Potential mechanisms of sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) accounts for 15% of all deaths in people with epilepsy and 50% in refractory epilepsy. The underlying mechanisms are not well understood, but seizure-induced cardiac and respiratory arrests are involved. The cardiovascular and respiratory systems are subject to precise reflex regulation to ensure appropriate oxygen supply under a wide range of circumstances. Barosensory and chemosensory afferents project into the nucleus tractus solitarius (NTS), which relays systemic data to higher brain centers for integration of homeostatic responses in heart rate, peripheral resistance, respiration, and other autonomic reactions. Being the afferent autonomic gatekeeper, NTS plays a critical role in cardiovascular and respiratory regulation. In the course of studying the kainic acid model, we became aware of progressive neuronal loss in the NTS and noted SUDEP-like deaths in rats with frequent convulsions. Increased autonomic susceptibility with inhalation anesthetics was also observed, often seen after impairment of baroreceptor and chemoreceptor reflex loops. Seizure-induced neuron loss in NTS may play a role impairing the integrative functions of NTS resulting in poor homeostatic responses during seizures and leading to SUDEP.