Seizure-induced apnea causes sudden death independent of cortical spike wave discharge in mouse models of Tuberous Sclerosis Complex.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related mortality for people with epilepsy (PWE). Current evidence suggests that many cases of SUDEP are due to seizures that produce respiratory arrest, aka seizure-induced apnea. Patients with tuberous sclerosis complex (TSC) are at a significant risk of SUDEP, and mouse models of TSC have early mortality. Previous reports in TSC mouse models demonstrate that although Vigabatrin suppresses seizures, it does not improve survival. In other mouse models, our team has demonstrated that seizure-induced apnea occurs during tonic seizures, and that cortical spike-wave discharge (SWD) is not necessary to produce apnea during exogenously stimulated seizures. We hypothesized that seizure-induced apnea drives fatality independent of SWD in the spontaneous seizures of TSC mouse models, and this is why Vigabatrin treatment is ineffective. Two TSC mouse models were continuously monitored with electroencephalography, electrocardiography, plethysmography, and video recording to detect spontaneous seizures and SUDEP events. A subset of mice received daily Vigabatrin. Both TSC mouse models exhibited two spontaneous seizure types: clonic seizures with SWD and tonic seizures without SWD. All seizure-related fatalities were due to seizure-induced apnea. Across 21 SUDEP events, 20 occurred immediately after tonic seizures. Vigabatrin nearly eliminated clonic seizures but did not prevent tonic seizures and the concurrent apnea. In addition, Vigabatrin-treated mice exhibited cardiac signals that declined hours before SUDEP. These findings underscore the need for SUDEP-specific interventions beyond seizure suppression.