Sleep biomarkers of sudden unexpected death in epilepsy: Data from the Kv1.1 mouse model.

Abstract

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, often occurring during sleep and lacking reliable predictive biomarkers. Here we used the Kv1.1mouse model of SUDEP to examine sleep-related biomarkers. Kv1.1and wild-type mice were implanted with electroencephalography (EEG) and electromyography (EMG) electrodes for continuous video-EEG recording. Vigilance states were scored in 4-s epochs, and spectral power was analyzed across frequency bands. Sleep homeostasis (SH) was assessed by: a) the decay of slow-wave activity (SWA; 0.5-4&#xa0;Hz) during NREM sleep, b) SWA increase with prior wakefulness, and c) NREM and SWA rebound following sleep deprivation (SD). Kv1.1mice exhibited spontaneous seizures of varying frequency. Compared to wildtypes, Kv1.1mice had reduced time in NREM and REM sleep, that were worse on days with seizures (p&#xa0;<&#xa0;0.001). The diurnal oscillation of NREM and REM was impaired in Kv1.1mice regardless of seizures. SH was abnormal in Kv1.1mice with absence of SWA decay during lights-on when mice sleep (p&#xa0;=&#xa0;0.002) and no increase in SWA with wakefulness after sleep onset (p&#xa0;=&#xa0;0.005). In Kv1.1mice SWA remained unchanged in 10-day recordings with no SD (p&#xa0;=&#xa0;0.22) or as mortality approached in the SD group (p&#xa0;=&#xa0;0.15). Furthermore, sleep deprivation (SD) resulted in rebound increase NREM sleep (p&#xa0;<&#xa0;0.0001) and SWA (p&#xa0;=&#xa0;0.01) in wild-types but not in Kv1.1mice. These findings suggest that abnormalities in SH may serve as candidate biomarkers of SUDEP. The data also support translational studies to develop sleep-targeted interventions to reduce SUDEP risk.