Associations Between Fatigue and Disability, Functional Mobility, Depression, and Quality of Life in People with Multiple Sclerosis

Data were collected from individuals with MS referred to a rehabilitation and wellness program at the University of Utah MS Rehabilitation and Wellness Clinic (Salt Lake City). As part of the program, each individual underwent a baseline medical evaluation of physical status and function to determine his or her specific exercise prescription. Evaluations were conducted by trained staff and included a comprehensive neuromuscular examination, functional mobility testing, and health status and fatigue questionnaires. Participants had signed a University of Utah institutional review board–approved consent form and agreed to utilization of their clinical data for cross-sectional research analyses. Baseline data from individuals referred to the program between 2007 and 2013 were included in this study.

The inclusion criteria were a clinically definite MS diagnosis, an Expanded Disability Status Scale (EDSS) score of 1 to 8 to encompass individuals with MS across a wider disability spectrum, and age older than 18 years. The exclusion criteria included a history or evidence of an acute exacerbation (<3 weeks). All the MS wellness program participants were referred by their neurologists, who screened and addressed other significant medical conditions before their participation in the program.

Participant interviews provided information on demographic characteristics. Functional mobility tests and self-report assessments were performed with rest periods in between as required. The disability status measurements were conducted on a separate occasion to minimize fatigue. All testing was completed within 2 to 3 weeks.

Fatigue was determined by the MFIS-5, developed by the Multiple Sclerosis Quality of Life Inventory panel to assess the impact of fatigue on the lives of individuals with MS. The short version was used for time efficiency; participants required less than 5 minutes to complete the self-report questionnaire. The items on the MFIS-5 inquired about the following: Because of fatigue during the past 4 weeks, have you been less alert? Have you been limited in your ability to do things away from home? Have you had trouble maintaining physical effort for long periods? Have you been less able to complete tasks that require physical effort? Have you had trouble concentrating? The MFIS-5 total score ranges from 0 to 20, with higher scores indicating greater fatigue. For this study, all the participants were divided into two groups: group LF included people with MS with MFIS-5 scores of 10 or less, indicating low levels of fatigue, and group HF included people with MS with MFIS-5 scores greater than 10, indicating high levels of fatigue. A cutoff score of greater than 10 was used to identify individuals with MS reporting a greater than “sometimes” impact of fatigue in performing daily activities on all the questions of the MFIS-5. Chwastiak et al.15 used this scale to categorize people with MS into groups of disabling and nondisabling fatigue. The longer version of the MFIS is a multidimensional scale to measure the perceived impact of fatigue on various activities of daily living and has been found to have good reliability and validity in MS.19,20 

The functional mobility measures included the 8-foot Timed Up and Go (TUG) test, the Activities-specific Balance Confidence (ABC) scale, and the 12-item Multiple Sclerosis Walking Scale (MSWS-12). For the TUG test, participants were instructed to start from a seated position and rise to standing, walk forward 8 feet, turn around, and return to sitting as quickly as possible. Time was recorded to the nearest 0.01 second from the time of the word “go” until return contact with the buttocks on the chair.21 The fastest time of the two trials was used for analysis. Concurrent validity22 and reliability23 have been assessed in individuals with MS.

The ABC scale is a 16-item self-reported measure of balance confidence in performing various activities of daily living. Each question requires the individual to grade himself or herself on a scale from 0% to 100% for their level of confidence,24 and higher scores indicated greater balance confidence in performing these activities. The mean score for 16 items was analyzed in this study. The reliability and validity of the ABC scale have been studied in people with MS.22,25 

The MSWS-12 is a 12-item measure of self-reported walking ability and balance in standing activities. Each item was scored on a scale from 1 to 5. Total MSWS-12 scores were generated by summing the scores from all items, subtracting the minimum score (12), dividing by the maximum score (48), and then multiplying by 100. High scores indicate a greater effect on walking ability. The test is reliable and correlates well with other self-rating measures, such as the physical areas of the 29-item Multiple Sclerosis Impact Scale, the 36-item Short Form Health Status Survey (physical functioning), the Functional Assessment of Multiple Sclerosis (mobility scale), and the Performance Scales.26 The reliability (intraclass correlation coefficient = 0.93) and precision (standard error of measurement = 8%, coefficient of variation = 27%) have been determined by Learmonth et al.27 

Depression was assessed by the modified Beck Depression Inventory (BDI-Fast Screen [BDI-FS]). This is a modified seven-item version of the traditional BDI. The BDI-FS is a self-reported survey with total responses ranging from 0 to 21, where higher scores indicated higher levels of depression. The BDI-FS has been previously validated in MS.28 

Quality of life was measured using the Multiple Sclerosis Quality of Life-54 Instrument (MSQOL-54), a multidimensional self-report measure that includes both MS-specific and generic items. It generates 12 subscales, 2 summary scores, and 2 single-item measures.29 The two summary scores (physical QOL and mental QOL) were used for the study. Özakbas et al.30 compared the MSQOL-54 with two other QOL instruments and found it to be the most reliable measure of QOL in people with MS.

Neurologic disability was assessed by the EDSS. Disability status was measured as part of a standardized neurologic examination performed by an experienced licensed physical therapist using the Neurostatus assessment for determination of Kurtzke Functional System Scores and EDSS scores (Neurostatus Systems AG, Basel, Switzerland).31 

Nonparametric statistical methods were used because the assumptions of normality were not met. Mann-Whitney U tests for independent samples were conducted to determine the differences in dependent variables, which included neurologic disability status, functional mobility, depression, and physical and mental QOL. The independent variable was group membership; group LF included people with MS with MFIS-5 scores of 10 or less, indicating low levels of fatigue, and group HF included people with MS with MFIS-5 scores greater than 10, indicating high levels of fatigue. Effect size (ES) estimates were calculated by dividing the z score of test statistics by the square root of N, where N is the total number of observations. A statistical software program (IBM SPSS Statistics for Windows, version 20.0, IBM Corp, Armonk, NY) was used, and the significance level was set at P ≤ .05.

Of 89 participants, 59 (66%) were women. High levels of fatigue (MFIS-5 score >10) were reported by approximately 64% of the study sample (Table 1).

Compared with group LF, group HF demonstrated significantly (P < .05) greater impairments in TUG test (ES = 0.20), ABC scale (ES = 0.31), and MSWS-12 (ES = 0.42) scores, indicating that people with MS who report higher levels of fatigue also exhibit significantly higher impairments in objective and self-reported measures of functional mobility (Figure 1; Table 1).

Similarly, group HF demonstrated significantly (P < .05) higher BDI-FS scores (ES = 0.34) and decreased physical (ES = 0.61) and mental (ES = 0.33) QOL compared with group LF, indicating that people with MS who report greater levels of fatigue also exhibit greater signs of depression and diminished QOL (Figure 1; Table 1).

However, EDSS scores were not significantly different between groups (P > .05), demonstrating that both groups had similar disability status irrespective of the level of fatigue (Figure 1; Table 1).

Fatigue is a common symptom in people with MS, but its associations with disability, functional mobility, depression, and QOL remain less studied. This study aimed to determine the associations between different levels of fatigue and neurologic disability, functional mobility, depression, and physical and mental QOL in people with MS. The results demonstrated that individuals with MS reporting a score greater than 10 on the MFIS-5 concomitantly demonstrated greater functional mobility impairments, increased depression, and decreased QOL as opposed to individuals with MS who report a score of 10 or less. Neurologic disability, however, was found to be similar across both groups.

The present study is the first to cross-sectionally examine the associations between different levels of fatigue and performance-based (TUG test) and self-reported (ABC scale and MSWS-12) measures of functional mobility in people with MS. Previous reports have determined that self-reported fatigue increases but that walking performance does not change from morning to afternoon in people with MS.32,33 A few studies have shown decreased performance of usual activities in people with MS who report high levels of fatigue.1,11,15,34 Although these studies effectively demonstrated a relationship between fatigue and daily activity in MS, the effect of differing fatigue levels on functional performance remained unclear. We determined that individuals with MS who scored greater than 10 on the MFIS-5 (group HF) took longer to perform the TUG test, reported decreased balance confidence in performing daily activities, and demonstrated a greater impact of MS on their walking ability. Significant mean differences with low-to-moderate ESs for the functional mobility measures were found between the groups (Table 1). This finding can be significant for a health-care provider to appropriately assess and manage a person with MS presenting with complaints of fatigue. Moreover, a time-efficient fatigue screening tool, such as the MFIS-5, can help the provider in early identification and suitable treatment of MS-related fatigue.

This study also demonstrated that people with MS who reported a score greater than 10 on the MFIS-5 (group HF) had higher scores on self-reported depression as measured by the BDI-FS. Depression has been identified as a contributor to secondary fatigue and vice versa.35 Bakshi et al.14 determined that MS-related fatigue is associated with depression even after controlling for physical disability, thereby suggesting that MS-related fatigue and depression share common mechanistic neural pathways. Although the design and analysis of the present study restricted us in controlling for neurologic disability, we found significant differences in depression scores across the groups along with no differences in neurologic disability, which is consistent with Bakshi et al.14 In contrast, Krupp et al.10 and Vercoulen et al.11 found no correlations between MS-related fatigue and depression. Both these studies had similar limitations in the study design, such as inclusion of individuals with lower disability scores on the EDSS, vague inclusion criteria, and the use of a less reliable and valid measure of fatigue, which might have been responsible for their findings. Recent studies, however, have used more sensitive measures of fatigue and have demonstrated a strong relationship between fatigue and depression in MS.14,15 The present study included a wider disability range and an abbreviated version of a sensitive fatigue measure (MFIS) previously used in MS, thus improving the relevance of these results to people with MS. The present findings confirm that an association between fatigue and depression is seen in MS; however, the causality and the direction of causality cannot be determined from these results.

The results of this study were found to be consistent with those of previous studies in determining a strong association between fatigue severity and the impact on QOL in people with MS. However, a greater ES was noted for physical QOL as opposed to mental QOL, suggesting a stronger link between self-reported fatigue and physical QOL. Janardhan and Bakshi36 determined that fatigue was independently associated with QOL and suggested that early detection and treatment of fatigue can improve QOL in people with MS. Amato et al.17 identified fatigue as an independent predictor of QOL in MS and demonstrated significantly high correlations between fatigue and physical (r = −0.66) and mental (r = −0.69) composite scores on the MSQOL-54. Although both of these studies reported a strong correlation between self-reported fatigue and QOL, they used a different measure to assess fatigue (Fatigue Severity Scale) in their samples. The present study demonstrated that people with MS who reported greater fatigue (a score of >10 on the MFIS-5) simultaneously exhibited impairments in physical as well as mental QOL compared with individuals who reported a score of 10 or less on the MFIS-5, thereby suggesting that a relationship between fatigue and QOL exists irrespective of the measurement instrument.

The present study also demonstrated that neurologic disability (EDSS) did not differ in people with MS who report high levels of fatigue compared with people with low levels of fatigue. These results indicate that the neurologic status of individuals with MS may not adequately predict the severity of fatigue experienced by them. These findings are consistent with previous work by Bakshi et al.,14 who found no significant relationship between fatigue (measured by the Fatigue Severity Scale) and EDSS score prospectively in a large sample of people with MS. Krupp et al.10 also demonstrated no significant associations between fatigue severity (measured by visual analogue scale) and EDSS score in people with MS.

Several limitations were identified in the present study. The retrospective and cross-sectional research study design limits formation of a cause-and-effect relationship between fatigue and other study variables. Thus, a prospective study elaborating on the effects of fatigue on different variables is warranted. An additional drawback of this study was that the study participants were not medically evaluated for other causes of fatigue (eg, anemia and hypothyroidism). However, the participants were screened by neurologists for significant medical conditions before their participation in the wellness program. This study used an abbreviated measure of fatigue (MFIS-5) that has not been well evaluated in MS. However, the short version was deduced from its parent version (the 21-item MFIS), which has been previously validated in MS. Another limitation of this study is that the participants were referred to and agreed to participate in a wellness and rehabilitation program and, therefore, may not be fully representative of the general MS population. Last, this study used separate Mann-Whitney U tests to determine between-group differences, which may have inflated the rate of type I error.

Fatigue was found to be a predominant symptom (>60%) in the study participants. Individuals reporting high levels of fatigue simultaneously exhibited greater impairments in performance-based and self-reported functional mobility, depression, and physical and mental QOL. These findings can be significant for appropriate assessment and management of an individual with MS presenting with complaints of fatigue. Neurologic disability, however, was not found to be associated with the level of fatigue experienced, suggesting that fatigue needs to be assessed in individuals with MS regardless of their disability level.