Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP tends to occur at night, but whether this is a simply a coincidence, or whether this speaks to a specific circadian-dependent or sleep state-dependent mechanism is unknown. Respiratory and cardiac arrest are the most commonly implicated etiologies for SUDEP. Control of both breathing and cardiac function are subject to circadian and sleep state-dependent regulation. Seizures themselves are modulated in a sleep state- and circadian-dependent manner. Here we set out to determine whether there are circadian and/or state-dependent effects of seizures on respiratory and cardiac function that contribute to seizure-related death.Methods: EEG, EMG and EKG electrodes were implanted in adult male mice. Seizures were induced with maximal electroshock (MES; 50 mA, 200 ms, 60 Hz) during wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep during mid-day and mid-night and EEG, EMG, EKG, and breathing were assessed. Vigilance state was determined on-line in real time based on EEG and EMG characteristics using standard parameters.Results: Seizures that occurred during sleep were more likely to be fatal, especially those induced during REM, and those induced during the daytime. In all instances, death ensued due to primary respiratory arrest. Non-fatal seizures induced during NREM were associated with longer duration post-ictal respiratory suppression, reduced ventilation, and increased respiratory rate variability compared to those induced during waking. All mice died when seizures were induced during REM sleep, therefore this analysis could not be conducted for REM sleep. In addition, there was increased baseline variability in the respiratory rhythm in mice that died compared to those that survived.Conclusions: These data indicate that seizures that occur during sleep, especially during the circadian phase associated with less activity, can have detrimental effects on breathing which may contribute to increased seizure related death.