Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1357-0) contains supplementary material, which is available to authorized users.
Highlights
The sudden infant death syndrome (SIDS) is the sudden and unexpected death of an infant less than 1 year of age that remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history [60]
It is prone to the generation and propagation of seizures [42, 48], and hippocampal lesions are associated with temporal lobe epilepsy and sudden unexplained death in epilepsy (SUDEP) [1, 2, 5, 17, 37]
We focused upon the hippocampus in sudden unexplained deaths in infants because of the potential for elucidating the role of seizures in such deaths, as well as a possible continuum of hippocampal/ seizure-related deaths linked to sudden death across the age spectrum, including sudden unexplained death in childhood (SUDC) and SUDEP [27]
Summary
The sudden infant death syndrome (SIDS) is the sudden and unexpected death of an infant less than 1 year of age that remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history [60] It is the leading cause of postneonatal infant mortality in the United States today with an overall incidence of 0.57/1,000 live births [38]. The possibility that sudden unexplained death in infants is due to a lethal (unwitnessed) seizure has been postulated [16, 50, 55] In support of this idea, we recently reported on a previously healthy infant (separate from the cohort presented below) who was discovered seizing by his father during a sleep period, and whose autopsy was unrevealing [24]. We suggest that hippocampal disorganization in a predisposed infant may lead to cardiorespiratory instability (before the clinical onset of seizures) by functional impairment of the limbic– brainstem homeostatic network and death
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