Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the primary cause of death in patients with intractable epilepsy. There is a nocturnal predilection for SUDEP, but why this is the case remains a mystery. Respiratory and cardiac dysregulation have been implicated as etiologies for SUDEP, and control of both breathing and cardiac function is subject to sleep state-dependent and circadian regulation. Seizures themselves are also subject to state- and circadian-dependent modulation. The purpose of this study was to determine whether state- and/or circadian-dependent effects of seizures on cardiac and respiratory function contribute to seizure-related death. Methods: EEG, EMG and EKG electrodes were implanted in adult male mice with or without a bipolar stimulating/recording electrode in the right centrolateral nucleus of the amygdala. Seizure induction was accomplished via maximal electroshock (MES; 50 mA, 200 ms, 60 Hz) or amygdala kindling (100-180 mA, 1 ms biphasic square wave, 1 s, 60 Hz) during wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, if possible. EEG, EMG, EKG, and breathing were then assessed (n = 8 per state). Standard mouse sleep scoring parameters based on EEG, EMG and behavioral characteristics were used to determine vigilance state on-line and in real time, and verified off-line post-hoc.. Another set of animals (n = 6) were rendered "epileptic" with pilocarpine (275-400 mg/kg, i.p.) induced status epilepticus and epileptogenesis. In these experiments, data were analyzed post-hoc for vigilance state and circadian time of seizure occurrence and effects on breathing and cardiac activity were assessed. Results: In the MES model, seizures that occurred during sleep, especially those induced during REM, were more likely to be fatal. In all cases, death was due to primary respiratory arrest. There was increased respiratory rate variability and a higher number of apneas following seizures that were induced during NREM in both the MES and kindling models. As has been seen previously, seizures could not be induced during REM in the kindling model. Also, seizures occurred rarely during REM in the spontaneously seizing model. Conclusions: These data indicate that seizures that occur during sleep can have detrimental effects on breathing and cardiac activity, which may contribute to increased seizure related death.