Preliminary evidence of a relationship between sleep spindles and treatment response in epileptic encephalopathy

Objective Epileptic encephalopathy with spike wave activation in sleep (EE-SWAS) is a challenging neurodevelopmental disease characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The mechanism of cognitive dysfunction is unknown, but treatment with high-dose diazepam may improve symptoms. Spike rate does not predict treatment response, but spikes may disrupt sleep spindles. We hypothesized that in patients with EE-SWAS: 1) spikes and spindles would be anticorrelated, 2) high-dose diazepam would increase spindles and decrease spikes, and 3) spindle response would be greater in those with cognitive improvement. Methods Consecutive EE-SWAS patients treated with high-dose diazepam that met criteria were included. Using a validated automated spindle detector, spindle rate, duration, and percentage were computed in pre- and post-treatment NREM sleep. Spikes were quantified using a validated automated spike detector. Cognitive response was determined from chart review. Results Spindle rate was anticorrelated with spike rate in the channel with the maximal spike rate ( p =0.002) and averaged across all channels ( p =0.0005). Spindle rate, duration, and percentage each increased, and spike rate decreased, after high-dose diazepam treatment ( p≤ 2e-5, all tests). Spindle rate, duration, and percentage ( p ≤0.004, all tests) were increased in patients with cognitive improvement after treatment, but not those without. Changes in spike rate did not distinguish between groups. Interpretation These findings confirm thalamocortical disruption in EE-SWAS, identify a mechanism through which benzodiazepines may support cognitive recovery, and introduce sleep spindles as a promising mechanistic biomarker to detect treatment response in severe epileptic encephalopathies.