Measurements and management of multiple sclerosis-related fatigue: an umbrella review and meta-analysis

Abstract

PURPOSE: This study aims to synthesize and appraise systematic reviews with meta-analyses that assessed pharmacological, non-pharmacological, and neuromodulatory interventions for MS-related fatigue. MATERIAL AND METHODS: PubMed, WOS, Scopus, Epistemonikos, and the Cochrane Database of Systematic Reviews were searched till Nov 2025. Effect sizes are reported as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Methodological quality was graded with AMSTAR-2. An exploratory meta-meta-analysis was also performed. RESULTS: Forty-six systematic reviews with meta-analyses covering 287 primary studies were included. Exercise provided the most consistent benefit: aerobic training produced a modest but reliable reduction in fatigue (SMD -0.32), while resistance exercise (-1.09) and yoga/mind-body formats (-0.70) showed larger but more heterogeneous effects. Cognitive behavioral therapy (CBT) and mindfulness/acceptance therapies yielded small to moderate improvements, while energy-conservation education showed a modest benefit. Vitamin D supplementation yielded a small effect (-0.18). Among neuromodulation approaches, transcranial direct current stimulation demonstrated a significant short-term impact (-1.02). CONCLUSION: Structured exercise supported by CBT or mindfulness offers the most clinically meaningful relief from MS-related fatigue. Future RCTs should adopt longer follow-up, and use standardized outcome fatigue scales. These conclusions should be interpreted considering the generally low methodological quality of the included reviews.