Fatigue in multiple sclerosis - Insights into evaluation and management

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system, characterized by the accumulation of numerous neurological symptoms and signs throughout its course. Fatigue is one of the most distressing complaints that MS patients may experience over their lifetime. In spite of its high prevalence, the pathophysiology of MS fatigue is far from being fully elucidated and a constellation of mechanisms seems implicated in this setting. Several factors could contribute to its development and/or exacerbation, and this requires a careful workup in order to search for all possible underlying causes, such as sleep disturbances, endocrine dysfunction and mood disorders, to cite a few. The aim of this review is to revisit the definition of MS fatigue, provide an overview of its pathophysiology, and reappraise its clinical, structural and functional correlates. Additionally, we discuss the available assessment tools, as well as the various management strategies including pharmacological and non-pharmacological interventions. Special emphasis will be placed on the role of noninvasive brain stimulation techniques in this field. Finally, we propose a "road map" to facilitate the diagnosis and guide the therapeutic regimens of this multifactorial and multidimensional construct.