Diagnostic challenges and forensic implications in a case of infantile fatal myocarditis.

We present the case of a 23-month-old child who died less than 24 h after the onset of cardiac symptoms, despite being admitted to the hospital 72 h earlier. Autopsy revealed no significant macroscopic changes, and histologic examination revealed focal lymphocytic myocarditis with myocyte disruption, diffuse alveolar damage in the exudative phase, and generalized lymphocytic immune activation in other organs. Ante-mortem and post-mortem microbiological exams did not clearly prove a causative role of infectious agents. The peculiarity of this case was characterized by the contrast between the severe clinical features and the mild cardiac histological findings. This discrepancy, coupled with the suspicion of a viral causative role based on both ante-mortem and post-mortem microbiological examinations, presented significant challenges in reaching an etiological diagnosis. This case also confirms that the diagnosis of myocarditis in children cannot be made solely on the basis of histological cut-offs or microbiological results. Using abductive reasoning, various diagnostic hypotheses were formulated and evaluated to arrive at the final diagnosis of fatal myocarditis of viral or post-viral origin. Data from post-mortem examination are often the only source of information that is available to the experts, especially in cases of sudden infant death syndrome. In such cases, the forensic pathologists should accurately evaluate findings that may appear to indicate a different etiology, and, in the absence of clinical or radiological data, interpret post-mortem data in a logically correct manner. The autopsy is the first essential step to evaluate the cause of death and must be integrated with the results of ante- and post-mortem diagnostic tests in a holistic approach, which is crucial to allow forensic pathologists to provide an appropriate and relevant opinion.

Changes in orexinergic immunoreactivity of the piglet hypothalamus and pons after exposure to chronic postnatal nicotine and intermittent hypercapnic hypoxia.

We recently showed that orexin expression in sudden infant death syndrome (SIDS) infants was reduced by 21% in the hypothalamus and by 40-50% in the pons as compared with controls. Orexin maintains wakefulness/sleeping states, arousal, and rapid eye movement sleep, abnormalities of which have been reported in SIDS. This study examined the effects of two prominent risk factors for SIDS, intermittent hypercapnic hypoxia (IHH) (prone-sleeping) and chronic nicotine exposure (cigarette-smoking), on orexin A (OxA) and orexin B (OxB) expression in piglets. Piglets were randomly assigned to five groups: saline control (n = 7), air control (n = 7), nicotine [2 mg/kg per day (14 days)] (n = 7), IHH (6 min of 7% O2 /8% CO2 alternating with 6-min periods of breathing air, for four cycles) (n = 7), and the combination of nicotine and IHH (N + IHH) (n = 7). OxA/OxB expression was quantified in the central tuberal hypothalamus [dorsal medial hypothalamus (DMH), perifornical area (PeF), and lateral hypothalamus], and the dorsal raphe, locus coeruleus of the pons. Nicotine and N + IHH exposures significantly increased: (i) orexin expression in the hypothalamus and pons; and (ii) the total number of neurons in the DMH and PeF. IHH decreased orexin expression in the hypothalamus and pons without changing neuronal numbers. Linear relationships existed between the percentage of orexin-positive neurons and the area of pontine orexin immunoreactivity of control and exposure piglets. These results demonstrate that postnatal nicotine exposure increases the proportion of orexin-positive neurons in the hypothalamus and fibre expression in the pons, and that IHH exposure does not prevent the nicotine-induced increase. Thus, although both nicotine and IHH are risk factors for SIDS, it appears they have opposing effects on OxA and OxB expression, with the IHH exposure closely mimicking what we recently found in SIDS.

Cholinergic and oxidative stress mechanisms in sudden infant death syndrome.

AIM: To determine whether biochemical parameters of cholinergic and oxidative stress function including red cell acetylcholinesterase (AChE), serum/plasma thyroglobulin, selenium, iron, ferritin, vitamins C, E, and A affect risk in apparent life-threatening event (ALTE), sudden infant death syndrome (SIDS), and sudden unexpected death in infancy (SUDI). To assess these biochemical parameters as a function of age; and for influence of pharmacology and epidemiology, including infant health, care, and feeding practices. METHODS: A multicentre, case-control study with blood samples from 34 ALTE and 67 non-ALTE (control) infants matched for age, and 30 SIDS/SUDI and four non-SIDS/non-SUDI (post-mortem control) infants. RESULTS: Levels/activity of the biochemical parameters were not significantly different in ALTE vs. control infants, with the exception of higher vitamin C levels in the ALTE group (p = 0.009). In ALTE and control groups, AChE and thyroglobulin levels increased and decreased respectively from birth to attain normal adult levels from 6 months. Levels of iron and ferritin were higher in the first 6 month period for all infant groups studied, intersecting with vitamin C levels peaking around 4 months of age. CONCLUSION: Lower AChE levels and higher combined levels of iron and vitamin C in the first 6 months of life may augment cholinergic and oxidative stress effect, particularly at the age when SIDS is most prevalent. This may contribute to risk of ALTE and SIDS/SUDI events during infancy.

Sudden infant death syndrome: selenium administered above dietary needs stabilizes the electrocardiograms of subjects deprived of exercise stimuli to the brain.

The human foetus begins preparation for extrauterine life in the 26th week of gestation. Victims of sudden infant death syndrome (SIDS) were described as having less-intensive reactions to environmental stimuli than their siblings. They were described as less-active physically and more breathless and exhausted during feeding. These foetal-like qualities are similar to the microgravity deconditioning of the space traveller and the autonomic dysfunction of hypokinetic humans. During quiet sleep, a group of near-miss SIDS victims displayed a faster heart-rate and a decreased movement-time, compared to controls. Another group of SIDS victims linked delayed repolarisation and sympathetic overactivity of the nervous system. The excessive Q-T wave intervals, cardiac instability and autonomic dysfunction tended to coincide with the peak incidence of SIDS which is the normal period of autonomic transformation at 2-3 months of age. Sympathetic hyperactivity transforms the subject into an energy-intensive species with an accelerated heartbeat, intensive vasoconstriction and general reactions to a hostile environment. Energy-intensive species (flight-oriented species) were sensitive to selenium (Se) deficiency. Altered mitochondrial structure and defective electron transport of heart mitochondria were features of this syndrome. Runaway excessive sympathetic autonomic activity transforms the subject into an energy-intensive species responsive to selenium. Groups of Se-deficient lambs confined for eight weeks developed abnormal electrocardiograms (ECGs). Groups exercised daily on a treadmill or Se-supplemented groups retained virtually normal ECGs. Foetuses and subjects unreactive to the environment are space travellers lacking parasympathetic stimuli to the brain. Decreased movement-time deprives the brain receptors of the stimulus induced by gravity.

Tragedy, utopia and medical progress.

In this article, tragedy and utopia are juxtaposed, and it is proposed that the problem of "medicalisation" is better understood in a framework of tragedy than in a utopian one. In utopia, it is presupposed that there is an error behind every setback and every side effect, whereas tragedy brings to light how side effects can be the result of irreconcilable conflicts. Medicalisation is to some extent the result of such a tragic conflict. We are given power by medical progress, but are also confronted with our fallibility, thus provoking insecurity. This situation is illustrated by the sudden infant death syndrome (SIDS). Recent epidemiological investigations have shown that infants sleeping in a prone position have a 15-20 times higher risk of dying from SIDS than infants sleeping in a supine position. A simple means of preventing infant death is suggested by this discovery, but insecurity is also created. What else has been overlooked? Perhaps a draught, or wet diapers, or clothes of wool are just as dangerous as sleeping prone? Further investigations and precautions will be needed, but medicalisation prevails.

Effects of maternal cigarette smoking and cocaine use in pregnancy on fetal response to vibroacoustic stimulation and habituation.

BACKGROUND: Cigarette smoking and cocaine use in pregnancy are common in the US and both are risk factors for sudden infant death syndrome (SIDS). Although the cause of SIDS is not known, one postulated mechanism involves abnormalities of arousal and arousal regulation. Cigarette smoking and cocaine use may cause deficits of arousal. Many believe arousal deficits occur prenatally. AIMS: The aim of this study was to assess the effects of cigarette smoke and cocaine exposure during pregnancy on measures of fetal arousal and arousal competency: 1) the fetal response to vibroacoustic stimulation (VAS) and 2) habituation to VAS. HYPOTHESIS: Maternal cigarette smoking and cocaine use in pregnancy are associated with altered arousal and arousal regulation in the fetus. METHODS: Three groups of mother-fetal dyads were enrolled: 1) cigarette smokers (n = 54), 2) cocaine users (n = 30), and 3) controls (n = 60). One hundred eight fetuses were tested at 29-31 wk gestation, 119 at 32-35 wk, and 118 at 36+ wk. The fetal response to VAS was assessed using real-time ultrasound and a paradigm of arousal responsiveness. Responders were tested with repeated VAS to assess habituation. Also, the quality of fetal reactivity to repeated stimuli was assessed as a measure of arousal and arousal regulation competence (Behavioral Reactivity Scale). RESULTS: The control group had a larger proportion of fetuses who were too active to initiate testing ("too active to test") (p = 0.013); the proportion of fetuses too active to test decreased with increasing gestational age. The majority of the fetuses who could be tested responded to the initial VAS, and there were no group differences. The proportion of fetuses that habituated and the rate of habituation did not differ between the groups. Behavioral reactivity did not differ between groups. CONCLUSIONS: The original hypotheses were not confirmed. However, the chosen assessment paradigms may have lacked sensitivity. The proportion of fetuses that were "too active to test" decreased with gestational age. The control group had a larger proportion of fetuses that were "too active to test" compared with the exposure groups. We speculate that these findings indicate that prenatal exposure to these neuroteratogens may have produced an acceleration of the behavioral response to vibroacoustic stimulation.

The Brugada syndrome. Its relevance to paediatric practice.

The diagnostic and therapeutic aspects of Brugada syndrome, one of the important genetic arrhythmias which causes sudden cardiac death in young people, and the relevance of this diagnostic entity to the paediatric population are briefly summarised. The role of diagnostic testing (genetic, pharmacologic and invasive electrophysiologic) for establishing the diagnosis and for risk stratification are discussed. Finally, while the implantable defibrillator is the only therapy of proven effectiveness in preventing sudden cardiac death, alternative therapies which are being considered (pharmacologic, hormonal and catheter ablation) are overviewed. The aim of this manuscript is to raise the awareness among doctors caring for young patients to the possibility of Brugada syndrome in patients presenting with potentially life-threatening symptoms of syncope or near-miss sudden death, and in index patients with a similar family history.

New data on the importance of gestational Mg deficiency.

Chronic primary Mg deficiency is frequent. About 20% of the population consumes less than two-thirds of the RDA for Mg. Women, particularly, have low intakes. For example, in France, 23% of women and 18% of men have inadequate intakes. Mg deficiency during pregnancy can induce maternal, fetal, and pediatric consequences that might last throughout life. Studies of gestational Mg deficiency in animals show that Mg deficiency may have marked effects on parturition and postuterine involution. It has interfered with fetal growth and development, and caused morbidity from hematological effects and disturbances in temperature regulation, to teratogenic effects. Emphasis, here, is on effects of chronic clinical gestational Mg deficiency as it affects the infant. Premature labor, contributed to by uterine hyperexcitability caused by chronic maternal Mg deficiency, that can be intensified by stress, gives rise to preterm birth. If the only cause of uterine overactivity is Mg deficiency, its supplementation constitutes nontoxic tocolytic treatment, as an adjuvant treatment, that is devoid of toxicity and enhances efficacy and safety of tocolytic drugs such as beta-2 mimetics. Evidence is considered that Mg deficiency or Mg depletion can contribute to the Sudden Infant Death Syndrome (SIDS). SIDS may be a fetal consequence of maternal Mg deficiency through impaired control of Brown Adipose Tissue (BAT) thermoregulation mechanisms leading to a modified temperature set point. SIDS can result from dysthermias: hypo- or hyperthermic forms. Possibly, simple nutritional Mg supplements might be preventive. Various stresses in an infant can transform simple Mg deficiency into Mg depletion. For example, lying prone can be stressful for the baby, as can parental smoking. The role of chronopathological stress appears to be often neglected, as it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (6 SMT)]. SIDS might be linked to impaired maturation of both the photoneuroendocrine system and BAT. Prophylaxis of this form of SIDS should include atoxic nutritional Mg therapy for pregnant women with total light deprivation at night for the infant. Consequences of maternal primary Mg deficiency have been inadequately studied. To determine ultimate outcomes of gestational Mg deficiency in infants, a long-term multicenter placebo-controlled prospective study should undertaken on effects of maternal nutritional Mg supplementation on lethality/morbidity in fetus, neonates, infants, children and adults, not only during pregnancy and the baby's first year, but throughout life.

Vitamin A and sudden infant death syndrome in Scandinavia 1992-1995.

AIM: To assess the effect of vitamin supplementation on the risk of sudden infant death syndrome (SIDS). METHODS: The analyses are based on data from the Nordic Epidemiological SIDS Study, a case-control study in which parents of SIDS victims in the Scandinavian countries were invited to participate together with parents of four matched controls between 1 September 1992 and 31 August 1995. The odds ratios presented are computed by conditional logistic regression analysis. RESULTS: The crude odds ratio in Scandinavia for not giving vitamin substitution was 2.8 (95% CI (1.9, 4.3)). This effect was statistically significant in Norway and Sweden, which use A and D vitamin supplementation, but not in Denmark, where only vitamin D supplementation is given. The odds ratios remained significant in Sweden when an adjustment was made for confounding factors (OR 28.4, 95% CI (4.7, 171.3)). CONCLUSION: We found an association between increased risk of sudden infant death syndrome and infants not being given vitamin supplementation during their first year of life. This was highly significant in Sweden, and the effect is possibly connected with vitamin A deficiency. This effect persisted when an adjustment was made for potential confounders, includingsocioeconomic factors.

Heart rate changes in response to mild mechanical irritation of the high cervical spinal cord region in infants.

Alterations in the heart rate were monitored before, during and after the application of a unilateral mechanical impulse to the high cervical spinal cord region which was administered strictly in connection with the so called manual therapy (diagnosis= KISS). The investigation is based on a survey of 695 infants between the ages of 1 and 12 months. A notable change in the heart rate was evident in 47.2% of all examined infants (n= 695). In 40.1% of these infants, the change in heart rate was characterized by heart rate decrease of 15-83% compared to control conditions. Infants in their first 3 months of life responded more often with a severe bradycardia (50-83% decrease), older infants (7-12 months) more often with a mild bradycardia (15-49.9% decrease). This comparison revealed a significantly increased occurrence of severe bradycardia in the younger age group compared to the group of children >3 months (significance 0.0017). In 12.1% (n= 84) of the infants, the bradycardia was accompanied by an apnea. We discuss the hypothesis that mechanical irritation of the high-cervical region serves as a trigger that may be involved in sudden infant death (SID).

Magnesium deficit and sudden infant death syndrome (SIDS): SIDS due to magnesium deficiency and SIDS due to various forms of magnesium depletion: possible importance of the chronopathological form.

Sudden Infant Death Syndrome (SIDS) might be due to the fetal consequences of a Mg maternal deficiency, which might be prevented by simple atoxic nutritional Mg intake by the mother. Various stresses in the pregnant women or in the infant may transform a simple Mg deficiency into Mg depletion which may not be cured by nutritional Mg supplement, but requires a correction of its causal dysregulation. Beside the well established risk factors in baby care and in the environment, it is important to stress the possible role of a primary hypofunction of the biological clock. This may be treated by darkness therapy: total light deprivation at night for the infant and atoxic nutritional Mg supplement for the pregnant women. The place in the prevention of SIDS of Mg therapy for the infant and of the use of melatonin, L-tryptophan and taurine is now uncertain yet.

Sudden infant death syndrome and enteric infection.

The association of Helicobacter pylori in the stomach, trachea and lungs with the incidence of SIDS, gastric ulcers and cancer may have a counterpart in animals. In field studies of white muscle disease (WMD) and hepatic necrosis in selenium-deficient pigs dying suddenly, veterinarians identified gastric ulcers in 40% of inspected piglets. The lesion was also commonly observed by researchers in experimentally produced vitamin E-selenium deficiency and other researchers suspected that gastric ulcers in swine may be associated with vitamin E-selenium deficiency. Mice preferentially concentrated (75)selenium in peritoneal exudative cells (PEC) when (75)selenium as selenium selenate was administered by stomach tube to selenium-deficient mice. Selenium concentrated in PECs as glutathione peroxidase (GSHP(x)). GSHP(x)-deficient leucocytes in peritoneal exudate failed to kill yeast cells. GSHP(x) deficiency has also been associated with decreased microbicidal activity of leucocytes in patients with chronic granulomatosis. The selenium-deficient swine were usually growing rapidly in crowded conditions, and, apart from WMD and hepatic necrosis, edema was prominent in the spiral colon, subcutaneous tissues, lungs and submucosa of the stomach. The elevated immunological response in the spleen and lungs of SIDS victims suggests an initial defective microbicidal propensity of the peritoneal exudative cells.

A triple-risk model for the sudden infant death syndrome (SIDS) and the apparent life-threatening episode (ALTE): the stressed magnesium deficient weanling rat.

A triple risk model for the sudden infant death syndrome (SIDS) as described by Filiano and Kinney involves the intersection of three risks: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). The triple risk model aptly describes the dynamics of an animal model for SIDS: (1) a vulnerable animal that is young and magnesium deficient: (2) a critical developmental period revealed by hyperirritability, labile cardiovascular and respiratory control; and (3) an exogenous stressor such as soft, high-pitched noise; motion or handling; or a chill. Together these three risks may trigger a shock-like episode of apnea, unconsciousness and bradycardia. The lung is the shock organ. An animal that dies quietly or after physical activity following the episode, models SIDS. However, if the shock-like episode resolves spontaneously or after resuscitation, the survivor is a model for an apparent life-threatening episode (ALTE). If, while still in the critical developmental period the ALTE survivor is stressed again, there is a risk for a recurrent episode, with the final outcome still unpredictable but with increasing risk for SIDS with multiple recurrences. The purpose of this communication is to present an illustrated review of the magnesium deficient weanling rat as an animal model for SIDS/ALTE, showing pertinent physical, electrocardiographic and pathological features. In the weanling rat, magnesium deficiency appears to be the single common pathway upon which multiple stressors may impinge to produce sudden death during the relatively brief critical developmental period, while magnesium supplements may protect the animal. If significant magnesium deficiency is subsequently diagnosed in a properly controlled study of human SIDS tissue, it is likely that a high proportion of SIDS deaths could be prevented by simple oral magnesium supplementation to infants during the first critical weeks and months of life.

Exposure to prenatal carbon monoxide and postnatal hyperthermia: short and long-term effects on neurochemicals and neuroglia in the developing brain.

The effects of prenatal exposure to carbon monoxide (CO), a major component of cigarette smoke, was studied alone or in combination with postnatal hyperthermia, on the structural and neurochemical development of the postnatal brain at 1 and 8 weeks. Pregnant guinea pigs (n = 11) were exposed to 200 p.p.m CO for 10 h/day from midgestation until term (68 days), whereas control mothers (n = 10) breathed room air. On postnatal day 4, neonates from the control and CO-exposed pregnancies were exposed to hyperthermia (35 degrees C) for 75 min or remained at ambient (23 degrees C) temperature. Using semiquantitative immunohistochemical techniques the following neurotransmitter alterations were found in the medulla at 1 week: a decrease in met-enkephalin-immunoreactivity (IR) following postnatal hyperthermia and an increase in 5-hydroxytryptamine-IR following a combination of CO and hyperthermia. No alterations were observed in substance P- or tyrosine-hydroxylase-IR in any paradigm. At 8 weeks of age the combination of prenatal CO exposure followed by a brief hyperthermic stress postnatally resulted in lesions throughout the brain and an increase in glial fibrillary acidic protein-IR in the medulla. Such effects on brain development could be of relevance in cardiorespiratory control in the neonate and could have implications for the etiology of Sudden Infant Death Syndrome, where smoking and hyperthermia are major risk factors.

Evaluation of cot mattress inner foam as a potential site for microbial generation of toxic gases.

Recent reports of biovolatilisation of phosphorus and antimony by anaerobic bacteria and of leaching of phosphorus and antimony fire-retardant additives from PVC cot mattress covers, indicate that the polyurethane inner-foam of cot mattresses could be a site for generation of toxic gases of group 15 elements. A toxic gas hypothesis for sudden infant death syndrome (SIDS) involving polyurethane foam of cot mattresses was proposed and tested experimentally. Levels of antimony, phosphorus, arsenic and bismuth were determined at four sites for 44 SIDS and 50 control (no death) cot mattress foams. There was no evidence to suggest that the levels of these elements in cot mattress foam have a causal relation to SIDS. Leaching of antimony trioxide from PVC mattress covers could account for detectable levels of this element in 52% of the cot mattress samples analysed. Volatile forms of antimony, phosphorus, arsenic and bismuth was not detected in the headspace of mixed or monoseptic cultures of anaerobic bacteria containing polyurethane foam. Past microbial activity had given rise to involatile methylated species of antimony in some of the cot mattress foams tested (61%, n = 24). Abiotic oxidation of biogenic trimethylantimony together with physical adsorption of methylantimony forms to the polyurethane foam matrix could account for the apparent absence of "escaped" volatile antimony species in culture headspaces of incubation vial. There was no evidence to suggest that levels of trimethylantimony or total methylantimony forms in cot mattress foams have a causal relation to SIDS.

Sudden infant death syndrome: hypothalamic failure to sense elevated blood pyrogens.

Sudden infant death syndrome (SIDS) is frequently associated with a mild infection, the incidence peaking during the third month of life. We hypothesize that the neonatal immaturity of both the acute febrile response and hypothalamus promote neonatal protection from SIDS. Vagal afferents modify the febrile response. Vagotomized rodents displayed a loss of febrile responsiveness in a 'non-sensing' brain. The failure of a 'non-sensing' brain to react to elevated blood pyrogens leads to failure of the febrile response and to a shock-like state. SIDS infants may appear well yet, within hours of this observation, may be found dead. There is a mismatch between the acute febrile response and hypothalamic hypoactivation. The discrepancy increases with development. There is an elevated cytokine response in endothelial cells which induces nitric oxide (NO) production and retarded development of the hypothalamus. Cigarette smoke also induces NO production and retards hypothalamic development by augmented apoptosis. Zinc inhibits this effect in mouse thymocytes. Fetal haemoglobin (HbF) induces hypoxia, which is a stimulator of the immune response while vasodilator gases (carbon monoxide (CO), NO) reduce hypothalamic function. The hypothalamic failure to sense elevated blood pyrogens induces toxic shock - a feature of SIDS.