Fiona Bright

Wischnewski spots and hypothermia: sensitive, specific, or serendipitous?

Hypothermia develops when regulatory mechanisms suchas vasoconstriction and heat production fail to compensatefor heat loss to the environment and the core temperature ofthe body falls below 35 C. Severe cases may be fatal withdeath resulting from myocardial ischemia and/or hypoxia,exacerbated by electrolyte abnormalities and elevated cat-echolamine levels. The mortality rate exceeds 70 % whenthe core temperature drops to 30 C, and reaches 90 % at26 C[1, 2].Causes of hypothermia include accidental exposure tolow environmental temperatures, either outdoors or inside,the latter occurring from inadequately heated houses. It hasbeen shown that hypothermic deaths may occur in areaswhere the external temperatures are not markedly lowered.Exacerbating factors include damp conditions, inadequateor wet clothing and air movement [3]. Individual suscep-tibility is increased by the ingestion of alcohol and certainprescribed or illicit drugs. In addition, low muscle mass,immobility, trauma, open injuries, and certain cardiovas-cular, neurological, endocrine and psychiatric disordersincrease the risk. An age-related susceptibility is alsofound, with children and the elderly being the most vul-nerable [1].The pathological diagnosis of hypothermia may be dif-ficult, as body temperatures at the time of death are usuallynot available at autopsy and so the circumstances of deathare of considerable importance in formulating the diagno-sis. In addition, morphological features are subtle and notwell understood. Characteristic findings that have beendescribed at autopsy include pinkish discoloration of theskin over the extensor surfaces of large joints, such as theelbows, knees and hips, acute pancreatic inflammation withfat necrosis, fatty change in cells of the heart, liver andkidneys, skeletal muscle hemorrhage, vacuolization ofrenal tubular cells, and superficial gastric lesions that havebeen called Wischnewski spots [1, 2, 4–7]. It is the latterfinding that we would like to examine in greater detail.In 1895 a Russian district medical officer, SM Wisch-newski, reported multiple superficial hemorrhagic lesionsof the gastric mucosa in 91 % of the cases of fatal hypo-thermia that he had examined. A contemporary translationof his original paper states: ‘‘On the mucous membrane ofthe stomach in humans who have died exclusively from theeffects of low temperatures, 5–100 hemorrhages areinvariably present. Their size ranges from 0.5 to 1.0 cm.They have a round to oval form. Sometimes they arepunctiform and lie about 1–2 inches apart. These hemor-rhages are raised slightly above the surface of the mucousmembrane, can be very easily scrapped (sic) away andleave behind nothing conspicuous on the gastric mucosa.’’[8] (Fig. 1). They have also been documented in ectopi-cally situated gastric mucosa [9].Although Wischnewski described raised hemorrhagicareas that could be easily removed from the mucosa, theywere subsequently considered to be ulcers or erosions[3, 10, 11]. In an immunohistochemical study by Tsokoset al. however it was proposed that the lesions resultedfrom the action of gastric acid on hemoglobin in areas ofinterstitial mucosal hemorrhage, and not from ulceration[7]. A photomicrograph in a chapter by Madea et al. [2](Fig. 1.4B) clearly demonstrates protrusion of one of thespots above the surface of the surrounding mucosa, and notulceration. Conversely, Hirvonen and Elfving reportedthat the erosions extended ‘‘halfway through the mucosa’’and that hemorrhage was ‘‘not always present’’ [12].

Why are Wischnewski spots not always present in lethal hypothermia? The results of testing a stress-reduced animal model

Hypothermic fatalities in humans are characterized by a range of often subtle pathological findings that typically include superficial erosive gastritis (Wischnewski spots). Experimental studies have been successfully performed using animal models to replicate this finding, however study animals have inevitably been subjected to a variety of additional stressors including food deprivation, restraint and partial immersion in water while conscious. As it is recognised that stress on its own may cause superficial erosive gastritis, a model has been developed to enable the study of the effects of hypothermia in isolation. 42 Sprague-Dawley rats were allowed free social contact and were fed and watered ad libitum prior to being anaesthetized with isoflurane. Once unconscious, rats were placed on drape cloth covering metal mesh platforms in a styrofoam box packed with ice. The apparatus enabled both maintenance of a specific low temperature (26 °C) in 14 animals, and continued reduction of core temperatures in the remaining 28 (who all died of hypothermia under anaesthesia). Examination of the gastric mucosa in both groups macroscopically and microscopically failed to demonstrate typical Wischnewski spots in any of the 42 animals. Thus, in this model, death from hypothermia occurred without the development of these lesions. These results suggest that stress may be a significant effect modifier in the development of Wischnewski spots in lethal hypothermia.

Lethal hypothermia – a sometimes elusive diagnosis

Significant hypothermia occurs when the body core temperature falls from its usual 37 °C to below 35 °C. The findings at autopsy can be quite subtle and there is a lack of accord on the necessary features required to make the diagnosis [1–4]. It is even less clear to what degree hypothermia may contribute to lethal outcomes in the presence of significant underlying organic illnesses. For example, the relationship between hypothermia and the metabolic derangements that occur in elderly individuals with frailty syndrome has only recently been explored [5]. The following discussion looks at the complexities of this diagnosis and points out the gaps in our knowledge which could result in under diagnosis. Diagnostic issues with hypothermia were summarized quite succinctly and presciently by Casper in the nineteenth century. Over a century and a half ago he commented that “even in regard to the appearances found on dissection, there is not one which can with any certainty justify the assumption of death from cold” [6]. Hypothermia still carries a significant risk of death with >70% mortality with core temperature of 30 °C, increasing to 90% at 26 °C [7]. Environmental factors clearly play a significant role in deaths attributed to hypothermia with a common scenario being individuals who have been lost in areas with sub-zero temperatures. The finding of a non-traumatized body with no significant underlying disease and a high alcohol level in a snow bank is strong supportive evidence for death from hypothermia. Cases become more complex, however, where there has been an elderly individual found at their home address having collapsed from a cardiovascular, orthopedic, neurological or endocrine event [8]. Exacerbating factors include cold flooring, damp conditions, wet or inadequate clothing, low muscle mass, immobility, certain drugs, and some psychiatric conditions [7, 9]. Poor home insulation and heating are recently recognized factors that have produced the counter-intuitive finding of higher death rates from hypothermia in South Australia with its Mediterranean climate than in Sweden [10, 11]. This has also been reported in other temperate areas [12]. Individuals die of hypothermia because of failure of hypothalamic counter-regulatory mechanisms that initiate and maintain chemical thermogenesis and vasoconstriction [13, 14]. Death likely results from a combination of events such as ventricular fibrillation or asystole, initiated or exacerbated by hypoxia, myocardial ischemia, increased circulating catecholamines and electrolyte derangements [1, 9, 15]. The major problems for forensic pathologists are firstly how to accurately identify cases, and then how to make a credible diagnosis. As with cases of hyperthermia, the core temperature of a decedent at the time of death is not usually available, and so evaluation of potential cases at autopsy requires a clear understanding of the circumstances of the death (ideally with a recording of the ambient temperature) and the exclusion of other possibilities [3, 8, 16]. Issues occur with differences in diagnostic practices arising from the nonspecific and subtle nature of findings at autopsy, and the possibility of inflicted injury due to the sometimes bizarre nature of behavior that may occur before death [17–19]. Biochemical markers are not currently routinely assessed in these cases [2, 20]. The peri-mortem behavior of individuals who have succumbed to hypothermia that may create concerns of a suspicious death include so-called paradoxical undressing where, most typically, an individual has sequentially removed clothes * Roger W. Byard roger.byard@sa.gov.au

A Comparison of Hypothermic Deaths in South Australia and Sweden

Case files from Forensic Science South Australia and the Swedish National Forensic Database were reviewed over a 6‐year period from 2006 to 2011 for cases where hypothermia either caused, or significantly contributed to, death. Data were analyzed for age, sex, time of year/season, place of discovery, circumstances of death, and underlying medical conditions. Despite the considerable demographic, geographic, and climatological differences, hypothermic deaths occurred at very similar rates in South Australia (3.9/100,000) and Sweden (3.3/100,000). Deaths from hypothermia in South Australia occurred predominantly indoors at home addresses, involving elderly females with multiple underlying illnesses and limited outside contacts. In contrast, Swedish hypothermic deaths generally occurred outdoors and involved middle‐aged elderly males. These data show that hypothermia may be a risk in warmer climates particularly for elderly, socially isolated individuals.

Reduced body mass index and lethal hypothermia

Sixty-two individuals dying of hypothermia had their body mass indexes (BMIs) compared with a group of age- and sex-matched controls who had died of accidental trauma (age 30–89 yrs, average 67 yrs, M:F = 13:18). The hypothermic cases had BMIs ranging from 11.6–38.8, median 20.24, mean 21.59, which was significantly lower than the controls’ (p < 0.001): range 18.5–42.2, median 26.78, mean 27.21. This study has demonstrated that a group of individuals dying of hypothermia had significantly lower BMIs than the control cases. Although the precise reasons for this difference cannot be determined from the current data, features associated with low BMI that have been identified in other studies, such as older age, female sex, reduced muscle bulk, inter-current organic disease and social isolation, are likely to play a role. Of note, as these features are also markers for the frailty syndrome, low BMIs may also suggest a possible connection between these two conditions. Further inquiries into the circumstances of death (e.g. scene temperature, adequacy of heating and insulation etc.) in decedents presenting to autopsy with characteristics of frailty syndrome may help to clarify this possible link.

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases.

Medullary Serotonin Neuron Abnormalities in an Australian Cohort of Sudden Infant Death Syndrome

Serotonin (5-hydroxytryptamine [5-HT]) neurons in the medulla oblongata project extensively to key autonomic and respiratory nuclei in the brainstem and spinal cord regulating critical homeostatic functions. Multiple abnormalities in markers of 5-HT function in the medulla in sudden infant death syndrome (SIDS) have been reported, informing the hypothesis that at least a subset of SIDS cases is caused by deficits in 5-HT function resulting in impaired homeostatic responses to potentially life-threatening events during sleep. To investigate medullary 5-HT defects in SIDS further, we undertook qualitative analysis immunohistochemical assessment of 5-HT neuron expression within the medulla of SIDS infants (n41) and nonSIDS controls (n = 28) in an independent cohort from Forensic Science South Australia. Compared with controls SIDS cases had significantly higher 5-HT neuron numbers and density in addition to significantly altered 5-HT neuron morphology. Thus, for the first time, we replicated and corroborated previous observations of a significant abnormality in medullary 5-HT neuron expression in SIDS in a separate independent SIDS cohort. This study further supports the hypothesis that medullary 5-HT defects contribute to the pathogenesis of a subset of SIDS victims and provides additional evidence of a more complex abnormality in 5-HT neuron dysfunction specifically within the different caudal and rostral medullary 5-HT domains.

Why is a prone sleeping position dangerous for certain infants

The prone (face down) sleeping position is known to be associated with a significantly increased risk of sudden and unexpected death in infancy (sudden infant death syndrome or SIDS), however, the reasons for this are unclear. Suggested mechanisms have involved suffocation from occlusion of the external airways by soft bedding/pillows or from flattening of the nose with backward displacement of the tongue, rebreathing of carbon dioxide, blunting of arousal responses with decreased cardiac responses to auditory stimulation, diaphragmatic splinting or fatigue, lowering of vasomotor tone with tachycardia, nasopharyngeal bacterial overgrowth, overheating, alteration of sleep patterns, compromise of cerebral blood flow and upper airway obstruction from distortion of nasal cartilages. Recent studies have, however, shown a significant reduction in substance P in the inferior portion of the olivo-cerebellar complex in SIDS infants which is crucial for the integration of motor and sensory information for the control of head and neck movement. This deficit may explain why some infants are not able to move their faces away from potentially dangerous sleeping environments.

Extremes of Temperature: Hypothermia

The most common cause of lethal hypothermia is accidental exposure to low environmental temperatures, contributed to by inadequate or wet clothing, and damp or windy conditions. Other exacerbating factors include low muscle mass, alcohol and drug ingestion, trauma, open injuries, immobility, and certain underlying illnesses. Those at the extremes of age are at highest risk. Typical findings at autopsy include superficial gastric lesions, so-called Wischnewski spots, pink discoloration of the skin over the large joints, acute pancreatic inflammation with fat necrosis, fatty change in cells of the heart, liver and kidneys, skeletal muscle hemorrhage, and vacuolization of renal tubular cells.

The potential role of substance P in brainstem homeostatic control in the pathogenesis of sudden infant death syndrome (SIDS)

Victims of sudden infant death syndrome (SIDS) are believed to have an underlying dysfunction in medullary homeostatic control that impairs critical responses to life threatening challenges such as hypoxia, hypercarbia and asphyxia, often during a sleep period. This failure is thought to result from abnormalities in a network of neural pathways in the medulla oblongata that control respiration, chemosensitivity, autonomic function and arousal. Studies have mainly focused on the role of serotonin, 5-hydroxytyptamine (5HT), although the neuropeptide substance P (SP) has also been shown to play an integral role in the modulation of medullary homeostatic function, often in conjunction with 5-HT. Actions of SP include regulation of respiratory rhythm generation, integration of cardiovascular control, modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may, therefore, also play a significant role in homeostatic dysfunction of the neurotransmitter network in SIDS. This review focuses on the pathways within the medulla involving SP and its tachykinin NK1 receptor, their potential relationship with the medullary 5-HT system, and possible involvement in the pathogenesis of SIDS.