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Meta-Analysis
. 2025 Dec 6;273(1):7.
doi: 10.1007/s00415-025-13522-1.

Non-invasive neurostimulation for drug-resistant epilepsy: systematic review and meta-analysis of effectiveness, safety, and optimal stimulation parameters

Sayumi Premaratne  1 , Maryam Zoghi  2 , Ana Antonic-Baker  1 , Zhibin Chen  1 , Leo Chen  1   3   4   5 , Ryan Hamer  6   4   5 , Brendan Major  1 , Elizabeth H X Thomas  1   3   4   5 , Patrick Kwan  1   3 , Terence J O'Brien  1   3 , Brian N Lundstrom  7 , Hugh D Simpson  8   9
Affiliations
Meta-Analysis

Non-invasive neurostimulation for drug-resistant epilepsy: systematic review and meta-analysis of effectiveness, safety, and optimal stimulation parameters

Sayumi Premaratne et al. J Neurol. .

Abstract

Drug-resistant epilepsy is a common and disabling condition, with few non-surgical treatment options. Non-invasive neurostimulation is an emerging therapy for drug-resistant epilepsy, though evidence is mixed and comparisons between modalities remain challenging. This review systematically appraises and compares the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), low-intensity focused ultrasound (LI-FUS), transcutaneous vagus nerve stimulation (tVNS) and trigeminal nerve stimulation (TNS) in drug-resistant epilepsy. A meta-analysis was performed to evaluate the effectiveness in seizure reduction (primary outcome), and a meta-regression analysis was conducted to investigate optimal parameters. Sixty-three studies (1342 active participants, 505 controls) were included. At the end of follow-up, pooled mean changes in seizure frequency were: rTMS - 30.2% (95% CI: [- 49.6, - 10.7%]), tDCS - 46.9% (95% CI: [- 66.6, - 27.3%]), and tVNS - 49.2% (95% CI: [- 86.7, - 11.8%]). There was insufficient data to determine effect sizes in tACS, LI-FUS and TNS. Responder rates (percentage of participants with a > 50% decrease in seizure frequency) were: rTMS 38% (95% CI: [24, 51%]), tDCS 49% (95% CI: [32, 66%]), tVNS 29% (95% CI: [7, 50%]), and TNS 42% (95% CI: [24, 60%]); with inadequate data for tACS and LI-FUS. No serious adverse events were reported, and seizure precipitation was rare. rTMS and tDCS demonstrate the strongest evidence for effectiveness, while tVNS and TNS show promise, and tACS and LI-FUS require further study. These findings, while encouraging, should be interpreted in the context of methodological heterogeneity between studies and overall low certainty of evidence.

Keywords: DRE; Epilepsy; NIN; Neuromodulation; Neurostimulation; Seizure.

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Conflict of interest statement

Declarations. Conflicts of interest: B.N. Lundstrom declares intellectual property licensed to Cadence Neuroscience Inc (contractual rights waived, all funds to Mayo Clinic) and Seer Medical Inc (contractual rights waived, all funds to Mayo Clinic), site investigator (Medtronic EPAS, Neuroelectrics tDCS for Epilepsy), and industry consultant (Epiminder, Medtronic, Neuropace, Philips Neuro, all funds to Mayo Clinic); R. Hamer is a consultant for Nexstim (Helsinki, Finland); The remaining authors have no competing interests to declare that are relevant to the content of this article. Ethics approval/patient consent: This review draws exclusively on previously published work. Therefore, ethical approval from an Ethical Review Board and written informed patient consent were not required.

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