Abstract
Sudden infant death syndrome (SIDS) is understood as a syndrome that presents with the common phenotype of sudden death but involves heterogenous biological causes. Many pathological findings have been consistently reported in SIDS, notably in areas of the brain known to play a role in autonomic control and arousal. Our laboratory has reported abnormalities in SIDS cases in medullary serotonin (5-HT) receptor 1A and within the dentate gyrus of the hippocampus. Unknown, however, is whether the medullary and hippocampal abnormalities coexist in the same SIDS cases, supporting a biological relationship of one abnormality with the other. In this study, we begin with an analysis of medullary 5-HT1A binding, as determined by receptor ligand autoradiography, in a combined cohort of published and unpublished SIDS (n = 86) and control (n = 22) cases. We report 5-HT1A binding abnormalities consistent with previously reported data, including lower age-adjusted mean binding in SIDS and age vs. diagnosis interactions. Utilizing this combined cohort of cases, we identified 41 SIDS cases with overlapping medullary 5-HT1A binding data and hippocampal assessment and statistically addressed the relationship between abnormalities at each site. Within this SIDS analytic cohort, we defined abnormal (low) medullary 5-HT1A binding as within the lowest quartile of binding adjusted for age and we examined three specific hippocampal findings previously identified as significantly more prevalent in SIDS compared to controls (granular cell bilamination, clusters of immature cells in the subgranular layer, and single ectopic cells in the molecular layer of the dentate gyrus). Our data did not find a strong statistical relationship between low medullary 5-HT1A binding and the presence of any of the hippocampal abnormalities examined. It did, however, identify a subset of SIDS (~25%) with both low medullary 5-HT1A binding and hippocampal abnormalities. The subset of SIDS cases with both low medullary 5-HT1A binding and single ectopic cells in the molecular layer was associated with prenatal smoking (p = 0.02), suggesting a role for the exposure in development of the two abnormalities. Overall, our data present novel information on the relationship between neuropathogical abnormalities in SIDS and support the heterogenous nature and overall complexity of SIDS pathogenesis.
Highlights
The sudden and unexpected death of an apparently healthy infant during a sleep period has long been recognized as a medical entity requiring investigation, but its cause remains unknown
We used a combined analytic cohort of sudden infant death syndrome (SIDS) cases from our laboratory to statistically address the hypothesis that hippocampal abnormalities and medullary 5-HT1A abnormalities are associated, with one dependent on the presence of the other
We hypothesized that evidence supporting a dependent relationship between the two lesions would be demonstrated in either [1] decreased medullary binding in the presence of one or more hippocampal lesions, [2] an increased prevalence of hippocampal abnormalities in the cases with the lowest medullary binding, and/or [3] a uneven distribution of cases across the 4 designated subsets with an increased number of SIDS cases with both abnormalities present compared to SIDS cases with only one abnormality
Summary
The sudden and unexpected death of an apparently healthy infant during a sleep period has long been recognized as a medical entity requiring investigation, but its cause remains unknown. Since the middle of the twentieth century, various definitions have been proposed for this phenomenon. It has usually been labeled as a “syndrome,” which is a set of medical signs and symptoms that correlate strongly with each other without an established unifying cause. The typical phenotype of sudden infant death syndrome (SIDS) is the unique age distribution with a peak at 2– 4 postnatal months, occurrence of death associated with a sleep period, socioeconomic disadvantage, and male predominance. SIDS is a diagnosis of exclusion and its differential diagnosis is broad and heterogeneous, including various causes that may be found on autopsy, e.g., inborn errors of metabolism, congenital heart disease
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