Abstracts

Rationale: Sleep disorders are common among people with epilepsy. Chronic sleep deficiency is associated with early mortality. There is also higher risk of premature mortality in patients with epilepsy than the general population. Sudden unexpected death in epilepsy (SUDEP) has been identified as the most common cause of mortality among people with epilepsy affecting 1 in 1000 people each year. Here, we aimed to determine whether chronic sleep deficiency is associated with sudden death in epilepsy. Methods: We utilized the Kv1.1 knockout (KO) mouse model of epilepsy with sleep disorders and sudden death in epilepsy. We used non-invasive actimetry to continuously monitor rest throughout the lives of KO and wild type littermates (from weaning until sudden death). A second cohort were treated with the ketogenic diet (KD). The KD is one of the only effective clinically available, non-surgical treatment options for refractory seizures, a risk factor of SUDEP. We have previously reported that KD treatment significantly reduces seizures of KO mice. Interestingly, even though KD treatment significantly increases longevity of KO mice, they still succumb to sudden unexpected death. The aim of this study was to determine whether the rest profiles of KO and KOKD mice worsen with age and/or immediately prior to death. Results: We report that (1) as KO mice age, rest is reduced when compared within group to younger ages (p < 0.0001) and between groups to age-matched wild type mice (p < 0.0001). (2) Rest is significantly improved in KD-treated KO mice (p < 0.0001), which resemble wild type values. (3) However, when age is removed as a variable and the data points are aligned at the time of death, the rest profile of the final days of KOKD mice resemble those of KO mice. (4) Acute analyses of the amount of rest during the last day or last two days are not sensitive to the timing of death. (5) However, the chronic rest deficiency profiles at 10 and 15 d prior to death were indistinguishable between KO and KOKD groups. (6) The chronic accumulation of rest deficiency over the final 15 d was associated with 75% of deaths (9/12 mice) with a 1.5 fold increase for KO mice and a 2.8 fold increase for KOKD mice. Conclusions: Our data suggest that the accumulated deficiency in rest is associated with the sudden death in KO and KOKD mice. These data (i) support the proposed clinical hypothesis that chronic sleep deficiency may be associated with early mortality in patients with epilepsy and (ii) warrant future pre-clinical and clinical studies on sleep monitoring in patients at risk for sudden death. Funding: The authors wish to thank the NIH NINDS NS072179 (KAS) and the Citizens United for Research in Epilepsy (KAS) for funding this research.