardial cell may stop functioning in irreversible relaxation, in contraction, or may progressively lose its force and velocity. Each situation produces a different morphological form of irreversible myocardial damage. Infarct necrosis is observed when myocytes lose their capability to contract, becoming passive and extensible elements. This loss of contraction can

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Fig. 4. Schematic presentation of active plaque formation.

be seen within a few seconds when experimentally occluding a dog’s coronary artery. The acutely ischemic myocardium becomes cyanotic and because of intraventricular pressure shows a paradoxical systolic bulging. The term “coagulation necrosis” seems inappropriate because of the lack of coagulation of structures in various phases. The term “infarct necrosis” seems more appropriate. The histological counterpart of this flaccid paralysis (with stretching and reduction in thickness of the infarcted wall) is a thinning of the mildly eosinophilic necrotic myocytes with elongation of sarcomeres and nuclei (Fig. 5). These changes are visible within 1 hour of experimentally induced coronary artery occlusion. Other histological changes in chronological sequence are seen in both animal experiments and human tissue: a centripetal polymorphonuclear (PMN) leukocytic infiltration from the periphery of the infarct occurs within 6–8 hours with minimal exudate of edema fluid, fibrin, and red cells. PMN leukocytes increase in number during the next 24 hours and disappear by lysis within the first week of onset, without evident destruction of necrotic myocytes. Large infarcts may show a central area where the sequence of changes described does not occur. Rather, the mildly eosinophilic, stretched, dead myofibers persist. This is due to a blockage of PMN leukocytic penetration caused by maximal stretching of the central part of the dead tissue. Furthermore,

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Fig. 5. Early infarct necrosis. Stretching of flaccid paralyzed myofibers by intraventricular pressure with elongation of nuclei and sarcomeres, a change visible within 1 hour in experimental coronary occlusion. Note the absence of edema, hemorrhage, vacuolization, and pathological contraction bands (hematoxylin and eosin, original magnification × 250).

if a marked PMN leukocytic infiltration develops at the edge of sequestered, dead myocardium, the overall appearance may resemble an abscess with myocyte destruction. Fibrin/platelet thrombotic occlusion of intramural vessels included in the infarcted zone occurs parallel to, but not before, PMN infiltration. The healing process, which starts 1 week after infarction, begins at the periphery by macrophagic digestion of necrotic material within sarcolemmal tubes and is followed by progressive collagenization. Three further findings and three comments complete histological observations in this type of necrosis. First, the registered order of sarcomeres may be maintained for a long time in remnants of dead myocytes in healed infarcts (>30 days) and if entrapped in a scar. Second, the lack of filling by postmortem injection of intramural arterial vessels is noticeable in an acute infarct (“avascular area”). Third, this type of necrosis usually presents as one focus. It may affect the subendocardial zone or a greater width of the ventricular wall and can be transmural. Its size ranges from less than 10% to more than 50% of

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Fig. 6. Contraction band necrosis: markedly thickened Z-lines and extremely shortened sarcomeres (hematoxylin and eosin; original magnification × 80).

the left ventricular mass. Very rarely it presents as small multiple foci in the subendocardium. A last comment concerns the so-called “wavy fibers,” undulated myocardial fibers proposed as an early sign of myocardial ischemia. When found, their lack of specificity does not permit, per se, a diagnosis of ischemia. In fact, wavyness of normal myocytes is usually observed around hypercontracted myocardial fibers. Contraction band necrosis presents an opposite pattern to infarct necrosis. Here the myocyte is unable to relax and its function arrests in contraction, or more precisely in hypercontraction, because of an extreme reduction in sarcomere length, much less than 1.5 µm as it is calculated for normal contraction. Histologically, this form of myocardial necrosis is characterized by irreversible hypercontraction of the myocyte with a breakdown of the whole contractile apparatus with markedly thickened Z-lines and extremely short sarcomeres (Figs. 6 and 7). This breakdown varies from irregular, pathological, and eosinophilic cross-bands consisting of segments of hypercontracted or coagulated sarcomeres to a total disruption of myofibrils, the whole cell assuming a granular aspect without visible clear-cut pathological bands (Figs. 8 and 9). These deeply staining cytoplasmic bands in hematoxylin and eosin sections alternate with clear, empty spaces or with spaces filled by small dark

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Fig. 7. Foci of about 10 hypercontracted sarcomeres without myofibrillar rhexis (hematoxylin and eosin, original magnification × 80).

granules (9). Ultrastructurally, a transverse band appears as a small group of hypercontracted sarcomeres with highly thickened Z-lines or as amorphous, darkly electronmicroscopical dense material that is likely the result of coagulation of contractile proteins. The clear spaces are filled by normal or slightly swollen mitochondria containing dense, fine granules and occasionally showing rupture of their cristae. The sarcotubular system is totally disrupted whereas the basement membrane is essentially intact; only occasionally are interruptions seen in its continuity. Folding of the sarcolemma expresses the hypercontractile state of sarcomeres. Glycogen deposits disappear without evidence of intracellular or interstitial edema. There is no damage to blood vessels and hence no associated hemorrhage with the myocyte necrosis nor are platelet aggregates or platelet/fibrin thrombi to be found. It seems likely that the degree of fragmentation of the rigid, inextensible myocytes in irreversible hypercontraction is a consequence of the mechanical action of the normal contracting myocardium around them. Contraction band necrosis, as defined above, is reproduced experimentally by intravenous infusion of catecholamines, is not an ischemic change, and is observed in many human pathological entities such as pheochromocytoma, ischemic heart disease, electrocution, malignant hyperthermia, magnesium deficiency, psychological stress, and so on. It ranges from foci formed by one or a few myocytes to large zones in the absence of interstitial/ intermyocellular hemorrhage.

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Fig. 8. (A,B,C,D,F) Clear paradiscal band (electron microscopy, original magnification × 3500). (E) Hypercontraction of relatively few sarcomeres adjacent to an intercalated disk produces a paradiscal lesion (phosphotungstic acid hematoxylin, original magnification × 640).

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Fig. 9. (A,B) Evolving contraction band necrosis. (C) Progressive destruction of myofibrillar remnants associated with monocytes/macrophages leading to an alveolar pattern formed by empty sarcolemmal tubes infiltrated by macrophages loaded by lipofuscin. (D) A healing phase with progressive collagenisation ending in a fibrous scar. (E) Monocytic infiltration. (F,G) Hypercontraction produces a scalloped sarcolemma and wavyness of adjacent normal myocytes (hematoxylin and eosin, original magnification × 250).

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Fig. 10. Contraction band necrosis. Diffuse early pattern without cellular infiltrate (hematoxylin and eosin, original magnification × 400).

However, in many conditions, the frequency and extent of contraction band necrosis indicate an adrenergic role in its natural history, for example, in ischemic heart disease, intracranial hemorrhage and congestive heart failure— all diseases in which there is a general consensus for a sympathicomimetic overtone. In other words, sympathicotonic-prone individuals may have an “adrenergic crisis” any time a physical and/or psychological stress occurs, which explains the high variability among subjects of the same group. This concept is supported by the presence of all stages of the lesion (e.g., crossbands, alveolar healing) in the same heart, particularly in excised hearts deriving from transplantation surgery (Figs. 10–12). The latter is a unique model since agonal stimuli and reanimative, terminal therapeutic procedures are absent. It has to be stressed that in animal experiments, hearts excised from control animals did not show contraction bands of any type. The early contraction band necrosis in human hearts deriving from transplantation surgery may be related to presurgical adrenergic stress in patients with an already increased sympathetic overtone. Accordingly, the threshold for a diagnosis of sympathetic stress seems to be a number of foci and myocytes/100 mm2 with the range of those found in the previously mentioned diseases and the presence of foci of contraction band necrosis of any stages. The significantly higher extent of this lesion in sudden, unexpected cardiac death cases with preceding resuscitation attempts seems more likely to be because of a longer survival rather than any iatrogenic effects. In fact, the frequency and extent of early

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Fig. 11. Contraction band necrosis. Leukocytic infiltrate suggestive of a macrophagic reaction secondary to coagulative myocytolysis (hematoxylin and eosin, original magnification × 400).

Fig. 12. Alveolar pattern of empty sarcolemmal tubes preceding collagenization (Movat, original magnification × 100).

changes were similar in treated and nontreated subjects, all showing older phases of contraction band necrosis, a concept supported by intracranial hemorrhage and head trauma groups with a greater extent related to survival despite a terminal therapy in the former and no therapy in the latter. A last point is that multifocal and/or interstitial intermyocellular fibrosis may be owing to

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Fig. 13. Colliquative myocytolysis in a case of acute myocardial infarction. The myocellular damage is limited to the (A) subendocardial and (B) perivascular regions. (C) Old myocardial infarction: preserved myocytes in the perivascular region C (hematoxylin and eosin; original magnification × 400).

repetitive loss of myocytes with collagen substitution secondary to catecholamine myotoxicity with the false impression of a primary collagen matrix proliferation or reparative ischemic fibrosis. The evolving pathology of this necrosis can be distinguished as follows: (a) hypercontraction/cross-bands as an early change, (b) progressive destruction of myofibrillar remnants that is associated with infiltration by monocytes/ macrophages resulting in an alveolar pattern formed by empty sarcolemmal tubes loaded by lipofuscin, and (c) a healing phase with progressive collagenization ending in a fibrous scar. In the third pattern (colliquative myocytolysis), in contrast to the previously described types of myonecrosis, the cell maintains its function with a gradually reduced capacity to contract thus leading to heart insufficiency. The histological marker is a progressive loss of myofibrils associated with intracellular edema and with different degrees of damage from mild vacuolization (“moth-eaten pattern”) to total disappearance of myofibrils (Figs. 13 and 14). This produces an alveolar pattern but, in contrast to the other forms of

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Fig. 14. Colliquative myocytolysis. Mild loss of myofibrils in a transverse section producing an alveolar pattern (hematoxylin and eosin, original magnification × 600).

myonecrosis mentioned above, the alveolar pattern lacks macrophages or any other cell reaction. The impression is that of a colliquation or washout of myofibrils that leaves a sarcolemmal sheath with a clear alveolar appearance with a cytoplasm filled by edema and/or packed with small granules (mitochondria) (Fig. 15). Recently, we described a morphofunctional myocardial pattern linked with ventricular fibrillation defined as “myofiber break-up.” Myofiber breakup includes the following histological patterns: (a) bundles of myocardial cells in distension alternated with hypercontracted ones. In the latter, widening or rupture (segmentation) of the intercalated discs occurs. Myocardial nuclei in the hypercontracted cells assume a “square” aspect rather than the ovoid morphology seen in distended myocytes, (b) hypercontracted myocytes standing in line that are alternated with hyperdistended ones, often divided by a widened disk, and (c) noneosinophilic bands of hypercontracted sarcomeres alternated with stretched, often apparently separated sarcomeres. Each of the functional forms of myocardial damage described above has a distinct structural and biochemical nature. In irreversible relaxation, intrac-

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Fig. 15. Colliquative myocytolysis: total disappearance of myofibrils in a transverse section (hematoxylin and eosin, original magnification × 100).

ellular acidosis displaces Ca++ from troponin. During irreversible hypercontraction, intracellular alkalosis induces a rapid loss of adenosine adenosine 5'-triphospate with a lack of energy to remove Ca++ from troponin and/or a massive intracellular influx of Ca++ from increased membrane permeability. In the failing death of myocytes, the sarcotubular system and mitochondria have a reduced capacity to bind Ca++. The finding of contraction band necrosis, even if microfocal, could be an important histological signal for interpreting the cause of death and the natural history of a disease in any single patient. In particular, in a sudden death resulting from myocardial infarction that is otherwise not detectable histologically (26–28), the finding of contraction band necrosis could be the marker explaining cardiac arrest as secondary to adrenergic stress. However, one must remember that in people who die suddenly and unexpectedly, the frequency of a myocardial infarction is about 20% as shown in resuscitated and electrocardiographically monitored patients (9). Therefore, the finding of foci of catecholamine-induced damage in a case of sudden cardiac death that occurred within 6 hours after the onset of symptoms does not necessarily confirm the presence of an underlying myocardial infarction (29). The obvious need is to

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discriminate between contraction band necrosis resulting from preterminal stimuli and its presence as a histological sign of adrenergic overdrive during the course of the disease. A significant variability of this lesion in different normal and disease patterns exists. For instance, contraction band necrosis is absent in carbon monoxide intoxication, whether accidental or suicidal, suggesting an antiadrenergic effect of lethal anoxia despite a longer survival period. Only if reoxygenation is restored, contraction bands lacking interstitial hemorrhage will be present (30). In other words, we need to know the frequency, extent, and stages of this lesion to interpret both the natural history of a disease and the mode of death. Beyond a histological threshold of 37 ± 7 foci and 322 ± 99 myocytes/100 mm2, the lesion may indicate sympathetic overdrive in the natural history of a disease and associated arrythmogenic supersensitivity.

6. CONCLUSION Knowledge of the many biochemical, functional, and morphological changes that occur in the heart in sudden cardiac death stimulated the development and refinement of techniques to aid in the postmortem diagnosis. Although some biochemical and functional abnormalities begin virtually immediately at the onset of severe ischemia (e.g., anaerobic glycolysis and loss of myocardial contractility occur within 60 seconds), other changes evolve over a more protracted interval, and loss of cell viability is not immediate (29). Although some techniques have considerable merit in the research setting, many factors limit their practical use in forensic pathology, particularly when autolysis is present. The possibility that immunohistochemical and biochemical methods, quantitative morphometry, and demonstration of apoptosis in the myocardium might enhance the detection of the early cardiac changes in cases of sudden cardiac death is an exciting field of research (31–33). With the recognition that there exists no highly specific and sensitive “gold standard” for the recognition of early myocardial pathological changes, the use of a combination of techniques in a standardized protocol might be appropriate in sudden cardiac death cases. Perhaps the most pressing issue related to the use of these techniques is how to select best those applicable to diagnostic purposes (34). At present, further studies are needed to confirm the best accuracy of these methods (35). In conclusion, progress to ultimate knowledge of cardiac morphology in sudden cardiac death cases requires to accredit facts and an intellectual challenge in which both agonistic and antagonistic ideas are needed. Also bear in mind that the value of any investigation may lie more in the questions it raises than in those it answers (9).

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APPENDIX: HEART MORPHOLOGY STUDY Ord. N. ................... Source ................... Autopsy No. ................... Death-autopsy interval (hours) ...................... Last name ...................................................... First name .............................. Sex ................... Age (yrs.) ................... Body weight (kg) ................... Height (cm) ......... Interval first episode-death ................... minutes ................... hours Ischemic heart disease .............. 1. no 2. angina 3. infarct 4. unknown Cardiac failure ................... 1. no 2. yes 3. unknown Cardiac arrest ................... 1. ventric. fibrill. 2. asystole 3. failure 4. elect. mech. diss. 5. unknown Other data ....................................................................................................... .............................................................................................................................. HEART GROSS EXAMINATION Weight (g) .......... body weight (kg) ..........% .......... Diameter longitudinal (mm) .......... transverse .......... antero-poster. .......... Wall thickness (mm) ANT/SUP POST/SUP LV .......... .......... RV .......... SPT .......... Other data ....................................................................................................... HEART HISTOLOGY CORONARY ARTERIES LM LAD

LCX RCA RCA RCA sup ant marg post Stenosis (%) ........ ........ ........ ........ ........ ........ Stenosis type ........ ........ ........ ........ ........ ........ 1. nodular 2. semilunar 3. concentric Plaque ........ ........ ........ ........ ........ ........ 1. Fibrous 2. +s.m.c. 4. basophilia 8. atheroma 16. calcif. 32. hemorrhage 64. lymph-plasm. Thrombus mural ........ ........ ........ ........ ........ ........ 1. no 2. yes

RCA ........ ........ ........

........

........

........

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Thrombus ........ ........ ........ ........ ........ ........ ........ ........ occlusive 1. no 2. acute 3. recent 4. organized Other findings................................................................................................. .............................................................................................................................. MYOCARDIUM

LV LV RV RV SPT ant post ant post Area mm2 ...... ....... ...... ...... Infarct necrosis % ...... ...... ....... ...... ...... Histological pattern ...... ...... ....... ...... ...... 1. eosinoph+PMN 2. PMN exud. 3. macroph. 4. early fibr. 5. fibr+necr tissue Wall location ...... ...... ...... ...... ...... 1. subend. 2. intern. 4. subep. Base-apex ...... ....... ...... ...... ...... location 1. superior 2. middle 4. inferior 8. apex Coagulative myocytolysis No. foci ...... ...... ...... ...... ...... No. of myocytes...... ...... ....... ...... ...... Wall location ...... ...... ....... ...... ...... 1. subend. 2. intern. 4. subep. Type ...... ....... ...... ...... ...... 1. monofocal 2. multifocal 3. confluent 4. massive Base-apex ...... ...... ....... ...... ...... location 1. superior 2. middle 4.inferior 8. apex Histological ...... ...... ....... ...... ...... pattern 1. hypercontr. + rhexis 2. holocytic 4. paradiscal 8. alveolar 16. organizing Associated ...... ...... ....... ...... ...... monocytes 1. no 2. micro 3. extensive Myofiber...... ...... ....... ...... ...... breakup/VF 1. no 2. yes

Sudden Cardiac Death LV ant ......

LVP ant ......

165 LV post .......

RV ant ......

RV post .......

SPT

Colliquative ....... myocytolysis Grade 0. 1. 2. 3. Base-apex ...... ...... ....... ...... ....... ....... location 1. superior 2. middle 4. inferior 8. apex Wall location ...... ...... ....... ...... ....... ....... 1. subend. 2. intern. 4. subep. Histological ...... ...... ....... ...... ....... ....... pattern 1. lysis 2. vacuolar 4. alveolar Fibrosis % ...... ...... ....... ...... ....... ....... Age ...... ...... ....... ...... ....... ....... 1. old 2. recent Type ...... ...... ....... ...... ....... ....... 1. monofocal 2. multifocal 4. confluent 8. perivasc/interfasc 16. intermyocellular Wall location ...... ...... ....... ...... ....... ....... 1. subend. 2. intern. 4. subep. Base-apex ...... ...... ....... ...... ....... ....... location 1. superior 2. middle 4. inferior Fibrosis ...... ...... ....... ...... ....... ....... endocardial 1. no 2. yes 4.+s.m.c. 8.+monocytes 16. s.m.c. sine end. fibrosis Type ...... ...... ....... ...... ....... ....... 1. focal light 2. focal severe 3. diffuse light 4. diffuse severe Fibrosis ...... ...... ....... ...... ...... ...... epicardial 1. no 2. yes 4. + monocytes 8. + fibrin Type ...... ...... ....... ...... ...... ...... 1. focal light 2. focal severe 3. diffuse light 4. diffuse severe Constrict. .......... pericard. 1. no 2. yes

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Lymphocyte infiltrates LV LV RV RV SPT ant pos ant pos No. foci ...... ...... ....... ...... ....... perivascular ...... ...... ....... ...... ...... intramyocardial ...... ...... ....... ...... ...... intramyocardial ...... ...... ....... ...... ...... + myoc. necr. Other infiltrates ......... 1. no 2. PMN 3. PMN+necrosis 4. Eosinophils 5. Eosinophils+necrosis Extension ...... ....... ...... ...... ...... 1. focal light 2. focal severe 3. diffuse mild 4. diffuse severe Hypertrophy ...... ...... ....... ...... ...... 1. no 2. yes Disarray ...... ...... ....... ...... ....... 1. no 2. focal 3. diffuse Other findings................................................................................................. ..............................................................................................................................

REFERENCES 1. Davis JH (1998) The determination of sudden cardiac death. A philosophical approach. In Turillazzi E, ed., La dimensione medico-legale della medicina dello sport. Sports medicine: a forensic approach. Edizioni Colosseum, Roma, pp. 21–32. 2. Sampson BA (2001) Cardiac death—current concepts. Cardiovasc Pathol 10, 269. 3. Zheng ZJ, Croft JB, Giles WH, Mensah GA (2001) Sudden cardiac death in the United States, 1989 to 1998. Circulation 104, 2158–2163. 4. Virmani R, Burke AP, Farb A (2001) Sudden cardiac death. Cardiovasc Pathol 10, 275–282. 5. Cohle SD, Sampson B (2001) The negative autopsy: sudden cardiac death or other? Cardiovasc Pathol 10, 219–222. 6. Little DAL, Silver MD (1998) Non atherosclerotic causes of sudden death in adults. In Turillazzi E, ed., La dimensione medico-legale della medicina dello sport. Sports medicine: a forensic approach. Edizioni Colosseum, Roma, pp. 217–240. 7. Reiner L (1968) Gross examination of the heart. In Gould SE, ed., Pathology of the heart and blood vessels. Thomas CC, Springfield, Ill, pp. 1136–1146. 8. Silver MM, Silver MD (2001) Examination of the heart and of cardiovascular specimens in surgical pathology. In Silver MD, Gottlieb AI, Schoen FJ, eds., Cardiovascular pathology. Churchill Livingston, New York, pp. 1–29.

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9. Baroldi G, Silver MD (1995) Sudden death in ischemic heart disease. An alternative view on the significance of morphologic findings. Springer R.G. Landes Company, Austin, TX, p. 59. 10. Baroldi G, Radice F, Schmid C, Leone A (1974) Morphology of acute myocardial infarction in relation to coronary thrombosis. Am Heart J 87, 65–75. 11. Fineschi V, Baroldi G (2004) Cardiovascular pathology and sudden death. CEDAM, Padua. 12. Roberts WC, Siegel RJ, Zipes DP (1982) Origin of the right coronary artery from the left sinus of Valsalva and its functional consequences: analysis of 10 necropsy patients. Am J Cardiol 49, 863–868. 13. Lipsett J, Byard RW, Carpenter BF, Jimenez CL, Bourne AJ (1991) Anomalous coronary arteries arising from the aorta associated with sudden death in infancy and early childhood. An autopsy series. Arch Pathol Lab Med 115, 770–773. 14. Steinberger J, Lucas RV, Edwards, JE, Titus JL (1996) Causes of sudden unexpected cardiac death in the first two decades of life. Am J Cardiol 77, 992–995. 15. Thiene G, Basso C, Corrado D (2001) Cardiovascular causes of sudden death. In Silver MD, Gottlieb AI, Schoen FJ, eds., Cardiovascular pathology. Churchill Livingston, New York, pp. 326–374. 16. Mahowald JM, Blieden LC, Coe JI, Edwards JE (1986) Ectopic origin of a coronary artery from the aorta; sudden death in 3 of 23 patients. Chest 89, 668–672. 17. Taylor AJ, Rogan KM, Virmani R (1992) Sudden cardiac death associated with isolated congenital coronary artery anomalies. J Am Coll Cardiol 20, 640–647. 18. Land RN, Hamilton AY, Fuchs PC (1994) Sudden death in a young athlete due to an anomalous commissural origin of the left coronary artery, and focal intimal proliferation of aortic valve leaflet at the adjacent commissure. Arch Pathol Lab Med 118, 931–933. 19. Garfia A, Rodriguez M, Chavarria H, Garrido M (1997) Sudden cardiac death during exercise due to an isolated multiple anomaly of the left coronary artery in a 12-yearold girl: clinicopathologic findings. J Forensic Sci 42, 330–334. 20. Frescura C, Basso C, Thiene G, Corrado D, Pennelli T, Angelini A, et al. (1998) Anomalous origin of coronary arteries and risk of sudden death: a study based on an autopsy population of congenital heart disease. Hum Pathol 29, 689–695. 21. Fineschi V, Paglicci Reatelli L, Baroldi G (1999) Coronary artery aneurysm in a young adult: a case of sudden death. A late sequelae of Kawasaki disease. Int J Legal Med 112, 120–123. 22. Chiasson DA, Ipp M, Silver MM (1990) Clinical Conference. Acute heart failure in an 8 year-old diabetic girl. J Pediatr 116, 472. 23. Sheppard M, Davies MJ (1998) Practical cardiovascular pathology. Arnold, London. 24. Angelini A, Thiene G, Frescura G, Baroldi G (1990) Coronary arterial wall and atherosclerosis in youth (1–20 years): a histologic study in a northern Italian population. Int J Cardiol 28, 361–370. 25. Wight TN, Curwen KD, Litrenta MM, Alonso DR, Minick CR (1983) Effect of endothelium on glycosaminoglycan accumulation in injured rabbit aorta. Am J Pathol 113, 156–164.

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26. Brinkmann B, Sepulchre MA, Fechner G (1993) The application of selected histochemical and immunohistochemical markers and procedures to the diagnosis of early myocardial damage. Int J Legal Med 106, 135–141. 27. Thomsen H, Held H (1995) Immunohistochemical detection of C5b-9(m) in myocardium: an aid in distinguishing infarction-induced ischemic heart muscle necrosis from other forms of lethal myocardial injury. Forensic Sci Int 71, 87–95. 28. Ortmann C, Pfeiffer H, Brinkmann B (2000) Demonstration of myocardial necrosis in the presence of advanced putrefaction. Int J Legal Med 114, 45–55. 29. Hopster DJ, Milroy CM, Burns J, Roberts NB (1996) Necropsy study of the association between cardiac death, cardiac isoenzymes and contraction band necrosis. J Clinic Pathol 49, 403–406. 30. Fineschi V, Agricola E, Baroldi G, Bruni G, Cerretani D, Mondillo D, et al. (2000) Myocardial morphology of acute carbon monoxide toxicity: a human and experimental morphometric study. Int J Legal Med 113, 262–270. 31. Vargas SO, Sampson BA, Schoen FJ (1999) Pathologic detection of early myocardial infarction: a critical review of the evolution and usefulness of modern techniques. Mod Pathol 12, 635–645. 32. Rodriguez-Calvo MS, Tourret MN, Concheiro L, Munoz JI, Suarez-Penaranda JM (2001) Detection of apoptosis in ischemic heart. Usefulness in the diagnosis of early myocardial injury. Am J Forensic Med Pathol 22, 278–284. 33. Ribeiro-Silva A, Martin CCS, Rossi MA. (2002) Is immunohistochemistry a useful tool in the postmortem recognition of myocardial hypoxia in human tissue with no morphological evidence of necrosis? Am J Forensic Med Pathol 23, 72–77. 34. Ludwig J (2002) Autopsy practice, 3rd ed. Humana Press., Totowa, NJ. 35. Edston E, Grontoft L, Johnsson J (2002) TUNEL: a useful screening method in sudden cardiac death. Int J Legal Med 116, 22–26.

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6 Medicolegal Problems With Neonaticide Roger W. Byard, MBBS, MD CONTENTS INTRODUCTION MOTIVATION MATERNAL CHARACTERISTICS SCENE EXAMINATION ROLE OF THE PATHOLOGIST AUTOPSY EXAMINATION METHODS FOR DETERMINING LIVE BIRTH CAUSES OF DEATH CONCLUSION REFERENCES

SUMMARY Neonaticide, or the killing of an infant within the first month of life, presents many difficulties for pathologists and courts. Births are often concealed and the victims’ bodies hidden. Pathological findings tend to be nonspecific, particularly where deaths have been caused by suffocation, drowning, or failure to provide adequate care and support of newly born infants. Determination of live or stillbirth may not be possible in cases of concealed births as independent witnesses are usually not available to verify mothers’ histories. Whereas changes of maceration indicate intrauterine death, a vital reaction in the umbilical cord stump with milk within the stomach indicates survival for some time after birth. The latter findings will not, however, be present in most deaths that typically occur soon after delivery. Failure to demonstrate From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 171

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inflation of lungs or gas within the stomach does not exclude live birth, and conversely such aeration may occur from resuscitation or postmortem putrefaction. The flotation test is an unreliable indicator of prior respiration. Lack of precise pathological markers for live birth, and/or cause of death, often precludes definitive statements about the manner of death. Stillbirth cannot be excluded in cases where considerable doubts exist. Key Words: Concealed birth; homicide; infanticide; neonaticide; stillbirth.

1. INTRODUCTION Although terminology differs slightly, neonaticide usually refers to the killing of young infants under 1 month of age, and infanticide to deaths before 1 year. One month has been taken as 28 or 30 days, although on occasion, neonaticide has been used only for deaths resulting from inflicted injury or omission of adequate care within the first day of life, as these deaths generally occur very soon after delivery (1–3). Neonaticide has been separated from infanticide owing to the unique nature of the immediate postpartum period, and the typical features exhibited by many cases that differ from physical abuse in later infancy (4).

2. MOTIVATION Reasons for killing newborn infants are varied and have differed among communities and over time. Community-sanctioned neonaticide has been practiced in many populations ranging from the Spartans of Ancient Greece to contemporary nomadic groups such as the Inuit. Infants were either smothered or drowned, or abandoned to die of exposure or animal attack. The justification for such practices was maintenance of a sustainable population in times of need, or the removal of physically or intellectually impaired infants who may have placed a burden on a community. Female infants were particularly at risk (5,6). Infants have been used as sacrificial offerings in religious ceremonies (7), a practice that may continue among certain modern cults (8). In more recent times, infanticide may be provoked by fears of shame or rejection by family members, particularly when pregnancy has occurred in young, unmarried women. Such pregnancies may have continued owing to failure to seek an abortion because of naïveté, denial, or strict religious, family, or societal restrictions against this procedure. Greater tolerance of pregnancy outside marriage has seen a reduction in numbers of such deaths, as have improvements in contraception and contraceptive advice. Infanticide may occur if a pregnancy has been the result of an extramarital affair, in an attempt

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to hide the event from a spouse, or if there are financial concerns regarding the cost of another child, or the loss, or restriction of, employment (2,9). Although many mothers do not manifest psychiatric symptoms (10) depersonalization with dissociative hallucinations has been reported (11). Infanticide may be a manifestation of psychotic illness that has in some cases been triggered by pregnancy. The possibility of a puerperal association with mental illness has been long recognized and legislation in the United Kingdom has reflected this by stating that a mother’s mental state may be “disturbed by reason of her not having fully recovered from the effect of giving birth” (1,7). For this reason, a separate crime of infanticide has been maintained in some jurisdictions with lesser penalties than for murder. Repeated episodes of infanticide by some mothers over many years (12) with minimal attempts to either dispose of the bodies of the victims or disguise recent pregnancies also suggest mental disturbance. An example of the latter is the presentation of a mother to hospital with significant vaginal bleeding due to a retained placenta with complete denial of either the pregnancy or delivery. Carefully planned clandestine deliveries with complex methods of disposal of the body, such as encasement in cement and hiding within an attic, in other cases would seem to indicate an absence of incapacitating mental impairment or illness.

3. MATERNAL CHARACTERISTICS Mothers are often young, poor, and unmarried with low levels of formal education (13). As noted previously, there may be evidence of underlying mental illness. Whereas in some cases pregnancies may have been concealed, occasionally mothers have simply not realized that they were pregnant (14). Spontaneous delivery into toilet bowls sometimes characterizes the latter group. Perpetrators usually do not have a criminal record.

4. SCENE EXAMINATION The likely sequence of events may not be difficult to piece together if an infant and mother have been found soon after delivery. Copious amounts of blood within a bed or bathroom will indicate the place of delivery, and concealment of the body may show lack of forethought when a cupboard or container within the mother’s room or house has been used (Fig. 1). Attics, floor spaces, and garden beds may also be used as convenient and accessible hiding places (Fig. 2). Infants’ bodies may be thrown over fences into neighboring yards, or may be taken some distance from the mother’s place of residence and placed in rubbish dumpsters, left in public washrooms, or hidden in scrubland (Fig. 3).

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Fig. 1. Infant body wrapped in a towel and blanket found hidden in a cupboard following a concealed home delivery. No injuries were discernible at autopsy.

Occasionally, garments of the mother are disposed with the body thus facilitating identification of the mother (Fig. 4). The placenta is often disposed of separately. The farther away from a mother’s residence that disposal takes place and when no personal items are present, the more difficult it may be to link an infant with a particular woman, unless problems associated with the delivery have resulted in medical attention and treatment. Different methods of disposal occur in different communities, with abandonment and disposal of infants in coin-operated lockers in railway stations being a method that has been utilized in Japan (15). In these cases, significant information may be obtained from station security cameras. Careful examination of a scene may produce significant information linking a particular infant and mother. For example, the presence of obvious injuries may indicate the type of weapon used, and material used to wrap or transport an infant, such as blankets or supermarket bags, may help to identify or locate the maternal residence. Adjacent household rubbish may also help in this regard.

5. ROLE OF THE PATHOLOGIST Various questions need to be answered by a pathologist handling a case of suspected neonaticide. These include estimating the gestational age of

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Fig. 2. Skeletal remains (mandibles and maxillae) from at least three infants were found beneath the floor of a house during renovations. Origin of the remains and causes of death could not be established.

an infant, determining whether there are indications of live or stillbirth, checking for the presence of lethal underlying organic diseases, documenting lethal and nonlethal injuries, helping to establish the identity of the mother, and determining cause, mechanism, and manner of death if possible. Gestational age can most reliably be determined by comparing careful measurements of an infant to standard growth charts (16). Radiological evaluation will also be a useful adjunct by enabling ossification sites to be assessed against known developmental data. Although estimation of placental age by examination of chorionic villus maturation should be undertaken, this is a less reliable means of determining gestational age than morphometric measurements of an infant. Blood and tissue samples should be taken for possible matching with maternal blood groups and DNA if these become available. If a mother is

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Fig. 3. The body of a recently delivered infant wrapped in paper and poorly concealed in long grass (arrow).

located, she can also be checked for various conditions that are associated with an increased risk of fetal demise including hypertension, diabetes mellitus, anemia, and renal or cardiac disease. A history of prolonged gestation (>42 weeks) and a high number of previous pregnancies may be significant.

6. AUTOPSY EXAMINATION 6.1. Examination of the Infant The autopsy examination of such infants should be undertaken by a pathologist with pediatric/perinatal experience and should follow standard guidelines (17), commencing with a full external examination with photography and radiology. Routine parameters that are measured include weight, crown-heel, crown-rump, and foot length. The presence of dysmorphic features should be documented, again with careful photographs, and karyotyping should be considered if significant abnormal features are noted, particularly if these correspond to known genetic conditions such as trisomy 21. If abnormal features are noted, attendance at the autopsy by, or consultation with, a medical geneticist may provide useful information regarding specific features that should be checked for on internal examination. Descriptions should include

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Fig. 4. A mother’s garments that she was wearing prior to birth, which were disposed with the infant´s body in a plastic bag. Note the blood on the clothing. In this case, the clothing gave the first hint for a later identification of the mother. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

the absence or presence of vernix caseosa and blood (Fig. 5) indicating recent delivery, or washing of the body before disposal. Any injuries should be examined and photographed. Injuries that may have been inflicted with the aim of killing an infant include: strangulation marks around the neck with bruising from hands, or parchmented abrasions from ligatures that may have been left in situ; craniocerebral trauma that may include bruising with subgaleal, extradural, and subdural hemorrhages, skull fractures and cerebral lacerations, and contusions from blows to the head with blunt objects; and stab wounds. Drowning and smothering may leave minimal findings; neither strangulation nor smothering are usually associated with facial petechiae in infants. Inflicted injuries should be carefully distinguished from injuries owing to birth trauma, normal anatomical features, and postmortem damage.

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Fig. 5. Clotted blood on the face and vernix caseosa on the left cheek, neck, shoulders, and upper chest indicating recent delivery. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

The process of delivery may cause a number of characteristic injuries to infants such as hemorrhage and edema within the scalp (caput succadeum) and subperiostial hemorrhage (cephalhematoma). Fractures are uncommon and may involve the clavicles and long bones in breech deliveries or when there has been malpresentation or cephalopelvic disproportion. Internal injuries to the spleen and liver may also occur with obstructed labor. Separation of parts of the occipital bone, occipital osteodiastasis, may also be a feature of breech deliveries that causes cerebellar lacerations and tearing of dural venous sinuses with subdural bleeding (16). Precipitate delivery with excessive molding of the head may also cause intracranial hemorrhage. Unfortunately, assessment of the likely significance of certain of these lesions may be complicated by a lack of history of the delivery. Scratch marks or even a ligature around the neck may not necessarily indicate attempted strangulation, as these may be found if a mother has attempted to manually extract an infant, or has used a loop of cloth to assist with traction. Similarly, pressure from an umbilical cord wrapped around the neck may also leave circumferential grooving that should not be confused

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Fig. 6. (A) Umbilical cord entanglement around the neck. (B) When the umbilical cord is removed prior to autopsy, circumferential grooving can be confused with ligature indentation. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

with ligature indentation (Fig. 6A,B). Normal fat folds may also produce circumferential markings (18). Precipitate delivery may cause asphyxia in small infants, who can also sustain head injuries if a mother has delivered in a standing or squatting position with an umbilical cord long enough for an infant to strike the ground or floor. Asphyxia may also complicate obstructed labors from shoulder dystocia or cephalopelvic disproportion in larger infants. Evidence of acute asphyxia at autopsy includes thymic, pleural, and epicardial petechiae with intraalveolar hemorrhage, and meconium and shed fetal skin (squames) within distal air passages (16). More chronic stress may be manifested by evidence of growth retardation, decreased amounts of subcutaneous fat, and meconium staining of skin and fingernails. The body of an infant may also be damaged after death, particularly if it has been moved or compressed within a rubbish dumpster. Exposure of a body to animal and insect activity may also result in quite extensive soft-tissue trauma

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(19). Putrefactive and autolytic changes will be additional factors complicating assessment of the presence or absence of injuries. Another important aspect of the autopsy is to check for the presence or absence of lethal natural diseases. Certain conditions such as anencephaly and congenital diaphragmatic hernia with significant pulmonary hypoplasia should be readily identifiable, although subtle cardiovascular or metabolic abnormalities may be more difficult to diagnose. Full microbiological workup of both the infant and the placenta, if available, should be undertaken, along with histological examination of all major organs and tissues to check for sepsis.

6.2. Examination of the Placenta Placental examination is a vital part of any perinatal autopsy, however, because of the unusual circumstance surrounding concealed deliveries and possible neonaticides the placenta may not always be available for pathological assessment. Various placental conditions may result in the stillbirth of otherwise completely normal infants (20). Premature separation of the placenta from its uterine attachments (abruptio placentae) may be associated with extensive retroplacental bleeding and compromise of placental and infant oxygenation. This may be manifested by persistence of clot adhering to the maternal surface of the placenta, or an indentation into the placental parenchyma indicating its position if it has become detached. Obstruction of the entrance to the birth canal by the placenta (placenta previa) may lead to massive hemorrhage once labor is initiated, with death of both mother and infant unless urgent medical intervention has occurred. Vasculopathy may result in extensive placental infarction and there may be evidence of sepsis in the form of acute chorioamnionitis and funisitis. Umbilical cord problems may also cause precipitate deterioration in an infant’s condition from a variety of mechanisms. Excessively long cords may cause blood flow obstruction if prolapse, torsion, or knotting occur. Long cords may also wrap around an infant’s neck. Conversely, blood flow in short cords may also be compromised if there is excessive traction during delivery. The average cord length is 54–61 cm with short cords measuring less than 30 cm and long cords measuring greater than 100 cm (16). Although possible twisting or knotting of cords may be difficult to assess, true knots should be tight, with congestion of vessels on one side and pallor on the other. There may be thrombi demonstrable histologically. Significant hemorrhage may occur during delivery if cord vessels overlie the entrance to the birth canal (vasa previa) or if vessels insert into the

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Fig. 7. Incised end of an umbilical cord (arrow) in a case of neonaticide.

more fragile membranes rather than the placental parenchyma (velametous insertion) where they are more likely to be traumatized. Examination of the ends of the cord must be undertaken macroscopically and microscopically. This will reveal whether the ends of the cord have been cut (Fig. 7), or have torn, possibly indicating a precipitate delivery.

7. METHODS FOR DETERMINING LIVE BIRTH 7.1. General Aspects Determination of whether an infant was born alive or dead is one of the most difficult aspects of these cases. A further problem is that the definition of what constitutes “live birth” legally differs from jurisdiction to jurisdiction. Requirements have included complete expulsion from the birth canal with a heart beat and/ or respiratory efforts. Unfortunately, an autopsy examination simply cannot determine whether a heart has functioned or whether the body was completely expelled prior to death, and so pathological opinion relies on an assessment of the degree of pulmonary inflation, the presence or absence of a vital reaction in the tissues, or evidence of feeding. The age of viability also varies among jurisdictions with 24 and 28 weeks being cited as the lower limits of potential survival (21).

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Signs of intrauterine death, caused by a process of sterile tissue breakdown or maceration, may be present indicating that live birth has not occurred. During this process the body undergoes a series of characteristic changes beginning with reddening, slippage, and peeling of the skin after 12 hours, followed by purple discoloration and blister formation after 24 hours, and the development of pleural, peritoneal, and pericardial effusions after 48 hours (16). After several days the body has lost tone, joints become hypermobile, and cranial bones have collapsed producing Spalding’s sign on radiography. An infant with changes of maceration has not been alive outside the uterus. The assertion that intraalveolar squames and/or meconium indicates stillbirth (22) is not correct as these findings merely indicate that some degree of fetal distress has occurred and may be found in living infants some time after birth. The most reliable evidence of live birth is an independent and reliable witness who has either seen the infant moving or heard the infant crying. Milk within the stomach indicates that the infant was alive long enough to feed and was capable of such activity. Drying and separation of the umbilical cord stump, which occurs after 24–48 hours, with histological evidence of a tissue reaction, may also be useful, but does not help with deaths in the immediate postdelivery period.

7.2. Flotation Test One of the most time-honored tests used to assess the amount of pulmonary inflation that has occurred is the flotation test. This is based on the hypothesis that the lungs from an infant who has breathed will be expanded and filled with air and therefore will float in water, in contrast to the noninflated lungs of a stillborn infant, which will sink (4). Some authors suggest that it is better to attempt to float the lungs and heart en bloc to increase the sensitivity of the test (21). Unfortunately, interpretation of this test is fraught with difficulty as there are numerous false positives and negatives, making this test of dubious usefulness in isolation. For example, lungs from a stillborn infant may float if there has been attempted resuscitation, with forcing of air into distal airspaces, or if there has been generation of gas within lung tissues by putrefactive bacteria. Similarly, lungs from a live-born infant may not have been inflated sufficiently to float if respiratory efforts have been weak. It has even been asserted that moving a dead infant may cause air to be aspirated into the lungs (21). However, though considering these caveats it can certainly be said that salmon-pink spongy lungs that float in water, in the absence of resuscitation and putrefaction, are most in keeping with lungs from an infant who has breathed (Fig. 8).

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Fig. 8. Aerated lungs floating in water in a case of alleged stillbirth without resuscitation.

Radiographs may be used to assess the degree of pulmonary inflation and also to detect air within the stomach and upper gastrointestinal tract. If resuscitation or putrefaction have not occurred, it is assumed that air has reached the gut from swallowing. The stomach may also float in water if distended by air. The usefulness of attempting to demonstrate air within the middle ears is debatable and the relationship between the presence of pulmonary interstitial emphysema and possible live birth is yet to be clarified (23).

7.3. Lung Weights Another measurement that has not proven of much use is comparison of lung to body weights. This was based on the observation that inflated and perfused lungs are heavier than lungs where respiration has not occurred. Again considerable inaccuracies occur.

7.4. “Birth-Line” The so-called “birth-line” in teeth refers to a line caused by disturbance of ameloblast activity at birth that can be detected after several weeks. Although scanning electronmicroscopy has been used to identify this finding within several days of birth, its practical usefulness is not great given that most deaths occur earlier than this.

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8. CAUSES OF DEATH Deaths are most often a result of airway obstruction from smothering or strangulation. An infant’s nose and mouth may be blocked with a hand in an attempt to prevent the infant’s cries from being heard. Infants may also asphyxiate if placed in plastic bags and hidden while a mother cleans up after delivery and determines what she is to do. Drowning may occur if an infant is delivered into a toilet bowl and left there, or is held under water in a bath (24). Blunt head trauma may occur. Although stabbing is less common, occasionally a throat may be cut (2,9,10). Deaths may also occur from failure to provide appropriate care of a vulnerable newborn. Failure to tie off the cut umbilical cord may result in lethal blood loss, and airway occlusion from secretions may compromise respiration if not cleared. Failure to adequately clothe or place an infant in a warm environment may result in fatal hypothermia.

9. CONCLUSION Given that the causes of death may not be found at autopsy in unexpected near-term stillbirths that occur in hospitals under highly controlled conditions, it is perhaps not surprising that determination of lethal mechanisms may not be possible in cases where infants have been found abandoned some days after delivery. In these cases, stillbirth must be assumed until there is firm evidence to the contrary.

REFERENCES 1. Marks MN, Kumar R (1996) Infanticide in Scotland. Med Sci Law 36, 299–305. 2. Pitt SE, Bale EM (1995) Neonaticide, infanticide and filicide: a review of the literature. Bull Am Acad Psychiatr Law 23, 375–386. 3. Adelson L (1991) Pedicide revisited. The slaughter continues. Am J Forensic Med Pathol 12, 16–26. 4. Cohle SD, Byard RW (in press) Intentional trauma. In Byard RW, ed., Sudden death in infancy, childhood and adolescence, 2nd ed. Cambridge University Press, Cambridge. 5. Ober WB (1986) Infanticide in eighteenth-century England. William Hunter’s contribution to the forensic problem. Pathol Annu 21, 311–319. 6. Coon CS (1971). The hunting people. Little, Brown and Company, Boston. 7. Kellett RJ (1992) Infanticide and child destruction—the historical, legal and pathological aspects. Forensic Sci Int 53, 1–28. 8. Johnson CF (1990) Inflicted injury versus accidental injury. Pediatr Clin Nth Am 37, 791–814.

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9. Saunders E (1989) Neonaticides following “secret” pregnancies: seven case reports. Pub Health Rep 104, 368–372. 10. Mendlowicz MV, Jean-Louis G, Gekker M, Rapaport MH (1999) Neonaticide in the city of Rio de Janeiro: forensic and psycholegal perspectives. J Forensic Sci 44, 741–745. 11. Spinelli MG (2001) A systemic investigation of 16 cases of neonaticide. Am J Psychiatr 158, 811–813. 12. Funayama M, Ikeda T, Tabata N, Azumi J-I, Morita M (1994) Case report: repeated neonaticides in Hokkaido. Forensic Sci Int 64, 147–150. 13. Overpeck MD, Brenner RA, Trumble AC, Trifiletti LB, Berendes HW (1998) Risk factors for infant homicide in the United States. N Engl J Med 339, 1211–1216. 14. Wissow LS (1998) Infanticide. N Engl J Med 339, 1239–1241. 15. Kouno A (2000) Coin-operated locker babies: murder of unwanted infants and child abuse in Japan. In Marvasti JA, Manchester CT, eds., Child suffering in the world. Child maltreatment by parents, culture and governments in different countries and cultures, Sexual Trauma Center Publication, Manchester, pp. 285–298. 16. Keeling J (1987) Fetal and neonatal pathology, Springer, London. 17. Bove KE and the Autopsy Committee of the College of American Pathologists (1997) Practical guidelines for autopsy pathology. The perinatal and pediatric autopsy. Arch Pathol Lab Med 121, 368–376. 18. Byard RW (2004) Sudden infant death syndrome. In Byard RW, ed., Sudden death in infancy, childhood and adolescence, 2nd ed. Cambridge University Press, Cambridge, pp. 491–575. 19. Byard RW, James RA, Gilbert JD (2002) Problems associated with cadaveric trauma due to animal activity. Am J Forensic Med Pathol 23, 238–244. 20. Ito Y, Tsuda R, Kimura H (1989) Diagnostic value of the placenta in medico-legal practice. Forensic Sci Int 40, 79–84. 21. Knight B (1996) Infanticide and stillbirth Ch 20. In Knight B, ed., Forensic pathology, 2nd ed. Arnold Press, London, pp. 435–446. 22. Bowen DAL (1989) Concealment of birth, child destruction and infanticide. In Mason JK, ed., Paediatric forensic medicine and pathology. Chapman and Hall Medical, London, pp. 178–190. 23. Lavezzi WA, Keough KM, Der’Ohannesian P, Person TLA, Wolf BC (2003) The use of pulmonary interstitial emphysema as an indicator of live birth. Am J Forensic Med Pathol 24, 87–91. 24. Mitchell EK, Davis JH (1984) Spontaneous births into toilets. J Forensic Sci 29, 591–596.

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7 Diagnostic and Medicolegal Problems With Sudden Infant Death Syndrome Roger W. Byard, MBBS, MD and Henry F. Krous, MD CONTENTS INTRODUCTION CHARACTERISTICS DEFINITION OF SUDDEN INFANT DEATH SYNDROME DIAGNOSTIC PROBLEMS PROBLEMS IN COURT CONCLUSION REFERENCES

SUMMARY Although many cases of unexpected infant death have been attributed to sudden infant death syndrome (SIDS), it remains a contentious entity with arguments for and against it as a distinct “diagnostic entity.” Major problems exist owing to the lack of pathognomonic features at autopsy; however, there is no doubt that infants between the ages of 2 and 4 months have an increased risk of dying unexpectedly during sleep. This risk is exacerbated by sleeping face down, covering with bed clothes, and exposure to cigarette smoke. Difficulties arise in evaluating cases of infant death as there is no uniformity in approach to cases, or use of standard definitions, despite the ready availability of the National Institute of Child Health and Human Development (NICHD) definition for SIDS, the International Standardized Autopsy Protocol for Sudden Unexpected Infant Death, and the Sudden Unexplained Infant Death From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 189

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Investigation Report Form. Similarities in the pathological findings at autopsy in infants whose deaths have been attributed to SIDS or to accidental or inflicted asphyxia emphasize the need for extensive background and scene information, with standard methods being utilized. Variations in approach make the assessment of cases even more difficult if they come to court. Although conflicting opinions, absence of requisite investigations, lack of pathognomonic findings, and the introduction of speculative research are certainly not unique to this area, they do feature particularly prominently. Courts attempt to deal with this tangle of complex causative mechanisms and theories, which are either not proven or are only poorly understood, by simplifying and summarizing. This sometimes results in loss of critical “gray” areas and important qualifiers, with resultant overstated and simplistic conclusions that are considered to be more easily understood by juries. Whereas researchers are better able to deal with the inconclusive results and uncertainties that beset this field, courts appear not as well equipped to do so. Key Words: Sudden infant death syndrome (SIDS); infant death; pathology; pediatric forensic pathology; court.

1. INTRODUCTION Despite marked reductions in the incidence of infant deaths in communities where there has been active promotion of campaigns to inform parents and infant carers of risk factors, sudden infant death syndrome (SIDS) remains one of the major causes of unexpected, postneonatal infant death (1–3). The diagnosis of SIDS is still, however, controversial, with calls being made for the abandonment of the term based partially on cases of infanticide that had been ascribed initially to SIDS (4,5). This chapter deals with problems that arise in trying to separate SIDS from other causes of unexpected infant death.

2. CHARACTERISTICS There is no doubt that SIDS is a useful term to use when infants die suddenly and unexpectedly during sleep and the cause remains unknown. The clinicopathologic profile of classic SIDS is characterized by recent antemortem good health, male gender, prone sleep position, maternal smoke exposure, and higher death rates during winter months. Other risk factors include premature birth, low birth weight, multiple births, lower socioeconomic status, minority ethnicity, bed sharing, being covered by blankets, and young maternal age (6–9). Unfortunately, similar features characterize many infants who have died of accidents, inflicted injuries, or definable natural diseases.

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Thorough autopsies in SIDS infants do not, however, reveal significant underlying organic diseases or evidence of inflicted injury (10,11).

3. DEFINITION OF SUDDEN INFANT DEATH SYNDROME Various different definitions of SIDS have been promulgated over the past decade. Definitions have variously required that death scene examinations and review of clinical history be performed, that there be a clear association with sleep, that the upper age limit should be 8 months, 1 year, or not specified, and that extensive ancillary postmortem investigations such as microbiological testing and toxicology should be undertaken (12–15). The significance of including minor pathological findings has been debated (16–18). Given this range of proposals, it is perhaps not surprising that there is confusion among pathologists and researchers regarding diagnostic requirements for SIDS and criteria for establishing other causes of death. In 1991, a definition was formulated by an expert committee brought together by the National Institute of Child Health and Human Development (NICHD). This stated that SIDS refers to “the sudden death of an infant under one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene and review of the clinical history” (19). Although the NICHD definition has not gained universal acceptance, most pathologists and researchers would recognize the value of the points that have been made, and although there is continued concern about the cutoff point of 1 year of age, it is acknowledged that unexpected deaths after infancy are very rare. More recently, Beckwith has proposed stratification of the definition with a graded classification ranging from SIDS cases that fulfill all of the required investigative steps to cases that are unclassifiable because of absence of significant information (20). Invited commentaries were in agreement with the need to redefine SIDS given the marked recent increase in knowledge in this area (21–26).

4. DIAGNOSTIC PROBLEMS Unfortunately, SIDS is not so much a “diagnosis” as a conclusion that is reached by a process of exclusion. As a result, there is certainly no doubt that cases of infanticide and fatal accidents have been, and will continue to be, misdiagnosed as SIDS (10,27–29). This occurs in part because of the nonspecificity of postmortem findings in infants who have died of SIDS or of “soft” suffocation, and also because the standard of investigation of cases of infant death varies widely among jurisdictions (30).

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In an attempt to reduce the numbers of these cases being misclassified, protocols have been devised that provide detailed guidelines for both death scene and autopsy examinations in cases of unexpected infant death (31,32). Although these protocols set a “gold standard” for the investigation of such cases, significant problems remain. For example, a major concern is that the diagnosis of SIDS is continually being made without fulfilling the criteria stated in the NICHD definition (30). In parts of Europe in the recent past, it has been stated that only 30–40% of cases of infants whose deaths were attributed to SIDS even had autopsies (1). In areas of Australia, cases may still be called SIDS with autopsies that are either incomplete or not performed by pathologists (30). Although conclusions are drawn on SIDS rates in isolated, indigenous, rural communities (33), it is difficult to believe that adequate examinations were always performed because of the logistical problems involved. Given this state of affairs, further dissemination and implementation of the Centers for Disease Control Guidelines and International Standardized Autopsy Protocol for sudden, unexpected infant death should be undertaken. It is noteworthy that these protocols have been endorsed by the Society for Pediatric Pathology and the National Association of Medical Examiners in the United States. The significance of misdiagnosis is far from academic. Other and future children in the family may be in jeopardy if rare inherited conditions are not characterized accurately. Failing to correctly diagnose accidental asphyxia due to an unsafe cot or cradle may result in a dangerous product being left in the marketplace, and lack of identification of infanticides may leave other children in the family at significant risk of injury or death. Research based on cohorts of infants or their families in whom inadequate investigations were undertaken must, therefore, be treated with circumspection. National or large multicenter studies are particularly vulnerable to this error as researchers often do not have control over the cases being passed to them, or complete understanding regarding the rigor with which other diagnoses were excluded. Papers that are now reporting SIDS research should always clearly specify not only the exact criteria followed to establish the diagnoses, but also the precise percentage of cases falling outside the NICHD definition. In addition, if research papers that were published before the current definition was formulated are being cited, this fact should be acknowledged. SIDS studies should also state whether the actual scene was investigated or whether scene information was collected only from questionnaires. It is time to re-evaluate SIDS research and possibly grade studies on the rigor with which diagnoses have been established. For example, cases would receive a high grading where

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death scene, clinical history, and full autopsy examinations were conducted by members of an investigative team according to established and accepted definitions and protocols. Research based on cases diagnosed many years ago when scenes and clinical history were not considered important should carry less weight, and studies using a significant number of cases where autopsies were not done will in all likelihood be uninterpretable. The value of protocols can be seen in the increase in diagnoses of deaths owing to such entities as accidental asphyxia because of unsafe sleeping environments, with the portion of unexpected infant deaths resulting from other causes now reaching 25% in some communities. This means that as many as one in four unexpected infant deaths could be incorrectly labeled as SIDS without proper investigation (34). This also raises the possibility that conflicting data that abound in SIDS research may be partly a reflection of the lack of precision with which the initial characterization of cases was undertaken, rather than an inherent heterogeneity in the underlying mechanism.

5. PROBLEMS IN COURT Dealing with cases of unexpected infant deaths in the court system adds yet another dimension of complexity. As many of these cases may have no, or only subtle pathological findings, it may be difficult to support or refute a diagnosis based purely on pathological findings. Cases that present particular difficulties concern families where multiple infant deaths have occurred. The concept of a third infant death in a family automatically representing a homicide is an extreme position as certain inherited conditions may be responsible for such a series of deaths. Examples of inherited conditions that may cause sudden and unexpected deaths in infants within a single family include prolonged QT syndrome and medium-length acyl-CoA dehydrogenase (MCAD) deficiency. Prolonged QT syndrome is caused by mutations involving genes that are involved in cardiac potassium and sodium channels resulting in lethal arrhythmias. MCAD deficiency is one of the most common inborn metabolic errors and has an estimated frequency of 1 per 20,000 newborns with a higher frequency among people of Northern European descent. The inheritance of the acyl-CoA dehydrogenase deficiencies is autosomal recessive and affected infants may die unexpectedly from metabolic disturbances. Mutations in both of these conditions can be detected by performing molecular studies on victims and close family members (1,35–37). Alternatively, problems may arise when hypothetical links to underlying findings in certain SIDS infants, such as inflammatory mediators like cytokines

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(38,39), are given undue weight and used as “proof” in court that a particular infant death must be due to SIDS. It is important to recognize that such hypotheses are theoretical and unproven and cannot, therefore, be used as confirmatory “evidence” for a cause of death. Different problems also occur in different countries. For example, infant carers in certain jurisdictions have been charged with manslaughter when infants in their care have died while sleeping face down. The assumption has been made that there has been negligence in leaving such infants in a position where they are at risk of asphyxiation. The basis for this is, however, incorrect. As the majority of infants who sleep face down do not die, the mechanism of death is not simple asphyxia in most circumstances and must include a range of interactions involving diaphragmatic splinting, overheating, carbon dioxide rebreathing, in addition to possible airway occlusion, in an infant with inherent vulnerabilities (40–43). Death cannot, therefore, be attributed to suffocation purely on the grounds of an infant being found in the prone position. Other problems arise in cases of unexpected infant death when nonpediatric-trained forensic experts become involved in cases. For example, in a recent widely publicized case in the United Kingdom, retinal congestion was mistaken for antemortem retinal hemorrhage, leading to an incorrect diagnosis of shaken infant syndrome. In the same case, lacerations to the brain caused by postmortem removal were mistaken for inflicted antemortem trauma. Finally, isolation of the bacteria Staphylococcus aureus in pure growth from multiple sites, including the cerebrospinal fluid, was not regarded as significant. These errors led to a mother being convicted of the murder of two of her infants. The conviction was eventually overturned upon special review. The proffering of expert opinion by individuals who are peripheral to, or not actively involved in, pediatric forensic pathology often leads to confusing and conflicting information. Courts attempt to deal with masses of contradictory information by simplifying, which unfortunately often does not work. Attempting to summarize and categorize these extremely complicated cases into a series of questions with yes/no answers is akin to producing a one-page summary of a Russian novel. Although no one would disagree that the essentials of the plot could be captured by such an exercise, there is no doubt that important nuances conveying the true meaning and conclusions would be lost. Most would agree that such an exercise would be pointless. An example of incorrect expert opinion in the past has been the assertion that the bulk of cases attributed to SIDS have been homicides. This has been shown to be incorrect following the dramatic fall in numbers of SIDS deaths

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following “reducing the risk” campaigns. Put simply, avoidance of cigarette smoke and prone sleeping are not preventative factors for murder. Certainly some cases of homicide have been misdiagnosed as SIDS; however, these undoubtedly represent a small percentage of overall cases of infant death.

6. CONCLUSION A number of years ago, John Emery created a certain amount of controversy by asking whether the diagnosis of SIDS was being made too readily, resulting in a “diagnostic dustbin” into which a wide range of disorders were hastily placed (44). More recently, Meadow has asked whether the diagnosis of SIDS should be discontinued, given the number of misdiagnosed cases of homicide that were initially placed under the SIDS banner (4). Both of these papers highlighted inadequacies in the investigation of cases of unexpected infant death and there is no doubt that deaths have been attributed to SIDS in the past too readily and without due consideration of numerous pertinent facts (45,46). The “diagnosis” of SIDS cannot be made solely on the basis of autopsy findings and the 1991 definition clearly indicates this. The challenge, however, is to improve investigations into causes of infant death, including SIDS, rather than to revert to a situation where any complex or confusing case, or any case with potentially controversial diagnostic features is too readily relegated to an even larger “dustbin” of “undetermined” or “unascertained.” Although this may at times be the only conclusion possible, given the paucity of findings, it unfortunately does little to assist in the assessment and understanding of these complicated and emotive cases and should not be an excuse for incomplete investigations.

REFERENCES 1. Byard RW (2004) Sudden death in infancy, childhood and adolescence, 2nd ed. Cambridge University Press, Cambridge. 2. Byard RW, Krous HF (2001) Sudden infant death syndrome: Problems, progress and possibilities. Arnold, London. 3. Fleming P, Bacon C, Blair P, Berry PJ (2000) Sudden unexpected deaths in infancy: the CESDI SUDI studies 1993–1996. The Stationery Office, London. 4. Meadow R (1999) Unnatural sudden infant death. Arch Dis Child 80, 7–14. 5. Gilbert-Barness E (1993) Is sudden infant death syndrome a cause of death? Am J Dis Child 147, 25–26. 6. Hauck FR (2001) Changing epidemiology. In Byard RW, Krous HF, eds., Sudden infant death syndrome: problems, progress and possibilities. Arnold, London, pp. 31–57.

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7. Adams EJ, Chavez GF, Steen D, Shah R, Iyasu S, Krous HF (1998) Changes in the epidemiologic profile of sudden infant death syndrome as rates decline among California infants: 1990–1995. Pediatrics 102, 1445–1451. 8. Daltveit AK, Irgens LM, Oyen N, Skjaerven R, Markestad T, Alm B, Wennergren G, et al. (1998) Sociodemographic risk factors for sudden infant death syndrome: associations with other risk factors. The Nordic Epidemiological SIDS Study. Acta Paediatr 87, 284–290. 9. Byard RW (1995) Sudden infant death syndrome - A “diagnosis” in search of a disease. J Clin Forensic Med 2, 121–128. 10. Berry PJ (1992) Pathological findings in SIDS. J Clin Pathol 45, 11–16. 11. Rognum TO (2001) Definition and pathologic features. In Byard RW, Krous HF, eds., Sudden infant death syndrome: problems, progress and possibilities. Arnold, London, pp. 4–30. 12. Cordner SM, Willinger M (1995) The definition of sudden infant death syndrome. In Rognum TO, ed., Sudden infant death syndrome: new trends in the nineties. Scandinavian University Press, Oslo, pp. 17–20. 13. Beckwith JB (1993) A proposed new definition of sudden infant death syndrome. In Walker AM, McMillen C, eds., Second SIDS International Conference. Perinatology Press, New York, pp. 421–424. 14. Sturner WQ (1998) SIDS redux: is it or isn’t it? Am J Forensic Med Pathol 19, 107–108. 15. Rambaud C, Guilleminault C, Campbell PE (1994) Definition of the sudden infant death syndrome. Brit Med J 308, 1439. 16. Byard RW, Krous HF (1995) Minor inflammatory lesions and sudden infant death: cause, coincidence, or epiphenomena? Pediatr Pathol Lab Med 15, 649–654. 17. Rambaud C, Cieuta C, Canioni D, Rouzioux C, Lavaud J, Hubert P, et al. (1992) Cot death and myocarditis. Cardiol Young 2, 266–271. 18. Krous HF, Nadeau JM, Silva PD, Blackbourne BD (2003) A comparison of respiratory symptoms and inflammation in sudden infant death syndrome and in accidental or inflicted infant death. Am J Forensic Med Pathol 24, 1–8. 19. Willinger M, James LS, Catz C (1991) Defining the sudden infant death syndrome (SIDS): deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 11, 677–684. 20. Beckwith JB (2003) Defining the sudden infant death syndrome. Arch Pediatr Adolesc Med 157, 286–290. 21. Haas JE (2003) I agree with Beckwith. Arch Pediatr Adolesc Med 157, 291. 22. Krous HF (2003) Reflections on redefining SIDS. Arch Pediatr Adolesc Med 157, 291–292. 23. Becroft DM (2003) An international perspective. Arch Pediatr Adolesc Med 157, 292. 24. Cutz E (2003) New challenges for SIDS research. Arch Pediatr Adolesc Med 157, 292–293. 25. Rognum TO (2003) Sudden infant death syndrome: need for simple definition but detailed diagnostic criteria. Arch Pediatr Adolesc Med 157, 293. 26. Berry PJ (2003) SIDS: permissive or privileged “diagnosis”? Arch Pediatr Adolesc Med 157, 293–294.

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27. Krous HF (1988) Pathological considerations of sudden infant death syndrome. Pediatrician 15, 231–239. 28. Byard RW, Hilton J (1997) Overlaying, accidental suffocation and sudden infant death. J SIDS Infant Mort 2, 161–165. 29. Byard R, Krous H (1999) Suffocation, shaking or sudden infant death syndrome: can we tell the difference? J Paediatr Child Health 35, 432–433. 30. Byard RW (2001) Inaccurate classification of infant deaths in Australia: a persistent and pervasive problem. Med J Aust 175, 5–7. 31. Krous HF, Byard RW (2001) International standardized autopsy protocol for sudden unexpected infant death. Appendix I. In Byard RW, Krous HF, eds., Sudden infant death syndrome: problems, progress and possibilities. Arnold, London, pp. 319–333. 32. Centers for Disease Control and Prevention (1996) Guidelines for death scene investigation of sudden unexplained infant deaths. Recommendations of the Inter-agency Panel on Sudden Infant Death Syndrome. Morbid Mort Week 45, 1–22. 33. Alessandri LM, Read AW, Burton PR, Stanley FJ (1996) An analysis of sudden infant death syndrome in aboriginal infants. Early Hum Dev 45, 235–244. 34. Mitchell E, Krous HF, Donald T, Byard RW (2000) An analysis of the usefulness of specific stages in the pathologic investigation of sudden infant death. Am J Forensic Med Pathol 21, 395–400. 35. Schwartz PJ (2001) QT Prolongation and SIDS—From Theory To Evidence. In Byard RW, Krous HF, eds., Sudden infant death syndrome: problems, progress and possibilities. Arnold, London, pp. 83–95. 36. Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, Stramba-Badiale M, et al. (2000) A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 343, 262–267. 37. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, et al. (2001) Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 286, 2264–2269. 38. Guntheroth WG (1989) Interleukin-1 as intermediary causing prolonged sleep apnea and SIDS during respiratory infections. Med Hypotheses 28, 121–123. 39. Blackwell CC, Weir DM, Busuttil A, Saadi AT, Essery SD, Raza MW, et al. (1995) Infection, inflammation, and the developmental stage of infants: A new hypothesis for the aetiology of SIDS. In Rognum TO, ed., Sudden infant death syndrome: new trends in the nineties. Scandinavian University Press, Oslo, pp. 189–198. 40. Stanley FJ, Byard RW (1991) The association between the prone sleeping position and sudden infant death syndrome (SIDS): an editorial overview. J Paediatr Child Health 27, 325–328. 41. Mitchell EA, Ford RP, Taylor BJ, Stewart AW, Becroft DM, Scragg R, et al. (1992) Further evidence supporting a causal relationship between prone sleeping position and SIDS. J Paediatr Child Health 28, Suppl 1: S9–S12. 42. Fleming PJ, Blair PS, Bacon C, Bensley D, Smith I, Taylor E, et al. (1996) Environment of infants during sleep and risk of the sudden infant death syndrome: results of 1993-5 case-control study for confidential inquiry into stillbirths and deaths in

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infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. BMJ 313, 191–195. Kleemann WJ, Schlaud M, Poets CF, Rothämel T, Tröger HD (1996) Hyperthermia in sudden infant death. Int J Legal Med 109, 139–142. Emery JL (1989) Is sudden infant death syndrome a diagnosis? BMJ 299, 1240. Bacon CJ (1997) Cot death after CESDI. Arch Dis Child 76, 171–173. Anonymous (1999) Unexplained deaths in infancy. Lancet 353, 161.

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8 Fatal Respiratory Tract Infections With Mycoplasma pneumoniae Histopathological Features, Aspects of Postmortem Diagnosis, and Medicolegal Implications Michael Tsokos, MD CONTENTS INTRODUCTION ORGANISM, PATHOGENESIS, AND PATHOPHYSIOLOGY: A BRIEF OUTLINE HISTOPATHOLOGY POSTMORTEM DIAGNOSIS OF M. PNEUMONIAE INFECTION USING SEROLOGY AND PCR MEDICOLEGAL ASPECTS OF FATAL M. PNEUMONIAE INFECTIONS REFERENCES

SUMMARY Mycoplasma pneumoniae is a prokaryotic microorganism that lacks a rigid cell wall and has a high affinity for respiratory epithelial cells. M. pneumoniae has been shown to be a major pathogen leading to severe, potentially lifethreatening respiratory tract infections. The organism itself is too small to be detected at light microscopy. Histopathological features of the disease include two patterns of injury represented by (a) circumscribed bronchiolitis and (b) organizing pneumonia, the latter corresponding to a generalized inflammatory process spreading from M. pneumoniae’s primary target zone, the bronchi and bronchioli. In M. pneumoniae-associated bronchiolitis, the mucosa of the upper and lower airways appear edematous and infiltrated by a dense preFrom: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 201

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dominantly mononuclear infiltrate accompanied by an intraluminal exsudate of neutrophils and, to a lesser extent, macrophages. Occasionally, plugs of granulation tissue within the lumen of bronchi and bronchioli corresponding to bronchiolitis obliterans can be seen. M. pneumoniae-organizing pneumonia is characterized by a dense mononuclear infiltrate in alveolar septa and alveolar spaces that is frequently accompanied by intraalveolar hemmorhages and edema. The lungs may additionally show features of diffuse alveolar damage including type II pneumocyte hyperplasia, squamous metaplasia, and hyaline membranes as well as occlusive venous thromboses. To enable etiopathogenetic conclusions concerning a causal relationship between M. pneumoniae infection and fatal outcome, for example, in cases of alleged medical malpractice, the forensic investigation should ensure postmortem blood sampling as early as possible with subsequent enzyme-linked immunosorbent assay-based serological determination of IgA and IgM antibodies as well as an immediate autopsy to obtain native lung specimens for direct detection of M. pneumoniae using standard polymerase chain reaction. Intrinsic and extrinsic risk factors predisposing to the development of fatal M. pneumoniae infection have to be considered carefully in the following expert witness. From the medicolegal point of view, the sudden, unexpected death of an individual occurring outside hospital as the sequel of a rapidly progressive course of M. pneumoniae infection will have to be regarded as unavoidable in most cases. However, data obtained from such instances are valuable since fatal respiratory tract infections with M. pneumoniae in individuals dying outside hospital are probably underestimated. Key Words: Mycoplasma pneumoniae; community-acquired pneumonia; organizing pneumonia; bronchiolitis obliterans; fatal infection; forensic histopathology.

1. INTRODUCTION Mycoplasmas are prokaryotic microorganisms that lack a bacterial cell wall. Several mycoplasma species including Mycoplasma orale, Mycoplasma salivarium, Mycoplasma faucium and Mycoplasma buccale are encountered as part of the normal oropharyngeal human flora, but only Mycoplasma pneumoniae, which has a high affinity for respiratory epithelial cells, has been shown to be a major pathogen leading to severe, potentially life-threatening respiratory tract infections. M. pneumoniae infection is endemic in most regions of the world, although it is more common in temperate zones. M. pneumoniae is transmitted by respiratory droplet secretions (1). There are relatively few data on the pulmonary micromorphology of M. pneumoniae infections. The knowledge of the histopathological features of

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the disease is based on a paucity of observations from open lung biopsy specimens (2–4), experimental studies (5,6) and rare fatal cases (7–10). After briefly reviewing the pathogenesis and pathophysiological properties of M. pneumoniae, the different histopathological features of respiratory tract infections with M. pneumoniae are presented. The role of postmortem diagnostic procedures such as serology and standard polymerase chain reaction (PCR) from native (fresh) lung autopsy material to provide evidence of M. pneumoniae as the etiological agent in question is also considered. In addition, medicolegal issues related to fatal outcome of the disease are discussed.

2. ORGANISM, PATHOGENESIS, AND PATHOPHYSIOLOGY: A BRIEF OUTLINE Mycoplasmas are the smallest self-replicating organisms capable of causing infections in humans (11,12). These microorganisms lack a rigid cell wall and are bound by a single membrane, the plasma membrane. The lack of a cell wall is used to distinguish these microorganisms from ordinary bacteria and to include them in a separate class named Mollicutes. So far, 16 mycoplasma species have been identified in humans (13). The best studied is M. pneumoniae whose entire genome has been sequenced recently. It has a size of 816,394 base pairs with an average G + C content of 40.0 mol% (14). M. pneumoniae is a rod-shaped organism that has a polar, tapered cell extension at one end. This structure, a specialized terminal filament that is termed the tip organelle, functions as an attachment organelle in cytadherence as well as gliding motility and cell division (15,16). Because of its size of 10 × 200 nm, this Gram-negative organism escapes detection at light microscopy. M. pneumoniae adheres tenaciously to the epithelial lining cells of the respiratory tract. This adhesion of M. pneumoniae to the respiratory epithelium is a prerequisite for colonization and subsequent infection (17). Current theory holds that mycoplasmas remain attached to the surface of epithelial cells (18), although some mycoplasmas have evolved mechanisms for entering host cells that are not naturally phagocytic. The lack of a rigid cell wall allows direct and intimate contact of the mycoplasma membrane with the cytoplasmic membrane of the host cell. The receptors on host cell membranes responsible for mycoplasma attachment that have been identified so far are mostly sialoglycoconjugates and sulfated glycolipids (11,18). Most recent findings demonstrate that M. pneumoniae interacts in the respiratory system also with the surfactant proteins A and D and that primary determinants recognized on the organism are lipid components of the cell membrane (19,20). The

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attachment of mycoplasmas to the surface of host cells may interfere with membrane receptors or alter transport mechanisms of the host cell. The host cell membrane is also vulnerable to cytotoxic metabolites, cytolytic enzymes, and peroxide and superoxide radicals released by the adhering mycoplasmas causing ciliostasis, epithelial cell necrosis, and desquamation of mucosal cells into the airway lumen, the latter responsible for the cough that defines clinical presentation (1,16,21). M. pneumoniae infection is spread from one person to another by respiratory droplets produced by coughing. Spread of infection from person to person is very slow and a very close contact seems a prerequisite for infection (22). M. pneumoniae has an incubation period of 2–3 weeks (1,22) and epidemic outbreaks of M. pneumoniae pneumonia occur in 4- to 5-year-cycles (23). Outbreaks of illness attributable to mycoplasmas commonly occur in closed or semiclosed communities (23). These outbreaks are difficult to contain because of delays in outbreak detection, and the long incubation period of the organism (24).

3. HISTOPATHOLOGY A variety of pulmonary complications has been reported to occur with M. pneumoniae infection. These include organizing pneumonia, tracheobronchitis, obliterative bronchitis, bronchiectasis, pneumatocele formation, pleural effusions, interstitial fibrosis, lung abscess, and bronchiolitis obliterans (25–32). But because in a number of reports the affected individual suffered from severe underlying debilitating illnesses or immunological deficiencies that contributed to the onset of M. pneumoniae infection, it is tempting to speculate that the pathological features reported there may have been influenced, at least, to a certain degree by the pathophysiology and pathology of these underlying conditions. Furthermore, in most clinical cases reported, a detailed histopathological diagnosis is lacking. Therefore, this section focuses primarily on the pathological features of M. pneumoniae pneumonia that were observed in patients without immunocompromisation or co-existing lung diseases of other origin and were verified by histopathology. In a hamster model of M. pneumoniae infection, intratracheal inoculation of the organism produced a bronchiolitis characterized by peribronchiolar and perivascular lymphocytic infiltrates with neutrophils and macrophages within the bronchiolar lumen (6). At autopsy, infection with M. pneumoniae limited to bronchiolitis is merely characterized by patchy changes of the bronchioli, but this finding might escape macroscopical notice when the disease process is negligible. Widespread pneumonia caused by M. pneumoniae shows a patchy consolida-

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Fig. 1. Bronchiolitis in Mycoplasma pneumoniae infection: edematous bronchiolar wall showing a dense inflammatory infiltrate of predominantly mononuclear cells and vascular congestion. Note the loss of mucosal integrity with subsequent epithelial cell necrosis and desquamation of mucosal cells into the airway lumen (hematoxylin and eosin).

tion of one or more lobes of the lungs with confluent whitish-yellowish speckles on the cut surfaces. Vascular congestion is frequent. Depending on the presence and extent of pulmonary vessel thrombosis that usually escapes macroscopic examination, circumscribed pulmonary infarctions may be present. As with gross pathology, two distinctive pathological features of M. pneumoniae infection-associated pulmonary lesions can be distinguished on the micromorphological level, too. First, a bronchiolocentric pattern of injury reflected by a circumscribed bronchiolitis and second, a generalized inflammatory process spreading from M. pneumoniae’s primary target zone, the bronchi and bronchioli, to alveolar spaces and interstitium of one or more lobes of the lung. Referring to the histopathology of the bronchiolocentric pattern of injury, the mucosa of the upper and lower airways (primarily the terminal and respiratory bronchioles) appears edematous and infiltrated by a dense predominantly mononuclear infitrate. The release of cytotoxic and cytolytic substances by M. pneumoniae leads to loss of mucosal integrity with subsequent epithelial cell necrosis and desquamation of mucosal cells into the airway lumen (Fig. 1). This bronchiolitis is frequently accompanied by a dense intraluminal exsudate of neutrophils and, to a lesser extent, of macrophages (Fig. 2A,B). The organism itself is too small to be detected at light microscopy. The bronchiolar

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Fig. 2. Bronchiolitis in Mycoplasma pneumoniae infection. (A) Intraluminal exsudate of neutrophils and macrophages in a terminal bronchiolus. (B) Highpower view of excessive accumulation of neutrophils and macrophages within the lumen of a bronchiolus (hematoxylin and eosin).

epithelium is frequently destroyed, but one has to be aware that this phenomenon may also be a sheer consequence of autolysis and consequently this finding can only be considered as a true sequel of infection when bronchiolar epithelium loss is partly replaced by a layer of granulation tissue (Fig. 3). In more rare cases, one may observe plugs of granulation tissue within the lumen of bronchi and bronchioli corresponding to bronchiolitis obliterans (Fig. 4A,B).

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Fig. 3. Bronchitiolitis in Mycoplasma pneumoniae infection. The bronchial epithelium is destroyed and partly replaced by a layer of granulation tissue and capillary proliferation (hematoxylin and eosin).

Ebenöther and coworkers recently investigated the cellular subtypes of the bronchiolar infiltrate in M. pneumoniae infection-associated bronchiolitis using immunohistochemistry (4). These authors found that the bronchiolar infiltrate consisted mainly of CD3-positive lymphocytes (accounting for 35% of mononuclear cells), CD8-positive lymphocytes (21%), and CD68-positive macrophages (30%) (Fig. 5A,B). Forty percent of nuclei within the bronchiolar wall tissue stained positive with MIB-1a. Because this antibody recognizes a nuclear antigen that appears in all phases of the cell cycle except the G0 phase, this observation indicates high proliferative activity of the mononuclear cells. Previously reported respiratory tract infections with M. pneumoniae associated with bronchiolitis obliterans have been described with and without organizing pneumonia (2–4,32–35). The term “organizing pneumonia” is defined pathologically by the presence of buds of granulation tissue progressing from fibrin exsudates to loose collagen containing fibroblasts that occur predominantly within the alveolar spaces but may also occupy the bronchiolar lumen (36,37). This pathological pattern, which is characterized by a remarkably preserved pulmonary architecture, has to be considered an unspecific inflammatory process resulting from a number of underlying etiologies. Organizing pneumonia can be regarded as a failure of resolution of acute pneumonia and as a kind of “limited wound healing reaction” of the lung parenchyma (38). Organizing pneumonia may be classified into three categories according to its cause: organizing pneumonia of determined cause (e.g., bacterial, viral, parasitic, and fungal infections, drug-induced, associated with radiation pneumonitis), organizing pneumonia of undetermined cause but occurring in a specific and relevant context (e.g., in association with connec-

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Fig. 4. Bronchiolitis obliterans in Mycoplasma pneumoniae infection. (A) Necrotic bronchiolar epithelium, lymphoplasmacytic infiltrate in the bronchiolar wall and a plug of granulation tissue occluding the bronchiolar lumen (hematoxylin and eosin). (B) Same visual field as before. Using phosphotungstic acid hematoxylin staining the fibrin network can be clearly distinguished.

tive tissue disorders such as Wegener’s granulomatosis or rheumatoid arthritis), and cryptogenic (idiopathic) organizing pneumonia (38). Several possible causes and/or associated disorders may coexist in the same patient. Therefore, the histological finding of organizing pneumonia with or without bronchioli-

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Fig. 5. (A,B) Mycoplasma pneumoniae-organizing pneumonia. High-power view of immunohistochemical staining of macrophages with CD68 within the intraluminal exsudate. Note the vacuolation of the cytoplasm (so-called “foam cells”) (CD-68).

tis obliterans in autopsy cases of suspected fatal outcome of M. pneumoniae infection is highly unspecific. Severe, generalized lung injury in M. pneumoniae pneumonia is characterized by a dense mononuclear (lymphoplasmacytic) infiltrate in alveolar septa and alveolar spaces that is frequently accompanied by intraalveolar hemorrhages and edema (Fig. 6A–C).

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The lungs may additionally show features of diffuse alveolar damage including type II pneumocyte hyperplasia, squamous metaplasia, and hyaline membranes (Fig. 7). Occasionally, occlusive venous thromboses may be also present (Fig. 8A,B). Circumscribed microabscesses can be found only in cases of bacterial superinfection. M. pneumoniae has also been reported to exacerbate other respiratory disorders such as asthma (39,40) and chronic obstructive pulmonary diseases (41).

4. POSTMORTEM DIAGNOSIS OF M. PNEUMONIAE INFECTION USING SEROLOGY AND PCR Serologic assays for immunoglobulin A and immunoglobulin M determination are mostly based on the enzyme-linked immunosorbent assay (ELISA) principle and various test kits are available from different companies. To achieve a conclusive diagnosis, separate detection of IgM or IgA antibodies is essential. IgM antibodies appear during the first week of the illness, and reach peak titers during the third week (42). In clinical practice, elevated IgM antibodies represent a reliable indicator of mycoplasma infection in children (43,44). IgM antibodies titer decline below the cutoff value of commercial assays within months. In a recent medicolegal investigation, using a highly specific enzyme immunoassay (Virion, Würzburg, Germany), our investigative group was able to detect an elevated IgM antibody titer (57 U/ml) against M. pneumoniae (normal range <13 U/ml) in a venous blood sample obtained at autopsy from a 12-year-old girl who died of community-acquired M. pneumoniae pneumonia (unpublished results). Consequently, serological measurement of IgM postmortem should also be considered useful in fatalities of pediatric patients to achieve a definite diagnosis of M. pneumoniae as the causative agent. A major disadvantage of IgM-based diagnosis of M. pneumoniae infection in adults is that these antibodies are not constantly produced in the elderly, most likely as a result of multiple previous infections (45). Therefore, a negative IgM result does not rule out acute M. pneumoniae infection in the adult and IgA-based diagnosis provides higher sensitivity in older patients

Fig. 6. Mycoplasma pneumoniae pneumonia. (A) Panoramic view of intraalveolar and interstitial lymphoplasmacytic infiltrates with intraalveolar hemorrhages and edema (hematoxylin and eosin). (B,C) High-power views of lymphoplasmacytic infiltrate in interstitium and alveoli with intraalveolar hemorrhages and edema (hematoxylin and eosin).

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Fig. 7. Mycoplasma pneumoniae pneumonia. High-power view of diffuse alveolar damage with type II pneumocyte hyperplasia, squamous metaplasia, and thick PAS-positive hyaline membranes lining the alveolar wall (periodic acid-schiff).

(46). A Western immunoblot technique for M. pneumoniae, enabling the detection of lower antibody levels than other assays, has been recently developed and is now commercially available (Virotech, Rüsselsheim, Germany). This method is currently probably the most specific technique for indirect detection of M. pneumoniae, but postmortem experience with this method within the forensic setting has not been established so far. To rule out the possibility that elevated antibodies are owing to past infection, standard PCR is currently the method of choice for direct detection of M. pneumoniae. PCR has replaced hybridization and direct antigen detection because of its higher sensitivity (45). In forensic autopsy practice, standard PCR for detection of M. pneumoniae from native (fresh) lung autopsy material is also a useful tool.

5. MEDICOLEGAL ASPECTS OF FATAL M. PNEUMONIAE INFECTIONS The term and concept of atypical pneumonia derives from Reiman, who in 1938 described a series of cases in which patients had symptoms that differed from the typical symptoms of pneumococcal pneumonia (47). Differences included lack of response to penicillin, a longer duration of illness, and upper as well as lower respiratory tract symptoms. No bacterial pathogens were detected in these patients, and atypical pneumonia was attributed to pos-

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Fig. 8. (A,B) Occlusive venous thrombosis with cellular debris and fibrin deposits in Mycoplasma pneumoniae pneumonia (phosphotungstic acid hematoxylin).

sible viral infections. Finally, M. pneumoniae was identified as the etiological agent responsible for these cases of atypical pneumonia. Subsequently, atypical pneumonia became associated with other pathogens such as Chlamydia pneumoniae and Legionella that cause similar clinical presentations. M. pneumoniae accounts for 30–50% of community-acquired pneumonia and is one of the most frequent causes of pneumonia particularly among young adults (1,21,48–50). Approximately 20% of infected adult subjects are asymptomatic, the majority of cases (about 75%) develop minor respiratory

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tract diseases including pharyngitis and tracheobronchitis, and only 3–10% of infected subjects show serious clinical symptoms, mostly because of bronchopneumonia (49,51). In children under 5 years of age, M. pneumoniae infection is mostly nonpneumonic but in children between 5 and 15 years of age, the risk for M. pneumoniae pneumonia is highest (22). More than 30% of M. pneumoniae infections in this age group result in pneumonia (52). After a 2–3 week incubation period, the disease has an insidious onset composed of fever, malaise, headache, and cough. The latter, relatively constant and nonproductive, is the clinical hallmark of M. pneumoniae infection. The frequency and severity of cough increase over the next 1–2 days and the patient may become dyspnoic (1,22). As M. pneumoniae lacks a cell wall, this organism is not susceptible to penicillins or other antibiotics acting on this structure. The bacteriostatic antibiotics tetracycline and macrolides are effective in the treatment of M. pneumoniae infection (53,54). In children under the age of 8 years, tetracyclines are contraindicated and macrolides are the first choice (22). For detailed clinicopathological data on the symptoms and course of M. pneumoniae respiratory tract infections as well as diagnostic procedures and treatment, refer to the comprehensive clinical literature related to these topics. The forensic pathologist may be confronted with fatal M. pneumoniae respiratory tract infections presenting in the following constellations: (a) death of an individual who had consulted a physician prior to death but the correct diagnosis was not established because symptoms were misinterpreted for another disease and/or the applied diagnostic procedures were insufficient to achieve the correct diagnosis, (b) death of an individual who had consulted a physician prior to death and the correct diagnosis was established but treatment was inadequate, or (c) sudden, unexpected of an individual (usually occuring outside hospital) as the sequel of a rapidly progressive course of M. pneumoniae infection. To enable etiopathogenetic conclusions concerning the causal relationship between iatrogenic malpractice and fatal outcome of M. pneumoniae infection, the forensic investigation should ensure postmortem blood sampling as early as possible with subsequent serological determination of IgM or IgA antibody titers as well as an immediate autopsy to obtain native lung specimens for direct detection of M. pneumoniae using standard PCR. A thorough histological investigation as well as toxicological analysis is necessary to rule out concomitant diseases and/or intoxications, respectively, that may have contributed to fatal outcome. Intrinsic and extrinsic risk factors predisposing to the development of severe M. pneumoniae infection such as different kinds

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of immunodeficiency syndromes, drug-induced immunosuppression, sickle cell disease, and pre-existing cardiopulmonary dysfunction (21,55,56) have to be considered carefully in the following expert witness. For the forensic examiner evaluating a questioned case of fatal M. pneumoniae infection, for example, under aspects of alleged medical malpractice, the most essential question is whether the fatal outcome could have been prevented in all probability by an early and right medical diagnosis and effective treatment. From the medicolegal point of view, the sudden, unexpected of an individual occuring outside hospital as the sequel of a rapidly progressive course of M. pneumoniae infection will have to be regarded as unavoidable in most cases. Nonetheless, data obtained from such instances are valuable because fatal respiratory tract infections with M. pneumoniae in individuals dying outside hospital are probably underestimated because testing for this organism is not often performed in the outpatient setting and such fatalities are probably highly underrepresented in the field of clinical pathology when compared to the forensic autopsy setting.

REFERENCES 1. Baum SG (1995) Mycoplasma pneumoniae and atypical pneumonia. In Mandell GL, Bennett JE, Dolin R, eds., Mandell, Douglas and Bennett’s principles and practice of infectious diseases. Churchill Livingstone, New York, Edinburgh, London, Melbourne, Tokyo, pp. 1704–1713. 2. Rollins S, Colby T, Clayton F (1986) Open lung biopsy in Mycoplasma pneumoniae pneumonia. Arch Pathol Lab Med 110, 34–41. 3. Llibre JM, Urban A, Garcia E, Carrasco MA, Murcia C (1997) Bronchiolitis obliterans organizing pneumonia associated with acute Mycoplasma pneumoniae infection. Clin Infect Dis 25, 1340–1342. 4. Ebenöther M, Schoenenberger RA, Perruchoud AP, Soler M, Gudat F, Dalquen P (2001) Severe bronchiolitis in acute Mycoplasma pneumoniae infection. Virchows Arch 439, 818–822. 5. Hu PC, Collier AM, Baseman JB (1976) Interaction of virulent Mycoplasma pneumoniae with hamster tracheal organ cultures. Infect Immun 14, 217–224. 6. McGee ZA, Taylor-Robinson D (1981) Mycoplasmas in medical microbiology and infectious disease. In Braude AI, ed., Medical microbiology and infectious diseases. Saunders, Philadelphia, PA, pp. 522–528. 7. Fraley DS, Ruben FL, Donnelly EJ (1979) Respiratory failure secondary to Mycoplasma pneumoniae infection. South Med J 72, 437–440. 8. Halal F, Brochu P, Delage G, Lamarre A, Rivard G (1977) Severe disseminated lung disease and bronchiectasis probably due to Mycoplasma pneumoniae. Can Med Assoc J 117, 1055-1105. 9. Meyers BR, Hirschman SZ (1972) Fatal infections associated with Mycoplasma pneumoniae: discussion of three cases with necropsy findings. Mt Sinai J Med 39, 258–264.

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10. Koletsky RJ, Weinstein AJ (1980) Fulminant Mycoplasma pneumoniae infection. Report of a fatal case, and a review of the literature. Am Rev Respir Dis 122, 491–496. 11. Razin S, Yogev D, Naot Y (1998) Molecular biology and pathogenicity of Mycoplasmas. Microbiol Rev 63, 1094–1156. 12. Razin S (1997) The minimal cellular genome of mycoplasma. Indian J Biochem Biophys 34, 124–130. 13. Tully JG (1993) Current status of the mollicute flora of humans. Clin Infect Dis 17, Suppl 1: S2–S9. 14. Himmelreich R, Hilbert H, Plagens H, Pirkl E, Li BC, Herrmann R (1996) Complete sequence analysis of the genome of the bacterium Mycoplasma pneumoniae. Nucleic Acids Res 24, 4420–4449. 15. Krause DC, Balish MF (2001) Structure, function, and assembly of the terminal organelle of Mycoplasma pneumoniae. FEMS Microbiol Lett 198, 1–7. 16. Rottem S (2003) Interaction of Mycoplasmas with host cells. Physiol Rev 83, 417–432. 17. Barile MF, Rottem S (1993) Mycoplasmas in cell cultures. In Kahane I, Adoni A, eds., Rapid diagnosis of Mycoplasmas. Plenum, New York, pp. 155–193. 18. Razin S, Jacobs E (1992) Mycoplasma adhesion. J Gen Microbiol 138, 407–422. 19. Chiba H, Pattanajitvilai S, Evans AJ, Harbeck RJ, Voelker DR (2002) Human surfactant protein D (SP-D) binds Mycoplasma pneumoniae by high affinity interactions with lipids. J Biol Chem 277, 20379–20385. 20. Chiba H, Pattanajitvilai S, Mitsuzawa H, Kuroki Y, Evans A, Voelker DR (2003) Pulmonary surfactant proteins A and D recognize lipid ligands on Mycoplasma pneumoniae and markedly augment the innate immune response to the organism. Chest 123, 3 Suppl: 426S. 21. Gal AA (1997) Mycoplasma pneumoniae infections, In Connor DH, Chandler FW, Schwartz DA, Manz HJ, Lack EE, eds., Pathology of infectious diseases, Vol. 1. Appleton & Lange, Stamford, CT, pp. 675–680. 22. Ferwerda A, Moll HA, de Groot R (2001) Respiratory tract infections by Mycoplasma pneumoniae in children: a review of diagnostic and therapeutic measures. Eur J Pediatr 160, 483–491. 23. O’Handley J G, Gray LD (1997) The incidence of Mycoplasma pneumoniae pneumonia. J Am Board Fam Pract 10, 425–429. 24. Ancel Meyers L, Newman ME, Martin M, Schrag S (2003) Applying network theory to epidemics: control measures for Mycoplasma pneumoniae outbreaks. Emerg Infect Dis 9, 204–210. 25. Leong MA, Nachajon R, Ruchelli E, Allen JL (1997) Bronchitis obliterans due to Mycoplasma pneumoniae. Pediatr Pulmonol 23, 375–381. 26. Stokes D, Sigler A, Khouri NF, Talamo RC (1978) Unilateral hyperlucent lung (Swyer–James syndrome) after severe Mycoplasma pneumoniae infection. Am Rev Respir Dis 117, 145–152. 27. Solanki DL, Berdoff RL (1979) Severe mycoplasma pneumonia with pleural effusions in a patient with sickle cell-hemoglobin C (SC) disease—case report and review of the literature. Am J Med 66, 707–710.

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28. Koletsky RJ, Weinstein AJ (1980) Fulminant Mycoplasma pneumoniae infection. Am Rev Respir Dis 122, 491–496. 29. Tablan OC, Reyes MP (1985) Chronic interstitial pulmonary fibrosis following Mycoplasma pneumoniae pneumonia. Am J Med 79, 268–270. 30. Kaufman JM, Cuvelier CA, Van der Straeten M (1980) Mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis. Thorax 35, 140–144. 31. Siegler DIM (1973) Lung abscess associated with Mycoplasma pneumoniae infection. Br J Dis Chest 67, 123–127. 32. Coultas DB, Samet JM, Butler C (1986) Bronchiolitis obliterans due to Mycoplasma pneumoniae. West J Med 144, 471–474. 33. Wachowski O, Demirakça S, Müller KM, Scheurlen W (2003) Mycoplasma pneumoniae associated organising pneumonia in a 10 year old boy. Arch Dis Child 88, 270–272. 34. Chan ED, Welsh CH (1995) Fulminant Mycoplasma pneumoniae pneumonia. West J Med 162, 133–142. 35. Chan ED, Kalayanami T, Lynch DA, Tuder R, Arndt P, Winn R, et al. (1999) Mycoplasma pneumoniae-associated bronchiolitis causing severe restrictive lung disease in adults: report of three cases and literature review. Chest 115, 1188–1194. 36. Colby TV (1992) Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 102, 38S–43S. 37. Sulavik SB (1989) The concept of “organizing pneumonia.” Chest 96, 967–969. 38. Cordier JF (2000) Organising pneumonia. Thorax 55, 318–328. 39. Gil JC, Cedillo RC, Mayagoitia BG, Paz MD (1993) Isolation of Mycoplasma pneumoniae from asthmatic patients. Ann Allergy 70, 23–25. 40. Kraft M, Cassell GH, Henson JE, Watson H, Williamson J, Marmion BP, et al. (1998) Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med 158, 998–1001. 41. Melbye H, Kongerud J, Vorland L (1994) Reversible airflow limitation in adults with respiratory infection. Eur Respir J 7, 1239–1245. 42. Jacobs E, Bennewitz A, Bredt W (1986) Reaction pattern of human anti-Mycoplasma pneumoniae antibodies in enzyme-linked immunosorbent assays and immunoblotting. J Clin Microbiol 23, 517–522. 43. Vikerfors T, Brodin G, Grandien M, Hirschberg L, Krook A, Pettersson CA (1988) Detection of specific IgM antibodies for the diagnosis of Mycoplasma pneumoniae infections: a clinical evaluation. Scand J Infect Dis 20, 601–610. 44. Waris ME, Toikka P, Saarinen T, Nikkaris S, Meurman O, Vainionpaa R, et al. (1998) Diagnosis of Mycoplasma pneumoniae pneumonia in children. J Clin Microbiol 36, 3155–3159. 45. Sillis M (1990) The limitations of IgM assays in the serological diagnosis of Mycoplasma pneumoniae infections. J Med Microbiol 33, 253–255. 46. Daxboeck F, Krause R, Wenisch C (2003) Laboratory diagnosis of Mycoplasma pneumoniae infection. Clin Microbiol Infect 9, 263–273. 47. Reiman HA (1938) An acute infection of the respiratory tract with atypical pneumonia. JAMA 26, 2377–2384.

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48. Mansel JK, Rosenow EC 3rd, Smith TF, Martin JW Jr. (1989) Mycoplasma pneumoniae pneumonia. Chest 95, 639–646. 49. Clyde WA Jr. (1993) Clinical overview of typical Mycoplasma pneumoniae infections. Clin Infect Dis 17, Suppl 1: S32–S36. 50. Lieberman D, Schlaeffer F, Lieberman D, Horowitz S, Horovitz O, Porath A (1996) Mycoplasma pneumoniae community-acquired pneumonia: a review of 101 hospitalized adult patients. Respiration 63, 261–266. 51. Brunner H (1981) Mycoplasma pneumoniae infections. Isr J Med Sci 17, 516–523. 52. Taylor-Robinson D (1996) Infections due to species of Mycoplasma and Ureaplasma: an update. Clin Infect Dis 23, 671–682. 53. Mazzei T, Mini E, Novelli A, Periti P (1993) Chemistry and mode of action of macrolides. J Antimicrob Chemother 31, Suppl C: 1–9. 54. Alvarez-Elcoro S, Enzler MJ (1999) The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 74, 613–634. 55. Broughton R A (1986) Infections due to Mycoplasma pneumoniae in childhood. Pediatr Infect Dis 5, 71–85. 56. Luby JP (1991) Pneumonia caused by Mycoplasma pneumoniae infection. Clin Chest Med 12, 237–244.

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9 Pathological Features of Waterhouse–Friderichsen Syndrome in Infancy and Childhood Jan P. Sperhake, MD and Michael Tsokos, MD CONTENTS INTRODUCTION EXEMPLARY CASE STUDIES FATALITIES RESULTING FROM WATERHOUSE–FRIDERICHSEN SYNDROME MEDICOLEGAL ASPECTS CONCLUSIONS FOR THE PATHOLOGIST REFERENCES

SUMMARY Between 1997 and 2002, five cases of fatal Waterhouse–Friderichsen syndrome (WFS) that occurred in infancy or childhood were investigated in our institute. The diagnosis of WFS was based on the following clinical as well as morphological criteria: (a) fulminant sepsis, (b) patchy purpura of the skin as a result of disseminated intravascular coagulation (DIC), and (c) bilateral hemorrhagic necroses of the adrenals. All cases had a very rapid clinical course of the disease (about 1 day or less). In two cases, postmortem microbiological examinations yielded meningococci as the infective agent. In both cases, the children examined underwent autopsy very early after death (5 hours and 24 hours, respectively) and did not receive antibiotics prior to death. In two other cases, meningococci were cultured in antemortem blood samples. From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 219

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Macroscopically, the leptomeninges looked inconspicious in all five cases investigated. However, histology revealed meningitis to a mild or moderate degree in four cases. A previously clinically undiagnosed interstitial myocarditis was diagnosed in three cases by histological means, of which two cases showed Gram-negative diplococci in the myocardial lesions. For the pathologist investigating cases of WFS in infancy and childhood, the following points have to be emphasized: (a) when performing a medicolegal autopsy in a case of suspected WFS, the postmortem interval should be as short as possible (not longer than 24 hours) to provide the opportunity for an accurate microbiological examination of postmortem swabs; (b) in cases of WFS, meningitis does not seem to play a leading role for the clinical course of the disease or the actual cause of death; however, histologically a mild to moderate degree of meningitis is a frequent finding; (c) the presence of Gram-negative diplococci in myocardial lesions by histological means suggests that invasion of meningococci might be a causative factor for myocarditis in WFS; and (d) in accordance with the literature, myocarditis is often present in cases of WFS and therefore might be of importance for the clinical course. It is not certain yet if all children die from shock or DIC or rather, if myocarditis, leading to complete heart block, forward failure of the heart, or arrhythmia, is the actual cause of death. Key Words: Waterhouse–Friderichsen syndrome (WFS); infancy; childhood; Neisseria meningitidis; diplococci; meningitis; myocarditis; disseminated intravascular coagulation (DIC); postmortem microbiology; histopathology.

1. INTRODUCTION Apoplexy of the adrenals in children was independently described by Waterhouse in 1911 and by Friderichsen in 1918 (1,2). The diagnosis of Waterhouse–Friderichsen syndrome (WFS) is mainly based on the combination of bilateral adrenal hemorrhage, purpura of the skin, and meningococcal infection (3). Cases with hemorrhage of only one adrenal have been reported, too (4). Various other germs, for example, pneumococci, Haemophilus influenzae, and streptococci, are also well-recognized as etiologic germs of WFS (5–14). Mortality of the syndrome is still considerably high. Whereas adult cases are rare, WFS occurs frequently in infancy and childhood. Because of the sudden onset of symptoms, short clinical course, and sudden, unexpected death, WFS is often a matter of medicolegal investigations. In this study, special focus is put on the pathology and postmortem microbiological findings as well as on medicolegal aspects of the disease.

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2. EXEMPLARY CASE STUDIES 2.1. Material and Methods Between 1997 and 2002, five cases of fatal WFS that occurred in infancy or childhood were investigated in our institute. The youngest child was 9 months old, the oldest 13 years of age. Three girls and two boys were affected. In all cases, diagnosis of WFS was based on the following clinical as well as morphological criteria: (a) fulminant sepsis, (b) petechial and/or patchy purpura of the skin as a result of disseminated intravascular coagulation (DIC), and (c) bilateral hemorrhagic necroses of the adrenals. The interval between death and autopsy ranged from a few hours to 6 days. Swabs for postmortem microbiological investigations were routinely taken from the leptomeninges, cerebrospinal fluid, and heart blood. In each case, all internal organs including the brain underwent a thorough histological examination using the following stainings: hematoxylin-eosin, perodic acid-schiff, Giemsa, Gram, and Elastica van Gieson.

2.2. Case Reports 2.2.1. Case 1 A 9-month-old girl developed fever (40°C) and mild apathy 1 day before death. An antiphlogistic suppository was administered by the consulted pediatrician. In the early morning of the next day, a rash was observed by the mother. Death occurred shortly thereafter on the way to hospital. A medicolegal autopsy was performed 5 hours after death. Petechial and patchy hemorrhages in the skin (Fig. 1) and on the serous layers of the viscera as well as bilateral adrenal hemorrhage (Fig. 2) were present. Macroscopically, there were no signs of meningitis. At histological examination, mild meningitis with Gram-negative diplococci was observed. Postmortem swabs of the leptomeninges and postmortem blood cultures led to the cultural growth of Neisseria meningitidis serogroup B. The pediatrician was prosecuted but the proceeding was stopped because medical malpractice could not be proved against him.

2.2.2. Case 2 A 3-year-old boy fell ill with vomiting and fever up to 38.5°C. The consulted pediatrician prescribed an antiemetic. In the following night, the mother called the pediatrician on the phone because the boy developed red patchy spots on his trunk. On the phone, the doctor suspected urticaria and advised the mother to visit his consultation hour the following morning. One hour

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Fig. 1. Case 1: 9-month-old girl with the typical rash of WFS that should not be confused with livores.

Fig. 2. Case 1: In situ appearance of adrenal hemorrhage in the opened abdominal cavity after evisceration of liver, stomach, duodenum, pancreas, and spleen.

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Fig. 3. Case 2: Cut surfaces of the adrenals showing diffuse hemorrhage.

after the phone call, the worried mother brought the boy to a hospital where he died despite antibiotic therapy. Blood cultures grew meningococci (without subspecification). A medicolegal autopsy was conducted 6 hours postmortem. Major pathological findings were petechial and patchy hemorrhages of the skin of the trunk and the limbs (in part appearing like livores) and on serous layers, bilateral adrenal hemorrhage (Figs. 3 and 4), and lung edema. Macroscopically, there were no signs of meningitis. Histologically, the presence of mild meningitis could be established (Fig. 5). In cutaneous blood vessels, Gramnegative diplococci were detected. Microbiological investigations did not reveal the etiologic germ. Initially, the pediatrician was prosecuted but the legal measures were stopped later because it could not be ascertained beyond a reasonable doubt that the child could have been saved at the time of the consultation on the phone.

2.2.3. Case 3 A 13-year-old girl came home from school with fever up to 40°C. The family physician prescribed paracetamol. A few hours later, the mother recognized “red spots” all over the girl’s body. Shortly thereafter, the girl died despite resuscitation attempts. At autopsy, 24 hours postmortem, petechial hemorrhages on the girl’s skin and on the serous layers of the viscera were abundant. Both adrenals showed hemorrhagic necroses. Signs of circulatory shock were apparent. Histologically, interstitial myocarditis with phagocytized diplococci was detected (Fig. 6). There was no hint of any inflammatory

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Fig. 4. Case 2: Panoramic view of an adrenal gland with fresh hemorrhagic necrosis of cortex and medulla (hematoxylin and eosin, original magnification × 20).

Fig. 5. Case 2: Moderate meningitis showing a mixed cellular infiltrate (hematoxylin and eosin, original magnification × 100).

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Fig. 6. Case 3: Interstitial myocarditis (hematoxylin and eosin, original magnification × 150).

process in the leptomeninges neither by macroscopy nor by microscopical means. Postmortem swabs of the leptomeninges grew N. meningitidis serogroup C.

2.2.4. Case 4 A 2-year-old girl suffered from several episodes of vomiting that started 1 day prior to death. Death occurred during sleep in the parental bed. On external examination, multiple hemorrhagic purpura of the skin were obvious. Autopsy was conducted 2 days postmortem. Autopsy revealed bilateral hemorrhages of the adrenals and patchy hemorrhages on the serous membranes. There were no macroscopical signs of meningitis. Histology showed interstitial myocarditis with focal necroses of muscle fibers. Gram-negative diplococci were abundant in the myocardial lesions, partly incorporated in macrophages (Fig. 7) and granulocytes. Mild meningitis with infiltration of granulocytes and lymphocytes and clusters of diplococci was also present. Postmortem microbiology failed to detect any germs.

2.2.5. Case 5 A 13-year-old boy was admitted to hospital with clinical signs of sepsis and DIC. A blood culture grew meningococi (without subspecification).

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Fig. 7. Case 4: High-power view of myocardial lesions with arrows pointing at phagocytized diplococci (Giemsa, original magnification × 800).

Despite antibiotic therapy, the boy died a few hours after admission. At medicolegal autopsy, performed 6 days postmortem, petechiae and purpura of the skin, bilateral adrenal hemorrhage, severe brain edema, and edema of the lungs were present. Histological examination revealed interstitial myocarditis and mild meningitis. Postmortem microbiology did not detect any germs.

3. FATALITIES RESULTING FROM WATERHOUSE–FRIDERICHSEN SYNDROME 3.1. General Aspects WFS is a dramatic pediatric emergency that carries a high mortality. Whereas the mortality rate of meningococcal disease and meningococcemia (without WFS) ranges from 10 to 30% (15–18), the mortality rate rises up to 95% in WFS (19–21). It has to be taken into account that mortality rates are often calculated on the basis of hospitalized children and do not consider those fulminant cases that never reach the hospital. The fatalities studied here have to be considered typical for the disease in many respects. All cases have in common that each individual presented with a fulminant clinical course of about 24 hours or less. Only two of the children reached the hospital. Three out of the

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five children saw a pediatrician or a family physician prior to death in an earlier state of the disease, a fact that led to legal repercussions in two of the cases.

3.2. Specific Aspects 3.2.1. Etiologic Germs According to the literature, more than 80% of the cases of WFS are caused by meningococci (22). It is likely that all of our cases were caused by meningococci. In Cases 1 and 3, postmortem microbiological investigations yielded meningococci as the infective agent. In Cases 2 and 5, meningococci were cultured in antemortem blood samples. In Case 4, Gram-negative diplococci were detected by histological means in the myocardium and leptomeninges. Taking a closer look at the cases with a positive outcome of postmortem microbiology, it becomes obvious that the individuals examined underwent autopsy very early after death (5 hours and 1 day, respectively) and did not receive antibiotics prior to death. The cases with negative postmortem microbiological results either did receive antibiotics prior to death (Cases 2 and 5) or the postmortem interval was 2 days or more (Cases 4 and 5), which is probably too long a time interval for the fragile and fastidious meningococci. This observation suggests the importance of an immediate autopsy, at least in cases without preceding antibiotic therapy. Postmortem swabs should be taken very carefully under sterile precautions (23).

3.2.2. Meningitis Our results point to the leptomeninges as a promising tissue for the postmortem microbiological detection of meningococci. This was somewhat surprising because in none of the cases was meningitis diagnosed by gross examination at autopsy. However, histology revealed meningitis to a mild or moderate degree in all cases with the exception of Case 3. Regardless of this, postmortem swabs of the leptomeninges grew meningococci in this case. In three cases, diplococci were detected by histology in the leptomeninges. Therefore, the leptomeninges seems to be a regular target of meningococci in cases of WFS without having a major clinical significance. This corresponds to clinical observations of WFS cases (24,25). Meningococcemia without clinical signs of meningitis seems to carry a particularly high mortality (26). Encephalitis or intracerebral vasculitis was not observed in our cases.

3.2.3. Myocarditis A case report by Detsky and Salit described a 41-year-old man with meningococcemia who died of a complete heart block (27). The authors observed

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myocarditis with focal necroses of the conduction system on the histological level. It has to be emphasized that we found prior clinically undiagnosed interstitial myocarditis in our series by histology in Cases 3, 4, and 5, a finding that is well in line with Böhm, who reported on 10 cases of WFS, 9 of which displayed interstitial myocarditis with vasculitis (22,28). With the exception of one case, myocarditis had not been diagnosed prior to death in the study by Böhm. He concluded that myocarditis (and not shock) might be the leading cause of death in many cases of WFS. He suspected endotoxinic vascular damage to be the cause of myocarditis rather than a direct invasion of meningococci into the myocardial tissue. According to the observations by Böhm, we found the infiltrate in the myocardial lesions to be composed of granulocytes, lymphocytes, and mast cells. These lesions were restricted to the left ventricle. However, we did not observe any hints toward an accompanying vasculitis in any of our cases. In contrast to Böhm, who emphasized that he did not find any bacteria in the myocardium, we detected Gram-negative diplococci in two of our cases. In both cases, intra- and extracellularly Gram-negative diplococci were visible by light microscopy. This finding shows that direct invasion of Gram-negative diplococci in the heart does play a role in the pathogenesis of myocarditis in WFS. Although to some extend this stands in contradiction to the clinical observations of other authors, who state that electrocardiogram changes are rare in cases of WFS (29), we agree with Böhm and Detsky (22,27) that myocarditis is responsible for the poor outcome in many WFS cases.

4. MEDICOLEGAL ASPECTS In fatalities resulting from WFS in infancy and childhood, almost inevitably the question arises whether the child could have been saved if there was an earlier diagnosis (19). Especially if a physician has been consulted in the beginning of the disease, medical malpractice seems to be obvious for the parents. Because of the rapid clinical course of the disease and the rather unspecific findings in its beginning, it can be impossible even for the clinical professional to distinguish the disease from a common cold or an enteritis. Even if medical help is sought in an early stage of the disease, it is impossible to predict the outcome in an individual case (30). At the time when the rash is present, it is often too late to save the child’s life. However, in Case 2 the pediatrician felt comfortable with the diagnosis of urticaria without even having seen the child, which is definitely unacceptable from the medicolegal point of view. The (forensic) pathologist should not forget to protect her- or himself. Performing an autopsy on a child with WFS is a close contact and can put the

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medical staff at a high risk for infection. Therefore, a mask and eye protection are obligatory. After autopsy, a postexposition chemoprophylaxis, for example, a single dose of 500 mg Ciprofloxacin, is strongly recommended by the Centers for Disease Control and Prevention (31).

5. CONCLUSIONS FOR THE PATHOLOGIST When performing a medicolegal autopsy in a case of suspected WFS, the postmortem interval should be as short as possible (not longer than 24 hours) to provide the opportunity for an accurate microbiological examination of postmortem swabs. In cases of WFS, meningitis does not seem to play a leading role for the clinical course of the disease or the actual cause of death; however, histologically a mild to moderate degree of meningitis is a frequent finding. The presence of Gram-negative diplococci in myocardial lesions by histological means suggests that invasion of meningococci might be a causative factor for myocarditis in WFS. In accordance with the literature, myocarditis is often present in cases of WFS and therefore might be of importance for the clinical course; it is not certain yet if all children die from shock or DIC or rather if myocarditis, leading to complete heart block, forward failure of the heart, or arrhythmia, is the actual cause of death.

REFERENCES 1. Waterhouse R (1911) A case of suprarenal apoplexy. Lancet 1, 577. 2. Friderichsen C (1918) Nebennierenapoplexie bei kleinen Kindern. Jahrb Kinderheilk 87, 109. 3. Harris P, Bennett A (2001) Waterhouse–Friderichsen syndrome. N Engl J Med 345, 841. 4. Mühlig K, Theile J, Dalitz E (1995) Einseitige Nebennierenblutung–ein Waterhouse Friderichsen-Syndrom? Ultraschall Med 16, 293–296. 5. Külz J, Kroll O (1984) Zur aktuellen Problematik des sogenannten Waterhouse– Friderichsen-Syndroms im Kindesalter. Kinderärztl Praxis 52, 3–15. 6. Ryan CA, Wenman W, Henningsen C, Tse S (1993) Fatal childhood pneumococcal Waterhouse-Friderichsen Syndrome. Pediatr Infect Dis J 12, 250–251. 7. Tsokos M (2003) Fatal Waterhouse–Friderichsen syndrome due to Ewingella americana infection. Am J Forensic Med Pathol 24, 41–44. 8. Mirza I, Wolk J, Toth L, Rostenberg P, Kranwinkel R, Sieber SC (2000) Waterhouse– Friderichsen syndrome secondary to Capnocytophaga canimorsus septicemia and demonstration of bacteremia by peripheral blood smear. Arch Pathol Lab Med 124, 859–863. 9. Jacobs RF, Hsi S, Wilson CB, Benjamin D, Smith AL, Morrow R (1983) Apparent meningococcemia: clinical features of disease due to Haemophilus influenzae and Neisseria meningitidis. Pediatrics 7, 469–472.

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10. Lineaweaver W, Franzini D, Dragonetti D, McCarley D, Rumley T (1986) Haemophilus influenzae meningitis and Waterhouse–Friderichsen syndrome in an adult. South Med J 79, 1034–1036. 11. McKinney WP, Agner RC (1989) Waterhouse–Friderichsen syndrome caused by Haemophilus influenzae type b in an immunocompetent young adult. South Med J 82, 1571–1573. 12. Ip M, Teo JG, Cheng AF (1995) Waterhouse–Friderichsen syndrome complicating primary biliary sepsis due to Pasteurella multocida in a patient with cirrhosis. J Clin Pathol 48, 775–777. 13. Agraharkar M, Fahlen M, Siddiqui M, Rajaraman S (2000) Waterhouse–Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis. Am J Kidney Dis 36, 396–400. 14. Karakousis PC, Page KR, Varello MA, Howlett PJ, Stieritz DD (2001) Waterhouse– Friderichsen syndrome after infection with group A streptococcus. Mayo Clin Proc 76, 1167–1170. 15. Busund R, Straume B, Revhaug A (1993) Fatal course in severe meningococcemia: clinical predictors and effect of transfusion therapy. Crit Care Med 21, 1699–1705. 16. Cremer R, Leclerc F, Martinot A, Sadik A, Fourier C (1997) Adverse outcome in children with meningococcemia. J Pediatr 131, 649–651. 17. Havens PL, Garland JS, Brook MM, Dewitz BA, Stremski ES, Troshynski TJ (1989) Trends in mortality in children hospitalized with meningococcal infections, 1957 to 1987. Pediatr Infect Dis J 8, 8–11. 18. Sørensen HT, Steffensen FH, Schønheyder HC, Nielsen GL, Hansen I, Madsen KM, et al. (1998) Trend in incidence and case fatality of meningococcal disease over 16 years in Northern Denmark. Eur J Clin Microbiol Infect Dis 17, 690–694. 19. Gradaus F, Klein RM, von Giesen H-J, Arendt G, Heintzen MP, Leschke M, et al. (1999) Klinischer Verlauf und Komplikationen der Meningokokkensepsis. Med Klin 94, 633–637. 20. Mok Q, Butt W (1996) The outcome of children admitted to intensive care with meningococcal septicaemia. Intensive Care Med 22, 259–263. 21. Schroten H (2000) Meningokokkeninfektionen. In: Deutsche Gesellschaft für pädiatrische Infektiologie e.V., ed., Infektionen bei Kindern und Jugendlichen, 3rd ed. Futuramed, München, pp. 437–442. 22. Böhm N (1982) Adrenal, cutaneous and myocardial lesions in fulminating endotoxinemia (Waterhouse–Friderichsen syndrome) Pathol Res Pract 174, 92–105. 23. Tsokos M, Püschel K (2001) Postmortem bacteriology in forensic pathology: diagnostic value and interpretation. Legal Med 3, 15–22. 24. Rosenberg H, Bortolussi R, Gatien JG (1981) Rash resembling anaphylactoid purpura as the initial manifestation of meningococcemia. Can Med Assoc J 15, 179–180. 25. Vos GD, Wiegman A, Romijn JA, Meurs AM, Bruins-Stassen MJ, Bijlmer RP, et al. (1989) Not meningitis but septic shock is the killer in acute meningococcal disease. Ned Tijdschr Geneeskd 133, 772–775. 26. Riordan FAI, Marzouk O, Thomson APJ, Sills JA, Hart CA (1995) The changing presentations of meningococcal disease. Eur J Pediatr 154, 472–474.

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27. Detsky AS, Salit IE (1983) Complete heart block in meningococcemia. Ann Emerg Med 12, 391–393. 28. Böhm N (1978) Waterhouse-Friderichsen-Syndrom: Morphologische Befunde und Aspekte zur Pathogenese. Verh Dtsch Ges Path 62, 449–455. 29. Schütte B (1978) Waterhouse-Friderichsen-Syndrom—Klinischer Verlauf und Gerinnungsstatus. Verh Dtsch Ges Path 62, 442–448. 30. Dashefsky B, Teele DW, Klein JO (1983) Unsuspected meningococcemia. J Pediatr 102, 69–72. 31. CDC (1997) Control and prevention of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 46 (No. RR-5), 1–10.

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10 Accidental Autoerotic Death A Review on the Lethal Paraphiliac Syndrome Stephan Seidl, MD CONTENTS INTRODUCTION “PARAPHILIA” IN DSM–IV AND ICD–10 PRACTICES OF AUTOEROTICISM A COMPARISON OF AUTOEROTICISM IN MALES AND FEMALES MEDICOLEGAL ASPECTS OF ACCIDENTAL AUTOEROTIC DEATH: THE DEMARCATION FROM SUICIDES AND HOMICIDES REFERENCES

SUMMARY Accidental autoerotic death (AAD) is defined as a solitary, accidental death caused by a lethal paraphilia including hanging, strangulation, invert suspension, plastic-bag asphyxiation, electrophilia, and anesthesiophilia. Young white men comprise the largest group of victims, whereas the number of female AADs reported in literature is extremely small. In both sexes, AAD is most often seen in young to middle-aged adults. Practitioners tend to utilize a great range of elaborate devices and props, often designed to cause real or simulated pain, with pornographic material and evidence of cross-dressing and fetishism like intimate feminine garments. The absence of typical props in the majority of female AADs may impede the differentiation of AADs from suicides or homicides. To exclude the possibility of sexual homicide or suicide, investigators must establish the presence of key death scene characteristics before the death can be appropriately classified as an autoerotic fatality. The location elected for the autoerotic performance is usually secluded, often with evidence of repeated autoerotic behavior. Bondage is common, and death From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 235

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scene investigators must ensure that any bondage could have been secured by the deceased himself. Padding of the rope, especially in neck ligatures, to prevent subsequently detectable abrasions or bruises is regularly found. Because of the accidental nature of AAD, a failed rescue mechanism is usually evident. A lack of features of suicide with no antemortem evidence of suicidal ideation or depression is diagnostic for AAD; an overt suicide note is usually not present. Thorough investigations regarding life and environment of the victim and the circumstances of death may be effective in the determination of the manner of death in equivocal cases. Twelve general behavioral characteristics that investigators can look for to help them identify autoerotic death scenes are listed. Key Words: Accidental autoerotic death (AAD); autoerotic asphyxia; hypoxyphilia; lethal paraphiliac syndrome; paraphilia; asphyxiophilia; anesthesiophilia; electrophilia.

1. INTRODUCTION Sexual “normality” and “deviancy” vary with the accepted moral attitudes of the particular society and with the particular times in which these societies are living. Inducing cerebral hypoxia for sexual gratification has been described by anthropologists and literates for centuries (1–6). Pressure on the neck during sexual activity was a common practice of Eskimos and Southeast Asians (1,4,5,7,8). Prostitutes have been experts in sexual asphyxiation for a long time, and during the Victorian era in London, men could satisfy their sexual urges through controlled hangings in the “Hanged Men’s Club” (6,9). Both the classical writer Peter Anthony Motteux and Frantisek Koczwara, composer of “The Battle of Prague,” died in the 18th century because of sexual asphyxia assisted by a prostitute (10,11). The death of Koczwara led to the suggestion of the term “Koczwarraism” for behavior utilizing asphyxial augmentation for the sexual response (2,12). Despite a strong tendency toward sexual repression in Western cultures, as early as in 1791, the year of Koczwara’s death, the Marquis de Sade described altered sexual behavior with self-induced asphyxia for the purposes of sexual gratification in his book Justine (4). Autoerotic behavior is any act that is sexually self-gratifying. An accidental autoerotic death (AAD) may occur during autoerotic behavior in which a device, apparatus, prop, chemical, or behavior that is engaged to enhance sexual stimulation causes death, if there is failure of the various self-rescue mechanisms that are specifically aimed at preventing such an occurrence (2,3,13–15). Scientific analyses of autoerotic deaths were not published in the

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medicolegal literature until the 1920s (14,16–20). The first extensive series of 50 AAD cases was published by Weimann (21). Forensic pathologists rapidly recognized the difficulty of distinguishing between AADs, suicides, and homicides, and an increasing number of case reports was published in the following decades. As the vast majority of autoerotic deaths are asphyxial deaths resulting from asphyxia due to hanging, strangulation, injurious agents, or other causes of asphyxia, autoerotic asphyxial deaths were categorized as typical cases in the 1960s and 1970s, and autoerotic deaths without asphyxia were denoted as atypical cases. Because of this definition and in contrast to the suggestions of Schwarz and Weimann (14,21), many cases that should have been classified as natural deaths during autoerotic activity were labeled and sometimes published as atypical autoerotic deaths, only because of the presence of associated unusual props (14,20,22–26). The case report “Vacuum Cleaner Use in Autoerotic Death” by Imami and Kemal, for example, deals with a natural death (myocardial infarction) during autoerotic activity and not with an AAD (22). Byard and Bramwell consequentially have issued a warning of an “overdiagnosis” of AADs and proposed to apply the broad term autoerotic death only to accidental deaths that occur during individual, usually solitary, sexual activity in which some type of apparatus that was used to enhance the sexual stimulation of the deceased caused unintended death (23). Furthermore, they suggested applying the term autoerotic asphyxial death to fatal episodes that result from asphyxia, thus maintaining the distinction from rarer cases involving other quite different mechanisms such as electrocution. In 1995, Behrendt and Modvig proposed a new classification of autoerotic deaths that focused less on the presence of asphyxiation but was built on the classification of paraphilias, an unusual act or bizarre imagery necessary for sexual gratification (27,28): persons who engage in paraphilic behavior may “overdo” the potentially lethal paraphilia needed for their sexual arousal and orgasm. In fatal cases, the lethal paraphilia, like asphyxiophilia, masochism, electrophilia, or anesthesiophilia, is the unintended and direct cause of death. Therefore, an AAD may be diagnosed if it is solitary, accidental, and caused by any lethal paraphilia (Table 1). According to this definition, the subclassification into typical and atypical AADs depends on the presence or absence of accompanying non-lethal paraphilia and/or props (29): in cases of typical AAD, nonlethal paraphilia and/or props like pornography, vibrators, or other phallic objects are present, but not in atypical cases. In this context, props are personal paraphernalia assumed to have been used actively or passively for sexual imagination and arousal and not for bondage, fetishism, or transvestism (Table 2) (27, 29).

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Paraphilia

Examples and variations

Sexual asphyxiophilia

Neck ligatures (hanging, strangulation) Invert suspension Complex ligatures Restrictive bondage (wrapping, cocooning) Face mask asphyxiation (gas, diving, anesthetic mask) Plastic-bag asphyxiation Mouth gag asphyxiation including sealing of the mouth Chest compression Immersion Nitrous oxide Ketamine Ether Chloroform and other halogenated hydrocarbons (i.e., fluorocarbons) Aerosols like glue spray (e.g., toluene) Gasoline, propane, butane sniffing Drugs (i.e., amphetamine, cocaine) Direct electrical wiring from house current outlets, from electrical devices (television set, table lamp), or from low-voltage devices (e.g., toy train transformer) to penis, rectum, and/or nipples Insertion of foreign bodies such as oversize or unclean fetishized objects into orifices. Apparatus to induce peritoneal pain with knifes.

Sexual anesthesiophilia

Sexual electrophilia

Sexual masochism

Note. Modified according to ref. 44

The definitions of Byard and Bramwell as well as Behrendt and Modvig both seem to be well qualified for the distinction between fatal cases during autoerotic practice and autoerotic deaths, thus avoiding an overdiagnosis of autoerotic deaths.

2. “PARAPHILIA” IN DSM–IV AND ICD–10 As early as in the year 1886, the psychiatrist von Krafft-Ebing published his phenomenology of sexual behavior called Psychopathia sexualis (30). He classified homosexuality, sadism, and masochism as well as fetishism as “paresthesias” of sexual perception and as “perversions” of the sex drive. In 1940, the psychologist Clifford Allen eschewed the pejorative term “perver-

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Table 2 Nonlethal Paraphilia (NLP) and Props Occurring in Typical AADs

Nonlethal paraphilia

NLP/prop

Example

Fetishism Transvestism Bondage (physically bound or restrained with handcuffs or chains) Oral fetish

Plastic, rubber, or leather attire, etc. Cross-dressing, cosmetics

Props (personal paraphernalia) Penis fetish Other fetishes

Pornography Mirror Video camera

Female underwear placed on or in the mouth Female undergarments Anal stimulation devices, vibrators, and other phallic objects; horsewhip, etc. Photographs, videotapes

Note. Modified according to ref. 27.

sion” and called sexualities departing from ordinary heterosexuality “paraphilias” (31). The most recent fourth edition of the handbook of the American Psychiatric Association, the Diagnostic and Statistical Manual of Mental Disorders (DSM–IV) (32), defines “paraphilia” as recurrent, intense sexual urges, fantasies, or behaviors that involve unusual objects, activities, or situations and cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Eight numerically coded paraphilias are listed: pedophilia (302.2), transvestic fetishism (302.3), exhibitionism (302.4), fetishism (302.81), voyeurism (302.82), sexual masochism (including automasochism, 302.83), sexual sadism (302.84), frotteurism (302.89), and “paraphilia not otherwise specified” (302.9). Autoerotic asphyxia is discussed under 302.83 Hypoxyphilia involves sexual arousal such that the person produces oxygen deprivation by means of a noose, ligature, plastic bag, mask, chemical (often a volatile nitrite that produces temporary decrease in brain oxygenation by peripheral vasodilatation), or chest compression, but allows him/herself the opportunity to escape asphyxiation prior to the loss of consciousness (6,32).

The 10th revision handbook of the World Health Organization, the International Classification of Mental and Behavioral Disorders (ICD–10), does

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not use the term “paraphilia,” but paraphrases sexual deviations with the term “Disorders of Sexual Preference” (33). In this classification, seven numerically coded disorders are listed: fetishism (F 65.0), fetishistic transvestism (F65.1), exhibitionism (F 65.2), voyeurism (F65.3), pedophilia (F65.4), and sexual sadism and masochism (F65.5). F 65.6 allows one to code the combination of several disorders in one person. F 65.8 (“Other disorders of sexual preference”) subsumes disorders like frotteurism, zoophilia (sodomism), telephone scatologia, necrophilia, and coprophilia, and the use of (self-)strangulation for intensifying sexual excitement. Regarding autoerotic practices, it is exemplified that “masturbatory rituals of various kinds are common, but the more extreme practices, such as the insertion of objects into the rectum or penile urethra, or partial self-strangulation, when they take the place of ordinary sexual contacts, amount to abnormalities.” As many cases of autoerotic deaths show combined aspects of masochism, transvestism, or transvestic fetishism, which disclose different degrees of sexual identification that are fundamental in reaching orgasm, the correct grading of AADs is difficult in both classifications, DSM–IV and ICD–10 (3,34). For these combined paraphilic cases, the term “multiplex paraphilias” was suggested (28, 35).

3. PRACTICES OF AUTOEROTICISM 3.1. Sexual Asphyxia (Asphyxiophilia) Most cases of sexual asphyxiophilia occur with both heterosexual and homosexual partners and not in solitary sexual activity (2,36). However, the vast majority of autoerotic accidents and deaths are of an asphyxial nature (4,5,27,37). Of 46 AAD cases in Denmark, 38 were asphyxial deaths, 53% of these a result of hanging, 5% each owing to strangulation and invert suspension, and 37% resulting from plastic-bag asphyxiation (27). In accordance with this study, most authors reported a preponderance of hanging (17,20–22,38–41). The basic mechanism of all sexual asphyxias is the production of cerebral hypoxia in order to induce a semihallucinogenic and euphoric state and thus to heighten the sexual response (5,14,21,28,42,43). The three general categories of asphyxial autoerotic deaths are strangulation, suffocation, and chemical asphyxia by anesthetic agents and volatile substances (36,44). The most common technique to gain cerebral hypoxia is strangulation including hanging (6). Unconsciousness may be produced in less than 10 seconds with only 7 pounds of pressure on the common carotid artery (45,46). Independent of the particular technique, the practitioners often use protective padding like scarfs or towels to avoid abrasions or grooves. In some cases of hanging, the

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rope, dog collar, or chain is attached to some overhead support like ceiling joists, pipes, or perches, and the tension of the noose is gained by bending the legs and plumping against the pull of the rope (4,5,23,47,48). According to the definition as an accident, an intended free hanging (“typical hanging”) without contact of any part of the body with various objects like floor, bed, or chair is never seen in AADs, whereas all variations of so-called atypical (incomplete) hanging were portrayed. In one case reported by O’Halloran et al., the rope was hooked on the raised shovel of a backhoe tractor. The practitioner had constructed a kind of remote control with a broom stick, and thus was able to raise or lower the hydraulic shovel (49). The loss of consciousness secondary to cerebral hypoxia can result in a loss of balance, loss of the control position, and, finally, partial or complete suspension. Risse and Weiler communicated a case in which the fatal outcome of an autoerotic hanging was videotaped by the practitioner himself (50). The man wore a long nightgown, a bra, earrings, and a woman’s wig. He sat down on an office chair, sealed his mouth with six strips of duct tape, tied his feet to the chair, put his head in an open loop mounted at the ceiling, and tied his hands behind his back. During the next 25 seconds, the loop was tightened by turning the head and moving the chair, and then the practitioner tightened the rope again by pressing the hand lever of the seat height adjustment. During the next 55 seconds, the man got more and more agitated, head and body were moved back and forth jerkily. Having acquitted himself of the handcuffs, he tried to grab at the hand lever of the seat height adjustment again, but abruptly lost consciousness. The unconscious victim reared up in a cramp, and in the following 2 minutes deep inspiratory movements occurred, whereby the body repeatedly abutted upon the chair. During the following 6 minutes until the exitus, several motionless phases occurred, each lasting 10–45 seconds, with an intermediate rearing-up of the body. The video underlines impressively the abrupt loss of consciousness, which makes it impossible to use existing selfrescue mechanisms. Other practitioners pass the rope over a support and either attach a weight to the free end, which produces tension (36), or join the free end to their wrists or ankles and tighten the rope by movement of their extremities (4,51). In many more cases, fixed nooses are placed around the neck, often joined to one or both wrists or ankles, sometimes with additional bondage that encircles the genitals (3,21,29,42,52,53). If the legs or the arms are extended, the noose around the neck is tightened and the genitals are stimulated. On the other hand, the compression will cease as soon as muscular tension on the free end of the noose is relaxed (3,36). However, the ability of the practitioner to escape injury

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or death may be seriously impaired by his already altered euphoric and hypoxic state of mind (3,23,34,52). Moreover, a sudden exaggerated bilateral pressure on the carotid sinuses may result in an immediate loss of consciousness (3). In one of this author’s cases, a 44-year-old man who suffered from epilepsy with approximately one attack per week was found dead on the floor of the living room (Fig. 1A,B). The apartment was locked from inside. The man was wearing a brassiere and a slip with traces of an obvious emission of semen. He had placed an open noose of a silken scarf around his neck, and the free ends were joined to his wrists. The scarf decussated anterior and made it possible for the practitioner to open the noose simply by moving his wrists each to the opposite side. Next to the body, a pair of scissors was found on the floor. The skin of the head and the neck above the scarf showed a massive congestion. Autopsy revealed the typical signs of an asphyxial death. Because of the autopsy finding of a tongue bite, it was discussed that the man might have suffered an epileptic attack during his autoerotic activity and, therefore, was not able to relax the noose or to grab at the scissors. The frequent presence of self-rescue mechanisms like knives show that the practitioners are usually well aware of the possibility of accidental injury or death (23,40,54). Nevertheless, many deaths occur, usually as a result of an accidental fall while suspended from the neck during sexual arousal, or an overzealous application of neck ligatures (42). In one of our cases, a 43-yearold man was found naked on the floor of his living room, which was locked from inside. Some pornographic material as well as female underwear was found around the body. The man wore two necklets and had a studded leather belt around his neck. The belt buckle was locked and no rescue mechanisms were present. At autopsy, a single horizontal rope mark was seen, reflecting exactly the studs of the belt (Fig. 2A,B). Because of the signs of death from suffocation and the absence of natural diseases, it has to be assumed that the victim lost consciousness during his autoerotic activities and was no longer able to open the belt buckle. Besides neck ligatures, and sometimes combined with them (21,46), there is a great variety of devices to induce hypoxia such as mouth gags, anesthetic masks, adhesive tapes, or plastic bags with or without additional anesthetics like ether or aerosols (see Subheading 3.2., Anesthesiophilia). In another of our cases, a 39-year-old man was found dead in his locked bedroom, lying supine in his bed. The man wore a respirator mask, which was firmly fixed to his head by elastic bands. A rubber balloon was attached to the free end of a tube, which was connected with the mask (Fig. 3A,B). The man wore a red

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Fig. 1. (A,B) AAD of a 44-year-old man who suffered from epilepsy. Around the neck is a silken scarf with an open noose; the free ends are joined to the wrists. The vasculature of the skin of head and neck above the scarf is congested. Autopsy revealed an asphyxial death. The autopsy finding of a tongue bite led to the assumption that an epileptic attack might have foiled the escape mechanisms in this case.

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Fig. 2. AAD of a 43-year-old man by strangulation with a studded leather belt. (A) Belt. (B) Single horizontal rope mark, reflecting exactly the studs of the belt.

rubber pinafore tied up with a rubber band. A massage vibrator located by the rubber band above the genitals, was still running when the man was found. Another technique of asphyxiophilia is to wrap the body tightly in sheets of plastic (Fig. 4A,B), blankets, or chains (2,3,7,40,55–58). One of the first AAD cases portrayed by Weimann involved a 49-year-old man who died due to body compression by chest and abdominal ligatures (19). A lethal compression of the body with a high abdominal ligature, involving a suspension apparatus, has been described by Thibault et al. (40,59). Madea portrayed the AAD

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Fig. 3. AAD of a 39-year-old man. (A) The man wore a respirator mask, which was firmly fixed to his head by elastic bands. (B) A rubber balloon was attached to the free end of a tube, which was connected with the mask. The man wore a red rubber pinafore tied up with a rubber band. A massage vibrator was located by the rubber band above the genitals.

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Fig. 4. (A,B) AAD of a 38-year-old man who was found dead hanging in a plastic sack. The rope for hanging was fixed to a permanent hook on the ceiling. The cause of death was atypical strangulation owing to a neck ligature which was actually a dog collar. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

of a 56-year-old man who was found dead in a head-down position, hanging in a sack (60,61). Death was caused by asphyxia owing to compression of the chest and by insufficient blood supply to the heart caused by the head down position. Minyard communicated an AAD of a 34-year-old security guard who had wrapped his complete body with clear adhesive tape (7). A snorkel apparatus protruded from one end of the wrapping. Within his cocoon, the victim was found nude except for a rubber hat on his head. The snorkel device had become detached from the face and mouth area where it had been inserted. In the left hand of the victim, a pocket knife for use as an escape mechanism was found. The knife blade protruded through the wrapping over the man’s left hand. O’Halloran and colleagues (49) reported an interesting case, where the victim had tied his ankles to a segment of pipe so that his legs were spread. A

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yoke was attached to the center of the pipe, which was attached by a chain above the front loader bucket of a tractor. Fully raising the hydraulic bucket caused complete suspension of the inverted body by the ankles. Two ropes led from the victim to the control lever on the tractor for raising and tilting the bucket. The man had placed a piece of lumber next to his body under the tractor scoop as a safety measure to prevent it from drifting down. When the victim was found, the tractor engine was stalled, the board was snapped, and the scoop rested on the back of the body. The man died of positional asphyxiation by chest compression. Another bizarre case of a fatal chest compression was reported by Rothschild and Schneider (62). A 19-year-old man was found dead in his room, tied to his bed, and wearing a compressed-air overall as used by jet-fighter pilots to improve the venous blood flow (Fig. 5A,B). The overall was connected to a 12-V-compressor by a flexible pressure tubing. The man wore a motorbike helmet, and under his overall had on an unitard and several face masks. The cause of death was an extensive chest compression by the overall, which was overfilled with air. Schwarz (14) and Sivaloganathan (63) reported cases of autoerotic submersion, and Du Chesne communicated a case of drowning during autoerotic activity, where the water might have taken the role of a fetish (20).

3.2. Anesthesiophilia and AAD by Other Chemical Agents The inhalation of anesthetics, inhalants, and solvents mostly occurs in combination with plastic-bag asphyxiation, and sometimes with other appropriate devices like gas masks, anesthetic masks, diving masks, or even anesthetic machines. Similar to so-called “glue sniffing” of solvents for adhesives like toluene, the practitioners may simply inhale the substances (21) or often soak a rag with a solvent, and then insert the rag in the mouth to inhale the fumes, which is consistent with a practice known as “huffing” (64). In these cases, the oral prop becomes the lethal paraphilia (27). The substances that are used, like glue spray, butane, propane, xylene, benzene, or gasoline, are obtainable at most everywhere, and the inhalation of anesthetic gases such as ether or chloroform for their euphoric and narcotic effects has been described for many years (14,21,22,54,65). Jones et al. reported an AAD with plastic-bag asphyxiation in combination with inhaled glue spray (55), and Gowitt and Hanzlick described two cases with an involvement of 1-1-1-trichloroethane, a compound commonly found in typewriter correction fluid (65). Weimann and Schellmann reported AADs involving other halogenated hydrocarbons like ethyl chloride (21) and carbon tetrachloride (54), and Hazelwood as well as

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Fig. 5. Fatal asphyxiophilia of a 19-year-old man who wore a compressedair overall as used by jet-fighter pilots to improve venous blood flow. (A) Front view. (B) Back view. (Courtesy of Prof. Markus Rothschild, Cologne, Germany.)

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Gowitt and Hanzlick presented fatal AADs owing to inhalation of the fluorocarbon dichlorodifluoromethane (Freon 12) (65,66). Isenschmid et al. reported an interesting case where the victim was found in a conversion van with a plastic bag around his head that was tightly secured with a piece of panty hose (64). The plastic bag contained a folded towel and a pressurized can of Fix-A-Flat tire repair, containing chlorodifluoromethane (FC-22), tetrachlorethylene (perchloroethylene), and a “trade secret,” was found close by the deceased. The man was clad in a nylon body stocking, which contained an opening in the crotch exposing his genitals. His penis was tied with an additional piece of stocking material, and his waist was bound loosely with a buckled leather belt. Concentrations of tetrachlorethylene, obtained by GC-ECD analysis, were 62 mg/L in blood, 341 mg/kg in liver, 47 mg/kg in lung, and negative in urine and were consistent with an acute lethal tetrachlorethylene intoxication. Sometimes, elaborate techniques are found in anesthesiophilia. One of the first AADs involving nitrous oxide was portrayed by Schwarz in 1933 (18). The practitioner had used a complicated system of tubes, valves, and rubber balloons to apply laughing gas, which he had stolen from his father’s medical practice. Rothschild and Schneider communicated a case of a lethal anesthesiophilia owing to nitrous oxide from cream dispenser cartridges (62). The nitrous oxide was applied by a homemade closed system of anesthetic tubes, plastic bags, and an anesthetic face mask. Enticknap published the case of a 19-year-old female dental receptionist who was found in the surgery with the anesthetic face piece of a Walton No. 2 anesthetic machine in position over the nose (67). The woman died as a result of accidental nitrous oxide poisoning. Leadbeatter reported an AAD of an antiques dealer, who sat in a chair in front of which a Walton anesthetic machine was placed (56). Anesthetic tubing connected this machine to a firmly fixed anesthetic face mask. The setting of the machine indicated delivery of a gas mixture of 95% nitrous oxide and 5% oxygen; the indicator on the face mask attachment was in the “no valves” position. Although the toxicological analysis revealed just traces of nitrous oxide in blood as a consequence of the long time interval between death and autopsy, the death could be ascribed to hypoxia resulting from inhalation of nitrous oxide. Breitmeier et al. reported a bizarre autoerotic accident owing to multiplex paraphilia involving a fatal combination of asphyxia by suffocation and intoxication with ketamine, which was self-administered by an intravenous catheter (39). The toxicological analysis of blood taken from the femoral vein revealed a ketamine concentration of 2.5 µg/ml, which is well within the therapeutic range.

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The death occurred as a result of the dual effects of the mouth gag (rubber ball) and a drug-induced respiratory depression combined with cerebral edema (39). Drugs like cocaine, lysergic acid diethylamide (LSD), cannabis, or amphetamines are also used to enhance sexual excitement, sometimes combined with unusual application modes. Schwarz, for example, communicated an AAD owing to a lethal intoxication with rectally administered cocaine (14).

3.3. Electrophilia Compared to asphyxiophilic deaths, reports on autoerotic deaths resulting from electrophilia are rare and, apart from one case communicated by Weimann (21), comprise exclusively men, if the published cases (14,24,38,68–74) are scrutinized according to the AAD definitions of Byard and Bramwell as well as Behrendt and Modvig (23,27). Autoerotic electrocutions usually involve low-voltage alternating current, and a variety of devices is used to gain direct autoerotic stimulation, most of which involved household or homemade electrical devices like electrical wiring from a television set, a table lamp, or a defective toy train transformer (2,13,22,49,68–70). Sometimes practitioners simply use Y-shaped cables with a plug for house current (220 V) at one end and self-made electrodes at the other ends (own case and ref. 38). In both of these cases, one electrode was introduced in the anus, whereas the other electrode was applied to the penis. Rectal application of electricity is a common practice for obtaining semen from bulls (“electroejaculation”) (21,38) and might be the idea behind this uncommon method of masturbation. Another favored location for the placement of electrodes are the nipples. One of the first electrophilic AADs that involved house current (220 V) applied to the nipples was reported by Schwarz (14). As a rescue mechanism, the 27-yearold electrical-engineering technician had integrated in the circuit a preset potentiometer (dropping resistor), but seems to have oversized the dosage applied to the electrodes. Schott and colleagues reported an AAD of a 18-year-old man who was wearing two brassieres (13). Underlying each brassiere cup were two wet folded terry cloths, with a metal washer loosely adhered to the outer cloth. The washers were wrapped in exposed wires from the two short ends of a Y-shaped electrical cord. The long end of this cord was connected to a functional electrical outlet (110 V) via a two-pronged plug. Autopsy disclosed patterned second- and third-degree burns of the bilateral mammary regions. The authors attributed death to acute cardiac dysrhythmia secondary to lowvoltage electrocution. A similar case was portrayed by Hazelwood et al. where a 30-year-old man wore a brassiere and wet terry cloth towels that were attached via tin foil and rotisserie to the house current (66).

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Sometimes the circuits are elaborate and comprise several body parts. Weimann reported a case of a 15-year-old electrician apprentice, who connected a teaspoon in his rectum, aluminum around his penis, and a glow lamp mignon holder in his mouth with the house current in such a way that he was able to control the strength of the current with his lips by fastening or unscrewing the bulb similarly to a potentiometer (21). The death occurred because of the bad insulation of the glow lamp cables, leading to an exclusion of the glow lamp from the circuit. In cases of electrophilia with fatal outcome, pornographic literature or devices for deviant sexual gratification are regularly found (38,75), whereas the death scenes seem to be of a less bizarre imagery than in asphyxiophilic cases (20).

3.4. Other Practices of Autoeroticism The practices discussed in this section regularly comprise techniques that extravagate to sexual masochism. The insertion of foreign objects into the mouth, penis, vagina, or rectum is a known and dangerous autoerotic practice. Death may result particularly from bleeding or peritonitis, especially if perforations occur that lead to an opening of the abdominal cavity (43). Byard et al. reported a septic autoerotic death where a pencil was found in the peritoneal cavity (76). The perforation of the bladder led to the suggestion that the pencil had been introduced through the penile urethra. A similar case in which death occurred owing to massive abdominal hemorrhage secondary to bladder rupture was communicated by Diggs (77). In this case, the foreign body used to inflict the traumatic injuries was a chopstick. Sivaloganathan portrayed the death of a 23-year-old man resulting as a late complication of autoerotic practice (78); the man died of bronchopneumonia as a sequel of renal failure (bilateral pyelonephritis) following a bladder calculus that had formed around a coiled plastic tube with an entire length of 20–30 cm. Schmeling et al. communicated an AAD of a 23-year-old man who was found dead in his room, wearing female underwear (79). The man had constructed an apparatus to induce peritoneal pain, consisting of a wooden slat that was attached by a hinge to the wall unit beside the bed. A vise with two inserted knives was affixed to the other end of the slat. Lying back on his bed, the man was able to move the slat up and down by an electric motor that was operated by remote control. The drive train was performed by a cord with a counterweight. The length of the cord was adjusted in such a way that the knives contacted the abdominal skin in the “down” position of the slat. When the cord twitched, the knifes penetrated the abdominal wall and death occurred as a result of internal bleeding.

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4. A COMPARISON OF AUTOEROTICISM IN MALES AND FEMALES Whereas approximately 50 AAD cases per year were estimated in 1972 (4), conservative estimates suggest now that 500–1000 AADs occur annually in the United States alone (3,6,80,81,82). The age range of male and female victims is wide, from 9 to 80 years in men (2,4,27,41), and from 17 to 68 years (2,29) in women. In both sexes, however, AAD is most often seen in young to middle-aged adults. Whereas young white men comprise the largest group of victims (23,32,40,80,81), the number of female AADs reported in the literature is extremely small (2,4,20,51,82). In the 1950s, Schwarz explained the nonexistence of female AADs with the presumption that women were less active in erotic matters and would get by with simple means for masturbation instead of elaborate apparatus (14). Although Meixner had reported a female AAD case as early as 1952 (21,83), Resnick stated as late as 1971 an absolute absence of AAD in females (1). In the same year, Henry published the first case of a typical female AAD in the English medicolegal literature (84), and, to our knowledge, in the following decades up to now only 62 cases have been communicated. Omitting identical cases and cases that do not fulfill the criteria for AAD according to the definition of Behrendt and Modvig (27), there remain just 15 published typical female AAD cases (29). Gosink and Jumbelic quoted a male to female ratio of more than 50:1 (41). Males tend to utilize a great range of elaborate devices and props, often designed to cause real or simulated pain, with pornographic material and evidence of cross-dressing and fetishism like intimate feminine garments (Fig. 6) (2–6,28,41). Frequently, the paraphernalia associated with the practice becomes more elaborate as the participant ages and becomes more experienced (41). In the largest published series to date, 26 (20.5%) of 127 males dying of autoerotic asphyxiation were cross-dressed at the time of death, 5 of whom had been observed by others to have repeatedly cross-dressed in the past, and another 5 who had sizable or diverse collections of women’s clothing or makeup (49,85). Additionally, mirrors are often placed by male practitioners to enable them to observe their activities (2,4,5,36,86). In contrast, the female AAD seems to have a less obvious presentation (5,52). As just one case was published until 2002 where a woman was wearing unusual “harem-style” clothing with an elaborate system of rope bindings (84), it was thought for a long time that females are usually found without unusual or bizarre equipment, naked with only a single ligature, tightened either by lowering the body or by pulling an attached cord tied to the hands or legs (2,40,42,87). The four cases published by Behrendt et al., however, confirm that females may be as elaborate

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Fig. 6. AAD (positional asphyxia) of a 19-year-old man who wore feminine garments and high-heeled shoes. (Courtesy of Dr. Wolfgang Huckenbeck, Düsseldorf, Germany.)

with nonlethal paraphilias and props as are known to be men (29). Besides bizarre equipment like a horsewhip, pornographic material, a plastic bag with ether, and elaborate bondage encircling the limbs and/or the vulva, there was one case in which the bondage with chains was similar to a typical homicide ritual of the Italian mafia called “incaprettamento” (29,88). Therefore, it has to be stated that female AADs may very closely resemble a typical male AAD (29). In the majority of female AADs, however, the absence of typical props like pornographic material, cross-dressing, or elaborate and often bizarre equipment, as it is nearly regularly used by men, may impede the identification of a female AAD (42).

5. MEDICOLEGAL ASPECTS OF ACCIDENTAL AUTOEROTIC DEATH: THE DEMARCATION FROM SUICIDES AND HOMICIDES AADs may very closely resemble a sadistic and/or ritualistic homicide or suicide (2,5,14,17,18,21,29,48,76,89–91). Madea portrayed the case of a homicide by throttling and strangulation that was first considered an AAD (89), and Naeve discussed the possibility of feigning an AAD in both suicide and homicide (90). To exclude the possibility of sexual homicide or suicide, the investigators have to establish the presence of key death scene characteristics before the death can be appropriately classified as an autoerotic fatality (1,2,4,6,21,41,44,48,52,55,80,92). Because of the desire for secrecy and privacy, the location for the performance of the activity is usually a secluded place, often with evidence of

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Fig. 7. Permanent hooks on the ceiling facilitating repetition of hanging for autoerotic behavior. (A) Note the pornographic pictures on the wall on the left side. (B) This construction was used as a block and pulley. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

repeated autoerotic behavior, for example, permanent hooks on the walls or ceiling (Fig 7A,B) to facilitate repetitive hanging (1–4,14,21,44,52,81,93). The victims are found alone, often in isolated areas outdoors but mostly, however, in rooms locked from inside. Mirrors that allow the practitioner to observe his activities (2,4,21,86) are no secure criterion for an AAD, as this finding has also been described in cases of suicide (94). Bondage (Fig. 8) is common, with often elaborate and bizarre methods of restriction and a variety of ropes and cords tied to and around the genitals (1,2,4,23,34,36,42). The death scene investigators have to ensure that any bondage could have been secured by the deceased himself (36,41,44). A further important piece of evidence against suicide is padding of the rope, especially in neck ligatures, to prevent subsequently detectable abrasions or bruises (2,4,5,36,41,80,81). Because of the accidental nature of AAD, one or sometimes several failed escape mecha-

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Fig. 8. AAD with deliberate bondage around ankles and legs. The practitioner is wearing female underwear.

nisms are usually evident (2,3,21,46,49). The emission of semen is compatible with, but does not necessarily confirm sexual activity in itself, since a near-terminal reflex neurophysiological response to hypoxia is common, as is postmortem discharge of semen from the meatus, in any type of death, not only in asphyxia (1–3,36). Abrasions and bruises are no definite sign of homicide, as body movements occur especially in asphyxiophilia and electrophilia, and the body may repeatedly bump against surrounding structures (50). A lack of features of suicide with no antemortem evidence of suicidal ideation or depression is diagnostic for AAD; an overt suicide note is usually not present (2,4,23,36,86). Turvey, however, discussed the possibility that a suicide note might be present as a prop, a part of a victim’s masochistic fantasy (44). In some cases, the differentiation between AAD and suicide remains impossible: although the death scene with sexual attributes suggests an AAD, predictable fatal autoerotic techniques and insufficient rescue mechanisms make it inevitable that the victim must have been aware of the fatal outcome (9,20,56). Knight assumed a mixed motivation in these infrequent cases (36), and Byard and Botterill warned that in certain cases suicide or undetermined might be more appropriate conclusions regarding the manner of death (93). Contostavlos argued as well that at least some of these cases (suspension or extremely restrictive bondage) were similar in nature to Russian roulette, and were more properly labeled “manner undetermined” (95). Thorough investigations regarding life and environment of the victim and the circumstances of death, sometimes referred to as “psychological autopsy,” may be effective in the determination of the manner of death in equivocal cases (28,59,77,96,97). Jobes et al. showed

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Table 3 Twelve Characteristics for a Determination of Autoerotic Death Characteristic

Explanation

1*

Location

Secluded or isolated area with a reasonable expectation of privacy; rooms locked from inside. Evidence of solo sexual activity.

2

Body position

No free hanging in asphyxial hanging deaths: the victim’s body may be partially supported by the ground, or the victim may even appear to have simply been able to stand up to avoid strangulation.

3

High-risk elements

Potentially lethal devices, apparatus, or chemicals brought in to the autoerotic activity that enhance physical or psychological pleasure and increase the risk of death.

4

Self-rescue mechanisms

Any provision that allows the victim to voluntarily stop the effect of the high-risk element (e.g., slip knot, knife).

5

Bondage

Use of special materials or devices that physically restrain the victim and have a psychological/fantasy significance to the victim. It is important that any bondage could have been secured by the deceased himself.

6

Masochistic behavior

Inflicting physical or psychological pain on sexual areas of the body, or other body parts: indicators of current use (e.g., genital restraints, ball-gag, nipple clips, or suspension) and/or healed injuries suggesting a history of autoerotic behavior.

Seidl

Attire

The victim may be dressed in fetishistic attire or in one or more articles of female clothing/cross-dressing. Both may be absent! The victims may be fully dressed, nude, or partially undressed.

8

Protective padding

To avoid visibility to others, injuries may be inflicted only to areas that are covered by clothing, and/ or protective padding like scarfs or towels are used to prevent abrasions or grooves.

9

Sexual paraphernalia and props

Items found on or near the victim that assist in sexual fantasy (vibrators, dildos, mirrors, erotica, diaries, photos, films, female undergarments, etc.).

10

Masturbatory activity

Absence and presence of semen from the scene are no reliable indicators of autoerotic death. Masturbation may be suggested by the presence of semen on hands and towels.

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11* Evidence of Evidence of behavior similar to that found in scene that predates the fatality, e.g., permanently affixed prior autoerotic protective padding, plastic bags with repaired “escape” holes, complex high-risk elements, complex activity escape mechanisms, healed injuries, grooves worn in a beam (from repeated ligature placement), etc. 12* No apparent suicidal intent

The victims have made plans for future events in their life (e.g., plans to see friends or go on trips). Absence of a suicide note is not always an indication of an autoerotic event. If one is present, it must be determined that it was written around the time of death, and is not a prop.

Note. Modified according to refs. 1, 44, and 66. Characteristics marked with an asterik are mandatory; unmarked features are facultative.

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that a standardized psychological autopsy technique in these cases may lead to a shift toward suicidal death (96). Finally, the death scene investigator should be alert to the fact that family members or acquaintances could have removed female clothing and props in an attempt to disguise the manner of death with its attendant social stigma (2,3,6,38,76). For example, Garza-Leal and Landron reported a case where the father of the victim admitted to having removed pornographic pictures from the scene (3). In continuation of Resnick’s criteria (1), Hazelwood (66) and Turvey (44) established general behavioral characteristics that investigators can look for to help them identify autoerotic death scenes (Table 3). It has to be mentioned that not all of these criteria need to be present. At least the following characteristics, however, are obligatory: (a) reasonable expectation of privacy, (b) evidence of solo sexual activity, (c) evidence of prior high-risk autoerotic practice, and (d) no apparent suicidal intent (44).

REFERENCES 1. Resnik HLP (1972) Erotized repetetive hangings: a form of self-destructive behavior. Am J Psychother 26, 4–21. 2. Byard RW, Hucker SJ, Hazelwood RR (1990) A comparison of typical death scene features in cases of fatal male and autoerotic asphyxia with a review of the literature. Forensic Sci Int 48, 113–121. 3. Garza-Leal JA, Landron FJ (1991) Autoerotic asphyxial death initially misinterpreted as suicide and a review of the literature. J Forensic Sci 36, 1753–1759. 4. Walsh FM, Stahl CJ, 3rd, Unger HT, Lilienstern OC, Stephens RG 3rd (1977) Autoerotic asphyxial deaths: a medicolegal analysis of forty-three cases. Leg Med Annu, 155–182. 5. Tournel G, Hubert N, Rouge C, Hedouin V, Gosset D (2001) Complete autoerotic asphyxiation: suicide or accident? Am J Forensic Med Pathol 22, 180–183. 6. Uva JL (1995) Review: autoerotic asphyxiation in the United States. J Forensic Sci 40, 574–581. 7. Minyard F (1985) Wrapped to death. Unusual autoerotic death. Am J Forensic Med Pathol 6, 151–152. 8. Emson HE (1983) Accidental hanging in autoeroticism: an unusual case occuring outdoors. Am J Forensic Med Pathol 4, 337–340. 9. Johnstone J, Huws R (1997) Autoerotic asphyxia: a case report. J Sex Marital Ther 23, 326–332. 10. Ober WB (1991) The man in the scarlet cloak. The mysterious death of Peter Anthony Motteux. Am J Forensic Med Pathol 12, 255-261. 11. Ober WB (1984) The sticky end of Frantisek Koczwara, composer of “The Battle of Prague.” Am J Forensic Med Pathol 5, 145–149. 12. Dietz PE (1983) Recurrent discovery of autoerotic asphyxia. In Hazelwood RR, Dietz PE, Burgess AW, eds., Autoerotic fatalities. Lexington Books, Lexington, pp. 13–44.

Accidental Autoerotic Death

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13. Schott JC, Davis GJ, Hunsaker JC, 3rd (2003) Accidental electrocution during autoeroticism: a shocking case. Am J Forensic Med Pathol 24, 92–95. 14. Schwarz F (1952) Unfallmäßige Todesfälle bei autoerotischer Betätigung. Beitr Gerichtl Med 19, 142–154. 15. Blanchard R, Hucker SJ (1991) Age, transvestism, bondage, and concurrent paraphilic activities in 117 fatal cases of autoerotic asphyxia. Br J Psychiatry 159, 371–377. 16. Ziemke E (1926) Über zufälliges Erhängen und seine Beziehungen zu sexuellen Perversitäten. Arch Kriminol 78, 262–263. 17. Schwarz F (1932) Tödliche Unfälle als Folgen perverser Neigungen. Dtsch Z gerichtl Med 85, 85–91. 18. Schwarz F (1933) Tödliche Lachgasvergiftung bei Selbstnarkose. Arch Kriminol 93, 215–217. 19. Weimann W (1935) Ein Fall zufälliger Erhängung aus sexuellen Motiven. Arch Kriminol 97, 62–63. 20. Du Chesne A, Kaupert A, Prokop A, Schropfer D, Hofmann V (1978) Autoerotische Unfälle. Z Ärztl Fortbild (Jena) 72, 136–139. 21. Weimann W (1966) Tödliche Unfälle bei autoerotischer Betätigung. In Prokop O, ed., Forensische Medizin. VEB Verlag Volk und Gesundheit, Berlin, pp. 297–316. 22. Imami RH, Kemal M (1988) Vacuum cleaner use in autoerotic death. Am J Forensic Med Pathol 9, 246–248. 23. Byard RW, Bramwell NH (1991) Autoerotic death. A definition. Am J Forensic Med Pathol 12, 74–76. 24. Cooke CT, Cadden GA, Margolius KA (1994) Autoerotic deaths: four cases. Pathology 26, 276–280. 25. Frazer M, Rosenberg S (1983) A case of suicidal ligature strangulation. Am J Forensic Med Pathol 4, 351–354. 26. Watanabe-Suzuki K, Suzuki O, Kosugi I, Seno H, Ishii A (2002) A curious autopsy case of a car crash in which self-strangulation and lung collapse were found: a case report. Med Sci Law 42, 261–264. 27. Behrendt N, Modvig J (1995) The lethal paraphiliac syndrome. Accidental autoerotic deaths in Denmark 1933-1990. Am J Forensic Med Pathol 16, 232–237. 28. Boglioli LR, Taff ML, Stephens PJ, Money J (1991) A case of autoerotic asphyxia associated with multiplex paraphilia. Am J Forensic Med Pathol 12, 64–73. 29. Behrendt N, Buhl N, Seidl S (2002) The lethal paraphiliac syndrome: accidental autoerotic deaths in four women and a review of the literature. Int J Legal Med 116, 148–152. 30. von Krafft-Ebing R (1997) Psychopathia sexualis. Matthes & Seitz, München. 31. Allen C (1979) The sexual perversions and abnormalities: a study in the psychology of paraphilia. Greenwood Press, Westport. 32. American Psychiatric Association (1994) DSM IV. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Publishing Inc, Arlington. 33. World Health Organization (1992) The ICD-10 Classification of mental and behavioral disorders. Clinical descriptions and diagnostic guidelines. WHO, Geneva.

260

Seidl

34. Hiss J, Rosenberg SB, Adelson L (1985) “Swinging in the park.” An investigation of an autoerotic death. Am J Forensic Med Pathol 6, 250–255. 35. Money J (1981) Paraphilias: phenomenology and classification. Am J Psychother 38, 164–179. 36. Knight B (1996) The sexual asphyxias: auto-erotic or masochistic practices. In Knight B, ed., Forensic pathology. Arnold, London, pp. 385–389. 37. Campbell M (1989) More on autoerotic death. J Am Acad Child Adolesc Psychiatry 28, 137. 38. Klintschar M, Grabuschnigg P, Beham A (1998) Death from electrocution during autoerotic practice: case report and review of the literature. Am J Forensic Med Pathol 19, 190–193. 39. Breitmeier D, Passie T, Mansouri F, Albrecht K, Kleemann WJ (2002) Autoerotic accident associated with self-applied ketamine. Int J Legal Med 116, 113–116. 40. Hazelwood RR, Burgess AW, Groth AN (1981) Death during dangerous autoerotic practice. Soc Sci Med [E] 15, 129–133. 41. Gosink PD, Jumbelic MI (2000) Autoerotic asphyxiation in a female. Am J Forensic Med Pathol 21, 114–118. 42. Byard RW, Bramwell NH (1988) Autoerotic death in females. An underdiagnosed syndrome? Am J Forensic Med Pathol 9, 252–254. 43. Shook LL, Whittle R, Rose EF (1985) Rectal fist insertion. An unusual form of sexual behavior. Am J Forensic Med Pathol 6, 319–324. 44. Turvey BE (2000) Autoerotic death. In Siegel JA, Saukko PJ, Knupfer GC, eds., Encyclopedia of forensic sciences. Academic Press, London, pp. 290–295. 45. Segura MA (1979) Death investigation: distinguishing between autoerotic and suicidal hanging. Forensic Sci Digest 5, 312–322. 46. Sinn LE (1993) The silver bullet. Am J Forensic Med Pathol 14, 145–147. 47. O’Halloran RL, Lovell FW (1988) Autoerotic asphyxial death following television broadcast. J Forensic Sci 33, 1491–1492. 48. Doychinov ID, Markova IM, Staneva YA (2001) Autoerotic asphyxia (a case report). Folia Med (Plovdiv) 43, 51–53. 49. O’Halloran RL, Dietz PE (1993) Autoerotic fatalities with power hydraulics. J Forensic Sci 38, 359–364. 50. Risse M, Weiler G (1989) Agonale and supravitale Bewegungsabläufe beim Erhängen. Beitr Gerichtl Med 47, 243–246. 51. Schumann M, Rauch E, Priemer F (1997) Ein erweiterter autoerotischer Unfall. Arch Kriminol 199, 27–31. 52. Byard RW, Hucker SJ, Hazelwood RR (1993) Fatal and near-fatal autoerotic asphyxial episodes in women. Characteristic features based on a review of nine cases. Am J Forensic Med Pathol 14, 70–73. 53. Schröer J, Sperhake J, Schulz F, Tsokos M (2001) Selbst beigebrachte Verletzungen bei Männern—Verletzungsmuster und Motivation. Arch Kriminol 208, 165–174. 54. Schellmann B, Scheithauer R (1983) Tödliche autoerotische Unfälle. Arch Kriminol 171, 19–25.

Accidental Autoerotic Death

261

55. Jones LS, Wyatt JP, Busuttil A (2000) Plastic bag asphyxia in southeast Scotland. Am J Forensic Med Pathol 21, 401–405. 56. Leadbeatter S (1988) Dental anesthetic death. An unusual autoerotic episode. Am J Forensic Med Pathol 9, 60–63. 57. Eriksson A, Gezelius C, Bring G (1987) Rolled up to death. An unusual autoerotic fatality. Am J Forensic Med Pathol 8, 263–265. 58. Grass H, Käferstein H, Schuff A, Sticht G (1998) Routinefall “autoerotischer Unfall”—überraschende Wendung in der Bewertung der Todesursache nach chem.tox. Analyse. Arch Kriminol 202, 75–80. 59. Thibault R, Spencer JD, Bishop JW, Hibler NS (1984) An unusual autoerotic death: asphyxia with an abdominal ligature. J Forensic Sci 29, 679–684. 60. Madea B (1993) Death in a head-down position. Forensic Sci Int 61, 119–132. 61. Madea B (1990) Tod in Kopftieflage. Arch Kriminol 186, 65–74. 62. Rothschild MA, Schneider V (1997) Über zwei autoerotische Unfälle: Tödliche Lachgasnarkose und Thoraxkompression. Arch Kriminol 200, 65–72. 63. Sivaloganathan S (1984) Aqua-eroticum. A case of auto-erotic drowning. Med Sci Law 24, 300–302. 64. Isenschmid DS, Cassin BJ, Hepler BR, Kanluen S (1998) Tetrachloroethylene intoxication in an autoerotic fatality. J Forensic Sci 43, 231–234. 65. Gowitt GT, Hanzlick RL (1992) Atypical autoerotic deaths. Am J Forensic Med Pathol 13, 115–119. 66. Hazelwood RR (1983) Autoerotic fatalities. Lexington Books, Lexington. 67. Enticknap JB (1961) A case of fatal accidental N2O poisoning. Med Sci Law 1, 404–409. 68. Cairns FJ, Rainer SP (1981) Death from electrocution during auto-erotic procedures. N Z Med J 94, 259–260. 69. Sivaloganathan S (1981) Curiosum eroticum—a case of fatal electrocution during auto-erotic practice. Med Sci Law 21, 47–50. 70. Tan CT, Chao TC (1983) A case of fatal electrocution during an unusual autoerotic practice. Med Sci Law 23, 92–95. 71. Händel K (1959) Zwei tödliche Unfälle durch elektrischen Strom bei autoerotischer Betätigung. Elektromed 4, 172–174. 72. Hirth L (1959) Ein weiterer Fall von Stromtod bei autoerotischer Betätigung. Dtsch Z Ges Gerichtl Med 49, 109–112. 73. Holzhausen G, Hunger H (1963) Stromtod eines Kleiderfetischisten bei autoerotischer Betätigung. Arch Kriminol 131, 166–172. 74. Schollmeyer W (1959) Todesfall durch Strom bei abwegiger sexueller Betätigung. Dtsch Z Ges Gerichtl Med 49, 213–217. 75. Dürwald W (1962) Zur Beurteilung autoerotischer Unfälle. Beitr Gerichtl Med 22, 91–101. 76. Byard RW, Eitzen DA, James R (2000) Unusual fatal mechanisms in nonasphyxial autoerotic death. Am J Forensic Med Pathol 21, 65–68. 77. Diggs CA (1986) Suicidal transurethral perforation of bladder. Am J Forensic Med Pathol 7, 169–171.

262

Seidl

78. Sivaloganathan S (1985) Catheteroticum. Fatal late complication following autoerotic practice. Am J Forensic Med Pathol 6, 340–342. 79. Schmeling A, Correns A, Geserick G (2001) Ein ungewöhnlicher autoerotischer Unfall: sexueller Lustgewinn durch Peritonealschmerz. Arch Kriminol 207, 148–153. 80. Bell MD, Tate LG, Wright RK (1991) Sexual asphyxia in siblings. Am J Forensic Med Pathol 12, 77–79. 81. Tough SC, Butt JC, Sanders GL (1994) Autoerotic asphyxial deaths: analysis of nineteen fatalities in Alberta, 1978 to 1989. Can J Psychiatry 39, 157–160. 82. Burgess AW, Hazelwood RR (1983) Autoerotic asphyxial deaths and social network response. Am J Orthopsychiatry 53, 166–170. 83. Meixner F (1952) Kriminalität und Sexualität. Verlag Kriminalistik, Heidelberg. 84. Henry R (1971) “Sex” hangings in the female. Med Leg Bull 214, 1–5. 85. Dietz PE, Burgess AW, Hazelwood RR (1983) Autoerotic asphyxia, the paraphilias, and mental disorder. In Hazelwood RR, Dietz PE, Burgess AW, eds., Autoerotic fatalities. Lexington Books, Lexington, pp. 55–76. 86. Sheehan W, Garfinkel BD (1988) Adolescent autoerotic deaths. J Am Acad Child Adolesc Psychiatry 27, 367–370. 87. Danto BL (1980) A case of female autoerotic death. Am J Forensic Med Pathol 1, 117–121. 88. Fineschi V, Dell’Erba AS, Di Paolo M, Procaccianti P (1998) Typical homicide ritual of the Italian mafia (“incaprettamento”). Am J Forensic Med Pathol 19, 87–92. 89. Madea B (1987) Vortäuschung eines Suizides unter dem Bild eines autoerotischen Unfalls zur Verdeckung eines Tötungsdeliktes. Arch Kriminol 179, 149–153. 90. Naeve W (1974) Selbstmorde und Tötungsdelikte unter Vortäuschung eines autoerotischen Unfalles. Arch Kriminol 154, 145–149. 91. Diamond M, Innala SM, Ernulf KE (1990) Asphyxiophilia and autoerotic death. Hawaii Med J 49, 11–12, 14–16, 24. 92. Kirksey KM, Holt-Ashley M, Williamson KL, Garza RO (1995) Autoerotic asphyxia in adolescents. J Emerg Nurs 21, 81–83. 93. Byard RW, Botterill P (1998) Autoerotic asphyxial death—accident or suicide? Am J Forensic Med Pathol 19, 377–380. 94. Riddick L, Mussell PG, Cumberland GD (1989) The mirror’s use in suicide. Am J Forensic Med Pathol 10, 14–16. 95. Contostavlos DL (1994) Commentary on “Autoerotic fatalities with power hydraulics.” J Forensic Sci 39, 1143–1144. 96. Jobes DA, Berman AL, Josselson AR (1986) The impact of psychological autopsies on medical examiners’ determination of manner of death. J Forensic Sci 31, 177–189. 97. Wesselius CL, Bally R (1983) A male with autoerotic asphyxia syndrome. Am J Forensic Med Pathol 4, 341–344.

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11 Lethal Hypothermia Paradoxical Undressing and Hide-and-Die Syndrome Can Produce Very Obscure Death Scenes Markus A. Rothschild, MD CONTENTS INTRODUCTION PARADOXICAL UNDRESSING HIDE-AND-DIE SYNDROME REFERENCES

SUMMARY Hypothermia is a relatively rare cause of death in temperate climate zones. In most cases of lethal hypothermia, elderly and mentally ill persons are affected as well as persons under the influence of alcohol or other substances. Although most cases of death from hypothermia are accidental, they, more often than other types of death from environmental conditions, produce a death scene that is at first obscure and difficult to interpret. The reason for this frequent obscurity is mainly because of the phenomenon of the so-called paradoxical undressing as well as the hide-and-die syndrome. In many cases, the bodies are found partly or completely unclothed and abrasions and hematomas are found on the knees, elbows, feet, and hands. The reason for the paradoxical undressing is not yet clearly understood. There are two main theories discussed: one theory proposes that the reflex vasoconstriction, which happens in the first stage of hypothermia, leads to paralysis of the vasomotor center thus giving rise to the sensation that the body temperature is higher than it really is, and, in a paradoxical reaction, the person undresses. The other theory From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 263

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says that it seems to be the effect of a cold-induced paralysis of the nerves in the vessel walls that leads to a vasodilatation giving an absurd feeling of heat. In 20% of cases of lethal hypothermia, the phenomenon of the so-called hideand-die syndrome also can be observed. Some of these bodies are situated in a kind of “hidden position,” for example, located under a bed or behind a wardrobe. Apparently, this finding is the result of a terminal primitive reaction pattern, which is probably an autonomous behavior triggered and controlled by the brain stem. It shows the characteristics of both an instinctive behavior and a congenital reflex. Key Words: Lethal hypothermia; paradoxical undressing; hide-and-die syndrome; death scene investigation; terminal burrowing behavior.

1. INTRODUCTION Hypothermia is a relatively rare cause of death in temperate climate zones. In most cases of lethal hypothermia, infants, elderly, and mentally ill persons are affected as well as persons under the influence of alcohol or other substances (1–5). The dangerous effects of cold do not necessarily develop only at temperatures below 0°C (32°F). Hypothermia can even occur at ambient temperatures of around 21°C (70°F). Cases of lethal hypothermia are found in about 1% of all autopsy cases examined in Institutes of Legal Medicine that are situated in bigger cities of Germany (6), whereas those institutes situated in smaller cities and with rural environment observe these cases in about 2% of all their autopsy cases. Approximately 50% of all victims of lethal hypothermia are under the influence of alcohol. Hypothermia is the result of an imbalance between an increased loss of body heat and an insufficient production of body heat. Hypothermia means all states with a core temperature of the body under 35°C (95°F). A prolonged process of hypothermia leads to a cold-induced diuresis and leaking of plasma into extracellular spaces and therefore results in an increase of blood viscosity and a decrease of blood circulation. With further progression, anuria occurs. If the body’s temperature decreases further, potassium will transfer from the extracellular to the intracellular compartments, whereas the sodium concentrations remain stabile. These changes in the ratio of potassium/sodium and the increased affinity of oxygen to hemoglobin can result in fatal ventricular fibrillation, acidosis, and edema of the brain. Although most cases of death from hypothermia are accidental and collectively amount to only a relatively small number of deaths encountered in the forensic pathologist’s or medical examiner’s practice, they more often than

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other types of death from environmental conditions produce a death scene that is at first obscure and difficult to interpret (7). The reason for the frequent obscurity of the death scene in cases of lethal hypothermia is mainly because of the phenomena of the so-called paradoxical undressing (1,8–12) and the hide-and-die syndrome (13,14). In many cases, the bodies are found partly or completely unclothed and abrasions and hematomas are seen on the knees, elbows, feet, and hands (8,11). Some of these bodies are found in a kind of “hidden position” (e.g., located under a bed or behind a wardrobe [14]). At first sight, these observations will strongly indicate a crime, as very often a naked female body raises the suspicion of a preceding sexual attack. As a consequence, the public prosecutor will, in such cases, demand an autopsy to clarify the cause of death. Similar to autopsy cases of death from asthma, epilepsia, or drowning, the gross autopsy findings may be nonspecific or any pathological features may be even totally absent. Therefore, it is very important for the forensic pathologist and medical examiner, respectively, to visit the death scene to get as many clues and hints toward the case as possible. However, in a large number of cases of death from lethal hypothermia, the autopsy shows a typical group of findings such as cherry-red or pink livores mortis, swelling and red-purple spots and sometimes abrasions over the joints, Wischnewski spots in the gastric mucosa, pancreatitis, high levels of acetone in blood and/or urine, and basal lipid accumulations in the epithelial cells of renal proximal tubules. Outcome of autopsy together with the results of the death scene investigation then very often obviously show that the police are dealing with a case of hypothermia without any hints for a preceding crime.

2. PARADOXICAL UNDRESSING The phenomenon of paradoxical undressing in cases of lethal hypothermia (Fig. 1) can be observed more often at moderately cold ambient temperatures from –5° to +5°C (23–41°F) and in a slow decrease of body temperature than in cases with very cold ambient temperatures and a rapid decrease of body temperature. The bodies are found inadequately clothed or completely naked. In cases of paradoxical undressing, two-thirds of the bodies are partially unclothed and one-third is totally naked (11,14,15). In the overwhelming number of cases, the clothes are strewn on the ground beside the body, sometimes forming a trail of scattered clothing over a distance of some meters. But cases where the clothes are scattered all over the place can also be observed. Although there seems to be no homogenous pattern of undressing, it seems that undressing in most cases had started with the lower half of the body. One reason for this could be linked with the well-known

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Fig. 1. Paradoxical undressing. This 51-year-old man was found dead on the floor of his flat in which heat and electricity had been switched off for weeks because the man was overdue with his fees. The ambient temperature in the flat was 10°C (50°F) and the outside temperature ranged between –4°C and –12°C (10–25°F) for several days. Except for underpants, the man was completely undressed. Note the spots (that were red-purple colored and attributed to hypothermia) and abrasions on the right knee. The blood alcohol concentration was 110 mg/dL. The finding situation and the results of the forensic autopsy indicated that the man had died of lethal hypothermia. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

phenomenon of cold-induced diuresis, where possibly the hypothermic person removes the urine-wet clothes. Another explanation could be a different number of heat receptors in the lower and in the upper half of the body thus resulting in different heat sensations. However, this is still unclear and further investigations are needed. The paradoxical undressing obviously happens in a state of severe mental confusion. Otherwise, why these persons behave like they do would not be understandable. In the case presented in Fig. 2, the 37-year-old mentally ill woman was walking around when she saw an open door leading to the basement of a building of a cleaning company. She entered the basement and accidentally was locked in. When she was found dead partly naked a few days later, she was lying on the lowest shelf of a steel storage shelving unit that was filled with a large number of frocks (an example of the so-called hide-and-die

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Fig. 2. Hide-and-die syndrome. This 37-year-old mentally confused woman was found dead lying on the lowest shelf of a steel storage shelving unit in the basement of a building. During the weekend, when she was accidentally locked in the building, the ambient temperature in the basement was between 12 and 15°C (54–59°F). Outcome of toxicology was negative. According to autopsy and circumstances at the death scene, the woman had died from lethal hypothermia.

syndrome; see next section). The ambient temperature in the basement was between 12 and 15°C (54–59°F). It would have probably saved her life if she had put on some of these frocks instead of taking her own clothes off. The reason for the phenomenon of paradoxical undressing is not yet clearly understood. We know that cold causes a reflectory vasoconstriction and opening of arteriovenous shunts. As a result, the temperature of the skin decreases and if the body stays in the cold environment, the body temperature will decrease as well. It is not clear what is happening then and two main

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theories are discussed (16–20): the first theory proposes that the reflex vasoconstriction, which happens in the first stage of hypothermia, leads to paralysis of the vasomotor center in the hypothalamus thus giving rise to the sensation that the body temperature is higher than it really is and, in a paradoxical reaction, the person undresses. The second theory says that paradoxical undressing is an effect of a cold-induced paralysis of the nerves in the vessel walls that leads to a vasodilatation thus giving an absurd feeling of heat.

3. HIDE-AND-DIE SYNDROME In cases of lethal hypothermia, the phenomenon of the so-called hideand-die syndrome can be also observed (13). We observed the hide-and-die syndrome in an earlier study of 69 cases of death from lethal hypothermia in 20% of the cases (14). In 80% out of the cases showing a paradoxical undressing, there seems to be a link with the hide-and-die syndrome and there seems to be no hide-and-die syndrome without paradoxical undressing (14). In the hide-and-die syndrome, the bodies are found in a position that at first raises suspicion of an attempt to hide the body (Fig. 3). But after a thorough investigation, including death scene investigation and autopsy, it is evident in most cases that no other person was involved and a crime will be excluded. Obviously, the strange positions in which the bodies are positioned are the result of a (pre-)terminal behavior. The situation in which the bodies are found and their positions always give the impression of a protective “burrowlike” or “cave-like” situation, as the bodies are found under the bed, behind the wardrobe, on a shelf, etc. The clothes are always strewn on the ground in front of the final position, sometimes forming a trail. In every case, the paradoxical undressing had obviously happened before this self-protective phenomenon occurred, which for good reasons is called hide-and-die syndrome (13). This is sustained by the fact that the removed clothing was never found directly at the final position where the body was found and some of the victims had obviously been crawling around (8,15,21,22). In most cases, the final position in which the bodies were found could be reached only by crawling on all fours or flat on the body, resulting in abrasions on the knees and elbows (8,11) (Fig. 4A,B). This crawling to the final position seems to have happened after the paradoxical undressing as there were abrasions to the skin but no damage to the corresponding parts of the removed clothing. Apparently the hide-and-die-syndrome is not a result of conscious acting but of a terminal primitive reaction pattern that is probably an autonomous behavior triggered and controlled by the brain stem. It shows the characteris-

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Fig. 3. Paradoxical undressing and hide-and-die syndrome. The bodies of two men, 34 and 52 years old, were found lying in a public park in a prone position on the ground, one in front of and one underneath a park bench. Both men were under considerable influence of alcohol (280 and 300 mg/dL, respectively). On the morning the men were found, the ambient temperature was 9°C (38°F). Forensic autopsy showed the typical findings of lethal hypothermia. (Courtesy of Prof. Klaus Püschel, Hamburg, Germany.)

tics of an instinctive behavior and a congenital reflex. This phenomenon gives the impression of a final program of the archencephalon. It seems to be an act of getting out of harm’s way and into safety. Furthermore, a state of severe mental confusion, which obviously plays a role in cases of hypothermia (1,16,21), seems to be a promoting factor. This behavior probably occurs with the objective of reaching a state of common safety rather than specifically to bring the body into warmth. Otherwise it is not understandable why the victims of hypothermia prefer to lie naked on a stone-cold floor rather than putting their clothes on again. As in other findings of hypothermia (3,22,23), this phenomenon also seems to be dependent on how rapid the body temperature decreases. Moderately cold ambient temperatures and a slow decrease of the body temperature induce a hide-and-die syndrome more often than environmental temperatures

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Fig. 4. Death from hypothermia. (Red-purple) spots attributable to hypothermia showing superficial abrasions on (A) knees and (B) elbows, most probably originating from crawling on all fours or flat on the body in a final state of mental confusion. (Courtesy of Dr. Michael Tsokos, Hamburg, Germany.)

far below 0°C (32°F) with a sudden state of severe hypothermia. Interestingly, there seems to be no significant relation between alcohol or other substances and the occurrence of paradoxical undressing or hide-and-die syndrome (14). There are many publications concerning hypothermia but hardly any specifically describe the hide-and-die syndrome only. Kinzinger et al. (11) reported on two completely undressed males who died in a public park due to hypothermia. Both men were found in a prone position with the arms close to the body, one directly under a bench, the other just in front of it. This clearly shows the situation of the hide-and-die syndrome, but the authors did not elaborate on this. Therefore, one can assume that this phenomenon occurs more often than it is described in the literature. Following the assumption that the hide-and-die syndrome is a primitive response pattern of the brain stem, there should be some parallels in the animal world. Unfortunately there are hardly any publications about animals dying because of hypothermia, but there exist numerous papers on hibernation. Various mammals encounter the problem of increased thermoregulatory energy demands by means of deep hibernation or daily torpor (24,25,27) in which they reduce their energy requirements to a fraction of their euthermic

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metabolic rate (24–27). Hibernators retreat into their hibernaculum, for example, a frost-protected cave or burrow, and relinquish most of their behavioral and territorial activities (28).

REFERENCES 1. DiMaio DJ, DiMaio VJM (1989) Forensic pathology. CRC Press, Boca Raton, London, New York, Washington. 2. Drese G (1984) Unterkühlung—Todesursache oder wesentlicher Nebenbefund? Kriminal Forensische Wiss 55/56, 184–189. 3. Hirvonen J (1976) Necropsy findings in fatal hypothermia cases. J Forensic Sci 8, 155–164. 4. Kortelainen ML (1987) Drugs and alcohol in hypothermia and hypothermia-related deaths. J Forensic Sci 32, 1704–1712. 5. Krjukoff A (1914) Beitrag zur Frage des Todes durch Erfrieren. Vjschr Gerichtl Med 47, 79–101. 6. Lignitz E (2003) Kälte. In Madea B, ed., Praxis Rechtsmedizin. Springer, Berlin, Heidelberg, New York, pp. 181–186. 7. Hirvonen J (1977) Local and systemic effects of accidental hypothermia. In Tedeshi CG, Eckert WG, Tedeshi LG, eds., Forensic medicine, Vol. 1. Saunders, Philadelphia, pp. 758–774. 8. Dreifuß H (1977) Tödliche Unterkühlung: Unfall oder Verbrechen? Kriminalistik 31, 205–206. 9. Duguid H, Simpson G, Stowers J (1961) Accidental hypothermia. Lancet 2, 1213–1219. 10. Goremsen H (1972) Why have victims of death from the cold undressed? Med Sci Law 12, 201–202. 11. Kinzinger R, Riße M, Püschel K (1991) “Kälteidiotie”—Paradoxes Entkleiden bei Unterkühlung. Arch Kriminol 187, 47–56. 12. Wedin B, Vanggaard L, Hirvonen J (1979) Paradoxical undressing in fatal hypothermia. J Forensic Sci 24, 543–553. 13. Knight B (1997) Forensic pathology, 2nd ed. Edward Arnold, London, Melbourne, Auckland, pp. 414–415. 14. Rothschild MA, Schneider V (1995) “Terminal burrowing behaviour”—a phenomenon of lethal hypothermia. Int J Legal Med 107, 250–256. 15. Sivaloganathan S (1986) Paradoxical undressimg and hypothermia. Med Sci Law 26, 225–229. 16. Buris L (1993) Forensic medicine. Springer, Berlin, Heidelberg, New York, pp. 146–148. 17. Hirvonen J, Huttunen P (1982) Increased urinary concentration of catecholamines in hypothermia deaths. J Forensic Sci 27, 264–271. 18. Molnár GW (1946) Survival of hypothermia by men immersed in the ocean. JAMA 131, 1046–1050. 19. Paton BC (1983) Accidental hypothermia. Pharmacol Ther 22, 331–377.

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20. Prescott LF, Peard MC, Wallace JR (1962) Accidental hypothermia, a common condition. BMJ 2, 1367–1370. 21. Reuter F (1933) Lehrbuch der gerichtlichen Medizin. Urban & Schwarzenberg, München, Wien, Baltimore. 22. Unterdorfer H (1977) Statistik und Morphologie des Unterkühlungstodes. Ärztl Praxis 29, 459–460. 23. Schneider V, Klug E (1980) Tod durch Unterkühlung. Gibt es neue Gesichtspunkte zur Diagnostik? Z Rechtsmed 86, 59–69. 24. Ruf T, Heldmaier G (1992) The impact of daily torpor on energy requirements in the djungarian hamster, Phodopus sungorus. Physiol Zool 65, 994–1010. 25. Ruf T, Klingenspor M, Preis H, Heldmaier G (1991) Daily torpor in the djungarian hamster (Phodopus sungorus): interactions with food intake, activity, and social behaviour. J Comp Physiol [B] 160, 609–615. 26. Heldmaier G, Ruf T (1992) Body temperature and metabolic rat during natural hypothermia in endotherms. J Comp Physiol 162, 696–706. 27. Heldmaier G, Steinlechner S (1981) Seasonal pattern and energetics of short daily torpor in the djungarian hamster, Phodopus sungorus. Oecologia 48, 265–270. 28. Heldmaier G (1993) Seasonal acclimatization of small mammals. Verh Dtsch Zool Ges 86, 67–77.

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12 Pathological Features of Maternal Death From HELLP Syndrome Michael Tsokos, MD CONTENTS INTRODUCTION MATERNAL COMPLICATIONS ASSOCIATED WITH HELLP SYNDROME DIFFERENTIAL DIAGNOSES MEDICOLEGAL ASPECTS REFERENCES

SUMMARY Hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome is a life-threatening complication of preeclampsia during pregnancy or postpartum. Serious complications occur in 12.5–65% of cases of HELLP syndrome and are associated with a maternal mortality between 1.1 and 3.4%. Despite active research for many years, the etiology of this disorder exclusive to human pregnancy has not been sufficiently clarified. In clinical practice, disseminated intravascular coagulation (DIC) is found in 4–38% of cases with HELLP syndrome. Despite the apparent correlation between the marked degree of DIC in laboratory tests and the extent of laboratory changes in HELLP syndrome and the rate of maternal complications, the manifestation of DIC is neither an initial nor a principal symptom of HELLP syndrome but rather reflects a secondary pathophysiological process of the primary disease state that can be regarded as a result of preeclampsia that was diagnosed and/or treated too late. Hepatic rupture as a sequel of subcapsular liver hematoma in the course of From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 275

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DIC, occurring in 1–1.8% of cases, is considered the most serious and lifethreatening maternal complication in HELLP syndrome. Hepatic rupture is located predominantly in the anterior-superior region of the right hepatic lobe and can occur both antepartum and postpartum. The main autopsy findings in HELLP syndrome are petechiae and suffusions in conjunctivae, skin and on mucous and serous surfaces of internal organs, cerebral edema, signs of acute respiratory distress syndrome (ARDS), edema of the lower extremities, hyperemia of the spleen, hydropericardium, and shock kidneys. Since these findings may be initiated by a variety of underlying pathologic conditions, they are highly unspecific. In contrast, liver pathology is a hallmark in the postmortem diagnosis of HELLP syndrome. At autopsy, the liver shows a rigid consistence with yellow-brown cut surfaces and confluent hemorrhagic foci on cross-sections of the liver parenchyma and occasionally subcapsular liver hematoma or hepatic rupture. The histopathological features of hepatic alterations in HELLP syndrome are periportal hepatocellular necrosis, hemorrhages sharply demarcated by an extended fibrin network from the surrounding unaffected liver parenchyma, and leukostasis in the liver sinusoids. In the kidneys, the glomeruli are primarily affected. They are enlarged and appear bloodless as a result of obliteration of the capillary lumina by swollen, vacuolated, and occasionally foamy endocapillary cells. In most cases, two characteristic capillary loop patterns of the glomeruli can be distinguished: (a) the cigar-shaped loop type presenting elongated, stretched, and obstructed loops, and (b) the pouting loop type showing enlarged glomerular tufts filling Bowman’s space with herniation of capillary loops into the proximal tubules. Relevant to medicolegal implications of a fatal outcome of HELLP syndrome is the point that the presenting symptoms of patients are generally highly unspecific. As a result, many of the patients are initially misdiagnosed with other medical or surgical disorders such as gastroenteritis, hepatitis, pyelonephritis, appendicitis, acute fatty liver of pregnancy, (AFLP), idiopathic thrombocytic purpura, and hemolytic uremic syndrome (HUS). Delay in diagnosis or expectant management of HELLP syndrome is implicated in a considerable number of cases with fatal outcome. Key Words: HELLP syndrome; pregnancy; maternal death; preeclampsia; eclampsia; disseminated intravascular coagulation (DIC); acute respiratory distress syndrome (ARDS); acute fatty liver of pregnancy (AFLP); thrombocytopenia; renal pathology.

1. INTRODUCTION In 1954, Pritchard et al. recognized the association between hemolysis, elevated liver enzymes, and thrombocytopenia in the setting of pregnancy (1).

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In 1982, Weinstein coined the term HELLP syndrome to describe the clinical manifestations in a group of preeclamptic/eclamptic patients with the finding of hemolysis (H), elevated liver enzymes (EL), and a low platelet count (LP) (2). Notwithstanding the fact that since then a large number of studies and case reports dealing with the search for predictive factors, diagnostic improvements, and clinical management of HELLP syndrome has appeared in the literature, the disease is still a severe complication of preeclampsia during pregnancy or postpartum tainted with a high risk of maternal and perinatal mortality and morbidity (3–10). Since the proposal of more strict criteria for the diagnosis of the “true” HELLP syndrome (11), it has been observed that many women with severe preeclampsia may have laboratory abnormalities such as isolated hemolysis, low platelet count, or elevated liver enzymes without the complete HELLP syndrome. This has been referred to as “partial” HELLP syndrome (10,12). The HELLP syndrome occurs in 0.2–0.6% of all pregnancies. Approximately 10% of patients with HELLP develop hypertension and proteinuria, and meet criteria for preeclampsia. Despite their similarities, HELLP is associated with a higher rate of maternal and fetal morbidity and mortality than preeclampsia (13). The incidence of the syndrome among patients with severe preeclampsia is 9.7% and is significantly higher in patients with delayed diagnosis of preeclampsia and/or delayed delivery (3).

2. MATERNAL COMPLICATIONS ASSOCIATED WITH HELLP SYNDROME 2.1. Clinical Presentations/Causes of Death Despite active research for many years, the etiology of this disorder exclusive to human pregnancy has not been sufficiently clarified. Recent evidence suggests that there may be several underlying causes or predispositions leading to the signs of hypertension, proteinuria, and edema (14). Current theories suggest altered prostaglandin synthesis, inappropriate sensitivity to angiotensin II, and immunologic factors as etiologies of preeclampsia (15) as well as an association of factor V and factor II mutations with preeclampsia (16). In most cases, HELLP syndrome is assumed to be initiated by inadequate placental vessel development with subsequent placental ischemia, leading to the release of circulating vasoconstrictors such as thromboxane A2, angiotensin, prostaglandin F2, and endothelin-1. The ischemic placenta also produces fewer vasodilators, such as prostacyclin, prostaglandin, E2, and nitric oxide. The ensuing imbalance in vasoactive substances causes intense systemic vasospasms and endothelial damage in multiple organs (17).

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Serious complications occur in 12.5–65% of cases of HELLP syndrome (6) and are associated with a maternal mortality between 1.1 and 3.4% (4,18). In 1993, Sibai et al. published the largest prospective cohort study of maternal complications in HELLP syndrome so far, including clinical data from 442 pregnancies with HELLP syndrome (4). The presenting symptoms of the patients were abdominal pain (65%), nausea or vomiting (36%), headache (31%), visual changes (10%), hemorrhage (9%), jaundice (5%), diarrhea (5%), and shoulder or neck pain (5%). As a result of the unspecifity of these symptoms, many of the patients were initially misdiagnosed with other medical or surgical disorders such as gastroenteritis, hepatitis, pyelonephritis, appendicitis, acute fatty liver of pregnancy, idiopathic thrombocytic purpura, and hemolytic uremic syndrome. In the series by Sibai et al., which can be regarded as representative for the disease, serious maternal complications were disseminated intravascular coagulation (DIC) (21%), abruptio placentae (16%), acute renal failure (8%), ascites (8%), pulmonary edema (6%), pleural effusions (6%), cerebral edema (1%), retinal detachment (1%), laryngeal edema (1%), subcapsular liver hematoma (1%), and acute respiratory distress syndrome (ARDS) (1%). In three out of four maternal deaths in this study, multiple organ failure lead to hypoxic brain damage as the immediate (clinical) cause of death. The remaining death was stated as multiple organ failure in a patient who had a ruptured subcapsular liver hematoma. However, the authors do not comment on whether these diagnoses were verified by autopsies. In a more recent clinical series conducted by Isler et al. in 1999, including 54 maternal deaths from HELLP syndrome, the clinical causes of death were stated as follows (19): cerebral hemorrhage (45%), cardiopulmonary arrest (40%), DIC (39%), ARDS (28%), renal failure (28%), sepsis (23%), hepatic hemorrhage (20%), and hypoxic ischemic encephalopathy (16%). From a pathophysiological viewpoint, this clinical classification is highly unsatisfactory for several reasons. First, one is tempted to speculate that cerebral hemorrhage may have occurred as a result of DIC. Second, cardiopulmonary arrest is, strictly speaking, the final cause of death in each fatality, for example, as a result of DIC or ARDS, and third, sepsis may have been the underlying cause of DIC in some cases where the diagnosis of sepsis was clinically missed. In a series of 14 fatal cases of HELLP syndrome from 150 maternal deaths encountered in Bavaria, Germany (population approximately 11.5 million persons), between 1983 and 1992, the clinical causes of deaths were intracerebral hemorrhage (n = 8), ruptured subcapsular liver hematoma (n = 2), and, in one case each, thrombosis of sinus cavernosus, acute renal failure, pulmonary insufficiency (not further specified), and myocardial infarction (18). In all eight

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cases of intracerebral hemorrhage, the diagnosis was made clinically by computed tomography. In this series, the clinical cause of death was verified by autopsies in six cases. In 2002, Soh et al. reported a case of fatal cerebellar infarction in a 39-yearold primipara with postpartum HELLP syndrome (20). DIC can be found in 4–38% of cases with HELLP syndrome (21). Despite the apparent correlation between the marked degree of DIC in laboratory tests and the extent of laboratory changes in HELLP syndrome and the rate of maternal complications (22), the manifestation of DIC is neither an initial nor a principal symptom of HELLP syndrome but rather reflects a secondary pathophysiological process of the primary disease state that can be regarded as a result of preeclampsia that was diagnosed and/or treated too late (6). Hepatic rupture as a sequel of subcapsular liver hematoma in the course of DIC is considered the most serious and life-threatening maternal complication in HELLP syndrome responsible for a maternal mortality between 50–77% (6,23–24). Hepatic rupture in HELLP syndrome has been reported to be located predominantly in the anterior-superior region of the right hepatic lobe (26–28) and can occur both antepartum and postpartum in 1.5–1.8% of cases with HELLP syndrome (23,24). In a Medline search covering the years 1990–1999, Reck et al. found 49 cases with HELLP syndrome-associated liver rupture published within this period (25).

2.2. Autopsy Features Although a considerable number of case reports dealing with fatal HELLP syndrome has appeared in the medical literature during the last decades, autopsy features have only been reported sporadically, leading to a primarily anecdotal rather than systematic approach toward the true pathology of the disease. The main gross pathology findings can be summarized as follows (29): petechiae as well as more widespread hemorrhages (suffusions) attributable to DIC in conjunctivae, skin, on mucous surfaces and serous coats of internal organs, and in the gray and white matter of the brain (purpura cerebri), cerebral edema, signs of ARDS such as fixed, edematous and congested lungs, edema of the lower extremities, hyperemia of the spleen, hydropericardium, and shock kidneys (Fig. 1). Because the aforementioned pathological features can be initiated by a variety of underlying pathologic conditions, these findings, when present, have to be considered as highly unspecific. In contrast, liver pathology appears to be one of the hallmarks in the postmortem diagnosis of HELLP syndrome (29,30). At autopsy, multiple blackish-reddish patches are a striking finding after opening of the abdominal cavity (Fig. 2). The liver

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Fig. 1. Maternal death from HELLP syndrome in the late third trimester. Uterus and pelvic organs after evisceration. Note the marked shock kidneys. (Courtesy of Prof. Franz Longauer, Koˇsice, Slovak Republic.)

Fig. 2. Maternal death from HELLP syndrome. Opened abdominal cavity: multiple blackish-reddish patches are present on the surface of the liver. (Courtesy of Dr. Friedrich Schulz, Hamburg, Germany.)

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Fig. 3. Maternal death from HELLP syndrome. Cross-section of the liver parenchyma showing confluent hemorrhagic foci. (Courtesy of Dr. Friedrich Schulz, Hamburg, Germany.)

shows a rigid consistence with yellow-brown cut surfaces and confluent hemorrhagic foci on cross-sections of the liver parenchyma (Fig. 3). Occasionally, subcapsular liver hematoma or even rupture of the liver may be present. In such cases, the immediate cause of death has to be considered hemorrhagic shock. In the remaining cases, lacking a clear-cut cause of death such as hepatic encephalopathy verified antemortem by clinical and laboratory means, the fatal outcome will have to be attributed to multiple organ failure (a combination of renal and hepatic failure, and ARDS), mainly as a result of DIC.

2.3. Histopathology Liver pathology is a hallmark for the postmortem diagnosis of HELLP syndrome. The histopathological features of hepatic alterations in HELLP syndrome, which can be considered pathognomonic for the disease especially when found combined, can be summarized as follows: (a) periportal hepatocellular necrosis and hemorrhages sharply demarcated by an extended fibrin network from the surrounding unaffected liver parenchyma (Fig. 4A,B), (a) leukostasis in the liver sinusoids; (c) bile stasis with swelling of Kupffer’s cells, and (d) absence of inflammatory cellular infiltrates and lack of fatty transformation of hepatocytes (29).

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Fig. 4. Maternal death from HELLP syndrome. (A,B) Periportal hepatocellular necrosis and hemorrhages sharply demarcated by an extended fibrin network from the surrounding unaffected liver parenchyma (phosphotungstic acid hematoxylin).

In the kidneys, preeclampsia primarily affects the glomerulus. The characteristic and diagnostic features of preeclamptic nephopathy are a combination of glomerular alterations rather than a single lesion. The glomeruli are enlarged and appear bloodless as a result of obliteration of the capillary lumina by swollen, vacuolated, and occasionally foamy endocapillary cells (29,31–33) (Fig. 5). The lack of intraglomerular cell proliferation (hypercellularity) and

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Fig. 5. Maternal death from HELLP syndrome. Enlarged glomerulus with capillary loops virtually devoid of erythrocytes. The capillary lumina are for the most part obliterated by swollen, vacuolated, and occasionally foamy endocapillary cells (periodic acid-schiff).

inflammatory changes in the glomeruli in HELLP syndrome is essential in differentiating acute glomerulonephritis (33). In most cases, two characteristic capillary loop patterns of the glomeruli (which may appear next to each other in one visual field) can be distinguished: a cigar-shaped loop type presenting elongated, stretched, and obstructed loops, and the pouting loop type showing enlarged glomerular tufts filling Bowman’s space with herniation of capillary loops into the proximal tubules (Fig. 6A,B). In both types, the loops are virtually devoid of erythrocytes, the mesangial cells appear swollen, and the endocapillary cells are vacuolated. Ballooning (dilatation) of the tips of the loops is another characteristic feature of preeclampsia (31). The most characteristic light microscopical features of liver and kidneys associated with HELLP syndrome are given in Table 1. Gerth et al. recently reported on a 26-year-old primigravida who developed HELLP syndrome 3 days after delivery of a healthy male infant. A renal biopsy performed on Day 12 postpartum showed partial obstruction of glomerular

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Fig. 6. Maternal death from HELLP syndrome. In the kidneys, two characteristic capillary loop patterns of the glomeruli can be distinguished: (A) the cigarshaped loop type with elongated, stretched, and obstructed loops, and (B) the pouting loop type showing enlarged glomerular tufts filling Bowman’s space with herniation of capillary loops into the proximal tubules (periodic acid-schiff).

capillaries by fibrin deposits. On Day 60 postpartum, a thrombotic microangiopathy of arterial vessels with narrowing of the vascular lumen and mononuclear cell infiltration of the vessel layers was seen (34). Controversy persists concerning the pathogenesis of the histopathological alterations of the renal structures. Some authors favor the theory that the

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Table 1 Histomorphological Alterations of Liver and Kidneys Found in HELLP Syndrome Liver

• Periportal hepatocellular necrosis (coagulation necrosis) and hemorrhages sharply demarcated by an extended fibrin network from the surrounding unaffected liver parenchyma • (Focal) leukocyte sticking (leukostasis) in liver sinusoids • Bile stasis with swelling of Kupffer’s cells • Lack of inflammatory cellular infiltrates in liver plates • Lack of fatty transformation of hepatocytes

Kidneys

• Bloodless glomeruli with swollen, vacuolated, and occasionally foamy endocapillary cells • Elongated and obstructed (“cigar-shaped”) capillary loops and enlarged glomerular tufts filling Bowman’s space with herniation of capillary loops (“pouting”) into the proximal convoluted tubules • Ballooning (dilatation) of the tips of the loops • Swelling of mesangial cells • Thrombi formation in glomerular capillaries and the vasa recta in cases with severe DIC

Note. Modified from ref. 29.

pathological changes of the glomeruli are, at least to a certain degree, a direct result of DIC (35,36). On the other hand, the occurrence of DIC is not specific for HELLP syndrome since DIC is a complication of preeclampsia in general that positively correlates in its intensity with the severity of preeclampsia (37). The frequency of DIC in HELLP syndrome depends not least on the presence and extent of placental abruption (4). However, signs of DIC on the micromorphological level such as microthrombi composed of fibrin and platelets can be seen infrequently in glomerular capillaries and vasa recta of the medulla as well as in smaller vessels and capillaries in various internal organs, for example, the lungs and intestinum (29). In addition, intraalveolar edema, activated alveolar macrophages and fibrin deposits covering the alveolar epithelium as hyaline membranes as a result of ARDS may be seen in the lungs. In the myocardium, focal contraction band necrosis without any accompanying inflammatory changes can be found frequently. Although an earlier study revealed the presence of contraction band necrosis in 35% of cases of fatal eclampsia in contrast to only 3% in controls and the authors attributed the frequent occurrence of myocardial contraction band necrosis in eclampsiaassociated deaths to preceding coronary artery spasms (38), myocardial

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contraction band necrosis is a well-known phenomenon to the forensic pathologist because it can be frequently observed not only in autopsy cases with myocardial ischemia of coronary origin but also in a variety of underlying pathologic conditions prior to death such as protracted agony, prolonged resuscitation attempts, preceding head trauma, repeated defibrillations with automatic implantable cardioverter-defibrillators, and in the sequel of administration of catecholamines during intensive care or before operation (39–44). For that reason, the finding of myocardial contraction band necrosis adds nothing to a definite postmortem diagnosis of preeclampsia or HELLP syndrome in specific autopsy cases in question.

3. DIFFERENTIAL DIAGNOSES When examining fatalities that occurred during pregnancy or postpartum, the forensic pathologist has to be aware of an underlying HELLP syndrome irrespective the preceding clinical course (because this may have been atypical) and regardless of whether the syndrome was clinically suspected or not. For clinical characteristics and laboratory findings and their interpretation in the light of suspected HELLP syndrome in the living as well as the controversy concerning the definition, diagnosis, cause, and management of the syndrome, refer to the comprehensive clinical literature on this topic (e.g., 3–6,9–12,15). Concerning the autopsy finding of intrahepatic hemorrhage and/or liver rupture, the (forensic) pathologist has to aware of possible differential diagnoses, especially liver rupture of traumatic origin. Underlying pathological conditions predisposing to spontaneous, nontraumatic liver rupture are malignant or benign liver tumors, hepatic amyloidosis, or peliosis hepatis (45–52). Because these conditions are difficult to diagnose in vivo and opportune life-saving surgery often fails, the definitive diagnosis is mainly established at autopsy in such cases. Another differential diagnosis is acute fatty liver of pregnancy (AFLP) characterized by microvesicular fatty infiltration of the liver, hepatic failure, and encephalopathy typically developing in the third trimester of pregnancy (53). DIC may be present in up to 75% of cases. Up to 50% of patients with AFLP also meet clinical criteria for preeclampsia (13). Fetal mortality remains at 15%, though maternal mortality occurs in less than 5% of cases (54). Other differential diagnoses that should be kept in mind in autopsy cases of suspected HELLP syndrome are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), both pregnancy-associated thrombocytopenias that are traditionally considered the main entities of thrombotic microangiopathies (55).

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4. MEDICOLEGAL ASPECTS When giving a medicolegal expertise in suspected cases of medical malpractice related to HELLP syndrome (e.g., under aspects of delayed diagnosis or stillbirth following expectant management of maternal symptoms) one has to bear in mind that the presenting symptoms of patients with HELLP syndrome are generally highly unspecific. As a result, many of the patients are initially misdiagnosed with other disorders (4). Delay in diagnosis of HELLP syndrome was implicated in 22 of 43 patients’ deaths (51%) in a study by Isler et al. (19). Management of HELLP is generally supportive, with the goal of medically stabilizing the patient prior to delivery (56). Conservative management has the primary goal and its only indication to gain time for further fetal lung maturation after administration of betamethasone or methylprednisolon. However, the effects of corticosteroids on the pathophysiological mechanisms in HELLP syndrome are still unknown (6). As shown recently in a large multicenter study, severe maternal complications in HELLP syndrome are significantly lower when the patient is delivered promptly after diagnosis, in contrast to expectant management (57). DIC requires immediate delivery by cesarean section before the manifestation of life-threatening maternal or fetal complications (6). Despite appropriate general and obstetric management, a subset of patients displays prolonged thrombocytopenia and multiple organ dysfunction with potential fatal outcome following delivery.

REFERENCES 1. Pritchard JA, Weisman R, Ratnoff OD, Vosburgh GJ (1954) Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of pregnancy. N Engl J Med 250, 89–98. 2. Weinstein L (1982) Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142, 159–167. 3. Sibai BM, Taslimi MM, el-Nazer A, Amon E, Mabie BC, Ryan GM (1986) Maternalperinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 155, 501–509. 4. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA (1993) Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) Am J Obstet Gynecol 169, 1000–1006. 5. Geary M (1997) The HELLP syndrome. Br J Obstet Gynaecol 104, 887–891. 6. Rath W, Faridi A, Dudenhausen JW (2000) HELLP syndrome. J Perinat Med 28, 249–260.

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7. Onrust S, Santema JG, Aarnoudse JG (1999) Pre-eclampsia and the HELLP syndrome still cause maternal mortality in The Netherlands and other developed countries; can we reduce it? Eur J Obstet Gynecol Reprod Biol 82, 41–46. 8. van Pampus MG, Wolf H, Westenberg SM, van der Post JA, Bonsel GJ, Treffers PE (1998) Maternal and perinatal outcome after expectant management of the HELLP syndrome compared with pre-eclampsia without HELLP syndrome. Eur J Obstet Gynecol Reprod Biol 76, 31–36. 9. Visser W, Wallenburg HC (1995) Maternal and perinatal outcome of temporizing management in 254 consecutive patients with severe pre-eclampsia remote from term. Eur J Obstet Gynecol Reprod Biol 63, 147–154. 10. Abbade JF, Pera oli JC, Costa RA, Calderon Id Ide M, Borges VT, Rudge MV (2002) Partial HELLP Syndrome: maternal and perinatal outcome. Sao Paulo Med J 120, 180–184. 11. Sibai BM (1990) The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet Gynecol 162, 311–316. 12. Audibert F, Friedman SA, Frangieh AY, Sibai BM (1996) Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 175, 460–464. 13. McCrae KR, Samuels P, Schreiber AD (1992) Pregnancy-associated thrombocytopenia: pathogenesis and management. Blood 80, 2697–2714. 14. Pridjian G, Puschett JB (2002) Preeclampsia. Part 1: clinical and pathophysiologic considerations. Obstet Gynecol Surv 57, 598–618. 15. Fadigan AB, Sealy DP, Schneider EF (1994) Preeclampsia: progress and puzzle. Am Fam Physician 49, 849–856. 16. Jones SL (1998) HELLP! A cry for laboratory assistance: a comprehensive review of the HELLP syndrome highlighting the role of the laboratory. Hematopathol Mol Hematol 11, 147–171. 17. Benedetto C, Marozio L, Salton L, Maula V, Chieppa G, Massobrio M (2002) Factor V Leiden and factor II G20210A in preeclampsia and HELLP syndrome. Acta Obstet Gynecol Scand 81, 1095–1100. 18. Welsch H, Krone HA (1994) Mütterliche Mortalität bei HELLP-Syndrom in Bayern 1983–1992. Zentralbl Gynakol 116, 202–206. 19. Isler CM, Rinehart BK, Terrone DA, Martin RW, Magann EF, Martin JN Jr. (1999) Maternal mortality associated with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 181, 924–928. 20. Soh Y, Yasuhi I, Nakayama D, Ishimaru T (2002) A case of postpartum cerebellar infarction with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Gynecol Obstet Invest 53, 240–242. 21. Reubinoff BE, Schenker JG (1991) HELLP syndrome—a syndrome of hemolysis, elevated liver enzymes and low platelet count—complicating preeclampsiaeclampsia. Int J Gynaecol Obstet 36, 95–102. 22. Van Dam PA, Renier M, Baekelandt M, Buytaert P, Uyttenbroeck F (1989) Disseminated intravascular coagulation and the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia. Obstet Gynecol 73, 97–102.

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23. Hüskes KP, Baumgartner A, Hardt U, Klink F (1991) Doppelseitige, mehrzeitige Spontanruptur der Leber bei HELLP-Syndrom. Chirurg 62, 221–222. 24. Rath W, Loos W, Graeff H, Kuhn W (1992) Das HELLP-Syndrom. Gynäkologe 25, 430–440. 25. Reck T, Bussenius-Kammerer M, Ott R, Muller V, Beinder E, Hohenberger W (2001) Surgical treatment of HELLP syndrome-associated liver rupture—an update. Eur J Obstet Gynecol Reprod Biol 99, 57–65. 26. Henny CP, Lim Cate JW AE, Brummelkamp WH, Buller HR, Ten Cate JW (1983) A review of the importance of acute multidisciplinary treatment following spontaneous rupture of the liver capsule during pregnancy. Surg Gynecol Obstet 156, 593–598. 27. Magann EF, Martin JN Jr. (1999) Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol 42, 532–550. 28. Sheikh RA, Yasmeen S, Pauly MP, Riegler JL (1999) Spontaneous intrahepatic hemorrhage and hepatic rupture in the HELLP syndrome: four cases and a review. J Clin Gastroenterol 28, 323–328. 29. Tsokos M, Longauer F, Kardosova V, Gavel A, Anders S, Schulz F (2002) Maternal death in pregnancy from HELLP syndrome. A report of three medicolegal autopsy cases with special reference to distinctive histopathological alterations. Int J Legal Med 116, 50–53. 30. Schneider H (1994) Leberpathologie im Rahmen des HELLP-Syndroms. Arch Gynecol Obstet 255, Suppl 2: S245–S254. 31. Sheehan HL (1980) Renal morphology in preeclampsia. Kidney Int 18, 241–252. 32. Hill PA, Fairley KF, Kincaid-Smith P, Zimmerman M, Ryan GB (1988) Morphologic changes in the renal glomerulus and the juxtaglomerular apparatus in human preeclampsia. J Pathol 156, 291–303. 33. Gaber LW, Spargo BH, Lindheimer MD (1994) The nephropathy of preeclampsiaeclampsia. In Tisher CC, Brenner BM, eds., Renal pathology with clinical and functional correlations. JB Lippincott Company, Philadelphia, pp. 419–441. 34. Gerth J, Busch M, Ott U, Grone HJ, Haufe CC, Funfstuck R, Sperschneider H, Stein G (2002) Schwangerschaftsassoziierte thrombotische Mikroangiopathie—eine diagnostische und therapeutische Herausforderung. Med Klin 97, 547–552. 35. Symonds EM (1980) Aetiology of pre-eclampsia: a review. J R Soc Med 73, 871–875. 36. Hill PA, Fairley KF, Kincaid-Smith P, Zimmerman M, Ryan GB (1988) Morphologic changes in the renal glomerulus and the juxtaglomerular apparatus in human preeclampsia. J Pathol 156, 291–303. 37. Rath W, Loos W, Kuhn W (1994) Das HELLP-Syndrom. Zentralbl Gynakol 116, 195–201. 38. Bauer TW, Moore GW, Hutchins GM (1982) Morphologic evidence for coronary artery spasm in eclampsia. Circulation 65, 255–259. 39. Todd GL, Baroldi G, Pieper GM, Clayton FC, Eliot RS (1985) Experimental catecholamine-induced myocardial necrosis. I. Morphology, quantification and regional distribution of acute contraction band lesions. J Mol Cell Cardiol 17, 317–338. 40. Armiger LC, Smeeton WM (1986) Contraction-band necrosis: patterns of distribution in the myocardium and their diagnostic usefulness in sudden cardiac death. Pathology 18, 289–295.

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41. Karch SB (1987) Resuscitation-induced myocardial necrosis. Catecholamines and defibrillation. Am J Forensic Med Pathol 8, 3–8. 42. Yoshida K, Ogura Y, Wakasugi C (1992) Myocardial lesions induced after trauma and treatment. Forensic Sci Int 54, 181–189. 43. Baroldi G, Mittleman RE, Parolini M, Silver MD, Fineschi V (2001) Myocardial contraction bands. Definition, quantification and significance in forensic pathology. Int J Legal Med 115, 142–151. 44. Baroldi G, Silver MD, De Maria R, Parolini M, Turillazzi E, Fineschi V (2003) Frequency and extent of contraction band necrosis in orthotopically transplanted human hearts. A morphometric study. Int J Cardiol 88, 267–278. 45. Ades, CJ, Strutton GM, Walker, NI, Furnival CM, Whiting, G (1989) Spontaneous rupture of the liver associated with amyloidosis. J Clin Gastroenterol 11, 85–87. 46. Cozzi, PJ, Morris, DL (1996) Two cases of spontaneous liver rupture and literature review. HPB Surg 9, 257–260. 47. Flowers, BF, McBurney, RP, Vera, SR (1990) Ruptured hepatic adenoma. A spectrum of presentation and treatment. Am Surg 56, 380–383. 48. Kühböck, J, Radaszkiewicz, T, Walek, H (1975) Peliosis hepatis, complicating treatment with anabolic steroids. Med Klin 70, 1602–1607. 49. Balasegaram M (1968) Spontaneous intraperitoneal rupture of primary liver-cell carcinoma. Aust N Z J Surg 37, 332–337. 50. Mokka R, Seppäla A, Huttunen R, Kairaluoma M, Sutinen S, Larmi TKI (1976) Spontaneous rupture of liver tumours. Br J Surg 63, 715–717. 51. Ooi LL, Lynch SV, Graham DA, Strong RW (1996) Spontaneous liver rupture in amyloidosis. Surgery 120, 117–119. 52. Ong GB, Taw JL (1972) Spontaneous rupture of hepatocellular carcinoma. Br Med J 4, 146–149. 53. Mabie WC (1991) Acute fatty liver of pregnancy. Crit Care Clin 7, 799–808. 54. Bacq Y (1998) Acute fatty liver of pregnancy. Semin Perinatol 22, 134–140. 55. Chang JC, Kathula SK (2002) Various clinical manifestations in patients with thrombotic microangiopathy. J Investig Med 50, 201–206. 56. McCrae KR, Cines DB (1997) Thrombotic microangiopathy during pregnancy. Sem Hematol 34, 148–158. 57. Faridi A, Heyl W, Rath W (2000) Preliminary results of the International HELLPMulticenter-Study. Int J Gynecol Obstet 69, 279–280.

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13 Injuries Resulting From Resuscitation Procedures Mario Darok, MD CONTENTS INTRODUCTION POSSIBLE INJURIES DURING RESUSCITATION PROCEDURES MEDICOLEGAL ASPECTS REFERENCES

SUMMARY Life-threatening situations deserve fast medical intervention but resuscitation procedures may have considerable effects on the patient’s health condition because (additional) trauma may occur. Additionally, these accidentally caused iatrogenic injuries might by themselves be life-threatening for the patient. The main injurious resuscitation measures include standard cardiopulmonary resuscitation (Std-CPR), active compression-decompression cardiopulmonary resuscitation (ACD-CPR), defibrillation, tracheotomy, coniotomy, tracheal intubation, puncture of veins or pericardium, and decompression of tension pneumothorax or mediastinal emphysema. In particular, injuries as a result of CPR are commonly encountered at autopsy and often not unexpected for the forensic pathologist. The most common cardiac resuscitation-related injuries are fractures of the ribs and sternum in 40–70% of cases. Above all, elderly patients are prone to such injuries. Trauma related to CPR is a rare complication in children. When encountering pediatric rib fractures, the forensic pathologist has to be aware of the differential diagnosis

From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 293

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of child abuse since rib fractures, especially when of different ages and affecting multiple adjacent ribs, are a hallmark of nonaccidental injury in children. CPR may lead to severe injuries of internal organs. Main factors influencing frequency and severity of injuries resulting from resuscitation procedures include length of resuscitation time, age of the patient, and degree of qualification of the medical personnel. From the medicolegal point of view, complications and accidental iatrogenic injuries will never be completely avoidable but their possibility has to be taken into consideration throughout further medical treatment. An undetected injury may result in impairment or even death of the patient and the responsible physician runs the risk of being prosecuted. To give a correct opinion, especially in cases of questioned medical malpractice, it is essential that forensic medical experts are familiar with resuscitation-related injuries and are able to distinguish them from the sequels of a natural disease process or trauma that occurred prior to resuscitation procedures. Key Words: Resuscitation; iatrogenic injury; medicolegal aspects; adverse effect; complication; expert opinion.

1. INTRODUCTION During resuscitation procedures the physician will always give priority to clearing the life-threatening condition. Nevertheless, as some resuscitation procedures consist of massive manipulations, they hold a high risk of injury to the patient. Physicians should be aware of these risks to avoid additional danger for the patient. Howard is said to have caused the first recorded injury resulting from resuscitation procedures. In 1860, he performed a kind of thorax compression. While presenting his new method in front of police officers, he fractured several ribs of a well-known personality. Thereupon, external cardiac massage was not performed for decades (1). Being of highest relevance for the outcome of the patient, injuries owing to resuscitation procedures also have a great importance in forensic medicine as they have to be distinguished from lesions of different origin, for example, in cases of polytrauma. Finally, there is an increasing number of autopsies taking place against the background of questioned medical malpractice associated with resuscitation procedures preceding death (2). A good knowledge of resuscitation procedures and related adverse effects is therefore essential for the forensic pathologist in order to give a correct medical expert opinion.

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2. POSSIBLE INJURIES DURING RESUSCITATION PROCEDURES 2.1. Resuscitation Procedures on the Airways 2.1.1. Intubation Tracheal intubation is one of the most common interventions in the treatment of life-threatening situations. Because securing of the patient’s airway deserves fast intervention, unintentional injuries cannot always be avoided. Even the assistance for intubation, namely traction and hyperextension of the neck, may lead to injury of the cervical soft tissue. The unconscious patient is incapable of showing any pain-elicited defense. If the patient’s neck is put in an extreme reclination by the assistant, a maximal straightening and, in consequence, a high tension load of the cervical column will occur, which might result in lesions of small vessels and retropharyngeal hemorrhage, respectively. According to autopsy data, the frequency of retropharyngeal hemorrhage as a sequel of resuscitation procedures is 9.2% (3). In a series of 65 primary atraumatic autopsy cases, Saternus and Fuchs found lesions of the carotid intima in 3 cases and explained this finding with the aforementioned maneuvers during tracheal intubation (3). Besides tracheal lesions, especially as a sequence of multiple attempts of intubation (4), tracheal intubation itself might result in further injury of cervical soft tissue, basically as a result of mechanical damage during the manipulations. These lesions include abrasion and hematoma of lips, tongue, and pharyngeal arch. According to an earlier autopsy study, the frequency of mucosal injury of the pharynx and larynx, respectively, is 18% (5). Fracture and dislocation of teeth, superficial injuries of the vocal cords, and pharyngeal hemorrhage are further intubation-related injuries. Although being a well-known complication to each physician, rupture of the stomach because of erroneous tube positioning into the esophagus and inflation of the stomach may occur (6–8). Other authors reported tube-induced esophageal perforation, especially in resuscitation of newborns (9,10). Lesions of the recurrent nerve, perforation of the piriform sinus, subluxation of the arytenoid cartilage, and tears of the vocal cords are exceptional findings in forensic autopsy practice, although they are possible from the anatomic point of view. In some cases, lesions of the trachea occur that result in pneumothorax and emphysema of subcutaneous tissue. Tracheal lesions are significantly more frequent in females than in males and more frequent in children than in adults. Lesions from tracheal intubation are always located in the membraneous part and situated in the longitudinal axis of the trachea (11).

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2.1.2. Tracheotomy/Coniotomy Tracheotomy or coniotomy are classical resuscitation measures. These iatrogenic wounds are indispensable to improving the life-threatening condition. The extent of this wound might accidentally exceed that which is necessary and thus threaten the life of the patient. Because of frequent complications, this method has a rigorous indication nowadays, after being performed generously in earlier decades. Mucosal lesions may derive from the tracheal incision and insertion of the cannula. Normally, these lesions would not lead to functional disorder and would heal without consequences. A “stab wound” of the dorsal tracheal wall might occur by accident resulting in local hemorrhage, mediastinal emphysema, subcutaneous parapharyngeal emphysema, or even pneumothorax. With coniotomy, the ramus of the superior thyroid artery, which is located at the lower margin of the thyroid cartilage, might be injured leading to hemorrhage (12). In the past few years, percutaneous needle cannulation of the trachea gained in importance for being a less invasive intervention because there is no surgical wound, unlike in tracheotomy, and tracheal cartilages are thought to remain untouched. The primary trauma of tissue is hence decreased but, nevertheless, iatrogenic injuries may occur. A postmortem study of 12 patients who had undergone percutaneous tracheotomy prior to death revealed fracture of at least one tracheal cartilage in 11 cases (13). Additionally, in two cases a fracture of the cricoid cartilage was seen. Other studies reported cases of tension pneumothorax, accompanied by subcutaneous and mediastinal emphysema, as a result of tracheal rupture following percutaneous tracheotomy (11,14).

2.2. Resuscitation Procedures on the Heart 2.2.1. Cardiopulmonary Resuscitation To the forensic and clinical pathologist the most common and well-known sign of external heart massage are superficial dermal abrasions above the sternum stemming from the hands of the person performing cardiac massage. Although these minor injuries of course do not have any forensic relevance, fractures of ribs and/or sternum cannot always be avoided during cardiac massage, particularly in elderly patients having a rigid thorax. The most common regions of fractures are ribs 2–7 on the left and 2–6 on the right side, respectively (15). According to the literature, the frequency of rib fractures as a sequel of cardiac massage varies from 19 to 80% and that of sternal fractures

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from 0 to 47%. In persons of higher age, an increase of fracture frequency is described unanimously. These thoracic fractures may lead to lung contusion or, in some cases, even to more severe lesions of the lung (16). As a result, a pneumothorax might develop, possibly leading to pneumoperitoneum when the gas escapes into the peritoneum through the epiploic foramen, primary lesions of the gastrointestinal tract, or the diaphragm (17,18). The location of resuscitation-related rib fractures is mainly in the medioclavicular line, thus close to the sternal joint, whereas sternal fractures are located horizontally in the lower two thirds. These sharp-edged bone fragments can be located close to the heart. Continued heart massage in combination with inward bone dislocation may result in lesions of the pericardium or even lead to life-threatening injury of the heart with pericardial tamponade (19). In cases of polytrauma, ruptures of aorta or vena cava are facilitated because of traumatic distortions and/or tears of the vessel wall (20). Rupture of the stomach or diaphragm might also be an effect of heart massage but are also a possible complication of the Heimlich maneuver. With artificial respiration, inflation and distension of the stomach can occur. In this case, additional compression during external heart massage can result in injuries to the gastric mucosa (16). A case of Mallory–Weiss syndrome with hematemesis following cardiopulmonary resuscitation (CPR) has been reported (21). Other rare complications of CPR include gastrointestinal hemorrhage (22) and aspiration (23). Injuries to sanguine internal organs like liver and spleen are also rare but much more dangerous (16,20,24) since in most cases intraabdominal hemorrhage will develop resulting in hypovolemic shock and death if the internal hemorrhage remains undetected. Too low positioning of thorax compression at the costal arch level in conjunction with violent pressure application is considered to be the cause of abdominal organ contusions (20). On the other hand, pre-existing organic damage like cavernous hemangioma and abnormal fragility of the liver owing to sepsis may worsen outcome (16). In the literature, some cases of CPR resulting in pulmonary barotraumas have been reported (25,26), thus possibly leading to massive fatal air embolism of cerebral vessels (27).

2.2.2. Active Compression-Decompression Cardiopulmonary Resuscitation Active compression-decompression cardiopulmonary resuscitation (ACDCPR) is one of the recent developments in emergency medicine. A plungerlike suction device, the so-called CardioPump®, has been developed and is commercially available. In particular, the decompression phase improves venous

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return and cardiac output as well (28). The typical sign of CardioPump® usage is a reddish ring on the skin at the sternum corresponding to the rubber suction cup of the CardioPump®. Several postmortem studies have been undertaken to assess the risk of injuries in ACD-CPR. The results showed a higher frequency of thoracic bone fractures using ACD-CPR than using standard CPR (Std-CPR). This frequency was even exceeded by those patients who had undergone ACD-CPR subsequent to Std-CPR (29). In two cases, massive injuries of the heart as a result of fractured sternal bone fragments were observed that were attributed to the use of the CardioPump® (30). In another case, massive laceration of the recently infarcted heart was observed after combined Std-CPR and incorrectly attempted ACD-CPR (31). In conclusion, possible injuries because of Std-CPR and ACDCPR are very similar but in principle there is no higher risk of being injured if ACD-CPR is performed correctly. However, in a study in cadavers, females were found to have a higher risk of sternal fractures, whereas elderly patients seem to have a higher risk of rib fractures (32). Another study reported that consequences of ACD-CPR are less severe than those of Std-CPR (33). Frequency and severity of injuries is significantly higher if Std-CPR and ACDCPR are applied in combination (29–31).

2.2.3. Defibrillation Apart from temporary erythema, no relevant injuries are observed as a sequel of defibrillation (15). One case study describes a case of a primary successful CPR lasting for 90 minutes, including 14 cardioversions, resulting in rhabdomyolysis of the thoracic musculature, myoglobinuria, and, finally, renal failure (34).

2.2.4. Intracardial Injection/Pericardiocentesis Intracardial injection is by itself an injury to the heart. Erroneous paracentesis of the heart or a coronary vessel may lead to pericardial hemorrhage and tamponade (15). Adjacent organs like lungs, liver, and mammarian artery and vein are also at risk of being damaged (12). Pericardiocentesis comprises the risk of myocardial lesions and the complications mentioned above.

2.3. Resuscitation Procedures on Other Thoracic Organs 2.3.1. Decompression of Mediastinal Emphysema Main complications include lesions of cervical organs like thyroid gland and large vessels with resulting retrosternal hemorrhage (12).

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2.3.2. Decompression of Tension Pneumothorax In pneumothorax, the lung is retracted from the thoracic wall and therefore out of risk from injury. Merely the lesion of intercostal vessels might cause a circumscribed hemorrhage, which is of no mayor consequence.

2.4. Resuscitation Procedures on Vessels 2.4.1. Puncture of a Vein In peripheral veins, paravenous positioning of a needle or catheter becomes apparent almost immediately and has no consequences. However, puncture of central veins holds many dangers. Erroneous puncture of the subclavian vein with puncture of the pleura will result in accumulation of air, blood, or infusion of fluid inside the thoracic cavity. Even if the catheter is positioned correctly inside the subclavian vein, a perforation of the vessel can occur, leading to soft-tissue hemorrhage of possibly large extent. If the catheter is pushed forward excessively, injuries of the heart valves or even atrial perforation and pericardial tamponade are possible. Incorrect positioning of the catheter might even result in embolic vascular occlusion. Possible injuries from jugular vein puncture include lesions of the carotid artery with the effect of soft-tissue hemorrhage, air embolism, and injuries of the heart valves.

3. MEDICOLEGAL ASPECTS According to unanimous reports from the literature, length of resuscitation time, age of the patient, and degree of qualification of the emergency personnel are the main factors influencing frequency and severity of injuries resulting from resuscitation procedures (15,16). Most of the methodical or accidental injuries due to resuscitation procedures are relatively minor as they have no relevant influence on the clinical outcome of the affected patient. On the other hand, even lethal injuries of internal organs can result. External cardiac massage is per se a blunt thoracic trauma with defined localization and dose (15). In accordance, most injuries are located on the thorax. CPR shows the highest frequency of injuries. According to data from the literature, the rate of complications in cardiac resuscitation is 20–55% (15,35). Injuries of ribs and/or sternum amount to 40% of cases, if the thorax is elastic, and to 70% of cases with a barrel-shaped thorax (36). Interestingly, a major study showed that resuscitation-related fragility of ribs 2–7 is dependent on age whereas fragility of ribs 3 and 4 is also dependent on the duration of the preceding cardiac massage (37). Fractures of ribs 1, and 8–12 are very

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rare after CPR (37,38) whereas abdominal visceral complications are noted in 30.8% of cases. (35). The frequency of intubation-related injuries is said to be 13% (16). Cervical injuries after intubation and thoracic injuries after CPR have a similar frequency (36). In a most recent study of 204 fatalities of children, injuries attributable to resuscitation procedures were detected in 42.5% of children who underwent resuscitation procedures (39). All but two of these injuries were of a minor nature consisting principally of bruises or abrasions. Two significant injuries were identified, both occurring as a result of readily identifiable resuscitation procedures. The likelihood of injury increased with the length of resuscitation: in children resuscitated for less than 60 minutes, the incidence of injury was 27% compared with 62% for children resuscitated for longer. Another report also indicates that trauma related to CPR is a rare complication in children (40). However, when encountering pediatric rib fractures, the forensic pathologist has to be aware of the differential diagnosis of child abuse since rib fractures, especially when of different ages and affecting multiple adjacent ribs, are a hallmark of nonaccidental injury in children. Basically, percental results should be responded to skeptically. The great majority of statistical studies is based on data from autopsy cases after unsuccessful resuscitation. Regarding the age distribution of the analyzed cases, it should be taken into consideration that not only morbidity and mortality increase with age but also the probability of an unsuccessful resuscitation attempt. In addition, the thoracic skeleton of the elderly patient shows a highly increased vulnerability because of degenerative alterations. Another contributory effect to high injury frequency is the fact that, in cases of multiple futile resuscitation attempts, a less experienced helper is likely to force his or her efforts excessively. In consequence, the physiological threshold might be exceeded resulting in massive injuries. Finally, an unsuccessful resuscitation will probably take more time than a successful one and thus the likelihood of injuries will increase. Complications and accidental iatrogenic injuries will never become completely avoidable in medicine in general nor in first aid. From the medicolegal point of view, problems arise if the possibility of a complication has not been taken into consideration and remains undetected, leading to impairment of health condition or even death of the patient. In this case, there might be repercussions on the physicians in charge: the responsible physicians might be prosecuted and/or civil action could be brought against them. A detailed and complete documentation is strongly recommended to prove the sequence of

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events as other evidence will most probably not be available months or years after the incident when the trial takes place. For the forensic medical expert, it is of great importance to have a good knowledge of injuries resulting from resuscitation procedures as they have to be distinguished from other trauma to give a correct opinion. Of course, this cannot always be decided with certainty, for instance, if trauma and/or preexisting organic disorders are present (31,41).

REFERENCES 1. Horatz K, Spindler R (1966) Die Geschichte der Wiederbelebung. Münch Med Wochenschr 108, 985–988. 2. Darok M, Glenewinkel F, Fodor M, Buris L, Leinzinger EP (2000) Medical malpractice in the “90s”—a study of autopsy protocols from three European countries. Book of Proceedings of the 13th World Congress on Medical Law, Helsinki, pp. 195–199. 3. Saternus KS, Fuchs V (1982) Verletzungen der A. carotis communis durch Reanimationsmaßnahmen. Z Rechtsmed 88, 305–311. 4. Jaeger K, Ruschulte H, Osthaus A, Scheinichen S, Heine J (2000) Tracheal injury as a sequence of multiple attempts of endotracheal intubation in the course of a preclinical cardiopulmonary resuscitation. Resuscitation 43, 147–150. 5. Maxeiner H (1988) Weichteilverletzungen am Kehlkopf bei notfallmäßiger Intubation. Anästh Intensivmed 29, 42–49. 6. Krause S, Donen N (1984) Gastric rupture during cardiopulmonary resuscitation. Can Anaesth Soc J 31, 319–322. 7. Mills SA, Paulson D, Scott SM, Sethi G (1983) Tension pneumoperitoneum and gastric rupture following cardiopulmonary resuscitation. Ann Emerg Med 12, 94–95. 8. Schvadron E, Moses Y, Weissberg D (1996) Gastric rupture complicating inadvertent intubation of the esophagus. Can J Surg 39, 487–489. 9. Eldor J, Ofek B, Abramowitz HB (1990) Perforation of oesophagus by tracheal tube during resuscitation. Anaesthesia 45, 70–71. 10. Topsis J, Kinas HY, Kandall SR (1989) Esophageal perforation—a complication of neonatal resuscitation. Anesth Analg 69, 532–534. 11. Kaloud H, Smolle-Jüttner FM, Prause G, List WF (1997) Iatrogenic ruptures of the tracheobronchial tree. Chest 112, 774–778. 12. Bauer H, Welsch KH (1976) Punktions-Techniken in der Notfallmedizin. Münch Med Wochenschr 118, 567–572. 13. Van Heurn LWE, Theunissen PHMH, Ramsay G, Brink PRG (1996) Pathologic changes of the trachea after percutaneous dilatational tracheotomy. Chest 109, 1466–1469. 14. Malthauer RA, Telang H, Miller JD, McFadden S, Inculet RI (1998) Percutaneous tracheostomy. Chest 114, 1771–1772. 15. Lignitz E, Mattig W (1989) Der iatrogene Schaden. Akademie-Verlag, Berlin

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16. Pracht U, Schulz E (1987) Befunde nach erfolgloser kardiopulmonaler Reanimation. Notarzt 3, 187–189. 17. Hargarten KM, Aprahamian C, Mateer J (1988) Pneumoperitoneum as a complication of cardiopulmonary resuscitation. Am J Emerg Med 6, 358–361. 18. Hartoko TJ, Demey HE, Rogers PE, Decoster HL, Nagler JM, Bossaert LL (1991) Pneumoperitoneum—a rare complication of cardiopulmonary resuscitation. Acta Anaesthesiol Scand 35, 235–237. 19. Noffsinger AE, Blisard KS, Balko MG (1991) Cardiac laceration and pericardial tamponade due to cardiopulmonary resuscitation after myocardial infarction. J Forensic Sci 36, 1760–1764. 20. Umach P, Unterdorfer H (1980) Massive Organverletzungen durch Reanimationsmaßnahmen. Beitr Gerichtl Med 38, 29–32. 21. Norfleet RG, Smith GH (1990) Mallory–Weiss syndrome after cardiopulmonary resuscitation. J Clin Gastroenterol 12, 569–572. 22. McGrath RB (1983) Gastroesophageal lacerations. A fatal complication of closed chest cardiopulmonary resuscitation. Chest 83, 571–572. 23. Lawes EG, Baskett PJ (1987) Pulmonary aspiration during unsuccessful cardiopulmonary resuscitation. Intensive Care Med 13, 379–382. 24. Adler SN, Klein RA, Pellecchia C, Lyon DT (1983) Massive hepatic hemorrhage associated with cardiopulmonary resuscitation. Arch Intern Med 143, 813–814. 25. Hillman K, Albin M (1986) Pulmonary barotrauma during cardiopulmonary resuscitation. Crit Care Med 14, 606–609. 26. Shulman D, Beilin B, Olshwang D (1987) Pulmonary barotrauma during cardiopulmonary resuscitation. Resuscitation 15, 201–207. 27. Yamaki T, Ando S, Ohta K, Kubota T, Kawasaki K, Hirama M (1989) CT demonstration of massive cerebral air embolism from pulmonary barotrauma due to cardiopulmonary resuscitation. J Comput Assist Tomogr 13, 313–315. 28. Guly UM, Robertson CE (1995) Active decompression improves the haemodynamic state during cardiopulmonary resuscitation. Br Heart J 73, 372–276. 29. Rabl W, Baubin M, Broinger G, Scheithauer R (1996) Serious complications from active compression-decompression cardiopulmonary resuscitation. Int J Legal Med 109, 84–89. 30. Rabl W, Baubin M, Haid C, Pfeiffer KP, Scheithauer R (1997) Review of active compression-decompression cardiopulmonary resuscitation (ACD-CPR). Analysis of iatrogenic complications and their biomechanical explanation. Forensic Sci Int 89, 175–183. 31. Klintschar M, Darok M, Radner H (1998) Massive injury to the heart after attempted active compression-decompression cardiopulmonary resuscitation. Int J Legal Med 111, 93–96. 32. Baubin M, Rabl W, Pfeiffer KP, Benzer A, Gilly H (1999) Chest injuries after active compression-decompression cardiopulmonary resuscitation (ACD-CPR) in cadavers. Resuscitation 43, 9–15. 33. Ellinger K, Luiz T, Denz C, Van Ackern K (1994) Randomisierte Anwendung der aktiven Kompression-Dekompressions-Technik (ACD) im Rahmen der präklinischen Reanimation. Anesthesiol Intensivmed Notfallmed Schmerzther 29, 492–500.

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34. Minor RL Jr, Chandran PK, Williams CL (1990) Rhabdomyolysis and myoglobinuric renal failure following cardioversion and CPR for acute MI. Chest 97, 485–486. 35. Krischer JP, Fine EG, Davis JH, Nagel EL (1987) Complications of cardiac resuscitation. Chest 92, 287–291. 36. Saternus KS (1981) Direkte und indirekte Traumatisierung bei der Reanimation. Z Rechtsmed 86, 161–174. 37. Saukko P (1980) Gerichtsmedizinische Gesichtspunkte für die Beurteilung von Schäden nach der äußeren Herzmassage. Zbl Rechtsmed 20, 8. 38. Kloss T, Püschel K, Wischhusen F, Welk I, Roewer N, Jungck E (1983) Reanimationsverletzungen. Anästh Intensivther Notfallmed 18, 199–203. 39. Ryan MP, Young SJ, Wells DL (2003) Do resuscitation attempts in children who die, cause injury? Emerg Med J 20, 10–12. 40. Price EA, Rush LR, Perper JA, Bell MD (2000) Cardiopulmonary resuscitationrelated injuries and homicidal blunt abdominal trauma in children. Am J Forensic Med Pathol 21, 307–310. 41. Zhu BL, Quan L, Ishida K, Taniguchi M, Oritani S, Kamikodai Y, et al. (2001) Fatal traumatic rupture of an aortic aneurysm of the sinus of Valsalva: an autopsy case. Forensic Sci Int 116, 77–80.

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14 Postmortem Alcohol Interpretation Medicolegal Considerations Affecting Living and Deceased Persons Donna M. Hunsaker, MD and John C. Hunsaker III, MD, JD CONTENTS INTRODUCTION CONSUMPTION OF ETHYL ALCOHOL AND ITS PATHOLOGICAL EFFECTS ON THE BODY THE INTERPRETATION OF ETHYL ALCOHOL RESULTS: MEDICOLEGAL ASPECTS REFERENCES

SUMMARY Ethyl alcohol (EA), the psychoactive ingredient in “alcoholic beverages,” is ubiquitous globally, and intemperate consumption is commonly associated with violence and disease. The most frequently detected drug by toxicology laboratories, it is the leading cause of drug-associated death and nonfatal trauma. As a central nervous system depressant, it acutely impairs human function and produces consistently documented, measurable neurophysiologic changes at advancing stages of intoxication. The pharmacokinetics of EA (absorption, distribution, elimination) is subject to multiple variables. Tolerance to EA from habitual consumption critically impacts the evaluation of both behavioral change and biochemical features. Toxicity from chronic consumption causes multiorgan pathology with considerable morbidity and mortality. Toxicologists have quantified EA in virtually all bodily organs, tissues, and secretions. Whole blood from the femoral or subclavian veins is the analytical “gold standard” for EA in official medicolegal death investigation. From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 307

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Many studies have established the comparative ratio of blood EA concentration (BAC) to matrices from extravascular compartments. Postmortem decomposition spuriously increases blood EA owing to endogenous production by overgrowth of normal, fermentative flora in the gut with substantial (~0.20%) artifactual elevations. Vitreous humor, typically sterile, is a reliable comparison medium to differentiate antemortem consumption from postmortem production. Fluids from embalmed bodies may be utilized selectively to estimate the antemortem BAC by comparison with constitutive volatiles in embalming fluid. Characteristic gross and histological pathology in various organ systems may be diagnostic of chronic alcoholism even without established history. Progressive toxic effects are commonly expressed in the liver, heart, pancreas, and the central nervous system. Clinically, many non-alcohol-related medical or drug-related conditions may mimic acute EA intoxication. The medicolegal investigator may be required to interpret analytical results in specimens from a survivor responsible for deaths in vehicular collisions. For this reason this review also addresses issues related to the collection and processing of specimens from living persons. Application of retrograde analysis and extrapolation to estimate the BAC at a time prior to collection may be cautiously considered only when the subject is clearly in the elimination phase. These estimations rely not only on the type and timing of collected specimens, but also on factors such as the individual’s physiology, the type of alcoholic beverage consumed, and the length and circumstances of the drinking period. In all medicolegal investigations, biochemical specimens invariably have future evidentiary relevance and materiality. Strict observance of the legal chain of custody in specimens obtained from both the deceased and survivors is mandatory to guarantee the reliability and integrity of the analysis on which the forensic pathologist as interpretative toxicologist relies. Properly recognized, obtained, packaged, transmitted, analyzed, and stored specimens facilitate admissibility of results and valid expert interpretation in court. Key Words: Blood ethyl alcohol concentration; pharmacokinetics; neuropsychological effects of alcohol; retrograde extrapolation; postmortem decomposition; forensic toxicology; forensic pathology; legal chain of custody.

1. INTRODUCTION Ethyl alcohol (EA) is the most commonly used and abused drug in the world (1,2). It is the most frequently detected drug in deaths from all causes, having the highest incidence in trauma (3). In the United States, EA use and abuse are responsible for around 100,000 deaths and well over $100 billion in economic costs annually (4). Not only is EA a toxin that contributes to natural

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disease (5), it is associated with a vast number of preventable, often fatal injuries (6–15). A comprehensive review of alcohol in medicolegal settings appears in the multiauthored text Medical-Legal Aspects of Alcohol edited by James Garriott (16). Body fluid EA levels can be reliably quantitated in blood, vitreous humor, urine, breath, cerebrospinal fluid, saliva, and bile. The “gold standard” in testing postmortem fluid EA levels for medicolegal purposes is whole blood (from the femoral or subclavian veins) by headspace gas chromatography (17–19). The blood alcohol content (BAC), which devolves from collection and analysis of the specimen at specific, discrete points in time, is dependent on the individual’s unique absorption, distribution, and metabolism of the drug (20). Correlation of the BAC to the level detected in a particular body fluid from one or more other body compartments is one of the most important components in the evaluation of a specific case (21,22). Consideration of the acute and chronic drinking status of the individual in question—ranging from naïve drinker to “social consumer” (23) to alcoholic (24)—aids in the overall interpretation of the neuropathophysiological effects of the BAC on the subject. The clinical stages of acute alcoholic influence and intoxication developed by Dubowski constitute a workable guideline for correlation of such measurable behavioral alterations with the whole-blood EA levels (25–27). The Widmark equation, conceived by the Swedish physiologist Erik M. P. Widmark (1889–1945), is a useful construct to provide retrograde and anterograde calculations for BAC estimations at a time different from the time of sample collection (28,29). This review also underscores the necessity of, and specifies the procedures for, maintaining the appropriate chain of custody for medicolegal purposes.

2. CONSUMPTION OF ETHYL ALCOHOL AND ITS PATHOLOGICAL EFFECTS ON THE BODY 2.1. Characteristics of Alcoholic Beverages An hydroxylated aliphatic hydrocarbon, the simple chemical or drug, EA (C2H5OH; molecular weight 46), itself is a clear colorless, odorless, flammable liquid with a warm burning taste. Chemically, it is only slightly polar, so that it easily passes through lipid cell membranes. For millennia it had been accepted as a social drug consumed in alcoholic beverages (30). A beverage that contains a least 0.5% EA is considered an alcoholic drink. Alcoholic beverages are numerous and varied. The availability and type of EA in beverages and other commodities depend on local customs, traditions, agricultural products, and industrial technology within a given cultural, social, or political setting.

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Overall, the most common means of EA exposure is by oral consumption. With wide industrial use of EA as a solvent or as an offshoot of many manufacturing processes, exposure from either inhalation of the vapor or cutaneous touching of the liquid may occur. At present, regulation prescribes the threshold for exposure in industry at 1000 ppm (1900 mg/m3) (31). Intravenous injection of EA, the fastest route of entry, is used uncommonly to treat methyl alcohol (32) or ethylene glycol poisoning, or to occasionally detoxify trauma patients under the influence of EA (33). Significant quantities of EA are commonly incorporated into medications including mouthwashes, over-the-counter drugs, and prescription medications or elixirs (1). Approximately 10–18% EA may be mixed in some mouthwashes and health tonics. Sundry cold medicines may contain up to 4–10% EA. The elixir of terpin hydrate, a prescriptive antitussive, may have EA content of 40% (34). A detailed list of these commercially available EA-containing products is referenced in Winek and Esposito’s chapter on antemortem and postmortem alcohol determination (1) and Garriott’s text (16). Calculation of the BAC after consumption of these products rests on determining the percent alcohol content within the medication and quantitating the established volume of the medication consumed (1). Methanol (wood alcohol), isopropanol (rubbing alcohol), and ethylene glycol (most commonly in antifreeze) may be ingested in desperation or confusion, particularly by alcoholics without a readily available source of EA, as a substitute for EA. In these cases, toxicity can be achieved at low blood levels (34). Fatalities attributed to ingestion of common household products containing EA are also described (35). EA for consumption (drinking alcohol) is prepared by fermentation of sugars and starches from various sources in the presence of yeast. Fermented beverages have a maximal alcohol content of 14–15% by volume. Corn and molasses, fruit juices, grain, rye, and barley are common raw materials for starting the fermentation process (1,36). Ordinary alcoholic beverages may be divided into three general classes, depending on the manufacturing process and the types of agricultural products used to make them (1). These products include wines, fermented malt beverages, and distilled “hard” liquors. Wines are essentially fermented juices of fruits, berries, and flowers. The final product is either artificially sweetened or fortified with additional alcohol. The average alcohol content in wines ranges between 10 and 20%. Fermented malt beverages, such as beer, ale, porter, and stout, typically have alcoholic contents ranging between 3 and 8%. Distilled or hard liquors with alcoholic contents ranging between 40 and 50% include rye, bourbon, blends of brandy,

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scotch, gin, vodka, and rum, to name a few. Manufacturers of whiskey, rum, brandy, gin, and other alcohol products use distillation, the process of superheating a mixture of alcohol and water with capture and cooling of the steam thus formed, to increase the percent alcohol concentration by volume (1,36). The EA content of a beverage may be stated in several ways. The most commonly used terminology is percent composition by weight (e.g., in the United States beer contains 3.2% EA by weight, which is equivalent to 4% EA by volume) (37). “Proof “is the quantity of alcohol in wines and distilled liquors expressed in the United States. The proof equals twice the percentage of EA by volume (i.e., 1 oz of 80 proof whiskey contains 40% EA by volume, which amounts to <0.5 oz of EA) (1). In the United States, a fifth of whiskey is considered a fifth of a gallon or 25.6 oz. In the metric system, a fifth of whiskey contains 750 mL or 25.4 oz. To calculate the volume of EA in a fifth of 80 proof whiskey, 750 mL is multiplied by 40% (0.4), which equals 30 mL. Then 40% is multiplied by the ounce weight (25.6 oz) equaling 10.2 oz of alcohol. The remaining volumetric constituents of the beverage consist of water, various sugars, and congeners. Congeners are organic compounds added to beverage to impart the characteristic flavor and unique odor (36,38). When an observer reports smelling EA in another’s breath, that observer in fact is detecting the added ingredients, not the odorless EA itself (39). A standard 12oz domestic beer manufactured in the United States has 14.2 mL of alcohol or 4% EA by volume. One ounce of distilled 100 proof liquor (50% by volume) and a 4-oz glass of table wine (12% by volume) have essentially the equivalent quantity of EA per serving (1). Obviously, the precise measurement of EA added to beverages ingested in the social setting is undetermined unless the EA content of the beverage is indicated by reference to the manufacture’s label on the container (1,34). As summarized aptly more than 40 years ago, “ . . . [e]thyl alcohol is the chemical agent that more frequently complicates a medicolegal investigation than does any other” (40). For medicolegal purposes, the forensic specialist (pathologist, toxicologist, pharmacologist, and biochemist) is specifically interested in determining the BAC (or equivalent in other medium such as breath) as the starting point in evaluating its effects on the individual. There are many varied, acceptable methods of reporting the analytical results for the BAC. Standard conversions for reporting results in the United States for 0.10% (weight/volume [wt/vol]) BAC, for example, are as follows: 0.10 g/100 mL whole blood = 0.10 g/dL = 100 mg/dL = 100 mg% = 1.0 g/L (41) = 21.71 mmol/L.

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2.2. Pathophysiological and Pharmacodynamic Effects of Ethanol An individual who is drinking EA cannot control or predict the type of social behavior or psychomotor changes he or she will experience during or within minutes to hours after the act of consumption (27). Lack of muscular coordination even at low BAC is coupled with increased reaction time to environmental stimuli. Cutaneous vasodilatation causes an increased blood supply to the venous plexus of the skin and results in cutaneous flushing (41). The person also feels warmer despite the insensible loss of body heat. Such peripheral dilatation accounts for the phenomenon observed in very cool or cold environmental conditions whereby a person under the influence of alcohol tends to become hypothermic, and even freeze to death, more quickly than one who is sober. Increased urine output from drinking alcoholic beverages is attributed to both greater water intake (water diuresis) and the inhibitory effect of EA on antidiuretic hormone, with resultant increased renal excretion (27). The principal pharmacodynamic actions of EA are attributable to its primary action as a central nervous system (CNS) depressant (27,41). The higher CNS centers (neocortex) are initially affected and, as the blood level rises sufficiently, EA interferes with the function of lower centers controlling respiration and circulation. As a CNS depressant, it acts as a sedative, a hypnotic, and an anesthetic. The depressant effect on individual neurons is directly proportional to the amount of intra- and perineuronal EA, which is reflected in the BAC, so that there is progressive deterioration of body functions as the blood level increases. The early effects produced by a relatively low BAC include reduction of tension, relaxation, release of inhibition, a sense of wellbeing, poor judgment, and mild euphoria (1, 27). These combined effects often lead to false courage and diminished ability to adjudge danger in a given situation. Such early effects create the common misconception by the uninitiated that EA is a stimulant. This phenomenon of apparent stimulation, more properly termed “pseudo-stimulation,” is a result of its ability at the very early phase of EA consumption to repress psychological inhibitory mechanisms that typically are controlling factors in behavior (26). Progressive psychomotor effects are well delineated in the adaptation of K. M. Dubowski’s Table of Stages of Alcohol Intoxication (1,25,27,41) (Table 1). The physiologic effects of alcohol are considerably more pronounced when the blood level is rising relative to levels attained at peak or plateau, or when the level is falling. This phenomenon is coined the Mellanby Effect (42). An extreme example is that reported of a 23-year-old comatose female following a single-driver motor vehicle collision (43). Shortly after the event

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Table 1 Modification of Dubowski’s Stages of Alcohol Intoxication Subclinical or sobriety (0.00–0.04%): The functional changes occur in the high cerebral cortex and affect perception and processing of information received by the special senses. Learned motor responses are spared. Euphoria (0.05–0.14%): This stage, considered to be “under the influence” of EA, is characterized by a diminished attention span, judgment, and control with incremental loss of motor response. There is mild euphoria, increased self-confidence, and sociability. Stimulation or excitement (0.15–0.24%): EA is to most observers demonstrably a central nervous system depressant. Personality and behavioral changes are unpredictable, with decreased inhibition and poor judgment. There is impairment of memory and comprehension. Decreased sensory response with increased motor reaction time and muscular incoordination supervene. Confusion (0.25–0.34%): This stage is associated with slurred speech and stumbling gait. There is decreased pain sense, impaired balance, and disturbance of perception of color, form, dimensions, and motion. Increased mental confusion with exaggerated emotional states (fear, anger, and grief) is very characteristic of this stage. Stupor (0.35–0.4%): The individual is apathetic with markedly decreased response to stimuli, impaired consciousness coexistent with arousable sleep. Coma (>0.40%): Complete unconsciousness without arousal; death ensues in 95% of cases where coma lasts greater than 12 hours. Death (0.45–0.60%): Forensic pathologists and other specialists agree that the minimum lethal level of alcohol is subject to many variables, such as the underlying health of the consumer or the rapidity of intake, and may be found at levels from 0.30 to 0.45% secondary to respiratory depression. Note. According to ref. 25.

her BAC was 780 mg/dL on hospital admission, and declined to a BAC of 190 mg/dL at discharge to police authority 11 hours later. At that time, she fulfilled the criteria for sobriety upon thorough neurological examination: full consciousness without any signs of neuropsychological impairment. In summary, the progressive effects, which become more pronounced with steadily increasing BAC, consist of intellectual deterioration, followed by impairment of motor coordination, loss of consciousness, respiratory depression, circulatory collapse, and death. EA acts selectively as a CNS depressant at low doses and initially affects the most sophisticated parts of the brain (i.e., the cerebral cortex), which control judgment and morals. At increasingly higher levels, EA is a more generalized depressant and triggers progressive dysfunction of the oldest portion of the brain, most importantly the brainstem, which

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regulates homeostatic control of autonomic body functions (27,41). Each person reacts differently at measured equivalent BAC levels secondary to individual psychomotor variability in response to EA as a drug. The physical effects of EA, which are subject to objective analysis, are dependent predominantly on the amount consumed. In contrast, the subjective intellectual and emotional effects are strongly influenced by the “set” and “setting.” The “set” is defined as the mood and attitudes of the individual at the time of consumption, that is, the individual’s underlying personality traits, which may become unmasked (“In vino veritas”). The “setting” refers to the external circumstances in which the consumption occurs (37). In assessing the effects of EA on human behavior, the forensic specialist must be aware of many other drugs and conditions—with or without the added presence of EA—that produce signs and symptoms similar or identical to those caused by EA (34). Factors comprising the differential diagnosis of causes of acute EA intoxication include nonalcoholic medical conditions with similar clinical manifestations such as diabetic ketoacidosis, hypoglycemia, craniocerebral trauma or neurodegenerative diseases, and spontaneous cerebrovascular events (stroke) (34,37). In view of the contemporary pharmacopeia and epidemic of substance abuse, the forensic investigator must be aware of the phenomenon of drug–drug interactions to reach sound medical conclusions about the effects of any drug on individual behavior. Certain non-alcohol-based therapeutic drugs such as anticonvulsants, narcotics, antihistamines, sedatives, analgesics, tranquilizers, hypnotics, and rarely antibiotics, such as streptomycin or sulfonamides, can alone create physical or mental changes in susceptible individuals, which may mimic the effects produced by EA (37). The combination of EA and many of these drugs usually creates either an accumulative or a synergistic effect that promotes higher levels of CNS depression. The difference between additive effect and synergistic effect may be summarized, as follows: the additive effect is essentially a one-to-one relationship whereby each chemical contributes equally to the resultant enhanced stage of impairment (1 + 1 = 2), whereas the synergistic (or superadditive) effect is greater than that expected in an individual by the combination of the two or more drugs (1 + 1 = 3). The synergism in turn exaggerates the combined ability of such drugs to cause deterioration in alertness, coordination, and concentration. A very common example of synergism reported in the United States is the combination of EA and cocaine. Cocaine ingested in concert with EA produces the metabolite through hepatic transesterification, cocaethylene (ethyl benzoylecgonine), which is longer acting, enhances the cocaine-induced euphoria, and is more toxic than the parent drug, cocaine, alone (44).

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Reduced effects, or antagonism, occur through interactions with drugs such as naloxone and naltrexone, both narcotic antagonists, which have been used in the clinical setting to treat effects of acute and chronic alcoholism (27). Individuals treated with disulfiram (Antabuse®) (45) or metronidazole (Flaygl®) (46), and who then ingest even small quantities of alcohol, may experience severe toxic reactions and, in some cases, death without prompt treatment. Rapid or continual consumption of EA resulting in a nonfatal but relatively high BAC may cause serious toxic biologic effects. Immediate toxic effects include dizziness and drowsiness, mental confusion, slurring of speech, excessive sweating, incoordination, nausea, headache, cardiac dysrhythmias, coma, acidosis, and circulatory collapse. Some individuals may sense eye irritation, narcosis, and vertigo (27). A BAC between 0.35 and 0.45% is generally reported by most investigators to represent the minimal lethal level. Caution in interpretation is mandatory in light of the great variation of human response to any substance introduced into the body, which unarguably includes EA. Considerably lower levels of BAC, for example, may trigger a lethal cardiac dysrhythmia in a susceptible person (41,47). The presence of a pre-existing disease or gastrointestinal surgeries may hasten death at a considerably lower BAC. On the other hand, a chronic alcoholic or otherwise habituated drinker who has developed marked tolerance may survive an extremely higher BAC (e.g., >0.50%), which would be deemed lethal in a nontolerant person (48–50). With chronic consumption of EA, various degrees of physical dependence and tolerance will develop. Chronic tolerance is a consequence of decreased effectiveness of the desired effects at a given amount of EA after prolonged, uninterrupted consumption of large quantities, as compared to the occurrence of acute tolerance developing after intake of a very large dose during a single episode (51). With cessation of use, the chronically tolerant subject characteristically experiences withdrawal symptoms (52). There are three types of tolerance (27,53). Metabolic tolerance is present when a variety of “activated” hepatocellular enzymes accelerate the rate of alcohol metabolism (elimination) by as much as 30%. Pharmacodynamic tolerance refers to the adaptive response to EA by the brain’s neurotransmitters (54). Behavioral tolerance, or accommodation, is evident when the chronic alcoholic psychologically and/or physically functions better than a nontolerant individual at a given or expected BAC (1). When increased quantities of EA are chronically consumed, delayed toxic biological effects ensue and include poisoning at the cellular level with resultant clinically obvious functional disturbances in various organ systems (53,55).

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Significant pathologies with pathophysiological sequelae may involve the liver (fatty liver, acute hepatitis, cirrhosis with liver failure, hepatocellular carcinoma), heart (alcoholic cardiomyopathy, secondary hypertension), brain (Wernicke–Korsakoff encephalopathy [vitamin B1 {thiamine} deficiency], superior cerebellar vermal atrophy, Marchiafava–Bignami disease, elevated risk for stroke, and seizure disorders), esophagus (submucosal varices, Mallory– Weiss syndrome, rupture, carcinoma), stomach and duodenum (alcoholic gastritis, gastric atrophy, peptic ulcer disease, carcinoma), pancreas (acute and chronic pancreatitis with pseudocysts), and genitourinary (diminution of testosterone production, dysfunctional penile tumescence, infertility in both sexes). EA toxicity occurs in pregnancy as well (fetal alcohol syndrome, spontaneous abortion, fetal EA withdrawal, teratogenesis). Concomitant poor nutritional intake leads to general malnutrition (56). Characteristic pathological clues at the autopsy allow the pathologist reasonable inferences about the chronicity of EA usage in many cases, even in the absence of supportive history. Most notably, micronodular cirrhosis without infectious hepatitis or intrinsic liver disease is very specific for chronic EA intake (53,55). An enlarged, fatty liver suggests the habitual use of alcohol in an established drinker of EA as first on the list of differential etiologies rather than a single act of EA consumption or binge (34). Various endstage or severe disease conditions primarily involving the liver, such as micronodular cirrhosis or “alcoholic hepatitis,” eventually cause inefficient, depressed alcohol metabolism and eventuate in impaired elimination (55). Clinically apparent sequelae include a variety of seizure disorders (57,58), among which delirium tremens ( “D-Ts” or “rum fits”) is the most serious clinically (59). This manifestation along with others constitutes complex withdrawal symptoms that may occur upon cessation of EA use by the binge drinker or alcoholic (53,55).

2.3. Pharmacokinetics of Ethyl Alcohol Pharmacokinetics refers to the fate of EA in the body after consumption. Although EA can enter the body through inhalation, injection, direct insertion per rectum, or absorption by direct skin contact, it typically is swallowed and travels from the mouth through the esophagus to the stomach (60). Negligible amounts of EA may be absorbed through the lining of the oral cavity, but the fluid leaves the mouth rapidly so it is free of alcohol after about 15–20 minutes. Easily miscible with water, EA requires no physical disintegration or digestion before entering the blood and capillaries of the upper gastrointestinal tract. When EA enters the upper gastrointestinal tract, it passes through the membranes of the gut by simple diffusion. A small percentage (<20%) of

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Table 2 Hepatic Alcohol Dehydrogenase Pathway ADH 1)

[EA] CH3CH2OH + NAD+ A [acetaldehyde] CH3CHO + NADH + H+ ALDH

2)

CH3CHO + NAD+ A [acetic acid] CH3COOH + NADH + H+ via Krebs cycle

3)

CH3COOH [acetate A acetyl CoA] A CO2 + H2O

EA is absorbed through the wall of the stomach, but upon entry into the proximal small intestine approximately 80% of the ingested substance is quickly absorbed and then distributed in the circulatory system without being bound to plasma proteins or forming complexes with other intravascular transport systems. The rate of flow from the stomach to the small intestine depends on various factors, including the amount and kind of food in the stomach, pathological conditions or prior surgery of the stomach or small intestine, or both, concentration, composition and amount of EA ingested, and the temperature of the alcoholic beverage. Once in the circulation, EA distributes rapidly throughout the compartments of body according to the water content: the corporeal concentration of EA is proportional to the water content in that fluid or compartment (34). More than 90% of EA is metabolized to carbon dioxide (CO2) and water (H2O) in the liver by the chemical process of oxidation, primarily via the alcohol dehydrogenase (ADH) pathway in the cytosol (61). Chemically, EA is metabolized through a series of well-understood enzymatic reactions: first, the hepatic enzyme ADH converts EA to acetaldehyde via an oxidation reaction. Acetaldehyde is further oxidized to acetate by acetaldehyde dehydrogenase (ALDH). Acetyl coenzyme forms as acetate combines with coenzyme A and enters the Kreb’s cycle, as a result of which H2O, CO2, and calories are generated (Table 2). As a carbohydrate EA yields approximately 7 calories per gram, yet has no nutritional value (1). At least two other metabolic pathways of lesser import are the microsomal ethanol-oxidizing system (MEOS) within the endoplasmic reticulum and the perioxidase-catalase system of the peroxisomes (P450dependent system). The MEOS is of import when the hepatic EA concentration rises because the Km Michaelis velocity constant of the Michaelis–Menten

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kinetics is four to five times higher than for the ADH system (62). The hepatic microsomal P450-enzyme-oxidation-system pathway appears to be increased with chronic EA intake and is regarded as a likely candidate responsible for the development of tolerance in habitual consumers (34).

3. THE INTERPRETATION OF ETHYL ALCOHOL RESULTS: MEDICOLEGAL ASPECTS 3.1. Physiology of Ethyl Alcohol and Widmark Equations Consideration of the absorption of EA after intake is the most difficult aspect of interpreting EA concentrations in the body because the absorption profile is dependent on an unruly, large number of variables, many of which may not be either discoverable or quantifiable in a specific case (63). The rate of absorption of EA is susceptible to both intraindividual and interindividual variation. The bioavailability of alcohol is considerably greater in women than men because of the relatively lower concentration of gastric ADH in women, which yields a lesser degree gastric first-pass metabolism (64). In general for a fasting person, most EA is absorbed in the stomach and small intestines within 20–30 minutes after a single dose. In contrast, with a full stomach of a fatty meal, the complete absorption may be greater than several hours because of delayed gastric transit to the bowel (65,66). Intrinsic or additional extrinsic factors promoting a relatively rapid rate of absorption in the gut include the following: an empty stomach: cholinergic agents, parasympathomimetic agents, gastric resection (67), the percent carbonation of beverage, gastric ulcers, gastritis, H2-receptor antagonists, (68), aspirin (acetylsalicylic acid) (69), erythromycin, and femaleness (64). Factors that decrease the rate of gut absorption include: a full stomach, anticholinergic agents, sympathomimetic agents, malignant gastric neoplasm, pyloric stenosis, stimulants such as nicotine or caffeine, opiates, tricyclic antidepressants, antidiarrheal agents, malnutrition/ starvation, fatty foods, emotional upset, extreme fear or pain, major injury or shock, very high or very low EA concentrations within the beverage ingested, nausea, strenuous exercise, or maleness (1,34). Absorption of EA via the stomach wall is slow. Any substance that may delay the emptying time of the stomach will retard the absorption of EA. Greasy foods will coat the gastric lining and retard absorption of alcohol (1,27). Fatty foods such as milk, cream, and butter will slow the stomach-emptying time. In these cases, absorption of EA will be delayed. Eating food products during or shortly after consumption of EA will delay the presentation of EA to the small bowel and thereby extend the absorption time. Therefore, on a full stomach as

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compared to an empty stomach, blood peak values will be lower and there will be a slower rise of the BAC. In other words, it requires a longer period of time and greater consumption of alcoholic beverages to reach an equivalent BAC for a person who is eating than for a person who is consuming an alcoholic beverage on an empty stomach. The absorption rate of EA depends on the amount, the dilution (concentration), and type (composition) of EA ingested. The maximal absorption rate of alcohol occurs with solutions that are approximately 20% EA. In beverages such as champagne with carbonation, absorption will be enhanced. Absorption is slower in very dilute and very strong alcohol beverages. The slower absorption rate observed in “strong” drinks is secondary to irritation of the gastric mucosa and delayed gastric emptying. Therefore, maximum absorption of EA occurs in those who partake of in moderate amounts (1). In the vast majority of cases (90%), peak BAC is reached during the first 60 minutes of ingesting a single dose EA (34). In the majority of fasting persons, the gastrointestinal tract will absorb most EA consumed orally within 20–30 minutes. Peak BAC levels may be delayed when several drinks are consumed rapidly approximately 45 minutes after the last ingested drink. Therefore, a BAC curve can be constructed based on incrementally elevated levels of blood EA that increases with each drink. The concentration curve will eventually plateau and decline from the maximum level after the maximum BAC is reached (1). Upon entering the circulation, EA is distributed throughout the entire organism passing from the portal vein to the liver then to the heart, the lungs, and then returns to the heart with generalized distribution throughout the body. When equilibrium is reached, EA is present in all compartments in proportion to their water content. The speed at which various organs reach equilibrium depends on the degree of their blood supply. The rates of attainment of alcohol equilibrium following distribution are variable among different individuals, between the sexes, and under different drinking conditions (37). Oral intake at a slow steady rate allows distribution to keep pace with absorption. Large volumes of strong alcoholic beverages that are rapidly consumed may cause distribution to body organs or compartments to lag behind the absorption rate. EA is not stored in the tissues; once it enters into the blood stream, the body almost immediately begins to eliminate alcohol by two simultaneous physiologic processes, metabolism and excretion. Excretion, as a form of elimination, of EA is relatively negligible and unimportant in terms of overall disposal of it. The major portion of the small fraction is lost to expired air, urine,

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tears, saliva, breast milk, sweat, and feces (1,27,60). Precisely because the relative amount excreted is so small, therapeutic efforts to lower the BAC short of extracorporeal or peritoneal dialysis have little effect. Accordingly, the combination of excretion and metabolism determines the rate at which EA is eliminated from the body. The rates vary from person to person and even from day to day in the same individual. Most studies conclude that alcohol is metabolized in a linear fashion or zero-order kinetics. This means that the dissipation in a given case is linear (X amount per Y period of time) and independent of the dose of EA in the body. For virtually all purposes impacting expert medicolegal evaluation, first-order kinetics, meaning that the rate of elimination nonlinearly increases as the concentration of EA increases, does not apply (70). However, investigators have reported rare exceptions to these approximations at the extremes of BAC, where first-order pharmacokinetics applies: BAC greater than 0.02% (71) or at “very high” BAC levels (43,72). Within these parameters the BAC curve can be constructed through reliance on the combination of excretion and metabolism rates. The BAC curve is a hypothetical construct graphically depicting the fate of absorbed EA in the body over time and is heavily dependent on multiple variables, as discussed above. It is composed of three parts: (a) absorption phase; (b) equilibrium or plateau phase, indicating the maximum BAC; and (c) elimination phase. Elimination rates reported in the medical literature are variable, typically ranging from the average of 0.015–0.018%/h (27). The rates at the lower level of the scale are generally associated with naïve drinkers, in contrast to higher rates typically found among the more experienced drinkers, which some studies report as high as 26.6 ± 7.0 mg/dL/h (70). In yet another set of controlled studies, investigators have reported ranges of EA elimination demonstrating a fourfold difference, from the slowest in a healthy male yielding a ß-slope of 9 mg/dL/h to the fastest, a male chronic alcoholic, at 36 mg/dL/h (70,73). Certainly, many factors, including dose of EA consumed, drinking patterns, and relation to kind and timing of food intake, alter the shape and maximum height of the BAC curve. As discussed above, the consumption of strong or diluted beverages delays the absorption of EA reflected by the gradual sloping and plateauing of the curve. It is obvious that the more EA a person consumes, the higher the BAC will become. However, both body size and relative adiposity determine the distribution of alcohol. A heavier lean person has higher water content and greater capacity for the generalized distribution of EA within the body. Therefore, a person whose body weight is 200 pounds will have a lower BAC after complete consumption of the identical amount of EA over the same time period than that of a person weighing 150 pounds or

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less. This notion is expressed mathematically by Widmark’s general equation, which will be described later in this chapter (1). Widmark developed several equations that helped explain the metabolism of EA in various individuals. Applications of the Widmark equation are threefold: (a) calculation of the amount of EA consumed for known BAC, (b) back calculation of BAC at a previous time based on a measured subsequent BAC, and (c) forward calculation to estimate an expected BAC based on the amount of EA consumed (34). The Widmark equation is based on the slope of a linear elimination phase ` seen in the BAC curve. This mathematically derived linear phase ` is equal to a mean of 0.0025 mg/gm/min or 0.0158 gm/dL/h with a range of 0.012–03.019 gm/dL/h as previously discussed. Interindividual values for adults may vary greatly. Intraindividual values are relatively stable and can be reproduced over time. The ` value does not change with the type of beverage, the amount of beverage consumed, or the rate of consumption (34). Extrapolation of the ` slope back to the Y intercept at T0 (or the time drinking began) yields C0, which represents the expected BAC after complete absorption of the entire dose. The Widmark equation begins with Ct = C – `t

where C equals a previous estimated BAC based on Ct (specific or measured BAC obtained at time t during the absorptive phase). The Widmark factor is designated as “r” (p or rho), which equals the ratio of percent EA in the body to the percent of EA in the blood. EA is soluble in water but not in fat. The r factor is a stable factor with interindividual variation based on body type. The ratio helps to equalize the BAC with the concentration of EA in the body and takes into account the relative proportion of fat to lean tissue mass. This is designed to allow for differentiation between large, obese individuals or thin individuals, and inherently distinguishes males from females. The average male r factor is 0.68 (range 0.51–0.85) and for females 0.55 (range of 0.49–0.76). The r value is lower in obese and higher in thin individuals. Children will have an r value that is up to 0.75. The r factor is also elevated in chronic alcoholics. The general Widmark equation is expressed as A/pr = C0.

where A is the amount of EA consumed, p is the body weight, r is the Widmark factor (see above), and C0 is the expected maximum BAC (assuming 100% absorption and no metabolism). Medicolegal forensic science experts, including toxicologists and pathologists, are frequently requested to determine whether the BAC of a person cor-

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responds to the reported quantity of EA ingested or to the estimate of the quantity of EA consumed based on a measured blood level at a given time. The minimal essential information necessary to make such estimations includes the individual’s body weight, percent of EA in the drink, the number of alcoholic beverages consumed, the length of the drinking period, and a given individual’s dissipation rate. Various formulas have been employed to answer such questions. Some of the formulas are geared to predict a BAC based on X number of drinks, their alcoholic percentage, and the weight of the individual. The following practical equation has been adapted from Widmark’s general equation: D = (C + `t) wr (0.389)

where D is the number of drinks consumed, C equals to the BAC in percentage (gram percent), ` is the metabolic rate (0.015%/hr), t is the time since drinking began in hours, w is the body weight in pounds, r is the Widmark factor (0.68 for men, 0.55 for women), and 0.389 represents the conversion factor (based on one drink of 0.50 fluid ounces of absolute alcohol). The conversion factor will help convert the body weight into pounds, the alcohol into volume, and the volume into number of drinks. The equation can be rearranged to calculate the expected BAC based on the number of drinks consumed as follows (34): C = D/wr (0.389) – `t.

Retrograde calculations to estimate the amount of EA in the individual’s body obtained from a given BAC can also be performed. When EA is lost by metabolism, time must be additionally calculated within the general Widmark equation. Thus, the calculation is: A = pr (Ct + `t).

This calculation is used for the maximum amount of EA consumed (A) based on a person’s later BAC at time t (time, in hours, since drinking began) (34). Widmark’s calculations and hypotheses, first developed in 1932, have limitations and drawbacks, but overall have gained considerable acceptance in many medicolegal applications. In circumstances in which there is a delay between collection of the sample of material containing EA and the actual occurrence (such as a motor vehicle collision), the process of retrograde extrapolation may be invoked for medicolegal purposes. Such a back calculation is permissible and accurate only when the individual is in the elimination phase of the blood alcohol curve. Because it is often difficult to quantify the variables in the mathematical for-

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mulas, this still remains a controversial extrapolation (74). As U.S. state legislatures continue to enact per se laws, where the BAC at the time of collection, as remote as 4 hours after the motor vehicle event, is the determinative factor, courts of final jurisdiction have held back extrapolation is unnecessary (75). Potential risks for erroneous application of this kind of extrapolation and sources of error may arise in the medicolegal arena. These confounders should be appreciated by all medical examiners facing expert testimony on blood EA in court: (a) retrograde extrapolation to determine earlier BAC assumes that the individual is in the postabsorptive phase—if only one BAC level is reported, one may be unsure whether or not blood EA is rising or falling at collection: (b) the ` and r values in the Widmark equation are averages for a population of individuals and not individually specific—reference to several ` and r values tend to eliminate this error, (c) specific time intervals since first to last drink cannot be determined unless strict observation of the individual is performed, and (d) equations, which are derived from experiments on individuals drinking under carefully controlled laboratory conditions and on empty stomachs, do not well represent real-life situations of hectic consumption patterns of a variety of alcoholic beverages over variable periods while eating all kinds of foods (34).

3.2. Antemortem and Postmortem Collection and Testing for Ethyl Alcohol: Interpretative Toxicology Logically, because the level of alcohol in the CNS directly affects behavior and activity, the best sample for measurement of EA concentration is brain (21). Obviously, this is not feasible for living individuals. Although brain tissue is usually readily available at autopsy, it is not the specimen of choice for several reasons: (a) blood from the vascular compartment is usually easier to obtain and process, (b) the BAC adequately reflects the effect of EA on the brain, and (c) it is more practical, technically efficient, and economically sound to analyze blood regularly when such high volumes are involved. Accordingly, the common test specimens collected by law enforcement agencies and medicolegal investigators to determine EA levels are blood (whole blood, plasma, and serum), breath alcohol content (BrAC), and urine alcohol content (UAC) (76–78). In contrast to the practices of clinical laboratories, which analyze either serum or plasma from living subjects for BAC, most toxicology laboratories evaluating postmortem samples report BAC from whole blood preserved in sodium fluoride. In death investigation, whole blood is the “gold standard” for measurement of BAC (21,79). Yet, because most forensic experts are frequently called upon to either interpret results from or analyze

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these antemortem serum or plasma samples, it is incumbent on the expert to appreciate the meaning of the different results from various analytes. Under most physiological conditions serum or plasma contains about 10–12% more water than the same volume of whole blood, so that the EA levels are correspondingly, but only slightly higher in these samples. The average EA ratio of whole blood to serum or plasma is approximately 1:1.8, with a reported range of 1.12–1.17. The following EA ratios obtain for conversion of these blood components to whole blood: serum = 1.12–1.17; plasma = 1.10–1.35 (21,79). EA is the most frequently analyzed drug by the toxicologist collaborating in consultation with coroners and medical examiners. Optimal specimens are required for accurate analysis by the laboratorian as practitioner of analytical toxicology, as well as for evaluation and interpretation of the analytical results by the forensic pathologist, the practitioner of interpretative toxicology. Specific analytical methods are necessary because of the potential interference by a variety of volatile substances in postmortem specimens (78,80). Gas chromatography is the “gold standard” for BAC analysis, affording specific identification and quantification of EA (81). Headspace chromatography is completely specific for EA. It is the only test method acceptable in most courts of law granting admissibility of analytical results on which to base expert testimony (34,78,80). The gas chromatograph separates volatile compounds on a column by a carrier gas, which is passed through a detector designed for either flame ionization or thermal conductivity. EA is initially separated, based on the appropriately calibrated gas chromatograph parameters and columns, and subsequently quantified. Headspace gas chromatographic methods use vapor samples in a closed system for injection. The headspace procedure employs blood samples placed in small, capped bottles from which the extracted vapor is injected into the chromatograph. Separation and detection of volatiles occurs upon this injection. Hospital and clinical laboratories commonly employ an enzymatic method to determine BAC (21,78), and resort to such methodologies because gas chromatographs are not universally available in the clinical laboratory (78). The coenzyme, nicotinamide adenine dinucleotide, is reduced as a byproduct of the oxidation reaction of EA to acetaldehyde. The resultant reduction product is measured by a spectrophotometer. This is a quick, easy, and automated method to detect EA; however, it lacks the specificity of headspace gas chromatography because the presence of other alcohols such as isopropanol may interfere chemically and yield an inconclusive, false-positive, or spurious result. Unlike head space chromatography, antigen–antibody reactions are subject to

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cross reaction with other substances within the blood and for that reason are not regarded as a reliable method for testing BAC in a medicolegal or juridical context (1,27,77). Clinical toxicologists regard serum as an easier medium to analyze, pointing to extensive surveys in which precision and span of values derived from serum are better than those recorded for whole blood (82). The researchers conclude, however, that using either serum or whole blood produces essentially equivalent results for clinical and forensic purposes, as long as the final report of analytical results clearly specifies the analyte (serum, plasma, whole blood). In most postmortem cases, there is greater opportunity to collect a variety of specimens for laboratory analysis. Utilizing multiple specimens from various compartments and subcompartments of the body is beneficial because the analysis of more than one sample tends to ensure accuracy in a given quantitative result and thereby facilitate optimal interpretation. In postmortem sampling, whole blood continues to be the sine qua non for analysis. At autopsy it is more desirable to collect at least two samples of blood, one from the heart region (central) and one from the peripheral vasculature (83). It is nevertheless necessary to specify unequivocally the source of the sample or the site of collection of whole blood. Arterial BAC may be at least 40% higher than venous BAC in the absorptive phase. Bloody fluid (which is not blood!) recovered from extravascular body cavities, from body surfaces, or from the relevant scene, especially in trauma, is a less reliable toxicological specimen to quantitate EA for various reasons (1). The bloody fluid may have either a higher or lower level of EA than that in intravascular blood per se (central or peripheral), and accordingly may make meaningful interpretation of the reported “BAC” virtually impossible. In collecting blood samples at autopsy, there are factors influencing the concentration of EA that are not pertinent to antemortem sampling techniques. Diffusion of significant amounts of EA out of the esophagus or stomach into the surrounding pericardial cavity and heart is likely to occur, and becomes increasingly significant as the postmortem interval increases with the time of delay between death and autopsy (84). Yet, if there is a great period of time, measured in hours, between the last drink and death, diffusion of EA from the gut to the “heart blood” will not be substantial. Under such circumstances where the autopsy is performed within 48 hours of death, diffusion of alcohol from the gut to the heart is fairly insignificant. Femoral and subclavian venous (peripheral) blood sites are preferable to central heart blood, but these may be difficult to obtain secondary to insufficient volume and in cases of traumatic hypovolemia (“empty heart sign”)

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(22,85). Taking a “blind” sample at autopsy via precordial percutaneous pericardiocentesis, to collect blood is indisputably flawed and to be avoided. Blood must be drawn from the chambers of the heart, or the great vessels exiting or entering the heart, as heart blood. In summary, external chest puncture is not considered an acceptable procedure for the collection of a blood sample for subsequent EA analysis (1,27,34). False elevations of EA in bloody fluid collected by external chest puncture can be confirmed by analysis of postmortem UAC (1). As a quality control measure, concomitant comparative quantitation of EA in the postmortem vitreous humor (vitreous alcohol content or VAC) is an excellent means for interpreting the reported BAC, whether central or peripheral. Because the intact, relatively avascular globe in the orbit is anatomically isolated from other tissues or fluid, it serves as an excellent compartment to obtain unadulterated vitreous humor for quantitation of EA. Characteristically, VAC lags approximately 1–2 hours behind BAC at the phase of equilibrium (86,87). Therefore, BAC in the absorptive phase is higher than VAC. At the plateau or equilibrium phase, the reported average ratio of BAC:VAC is 1.0:1.05 to 1.3. Logically, in the postabsorptive or elimination phase, VAC is higher than the BAC. Such comparative analysis is helpful in establishing whether or not the deceased was in the absorptive or elimination phase at the time of death. Given the well-documented BAC:VAC ratios, reference to the VAC is also very useful in inferring the probable BAC at death when intravascular blood or other body fluids are not readily available (1). As in all extrapolations drawing upon EA levels in other body compartments, caution is always prudent in estimating the BAC from the VAC at autopsy, as the EA distribution ratio (VAC/BAC) (femoral blood) exhibits wide variation in light of recent research encompassing 706 forensic autopsies (88). These authors recommend a conservative approach by dividing the postmortem VAC by 2.0 to arrive an estimate of the equivalent (femoral) BAC, which, although lower than the “true value,” may then be offered with a high degree of confidence in the medicolegal arena. In cases where vitreous humor is not available, such as in decomposition or trauma, other aqueous body tissues may be used to quantitate EA, because of its ready miscibility in water. Other tissues and samples (89) used for blood alternatives are bile (90), urine, gastric contents, bone marrow (91), solid organs, for example, liver, kidney, brain, spleen, and lung, cardiac, smooth, or skeletal muscle (92), intracerebral and paradural hematomas (93,94), synovial fluid (95), and cerebrospinal fluid (96). Many researchers have reported an

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established range and ratio of EA in these various specimens to BAC (21,97). These tabulations are helpful and afford reasonable inferences with respect to BAC when intravascular blood is unavailable (21,85). With qualification, urine is potentially an acceptable medium to estimate BAC and to determine the pharmacokinetic phase the subject is in at the time of collection. The preferred sample is ureteral urine in which excreted EA from the renal circulation is virtually identical to the BAC in that vascular compartment. Under most circumstances at autopsy, collection of ureteral urine is not practical. The urinary bladder acts as a storage container for the eliminated urine waste until the urine is voided (1). Pooled urine, which continuously enters and collects in the urinary bladder and thereby contains variable time-and-volume-dependent amounts of EA, is not an accurate medium for comparison to the BAC. There are collection problems inherent in the measurement of UAC. In living subjects, the stored urine must be voided and a subsequent urine specimen collected over time (30–60 minutes) during which consumption of EA does not occur. Voided urine should be used only as a qualitative test for EA. Toxicological analysis of urine may be done in a given situation, but generally it is of little or no value when used alone to estimate an individual’s BAC at a given time. At autopsy, UAC represents the cumulative or integrated sum of different BAC’s intra vitam over time, during which the individual may be or is passing through various phases of EA metabolism and the urinary bladder continuously receives urine from the kidneys as an excrement. Such pooled urine does not reflect a BAC at any particular point in time, but merely estimates an average urine concentration for that period of collection time and may be used for rough estimates of BAC in that time frame. The reported average UAC:BAC ratio is 1.33, but the experimentally determined range is great, reportedly from 0.21 to 2.17 to 2.44. (21,34). UAC:BAC comparisons can help delineate the stage of metabolism the individual is in at the time of specimen collection: absorptive phase—UAC:BAC <1.0; postabsorptive phase—UAC:BAC >1.3 (21,76). Because of the intimate association between alveolar air and the pulmonary circulation, EA is presumed to migrate from the pulmonary vessels by simple diffusion and suffuse the intraalveolar gas, which becomes laden with EA molecules. Alveolar air forcefully exhaled from these sites becomes breath, suitable as such for EA quantitation. Breath EA analysis is noninvasive and affords quick results. According to many experiments based on Henry’s law, EA distributes between pulmonary blood and the alveolar air (BrAC) on average at a fixed partition ratio of 1:2100. One milliliter of blood contains the

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same weight of alcohol as 2100 mL of alveolar air. The reported ranges, indicative of significant time-dependent intraindividual and interindividual variation, extend from 1:1142 to 1:3478 (1). In this regard, researchers point out the 1:2100 ratio undervalues the actual ratio for 86% of the population (falsely low) while overstating it for 14% (falsely high) (98,99). When employed properly, breath analysis, reported as BrAC, has been supported by investigators (100) and accepted in most jurisdictions, either as an independent determinant of intoxication or as a means of arriving at the BAC via the conversion ratio. Understandably, the assumptions involved in converting very low levels of EA in alveolar air to levels in the blood are subject to critical scrutiny, especially when individual may be subject to conviction of a given criminal offense based on a measured level as low as 0.001% BAC (60). With the dynamic evolution of the interface of science and law in regard to the question of driving under the influence of alcohol, some of the issues discussed above have become moot in the wake of enactment of per se statutes by many state legislatures. No conversion from BrAC to BAC is required. Before 2000, the state of Kentucky, for example, defined “alcohol concentration” as follows: . . .”either grams of alcohol per 100 milliliters of blood or grams of alcohol per 210 liters of breath” (101), which the legislature amended recently by lowering the minimal BAC (or breath equivalent) to 0.08%. In regard to expert testimony on retrograde extrapolation, the same statute made back calculation virtually unnecessary. Under defined conditions the statutory formulation focuses on the time of collection (102), not the BAC at the time of the traffic event: “ [a] person shall not operate . . . a motor vehicle . . . [h]aving an alcohol concentration of 0.08 or more as measured by a scientifically reliable test or tests of a sample of the person’s breath or blood taken within two (2) hours of cessation of operation . . . of a motor vehicle . . . [w]hile under the influence of alcohol. . . .” The Kentucky Supreme Court has upheld this language (103). Whenever fluids or analytes other than blood are submitted for EA analysis, a number of factors that influence the distribution ratio must be considered. The most critical factor influencing the distribution ratio is the stage of alcohol distribution in the body when samples are collected. The optimal specimen is one collected after a blood EA maximum is reached and begins the elimination phase. If the specimen is collected on the absorption side of metabolism curve, then total body distribution has not been achieved so that analysis of that sample will not properly reflect the BAC (1).

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3.3. Decomposition and Embalming: Confounders in Interpreting BAC Thorough intravascular embalming procedures render blood an unsuitable medium for specific BAC. Vitreous humor may serve as a suitable substitute. In such cases, the toxicologist requires a sample of the embalming fluid to compare with the analytical results of analysis of the vitreous humor. In general, many embalming fluids either do not contain EA or have relatively low levels compared to other volatiles (21,79). Embalming fluid is usually composed of formaldehyde. Other volatiles in the commercially manufactured embalming fluid may include acetone, methanol, isopropanol, and occasionally EA. Typical formulas distinguishing the components of embalming products, including various alcohols, are readily available. Another technical difficulty with analysis of EA in exhumed/embalmed bodies arises when dehydration of tissue or postmortem synthesis of alcohol is present after prolonged burial (1). Postmortem decomposition, even at an early stage, factitiously elevates BAC and is a confounding factor for the interpretative toxicologist. Fermentative bacteria, predominantly entering the vascular compartment after death and metabolizing glucose or protein, produce endogenous EA chemically identical to that in alcoholic beverages. Because of relative isolation from the putrefactive processes, urine from the urinary bladder and intraocular vitreous humor, as relative sterile compartments, are sometimes spared of this phenomenon. Zumwalt et al. report postmortem BAC as high as 0.22% attributable to endogenous production (104). In this study, the authors conducted simultaneous analysis of vitreous humor or urine, which contained no measurable levels of EA in 23 moderate to severely decomposed bodies. Bodies that have been stored in cold environments generally will have minimal endogenous alcohol production (104). This applies as well to victims of drowning, who frequently undergo severe decompositional change even in temperate climates. Dilutional factors may occur especially in freshwater drownings. Therefore, the BAC quantified from postmortem samples may actually be lower than the true level. Specific variations are not known at this time because of the lack of research in this area (1). Of note is that the endogenous generation of EA from glucose by microorganisms, primarily fungi and bacteria, is not unique to the postmortem period. Such considerations are also relevant to the living, particularly exemplified by subjects with multiple metabolic complications of diabetes mellitus and urinary

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1) 2) 3)

EM pathway: AA CO2 + Pyruvic acid Pyruvate decarboxylase: Pyruvic acid A Acetaldehyde Alcohol dehydrogenase: Acetaldehyde A EA

tract infections. Discrepancies between BAC and UAC, where the latter demonstrates abnormally elevated amounts of EA, are attributable to urinary retention and incontinence (105–107) whereby intravesical glucose fermentation occurs via the Embden–Meyerhof glycolytic pathways (Table 3). As a result of this phenomenon, postmortem UAC in diabetics is unreliable (108).

3.4. Establishing Legal Chain of Custody: Procedures for Preserving Chemical Evidence All personnel (e.g., pathologists or other physicians, nurses, toxicologists, biochemists, laboratorians, and police) handling or possessing any kind of physical evidence have a legal duty to maintain the evidentiary chain of custody (109). Preservation of the integrity of physical evidence undergoing subsequent analysis affords admissibility of test results at trial. The results may then be entered as proof of an issue in question by establishing credibility in the minds of the court and jury (77). This axiom applies particularly to specimens of biological or chemical evidence, which as a class may be consumed in analysis and are susceptible to tampering, contamination, or spoilage. The law requires written documentation reflecting positive identification and the absence of significant alterations or tampering of chemical specimens from the time of collection through laboratory analysis. Such documentation comprises not only the laboratorian’s reports and work sheets but also written notes, forms, or computer printouts establishing an uninterrupted chain of custody. To properly collect and preserve chemical evidence, a clearly detailed hierarchical chain of command must be designated. In the hospital setting, a physician, nurse, phlebotomist, or laboratory technician working under the direction of a physician is required to collect the samples. Specifically designed sterile collections tubes must be utilized. Depending on the design, these collection tubes may contain sodium fluoride (gray top in the United States), heparin or another anticoagulant (green or lavender top in the United States), or no additives at all (red top in the United States). The anticoagulant and bacteriostatic actions of sodium fluoride are optimal for preservation and storage of whole blood (34).

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In contrast to sample collection at autopsy, there are advantages and disadvantages related to the collection of each type of fluid specimen, that is, blood and urine, in the clinical setting. A specimen of blood, the “gold standard” for determination of the BAC, is unquestionably the most desirable sample to collect. In the clinical or hospital environment, however, such a sample may be difficult or impossible to obtain from living persons because of the unavailability of an appropriate phlebotomist or lack of consent from the individual whose BAC is in question. As noted above, the standard practice in the hospital of clinical laboratory is to centrifuge or otherwise separate whole blood, and then to analyze the plasma or serum for quantification of EA. Standard phlebotomy procedures involve percutaneous puncture of the antecubital vein as the usual location of a venipuncture site. If this location is inaccessible, a vein from the hand or leg may be entered. In selected instances, withdrawal from a central venous or other intravenous catheter is appropriate. The location of the source of blood must be documented. The specimen container must as a minimum have a legible notation of the individual’s name, the date and time drawn, the individual’s identification number, and the clear identity of witnesses observing and of the person drawing the specimen. Additional medicolegal information should be documented by the hospital or the police agency involved (77). In addition to the same information indicated on the specimen tube, the individual’s age and the type of disinfectant used in location of vena puncture should be documented in the medical report. Contamination of a blood specimen using a rubbing-alcohol cotton swab (70% EA) prior to the blood collection may cause erroneous elevation of the blood alcohol levels. The results of various controlled studies testing this confounding issue are contradictory (110). It is recommended that butadiene (aqueous povidone-iodine) or other non-alcohol-containing disinfectants are used in the collection of blood. A police official’s request for the blood and a consent form for established blood withdrawal must be completed prior to sample collection. When the custody of the blood specimen leaves the hands of one official to another, proper documentation of this transfer of evidence is legally mandatory. The person collecting the specimen initiates the legal chain of custody. Upon collection, the official first labels the container(s) with data identifying the subject, case number, time and date of collection, body site of collection, character of description of sample, and then legibly affixes his or her name or initials. A similar process applies mutatis mutandis to sample collection at autopsy. Contemporaneous with those notations, the initial collector of the sample enters the same data on a specially designed standard form consisting of a master sheet and duplicates.

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If the chemical evidence is not immediately transferred to a subsequent custodian, the collector then preserves the specimen in locked storage or refrigeration with clearly established limited access in preparation for transfer of custody to the next official in the chain for final delivery to the analyst. Transportation of the body fluid specimens should be performed in an expedient manner (1). It is mandatory that this evidence with proper documentation be secure at all times. If transportation delays are anticipated, refrigeration of the specimen is recommended. The best storage temperatures are between –20°C and –4°C (34). In cases of relatively short intervals between collection and analysis, refrigeration, though desirable, is not always necessary. Studies have been performed to compare any significant changes in BAC between stored room temperature blood specimens preserved in sodium fluoride and refrigerated specimens. These comparisons were performed over several days (2–14 days), and insignificant differences were found. Even with the absence of the storage preservative sodium fluoride, insignificant differences of analyzed blood alcohol levels were recorded after 14 days (1). Every person involved in the evidentiary escort of the physical evidence records similar data on the prepared form upon taking possession, and keeps a copy—not the original accompanying the evidence—for future reference in court. This procedure may involve few or many custodians. Ultimately, the clearly identified receiving analyst at the end of the chain records all data as to condition of seals on containers, date and time of receipt, time and type of analysis and report, and also notes whether and how any retained sample is stored. This paper trail of documentation may then be referred to at trial by any official witness in the chain as a means of establishing the integrity of the specimen (111,112). The results of analytical studies of samples collected clinically are inadmissible at trial without clear proof of the legal chain of custody (113). In summary, to avert legal challenges, the forensic pathologist of necessity must adhere to all of the following stages of evidence processing: “recognition, obtainment, preservation, transport and submission, and analysis” (114).

ACKNOWLEDGMENT The authors thank Carol Bibelhauser for excellent clerical support.

REFERENCES 1. Winek CL, Esposito FM (2003) Antemortem and postmortem alcohol determinations. In Wecht CH, ed., Forensic sciences, Vol. 2. Matthew Bender, New York, pp. 31B-1–31B-75.

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2. Charness ME, Simon RP, Greenberg DA(1989) Ethanol and the nervous system. N Engl J Med 321, 442–454. 3. Anda RF, Williamson DF, Remington PL (1988) Alcohol and fatal injuries among US adults: findings from the NHANES I epidemiologic follow-up study. JAMA 260, 2529–2532. 4. O’Connor PG, Schottenfeld RS (1998) Patients with alcohol problems. N Engl J Med 338, 592–602. 5. Lieber CS (1995) Medical disorders of alcoholism. N Engl J Med 333, 1058–1065. 6. Luna GK, Maier RV, Sowder L, Copass MK, Oreskovich MR (1984) The influence of ethanol intoxication on outcome of injured motorcyclists. J Trauma 24, 695–700. 7. Howland J, Hingson R (1987) Alcohol as a risk factor for injuries or death due to fires and burns: review of the literature. Pub Health Rep 102, 475–483. 8. Alleyne BC, Stuart P, Copes R (1991) Alcohol and other drug use in occupational fatalities. J Occup Med 33, 496–499. 9. Brewer HD, Sleet D (1995) Alcohol and injuries. Time for action. Arch Fam Med 4, 499–501. 10. Raffle PA (1989) Interrelation between alcohol and accidents. J Royal Soc Med 82, 132–135. 11. Herve C, Gaillard M, Roujas F, Hugenard P (1986) Alcoholism in polytrauma. J Trauma 26, 1123–1126. 12. Lowenfels AB, Miller TT (1984) Alcohol and trauma. Ann Emerg Med 13, 1056–1060. 13. Lowenstein SR, Weissberg MP, Terry D (1990) Alcohol intoxication, injuries, and dangerous behaviors—and the revolving emergency department door. J Trauma 30,1252–1257. 14. Hingson R, Howland J (1987) Alcohol as a risk factor for injury or death resulting from accidental falls. J Stud Alcohol 48, 212–219. 15. Mittelman RE, Wetli CV (1982) The fatal café coronary. JAMA 247, 1285–1288. 16. Garriott JC (1996) Medical-legal aspects of alcohol, 3rd ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ. 17. Jones AW (1991) Limits of detection and quantitation of ethanol in specimens of whole blood from drinking drivers analyzed by headspace gas chromatography. J Forensic Sci 36, 1277–1279. 18. Machata G (1972) Determination of alcohol in blood by gas chromatography headspace analysis. Perkin Elmer Clin Chem Newsl 4, 29–32. 19. Dubowski KM (1977) Manual for analysis of fluids of ethanol in biological fluids. U.S. Dept. of Transportation Report No. DOT-TSC-NI ITSA-76-4. 20. Jones AW, Jönsson KÅ (1991) Between-subject and within-subject variations in the pharmacokinetics of ethanol. Br J Clin Pharmacol 37, 427–431. 21. Caplan YH, Goldberger BA (2003) Blood, urine, and other fluid and tissue specimens for alcohol analyses. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ, pp. 149–161. 22. Marraccini JV, Carroll T, Grant S, Halleran S, Benz JA (1990) Differences between multisite postmortem ethanol concentrations as related to agonal events. J Forensic Sci 35, 1360–1366. 23. National Institute on Alcohol Abuse and Alcoholism (1990) The physician’s guide to helping patients with alcohol problems. National Academy Press, Washington, DC.

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24. Morse RM, Flavin DK (1992) The definition of alcoholism: the joint committee of the national council on alcoholism and drug dependence and the American society of addiction medicine to study the definition and criteria of alcoholism. JAMA 268, 1012–1014. 25. Dubowski KW (1989) Stages of acute alcohol influence/intoxication. The University of Oklahoma College of Medicine, Oklahoma City. 26. Wetli CV, Jones AM (1988) The medicolegal investigation of drug deaths ethanol. In Wetli CV, Jones AM, ed., The Pathology of Drug Abuse [seminar]. Am Soc of Clin Pathol, National Meeting, Las Vegas, NV, November, pp 11–15. 27. Garriott JC (2003) Pharmacology and toxicology of ethyl alcohol. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ, pp. 23–45. 28. Widmark EMP (1932) Die theoretischen Grundlagen und die praktischen Verwendbarkeit der gerichtlichen-medizinischen Alkoholbestimmung. Fortschr Naturwiss Forschung 11, 1–140. Available in English as Baselt RC (1981) Principles and applications of medicolegal alcohol determinations, Biomedical Publications, Davis, CA. 29. Simpson G (1988) Medicolegal alcohol determination: Widmark revisited. Clin Chem 34, 888–889. 30. Vallee BL (1994) Alcohol in human history. In Jansson B, Jornvali H, Rydberg U, Terenius L, Vallee BL, eds., Toward a molecular basis of alcohol use and abuse. Birkhauser Verlag, Basel, pp. 1–8. 31. Ethanol (2003). In Houts M, Baselt RC, Cravey RH, eds., Courtroom Toxicology, Vol. 4. Matthew Bender, New York, pp. Etha-1—Etha-30. 32. Agner K (1949) The treatment of methanol poisoning with ethanol with report of two cases. Q J Stud Alcohol 9, 515–522. 33. Craft PP, Foil MB, Cunningham PRG, Patselas PC, Long-Synder BM, Collier MS (1994) Intravenous ethanol for alcohol detoxification in trauma patients. South Med J 87, 47–54. 34. Scheinin LA (1999) Forensic aspects of alcohol intoxication. In ASCP Check Sample, Forensic Pathology No. 99-9 (FP-250), Am Soc Clin Pathol, Chicago IL, pp. 127–143. 35. Sperry K, Pfalzgraf R (1990) Fatal ethanol intoxication from household products not intended for ingestion. J Forensic Sci 35, 1138–1142. 36. McAnalley BH (2003) The chemistry of alcoholic beverages. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co., Inc., Tucson, AZ, pp. 1–22. 37. Adelson L (1974) Ethyl alcohol and homicide. In Adelson L, ed., The pathology of homicide. Charles C. Thomas, Springfield, IL, pp. 843–918. 38. Bonte W, Russmeyer P (1984) Zur Frage der Normalverteilung von Begleitstoffen in alkoholischen Getränken. Beitr Gerichtl Med 42, 387–394. 39. Freimuth HC (revised by Spitz WU) (1993) Forensic aspects of alcohol. In Spitz WU, ed., Spitz and Fisher’s Medicolegal Investigation of Death. Guidelines for the application of pathology to crime investigation, 3rd ed. Charles C. Thomas, Springfield, IL, pp. 767–775.

Postmortem Alcohol Interpretation

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40. Sunshine I (1959) What’s new in toxicology 1958. J Forensic Sci 4, 473–485. 41. Knight B (1996) Forensic pathology, 2nd ed. Arnold Press, London, pp. 543–550. 42. Mellanby E (1919) Alcohol: its absorption into and disappearance from the blood under different conditions. National Health Insurance Medical Research Committee, Report No. 31. 43. Hammond KB, Rumack BH, Rodgerson DO (1973) Blood ethanol: a report of unusually high levels in a living patient JAMA 226, 63–64. 44. Hearn WL, Rose S, Wagner J (1991) Cocaethylene is more potent than cocaine in mediating lethality. Pharmacol Biochem Behav 39B, 531–533. 45. Heath MJ, Pachar JV, Martinez ALP, Toseland PA (1992) An exceptional case of lethal disulfiram-alcohol reaction. Forensic Sci Int 56, 45–50. 46. Cina SJ, Russel RA, Conradi SE (1996) Sudden death due to metronidazole/ethanol interaction. Am J For Med Path 17, 343–346. 47. Albert CM, Manson JE, Cook NR, Ajani UA, Gaziano JM, Hennekens CH (1999) Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation 100, 944–950. 48. Perper JA, Twerski A, Wienand JW (1986) Tolerance at high blood alcohol concentrations: a study of 110 cases and review of the literature. J Forensic Sci 31, 212–221. 49. Berild D, Hasselbach H (1981) Survival after a blood alcohol of 1127 mg/dL. Lancet 2, 363. 50. Püschel K, Kleiber M, Brinkmann B (1979) Blutalkoholkonzentration von 6,2% überlebt. Blutalkohol 16, 217–220. 51. Goldstein DB (1983) Pharmacology of alcohol. Oxford University Press, New York. 52. Mendelson JH (1970) Biologic concomitants of alcoholism. N Engl J Med 283, 24–32. 53. Schuckit MA (2001) Alcohol and alcoholism. In Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson LJ, eds., Harrison’s principles of internal medicine, 15th ed. McGraw-Hill, New York, pp. 2561–2566. 54. Charness ME, Gordon AS, Diamond I (1983) Ethanol modulation of opiate receptors in cultured neural cells. Science 222, 1246–1248. 55. Kane AB, Kumar V (1999) Environmental and nutritional pathology. In Cotran RS, Kumar V, Collins T Robbins, eds., Pathologic basis of disease, 6th ed. W.B. Saunders Company, Philadelphia, PA, pp. 410–412 56. Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J (1997) Alcohols and glycols. In Ellenhorn MJ, ed., Ellenhorn’s medical toxicology diagnosis and treatment of human poisoning, 2nd ed. Williams and Wilkins, Baltimore, MD, pp. 1127–1165. 57. Victor M, Adams RD (1953) The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Mental Dis 32, 526–573. 58. Victor M, Brausch C (1967) The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 8, 1–20.

336

Hunsaker and Hunsaker

59. Isbell H, Fraser HF, Wikler A, Belleville RE, Eisenman AJ (1955) An experimental study of the etiology of “rum fits” and delirium tremens. Q J Stud Alcohol 16, 1–33. 60. Hume, DN, Fitzgerald EF (1985) Chemical tests for intoxication. What do the numbers really mean? Anal Chem, 57, Suppl: 876A–886A. 61. Lieber CS (1984) Metabolism and metabolic effects or alcohol. Med Clin North Am 68, 3–31. 62. Wilkinson PK. (1980) Pharmacokinetics of ethanol: A review. Alcohol Clin Exp Res 4, 6–21. 63. Jones AW, Jönsson KÅ, Neri A (1991) Peak blood-ethanol concentration and the time of its occurrence after rapid drinking on an empty stomach. J Forensic Sci 36, 376–385. 64. Frezza M, Di Padova C, Pozzato G, Terpin M, Baraona E, Lieber CS (1990) High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med 322, 95–99. 65. Wilkinson PK, Sedman AJ, Sakmar E, Lin YJ, Wagner JG (1977) Fasting and nonfasting blood ethanol concentrations following repeated oral administration of ethanol to one adult male subject. J Pharmacokinet Biopharm 5, 41–52. 66. Rose EF (1979) Factors influencing gastric emptying. J Forensic Sci 24, 200–206. 67. Elmslie RG, Davis RA, Magee DF, White TT (1964) Absorption of alcohol after gastrectomy. Surg Gynecol Obstet 119, 1256–1258. 68. DiPadova C, Roine R, Frezza M, Gentry T, Barona E, Lieber CS (1992) Effects of ranitidine on blood alcohol levels after ethanol ingestion. JAMA 267, 83–86. 69. Roine R, Geentry T, Hernández-Munõz R, Baraona E, Lieber CS (1990) Aspirin increases blood alcohol concentrations in humans after ingestion of ethanol. JAMA 264, 2406–2408. 70. Jones AW (2003). The biochemistry and physiology of alcohol: applications to forensic science and toxicology. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ, pp. 113–148. 71. Wagner JG, Wilkinson PK, Sedman AJ (1976) Elimination of alcohol from human blood. J Pharm Sci 65, 152–154. 72. Bogusz M, Pach J, Stasko W (1977) Comparative studies on the rate of ethanol elimination in acute poisoning and in controlled conditions. J Forensic Sci 22, 446–451. 73. Jones AW (1993) Disappearance rate of ethanol from the blood of human subjects: implications in forensic toxicology. J Forensic Sci 38, 104–118. 74. Jones AW (1988) Problems and pitfalls with back-tracking BAC to the time of driving. DWI J Law Sci 3, 1–5. 75. Love v. Commonwealth, Ky., 55 SW3d 816 (2001). 76. Biasotti AA, Valentine TE (1985) Blood alcohol concentration determined from urine samples as a practical equivalent or alternative to blood and breath alcohol tests. J Forensic Sci 30, 194–207. 77. Williams RH, Leikin JB (1999) Medicolegal issues and specimen collection for ethanol testing. Lab Med 30, 530–537.

Postmortem Alcohol Interpretation

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78. Williams RH, Leikin JB (1999) Assessment of ethanol intoxication and regulatory issues. Lab Med 30, 587–594. 79. Garriott JC (2003) Analysis for alcohol in postmortem specimens. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ, pp. 163–176. 80. Shaw RF (2003) Methods for fluid analysis. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ, pp. 213–227. 81. Mendenhall CL, Weesner RE, Parker KM (1996) Alcoholism: methods of analysis: alcohol. In Kaplan LA, Pesce AJ, eds., Clinical chemistry: theory, analysis, correlation, 3rd ed. Mosby-Year Book, St. Louis, MO, pp. 692–694. 82. Dubowski K, Gadsen G (1991) Alcohol analysis performance gratifying. CAP Today April, 31–34. 83. Prouty RW, Anderson WH (1987) A comparison of postmortem heart blood and femoral blood ethyl alcohol concentrations. J Anal Toxicol 11, 191–197. 84. Plueckhan VD, Ballard B (1967) Diffusion of stomach alcohol and heart blood concentration at autopsy. J Forensic Sci 12, 463–740. 85. Hirsch CS, Zumwalt RS (1986) The empty heart sign. Am J Forensic Med Pathol 7, 112–114. 86. Felby S, Olsen J (1969) Comparative studies of postmortem ethyl alcohol in vitreous humor, blood and muscle. J Forensic Sci 14, 93–101. 87. Coe JL, Sherman R (1970) Comparative study of postmortem vitreous humor and blood alcohol. J Forensic Sci 15, 185–190. 88. Jones AW, Holmgren P (1970) Uncertainty in estimating blood ethanol concentrations by analysis of vitreous humor. J Clin Pathol 54, 699–702. 89. Winek CL, Esposito FM (1981) Comparative study of ethanol levels in blood versus bone marrow, vitreous humor, bile and urine. Forensic Sci Int 17, 27–36. 90. Kirkpatrick LJ (1976) The use of bile as a toxicological fluid for the determination of ethanol concentration in humans. Master’s thesis, Duquesne University, Pittsburgh. 91. Winek CL, Jones T (1980) Blood versus bone marrow ethanol concentrations in rabbits and humans. Forensic Sci Int 16, 101–109. 92. Felby S, Olsen J (1969) Comparative studies of postmortem ethyl alcohol in vitreous humor, blood, and muscle. J Forensic Sci 14, 97–99. 93. Cassin BJ, Spitz WU (1983) Concentration of alcohol in delayed subdural hematoma. J Forensic Sci 28, 1013–15. 94. Smialek, JF, Spitz WU, Wolfe JA (1980) Ethanol in intracerebral clot: report of two homicidal cases involving prolonged survival after injury. Am J Forensic Med Pathol 1, 49–50. 95. Winek CL, Bauer J, Wahba WW, Collom WD (1993) Blood versus synovial fluid ethanol concentrations in humans. J Anal Toxicol 17, 233–235. 96. Gelbke HP, Lesch P, Spiegelhalder B, Schmidt G (1978) Postmortale Alkoholkonzentrationen II. Die Alkoholkonzentrationen im Blut und Liquor cerebrospinalis. Blutalkohol 15, 11–17.

338

Hunsaker and Hunsaker

97. Baselt RC (2002) Ethanol. In Baselt RC, ed., Disposition of toxic drugs and chemicals in man, 6th ed. Biomedical Publications, Foster City, CA, pp. 390–394. 98. Mason MF, Dubowski KF (1974) Alcohol, traffic and chemical testing in the United States: a resume and some remaining problems. Clin Chem 20, 126–140. 99. Mason MF, Dubowski KF (1976) Breath alcohol analysis: uses, methods and some forensic problems - review and opinion. J Forensic Sci 21, 9–41. 100. Biasotti AA (1984) The role of the forensic scientist in the application of chemical tests for alcohol in law enforcement. J Forensic Sci 29, 1164–1172. 101. Kentucky Revised Statues, Chapter 189A.005(1). 102. Kentucky Revised Statutes, Chapter 189A.010(1)(a)(b). 103. Commonwealth v. Wirth, Ky., 936 SW2d 78 (1996). 104. Zumwalt RE, Bost RO, Sunshine I (1982) Evaluation of ethanol concentrations in decomposed bodies. J Forensic Sci 27, 549–554. 105. Wooten DC, Susa J, Baskin L (2002) Conflicting whole blood results and urine ethanol levels. Lab Med 3, 227–228. 106. Alexander WD, Wills, PD, Eldred N (1988) Urinary ethanol and diabetes mellitus. Diabet Med 5, 463-464. 107. Ball W, Lichtenwalner M (1979) Ethanol production in infected urine. N Engl J Med 301, 614. 108. Alexander WD (1998) Postmortem urinary alcohol is unreliable in diabetics. Br Med J 317, 206. 109. Basteyns BJ (2003) Quality assurance. In Garriott JC, ed., Medical-legal aspects of alcohol, 4th ed. Lawyers & Judges Publishing Co. Inc., Tucson, AZ, pp. 229–235. 110. Dubowski KM, Essary NA (1983) Contamination of blood specimens for alcohol analysis during collection. Abstr Rev Alcohol Driving 4, 3–8. 111. Weedn VW (2003) Forensic evidence. In Froede RC, ed., Handbook of forensic pathology, 2nd ed. College of American Pathologists, Northfield, IL, pp. 23–30. 112. McCormick CT, Strong JW, Dix GE, Brown KS, Imwinkelried EJ, Mosteler RP, et al. (1999) McCormick’s hornbook on evidence, 5th ed. West Publishing, St. Paul, MN. 113. Rabovsky v. Commonwealth, Ky., 973 SW2d 6 (1998). 114. Graham MA, Hanzlick R (1997) The forensic pathologist and evidence. In Graham A, Hanzlick R, eds., Forensic pathology in criminal cases. Lexis Law Publishing, Carlsbad, CA, pp. 23–26.

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15 Iliopsoas Muscle Hemorrhage Presenting at Autopsy Elisabeth E. Türk, MD CONTENTS INTRODUCTION CAUSES OF ILIOPSOAS MUSCLE HEMORRHAGE CLINICAL ASPECTS POSTMORTEM FINDINGS AND THEIR INTERPRETATION FORENSIC MEDICAL ASPECTS OF ILIOPSOAS MUSCLE HEMORRHAGE REFERENCES

SUMMARY Iliopsoas muscle hemorrhage presenting at autopsy can result from a variety of underlying pathological conditions. Such conditions include primary (hemophilia) or secondary (disseminated intravascular coagulation, anticoagulant drugs) coagulation disorders, hypothermia, trauma, iatrogenic damage, and other, rare causes. Iliopsoas hemorrhage can be extensive and through the massive blood loss may account for fatal outcome, but the bleeding can also be small and carry only diagnostic relevance. In many cases of hypothermia, sepsis, or coagulation disorders, additional macroscopically visible pathological findings are discrete or completely absent, making it necessary to perform further investigations such as histology and laboratory tests to establish the right diagnosis. In some autopsy cases, however, the cause of the muscle hemorrhage cannot be made out. The clinical picture of iliopsoas muscle hemorrhage can vary from no symptoms at all over slight pain in the groin to life-threatening hemorrhagic shock. In the living, imaging techniques like ultrasound and computed tomography are needed for establishing the diagnosis. From: Forensic Pathology Reviews, Vol. 1 Edited by: M. Tsokos © Humana Press Inc., Totowa, NJ 341

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Because of the great differences in clinical presentation, as well as the rare occurrence of iliopsoas muscle hemorrhage, the disorder is sometimes overlooked in the clinical setting until severe and sometimes fatal complications develop. Thus, from the medicolegal point of view, questions concerning medical malpractice may arise in cases of iliopsoas muscle hemorrhage. Key Words: Iliopsoas muscle hemorrhage; medicolegal autopsy; differential diagnosis; surgery; medical malpractice.

1. INTRODUCTION Iliopsoas muscle hemorrhage is not rarely found at medicolegal autopsies, but frequently does not receive much attention from the forensic pathologist or is considered a finding of minor relevance. In some cases, however, the bleeding can have a certain diagnostic value for establishing the cause of death. This is especially true for causes of death where other characteristic features are only irregularly present, for example, Wischnewski spots of the gastric mucosa or frostbite-like lesions of exposed skin areas in hypothermia. In such cases, the presence of iliopsoas muscle hemorrhage can be one piece of the puzzle that in the end allows to establish the right diagnosis. On the other hand, the bleeding itself can account for fatal outcome resulting from massive blood loss and hemorrhagic shock, especially when the diagnosis is delayed in the clinical setting.

2. CAUSES OF ILIOPSOAS MUSCLE HEMORRHAGE 2.1. Anticoagulant Therapy Anticoagulant therapy can be considered the most frequent cause of iliopsoas muscle hemorrhage. The iliopsoas muscle is a relatively rare site for bleeding complicating anticoagulant therapy (1–3), and thus the hemorrhage may easily be overlooked. All kinds of anticoagulant drugs potentially bear the risk of spontaneous bleeding. Most cases appear to occur owing to anticoagulation with heparin (4). In patients receiving heparin, the overall bleeding complication rate has been reported to be 0.4% for fatal bleedings, 6% for major, and 16% for minor bleedings, respectively, with the iliopsoas muscle being a rare bleeding site (1). The risk of bleeding complications has been shown to increase in a dose-dependent manner, but individual parameters also seem to play a role (5,6). Although iliopsoas muscle hemorrhage can be one manifestation of heparin-induced thrombocytopenia (HIT), in most cases described in the literature it occurred in patients without evidence of HIT and with coagulation parameters within the therapeutic range of heparin (7,8).

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In patients receiving oral anticoagulant drugs, fatal, major, and minor bleeding complications have been reported to occur with average frequencies of 1%, 5%, and 17%, respectively (1). These bleeding complications most often occur because of accidental overanticoagulation (1,9). Additional risk factors include wrong diet, change of medication involving drugs that interact with oral anticoagulants, advanced age, and renal failure (6). Still, voluminous and even fatal iliopsoas hematoma can develop if anticoagulant levels are within the therapeutic range, even in the absence of additional risk factors (10). Antiplatelets therapy, for example, ticlopidine, may also be complicated by iliopsoas muscle hematoma (11). However, data on the frequency of this complication of antiplatelets drugs are missing in the literature.

2.2. Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) can result from different pathological conditions, for example, bacterial sepsis, massive trauma, or malignancies. Because of the release of thrombogenic factors, small thrombi are deposited throughout the microvasculature in the early phase of DIC. This leads to a consumption of coagulation factors and platelets, resulting in diffuse hemorrhage in the later phase of DIC. Thus, bleeding can develop virtually everywhere in patients with DIC. How frequently iliopsoas muscle hemorrhage occurs in these patients is undetermined. Major or even lifethreatening hemorrhage appears to be relatively rare, as the literature lacks reports on such cases. A case of massive bilateral iliopsoas hemorrhage has recently been reported in septic DIC (12), the blood loss accounting for fatal outcome together with septic multiple organ failure. It should be noted that the blood loss in major iliopsoas hemorrhage will lead to an increased consumption of coagulation factors and platelets as well as to volume depletion, and may thus aggravate the vicious circle of shock and DIC.

2.3. Iatrogenic Causes The most frequent iatrogenic cause of iliopsoas muscle hemorrhage is undoubtedly overanticoagulation, which is discussed separately above. There are, however, a few diagnostic and therapeutic interventions that may, though very rarely, be complicated by iliopsoas hematoma and should be considered if the respective symptoms are present. In orthopedic physical maneuvers, namely lumbar spinal decompression procedures, iliopsoas hematoma can occur as a rare complication even in patients without any evidence of coagulation disorders (13,14). Likewise, iliopsoas hematoma can occur after aortic vascular

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surgery (15) or even special coronary stenting procedures (16). Basically, any kind of surgical intervention in the retroperitoneal cavity bears the risk of this complication. As patients undergoing surgery regularly receive anticoagulant drugs, they are at high risk of developing major iliopsoas hemorrhages.

2.4. Trauma Trauma with hyperextension in the hip joint, like in a fall, can lead to symptomatic iliopsoas muscle hemorrhage resulting from the traumatic rupture of small blood vessels. This does not necessarily have to be a fall from a height; instead, a slip on the flat is sufficient to cause major hematoma (17). The bleeding can also result from muscle rupture in massive hyperextension (18). Rare cases of iliopsoas muscle bleeding due to hyperextension in athletes have been reported (19).

2.5. Hypothermia In hypothermia deaths, iliopsoas muscle hemorrhage has been suggested to be a characteristic pathological finding by some authors (20,21), but this is discussed controversially as the finding occurs only irregularly in hypothermia deaths and, therefore, has to be considered nonspecific (22–24). The underlying pathophysiological mechanism of the development of iliopsoas hemorrhage in hypothermia is yet unknown. An increased capillary permeability owing to hypoxic damage has been discussed (20). Major bleedings do generally not occur, and accordingly, the blood loss does not contribute to fatal outcome in these cases.

2.6. Miscellaneous Causes Any kind of noniatrogenic coagulation disorder predisposing for bleedings can also result in iliopsoas hematoma. The most common of these disorders is undoubtedly hemophilia. Thirty percent of all bleeding complications in hemophilic patients have been reported to occur within skeletal muscles (25). Iliopsoas muscle hemorrhage is often voluminous in these patients, frequently causing muscle function inhibition. Recurrent iliopsoas hemorrhages seem to occur in approximately 14% of these cases (25). Liver cirrhosis is another common disease associated with impaired coagulation, but has only once been reported to result in iliopsoas hematoma (26). Rare causes of iliopsoas hematoma resulting from impaired coagulation include thrombocytopenia in Gaucher’s disease (27) and leukemia (28). Finally, bone metastases of solid malignant tumors can cause coagulopathy and thus result in iliopsoas hematoma (29).

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Table 1 Potential Causes of Iliopsoas Muscle Hemorrhage Coagulation disorders

iatrogenic: overanticoagulation noniatrogenic: DIC, hemophilia, liver cirrhosis, inherited disease with thrombocytopenia (e.g., Gaucher’s disease), leukemia, bone metastases of solid malignancies

Rare iatrogenic causes

orthopedic physical maneuvers, aortic surgery, coronary stenting procedures

Trauma

hyperextension in the hip joint

Hypothermia Miscellaneous causes

ruptured retroperitoneal aneurysms, spontaneous hematoma

Other causes of iliopsoas hematoma are very rare. Single case reports exist about iliopsoas hemorrhage secondary to rupture of abdominal aortic or iliac artery aneurysms (30,31). Iliopsoas hemorrhage has furthermore been reported to occur spontaneously, without any history of coagulopathy or trauma (32). A summary of the pathological conditions that might result in iliopsoas muscle hemorrhage is given in Table 1.

3. CLINICAL ASPECTS 3.1. Presentation Depending on the source of the bleeding and on the patient’s coagulation parameters, symptoms can develop within a dramatically short period of time (10). In minor bleedings, symptoms are not necessarily present at all (31). Patients with iliopsoas muscle hemorrhage might present with pain in the loins (4,9), which can vary from mild to violent, depending on the volume of the bleeding as well as on the patient’s individual susceptibility to pain. As extension of the hip joint makes the pain worse, patients might present a “psoas position” with the hip joint flexed (13,33). Patients receiving analgesic therapy, or patients with a reduced sensitivity to pain, for example, owing to diabetic polyneuropathy, might not complain about pain even when major bleeding is present (10). In some patients, abdominal pain or pain in the back is present rather than pain in the loins (7,11) which may lead to diagnostic problems. A lower abdominal mass might be palpable depending on the size of the hematoma.

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Because of the close topographical proximity of the iliopsoas muscle to the femoral nerve, femoral neuropathy or even complete femoral paralysis might develop in patients with major bleedings causing femoral nerve compression (4,11,13,14,33). Voluminous hemorrhage can even cause lumbosacral plexopathy (15,34). Early symptoms of nerve compression might be quadriceps muscle fasciculation (14), which might progress into complete quadriceps muscle paralysis or paralysis of the whole leg together with an incomplete or complete loss of sensibility (15,34). It can take several days for symptoms to become so severe that further diagnostic steps have to be undertaken (34). Usually, these symptoms are fully reversible after successful treatment of the iliopsoas muscle hematoma (17,34). Hematuria has been described to occur in some patients (35). Anemia is present in patients with major blood loss. Some patients just complain about being unwell without any specific symptoms, and others do not have any recognizable symptoms at all unless severe or even fatal complications develop (10).

3.2. Complications The iliopsoas muscle can accumulate up to 10 times its own volume (36), making major blood loss quite likely, sometimes resulting in life-threatening and sometimes fatal hemorrhagic shock. In patients with a high degree of comorbidity, especially in patients with severe coronary artery sclerosis, even smaller hematoma can cause fatal internal blood loss. Owing to a compression of large veins by the hematoma, deep venous thrombosis in the leg or pelvis with the risk of subsequent pulmonary embolism complicates iliopsoas muscle hemorrhage in some patients, even if they receive anticoagulant drugs (37). Withdrawal of anticoagulants, which is often necessary in order to control the bleeding, increases the risk of thrombus formation. A possible urological complication is ureteral obstruction that might result in hydronephrosis if the hemorrhage is not treated in time (35). In rare cases, fistulas between the bleeding and the large bowel can develop, with subsequent infection of the iliopsoas muscle and the risk of sepsis (38).

3.3. Differential Diagnosis A plethora of diseases, many of them much more common than iliopsoas muscle hemorrhage, can cause the same or similar symptoms as iliopsoas bleeding, in some cases leading to a misdiagnosis in the first place. When taking the patient’s medical history, questions concerning bleeding disorders and prior trauma are indispensable.

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The differential diagnosis of iliopsoas muscle hemorrhage includes all expansive pathological conditions that involve the iliopsoas muscle such as neoplasms and infectious processes. Neoplastic lesions in the iliopsoas muscle are usually metastases of malignancies; primary tumors are very rare (39,40). Infection can occur as a direct extension from contiguous structures, or as pyogenic abscesses in bacterial sepsis. Pyomyositis, a bacterial infection with abscess formation in the skeletal muscles most frequently caused by Staphylococcus aureus, is difficult to diagnose as the symptoms are often nonspecific, but the disease should also be taken into consideration as otherwise the outcome is often fatal (41). In very rare cases, primary iliopsoas abscesses can be found (42). Retroperitoneal expansive pathological processes that do not involve the iliopsoas muscle can also mimic symptoms of iliopsoas muscle hemorrhage. Such processes include all kinds of tumors, infectious lesions, or hemorrhages in the retroperitoneal cavity, for example, kidney tumors or retroperitoneal abscesses (17,43). In patients with femoral neuropathy, the symptoms might easily be misinterpreted as signs of a spinal process, for example, a lumbar disc prolapse. Many patients do in fact have a lumbar disc prolapse visible in computed tomography (CT) or magnetic resonance tomography (MRT) scans, which is then mistaken to be the source of the patient’s symptoms. However, many lumbar disc prolapses are chronic, asymptomatic processes. One clinical diagnostic criterion is that in iliopsoas muscle hemorrhage, in contrast to a chronic asymptomatic lumbar disc prolapse, severe femoral neuropathy or lumbosacral plexopathy might develop within a very short period of time, for example, hours up to a few days. Another orthopedic differential diagnosis would be acute arthritis of the hip joint, which might also cause symptoms very similar to those of iliopsoas muscle hemorrhage (17). When anemia or hemorrhagic shock are the only symptoms of iliopsoas muscle hemorrhage, other bleeding sources than the iliopsoas muscle are often suspected in the first place, for example, a ruptured abdominal aortic aneurysm (10). If the patient presents with abdominal pain, there is a great number of diseases that might be suspected before the diagnosis of iliopsoas muscle hemorrhage is established, including splenic rupture after a trauma, gastrointestinal disease such as acute appendicitis, and many others (17).

3.4. Diagnosis and Treatment Clinical signs like a flexed hip joint, a palpable lower abdominal mass, or symptoms of femoral neuropathy may arise the suspicion of iliopsoas muscle

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hemorrhage. As the lesions are often undetectable by physical examination, the definite diagnosis has to be made by imaging techniques. Possible ways of detecting the bleeding are ultrasound, CT, and MRT. Ultrasound is, however, a poor tool for differentiating between different kinds of iliopsoas muscle pathology (44). MR imaging is most accurate in most cases, and often CT and MRT have complementary roles in establishing the diagnosis (44). Valuable criteria for the differentiation between a neoplasm, a hemorrhage, and an abscess by CT are irregular margins and accompanying bone destruction for neoplasms, low attenuation for abscesses, and diffuse involvement of the whole muscle for hemorrhages (45,46). Although these rather reliable features exist for each of the three diseases, it has been shown that in many cases it is impossible to distinguish between different diseases involving the iliopsoas by radiological imaging techniques alone (45,46). In these cases, it becomes necessary to perform a muscle biopsy, which allows the most accurate diagnosis of all diagnostic options (39,40,45,46). In active bleedings, spiral CT has been proven to be an especially valuable tool as it allows a better evaluation of vascular extravasation of contrast, and the examination time is markedly shorter than in conventional CT investigations (7). Some authors suggest that if an active bleeding site is documented in spiral CT to directly perform selective catheterization of the iliopsoas supply arteries, which is of diagnostic as well as of therapeutic value (7). In many cases, conservative management of the bleeding is possible. Bed rest with flexion in the hip joint should be applied, and deregulated anticoagulant drugs should be corrected (8,17). Some cases will require a temporary complete cessation of anticoagulant therapy to stop the bleeding (17). Ultrasound-guided percutaneous decompression using a pigtail catheter has proven to be an effective treatment for iliopsoas muscle hemorrhage (8). When active bleeding is present, selective transcatheter arterial embolization has been shown to be an effective, less invasive alternative to surgical decompression (7). In some cases of active bleeding, and in cases of severe femoral neuropathy with symptom progression, as well as in major traumatic damage to the iliopsoas muscle, early surgical intervention is still considered the therapy of choice for many authors (4,17,33,47). Complications often require treatment on an intensive-care unit. Septic complications must be treated with antibiotics. Deep venous thrombosis resulting from vein compression by the iliopsoas hematoma is a therapeutical problem, as anticoagulation to treat the thrombosis would increase the risk of further bleeding. However, guidelines on how to treat these patients are still missing in the literature.

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4. POSTMORTEM FINDINGS AND THEIR INTERPRETATION Morphological differences will in most cases not concern the bleeding itself, but rather additional autopsy findings associated with the respective underlying pathological condition. Depending on the size of the hematoma, small or larger parts of the iliopsoas muscle can be completely destroyed. In voluminous hematoma, the fascia might tear and blood might be found in the retroperitoneal cavity (12). If the bleeding has developed slowly, organized or partly organized hematoma can be found, making it possible to comment on the time of the onset of bleeding and on survival time. This can be elucidated in greater detail if histopathological investigations are performed. If questions concerning the wound age are aroused, Prussian Blue staining should be performed to allow a more accurate assessment of the age of the hematoma. In cases of fatal iliopsoas muscle hemorrhage, signs of internal blood loss, namely sparse postmortem lividity, pallor of the inner organs, and subendocardial hemorrhages can be expected (10). When DIC is the underlying cause of iliopsoas muscle bleeding, hemorrhages might be found throughout the body, especially in the mucosae (12). In sepsis, there are only unspecific macroscopical signs at autopsy, and even on the microscopical level, there is no specific finding to confirm the diagnosis. Thus, if sepsis is suspected, measurement of serum procalcitonin should be performed, as this marker has been shown to be a reliable parameter for the postmortem diagnosis of sepsis (48). In iliopsoas muscle hemorrhage as a complication of anticoagulant drugs, additional bleeding sites might be found, but in many cases described in the literature, iliopsoas muscle hemorrhage was the only manifestation of anticoagulant-related bleeding (7,8,10,11). In cases where anticoagulation with coumarin plays a role, it makes sense to perform toxicological analyses to address the question if serum coumarin levels were within the therapeutic range (0.16–3.6 µg/mL) (49). Coagulation parameters like international normalized ratio and partial thromboplastin time are, unfortunately, not reliable in postmortem casework. If the iliopsoas bleeding is traumatic, features characteristic of the sustained trauma will be present at autopsy. In most of these cases, the underlying trauma will be a fall from a height, and death will be a result of head or internal organ injuries. Iliopsoas muscle hemorrhage will, in most cases, not be relevant for fatal outcome. Still, the finding might carry a certain diagnostic value for the reconstruction of the fall, as a hyperextension in the hip joint can be suspected if iliopsoas muscle bleeding is found. This is especially true if inguinal tears of the skin are also present. In these cases, a feet- or knee-first impact is likely.

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In hypothermia deaths, extensive or streaky iliopsoas muscle hemorrhage might be found (20). On the microscopical level, fragmentation of skeletal muscle fibers as well as segmental or discoid fiber degeneration have also been described (20,21). Other autopsy features characteristic of hypothermia, namely Wischnewski spots of the gastric mucosa and frostbite-like reddish discoloration of exposed skin areas, are often absent. In these cases, an early death scene investigation with determination of the rectal temperature is highly desirable to confirm the diagnosis. In cases of fatal hypothermia, iliopsoas muscle hemorrhage is as such not sufficient to confirm the diagnosis. It might only further corroborate the diagnosis if other features suggestive of fatal hypothermia are present.

5. FORENSIC MEDICAL ASPECTS OF ILIOPSOAS MUSCLE HEMORRHAGE Above all, iliopsoas muscle hemorrhage potentially gains forensic medical relevance if it leads to fatal outcome and questions of medical malpractice are aroused. In a patient treated with anticoagulant drugs, the first questions will be if there has been an iatrogenic overanticoagulation and if the monitoring of the patient’s coagulation parameters has been performed tightly enough. This cannot be clarified by autopsy alone, and thus the careful evaluation of the patients’ medical records is necessary to elucidate such cases. Another important question concerning medical malpractice in cases of iliopsoas muscle hemorrhage is whether the diagnosis has been established in time, or if there was a delay that might have caused fatal outcome. In most cases, this can also be clarified only by carefully scrutinizing the patient’s medical records to answer if the patient had any of the characteristic symptoms mentioned earlier, which diagnostic steps had been undertaken, and if there had been any pathological findings that were overlooked. Sometimes, histological investigations are advantageous in such cases as they allow to estimate the age of the bleeding and thus give insight into how long the bleeding had not been diagnosed. In other iatrogenic causes of iliopsoas muscle hemorrhage, the questions will be (a) if the cause of the bleeding had been malpractice during the respective procedure, and (b) if the patient had been informed about the possibility of this complication before the procedure. However, irrespective of the exact wording of the question concerning medical malpractice, the responsible persons will very rarely be sentenced in criminal law, even if malpractice can be proven. This is because it will in most cases not be possible for the medical expert witness to state with almost complete certainty (the criminal standard

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“beyond a reasonable doubt”) that the bleeding would not have occurred or fatal outcome could have been avoided if the responsible medical staff had acted lege artis. In conclusion, the forensic pathologist should be aware of the differential diagnoses of iliopsoas muscle hemorrhage, as the disorder might carry a high forensic medical relevance in some cases.

REFERENCES 1. Seth Landefeld C, Beyth RJ (1993) Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 95, 315–328. 2. Wagner HE, Barbier PA, Schupfer G (1986) Acute abdominal pain in the patient with oral anticoagulant treatment. Schweiz Med Wochenschr 116, 1802–1809. 3. Marquardt G, Barduzal Angles S, Leheta F, Seifert V (2002) Spontaneous hematoma of the iliac psoas muscle: a case report and review of the literature. Arch Orthop Trauma Surg 122, 109–111. 4. Guivac’h M (1997) Hematoma of the iliac psoas muscle. 29 cases. J Chir 134, 382–389. 5. Morabia A (1986) Heparin doses and major bleedings. Lancet 1, 1278–1279. 6. Gulba DC (1996) Gerinnungshemmende Substanzen. Herz 21, 12–27. 7. Qanadli SD, El Hajjam M, Mignon F, Bruckert F, Chagnon S, Lacombe P (1999) Life-threatening spontaneous psoas haematoma treated by transcatheter arterial embolization. Eur Radiol 9, 1231–1234. 8. Holscher RS, Leyten FSS, Oudenhoven LFIJ, Puylaert JBCM (1997) Percutaneous decompression of an iliopsoas hematoma. Abdom Imaging 22, 114–116. 9. Casella R, Staedele H, von Weymarn A, Stoffel F, Bongartz G, Gasser TC (1999) Life-threatening spontaneous retroperitoneal bleeding: a rare complication of oral anticoagulation. Urol Int 63, 247–248. 10. Türk EE, Verhoff MA, Tsokos M (2002) Anticoagulant-related iliopsoas muscle bleeding leading to fatal exsanguination. Report of two autopsy cases. Am J Forensic Med Pathol 23, 342–344. 11. Nakao A, Sakagami K, Mitsuoka S, Uda M, Tanaka N (2001) Retroperitoneal hematoma associated with femoral neuropathy: a complication under antiplatelets therapy. Acta Med Okayama 55, 363–366. 12. Türk EE, Tsokos M (2003) Iliopsoas muscle bleeding as a complication of septic disseminated intravascular coagulation. Virchows Arch 443, 106–107. 13. Robinson DE, Ball KE, Webb PJ (2001) Iliopsoas hematoma with femoral neuropathy presenting a diagnostic dilemma after spinal decompression. Spine 26, E135–E138. 14. Seijo-Martinez M, Castro del Rio M, Fontoira E, Fontoira M (2003) Acute femoral neuropathy secondary to an iliacus muscle hematoma. J Neurol Sci 209, 119–122. 15. Crosby ET, Reid DR, DiPrimio G, Grahovac S (1998) Lumbosacral plexopathy from iliopsoas haematoma after combined general-epidural anaesthesia for abdominal aneurysmectomy. Can J Anaesth 45, 46–51.

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Türk

16. Brown AS, Hancock JE, Thomas MR (1996) Iliacus haematoma—an unusual complication of the percutaneous trans-radial approach for coronary stent implantation. Eur Heart J 17, 964–965. 17. Fealy S, Paletta GA Jr (1999) Femoral nerve palsy secondary to traumatic iliacus muscle hematoma: course after nonoperative management. J Trauma 47, 1150–1156. 18. Takami H, Takahashi S, Ando M (1983) Traumatic rupture of iliacus muscle with femoral nerve paralysis. J Trauma 23, 253–254. 19. Maffulli N, So WS, Ahuja A, Chan KM (1996) Iliopsoas haematoma in an adolescent Taekwondo player. Knee Surg Sports Traumatol Arthrosc 3, 230–233. 20. Dirnhofer R, Sigrist Th (1979) Muskelblutungen im Körperkern—ein Zeichen vitaler Reaktion beim Tod durch Unterkühlung? Beitr Gerichtl Med 37, 159–166. 21. Schneider V, Klug E (1980) Tod durch Hypothermie. Z Rechtsmed 86, 59–69. 22. Sigrist T, Markwalder C, Dirnhofer R (1990) Veränderungen der Skelettmuskulatur beim Tod durch Unterkühlung. Z Rechtsmed 103, 463–472. 23. Madea B, Oehmichen M (1989) Ungewöhnliche Befunde in einem Fall von Hypothermie. Z Rechtsmed 102, 59–67. 24. Hirvonen J (1976) Necropsy findings in fatal hypothermia cases. Forensic Sci 8, 155–164. 25. Fernandez-Palazzi F, Hernandez SR, De Bosch NB, De Saez AR (1996) Hematomas within the iliopsoas muscles in hemophilic patients: the Latin American experience. Clin Orthop 328, 19–24. 26. Kamura M, Tanahashi T, Yamakita N, Ikeda T (1998) A case of idiopathic iliopsoas hematoma associated with liver cirrhosis. Nippon Shokakibo Gakkai Zasshi 95, 1266–1269. 27. Flipo RM, Adenis-Lavignasse C, Cortet B, Chastanet P, Goudemand J, Duquesnoy B (1992) “Spontaneous” hematoma of the psoas in Gaucher’s disease (article in French). Rev Med Interne 13, 293–295. 28. Ribera JM, Muniz E, Ribera A, Junca J, Milla F (1989) Hematoma of the psoas as the only hemorrhagic manifestation in an immune thrombocytopenia associated with chronic lymphatic leukemia. Sangre (Barc) 34, 379–380. 29. Valero Puerta JA, Jiminez Gonzalo FJ, Sanchez Gonzales M, Valpuesta Fernandez I, Alvarez Santalo R (1998) Hematoma of the psoas, a hemorrhagic complication of prostatic cancer. Arch Esp Urol 51, 491–493. 30. Cumming MJ, Hall AJ, Burbridge BE (2000) Psoas muscle hematoma secondary to a ruptured abdominal aortic aneurysm: case report. Can Assoc Radiol J 51, 279–280. 31. Paivansalo M, Kerola T, Myllyla V, Rasanen O (1985) Asymptomatisches Hämatom des linken Psoasmuskels nach Rutur eines Aneurysmas der Arteria iliaca. Röntgenpraxis 38, 263–264. 32. Marquardt G, Barduzal Angles S, Leheta F, Seifert V (2002) Spontaneous haematoma of the iliac psoas muscle: a case report and review of the literature. Arch Orthop Trauma Surg 122, 109–111. 33. Tamai K, Kuramochi T, Sakai H, Iwami N, Saotome K (2002) Complete paralysis of the quadriceps muscle caused by traumatic iliacus hematoma: a case report. J Orthop Sci 7, 713–716.

Iliopsoas Muscle Hemorrhage

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34. Klein SM, D’Ercole F, Greengrass RA, Warner DS (1997) Enoxaparin associated with psoas hematoma and lumbar plexopathy after lumbar plexus block. Anesthesiology 87, 1576–1579. 35. Colapinto V, Comisarow RH (1979) Urologic manifestations of the iliacus hematoma syndrome. J Urol 122, 272–275. 36. Ray C, Wilbur A (1993) CT diagnosis of concurrent hematomas of the psoas muscle and rectus sheath: case reports and review of anatomy, pathogenesis and imaging. Clin Imaging 17, 22–26. 37. Marti J, Anton E (1999) Deep venous thrombosis secondary to hematoma of the psoas muscle in patients receiving anticoagulants. An Med Interna 16, 434. 38. Heaton DC, Robertson RW, Rothwell AG (2000) Iliopsoas haemophilic pseudotumors with bowel fistulation. Haemophilia 6, 41–43. 39. Torres GM, Cernigliaro JG, Abbitt PL, Mergo PJ, Hellein VF, Fernandez S, et al. (1995) Iliopsoas compartment: normal anatomy and pathologic processes. Radiographics 15, 1285–1297. 40. Nash S, Rubenstein J, Chaiton A, Morava-Protzner I (1996) Adenocarcinoma of the lung metastatic to the psoas muscle. Skeletal Radiol 25, 585–587. 41. Anders S, Koops E, Mack D, Tsokos M (2000) Letale “nicht-tropische” Pyomyositis— Falldarstellungen und Literaturübersicht. Rechtsmedizin 10, 159–165. 42. Baccaro FG (1999) Primary psoas abscess due to salmonella typhi. Med Gen Med 10, E16. 43. Wilshire P, Andre M, Gros N, Samama D, Crozier F, Vidal V, et al. (2000) Primitive neuroectodermal tumor of the kidney manifested as a spontaneous hematoma. J Radiol 8, 237–240. 44. Daly BD, McPhillips M, Leung AW, Evans RM, Metreweli C (1992) Ultrasound, computed tomography and magnetic resonance in the investigation of iliopsoas compartment disease. Australas Radiol 36, 294–299. 45. Lenchik L, Dovgan DJ, Kier R (1994) CT of the iliopsoas compartment: value in differentiating tumor, abscess, and hematoma. AJR Am J Roentgenol 162, 83–86. 46. Yeh PH, Jaw WC, Wang TC, Yen TY (1995) Evaluation of iliopsoas compartment disorders by computed tomography. Zhonghua Yi Xue Za Zhi 55, 172–179. 47. Kumar S, Anantham J, Wan Z (1992) Posttraumatic hematoma of the iliacus muscle with paralysis of the femoral nerve. J Orthop Trauma 6, 110–112. 48. Tsokos M, Reichelt U, Nierhaus A, Püschel K (2001) Serum procalcitonin (PCT): a valuable biochemical parameter for the post-mortem diagnosis of sepsis. Int J Legal Med 114, 237–243. 49. Schulz M, Wischhusen F, Schmoldt A (1991) Therapeutische und toxische Plasmakonzentrationen sowie Eliminationshalbwertszeiten gebräuchlicher Arzneistoffe. Anästhesiol Intensivmed Notfallmed Schmerzther 26, 37–43.

Index

355

Index maximum height, 320 measurement of, 323–328 peak, 319 plateau, 319, 320 specimens for, 325–328 breath analysis, 327, 328 and cocaine, 314 congeners, 311 contamination of specimen, 331 conversion factor, 322 decomposition, 329, 330 distillation, 311 distribution ratio, 328 driving under the influence, 328 effects on, behavior, 314 elimination, impaired, 316 embalming, 329, 330 endogenous generation, 329, 330 ethyl alcohol, 308–330 diffusion out of the esophagus or stomach, 325 physiology of, 318–323 ethylene glycol, 310 excretion, 319 gastric first-pass metabolism, 318 intoxication, differential diagnosis of, 314 isopropanol, 310 lethal hypothermia, 264 lethal level, 315

A Accidental autoerotic death (AAD), 235– 262 Abdominal wall, rupture of, 14 Acetaldehyde dehydrogenase, 317 Acute coronary syndromes, 149, 150 Acute fatty liver of pregnancy, 286 Adam, 102 Adenylyl-cyclase subtype I, 88 ADH. See Alcohol dehydrogenase Adrenals, apoplexy of, 220 hemorrhage, 220 necroses of, 221 Adrenergic crisis, 157 AFLP, See Acute fatty liver of pregnancy Alcohol, absorption, 318, 319 bioavailability, 318 blood alcohol concentration, analysis, 324–325 arterial, 325 calculation of, 321–323 confounders in interpreting, 329, 330 curve, 319, 320 absorption phase, 320, 326 elimination phase, 320, 326, 328 determining, 311 interpretation of, 325

355

356 metabolism, 317–323, 326 methanol, 310, 329 pathological effects, 309–318 pharmacodynamic effects, 312–316 pharmacokinetics, 316–318 first-order, 320 postmortem interpretation, 307–338 storage temperatures, 332 tolerance, 315 toxicity, in pregnancy, 316 UAC:BAC ratio, 327 urine alcohol content (UAC), 323, 326, 326, 330 vitreous alcohol content (VAC), 326 Alcohol dehydrogenase, 317 ALDH. See Acetaldehyde dehydrogenase Alteration, myocardial, 150–162 Alveolar pattern, 159, 160 Alzheimer´s disease, 64 Amphetamine abuse, cerebrovascular complications of, 98 effects, reinforcing, 98 sympathomimetic, 98 derivates, 102–104 neurotoxicity, 99–102 Amputation, of extremities due to burning, 14 Anesthesiophilia, 247–250 Angiitis, necrotizing, 84, 98 Animal activity, 179, 180 Anticoagulant therapy, 342, 343 iatrogenic overanticoagulation, 343, 349, 350 oral, bleeding complications, 343 Apolipoprotein E, 65 Apoptosis, in the myocardium, 162

Index Arteritis, cerebral, 84 Artifacts, due to heat, 10–22 Asphyxia, accidental, 193 autoerotic, 240–247 caused by kneeling on the thorax, 34 chemical, 240. See also Anesthesiophilia compression of the chest, 246 homicidal, 36 neonaticide, 179 plastic-bag, 240, 246 sexual, 240–247, 255 Asphyxiation. See Asphyxia Asphyxiophilia. See Asphyxia, sexual Astrocytes, 60, 64, 84 adult, 62, fibrous, 62 GFAP-positive, 62, 64 immature, 64 protoplasmatic, 62 reactive, 61, 62, 64 Autoeroticism. See also Autoerotic death females, 252, 253 Autoerotic death, 235–262 death scene characteristics, 253–258 demarcation from suicides and homicides, 253–258 drowning during, 246 electrocutions, 250 escape/(self-) rescue mechanisms, 242, 250, 254, 255, 256 practices, 240–251 septic, 251 Avascular area, 152 Axonal injury, See Diffuse axonal injury B BAC. See Alcohol, blood alcohol concentration Benzodiazepines, 89 Benzoylecgonine, 89

Index Birth line, 183 Bleeding. See Hemorrhage Blister, of the skin, 7 Blood alcohol concentration. See Alcohol Blood–brain barrier, 57, 89, 93 in fire victims, 21, 22 Blood vessels, formation of, following traumatic brain injury, 65 Blunt force, biomechanical mechanisms, 32 skin lacerations due to, 35 Bondage, 241, 253–255 Bones, changes in burning, 18 Boxer´s attitude. See Pugilistic attitude Burned bodies, destruction of, 12 morphological findings in, 3–27 Burning, 3–27 postmortem, 9, 17, 18 signs of vitality, 9, 15, 16, 17, 21 Burns, direct, 15 of the skin, 6–8 degrees, 6, 7,13,14 Brain, abscess, 85 damage, 60 hyperthermic, 20–22 hypoxic, 278 experimental, 57 septic foci, 85 Brain injury. See Brain, damage Bronchiolitis obliterans. See Mycoplasma pneumoniae C Calcination, 14 Cannabis. See also Tetrahydrocannabinol toxicity, acute, 96, 97 chronic, 97

357 Caput succadeum, 178 Carbon monoxide, hemoglobin, 5 intoxication, 82, 162 Cardiac death, 139–168 among U.S. residents, 141 with preceding resuscitation attempts, 157, 158 Cardiac diseases, 140. See also Cardiac death Cellular response, inflammatory, 56–58 late, in the brain, 57 Central nervous system, alterations in drug abuse, 79–136 in thermal trauma. See Brain damage, hyperthermic proliferative processes in, 65 Cephalhematoma, 178 Cephalopelvic disproportion, 178 Cerebral blood flow, 80 CGS. See Crow–Glassman Scale Charring, of a body, 7, 11, 14, 19 Chasing the dragon, 86, 87 Chemical evidence, procedures for preserving, 330–332 Chest compression, 247 Chlamydia pneumoniae, 213 Club drugs, 80 CNS. See Central nervous system Coagulation necrosis, 151 Cocaine, abuse, 89–95 autopsy findings in, 91, 93 cerebral vasospasm in, 91 cerebrovascular complications of, 90 movement disorders in, 94 neuroimaging in, 90 potential of, 90 and alcohol, 314 neurotransmitters,

358 alterations of, 94, 95 rectally administered, 250 Codeine, 89 Combustion, 18 spontaneous human, 8 Contraction band necrosis, 153–162, 285, 286 Contusion. See also Lesion, cortical cortical, 56, 62, 65 Convection, 6 Coprophilia, 240 Coronary artery, aneurysms, 146 anomalies, 145–150 occlusion, 151 spasm, 145, 149 stenosis, 145–150 Coronary atherosclerosis, 141, 146 Coumarin, 349 Crack dancing, 94 Cremations, 14, 15 Cross-dressing, 252, 253 Crow–Glassman Scale, 13 Crow´s feet, 9 Crumbling point, 15 D DAI. See Diffuse axonal injury Damage, thermal. See Burned bodies, Burns, Blister Dance drug, 102 Death scene, 251 Decomposition, 329, 330 Defense injuries. See Injuries Designer drugs, 80 DIC. See Disseminated intravascular coagulation Diffuse alveolar damage, 210 Diffuse axonal injury, 56 Disseminated intravascular coagulation, 221, 229, 278–281, 286, 343, 349 Dissociative hallucinations, 173 Disulfiram, 315

Index Diuresis, cold-induced, 266 Down syndrome. See Trisomy 21 Drug abuse. See also Cannabis, Cocaine, Opiates, changes in gene expression, 81 genetic risk factors for, 81 Drug dependence. See Drug abuse E Ecstasy, 80, 98, 102, 104 Electroejaculation, 250 Electrophilia, 250, 251, 255 Embalming, 329, 330 Embden–Meyerhof glycolytic pathways, 330 Endocannabinoids, 95, 96 Endocarditis, 85 Eosinophilia, cytoplasmic, 82 Erythema, 6, 7 Erythrophages, 59 Ethyl alcohol. See Alcohol Eve, 102 Exposure, of intestinal loops due to fire, 15 External findings, in burned bodies, 6–14 F Ferruginated neurons. See Red neurons Fetishism, 239, 240, 252 Fibrosis, myocardial, 146, 158 reparative, 159 Fire. See also Burned bodies, Burns, Burning annual deaths related to, 4 complete consumption by, 13 consumption by, 7,8 deaths, 3–27 fumes, inhalation of, 15 scene of, 13,14

Index smoldering, 8 victims, morphology of, 3–27 brain in, 20–22 Flatliners, 102 Flotation test, 182, 183 Forensic wound age estimation. See Wound age Fracture, calvaria, 34 facial bones, 34 ribs, 39 skull base, 34 sternum, 39 throat skeleton, 36 Fragmentocytes, 17 G Gastrointestinal tract, in burning, 18 GFAP. See Glial fibrillary acidic protein Glial fibrillary acidic protein, 61–64 Glue sniffing, 247 H Haemophilus influenzae, 220 Hair, singeing of, 8 Hanging, 237, 240, 241 repetitive, 254 Head-down position, 246 Healing phase, 159 Healing process. See Wound, healing process Heart, dissection of, 143–145 methods, inflow–outflow method, 143 postmortem chalk injection, 143 insufficiency, 159 Heat, changes of hair, 8 effects of, 3–27 prolonged exposure to, 9, 19

359 HELLP. See Hemolysis, elevated liver enzymes, low platelet count syndrome Hematoidin, 59 Hematoma, epidural, 19, 20 iliopsoas, 343, 344, 346, 349 liver, subcapsular, 278, 279, 281 Hemolysis, 17 Hemolysis, elevated liver enzymes, low platelet count syndrome, 275–290 acute respiratory distress syndrome (ARDS), 278, 285 autopsy features, 279–281 causes of death, 277–279 clinical presentations, 277–279 contraction band necrosis, 285, 286 differential diagnosis, 286, 287 disseminated intravascular coagulation (DIC), 278–281, 285, 286, 287 hepatic encephalopathy, 281 histopathology, 281–286 hypoxic ischemic encephalopathy, 278 kidneys, 282–285 liver pathology, 279–281 liver rupture, 279, 281, 286 maternal complications associated with, 277–286 maternal mortality, 279, 286 medicolegal aspects, 287 petechiae, 279 placental abruption, 285 sepsis, 278 Hemophilia, 344 Hemorrhage, adrenal, 220 cortical, 55 diapedetic, 55 epidural, 19, 20, 35 intraabdominal, 297 intraalveolar, 179, 209

360 intracerebral, 90, 91, 92, 98, 104, 158, 178, 278 intracranial. See intracerebral intrahepatic, 286 petechial, 10 postmortem, 20 retropharyngeal, 295 retroplacental, 180 retrosternal, 298 subarachnoid, 35, 85, 90, 92, 98, 104 subdural, 35, 177, 178 subendocardial, 349 subgaleal, 177 subperiostal, 178 Hemorrhagic shock, 346 Heparin, 342 Heparin-induced thrombocytopenia, 342 Hepatic failure, 104 Heroin, impure, 84 intoxication, 82–84, 87. See also Opiates maintenance treatment, 89 Hibernation, 270, 271 Hide-and-die syndrome, See Hypothermia HIT. See Heparin-induced thrombocytopenia HIV. See Human immunodeficiency virus-1 Homicide, sadistic, 253 Homosexuality, 238 Huffing, 247 Human immunodeficiency virus-1, 93 Hypothermia, 87, 184, 263–272 core temperature, 264 hide-and-die syndrome, 268–271 iliopsoas muscle hemorrhage, 342, 344, 350 mental confusion in, 269 paradoxical undressing, 265–268 vasoconstriction, 267, 268 ventricular fibrillation, 264

Index Hypoxia, autoeroticism, 242 cerebral, 82, 83, 87 secondary to respiratory depression, 84 Hypoxyphilia, 239. See also Autoerotic Death, Asphyxia I Iliopsoas muscle hemorrhage, 341–353 causes, 342–345 disseminated intravascular coagulation, 343 hypothermia, 344 iatrogenic 343, 344 trauma, 344 complications, 345 diagnosis, 346, 347 delay in, 350 differential diagnosis, 346 femoral paralysis, 346 forensic medical aspects, 350, 351 medical malpractice, 350, 351 presentation, 345, 346 recurrent, 344 trauma, 344, 349, 350 treatment, 346, 347 Infanticide, 172, 190–192. See also Neonaticide repeated episodes of, 173 Infarction. See Myocardial infarction Inflammatory cellular response. See Cellular response Inhalation, of hot gases, 15 of hot steam, 16, 17 Injury pattern, analysis of, in kicking and trampling, 31–47 three-dimensional documentation of, 42 Injuries, from defensive action, 42–45 kicking,

Index to head, 35, 36 to inner organs, 39–42 to neck, 3–39 to thorax, 39–42 Intubation. See Resuscitation procedures Ischemic heart disease, 147 Isopropanol. See Alcohol K Karyotyping, 176 Kawasaki disease, 146 Ketamine, 249 Kicking, 31–49 Killing, by burning, 4 Kupffer´s cells, 281 L Laceration, of the skin, 35 Laminin, 65 Legal chain of custody, 330–332 Lesion, cortical, 59, 60, 62, 64 ischemic, 90 Leukoencephalopathy, 104 Ligature, indentation, 178, 179 strangulation, 36 Lipofuscin, 159 Live birth, 175 methods of determining, 181–183 Liver, cirrhosis, 344 micronodular, 316 rupture. See Hemolysis, elevated liver enzymes, low platelet count syndrome M Maceration, 182 Macrophages, cerebral, 59, 60 pigment laden, 84

361 MAP. See Microtubule associated protein Masochism, 238, 256 sexual, 239, 251 Masochistic behavior, See Masochism Mellanby Effect, 312, 313 Meningitis, 85, 227 Meningococcal infection. See Meningococcemia Meningococcemia, 220, 226–229 Meningococci. See Meningococcemia MEOS. See Microsomal ethanol-oxidizing system Methadone, 89 Methamphetamine. See Amphetamine Methanol. See Alcohol Metronidazole, 315 Microglia, See Microglial cells Microglial cells, 59, 60, 84 Microsomal ethanol-oxidizing system, 317, 318 Microtubule associated protein, 56 Mollicutes, 203 Moth-eaten pattern, 159 Mycoplasma pneumoniae, 201–218 bronchiolitis obliterans, 204, 206–209 histopathology, 204–210 infection, iatrogenic malpractice related to, 214, 215 incubation period, 204 spread of, 204 treatment of, 214 pneumonia, 204, 207 postmortem diagnosis using serology and PCR, 210–212 thrombosis in, 205, 210 Myocardial infarction, 146, 150–162 Myocardial ischemia. See Myocardial infarction Myocardial necrosis. See Myocardial infarction Myocarditis, 141, 227–229 Myofiber break-up, 160

362 N Necrophilia, 240 Necrosis, hepatocellular, 281 myocardial. See Myocardial infarction Neonaticide, 171–185 autopsy, 176–183 causes of death, 184 examination of the placenta, 180, 181 maternal characteristics of, 173 motivation of, 172, 173 role of the pathologist in, 174–176 scene examination in, 173, 174 Nephropathy, preeclamptic, 282 Nerve cell damage, 104 hypoxic, 81, 82 Nerve cell loss. See Nerve cell damage Nerve injury, response to, 59 Neuron-specific enolase, 64, 65 Neuronal cell, cloudy swelling of, 55 damage, 81 Neuronal damage, after traumatic brain injury, 55, 56 primary, 84 Neuronal degeneration. See Neuronal damage Nitric oxide, 97, 102 NO. See Nitric oxide Nuclear pyknosis, 55 O Opiates, abuse, 81–89 autopsy findings in, 81, 82 cerebral atrophy in, 81 cerebrovascular complications of, 82–84 infections associated with, 85 neuroimaging in, 81 effects on the central nervous system, 87–89

Index hypoxic-ischemic leukoencephalopathy due to, 84 intoxication, hypoxia during, 82 neurotransmitters, alterations of, 87 Opioid receptors, 87 P Paradoxical undressing. See Hypothermia Paralysis, cold-induced, 268 Paraphernalia, 252, 257 Paraphilias, 237, 238–240. See also Autoerotic death multiplex, 240 nonlethal, 252, 253 Parkinson´s disease, 64, 95, 100, 102 Parkinsonism. See Parkinson´s disease PCR. See Polymerase chain reaction Pedophilia, 240 Petechiae, 179, 279 Phospholipase A2, 95 Placenta, abruptio, 180 infarction, 180 previa, 180 velametous insertion, 181 Plaque, active, 149 atherosclerotic, 147, eccentric, 147 fibrous, 147 progression of, 147 vascularized, 149 Pleura sign, 16 PMN. See Polymorphoneuclear leukocytes Pneumonia. See also Mycoplasma pneumoniae atypical, 212, 213 community-acquired, 213 Pneumothorax. See Resuscitation procedures

Index Polymerase chain reaction, 56, 210–212 Polymorphoneuclear leukocytes, infiltration, 151 Polysubstance abuse, 80 Postmortem effects, of heat, on the skin, 7 Postmortem microbiological investigations, 221–229 Preeclampsia, 282, 283, 286 Procalcitonin, 349 Protective padding, autoeroticism, 240, 257 Psoas position, 345 Pugilistic attitude, 10–12 Puppet organs, 15 Pyomyositis, 347 Q QT syndrome, 193 R Reactive gliosis. See Traumatic brain injury Recovery phenomenon, 100 Red neurons, 55, 56 Respiratory failure, primary, 84 Respiratory tract, changes, in burning, 15–17 Resuscitation procedures, airways, 295–296 cardiopulmonary, 296–298 active compression–decompression, 297, 298 rate of complications, 299 coniotomy, 296 esophageal perforation, 295 fracture of, cricoid cartilage, 296 ribs, 296 tracheal cartilage, 296 injection, intracardial, 298

363 injuries resulting from, 293–303 intubation, 295 frequency of related injuries, 300 lung contusion, 297 mediastinal emphysema, 296, 298 medical malpractice associated with, 294 medicolegal aspects, 299–301 pneumothorax, 295–297 puncture of vein, 299 retropharyngeal hemorrhage, frequency of, 295 stomach, inflation of, 295, 297 rupture of, 295, 297 tracheotomy, 296 S Sadism, 238 Scratch marks, 178 Seizure, cocaine-associated, 94 Self-immolation. See Self-incineration Self-incineration, 7 Sepsis, 221, 278, 343, 349 Sexual deviancy, 236 Sharp force, traces of, in burning, 19 Shoe, describing the sole pattern using special classification codes, 42 imprint of the sole of, 39 Shrinkage. See Tissue Siderophages, 59 SIDS. See Sudden infant death syndrome Sinus vein thrombosis, 104 Skin, splitting of by heat, 8, 9 Smooth muscle cell hyperplasia, 147 Smothering, 184 Soft tissue. See Tissue Spalding´s sign, 182

364 Species, determination of, 12 Spectrin, 56 Spheroids, 56 Spider´s web fracture, 19 Spongiform leukoencephalopathy, 86, 87 Stab wound, 64, 65, 177, 184. See also Wound Stabbing. See Stab wound Staphylococcus aureus. See Pyomyositis Stillbirth, 175, 182–184 Strangulation, 177, 178, 184, 237, 240, 253 Stroke, associated with, cocaine abuse, 90–93 amphetamine abuse, 98 in heroin addicts, 82–84 Subendocardial hemorrhage. See Hemorrhage Sudden cardiac death. See Cardiac death Sudden death, definition of, 140, 141 following physical exertion, 146 inherited conditions causing, 193 investigation of, 143 Sudden infant death syndrome, 189–198 definition, 191 diagnostic problems, 191–193 risk factors, 190 Suffocation, 191, 194, 240, 249. See also Asphyxia Surfactant proteins, 203 Syncopal episodes, 145, 146 Sympathicomimetic overtone, 157 T Takayasu disease, 146 TBI. See Traumatic brain injury Tenascin, 62, 64, 65 Tetrahydrocannabinol, abuse, 95–97 complications, 96, 97 neuroimaging, 97

Index neurotransmitters, alterations of, 97 receptors, 95, 96 THC. See Tetrahydrocannabinol Tissue, brain, damage, 60 cervical soft, injury of, 295 destruction, 59 healing phase after, 60 fluid, loss due to burning, 4,12 shrinkage due to burning, 6, 8, 9, 15, 18, 19, 20 Trampling, 31–49 Transverse myelitis, 85 Traumatic brain injury, 53–75 in rats, 59, 60 inflammatory cellular response to, 56–58 reactive gliosis, 60–65 Trisomy 21, 176 U Umbilical cord, 178, 179, 180, 181, 184 Urine alcohol content (UAC). See Alcohol V Vaporization of body fluids, 15 Vasculitis, 84, 93, 98, 228. See also Angiitis, Arteritis Vessel, wall, remodeling of, 147 Vimentin, 21, 59, 60, 62 Virchow–Robinson spaces, 21 Vitality, in burning, 9, 15, 16, 17, 21 Vitreous alcohol content (VAC). See Alcohol Voyeurism, 239, 240

Index W Washerwoman´s skin, differential diagnosis of, 7 Waterhouse–Friderichsen syndrome, 219–231 diagnosis, 220 etiologic germs, 227 medicolegal aspects, 228, 229 meningitis, 227 mortality rate, 226 Wavy fibers, 153 WFS. See Waterhouse–Friderichsen syndrome White matter, brain, spongiform changes of, 104

365 Widmark, equations, 318–323 factor, 321, 322 Wischnewski spots, 265, 342 Wound. See also Stab wound healing process, in human brain tissue, 60–65, 65 penetrating, 9 Wound age, estimation of, 54, 59, 60, 349, 350 in cortical contusions, 53–75 morphological parameters for, 54, 65–68 Z Z-lines, 153, 154

About the Editor Dr. Michael Tsokos is a Lecturer of Forensic Pathology and Legal Medicine at the University of Hamburg, Germany, and the Police Academy of the City of Hamburg, Germany. He is the primary or senior author of more than 90 scientific publications in international journals, the editor of a monograph on external examination before cremation (in German) and the editor of one book on sudden, unexpected death (in German). In 1998 and 1999, he worked for a time with the exhumation and identification of mass grave victims in Bosnia-Herzegovina and Kosovo under the mandate of the UN International Criminal Tribunal for the former Yugoslavia. He is a member of the International Academy of Legal Medicine and the German Identification Unit of the Federal Criminal Agency of Germany. He is a member of the Editorial Board of Legal Medicine and Assistant to the Editor-in-Chief of Rechtsmedizin (the official publication of the German Society of Legal Medicine). In 2001, Dr. Tsokos was honored with the national scientific award of the German Society of Legal Medicine for research on micromorphological and molecularbiological correlates of sepsis-induced lung injury in human autopsy specimens.