SCN1A variants cause a range of epilepsy syndromes, including Dravet syndrome, leading to early cognitive and functional impairment. Despite advances in medical management, drug-resistant epilepsy remains common. Vagal nerve stimulation (VNS) has been suggested reducing seizure frequency in these patients but there is a lack of long-term follow-up, quantitative analysis that corrected for confounding factors such as antiseizure medications (ASMs) and the impact of VNS settings on response. This two-center, retrospective cohort study analyzed 12-month and for the first time up to ten-year seizure outcomes in therapy-refractory epilepsy patients with loss-of-function SCN1A variants (93.75% Dravet Syndrome) who underwent VNS implantation. A ≥50% seizure frequency reduction was observed in 93.75% (15/16) of patients in the 12-month and 87.5% (14/15) in the ten-year period. Median seizure frequency was significantly lower in both follow-up periods than in the pre-implantation period. Linear mixed-effects regression showed that the reduction in seizure burden was independent of ASM use, and the VNS duty cycle was significantly associated with seizure reduction. Three individuals (18.8%) experienced minor side effects. Our results highlight the benefits of genotype-driven therapeutic interventions such as VNS in patients with SCN1A-related epilepsy. This study emphasizes the need for further implementation of genotype-driven clinical decision-making.

The authors have declared no competing interest.

This study was supported by the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) under grant R01 NS117544 (Principal Investigator: D.L.).

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Committee For the Protection of Human Subjects of the University of Texas Health Science Center at Houston gave ethical approval for this work. The Institutional Review Board of the Cleveland Clinic gave ethical approval for this work.

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