Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in epilepsy affecting 1:1000 epilepsy patients each year. Clinical studies indicate that severe seizures and cardiorespiratory dysfunction including bradycardia, apnea and severe hypoxia are major risk factors for SUDEP. There is a critical need to identify treatments that target the overall cardiorespiratory dysfunction in SUDEP. We have previously reported that the Kv1.1 KO (KO) mice, a model of SUDEP, have increased seizures, bradycardia, apnea and chronic intermittent hypoxia prior to death. This suggests a gradual weakening of the cardiorespiratory function as they approach death and may provide for a window for preventative therapeutic intervention. We have reported that the high fat, low carbohydrate ketogenic diet (KD) reduced severe seizures and increased longevity in the KO mice. Other studies in and outside of epilepsy have also reported that KD treatment reduced refractory seizures, apneas, hypoxia and cardiac dysfunction. Here, we hypothesize that chronic ketogenic diet (KD) treatment will improve cardiorespiratory function and thereby increase longevity in the Kv1.1 KO model of SUDEP.

Methods: Age-matched KO mice and wild-type (WT) littermates were weaned onto standard diet or KD, and cardiorespiratory parameters were measured starting postnatal day (P)21 until sudden death. Heart rate and blood O₂ saturation were determined noninvasively with ECGenie and pulse oximetry respectively. Respiration was measured with noninvasive airway mechanics. Frequency and severity of the seizures were recorded using EEG-video monitoring. Endpoints included survival, heart rate, incidence of bradycardia (heart rate< 600 bpm), intermittent hypoxia (< 90% blood O₂ saturation) and apnea.

Results: A 100% of the KO mice died by P56 ± 2.4 days. Compared to the WT controls, KO mice had a progressive decrease in heart rate, and experienced more bradycardia as these mice approached SUDEP age (p< 0.001). KD treatment normalized the KO heart rates to control levels (p< 0.01) and reduced the incidence of bradycardia. KO mice experienced higher incidence of apnea closer to SUDEP age (p< 0.001). KD treatment reduced the incidence of apnea in the KO mice (p < 0.01). We have previously reported that KO mice have increased episodes of intermittent hypoxia prior to death. Here we found that, KD treatment reduced the fraction of hypoxic episodes experienced by the KO mice from 25% to 6.8% (p < 0.001). KD treatment also significantly reduced their seizure burden (p< 0.01) and increased their survival by ~35% to P75 ± 5.9 days (p< 0.0001).