Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability.

Sudden unexplained death in infants, including the sudden infant death syndrome, is likely due to heterogeneous causes that involve different intrinsic vulnerabilities and/or environmental factors. Neuropathologic research focuses upon the role of brain regions, particularly the brainstem, that regulate or modulate autonomic and respiratory control during sleep or transitions to waking. The hippocampus is a key component of the forebrain-limbic network that modulates autonomic/respiratory control via brainstem connections, but its role in sudden infant death has received little attention. We tested the hypothesis that a well-established marker of hippocampal pathology in temporal lobe epilepsy-focal granule cell bilamination in the dentate, a variant of granule cell dispersion-is associated with sudden unexplained death in infants. In a blinded study of hippocampal morphology in 153 infants with sudden and unexpected death autopsied in the San Diego County medical examiner's office, deaths were classified as unexplained or explained based upon autopsy and scene investigation. Focal granule cell bilamination was present in 41.2% (47/114) of the unexplained group compared to 7.7% (3/39) of the explained (control) group (p < 0.001). It was associated with a cluster of other dentate developmental abnormalities that reflect defective neuronal proliferation, migration, and/or survival. Dentate lesions in a large subset of infants with sudden unexplained death may represent a developmental vulnerability that leads to autonomic/respiratory instability or autonomic seizures, and sleep-related death when the infants are challenged with homeostatic stressors. Importantly, these lesions can be recognized in microscopic sections prepared in current forensic practice. Future research is needed to determine the relationship between hippocampal and previously reported brainstem pathology in sudden infant death.

Witnessed sleep-related seizure and sudden unexpected death in infancy: a case report.

Witnessed reports of sudden death are rare, but critical to deciphering its mechanism(s). We report such a death in a seemingly healthy 8-month-old boy in whom seizures and respiratory distress in the prone position were witnessed upon discovery during a sleep period. Following cardiopulmonary resuscitation, anoxic encephalopathy resulted in "brain death" and withdrawal of life support after 2 days. The autopsy did not reveal a primary anatomic cause of death. Metabolic evaluation failed to uncover an inborn error of ammonia, amino, organic, or fatty acid metabolism. Seizures in this case may have been secondary to cerebral hypoxia-ischemia complicating cardiorespiratory arrest of unknown etiology. Yet, they may represent the first manifestation of idiopathic epilepsy, triggering cardiopulmonary arrest, analogous to the terminal events postulated in sudden and unexplained death in epilepsy. This report alerts the forensic community to the possibility that sudden and unexplained death in infants may be due to seizures.

Hippocampal asymmetry and sudden unexpected death in infancy: a case report.

The differential diagnosis of known entities associated with sudden unexpected death in infancy is ever expanding. Here we report the case of a 10-month-old infant boy whose clinical presentation mimicked that of the sudden infant death syndrome (SIDS). This presentation included the typical features of SIDS: sleep-related death; prone position upon discovery; and minor illness within 2 days of death. Nevertheless, neuropathologic examination revealed striking hippocampal asymmetry and microdysgenesis similar to that reported previously by us in toddlers with sleep-related sudden death. Hippocampal maldevelopment in the setting of sudden death in infants and toddlers is analogous to sudden unexpected death in epilepsy associated with temporal lobe pathology, and suggests a possible role for seizures in the terminal events leading to sudden death. This report serves to alert pediatric and forensic pathologists to hippocampal asymmetry and microdysgenesis in the differential diagnosis of sudden infant death mimicking SIDS.