Neuropathologic Changes in Sudden Unexplained Death in Childhood

Abstract

Sudden unexplained death in childhood (SUDC) affects children >1-year-old whose cause of death remains unexplained following comprehensive case investigation and is often associated with hippocampal abnormalities. We prospectively performed systematic neuropathologic investigation in 20 SUDC cases, including (i) autopsy data and comprehensive ancillary testing, including molecular studies, (ii) ex vivo 3T MRI and extensive histologic brain samples, and (iii) blinded neuropathology review by 2 board-certified neuropathologists. There were 12 girls and 8 boys; median age at death was 33.3 months. Twelve had a history of febrile seizures, 85% died during apparent sleep and 80% in prone position. Molecular testing possibly explained 3 deaths and identified genetic mutations in TNNI3, RYR2, and multiple chromosomal aberrations. Hippocampal abnormalities most often affected the dentate gyrus (altered thickness, irregular configuration, and focal lack of granule cells), and had highest concordance between reviewers. Findings were identified with similar frequencies in cases with and without molecular findings. Number of seizures did not correlate with hippocampal findings. Hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. The significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon.

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

“…Given the role of the dentate gyrus in epileptogenesis and epileptic neuropathology [44,45], we microdissected and analyzed the dentate gyrus proteome separately from CA1-3. Given the reduced size of the dentate gyrus, these samples were smaller than hippocampus and frontal cortex samples (4mm 2 versus 10mm 2 ; Figure 1A) and may explain the lower number of protein groups identified and higher coefficient of variation in dentate samples.…”

Sudden Unexplained Death in Childhood: A Neuropathology Review

“…A retrospective analysis of a large SUID cohort in an urban medical examiner setting, found FDGB in ∼40% of infants, and ∼8% of explained deaths (43). A similar distribution of GCL alterations has consistently been reported in explained "control" groups of SUDC cohorts (15,16). The apparent high prevalence of GCL alterations in pediatric deaths with explained causes raises questions about the etiologic specificity, and therefore biologic relevance, of the role of GCL alterations in the SUDC brain.…”

“…Whether these changes are necessary or sufficient to cause seizures in SUDC remains unproven and controversial (16,45,46). Unlike temporal lobe epilepsy, hippocampal sclerosis is rare or never occurs in SUDC while acquired hippocampal injury (e.g., neuronal loss or gliosis) is uncommon in SUDC (13,15,16).…”

“…Standardized, unrestricted whole brain examination is essential to elucidate the structural abnormalities, if any, in the SUDC brain. Thus, the SUDC Registry and Research Collaborative (SUDCRRC) at NYU Langone Health undertook a 5-year prospective analysis of 20 SUDC cases accrued through a registry where systematic sampling of whole brains was performed with blinded independent reviews conducted by neuropathologists (15). The observations were supplemented by 3T-MRI imaging, and whole exome sequencing to identify pathogenic variants relevant to death.…”

Hippocampal granule cell dispersion: a non-specific finding in pediatric patients with no history of seizures

“…Another retrospective study of 68 SUDEP (sudden unexpected death in epilepsy) cases showed no evidence of significant differences in hippocampal position or shape or GC abnormalities compared to 53 age-matched non-epilepsy controls, although neither DA nor TT were specifically evaluated [52]. Similarly, a recent study concerning sudden unexplained death in childhood (SUDC) cases also could not clearly relate hippocampal abnormalities to either cause or effect of seizures [39]. We are aware of only one report mentioning the existence of GCD in human patients with no history of epilepsy or seizures [25].…”