Sleep loss and abnormal sleep homeostasis as biomarkers of Sudden Unexpected Death in Epilepsy: Evidence 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. This study examined sleep-related biomarkers in the Kv1.1 ^-/- mouse model of SUDEP. The Kv1.1 ^⁻/⁻ and wildtype mice were implanted with electroencephalography (EEG) and electromyography (EMG) electrodes for continuous video-EEG recording. Vigilance states were scored in 4-second epochs, and spectral power was analyzed across frequency bands. Sleep homeostasis (SH) was assessed by: a) by decay of slow wave activity (SWA; 0.5–4 Hz) during NREM, b) SWA increase with prior wakefulness, and c) NREM and SWA rebound after sleep deprivation (SD). Kv1.1 ^-/- mice have spontaneous seizures and exhibit SUDEP with a terminal seizure followed by postictal EEG suppression, bradycardia, and asystole. Compared to wildtypes, Kv1.1 ^-/- had reduced sleep efficiency, NREM and REM duration, and spindle counts (p< 0.001). They also lacked normal SWA dynamics, including SWA decay during NREM (p = 0.002), SWA increase with prior wake (p = 0.005), and NREM (p<0.0001) and SWA (p=0.01) rebound following SD. These findings suggest that disrupted sleep architecture and SH may serve as candidate biomarkers for SUDEP, supporting further translational studies to develop predictive tools and sleep-targeted therapies to reduce SUDEP risk.