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 anti-correlated, (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 the 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. The cognitive response was determined from a chart review. Results: Spindle rate was anti-correlated with the 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 spindle rate but not changes in spike rate distinguished 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.

Automated summary

Objective: Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The study aimed to investigate the mechanism of cognitive dysfunction and the effect of high-dose diazepam treatment on spike and spindle activities in patients with EE-SWAS. Methods: EEG data were analyzed to quantify spike and spindle rates before and after treatment. Cognitive response was determined from a chart review. Results: The study found an anti-correlation between spike and spindle rates in patients with EE-SWAS. High-dose diazepam treatment increased spindle rates and decreased spike rates. Patients with cognitive improvement after treatment showed increased spindle rates, duration, and percentage, while those without cognitive improvement did not. Interpretation: These findings confirm thalamocortical disruption in EE-SWAS, provide insights into the mechanism of benzodiazepines in supporting cognitive recovery, and suggest sleep spindles as a potential biomarker for treatment response evaluation in severe epileptic encephalopathies.