Abstract

Abstract Sudden unexpected death in epilepsy (SUDEP) poses a significant risk to life expectancy for individuals with epilepsy. Mechanistic insight, while incomplete, has advanced through clinical observational studies and animal models. Yet we lack preventative therapies, which will depend on understanding SUDEP mechanisms. Recurrent convulsive seizures are the major SUDEP risk factor. Cardiorespiratory dysfunction precedes SUDEP, but whether cardiac arrhythmias are major proximate culprits for SUDEP remains to be determined. Here, we highlight recent data from mouse models and clinical studies that provide increasing support for respiratory depression and decreasing evidence for tachyarrhythmia-induced SUDEP. Further, we review data from genetic and chemoconvulsant mouse models that have enabled a deeper understanding for how seizures initiated in the central nervous system propagate to the autonomic nervous system and drive seizure-induced respiratory depression and subsequent SUDEP, rather than supporting a proximate cardiac arrhythmia cause. Ongoing research will continue to identify predictive SUDEP biomarkers, improve animal models, and translate basic research into precision medicine approaches. Identifying and understanding the brainstem circuits vulnerable in seizure-induced apnoea will enable therapeutic interventions to enhance the quality of life and life expectancy for individuals with epilepsy.