Background: Fatigue is the most commonly reported symptom in multiple sclerosis (MS). Purpose: This brief narrative review addresses the clinical features, pathophysiology, and management of MS fatigue, as well as the varied approaches to its definition and measurement. Methods: A literature search was conducted through Medline of studies published since 1984, with a focus on findings reported since 2008. Results: Studies of MS fatigue have primarily relied on the definition of fatigue as a subjective sense of tiredness measured through self-report. Additional studies have measured fatigability in MS, as demonstrated by a decline in cognitive or motor performance over time. The pathogenesis of fatigue remains poorly understood but disease characteristics, including structural and physiologic cerebral alterations as well as immune, endocrine, and psychological factors, may all contribute to its expression. Fatigue therapy has included pharmacologic approaches which have had either methodological limitations (e.g., small sample sizes) or inconclusive results and non-pharmacologic interventions, some of which have been effective in reducing fatigue. Conclusions: Fatigue remains a challenging symptom in MS. The most effective measurement approaches will likely be multidimensional and include both subjective and objective indicators, whereas therapy will likely require more than one type of intervention.

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