Non-invasive neuromodulation for the treatment of drug-resistant epilepsy: Protocol for a systematic review and meta-analysis investigating efficacy, safety, and optimal stimulation parameters.

BACKGROUND: Non-invasive neuromodulation presents as an exciting potential adjunctive therapy for people with drug-resistant epilepsy (DRE). A major advantage of this approach is the absence of the neurocognitive and systemic adverse events commonly associated with anti-seizure medications (ASM), and the significant risks that accompany both resective epilepsy surgery and invasive neuromodulation techniques. The proposed systematic review and meta-analysis will investigate the efficacy 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) for seizure reduction amongst patients diagnosed with DRE, with comparisons also being made between intervention types where applicable. Both immediate and long-term adverse events will also be discussed to offer greater insight into its use as a safe, viable, and reliable method of seizure control. The study's secondary aim will be to identify optimal stimulation parameters to better inform future clinical trial protocols and to maximise treatment efficacy in clinical applications. METHODS: PubMed, OVID Embase, OVID Medline, and Web of Science will be searched for studies investigating the efficacy and safety of non-invasive nerve and brain stimulation techniques for the management of DRE. Two authors will independently screen relevant studies in Covidence, extract data, and assess risks of bias, with discrepancies being resolved by a third reviewer. The primary outcome will be seizure reduction, measured by mean/median change in seizure frequency and responder rate. Secondary outcomes will include the percentage of patients reporting specified adverse events. A meta-analysis will assess the primary outcome. Subgroup analyses will be performed to investigate potential sources of heterogeneity and the optimal protocol settings for each intervention. Sensitivity analyses will also be conducted to evaluate the robustness of the results. DISCUSSION: This study will analyse all relevant non-invasive brain and nerve stimulation methods using a consistent protocol, uniquely allowing for rigorous comparisons and result-pooling to evaluate the overall efficacy and safety of each stimulation method. Additionally, it will identify optimal stimulation parameters, where possible, to facilitate the use of these methods in future trials and clinical applications. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023446051.