Neuropathology in the North American sudden unexpected death in epilepsy registry

Abstract

Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal, and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; p = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, p = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (p = 0.0005) and negatively correlated with epilepsy duration (p = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. focal cortical dysplasia, heterotopias), and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

Raphe and ventrolateral medulla proteomics in epilepsy and sudden unexpected death in epilepsy

“…10 Few other medullary differences were identified in SUDEP versus PWE. 10–13 , 15 Here, we observed one significant protein with a glial, oligodendrocyte, annotation (Tf). Tf was increased in the VLM of SUDEP compared with PWE and control cases (MBP, vimentin, connexin-43 were similar).…”

“…The midbrain of epilepsy patients is structurally normal. 15 , 46 , 47 No proteomic or histological studies beyond neuropathology examined the midbrain in epilepsy patients. Our results and previous studies indicate that the role of the midbrain DR in SUDEP deserves further investigation, particularly on mechanism, astrocytes versus neurons, disease progression, ASMs and other factors.…”

“… 55 With reciprocally connected brain regions, it may be of interest in future studies to evaluate how disease duration influences these protein changes particularly with progressive midbrain atrophy observed in SUDEP by MRI 8 and a negative correlation of brain weight and epilepsy duration in SUDEP. 15 …”

Sudden unexpected death in epilepsy: Investigation of autopsy-based studies

“…The common neuropathological findings include mild degrees of cerebral edema or congestion, traumatic brain lesions, hippocampal sclerosis, vascular malformations, low-grade neoplasms, cerebellar atrophy, and cortical malformations ( 32 , 33 ). The range of pathologies encompasses those commonly encountered in surgical epilepsy series, but no significant difference was shown in the frequency of neuropathological findings between the SUDEP cases and living patients with epilepsy ( 34 ). From a histological point of view, the most common finding was related to acute hypoxic neuronal changes, that is, eosinophilic neuronal changes, occurring in 55% of the SUDEP cases, most often in the hippocampus and also sometimes in the cortical and subcortical regions.…”

Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia

“…FCD may result from somatic mosaicism with pathogenic gene variants in the mTOR signaling pathway, particularly FCD type II with dysmorphic neurons [ 6 , 7 ]. Dysmorphic and balloon neurons are found histologically in TSC and FCD, with high ribosomal protein S6 phosphorylation (phospho-S6) due to increased mTOR pathway activation [ 6 , 8 ].…”