18.4: Exercise and Fatigue in People with Multiple Sclerosis

18.4.1. Definition and Description

Multiple sclerosis (MS) is an auto-immune disease, primarily affecting the brain and spinal cord. It is estimated that over 2.5 million people worldwide have MS, and MS is a leading cause of adult disability (Compston & Coles, 2008). The exact cause of MS is unknown but likely involves genetic and environmental factors. MS is characterized by the demyelination of axons in the central nervous system. It is believed that in people with MS, the immune system "attacks'' myelin, the insulating sheath around axons that enables efficient action potential transmission in the central nervous system. Failures in myelin-producing cells have also been indicated as a possible mechanism of MS. The loss of myelin causes dysfunction throughout the central nervous system and can cause problems with motor function (including weakness), sensory, autonomic and visual processes. The disease course of MS can be unpredictable, and the majority (~80%) of people with MS have relapsing‐remitting MS, meaning they experience periods with few or no symptoms (remission), which can be followed by periods where symptoms flare again (relapse). Eventually, relapsing‐remitting MS becomes what is known as secondary progressive MS, where symptoms get progressively worse (Compston & Coles, 2008).

Between 50–90% of all people with MS also report problems with fatigue, including adverse effects on activities of daily living, quality of life, and ability to work (Krupp et al., 1988). MS-related fatigue is defined as "a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities" (Multiple Sclerosis Council for Clinical Practice Guidelines, 1998, p. 2). For many people with MS, fatigue is the single most debilitating symptom they experience. Despite its prevalence and impact, the exact causes of fatigue in people with MS are unknown. Fatigue in people with MS can be thought of as either a primary or secondary symptom. Primary fatigue is assumed to be caused directly by the pathophysiology of the disease, such as inflammation, demyelination, and neurodegeneration. Secondary fatigue is thought to arise from associated psychological effects of MS, including sleep loss, depression, and pain. There are at present two primary suspected biological mechanisms for primary fatigue in MS: immune and neuroendocrine dysfunction and lesion-induced changes to brain activation. People with MS can have increased expression of pro-inflammatory cytokines, including interferon-γ and TNF-α. Systemic overexpression of these cytokines has been linked to "sickness-like" behaviours and symptoms, including increased fatigue. Alternatively, or even simultaneously, cortical, subcortical, and white matter lesions caused by successive demyelination and relatively unsuccessful remyelination seen in MS may also cause fatigue. The presence of these lesions may alter the structure and function of neural networks involved in cognition and sensorimotor planning and performance, causing increased feelings of effort and fatigue during physical and mental tasks. Secondary fatigue might be the consequence of other primary symptoms of MS. People with MS often have problems sleeping and increased pain, and these symptoms are linked to the experience of fatigue (Kos et al., 2008).

18.4.2. The Role of Exercise in Treating Fatigue in People with Multiple Sclerosis

Despite being advised for many years not to exercise, exercise and physical therapy are now recommended treatments for people with MS. Some of the proposed benefits of exercise for people with MS include improvements in strength and cardiorespiratory fitness, improved balance, walking performance, and proprioception (Amatya et al., 2017). Exercise is also suggested to be an effective treatment for fatigue in MS. In a 2015 Cochrane systematic review and meta-analysis, Heine et al., (2015) reported a moderate effect of exercise on fatigue in people with MS. There were very few side effects of exercise reported, including very few relapses, suggesting that exercise can be safely used to treat fatigue in people with MS. Compared to usual treatment, endurance exercise, mixed exercise (a mixture of strength and conditioning and endurance exercise), and alternative forms of exercise such as yoga and tai chi were all shown to have a moderate beneficial effect on fatigue. However, as with cancer, the literature in support of exercise as a treatment for fatigue in people with MS has some limitations. In their systematic review, Heine et al., (2015) found significant heterogeneity in the literature. This means that there were many differences in methods, study populations, and outcomes between studies. This makes it harder for us to be able to say with certainty that exercise reduces fatigue. Much more research is required, with careful and large replication of previous effects needed for us to become more confident in these results.

It is perhaps unsurprising, given that the exact causes of fatigue are unknown, that we do not know exactly how exercise alleviates fatigue in people with MS. Nonetheless, several candidate mechanisms have been proposed, and these depend on whether it is primary or secondary fatigue. Exercise has been shown to have positive effects on pro-inflammatory cytokine expression and neuroendocrine regulation, possible causes of primary fatigue in MS. Exercise has also been suggested to be neuroprotective and induce neuroplasticity, meaning it has been shown to protect against brain damage and encourage beneficial changes to the brain, both of which may help alleviate primary fatigue. Proposed mechanisms for the effect of exercise on secondary fatigue include reductions in depression and increased socialization. Perhaps surprisingly, at present, it is not clear whether there is a direct link between physical deconditioning and secondary fatigue. Nonetheless, it is possible that the effects of exercise on cardiorespiratory and muscular function may reduce secondary fatigue in people with MS (Langeskov-Christensen et al., 2017).

There is some evidence that endurance and strength exercise may help alleviate both primary and secondary fatigue in people with MS, and exercise appears to be safe and does not cause a significant relapse. However, despite the growing body of evidence linking increased exercise participation and a range of symptom improvements in people with MS, including fatigue, participation levels remain low. It is estimated that perhaps as few as 20% of people with MS participate in physical activity and activity levels appear to decline as the disease progresses. Many factors may limit participation, from direct physical causes such as increased pain or reduced mobility, psychosocial factors including depression, self-efficacy and social support, and environmental factors such as limited access to suitable facilities (Motl et al., 2017). At present, it is not clear what type of exercise and what dose of exercise is best to treat fatigue in people with MS. More research is required on both the mechanisms of fatigue in people with MS and the pathways by which exercise may impact these mechanisms so that the promise of exercise as medicine for people with MS who report fatigue is realized.