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Objective: There are three neurostimulation devices available to treat generalized epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). However, the choice between them is unclear due to lack of head‐to‐head comparisons. A systematic comparison of neurostimulation outcomes in generalized epilepsy has not been performed previously. The goal of this meta‐analysis was to determine whether one of these devices is better than the others to treat generalized epilepsy. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines, a systematic review of PubMed, Embase, and Web of Science was performed for studies reporting seizure outcomes following VNS, RNS, and DBS implantation in generalized drug‐resistant epilepsy between the first pivotal trial study for each modality through August 2022. Specific search criteria were used for VNS ("vagus", "vagal", or "VNS" in the title and "epilepsy" or "seizure"), DBS ("deep brain stimulation", "DBS", "anterior thalamic nucleus", "centromedian nucleus", or "thalamic stimulation" in the title and "epilepsy" or "seizure"), and RNS ("responsive neurostimulation" or "RNS" in the title and "epilepsy" or "seizure"). From 4409 articles identified, 319 underwent full‐text reviews, and 20 studies were included. Data were pooled using a random‐effects model using the meta package in R. Results: Sufficient data for meta‐analysis were available from seven studies for VNS (n = 510) and nine studies for DBS (n = 87). Data from RNS (five studies, n = 18) were insufficient for meta‐analysis. The mean (SD) follow‐up durations were as follows: VNS, 39.1 (23.4) months; DBS, 23.1 (19.6) months; and RNS, 22.3 (10.6) months. Meta‐analysis showed seizure reductions of 48.3% (95% confidence interval [CI] = 38.7%–57.9%) for VNS and 64.8% (95% CI = 54.4%–75.2%) for DBS (p =.02). Significance: Our meta‐analysis indicates that the use of DBS may lead to greater seizure reduction than VNS in generalized epilepsy. Results from RNS use are promising, but further research is required. [ABSTRACT FROM AUTHOR]

• VNS, RNS, and DBS are used to treat focal epilepsy but their comparative treatment efficacy is unclear. • We performed a meta-analysis comparing the efficacy of these modalities in years 1–3 after implantation. • We found seizure reduction efficacy of RNS and DBS to be higher than VNS, but this was significant only in year 1. Different neurostimulation modalities are available to treat drug-resistant focal epilepsy when surgery is not an option including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). Head-to-head comparisons of efficacy do not exist between them nor are likely to be available in the future. We performed a meta-analysis on VNS, RNS, and DBS outcomes to compare seizure reduction efficacy for focal epilepsy. We systematically reviewed the literature for reported seizure outcomes following implantation with VNS, RNS, and DBS in focal-onset seizures and performed a meta-analysis. Prospective or retrospective clinical studies were included. Sufficient data were available at years one (n = 642, two (n = 480), and three (n = 385) for comparing the three modalities with each other. Seizure reduction for the devices at years one, two, and three respectively were: RNS: 66.3%, 56.0%, 68.4%; DBS- 58.4%, 57.5%, 63.8%; VNS 32.9%, 44.4%, 53.5%. Seizure reduction at year one was greater for RNS (p < 0.01) and DBS (p < 0.01) compared to VNS. Our findings indicate the seizure reduction efficacy of RNS is similar to DBS, and both had greater seizure reductions compared to VNS in the first-year post-implantation, with the differences diminishing with longer-term follow-up. The results help guide neuromodulation treatment in eligible patients with drug-resistant focal epilepsy. [ABSTRACT FROM AUTHOR]