Abstracts

Rationale: The increased risk of SUDEP is particularly high in patients with drug refractory temporal lobe epilepsy (TLE). In fact, 40% of patients with pharmacoresistant epilepsy (~40% of the TLE population) have one or more abnormalities in cardiac function. One of the main risk factors for SUDEP is frequent, convulsive seizures. Methods: Chronic video-EEG, EKG, and periodic hippocampal auditory evoked potentials (AEPs) were recorded in rats with pilocarpine-induced epilepsy to address whether (1) alterations in the AEPs or (2) postictal depression (PID) may serve as electrophysiological biomarkers of increasing seizure burden and forecast risk of cardiac arrhythmias in chronic epilepsy (n=6 pilocarpine, n=4 control). Custom-written software incorporating machine-learning algorithms was used to analyze temporally-synched changes in simultaneously collected AEPs, hippocampal field potentials, EEG, and EKG. Heart rat variability (HRV) was analyzed in artifact-free interictal and baseline recordings and the presence of arrhythmia was noted in manually analyzed EKG. Results: Alterations in AEP morphology effectively probes hippocampal excitability and seizure burden as evidenced by suppression of the AEP following high-frequency seizures (i.e., seizure clusters) potentially indicating SUDEP risk. Durations of PID and seizure duration were directly correlated (p=.001) being significantly longer during convulsive seizures (p=.001). Additionally, temporal periods of high convulsive seizure load had the longest average PID (p=.05). PID was associated with the presence of arrhythmias in chronically epileptic animals. Measures of HRV (in the time and frequency domain) demonstrated no difference in chronically epileptic animals relative to control rats. One chronically epileptic animal having a significantly higher daily seizure frequency (p=.05) and a significantly higher proportion of convulsive seizures (p=.05) relative to the other epileptic rats died of SUDEP (n=1/6). Conclusions: The dynamic changes in AEP morphology and PID observed in the chronically epileptic brain (1) are directly associated with seizure severity and seizure frequency, (2) indicate active changes in brain excitability, (3) suggest increased SUDEP risk and (4) present targets for therapeutic development to prevent seizure-induced arrhythmias and cardiac arrest in at-risk, epileptic rats. Funding: 5K22NS083722 (HLG)