Autoresuscitation and SUDEP

Project Summary Approximately 30% of people with epilepsy are refractory to current anti-seizure medications and sudden unexpected death in epilepsy (SUDEP) occurs in ~1:150 per year for individuals with severe refractory generalized convulsive seizures (GCS). The long-term goals of our research program are to identify novel molecular targets with disease-modifying effects that may increase longevity in those susceptible to SUDEP. Evidence from the multi- center MORTEMUS study on SUDEP indicates that patients experienced a series of events promoting hypoxic and hypercapnic (HH) fluctuations in blood gases, from which they were unable to autoresuscitate and succumbed to terminal apnea. However, the relationship between SUDEP risk and the efficacy of the autoresuscitation response is unknown. The objective of the proposed project is to elucidate mechanisms of autoresuscitation failure in relation to SUDEP risk. The central hypothesis is that alterations in the network of chemosensitive cardiorespiratory neurons increases the probability of autoresuscitation failure and SUDEP risk. Our rationale is that SUDEP is often associated with a preceding GCS, but demise has also been associated with prone positions with no evidence of seizure. A variable or decline in autoresuscitation efficacy may explain succumbing to one GCS and not previous seizures or failing to arouse in situations of changing air supply. Our specific aims will test the hypotheses that maladaptive modulatory control of key central autoresuscitation centers disintegrates the network chemoresponse, causing deterioration of the response and the autoresuscitation response to fail. Upon conclusion, we will have delineated mechanisms underlying autoresuscitation failure in the context of epilepsy in a clinically relevant animal model of SUDEP. This information will offer new research avenues for understanding SUDEP, assessing risk and identifying therapeutic opportunities.