Non-invasive brain stimulation for fatigue in multiple sclerosis patients: A systematic review and meta-analysis

Background: To investigate the efficacy and safety of non-invasive brain stimulation for fatigue in multiple sclerosis patients. Methods: We searched MEDLINE, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Wanfang databases up to October 25, 2018 (PROSPERO registration number: CRD42018112823). Randomized or pseudo-randomized, sham-controlled clinical trials evaluating the effect of non-invasive brain stimulation (NIBS) such as transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), transcranial random noise stimulation (tRNS), transcranial alternating current stimulation (tACS), cranial electrotherapy stimulation, and reduced impedance non-invasive cortical electrostimulation were included. Two authors independently performed data extraction and risk of bias assessment according to Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The primary outcome was fatigue scores before and after stimulation and the secondary outcome was adverse events. Results: Data from cross-over and parallel group studies were pooled using a generic inverse-variance approach. A total of 14 studies (11 for tDCS, 2 for TMS, and 1 for tRNS) recruiting 207 patients were included in the systematic review and meta-analysis. No eligible tACS, cranial electrotherapy stimulation or reduced impedance non-invasive cortical electrostimulation studies were found. Short-term and long-term treatment effects were significant for tDCS, whereas TMS and tRNS were not superior to sham stimulation. The available evidence supported the effectiveness of the 1.5 mA subgroup and bilateral S1 subgroup of tDCS. Adverse events were minor and transient but comparable between real and sham stimulation. Conclusions: tDCS is a safe and effective treatment for fatigue in MS patients. However, further studies are required to confirm our results in a large-scale population and to investigate the effectiveness of other NIBS subtypes.