Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) in patients is often preceded by a generalized convulsive seizure, and one major proposed cause of SUDEP is depression of respiration. Seizure-induced respiratory depression, leading to death, is also common in the DBA mouse models of SUDEP and is induced by generalized convulsive audiogenic seizures (AGSz). Fortunately, human SUDEP occurs rarely. GEPR-9s are a different model of generalized convulsive AGSz, but these animals rarely exhibit seizure-induced death. Alcohol use and abuse is associated with seizures, both as a precipitating factor and as a risk factor for SUDEP in epileptic patients (Hesdorffer and Tomson, CNS Drugs 27:113, 2013). Therefore, we evaluated the effect of alcohol withdrawal (following binge administration) in GEPR-9s on respiration patterns and the incidence of seizure-induced death. Methods: GEPR-9s were subjected to the Majchrowicz binge alcohol protocol (Faingold, Current Protocols in Neuroscience, 2008; Chap 9: unit 9.28). GEPR-9s were given ethanol intragastrically in baby formula vehicle, starting at 5 gm/kg dose (and adjusted based on a behavior rating scale) every 8 h for 4 days. Subsequently, AGSz were induced in these animals, using an electrical bell at an intensity of 110 dB SPL for a maximum of 60 sec during the peak of ethanol withdrawal (ETX)-induced seizure susceptibility, 18-24 h after the last ethanol dose. We evaluated the pattern of respiration based on polygraph recordings from a transducer placed around the rats' abdomen during the post-ictal period. We quantified the duration of respiratory distress (gasping and agonal breathing, which are auto-resuscitation mechanisms) during the post-ictal depression period, which ranged from 28-144 sec. These patterns were compared to a control group of GEPR-9s that were given the vehicle every 8 h for 4 days. We also evaluated the survival rate of the ETX group in the post-seizure period as compared to vehicle treated GEPR-9s and the ability to resuscitate, using a rodent respirator (1 cc volume of air at 86 strokes/min). Results: In the ETX group, we observed a greater incidence of death as compared to vehicle control GEPR-9s (27.7 vs 0%) in the 24 h period after ETX. Death was preventable in one case by resuscitation immediately after the tonic seizure. The ETX group exhibited a significantly increased duration of gasping and agonal breathing as compared to control GEPR-9s in the post-ictal period (92.5±6.1 vs 49±5 sec, p<0.05, Repeated measures ANOVA, Independent T-test). Conclusions: ETX induced a greater incidence of seizure-induced deaths in GEPR-9s as compared to vehicle-treated GEPR-9s. Respiratory distress and increases in auto-resuscitation were seen in the ETX group, and external respiratory support prevented death in one animal. These data indicate that epileptic animals (GEPR-9s) that rarely die from their seizures exhibit a greater incidence of seizure-induced death and respiratory distress during ETX, which may be relevant to human SUDEP, which is also rare. (Support: Epilepsy Foundation).