• Toni Kulju, Ryan Verner, Maxine Dibué-Adjei, Atte Eronen, Sirpa Rainesalo, Kai Lehtimäki, Joonas Haapasalo, and Jukka Peltola.
• Department of Neurosciences and Rehabilitation, Tampere University Hospital, P.O. Box 2000, Tampere FI-33521, Finland; Tampere University, Faculty of Medicine and Health Technology, FI-33014 Tampere, Finland. Electronic address: toni.kulju@gmail.com.
• Epilepsy Behav. 2020 Sep 1; 110: 107144.

BackgroundResponsive vagus nerve stimulation (rVNS) utilizes an electrocardiograph (ECG)-based algorithm to detect rapid sympathetic activations associated with the onset of a seizure. Abrupt sympathetic activation may also be associated with nocturnal arousals between sleep cycles or transitioning from sleep to wakefulness, a period in which many patients with epilepsy experience seizures. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion.ObjectiveThe aim of this study was to assess the circadian rhythmicity of autostimulations in rVNS treatment in patients with drug-resistant epilepsy (DRE).Materials And MethodsWe performed a retrospective follow-up study of 30 patients with DRE treated with rVNS including 17 new implantations and 13 battery replacements at a single center in Finland. After initiation of autostimulation mode, the exact rVNS stimulation parameters and the timestamps of all individual autostimulations delivered were registered. A clustered autostimulation was defined as any autostimulation that occurred within the duration of the therapeutic cycle during the therapy "OFF" time compared with both the previous autostimulation and the following autostimulation.ResultsAutostimulations and especially autostimulation clusters show a higher probability of occurring in the morning and less at night. This trend appeared to follow the circadian rhythm of cortisol concentration.ConclusionsEarly morning peaks of autostimulations at low thresholds may reflect awakening-induced activation of the cardiovascular system, which is associated with a shift towards the dominance of the sympathetic branch of the autonomic nervous system. Cortisol release occurs in parallel driven by wakening-induced activation of the hypothalamic-pituitary-adrenal axis, which is fine-tuned by direct sympathetic input to the adrenal gland. This is of interest considering the known sympathetic hyperactivity in patients with epilepsy.Copyright © 2020 Elsevier Inc. All rights reserved.

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