The impact of regular physical activity on fatigue, depression and quality of life in persons with multiple sclerosis

Multiple Sclerosis (MS) is a relapsing or progressive neurological disease with an unknown etiology and only partially effective treatment. MS can have a negative impact on both physical and psychological well being [1, 2], and individuals with this disease often report lower quality of life (QoL) scores than when compared to healthy individuals [1]. Fatigue and depression levels are higher in MS patients than healthy individuals, and these conditions may negatively impact upon QoL. However, participation in regular physical activity has been suggested to positively influence feelings of fatigue [3, 4] and depression [5], as well as modify QoL [6, 7] in persons with MS.

Fatigue is the most common symptom reported by persons with MS [1, 8], and has been negatively associated with QoL scores [9]. The Multiple Sclerosis Council for Clinical Practice Guidelines defines fatigue 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" [10]. The pathophysiological basis of fatigue in MS is complex and its precise mechanisms unresolved. Fatigue in MS may result from primary factors, related to the disease process itself, or may be secondary due to factors such as sleep disturbance and depression [10]. Fatigue may be acute or chronic in nature. Chronic fatigue is persistent, defined as being present for any amount of time, on 50 percent of days for at least 6 weeks[10]. Acute fatigue is defined as new or a significant increase in fatigue in the previous 6 weeks[10]. Some persons with MS may also experience fatigability, where they may become exhausted after completing a period of physical activity [8]. Patients may also experience motor fatigue following a period of physical activity which may lead to symptom exacerbations [11], for example although not present at rest a subject may develop footdrop following a period of physical activity. This symptom exacerbation is temporary and will subside with a rest period [12]. Considering the symptoms, it is reasonable to suggest that fatigue, fatigability and symptom exacerbations deter individuals with MS from participating in physical activity. Nevertheless, studies have reported decreased fatigue levels in persons with MS following participation in regular physical activity [3, 13]. A decrease in the level of chronic fatigue and the ability to tolerate higher levels of activity (reduced fatigability) following a program of regular exercise might lead to improvements in QoL in persons with MS.

Depression is commonly observed in persons with MS, [14, 15] and has been negatively associated with QoL scores [16, 17]. Participation in regular physical activity is a potential moderator of depression. Cross-sectional analyses in non-MS populations suggest that individuals who participate in regular exercise are less likely to suffer from depression [18]. If regular physical activity also positively influences depression in persons with MS, then it follows that associated improvements in QoL may be observed.

The present study compared fatigue, depression and QoL scores in persons with MS who did and did not regularly participate in physical activity. It was hypothesised that persons with MS who participated in regular physical activity would report favourable fatigue, depression and QoL scores when compared to those with MS who were classified as Non-exercisers.

The purpose of this study was to compare fatigue, depression and QoL scores in persons with MS who did and did not participate in regular physical activity. A recent review of exercise intervention studies in persons with MS, found evidence to support the positive effect of exercise on QoL, however these authors concluded their was insufficient research in this area [31]. The findings of this study support the hypothesis that regular physical activity is associated with favourable fatigue, depression and QoL scores in persons with MS.

In the present study, subjects classified as Exercisers reported less fatigue on the Physical and Psychosocial scales and overall score of the MFIS. These results are supported by Trojan et al (2007) who preformed correlation analysis on the General, Mental and Physical scales of the Multidimensional Fatigue Inventory and found that physical activity was weakly correlated with the Physical but not the General or Mental scales of the Multidimensional Fatigue Inventory [32].

Fatigue in MS may be attributed to primary factors related to the disease process or secondary factors such as sleep disturbances, depression, pain and medication use [33]. Theories of primary fatigue in MS include hypo-functioning within the central nervous system [34], reduced glucose metabolism in the cortical regions of the brain [35], reduced inhibition of the primary motor cortex in the pre- and post- exercise period [36] and abnormal cytokine profiles [37, 38]. Both aerobic- and resistance-based exercise programs have been found to alter cytokine profiles in MS patients [39, 40] and this provides a plausible explanation for the improvement in fatigue seen in some patients following regular physical activity.

Alternatively, improvements in secondary factors such as depression with regular physical activity may explain the improvements seen in fatigue in some MS patients. Depression scores observed in the Exercisers in the present study were significantly lower when compared to Non-exercisers. It is well recognised that exercise is positively associated with psychological well being in the general population [41‐45]. It is unclear exactly how exercise improves depression in non-MS populations, however several theories have been proposed including: regulation of the hypothalamic-pituitary axis [46], increased β-endorphin levels [46], normalisation of hippocampal brain derived neurotrophic factor [47], regulation of central monoamines [46] and improved perceptions of self efficacy [48]. The hypothalamic-pituitary axis [49], brain-derived neurotrophic factor [50] and serotonin [51] have all been implicated in MS pathology. If exercise influences hypothalamic-pituitary axis function, brain-derived neurotrophic factor concentration or serotonin concentration in persons with MS, this provides a possible explanation for the decreased incidence of depression observed in persons with MS who regularly participate in physical activity. Alternatively, depression etiology in MS may have a psychological rather than neurobiological explanation. In persons with MS, a positive relationship between activity levels and self-efficacy has been reported [52]. Due to the relatively high incidence of depression in MS, both the etiology and the influence of exercise on depression are areas that warrant further investigation.

In the present study, Exercisers had significantly higher scores on all components of the SF-36, which is suggestive of a higher QoL. These findings are supported by Stuifbergen et al (2006) who found that exercise behaviour, measured using the exercise/physical subscale of the Health Promoting Lifestyle Profile II, was positively associated with QoL[7]. When QoL was assessed across the spectrum of disease severity, we found interaction effects between exercise status and disease severity for the Physical Function, Bodily Pain and Physical Component Summary Scores of the SF36 (Figures 4, 5 and 6). Visual interpretation of these figures suggests that although these scales were similar between Exercisers and Non-exercisers with mild MS (DSS ≤1), regular physical activity impacts favourably upon QoL in patients with a DSS between two and four. Once disease severity reached a DSS ≥5, QoL was again similar between Exercisers and Non-exercisers. Therefore, participation in regular physical activity appears to have the greatest positive influence on QoL in patients once visual abnormalities in gait have developed, until the point of time when patients become cane-dependant.

To date the majority of exercise intervention studies have focused on patients with mild-moderate MS, and although these studies have been associated with positive benefits for persons with MS [53, 54], little information is available on the influence of physical activity for persons across the disease spectrum. The results of this study suggest the exercise may have a greater effect on QoL in the physical domain in persons with moderate MS. The reason for this is unknown, however it may be speculated that regular physical activity improves a patients' ability to perform physical tasks, or improves a patients' perception of the impact their disability has on their physical functioning. This improved QoL in the physical function, and physical component summary scores of the SF36, may be particularly evident in patients with moderate MS. Perhaps in persons with mild MS, the physical limitations of the disease are minimal and therefore irrespective of exercise status the impact of the disease on QoL in the physical domain is minimal. Similarly, it maybe once disease severity and physical limitation become severe, that these limitations will significantly impact on QoL irrespective of exercise status. This is an area that warrants further investigation, in order for health care professionals to implement exercise intervention and management programs to those patients who will receive maximal benefit.

Cross-sectional studies investigating the role of physical activity on QoL in persons with MS have typically correlated activity levels and QoL scores [7, 55]. The present study reported significant weak correlations between both leisure and overall activity scores on the IPAQ, and some fatigue, depression and QoL scores in persons with MS. This suggests that there may not be a linear relationship between activity levels and fatigue, depression and QoL scores in persons with MS.

The current study classified Exercisers as subjects who completed at least two 30-min exercise sessions·wk^-1. This exercise volume does not meet the recommended dose of exercise prescribed by the American College of Sports Medicine [56]. It is unknown whether the completion of two 30-min exercise sessions·wk^-1 would elicit adaptations in cardiovascular fitness or reduce the risk of co-morbidities and unhealthy weight gain in this clinical population. However, the current study does suggest that completing at least two 30-min exercise sessions·wk^-1 may positively influence disease specific symptoms such as fatigue and depression in persons with MS.

Due to the cross-sectional nature of this study we cannot provide definitive conclusions on the direction of causality between activity levels and fatigue, depression and QoL scores. Subjects in this study were recruited from two separate patient databases. Although we have no reason to believe there would be any differences in the disease characteristics of the patients in the two databases utilised in this study we did not perform any analysis to confirm this. Data was collected in a de-identified manner and we were unable to provide information on responders vs. non-responders and we cannot guarantee that the sample population utilised in this study provides an accurate representation of all persons with MS living in Queensland, Australia. This study had a reasonably low response rate (31%) and it is possible that health conscious individuals may have been more inclined to participate in the study. This may be demonstrated by the relatively higher number of Exercisers in this study (43%) compared to a rate of 28.6% in a recent cross-sectional survey of men with MS [57]. Additionally it is worthwhile noting that although the sex distribution between subjects classified as Exercisers (23% male) and Non-exercisers (17% male) are not statistically significant, these numbers may in fact represent a difference that may impact on the results of this study.

Subjects recruited through the MS Society of Queensland's database had not had their MS diagnosis confirmed by a physician or neurologist, and disease course and severity are patient and not physician reported, this may provide a source of error in the patient characteristics reported. The final limitation to consider when interpreting the results of this study is that we found a statistically significant difference in the MSIS-29 score between Exercisers and Non-exercisers. The MSIS-29 measures the impact of the disease on the individual of the previous 2 weeks, it is possible that regular exercise may improve the MSIS-29 by improving either the perception or the ability of the individual to perform physical tasks, alternately, this difference in MSIS-29 score may indicate a difference in the baseline characteristics between the Exercisers and Non-exercisers in this study.

The strength of the current study is that although exercise intervention studies have been associated with improved fatigue, depression and QoL in small samples of MS patients, this study provides an overall view of these relationships. This study focused on patients across the entire disease spectrum and was not limited to those with mild-moderate MS.

In summary, subjects who participated in regular physical activity reported better results on the BDI, all scales of the SF36, and some scales of the MFIS. This suggests that persons with MS who regularly participate in physical activity have favourable fatigue, depression and QoL scores, when compared to persons with MS who do not regularly participate in physical activity. This study gives strength to previous suggestions that regular physical activity may improve fatigue, depression and QoL in persons with MS.

This study reinforces that health care providers should promote physical activity in persons with MS as a strategy to improve QoL. This study does highlight the need for exercise intervention studies to occur not only in persons with mild-moderate disability but in those patients with moderate-severe disability as well, in order to understand the potential for physical activity to improve QoL in all persons with MS. Further research investigating the mode of exercise that will provide maximum benefit to persons with MS, across the entire disease spectrum is warranted.