J Manipulative Physiol Ther. 2019 (Nov 23) [Epub]
Keira Leigh Byrnes, MChiroSc, Stephney Whillier, PhD
Sydney, NSW, Australia.
OBJECTIVE: The aim of this study was to conduct a meta-analysis of clinical trials on the effect of nonpharmaceutical treatments on outcomes for multiple sclerosis (MS).
METHODS: The CINAHL, Mantis, Medline, PEDro, PubMed, and Scopus databases were searched. Final papers meeting inclusion criteria were scored with the Physiotherapy Evidence Database for quality and included in a meta-analysis. Forty papers in the meta-analysis totaled 1673 participants. The interventions were grouped into 6 subcategories: physical activity, technology, rehabilitation, alternative, resistance training, and psychological.
RESULTS: The combined effect of interventions produced a large overall effect size for the outcome fatigue; medium effect sizes for functionality, balance, and quality of life; and no effect on pain or spasticity. Physical activity had the greatest effect, improving fatigue, function, and balance. Rehabilitation and resistance training had a large effect on functionality. Comparatively, psychological approaches had only a small effect on improving quality of life. Sample sizes of included papers tended to be small with large variability in design. Therefore, results should be interpreted cautiously.
CONCLUSION: Our results suggest there may be effective nonpharmaceutical treatment options available that can improve the symptoms of fatigue, poor functionality, balance, and quality of life. We found that physical activity, alternative approaches, rehabilitation, and resistance training were effective for improving the management of a number of MS symptoms.
KEY WORDS: Complementary Therapies; Meta-analysis; Multiple Sclerosis
From the FULL TEXT Article:
The worldwide estimated number of people with multiple sclerosis (MS) increased from 2.1 million in 2008 to 2.3 million in 2013, which is partly reflective of improved reporting, but an increase in the prevalence and incidence of this disease has been reported in Europe, in the Mediterranean Basin, and it is speculated, globally. [1–3] Multiple sclerosis is an autoimmune demyelinating and progressively degenerative disease of the central nervous system (CNS). [4, 5] The immune system attacks oligodendrocytes that myelinate central nervous system nerves. This results in a variety of symptoms that cause significant impairment in daily life. Symptoms may include weakness, spasticity, ataxia, tremor, and problems with coordination and balance. Fatigue, paresthesia, and pain are also typical. [6, 7] Pharmaceutical treatments for relapsing-remitting MS, the most common form of the condition, can modify the course of the disease or control the disease process, but there is presently no cure.  People managing MS are increasingly turning to nonpharmaceutical treatment options, [8, 9] thus this timely meta-analysis seeks to analyze the efficacy of such approaches.
Surveys suggest up to 70% of patients with MS have tried at least 1 form of alternative treatment for their symptoms,  and the longer they have had MS, the more they turn to complementary and alternative treatments.  Many also seek a holistic management of their disease and use multiple interventions simultaneously.  If this is the case, it becomes important to review the evidence for benefits that can be derived from these interventions to inform clinical decisions and future research.
Nonpharmaceutical treatments are broadly defined as interventions outside of the MS licensed therapies, the traditional pharmaceutical interventions aimed to reduce inflammation and slow progression of the condition. Nonpharmaceutical treatments include complementary, alternative, and allied interventions in the broadest sense. We have taken this approach because defining what complementary and alternative medicine (CAM) encompasses has been shown to be confusing. The Cochrane Collaboration group has discussed the difficulty in defining what is, and is not, CAM.  Their paper concludes: “We … question whether it is possible to arrive upon a definitive set of therapies that are universally agreed upon as CAM.” (p.12) We believe our broad approach gives a comprehensive overview of the effects of a variety of nonpharmaceutical treatments (NPTs) to inform treatment approaches and possible areas of future research.
A number of studies have looked at the evidence for specific symptom amelioration. [14–17] Other studies have concentrated on the effects of just 1 form of complementary therapy. [18, 19] A few systematic reviews have investigated randomized controlled trials of interventions that manage symptoms of MS. [13, 20–22] But to the best of our knowledge, no research has undertaken a meta-analysis of the evidence for a broad range of NPTs in the management of many and various symptoms of MS.
The primary purpose of this study was to determine the effect of NPTs on outcomes for adults over 18 years with mild to moderate MS. The specific outcomes measured were fatigue, functionality, quality of life, balance, pain, paresthesia, and spasticity.
This review identified 40 peer-reviewed publications that met inclusion criteria. By investigating a broad range of NPTs, this study allows for an overview of the options available to MS patients and the strengths and weaknesses in the management of particular symptoms of the disease. Overall, the combined effect of NPTs was most beneficial for the outcome fatigue, providing a large overall effect size with medium effect sizes for functionality, balance, and quality of life. Comparatively, the combined effect was not significant in pain or spasticity symptoms. This suggests that there may be evidence-based efficacious NPT options available for specific needs in MS populations, particularly improving symptoms of fatigue, poor functionality, balance, and quality of life. We were unable to investigate through which mechanism these approaches had an effect on specific symptoms. We are also unclear why certain approaches benefited specific symptoms but not others. Future research could consider why specific approaches have a targeted effect on certain symptoms.
A review of the specific NPT approaches identified trends in the most effective forms for different areas of function. Physical activity seemed to have the greatest effect, improving fatigue, function, and balance. Alternative approaches had a large effect on improving fatigue symptoms and quality of life, but no effect on function. Both rehabilitation and resistance-based treatment had a large effect on improving functionality. Comparatively, psychological approaches had no effect on improving fatigue or functionality, and a small effect on improving quality of life. Furthermore, technology-based approaches also had no effect on fatigue or functionality, but a small effect on improving balance.
The effectiveness of NPTs for a range of different outcomes, despite significant heterogeneity in the type of approach, suggests that there are options available to MS patients. As mentioned, however, no interventions showed a significant effect on pain or spasticity symptoms. There were only 3 studies investigating spasticity as an outcome, and each used a different intervention, contributing to a high score for heterogeneity. The same is true of pain, which was investigated in only 4 studies. These trends suggest a strong need for future research and innovative clinical interventions to be developed which target these symptoms.
The benefit of physical activity in MS is well evidenced in the literature. A 2004 Cochrane systematic review found exercise therapy beneficial for MS.  The review showed strong evidence for improving muscle power, exercise tolerance, and mobility; moderate evidence for improving mood; and no evidence for fatigue compared to no exercise therapy. Our results, of studies mostly conducted after 2004, did show that physical activity was greatly beneficial for improving fatigue, function, and balance. A 2017 systematic review of reviews  and a 2017 paper found exercise yielded beneficial effects on fatigue, a frequent symptom in MS. The latter paper also found that it improved muscle strength, balance, gait, and aerobic capacity. 
A 2017 systematic review of reviews investigated rehabilitation interventions,  including physical activity, psychological, occupational, whole-body vibration, dietary, and other interventions in MS. Similar to our study, they found physical therapies reduced fatigue. They also found physical therapies improved mobility, strength, and aerobic capacity. They rated the evidence for these outcomes to be of high quality. They found low-quality evidence for exercise improving balance. Another 2016 review of exercise training and cognitive rehabilitation found multidisciplinary interventions had a symbiotic effect in improving walking and cognition in multiple sclerosis.  Finally, Thomas et al conducted a 2006 systematic review of the benefits of psychological interventions for MS19 and concluded that cognitive behavioral therapy helped participants to cope and improved depression. Our study indicated that psychological approaches had a small effect on improving quality of life.
Not all studies are in agreement. A review of complementary and alternative treatments of MS conducted from 2001 to 2016 investigated “cannabis, diet, exercise, psychological approaches and other” interventions.  Their chosen interventions differ from our own, making comparisons difficult, and the heterogeneity they encountered prohibited a meta-analysis of their results. The authors of the study did, however, find that exercise, greatly represented in their review, improved health outcomes for MS patients, which is similar to our findings.
There are a number of limitations with the current meta-analysis. Many publications tended to report on small sample sizes and often lacked a control comparison group. These papers included a comparator rather than a control group. As a result, the results are compared to another treatment, and therefore may lead to differing margins of improvement between groups. There was also often large variability in the type of treatment, mode of delivery, and duration within treatment approaches. For example, the technology-based approaches, although intrinsically electronic-based, showed large variability in the type of technology, application, and goals. Furthermore, details about exact doses of treatments were often not explicitly reported, obscuring the effects of these treatments.
This meta-analysis was restricted to analyzing peer-reviewed publications to ensure results were based on more rigorous methodologies. We cannot be certain how great the risk of publication bias is, and how many studies have not been published due to nonsignificant findings. In particular, the studies that reported on fatigue, function, and quality-of-life outcomes produced funnel plots that appeared skewed, and Egger’s test produced a significant 1-tailed P value for all intercepts (P < .05), indicating these studies are likely to be subject to publication bias.
This meta-analysis strengthens the emerging evidence-base for the efficacy of nonpharmaceutical treatments (NPTs) to improve symptom management for adults with mild to moderate MS. The results suggest there may be effective NPT options available that can improve the symptoms of fatigue, poor functionality, balance, and quality of life. We found that physical activity, alternative approaches, rehabilitation, and resistance training were effective for improving the management of a number of MS symptoms. The evidence supporting NPTs reported here offers important options that could be pursued alongside other existing treatments, for a high-risk population managing a challenging chronic health condition.