Diverse mechanisms and treatment strategies to confront fatigue in multiple sclerosis : A systematic review

Firm conclusions about the applicability of treatment Background: methods other than pharmacotherapy in treating fatigue in multiple sclerosis (MS) remain elusive. Our objective is to synthesize and review the epidemiological literature systematically and find an effective therapeutic plan for fatigue. The effect of individual treatment and combined treatment strategies are studied. An electronic database search included EBSCO, PubMed, Methods: SCIENCE DIRECT and Scopus from January 1, 2013, to September 30, 2018. Search terms used are “Fatigue AND Multiple sclerosis AND therapy”. The articles included in the study are open access, published in last five years, not restricted to region and language. The search included randomized controlled trials (RCTs), observational studies, and systematic reviews. We included 13 systematic reviews, 10 RCTs and 7 observational Results: studies. A Cochrane review on 3206 patients showed exercise therapy to have a positive effect on fatigue in RRMS patients. The EPOC trial showed switching interferon therapy or glatiramer to fingolimod showed improved fatigue levels. The FACETS trial showed incorporating behavioral therapy to ongoing recommended therapy is beneficial. Few observational studies demonstrated that fatigue is influenced by pain, mood problems, and depression. The diverse pathology of fatigue related to MS is important in Conclusions: understanding and quantifying the role of each causal factor. Evidence reveals a positive effect on fatigue levels of RRMS patients with regular CBT and exercise-based combination therapy. Progressive forms of the disease have the worst prognosis. Individually aerobic exercises, behavioral therapy and pharmacotherapy have positive effects. A modified amalgamation of the same is a better hope for MS patients.


Introduction
"The idea that the brain can change its own structure and function through thought and activity is, I believe, the most important alteration in our view of the brain since we sketched out its basic anatomy and the workings of its basic component, the neuron."-Norman Doidge.
Fatigue is a major symptom of multiple sclerosis (MS), which can lead to the difficulty in the carrying out the daily errands and lowers the quality of life; it is prevalent in 80% of patients and hinders the quality of life in nearly 70% 1 .Fatigue is disabling as it causes problems in daily life necessitating the need for a caregiver, causes embarrassment at workplaces where timebound work is, employment issues that can lead to premature retirement 1 .Drugs used to treat MS are categorized as oral drugs, injectables, and infusions.Oral drugs include fingolimod, dimethyl fumarate, teriflunomide, and cladribine; injectables include INFβ1a/1b, daclizumab, and glatiramer acetate; infusions include natalizumab, alemtuzumab, and ocrelizumab 2 .Even upon arrival of new efficacious drugs which can halt the progression of the disease, fatigue remains the most troublesome symptom of patients, giving rise to forms of alternate treatment.This is a systematic review concerning how well pharmacological and non-pharmacological interventions influence fatigue levels in MS patients when compared to healthy adults.
MS is a chronic neurodegenerative disease characterized by disseminated plaque like sclerotic lesions distributed in space and time.They are seen in both grey and white matter of CNS.
MS is affecting 2,000,000 people worldwide and 400,000 people in the United States per year.The annual economic burden of the disease in the United States is approximately 10 billion dollars per year 1 .The 2015 statistics revealed MS disability-adjusted life year (DALY) count was 1234 (1033 to 1437) per 100,000 population, increase in DALY since 1990 to 2015 was 42.4% (31.8 to 57.3%) and age-standardized rate per 100 000 is 17 (14 to 20) per 100 000 3 .The epidemiological basis of MS is based on genetic and environmental risk factors 4 .Although we do not have the most recent data on widespread MS investigation, it is estimated that the numbers can be alarmingly higher than the previous records.
Distribution of disease burden according to a survey in 2013 is shown in Figure 1.
MS is characterised by autoreactive T cells like CD4+T cells in the perivascular space and CD8+T cells invading neural parenchyma causing damage to the myelin.Acute sclerosing plaques are due to astrocyte and microglial activation.Microglia clear the dysfunctional synapses that exhibit classical complement proteins C1q and C3.This clearing process can be pathologic if aberrant activation of astrocytes occurs, causing increased complement expression in synapses, resulting in increased degeneration.Neuronal changes, like ballooning of the cell and eccentric nucleus with increased amounts of phosphorylated neurofilaments in the grey matter, are signs of anterograde or retrograde degeneration which could be after effects of axonal disruption in white matter 1 .The oligodendrocyte precursor cells comprise 5% of CNS cells; they express a proteoglycan called NG2 and can differentiate into mature oligodendrocyte.They also participate in immune reactions by responding to inflammatory cytokines hence limiting our strategy to promote the differentiation of precursor cells to mature oligodendrocytes 1 .The genome-wide differences present in DNA methylation dictate the susceptibility of damage to oligodendrocytes 5 .Neuroinflammatory mediators such as INF gamma, TNFα and ILβ promote synaptopathy, demyelination and axonal loss 5 .This implies that if the inflammatory milieu is stopped, hence the subsequent progression of the disease.
There are four types of MS, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and primary relapsing MS (PRMS).Initially, the disease starts as RRMS and then progresses to SPMS.The disease occurs most commonly in those aged 20-50 years.It occurs more commonly in females than in males, as seen in other autoimmune conditions.The prognosis of the disease depends on the age of presentation and number of exacerbations or relapses of the disease since the initial presentation 6 .Actively demyelinating lesions in the background of inflammation causing bloodbrain barrier dysfunction as seen in RRMS 7 .Biomarkers of the disease include fetuin-A, nitric oxide synthase and osteopontin 8 .Symptoms of MS include fatigue, visual problems, cognitive problem, dizziness, gait problem, sensory symptoms, sleep and sexual dysfunction 9,10 .
The review describes fatigue treatment in MS using pharmacotherapy, exercise therapy and behavioral therapy in the last five years and their efficacy in treatment.

Methods
This review was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) statement, using the methodology described in Cochrane Handbook for Systematic review of interventions.

Data sources and search
The following electronic databases were searched for articles published from the database on September 30, 2018: EBSCO, PubMed, SCIENCE DIRECT and Scopus databases were searched from January 1, 2013, to September 30, 2018.The search strategy included following words "Fatigue and Multiple sclerosis" OR "multiple sclerosis" OR "exercise in MS" OR "pharmacotherapy in MS" OR "Cognitive behavioural therapy and MS".

Selection of studies
All abstracts identified by this search were independently screened by title and abstract by S.K. and T.S. Duplicates were removed by screening based on title of the article and author name.All relevant full-text articles were evaluated for eligibility against the inclusion criteria.Any dispute which arose was solved by mutual consensus.As the scope of the article was limited to systematic review, additional analysis such as sub-group analysis and meta-regression was not done.

Data extraction
The data was extracted independently by two authors S.K and T.S.We collected data from the included randomized controlled trials (RCTs) regarding characteristics of patients, baseline data, expanded disability status scale scores, duration of disease and treatment and outcomes in the study.The changes in fatigue according to different scales was noted in outcomes.We also collected data from systematic reviews in the form of the population included, intervention carried out, comparatives and outcomes of the review with their analytical results on a data extraction sheet.The data was compared and reported while scripting of the discussion.The data of systematic reviews has been exposed to quality analysis using AMSTAR grading shown in Table 1.

Inclusion/exclusion criteria
The articles included in the study are open access and not restricted by region or language.The selection included Randomized controlled trials, observational studies, and systematic reviews.We also included studies which has patients with clinically diagnosed MS and patients >18 years old with fatigue as their presenting complaint.We included studies which reported on patients with both primary and secondary MS.We excluded articles about neuroplasticity in diseases other than MS [22][23][24][25][26][27][28][29] .
A list of excluded studies is available as Extended data 50 .

Risk of bias assessment
Included studies were independently rated by S.K. and T.S. using the Cochrane Collaboration's tool for assessing risk of bias in randomised trials.The rating process followed the description in the Cochrane Handbook for Systematic Review of Interventions (part 2:8.5.1) using RevMan version 5.1.Any disagreements during the process was solved by mutual discussions.
The quality of the identified studies was appraised using AMSTAR guidelines 51 .

Study characteristics
The study characteristics and summary of systematic reviews is elaborated in Table 2.The study characteristics and summary of RCT is presented in Table 3.The study characteristics and summary of observational studies are depicted in Table 4.

Results observed in systematic reviews and meta-analysis
A Cochrane review showed exercise therapy to have a significant positive effect on fatigue in RRMS patients [standard mean deviation (SMD) -0.53, 95% confidence interval (CI) -0.73 to -0.33; P-value <0.01] but there was significant heterogeneity [I

Effect of interventions in RCTs
Trials based on pharmacotherapy have shown that a change to new drugs like oral fingolimod was beneficial to many patients for fatigue in MS as shown by EPOC trial.The TSQM Global satisfaction scores were superior after the switch from intravenous disease-modifying therapy iDMT to oral fingolimod [p<0.001] 67.
Aerobic training exercises were delivered in ambulatory MS patient which showed improvements.This view was supported by the TREFAMS-AT trial (p<0.014).The non-fatigue related outcomes such anxiety, depression, and cognition showed improvement in the certain trials, which explains the dynamic connections with fatigue as a symptom 67,68 .
Exercise therapy is a potential treatment modality, and when combined with education therapy it can cause behavior modification in many patients.This view was supported by the STEP IT UP and FACETS trial.It was able to prove that mobility was increased in intervention groups through the intervention time was relatively short (10 weeks) [68][69][70] .
The chronicity of symptoms in MS has a tremendous impact on the probability to show improvement to any therapy.It will be difficult to expect a positive change in a patient who has suffered chronic fatigue when compared to fatigue of new onset in MS patients.A study showed that multi-disciplinary rehabilitation on chronic fatigue patients was not effective in bringing the fatigue levels to a significant low that could be appreciated subjectively 71,72 .

Risk of bias analysis
All criteria were judged as low, high or unclear risk of bias.In summary, most of the studies had a low risk of bias.The risk of bias graph is show in Figure 3 and Figure 4. Calkwood et al. 67 , had high risk of bias as it lacks random sequence generation and allocation concealment.Calkwood et al. 67 , Thomas et al. 70 , failed to fulfil blinding of participants and outcomes in their respective studies, which were thus prone to performance and detection bias.It was unclear in a few studies whether allocation concealment and blinding of participants was carried out in studies like Heine et al. 71 and Rietberg et al. 72 .
As a result of heterogeneity among studies due to different study designs taken into consideration and a smaller number of participants in various studies owing to loss of follow up and the pathogenicity of the disease, a meta-analysis was not carried out.

Discussion
The primary outcomes in most of the trials used MSIS, FSS and CIS-20R scales [69][70][71] .MSIS is a subjective scale based on a patient experiencing fatigue.CIS-20R subscale measures     fatigue severity.FSS measures the impact of fatigue on normal functioning.The changes measured on any scale should be accompanied by a change in FSS scale to make it clinically meaningful to adopt as a standard measure for generalizability.Not every severely fatigued patient (in most cases of advanced MS) will give expected results on standard exercising protocol.It is an arguable viewpoint leading to reverse causality whether exercise therapy is worsening fatigue levels in MS patients as supported by a systematic review by Taylor et al. 17 .
Considering the therapeutic interventions for MS-related fatigue, a variety of exercise methods (pilates 85 , calisthenics 80 , Tai Chi 82 and aerobic) of exercises have gained attention.
Numerous studies have shed light on the efficiency of exercise for the PwMS, almost all studies designated the exercise as a remarkable factor in improving the fatigue and its related distress in MS 84 .Certain observational studies have been conducted to find out if the cause of fatigue in PwMS is the physical activity instead of neural demyelination and lack of neuroplasticity.One cross-sectional study ruled out the possibility of fatigue associated with the physical activity instead they found a strong association between the mental health and fatigue 84 .
Fatigue in MS can be due to depression, which intercedes the association between neuronal issues and physical conditions 84 .Pharmaceutical interventions like melatonin supplementation have been effective to treat the fatigue related to MS 79 .Melatonin can act as anti-inflammatory and immunomodulatory drug that does not cross the blood-brain barrier.The anti-oxidative effect can be used to treat MS patients as they have high oxidative stress owing to elevated levels of plasma lipid peroxide and activated nitrosative-oxidative pathways 79 .
An observational retrospective study showed that switching from interferon-β to glatiramer improved work productivity, activity impairment and health-related quality of life [HRQoL] and fatigue.Transcranial magnetic stimulation [TMS] is an innovative way to record neurophysiological responses by measuring corticospinal-neuromuscular pathway excitability.The persistent excitation of brain neurons plays an important role in progressive forms of the disease 83 .
Plasticity is a functional reorganization of neurons carried out through anatomical reorganization and axonal sprouting with synaptogenesis.Physical training is known to induce compensatory plasticity and increases activity-dependent synaptic potentiation.Exercise is known to cause an increase in endocannabinoid signalling 86 .
The summary of included observational studies can be found in Table 4.

Conclusion
The diversity of pathological phenomena involved in fatigue related to MS is a major concern in understanding and quantifying the role of each causal factor.Our study has found a significant positive effect on fatigue levels of RRMS patients with regular CBT and exercise-based combination therapy.These results were not supported in case of PPMS or SPMS patients due to the aggressive nature of the disease.Emphasizing the clinical significance of combinational therapy which can be prescribed in MS, yet this does not undermine the need for statistical analysis and correlation.Future research should focus on improving the quality of life of progressive forms of MS.
Factors responsible for a high drop-out rate should be studied and correlated with morbidity and mortality rates.We believe an amalgamation of sound mental health, physical health, and pharmacological health shall tone down or blunt the effect of fatigue in the daily life of MS patients.
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Figure 1 .
Figure 1.Global prevalence of MS in 2013.This shows that the disease has a high prevalence in cold countries especially The United States of America and Canada.©MSIF 2013; reproduced with permission.

Figure 2 .
Figure 2. PRISMA flow diagram representing the selection process.

Full
out literatures not related to purpose of study, ruled out literatures published 5 years ago, literatures on other neurocognitive disorders were excluded.

Table 1 . Quality appraisal using AMSTAR guidelines.
2,antadine2,11is anti-parkinsonian medication that gives an inconsistent improvement in 20-40% of patients over the short term.Yang et al. showed that amantadine might be the most effective drug for treating MS fatigue: SMD and CI were −1.09 [−1.30 to −0.87], and the z-score was 9.75 [P < 0.00001]; however, there was a high variation in number size of patients, causing heterogeneity to be 91% 11 .The two most effective drugs in treatment are natalizumab and alemtuzumab, but they cause progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus and autoimmune diseases of thyroid along with thrombocytopenic purpura with immune glomerulonephritis respectively.A 6-month study in 2016, ECTRIMS showed no increase in mortality.Ocrelizumab, the first drug effective to slow down PPMS and which targets B cells in RRMS and PPMS, is in a phase 3 trial 2 .A counter drug in SPMS is still to be discovered as IFNβ1b has not shown efficacy in American SPMS trials.Hence trials should be performed with combination therapy including ocrelizumab and IFNβ1b to counter SPMS, which has a poor prognosis 2 .

Table 2 . Summary of included systematic reviews.
EPHPP, Effective Public Health Practice Project; Cochrane RoB tool, Cochrane risk of bias tool.

Table 4 . Summary of included observational studies.
TAU, treatment as usual.