Low-frequency repetitive transcranial magnetic stimulation significantly reduces seizure frequency and abnormal brain electrical activity in patients with drug-resistant epilepsy, according to a systematic review and meta-analysis published in BMC Neurology. Evaluating pooled clinical data from randomized controlled trials that compared active stimulation against sham procedures, the study demonstrated sustained reductions in seizure rates across multiple follow-up intervals alongside improved responder rates. These findings provide quantitative evidence supporting non-invasive neuromodulation as a potential adjuvant therapy for patients who fail to respond to standard anti-seizure medications.

Drug-resistant epilepsy presents a major therapeutic challenge in clinical neurology. The condition is defined as the failure to achieve seizure freedom after adequate trials of at least two anti-seizure medications, affecting approximately one-third of individuals living with epilepsy. Because pharmaceutical options offer limited benefit once resistance develops, repetitive transcranial magnetic stimulation has emerged as a non-invasive neuromodulatory approach under active investigation.

To evaluate the therapeutic efficacy and clinical safety of this intervention, researchers conducted a comprehensive literature search across PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials up to October 31, 2025. The inclusion criteria were restricted to randomized controlled trials comparing low-frequency repetitive transcranial magnetic stimulation, defined as frequencies of 1 Hz or less, against sham stimulation in patients with drug-resistant epilepsy, ensuring rigorous evaluation of active treatment effects.

The systematic search identified eight randomized controlled trials that met all criteria for qualitative synthesis. Among these, five randomized controlled trials comprising 172 participants provided sufficient continuous outcome data for inclusion in the quantitative meta-analysis. Within this pooled sample, 88 participants received active low-frequency stimulation and 84 participants underwent sham stimulation. The study cohorts spanned both pediatric and adult populations, with the mean age of participants ranging from 8.9 to 40 years, reflecting clinical evaluation across diverse age groups facing drug-resistant epilepsy.

Continuous outcomes were synthesized using a random-effects model and reported as standardized mean differences with 95 percent confidence intervals. Active low-frequency stimulation produced statistically significant reductions in seizure frequency across all evaluated time points compared with sham controls. At two weeks following treatment, active stimulation achieved a standardized mean difference of -0.57 (95 percent confidence interval: -0.96 to -0.18; p = 0.004). This therapeutic reduction persisted at four weeks of follow-up, demonstrating a standardized mean difference of -0.62 (95 percent confidence interval: -1.03 to -0.21; p = 0.002). By eight weeks post-intervention, the reduction in seizure frequency remained marked, yielding a standardized mean difference of -0.65 (95 percent confidence interval: -0.98 to -0.32; p < 0.0001), indicating lasting benefits over the primary study observation period.

The researchers also conducted a subgroup analysis based on stimulation frequency to examine potential variation within low-frequency protocols. Interventions administering 1 Hz stimulation demonstrated a standardized mean difference of -0.51 in seizure frequency reduction (95 percent confidence interval: -1.12 to 0.09; p = 0.0932). Meanwhile, protocols delivering 0.5 Hz stimulation achieved a standardized mean difference of -0.61 (95 percent confidence interval: -1.13 to -0.10). The authors observed that these subgroup findings indicated comparable clinical effects between 1 Hz and 0.5 Hz stimulation parameters, suggesting that both low-frequency regimens confer similar neuromodulatory impacts.

In addition to seizure frequency, the meta-analysis examined key secondary neurophysiological and categorical clinical outcomes. Active stimulation produced a statistically significant reduction in interictal epileptiform discharge, reflecting decreased abnormal electrical discharges between seizures, with a standardized mean difference of -0.44 (95 percent confidence interval: -0.84 to -0.04; p = 0.03). Categorical outcomes further supported clinical benefit, as patients receiving active stimulation showed a substantially higher responder rate than those in sham groups. The pooled responder rate yielded a risk ratio of 6.94 (95 percent confidence interval: 2.54 to 18.95; p = 0.0002), demonstrating a significant increase in the proportion of participants experiencing meaningful clinical response.

Assessment of tolerability revealed a favorable safety profile across the included randomized controlled trials. Reported adverse events were predominantly mild in severity, and their overall occurrence was comparable between the active stimulation cohorts and the sham control groups. These findings confirm that low-frequency repetitive transcranial magnetic stimulation was well tolerated by participants, with no evidence of disproportionate adverse events associated with active treatment.

Based on these findings and systematic GRADE assessment, the authors concluded that low-frequency repetitive transcranial magnetic stimulation may serve as a safe and effective adjuvant therapy for reducing seizure frequency and epileptiform discharges in drug-resistant epilepsy. However, the researchers emphasized that existing evidence remains derived from five quantitative trials. Consequently, larger, well-designed randomized controlled trials with longer follow-up periods are required to definitively establish long-term clinical effectiveness, evaluate sustained outcomes, and optimize specific stimulation parameters for routine practice.

Subject of Research: Low-frequency repetitive transcranial magnetic stimulation for drug-resistant epilepsy

Article Title: Efficacy and safety of low-frequency repetitive transcranial magnetic stimulation in patients with drug-resistant epilepsy: a systematic review and meta-analysis of randomized controlled trials with GRADE assessment

Article References: Siam, A. M., Abbas, O. F., Salad, H. H., Ahmed, N. A. T., Haddad, R., Mahmoud, M. A. T., Waleed, S., Tahoun, M., & Uwishema, O. (2026). Efficacy and safety of low-frequency repetitive transcranial magnetic stimulation in patients with drug-resistant epilepsy: a systematic review and meta-analysis of randomized controlled trials with GRADE assessment. BMC Neurology. https://doi.org/10.1186/s12883-026-05528-7

Image Credits: AI Generated

DOI: 10.1186/s12883-026-05528-7

Keywords: repetitive transcranial magnetic stimulation, rTMS, drug-resistant epilepsy, seizure frequency, interictal epileptiform discharge, low-frequency stimulation, randomized controlled trials, meta-analysis, systematic review, GRADE assessment, sham stimulation, anti-seizure medications, neuromodulation, responder rate, adverse events, pediatric and adult epilepsy, BMC Neurology