Effectiveness and safety of implantable vagus nerve stimulation in people with primary generalized tonic–clonic seizures

OBJECTIVE: Most therapies for drug-resistant epilepsy (DRE) focus on focal-onset seizures, the most common seizure types. Studying primary generalized tonic-clonic seizures (PGTCS) is more challenging due to diagnostic and recruitment difficulties. While vagus nerve stimulation (VNS) therapy is globally established in DRE with focal-onset seizures, approved indications vary by region. This study assesses the safety and effectiveness of VNS therapy in individuals with drug-resistant PGTCS. METHODS: Data from five studies were included in the analysis. The PGTCS group included 170 participants with reported PGTCS who received VNS therapy and completed 24 months of follow-up. Outcomes included observed and Bayesian-estimated PGTCS responder rates (≥50% seizure reduction) and seizure frequency changes. Observed rates were determined from clinical studies, while Bayesian responder rates were estimated using a hierarchical model. RESULTS: The Bayesian hierarchical model estimated the 24-month PGTCS responder rate for patients in CORE-VNS to be 65.2% (95% credible interval: 55.1%-75.1%). The Bayesian estimate at 24 months for responder rates across all studies was 65.5%. Most responders (91.7%) maintained their response from 6 and 12 months to 24 months. Median seizure frequency decreased by 71.4% for PGTCS and 62.5% for all seizures at 24 months. Treatment-emergent adverse events (TEAEs) were low and consistent with those seen in people with focal-onset seizures treated with VNS therapy. No new safety concerns were identified, including no increased risk of Status Epilepticus (SE) or death. SIGNIFICANCE: These findings support VNS therapy as a safe and effective treatment for reducing PGTCS in participants with DRE. PLAIN LANGUAGE SUMMARY: Primary generalized tonic-clonic seizures (PGTCS) carry higher risks of complications and death than focal-onset seizures. Vagus nerve stimulation (VNS therapy) is approved for drug-resistant PGTCS outside the USA. Data from five LivaNova-sponsored clinical studies show that VNS therapy is safe and effective in adults and children. Among 170 participants, about 66% had a ≥50% reduction in PGTCS at 24 months, and 92% of early responders maintained improvement. Among 149 participants, median PGTCS frequency fell by 71%. Treatment-emergent adverse events were low, with no new safety concerns identified.