Treating fatigue in multiple sclerosis: Aerobic training

Multiple sclerosis (MS) is considered a chronic and debilitating autoimmune-mediated inflammatory and neurodegenerative disorder of the central nervous system. It is the number one neurological condition in young adults, affecting approximately 17.000 people in the Netherlands. Patients with MS often experience severe levels of chronic fatigue which, amongst others, affects societal participation. In the context of a progressive neurological disease patients often adopt a relative sedentary lifestyle. This, in turn may negatively affect their physical fitness and general health which subsequently increases the perceived fatigue severity. Following a vicious cycle, this may then lead to a more sedentary lifestyle.

The exact pathophysiology of MS-related fatigue is poorly understood leading to lack of consensus regarding definition and assessment tools (chapter 10). Various mechanisms have been proposed through which a structural exercise program may alleviate fatigue including an anti-inflammatory effect, a psychosocial effect, a neuroprotective effect, and an increase in physical fitness and general health. The first part of this thesis assessed the psychometric properties of the gold standard cardiopulmonary exercise test (CPET) for physical fitness, in patients with MS. CPET is reliable (chapter 3) and valid (chapter 4) in ambulant patients with MS. In patients that are not ambulant, the oxygen uptake efficiency slope (OUES) may prove a valid and reliable alternative measure for physical fitness in comparison to the convention peak oxygen uptake (chapter 5). The combined evidence of 40 studies that used CPET to assess aerobic capacity (i.e. physical fitness) in patients with MS suggested that aerobic capacity is on average ~17% lower in patients with MS compared to healthy controls (chapter 2), and further declines with an increase in disease severity (chapter 2 and 6). The magnitude of this decline is associated with secondary healthy risks.

A systematic review (chapter 7) indicated a moderate effect of aerobic training on fatigue, however in the studies underlying this review fatigue was often a secondary outcome which had implications on our confidence in the found effect size. In the second part if this thesis we described the protocol (chapter 8)and results (chapter 9) of a multi-center randomized clinical trial to study the effects of aerobic training on fatigue and societal participation in 90 severely fatigued patients with MS. The patients allocated to the aerobic training intervention, compared to the control condition, significantly improved their fatigue levels by 4.7 points on the primary fatigue outcome (checklist individual strength fatigue subscale, range 8 – 56). Unfortunately, the magnitude of improvement was below the a priory defined cut-off of 8 points to be clinically relevant. This notion was further supported by (1) the lack of improvement on the complementary fatigue questionnaires included, (2) by the finding the improvement did not sustain during the 10 weeks, and 36 weeks follow-up; and (3) that the improvement in fatigue did not lead to an improvement in societal participation. This, in the context of previous studies, led to the conclusion that aerobic training does not lead to clinically relevant reductions of MS-related fatigue nor improvements in societal participation.