The impact of physical exercise on the fatigue symptoms in patients with multiple sclerosis: a systematic review and meta-analysis

Multiple Sclerosis, a chronic disease which has a high prevalence in the world and also Iran, is a worldwide problem which requires considerable time and enormous financial resource to achieve the rehabilitation targets [1, 2]. Based on the scientific epidemiological studies, nearly 52.9 in one hundred thousand (100 k) people in Iran are affected with this disease, such that the prevalence of this disease in Tehran has reached 50 in 100 k people. This rate is very similar to the prevalence rate among the European countries. However, the prevalence rate of this disease in Isfahan, the third largest city in Iran, is 73 in 100 k people which resembles the rate in England. The mortality rate among the people with this disease in Iran is anxiously higher than the rest of the world [2]. Furthermore, numerous social and economic consequences of this disease are being imposed to the society, due to the destructive and disabling nature of this disease, particularly among the young people.

There are studies that have identified the influential factors in the formation of MS disease including immunodeficiency, genetics, viral diseases (e.g., Epstein-Barr), infectious mononucleosis, and influenza. These studies have also concluded that the MS symptoms are fatigue (75–90%), weakness (30.8%), optic neuritis symptoms (20.1%), nerve damage (19.6%), and ataxia (14.3%) [3‐5].

As explained above, the most common problems in MS patients is fatigue. There are various definitions of fatigue in patients with MS, the most important and comprehensive definition is the one presented by the American MS Association in 1998: “A subjective feeling of lack of physical and mental energy to perform and complete routine and favorite activities that is recognized by the caregiver or by the patient itself” [6]. A study conducted by Papalardo and Reggio found that 80% of MS patients suffer from fatigue which effects on their daily activities and affairs, some of whom lose their jobs because of fatigue. This will thus reduce individuals’ ability to perform individual and social tasks, work, activity and maintaining a normal life [7]. It is also reported that 71% of MS patients have more than usual sick-days off work, such that 28% of patients were forced to resign due to the severe fatigue, and 75% of patients were forced to change their jobs because of this, and had no choice but to accept other jobs with considerably lower income [8]. The pharmaceutical and non-pharmacological methods may be used to alleviate this severe fatigue symptom. Among the pharmaceutical medicines, amantadine and pamulin, which have many side effects, could generate more difficulties for the MS patients [8, 9]. In addition to pharmaceutical therapies, non-pharmacological methods have also attracted attention recently among the MS patients. These treatments are based on a community-based approach which can be used to enhance the patient’s physical and mental well-being through various methods including touch therapy, hypnosis, physical exercise, aromatherapy, acupuncture, acupressure, etc. [10, 11]. Sutherland and Anderson argued that just as the exercise has a beneficial effect on the physical ability of healthy individuals, it also has potential effects to reduce the risk of physical and mental illness. However, they strongly advise the MS patients to avoid severe exercise to minimize relapse of the disease and increase the fatigue resulted from the sever exercise. The MS patients should benefit from the constructive effects of the acceptable level of physical exercise as an important part of their treatment and lifestyle. A similar recommendation that regular exercise preserves physical and mental health and is able to reduce the risk of developing chronic diseases, increase the chance of survival and improve the quality of life over the years to come was also given in [12, 13]. It should be noted that the regular physical exercise allows the different parts of the muscle to interact to each other. As a result, there would be a desired range of motion in each joint, which is essential for maximum flexibility. The flexibility attained out of exercise is important not only for physical activity but also to prevent further injury. Inactivity among the MS patients causes the joints to lose their flexibility as the connective tissues become shorter [14].

There are several preliminary studies regarding the effects of exercise on fatigue reduction in MS patients. In a recent study conducted in Iran [15], the mean fatigue score before exercise was 1.43 and after exercise 8.32. In a similar study in Ireland [16], these scores were respectively 3, and 20. The mean fatigue score before and after exercise in the Switzerland experiment [17], were 1.5 and 4.4, respectively. One of the benefits of conducted meta-analysis in this paper is that it would provide plausible responds to the assumptions discussed above. The purpose of this study is thus to determine the effect of the physical exercise on fatigue in patients with MS in Iran and the world using a comprehensive meta-analysis.

In this study, all studies regarding the effect of the exercise on fatigue in patients with MS in Iran and the world without time limitation were systematically reviewed based on PRISMA checklist and PRISMA flow diagram. In the initial search, 1412 articles were identified, where eventually 31 studies, published between 1996 and September 2019, were included in the final analysis (Fig. 1).

The total number of participants selected in the meta-analysis was 1434 (720 in the control group and 714 in the intervention group). The characteristics of the studies included in the systematic review are shown in Table 1. It should be noted that all selected studies were clinical trials. Out of 31 articles selected to conduct the meta-analysis, 15 of them were published in Persian, and the rest were published in English (Table 1).

According to the available data, standardized mean difference indices and relative risk were used to finalize the effects of the studies. In the studies that the standard deviation of ± of mean were reported, that standardized mean difference index was used in the meta-analysis. The results of the meta-analysis showed that heterogeneity between the studies was obtained to be (I² = 99) before the intervention and (I² = 99) after the intervention. Therefore, the random effects model was used to combine these studies to derive the final outcome.

The Egger test was used to investigate the presence of bias in the studies. According to the Egger test results, there was no publication bias in the studies before (P = 0.177), and after the intervention (P = 0.279), (Fig. 2).

Based on the results derived from the meta-analysis, the standardized mean difference between the intervention groups before and after the intervention were estimated to be 23.8 ± 6.2 and 16.9 ± 3.2, respectively. This would suggest and confirm that the physical exercise will reduce fatigue in the patients with MS. In the forest plot (Fig. 3), the standardized mean difference index and its 95% confidence interval in each study, as well as the final estimation of the index from the combination of studies are all illustrated. In this figure, the weight of each study in the final combined value exhibits that the size of each square is appropriate to the weight that the study had in the meta-analysis. The horizontal line of each square also shows a 95% confidence interval (Fig. 3).

The meta-regression based on pre- and post-intervention, the year of doing studies (P = 0.000) and sample size (P = 0.000) with standardized mean difference before and after the intervention were investigated. As a result, a significant difference was observed between standardized mean difference before and after the intervention. The fitted models suggest that with the increase of the year of research and sample size, the standardized mean would also increase before and after the intervention (Figs. 4 and 5).

The purpose of this study was to determine the effect of exercise on fatigue in the patients with MS in Iran and the world using a comprehensive meta-analysis.

Fatigue is a common and annoying symptom in the MS patients and various factors such as lack of physical activity, muscle weakness and neurological problems are involved in this complication. The decreased endurance and muscle resistance would usually lead to the early fatigue and consequently decrease the level of patients’ activity level [44]. In general, the cause of fatigue in the MS patients is unclear, and has been reported in various sources as immune mechanisms, neuromuscular, thermal sensitivity, respiratory muscle weakness, and increased cost of respiratory muscles [45, 46].

The results of this study show that the severity of fatigue is higher than before the test and this indicates the importance of fatigue level and duration, and its effect on all aspects of life of these patients. A special attention must be paid to the young people as the efficient forces of society and the largest age group having this disease. Fatigue can even have devastating effects, and these patients may become an additional burden to the society. The more sedentary a patient is, the less energy he or she will have to work. This decrease in physical activity will result in reduction of muscle mass and further decrease functions [18].

The results of the present study showed that there is a significant difference between the mean scores of pre-test and post-test of fatigue severity in MS patients in the intervention group. The patients in the intervention group achieved a score of 16.9 in the fatigue severity score as a result of exercise.

The possible mechanism of fatigue reduction in the present study may be due to different and beneficial functions of exercise in the various aspects of these patients’ lives. However, the previous studies have suggested that increased skeletal muscle activity during exercise could be due to increased blood flow to the muscles. This would also increase the volume of left ventricle and consequently cardiac output during physical activity, particularly increase heart rate. On the other hand, as arterioles open in skeletal muscles, blood and oxygen transportation to muscle tissue will be increased, which eliminates the need for extra oxygen during physical activity because of increasing respiratory rate, vital lung capacity, and alveolar ventilation [28]. In fact, the early benefits of regular exercise of these patients include: increased cardio-respiratory fitness, increased muscle strength and endurance, reduced body fatigue, improved morale, and increased ability to perform daily tasks with greater force. This is also significantly effective in controlling MS symptoms and health improvement [47]. Since these patients frequently experience weakness (particularly, in the lower extremities) and fatigue; as a result of doing the exercises, they may be able to overcome the weakness in their lower extremities, which often results in fatigue and impaired walking. It will thus significantly reduce the severity of fatigue after exercise in MS patients [48‐51].

In this study, we find that exercise significantly reduces fatigue in Iranian MS patients compared to other countries. Because fatigue is a mental phenomenon and difficult to measure, and influenced by many factors, such as emotional changes and other disturbing symptoms associated with MS. Therefore, this could be the possible cause of different results reported in Iranian and foreign articles. Another plausible reason could be due to younger population of the country, which results in the increased number of younger patients eventually making up a larger percentage of the patients in the intervention group.

Since chronic diseases, including MS, affect economic, financial, social, and emotional aspects of the individual, family, and community, the nurses can play an imperative role in the rehabilitation of patients with physical and mental inabilities. They are able to help patients to improve their ability to perform their daily activities and to help them eliminate social, psychological and economic burdens. A nurse could guide the patient and family in the right direction by helping them determining the ways to control their complications. Among the many types of exercise, aerobic exercises that widely consume oxygen, cause significant metabolic changes such as improving metabolism; decreasing levels of epinephrine, norepinephrine, cholesterol and triglycerides; boosting the immune system; and, improving endorphin secretion, mood and mental status. The important thing is that the demethylation process does not change during these activities. In other words, when the musculoskeletal system is inactive, the duration of oxidation reduces, and this is an important factor in the incidence of fatigue and sluggishness of daily activities. By doing exercise, the oxidation capacity of the muscles is increased, thereby the aerobic biochemical system is stimulated to make the adaption and leads to increase the amount of oxygen intake in the body. Some diseases inhibit oxygen in each of the above stages and decrease functional capacity, but aerobic exercises are able to make physiological adaption to the efficiency of the aerobic energy system, enhance one’s functional ability, even improve disease progression and improve functional capacity. The other benefits of regular exercise for these patients are increased strength, improved body status, reduced fatigue, improved mood, increased self-esteem, and a sense of well-being. Furthermore, performing the physical exercise improves one’s independence and not only improves patients’ quality of life, but also affects patients’ balance through coordinating upper and lower extremities, and prevents cardiovascular diseases, diabetes, and so on [52]. Therefore, it is recommended that practitioners use regular exercise as a complementary treatment along with medications to help patients with MS.

The results of this study show that exercise significantly reduces fatigue in patients with MS. Therefore, a regular exercise program can be part of a rehabilitation program for patients with MS.