Abstract
BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Generalised-particularly nocturnal-convulsive seizures, longstanding epilepsy, and solitary living have been identified retrospectively as risk factors. No definitive electroclinical biomarkers have been prospectively ascertained. This study aimed to identify SUDEP risk markers using multimodality data with long-term follow-up. METHODS: This prospective, multicentre, observational cohort study, conducted at nine centres (eight in the USA and one in the UK), recruited children and adults with epilepsy who were undergoing prolonged video-electroencephalographic (EEG) monitoring. Inclusion criteria were diagnosis of epilepsy by an epilepsy specialist, with or without drug resistance; age older than 2 months; admission to the epilepsy monitoring unit of a participating centre, with video-EEG monitoring; and completion of at least one 6-month follow-up. Demographic, electroclinical, and cardiorespiratory data were collected at baseline. Participants were followed up long term through routine clinic visits, review of electronic health records, and telephone interviews to collect information about seizure frequency, medication status, and mortality. The primary endpoint was time to SUDEP. Cox proportional hazards models were used to assess significant risk factors. FINDINGS: Between Sept 17, 2011, and Dec, 30, 2021, 2632 children and adults with epilepsy were enrolled in this study; 164 were lost to follow-up. 38 (1·54%) of 2468 participants died from SUDEP (12 definite, 18 probable, and eight possible SUDEP cases) and two had near-SUDEP events. Incident SUDEP mortality rate was 4·76 (95% CI 3·37-6·53) cases per 1000 person-years, from a cohort of 7982 person-years. Living alone (hazard ratio 7·62, 95% CI 3·94-14·71), three or more generalised convulsive seizures in the previous year (3·1, 1·64-5·87]), longer ictal central apnoea (1·11, 1·05-1·18), and longer postictal central apnoea (1·32, 1·14-1·54]) were significant predictors of increased SUDEP risk. In a subanalysis excluding possible and near-SUDEP cases, longer ictal central apnoea was not significant. INTERPRETATION: This study shows an association between premortem peri-ictal apnoea and increased SUDEP risk. Cardiorespiratory monitoring during seizures might benefit assessments of epilepsy mortality risk. Together with solitary living and convulsive seizure frequency, peri-ictal apnoea (>14 s for postictal central apnoea and >17 s for ictal central apnoea) could inform the development of a validatable SUDEP risk index. FUNDING: US National Institutes of Health.