Beyond the seizure: unveiling the mechanism of death in SUDEP through integrated scene and autopsy analysis

Objective Sudden unexpected death in epilepsy (SUDEP) remains a major cause of mortality in epilepsy, yet its underlying mechanisms are incompletely understood. This study aimed to investigate respiratory- and cardiac-driven death mechanisms in SUDEP by integrating scene investigation findings, toxicology, and forensic autopsy data using composite indices. Methods We retrospectively analyzed 128 definite SUDEP cases autopsied between 2019 and 2024. Scene characteristics (body position, witness presence), toxicological results, organ weights, and histopathological findings were reviewed. Respiratory-related mechanisms were assessed using the Airway Protective Failure Index (APFIₑxt), Pulmonary Edema (PE) and Bleeding Index (PEBI), and Lung-to-Brain Ratio (LBR). Cardiac-related mechanisms were evaluated using the Coronary-Arrhythmic Burden Score (CABS) and Cardiac Vulnerability Index (CVI+). Penalized logistic regression models and receiver operating characteristic (ROC) analyses were applied to assess discriminative performance. Results The median age was 33 years, and 59. 4% of cases were male. Most deaths occurred unwitnessed, and 71. 9% of individuals were found in the prone position. Upper airway findings were frequent among prone cases, including tracheal froth (85. 1%), vomit (14. 9%), and laryngeal edema (10. 4%). PE was observed in 94. 5% of cases. APFIₑxt demonstrated strong discrimination for prone position (ROC-AUC ≈ 0. 92), whereas lung-weight–based indices alone showed limited discriminatory value. Higher body mass index was associated with prone position (p = 0. 015). Cardiac burden increased with age; CABS effectively identified cases with high cardiac vulnerability (CVI + ≥4; ROC-AUC ≈ 0. 79). Respiratory and cardiac features frequently coexisted, indicating overlapping rather than mutually exclusive mechanisms. Toxicological findings were infrequent and not at lethal levels. Discussion These findings support a predominantly respiratory-driven mechanism in SUDEP, characterized by postictal airway compromise and pulmonary stress, while highlighting a secondary cardiac vulnerability that may contribute in older individuals. Integrating scene investigation with autopsy-based composite indices provides a practical framework for phenotypic classification of SUDEP and may inform targeted prevention strategies focused on respiratory monitoring and positional risk reduction.