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
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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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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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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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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).
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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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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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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................................................................................................. ..............................................................................................................................
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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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Accidental Autoerotic Death
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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
