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

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 Kv1.1^-/- mouse model of SUDEP to examine sleep-related biomarkers. Kv1.1^-/- and 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 Hz) during NREM sleep, b) SWA increase with prior wakefulness, and c) NREM and SWA rebound following sleep deprivation (SD). Kv1.1^-/- mice exhibited spontaneous seizures of varying frequency. Compared to wildtypes, Kv1.1^-/- mice had reduced time in NREM and REM sleep, that were worse on days with seizures (p < 0.001). The diurnal oscillation of NREM and REM was impaired in Kv1.1^-/- mice regardless of seizures. SH was abnormal in Kv1.1^-/- mice with absence of SWA decay during lights-on when mice sleep (p = 0.002) and no increase in SWA with wakefulness after sleep onset (p = 0.005). In Kv1.1^-/- mice SWA remained unchanged in 10-day recordings with no SD (p = 0.22) or as mortality approached in the SD group (p = 0.15). Furthermore, sleep deprivation (SD) resulted in rebound increase NREM sleep (p < 0.0001) and SWA (p = 0.01) in wild-types but not in Kv1.1^-/- mice. 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.