Abstracts

Rationale: Sudden unexpected death (SUDEP) is a major cause of mortality in epilepsy and the second leading cause of years of patient life lost among neurological disorders. Clinical findings in witnessed cases have implicated cardiac and respiratory failure as key elements in SUDEP pathogenesis, and clinical studies are evaluating potential biomarkers for SUDEP risk. DBA/1 mice are a useful model of SUDEP. Prompt respiratory support consistently prevents seizure-induced death in these mice. However, the biomarkers that predict death in DBA/1 mice have not been determined and might be instructive in the search for human SUDEP biomarkers. The present study evaluated the time-point after seizure-induced respiratory arrest (S-IRA) at which efforts to revive the DBA/1 mice failed, and we recorded blood oxygen saturation levels (%SpO₂) and electrocardiogram for changes in heart rate (HR) until the time when the mice could no longer be successfully resuscitated.

Methods: DBA/1 mice (21-30 days old) (N=52) were tested for susceptibility to S-IRA induced by audiogenic seizure after 3-4 daily seizures (priming), using an electric bell (122 dB SPL). The ability to successfully resuscitate the mice at varying times after S-IRA was determined using a rodent respirator. Seizure behaviors and effects of resuscitation were recorded on video, quantified, and statistically compared off-line (Chi-square test). Pulse oximetry (%SpO₂ levels) changes were evaluated using MouseSTAT^TM (Kent Scientific) (N=12), and HR (N=10) was recorded simultaneously in DBA/1 mice for 50 s following S-IRA. These biomarkers were also measured in primed DBA/1 mice that did not undergo seizure but were anesthetized with isoflurane instead. Statistical comparisons were made using one-way ANOVA. 

Results: We found ~100 % of DBA/1 mice were successfully resuscitated between 5 and 15 s after S-IRA. However, a significant decline in the ability to revive the mice was seen at delays of 20 and 30 s, and mice could not be revived at 45s after S-IRA. A precipitous decline in %SpO₂ occurred at 10 s after S-IRA (to 90.1±4.0% vs. 99.0±0.5% at 1 s; p< 0.05), and declined further at 20 s and 45 s (to 84.4±3.8% and 71.2±3.2% (p < 0.001), respectively. However, no significant change in HR was observed until 15-20 s (p < 0.05), and declined progressively thereafter. However, the HR at 40-45 s after S-IRA was not significantly different from that seen in the isoflurane-anesthetized DBA/1 mice.