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

Drug-resistant epilepsy (DRE), defined as failure of at least two anti-seizure medications, affects nearly one-third of individuals with epilepsy and remains a significant therapeutic challenge. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulatory approach, has emerged as a potential treatment option for DRE. This systematic review aimed to evaluate the effectiveness of rTMS in reducing seizure frequency in this population. A comprehensive literature search of PubMed, Scopus, Web of Science, and the Cochrane Central was conducted up to October 31, 2025. Randomized controlled trials (RCTs) comparing low-frequency (≤ 1 Hz) rTMS with sham stimulation in DRE patients were included. Continuous outcomes were pooled using a random-effects model and reported as standardized mean differences (SMD) with 95% confidence intervals (CI). Eight randomized controlled trials met inclusion criteria for qualitative synthesis, of which five RCTs comprising 172 participants (88 active rTMS, 84 sham rTMS) were included in the quantitative meta-analysis. The mean age of participants ranged from 8.9 to 40 years. Active rTMS significantly reduced seizure frequency at two weeks (SMD = -0.57, 95% CI: -0.96 to -0.18; p = 0.004), four weeks (SMD = -0.62, 95% CI: -1.03 to -0.21; p = 0.002), and eight weeks (SMD = -0.65, 95% CI: -0.98 to -0.32; p < 0.0001). A subgroup analysis based on stimulation frequency showed comparable effects for 1 Hz (SMD = -0.51, 95% CI: -1.12 to 0.09, p = 0.0932) and 0.5 Hz (SMD = -0.61, 95% CI: -1.13 to -0.10). Additionally, active rTMS showed a significant change in interictal epileptiform discharge (SMD = -0.44, 95% CI: -0.84 to -0.04; p = 0.03) and a higher responder rate (RR = 6.94, 95% CI: 2.54 to 18.95, p = 0.0002). Adverse events were predominantly mild and comparable between active and sham groups, confirming a favorable safety profile. Low-frequency rTMS may serve as a safe and effective therapeutic intervention for reducing seizure frequency and interictal epileptiform discharge in patients with DRE. These findings support the potential role of rTMS as a promising adjuvant therapy in DRE management. Larger, well-designed trials with longer follow-up are required to confirm long-term effectiveness and optimize stimulation parameters.