title: Potential pathophysiological pathways that can explain the positive effects of exercise on fatigue in multiple sclerosis: A scoping review.
abstract: BACKGROUND
  Fatigue is one of the most common and most disabling symptoms of multiple sclerosis (MS). It is a multidimensional and complex symptom with multifaceted origins, involving both central and peripheral fatigue mechanisms. Exercise has proven to be safe for people with MS, with cumulating evidence supporting significant reductions in fatigue. However, the potential pathophysiological pathways that can explain the positive effects of exercise on fatigue in MS remain elusive.
  
  
  OBJECTIVE
  The objectives were, in PwMS (1) to update the knowledge on the pathophysiology underlying primary and secondary fatigue, and (2) to discuss potential pathophysiological pathways that can explain the positive effects of exercise on MS fatigue.
  
  
  METHODS
  A comprehensive literature search of six databases (PubMed, Embase, Cochrane Library, PEDro, CINAHL and SPORTDiscus) was performed. To be included, the study had to 1) enroll participants with definite MS according to defined criteria, 2) assess explicit pathophysiological mechanisms related to MS fatigue, 3) be available in English, Danish or French, and 4) had undergone peer-review.
  
  
  RESULTS
  A total of 234 studies fulfilled the inclusion criteria. Primary MS fatigue mainly originated from a dysfunction of central nervous system neuronal circuits secondary to increased inflammation, reduced glucose metabolism, brain atrophy and diffuse demyelination and axonal lesions. Secondary MS fatigue was linked with sleep disturbances, depression, cognitive impairments, and deconditioning. Cardiovascular, immunologic, neuroendocrine, and neurotrophic changes associated with exercise may alleviate primary MS fatigue while exercise may improve secondary MS fatigue through symptomatic improvement of deconditioning, sleep disorders, and depression.
  
  
  CONCLUSIONS
  >30 primary and secondary pathophysiological fatigue pathways were identified underlining the multidimensionality and complexity of MS fatigue. Though the underlying key cellular and molecular cascades still have to be fully elucidated, exercise holds the potential to alleviate MS fatigue, through both primary and secondary fatigue pathways.
authors.affiliation: Section of Sport Science, Department of Public Health, Aarhus University, Aarhus C, Denmark. Electronic address: mach@ph.au.dk.
authors.forename: Martin
authors.initials: M
authors.lastname: Langeskov-Christensen
authors.affiliation: School of Rehabilitation Therapy, Queen's University, Kingston, Canada.
authors.forename: Etienne J
authors.initials: EJ
authors.lastname: Bisson
authors.affiliation: School of Rehabilitation Therapy, Queen's University, Kingston, Canada.
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Finlayson
authors.affiliation: Section of Sport Science, Department of Public Health, Aarhus University, Aarhus C, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Dalgas
mesh_terms: D015444:Exercise / Q000502:physiology*; D005081:Exercise Therapy; D005221:Fatigue / Q000209:etiology / Q000503:physiopathology* / Q000534:rehabilitation*; D006801:Humans; D009103:Multiple Sclerosis / Q000150:complications / Q000503:physiopathology* / Q000534:rehabilitation*
keywords: Exercise therapy; Fatigue; Multiple sclerosis; Pathophysiology; Rehabilitation