Project Details
Description
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.
Status | Finished |
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Effective start/end date | 4/1/22 → 1/31/23 |
Funding
- National Institute of Neurological Disorders and Stroke: $307,521.00
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