The Role of Exercise on Fatigue Among Patients With Multiple Sclerosis in the King Fahad Hospital, Madinah, Saudi Arabia: An Analytical Cross-Sectional Study

Background Multiple sclerosis (MS) is a chronic autoimmune disease caused by multiple factors. It can lead to many physical and mental symptoms. Fatigue is one of the most commonly mentioned complaints among MS patients that can affect their quality of life. Physical activity has many benefits for the physical and mental health of patients with MS. Aim To assess the role of exercise on fatigue among patients with multiple sclerosis and identify the relationship between depression, sleep quality, sociodemographic variables, and fatigue. Methods This is an analytical cross-sectional study based on a sample size of 235 patients recruited from the MS clinic at King Fahad Hospital (KFH) in Madinah. The outcome of the study was fatigue among MS patients. Data were collected through telephone calls from February to May 2022 using a structured questionnaire and scales, such as the Godin Leisure-Time Exercise Questionnaire (GLTEQ), Modified Fatigue Impact Scale (MFIS), Patient Health Questionnaire (PHQ2), and Pittsburgh Sleep Quality Index (PSQI). Data were analyzed through SPSS version 20 (IBM Corp., Armonk, NY, USA). The correlation coefficient (r), Chi-square tests, and simple and multiple logistic regression were used as found appropriate. Results Out of the total samples, 37.4% were male and 62.6% were female. The median age of patients was 36 years. The prevalence of fatigue was 37% among patients, with a reported median fatigue score of 26. It was found that 63% of the patients were physically inactive; 32.2% were overweight, 14.2% were obese; 63.8% of patients had poor sleep quality. The fatigue score was negatively correlated with the GLTEQ score, but the results were not significant (r=−0.066; P-value (level of significance)=0.335). Nonetheless, a moderately significant correlation was observed between the MFIS and PSQI and MFIS and PHQ2 (r=0.505, P=<0.001 and r=0.520, P=<0.001, respectively). The Chi-square test showed a significant association between fatigue and progressive types of MS, the primary progressive MS (PPMS), secondary progressive MS (SPMS), and relapsing-remitting MS (RRMS) (odds ratio (OR)=4.4; 95% confidence interval (CI): 2.1-8.9), P=<0.001). Depressed patients were 9.7 times more likely to develop fatigue compared to non-depressed patients (P=<0.001). Those with poor sleep quality were 4.6 times more likely to develop fatigue compared to those with good sleep quality (P=<0.001). Fifty-six percent of fatigue among MS patients were predicted by low income, progressive types, unemployment, obesity, depression, and poor sleep quality. Conclusion Fatigue is a major complaint among MS patients. Most of the patients were found to be physically inactive, depressed, and have poor sleep quality. This study found an association between physical inactivity and fatigue, but the results were not significant. There was a significant association between sociodemographic factors like low income and unemployment, poor sleep quality, obesity, progressive types of MS, depression, and fatigue. Encouraging exercise practice and implementing a regular exercise program are needed, along with weight management plans. Further studies and psychological support meetings are required, with the importance of a holistic approach to patient care.


Introduction
Multiple sclerosis (MS) is a chronic autoimmune disease in which the axons in the central nervous system are demyelinated. Many factors may contribute to the development of the disease, including environmental and genetic factors, yet the main cause remains unknown [1]. Symptoms of the disease include numbness, weakness, fatigue, imbalance, low mood, depression, and visual and bladder problems [2]. According to a meta-analysis conducted on Iranian patients, the most common MS symptoms are fatigue and motor dysfunction, with an estimated prevalence of 71.1% and 56.3%, respectively [3]. The most common MS symptoms, according to the national MS registry in the Kingdom of Saudi Arabia (KSA), included the following: of the patients across all regions, muscle weakness was most common (57.1%), followed by visual symptoms (48.2%), and sensory symptoms (47.3%). The prevalence of fatigue in Saudi Arabia was found to be higher in females compared to males (61.95/100,000 among Saudi nationals) [4].
Fatigue was rarely listed as a symptom of MS until Freal published a report in which 78% (n=656) of patients with MS mentioned fatigue as one of their symptoms. Of the total patients, 28% mentioned that fatigue made symptoms more apparent, 43% mentioned that fatigue was similar to MS exacerbation, and 11% mentioned that it was the same as exacerbation. Due to these difficulties in distinguishing between true relapse symptoms and fatigue, under-reporting of relapses might occur [5]. In the previous 10-15 years, many researchers have found that engaging in physical activity helps patients with MS to manage symptoms, restore function, and optimize their quality of life (QOL). Exercise training was also found to be associated with improvements in muscular and cardiorespiratory fitness among patients with MS [6,7]. Hadjimichael [8]. In that study, the researchers used the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS), as well as questions related to symptom management. The progressive relapsing MS (PRMS) type had a higher prevalence of severe fatigue compared to relapsingremitting MS (RRMS) and primary progressive MS (PPMS). Patients with severe fatigue had higher MFIS scores. Fatigue scores in both FSS and MFIS were significantly increased when they were examined relative to the duration of MS for about the first 14 years.
Razazian et al. carried out a systematic review and meta-analysis to measure the impact of physical activities on fatigue among patients with MS. The study included 31 clinical trials and used the random effect to obtain the outcome. The standardized estimated mean difference in the fatigue score using the FSS score between groups before and after the intervention was 23.8 ± 6.2 and 16.9 ± 3.2, respectively. Based on this result, the study concluded that physical activities improve physical fatigue in patients with MS [9].
Halawani et al. conducted a case-control study to study the lifestyle factors, environmental factors, and socioeconomic factors that can lead to the development of MS in the western region of Saudi Arabia. It was found that obesity, smoking, and measles infections increase the risk of getting MS. On the other hand, it was found that vigorous exercise is not associated with the development of MS [10].
The primary objective of our study: to find the association between exercise and fatigue among MS patients in KFH, Madinah. Secondary objectives: to find the association between sociodemographic variables, depression, sleep quality, and fatigue among MS patients.
The prevalence of MS has been found to be increasing in KSA. It becomes a huge burden on patients and creates a huge economic burden for society by affecting young adults in their most productive years.
The study aims to assess the role of exercise on fatigue among patients with multiple sclerosis and identify the relationship between depression, sleep quality, sociodemographic variables, and fatigue.

Materials And Methods
For this analytical cross-sectional study, participants were selected from the MS clinic at the King Fahad Hospital (KFH) in Madinah between February and May 2022. The sample size was calculated to be 235 using the OpenEpi software program (population size: 600, expected frequency: 50%, margin of error: 5% and 95% CI). The whole list of patients was contacted until 211 samples were obtained (89% response rate). The inclusion criterion was the presence of MS in patients from the MS clinic at KFH, according to McDonald's criteria. The exclusion criteria were severe psychiatric disorders, other comorbidities that interfered with physical activities (for example, musculoskeletal problems), the terminal illness of MS, and pregnancy. Fatigue was the dependent variable, while sociodemographic factors, smoking, sleeping habits, exercise, use of vitamin D, body mass index (BMI), type of MS, number of relapses per year, use of multivitamins, use of MS medications, other comorbidities, family history of MS, duration of illness, and depression were independent variables.
Ethical approval was obtained from the Institutional Review Board (IRB), General Directorate of Health Affairs in Madinah (approval number: 001-2022). Informed consent was also obtained from the participating patients. Confidentiality and privacy of the data were ensured. The patient had the right to participate voluntarily and could withdraw at any time from the study.
Data were collected by senior neurology residents from patients via a telephone call and using a questionnaire, which included questions about sociodemographic status, type of MS, duration of illness, number of relapses per year, use of MS medications, use of vitamin D, use of multivitamins, family history of MS, exercise, sleeping habits, and depression. Regarding the (living) variable, patients were asked if they live in the city or in one of the villages near Madinah. In addition to using the Godin Leisure-Time Exercise Questionnaire (GLTEQ), the MFIS to measure fatigue, the Patient Health Questionnaire (PHQ2) to measure depression in patients, and the Pittsburgh Sleep Quality Index (PSQI) was used.

Measures
MFIS is a reliable and valid tool to measure fatigue. It measures the physical, cognitive, and psychosocial aspects of fatigue. The reported internal consistency of the MFIS scores was excellent according to the subsequent Cronbach's alpha values: total, 0.81; physical, 0.91; psychosocial, 0.81; and cognitive, 0.95 [11]. PHQ2 was used as a screening tool for major depressive disorder (MDD), with a pooled sensitivity of 0.76 and specificity of 0.87, with a cutoff point of ≥3. In addition to this, the pooled sensitivity was 0.91 and the specificity was 0.70, with a cutoff point of ≥2 [12]. PSQI was also added to assess sleep problems in patients with MS. In previous studies, Cronbach's alpha was 0.77, demonstrating the acceptable reliability of the questionnaire [13]. GLTEQ is a valid and simple tool used previously in patients with MS to assess physical activity [14].

Scoring
For MFIS, the cutoff point was a score of ≥38, and the score was directly proportional to the effect of fatigue on the life of the patient [11]. PSQI is a global score of sleep quality calculated by summation of the component scores and ranges from 0 to 21 with better quality of sleep associated with lower scores [13]. Sleep quality was determined to be: 0-4 indicating good sleep quality, and 5-21 indicating poor sleep quality. For PHQ2, the cutoff score was 2 [12]. The cutoff point for the "GLTEQ" scale was 24. Patients who scored 24 units or more were considered active, and patients with fewer scores were considered inactive [15].

Statistical analysis
Data were analyzed using SPSS version 20 (IBM Corp., Armonk, NY, USA). Continuous variables were analyzed as mean and standard deviation (SD) or median with interquartile range (IQR) in the case of nonnormally distributed data. Categorical data were analyzed in terms of frequency and proportion. The correlation coefficient (r) test was used to find the relationship between the PHQ2 score, GLTEQ score, PSQI score, and MFIS; the Chi-squared test was used to find an association between categorical independent variables and the outcome fatigue; and simple logistic regression was used to find an association between independent variables with more than two categories and fatigue; and a multiple logistic regression model was used for all significant variables. The significance level was predetermined at a P-value of <0.05 for all tests. An external pilot study was conducted on individuals, and information was not included in the analysis.

Results
The response rate was 89% (211 of 235 participants). The data were not normally distributed. Skewness was found in the data, and Kolmogorov-Smirnov and Shapiro-Wilk tests were significant for all variables. Table 1 shows the main characteristics of the participants by frequency and percentage. Among responders, 37.4% were male (n=79) and 62.6% were female (n=132). The median age of patients was 36 years. BMI was calculated with a median of 24.50 and an IQR of 6.3. Of the total patients, 32.2% were overweight (n=68) and 14.2% were obese (n=30). Among the participants, 63.5% were married (n=134) and 36.5% were unmarried (n=77). The median number of children was 1 with an IQR of 4. According to the smoking data, 26.1% were smokers (n=55) and 73.9% were non-smokers (n=156) (   About the scales used in this study, the median fatigue score was 26 (IQR, 37) with a cutoff on the MFIS of 38; 37% were categorized as fatigued (n=78). The median PSQI score of the sample was 5 (IQR, 3.50).
The median score on the GLTEQ was 9 with an IQR of 32. Of the total patients, 37% were considered physically active (n=78), and 63% were physically inactive (n=133). Regarding PHQ2, the median score was 2 with an IQR of 3, with 54% of patients being categorized as depressed (n=144) and 46% as non-depressed (n=97). The correlation between MFIS, PSQI, PHQ2, and GLTEQ was studied using Spearman correlation. Fatigue score was moderately significantly correlated with sleep quality score and depression score (r=0.505, P=<0.001; and r=0.525, P=<0.001), respectively. On the other hand, the fatigue score was negatively correlated with GLTEQ, but the association was not statistically significant (r=−0.067; P=0.335) ( Table 2).   According to weight, underweight MS patients were 80% less likely to develop fatigue compared to overweight patients (95% CI: 0.1-0.7; P-value: 0.008).
The most commonly prevalent type of MS among patients is RRMS; therefore, it was preferred to compare the outcome between common and rare types (PPMS and SPMS) to obtain meaningful evidence.
There was a statistically significant association between progressive types of MS compared to RRMS

Discussion
The incidence of fatigue among MS reached 90% in some studies. The most common MS symptom patients describe is fatigue. Fatigue deeply affects the social, professional, and familial domains of patients with MS. This results in significant health costs, and hence, fatigue should not be neglected. It is necessary to understand this symptom and adopt novel therapeutic approaches to manage it. Hence, the current study aimed to investigate the role of exercise on fatigue among patients with MS [16,17].
Fatigue prevalence among patients with MS in the present study was significant (37%  [20]. NARCOMS also found that the prevalence of severe fatigue among patients with MS was 74% [8]. In Norway, Broch et al. found that among 1182 patients with MS, 81% had fatigue [21]. This variation in fatigue prevalence might be interpreted through the differences in the way study subjects are chosen (since in the present study, patients with severe psychiatric disorders, other comorbidities that interfered with physical activities, and MS patients with terminal illness and pregnancy were excluded), methods used to assess fatigue, study time, and the size of the study population. In our study, we used MFIS to measure fatigue among 211 patients over four months; 50.7% of responders were young, and obesity was 14.2%. Besides these factors, the small sample size might be the cause of the lower prevalence of fatigue in our study compared to other studies.
Generally, fatigue can occur at all stages of MS. MS-related fatigue is distinguished into two types: primary fatigue, which is related to disease-specific mechanisms. Secondary fatigue is related to MS complications (reduced activity, sleep disorders, depression, and treatment adverse events) [17,22]. There are efforts to recognize the factors that contribute to fatigue among patients with MS [18].
Lately, nonpharmacological methods have been used to treat fatigue in patients with MS, such as physical exercise (aerobic work), cognitive behavioral therapy, cryostimulation, and energy conservation strategies [23]. Routine physical activity is highly recommended in MS fatigue cases as accumulated data has shown [24,25]. Patients with MS who are not physically active can be exposed to complications such as heart problems, osteoporosis, obesity, and deconditioning, while regular exercise might play a significant role in neuroprotection and help with spasticity and muscle strengthening [16]. More than 50% of patients in the current study did not exercise, which reveals the need to encourage physical activity and exercise among these patients. However, it should be considered that fatigue increases a higher level of disability, which in turn may lead to reduced motivation for exercise or physical activity [26]. Alsaedi et al. mentioned that younger age has a lower Expanded Disability Status Scale (EDSS), also time of diagnosis at a younger age, lower BMI, RRMS, and a duration of fewer than five years associated with a lower EDSS [27]. This, in turn, indicates that there is a need to identify factors for not exercising among patients with MS and try to find solutions to stimulate physical activity and exercise in those patients. In our study, 63% of the responders among all age groups were physically inactive (among young patients, 64% were physically inactive while only 35.5% were physically active). There was no correlation between exercise and fatigue in this study. A review suggested that the studies that evaluated the role of exercise treatment on MS fatigue showed various results. The general interpretation, though, is that exercise therapy has the potential to reduce fatigue in patients with MS [28]. The majority of patients with MS in the present study were female, which is compatible with the findings of many previous studies [29][30][31][32][33].
According to the current results, there is no association between fatigue and gender. This finding is not compatible with that of Broch et al., who suggested that fatigue was more prevalent in women [21]. Generally, men and women have different responses to pain due to genetics and psychosocial factors. This can lead to differences in tolerance to pain, sensitivity to it, and reporting it [34].
The current study showed that the patient's BMI is one of the factors predicting fatigue among patients. These findings are consistent with Rezaeimanesh et al.'s study, which found a positive correlation between BMI and fatigue score among 85 MS patients (P-value: 0.031; r: 0.23). Such findings highlight the importance of carrying out a comprehensive approach when dealing with MS patients, including weight management alongside pharmacotherapy treatment [35].
Recently, sleep disorders and their potential role in fatigue among patients with MS have been gaining attention. Specific sleep problems or disorders that may disproportionately affect patients with MS include restless legs syndrome (RLS), periodic limb movement disorder, circadian rhythm disturbances, and chronic insomnia [36]. The relationship between sleep disorders and fatigue in MS is still controversial, and the causes of and relationship between sleep disorders and fatigue in MS are not yet fully understood [37]. In the current study, the majority of patients with MS (64%) had poor sleep quality. The current findings are compatible with that of Nociti et al., who found a strict relation between fatigue and sleep disorders, in which MS was linked to a high prevalence of sleep complaints, including restless legs syndrome (RLS), excessive daytime sleepiness, subjectively poor sleep quality, and symptoms of obstructive sleep apnea syndrome (OSAS) [37]. The current study also showed a significant association between sleep quality and fatigue. Ghaem and Haghighi [38] also found that 87.2% of patients with MS in their study suffered from poor sleep.
The QOL of a patient is impacted by MS in part due to physical disability [39]. Depression also commonly accompanies MS with a prevalence of about 50% [36]. In the current study, the prevalence of depression among patients with MS was around 54%, and there was a significant association between depression and the presence of fatigue. These findings are compatible with those of previous studies [18,20,39].
Depression itself can be obvious from fatigue because the symptoms of fatigue are often mistaken, which makes this condition difficult to distinguish from MS fatigue. Depression should be addressed and treated regardless of any contribution to fatigue because it has a fundamental impact on QOL. MS severity and its subtype can influence the risk of fatigue. Patients with progressive subtypes of MS experience severe fatigue [36]. In the present study, there was a protective association between RRMS and fatigue compared to other types (PPMS and SPMS). This protective association might be explained by the nature of RRMS compared to the more complex aggressive types (PPMS and SPMS). Broch et al. have shown inconsistent results, as there was no significant difference in the rate of fatigue among patients with progressive MS and those with relapsing MS [21].
The current study has some limitations. Firstly, it was a single central study, and all cases were interviewed within four months, which is how the accuracy and generalizability of the results are affected to some extent. Secondly, data was collected through telephone calls, and disability scores were not collected.
Other limitations can be regarding study design and small sample size, recall bias, and limitations in resources.

Conclusions
The present study showed that fatigue is a common problem among MS patients, and the majority of patients do not practice exercises, which means there is a need to encourage physical activity and exercise among the patients, in addition, to applying for a regular exercise program as a part of their rehabilitation program. The current study showed that there is an association between fatigue and progressive MS types, low income, unemployment, obesity, depression, and poor sleep quality, but the association between exercise and the resolution of fatigue symptoms was not significant. Further studies on the same issue are needed with the importance of comprehensive care and holding psychological support meetings, sleep counseling to improve sleep quality and proper weight management plans for the patients.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board (IRB), General Directorate of Health Affairs in Madinah issued approval 001-2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.