Current perspectives in sudden unexpected death in epilepsy (SUDEP): epidemiology, research approaches and pathways to prevention.

People with epilepsy (PWE) are affected not only by the unpredictability of seizures, the risk of accidents, stigma, and comorbidities, but also by increased mortality. The most common directly epilepsy‑associated cause of death is sudden unexpected death in epilepsy patients (SUDEP). Across all PWE, SUDEP affects approximately 1 in 1,000 patients per year; depending on epilepsy severity, the annual SUDEP rate can exceed 10 per 1,000 patient years. Because many PWE live with the disorder for several decades, the cumulative SUDEP risk amounts to an average lifetime risk of 5–20%, rendering SUDEP a relevant contributor to mortality in PWE; however, considering its comparatively low annual incidence, SUDEP research remains challenging. Established risk factors and associated patient characteristics include frequent bilateral tonic–clonic seizures (BTCS) -especially when nocturnal-, living alone, long duration of epilepsy, and drug-resistant epilepsy. There are few observations in humans regarding the pathophysiological mechanisms underlying SUDEP, supplemented by findings from registries, animal models, and theoretical considerations. In the typical SUDEP cascade, a pathologically impaired arousal following a preceding, often nocturnal, BTCS appears to precipitate apnea and consequent bradycardia, progressing to fatal asystole. Various individual vulnerability factors contribute to this cascade. However, many aspects remain poorly understood. Two large, recently published prospective cohort studies have contributed valuable insights into biomarkers of SUDEP. Perisylvian epilepsies were identified as risk factors; furthermore, findings suggest dysfunctional brainstem respiratory regulation and impaired sleep homeostasis as potential mechanisms contributing to SUDEP. Nevertheless, on an individual level, it remains poorly understood why some patients die in the context of their first ever epileptic seizure, while others survive hundreds of BTCS. This narrative review provides an overview of the current state of SUDEP research and information on preventive measures used today, and delineates prospective directions for future investigation and prevention.