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

Sumanth Khadke; tehmina siddique

doi:10.12688/f1000research.18247.1

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Systematic Review

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

[version 1; peer review: 2 not approved]

Sumanth Khadke ^1-3, tehmina siddique^1,4

PUBLISHED 26 Apr 2019

Author details Author details

¹ california institute of behavioral neurosciences and psychology, Fairfield, California, 94534, USA
² Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals, Pune, Maharashtra, 411011, India
³ Our Lady of Fatima University, Valenzuela, Manila, Philippines
⁴ Women University Multan, Multan, Punjab, Pakistan

Sumanth Khadke
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

tehmina siddique
Roles: Methodology, Writing – Original Draft Preparation

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Firm conclusions about the applicability of treatment 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.
Methods: An electronic database search included EBSCO, PubMed, 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.
Results: We included 13 systematic reviews, 10 RCTs and 7 observational 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.
Conclusions: The diverse pathology of fatigue related to MS is important in 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.

Keywords

Multiple sclerosis, fatigue, cognitive behavioral therapy, combined therapy, fatigue in MS.

Corresponding author: Sumanth Khadke

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2019 Khadke S and siddique t. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Khadke S and siddique t. Diverse mechanisms and treatment strategies to confront fatigue in multiple sclerosis: A systematic review [version 1; peer review: 2 not approved]. F1000Research 2019, 8:563 (https://doi.org/10.12688/f1000research.18247.1) First published: 26 Apr 2019, 8:563 (https://doi.org/10.12688/f1000research.18247.1) Latest published: 26 Apr 2019, 8:563 (https://doi.org/10.12688/f1000research.18247.1)

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 retirement¹. 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 ocrelizumab². 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 year¹. 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 000³. The epidemiological basis of MS is based on genetic and environmental risk factors⁴. 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.

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.

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 matter¹. 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 oligodendrocytes¹. The genome-wide differences present in DNA methylation dictate the susceptibility of damage to oligodendrocytes⁵. Neuroinflammatory mediators such as INF gamma, TNFα and ILβ promote synaptopathy, demyelination and axonal loss⁵. 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 presentation⁶. Actively demyelinating lesions in the background of inflammation causing blood-brain barrier dysfunction as seen in RRMS⁷. Biomarkers of the disease include fetuin-A, nitric oxide synthase and osteopontin⁸. 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 Meta-analysis (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.

Table 1. Quality appraisal using AMSTAR guidelines.

STUDY	1	2	3	4	5	6	7	8	9	10	11	SCORE (On 11)
T. Yang et al.¹¹	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No	8
P. Miller and A soundly¹²	No	Yes	Yes	No	Yes	Yes	Yes	No	No	No	No	5
M. Pearson et al.¹³	No	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	No	8
L.E. van den Akker et al.¹⁴	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No	8
A.E. Latimer-Cheung et al.¹⁵	No	Yes	Yes	No	Yes	Yes	No	Yes	No	No	No	5
Fary Khan, Bhasker Amatya¹⁶	UA	Yes	Yes	Yes	Yes	Yes	Yes	No	No	No	No	6
E. Taylor, R.E. Taylor-Piliae¹⁷	No	Yes	Yes	No	Yes	Yes	Yes	Yes	No	No	Yes	7
Pagnini et al.¹²	Yes	No	Yes	No	No	Yes	No	No	No	No	Yes	4
Phyo et al.¹	UA	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	8
Heine M et al.¹⁸	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	10
M.Asano, M.L. Finlayson¹⁹	No	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	Yes	8
H Cramer et al.²⁰	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	No	9
Wendebourg et al.²¹	No	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes	No	7

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^22–29. We excluded articles which focussed on non-motor aspects of MS or where experimental studies^30–42 opinion article^43–45, updates⁴⁶ Letters⁴⁷ study protocols⁴⁸ and extended abstracts⁴⁹. A list of excluded studies is available as Extended data⁵⁰.

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 guidelines⁵¹.

Results

Studies identified

We identified 1343 articles from the database search using Scopus, Science Direct, EBSCO and Pub med with no additional articles from other sources (Figure 2). We found 1203 articles to be remaining after removal of duplicates. We excluded 1131 publications based on title and abstract and date of publication. We had 72 full-text articles assessed for eligibility of which 42 articles were excluded among which we excluded articles which related to cognitive changes^52–65. We included 10 RCT, 7 observational reviews and 13 systematic reviews^1,11–21,66 for the study. A flow diagram is shown in Figure 2.

Figure 2. PRISMA flow diagram representing the selection process.

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.

Table 2. Summary of included systematic reviews.

Study-place- year-design	Population	Intervention	Comparatives	Appraisal	Outcome	No. studies
T. Yang et al. China 2017¹¹	PwMS N=723 F=67.52%	Amantadine Vs n-acetyl carnitine Modafinil	Placebo	Jaded scale Cochrane risk of bias tool	Amantadine proved effective in treating fatigue in MS. L-carnitine was proposed to have similar effect as amantadine.	11 RCT from 5 databases
P. Miller and A Soundy UK 2017¹²	PwMS N=17469 M-17.8% F-31.7% Rest not known	Amantadine Prokarin, Pemoline Carnitine, Modafinil Vs CBT mindfulness	Reviews including education (active control) No intervention (inactive control)	Amstar grading (Avg=6.5)	Modafinil proved to be beneficial. Pemoline and Carnitine did prove to be beneficial. Combination of physical and cognitive strategy proved beneficial.	24 Reviews with systematic quantitative RCT From 6 databases
Pearson et al. Australia 2015¹³	PwMS N=655 M-169 F-463	aerobic endurance training. resistance training aquatics yoga	No exercise	Cochrane RoB tool	pwMS with exercise therapy had reduction in walking time in 10mWT of 1.76 sec. they also showed improvement in walking endurance(6m WT and 2m WT) (P< 0.001)	13 RCT From 5 databases
L.E. van den Akker et al. Netherlands 2016¹⁴	PwMS N=520 M-100 F-420	CBT	Relaxation telephone delivered education and local care	Cochrane RoB tool	Overall CBT had positive short-term effect on fatigue. The long-term effect of CBT based treatment was described in 3 studies.	6 RCT 9 databases
A.E. Latimer- Cheung et al. Canada 2013¹⁵	PwMS N=1338*	Aerobic training, resistance training, combined both.	No intervention	PEDro score for RCT Downs and Black scale for non RCT	Exercise done twice a week with moderate intensity increases aerobic capacity with muscle power. It may enhance mobility, fatigue, and health-related QoL.	23 RTC 31 NON-RTC 7databases
Fary Khan, Bhasker Amatya Australia 2017¹⁶	PwMS N=16602*	Multiple interventions	No intervention	AMSTAR	Physical therapy for enhanced activity and participation while educational programs reduced fatigue (strong evidence). Multidisciplinary rehabilitation had moderate evidence. Limited for psychological and symptom management programs (fatigue, spasticity).	15 Cochrane review 24 OTHER REVIEW 5 databases
E. Taylor, R.E. Taylor-Piliae USA 2017¹⁷	PwMS N=193*	Tai chi	Tai chi group vs non-tai chi or control group	An established tool with 16 study elements	One study proved enhanced cognition and psychosocial fatigue scores (p <0.05). One study reported worsening of fatigue in controls (p < 0.05).Rest revealed no significance	3 RCT 5 Quasi- experimental studies 13 databases
Pagnini et al. Italy 2014¹²	PwMS N= 5705*	CBT and other psychological treatments	Usual care	QUOROM statements	Fatigue improved following relaxation training, meditation, stress management, and coping.	22 RCT 4databases
Phyo et al. Australia 2018¹	PwMS N= 1249*	Psychological interventions CBT	comparators were non-active/active controls (relaxation or psychotherapy)	EPHPP Hamilton Tool	1. CBT decreased levels of fatigue w.r.t non-active controls (P= 0.07) and with active controls (P = 0.77). 2. Relaxation (P = 0.37) and mindfulness interventions (P= 0.59) decreased fatigue levels compared to non-active control	20 14 RCT 6- others From 4 databases
Heine M et al. Netherlands 2015¹⁸	PwMS N= 3206*	Exercise therapy alone vs endurance training vs mixed training vs others	No exercise group two exercise therapies	Cochrane RoB tool	1. Exercise therapy improved fatigue levels (P < 0.01) and so the others 2. Endurance exercise (P < 0.01) 3. Mixed exercise (P < 0.01) 4. Other exercise (P < 0.01)	72 RCT 8 databases
Asano, Finlayson Canada 2014¹⁹	PwMS N= 1499*	Pharmacological Exercise Education	Non-pharmacologic Non-exercise Non-education	Cochrane RoB tool	Rehabilitation- exercise and education have a strong effect in decreasing the impact or severity of fatigue compared to the fatigue medications prescribed very often like Amantadine and Modafinil. Rehabilitation could be the initial treatment of choice contrary to ongoing standards.	25 RCT 4 databases
Holger Cramer et al. Germany 2014²⁰	PwMS N= 670*	Yoga	Usual care, exercise non-pharmacological	Cochrane RoB tool	1. Yoga had short term effect on fatigue (p = 0.04) 2. No evidence found yoga to be better than exercise (p = 0.83)	7RCT 7 databases
Wendebourg et al. Germany 2017²¹	PwMS N=1021*	CBT	Non-CBT approaches(education)	Cochrane RoB tool	CBT based treatment approach has a positive effect on fatigue levels.a need for multidimensional treatment emphasized.	10 RCT 2 databases

EPHPP, Effective Public Health Practice Project; Cochrane RoB tool, Cochrane risk of bias tool.

Table 3. Summary of included randomized controlled trials.

First author	Crossover design? Randomized/ analyzed (n)	Age in years at baseline, mean (SD)	Characteristics of eligible participants	Treatment groups (n)	EDSS scores, median IQR(SD)	Duration of disease IN YEARS (SD)	Duration of treatment	Summary of findings
Susan Coote⁶⁹	No; 92/65	43.3 (9.9)	1. Physician- confirmed MS cases 2.EDSS score of 0-3 3.sedentary life style	Exercise + social cognitive therapy (SCT) (33) vs exercise + education (32)	3.3(0.7)	6.85 (5.9)	36 weeks	Both groups showed improvements in post- intervention in fatigue levels in PwMS at the end of 36 weeks. This showed a positive effect of behavioral therapy with exercise.
Sara Hayes⁷³	No; 92/65	42.6 (9.6)	1. Physician- confirmed MS cases 2.EDSS score of 0-3 3.sedentary life style	Exercise + SCT (33) vs exercise + education (32)	3.3(0.7)	6.85 (5.9)	36 weeks	ITT analysis showed no difference between the two groups of study. A secondary analysis showed a significant treatment effect favoring the intervention group (p=0.04).
Martin Heine⁷¹	No; 89/89	45.8 (9.7)	1. Age ≥18 and ≤70 years ambulant patients 2. expanded disability status scale (EDSS) ≤6.0. 3.no signs of an MS exacerbation or corticosteroid treatment <3months.	Aerobic exercise (43) vs consultation with MS nurse (46)	3.0 (2.0–3.6)	8.0 (2.0–15.3)	16 weeks 12 months follow up.	A short-lived post-intervention effect measured on CIS20r fatigue subscale was seen which did not sustained in follow up period.
Jonathan Calkwood⁶⁷	No; 1053/1053	44.4 to 47.5	1. 18–65 years 2. EDSS =0-5.5 3.All have RRMS 4.A single IDMT (except natalizumab) continuously for at least 6 months	1.GA to fingolimod( n=262) 2.remaining on GA(n=74) 3.IM IFN beta-1a to fingolimod (n=205) 4.continuing IM IFN beta-1a (n=48) 5.SC IFN beta-1a to fingolimod (n=196) 6.continuing on SC IFN beta-1a (n=58) 7.IFN beta-1b to fingolimod (n=125) 8.continuing IFN beta-1b (n=139)	1)2.5 (1.33) 2)2.4 (1.35) 3)2.5 (1.26) 4)2.4 (1.27) 5)2.4 (1.35) 6)2.3 (1.38) 7)2.4 (1.37) 8)2.5 (1.39)	13.1 (8.91) 12.2 (9.36) 12.0 (7.9) 11.5 (7.87) 11.1 (7.89) 11.4 (8.04) 12.2 (8.64) 12.3 (6.78)	6 months	A change to fingolimod from GA, IM IFN beta 1a, SC IFN beta 1 a, IFN beta 1b showed significant changes in TSQM global satisfaction scores. (P <0.001). Remarkable reduction in fatigue in those who switched to fingolimod from SC IFN beta 1 a, IFN beta 1b except those remaining on GA and in IFN beta 1a.
Ari J Green⁷⁴	Yes; 50/50	40.1(10.3)	1. Stable RRMS patients 2. Disease duration ≤15 years 3. Patients had a demyelinating injury in the visual pathway	1.Group 1 received 90-day clemastine fumarate followed by 60-day placebo. 2. Group 2 received 90-day placebo followed by 60-day clematine fumarate. There was no washout period	2.15(1.1)	4.3(4)	150 days	Greater improvement in latency in group 2 than in group1. Reduction in latency delay by 1.7msec/eye (p=0.0048) latency reduction was a clinical sign of oligodendrocyte precursor differentiation and re-myelination. Worsening of fatigue was noted on the MAF scale.
Arno Kerling⁷⁵	No; 60/60	42.3 ± 9.0(CWG) 45.6 ± 11.4 (EWG) with a mean of 43.9(10.2)	1.Maximum value of 6 on EDSS. 2. Adult age (18–65 years) 3. Clinical neurologist- confirmed cases	Combined work out group (30) Vs Endurance work out group (30)	2.85(1.2)	not mentioned	3 months	Combined workout group (CWG) and endurance work out group engaged in aerobic training exercise had improvement in aerobic capacity and maximum force. Both groups showed improved fatigue levels.
Alexander Tallner⁷⁶	No; 126/108	40.8 (9.9)	1.EDSS score of less than or equal to 4.0 2. At least 4 weeks of clinical stability	Internet based e-training (59) vs wait list control group (67)	2.7 (0.8)	9.5 (8.2)	6 months	No significant difference was found between the two groups(including fatigue) except peak expiratory flow (p = 0.01)
Fred D. Lublin⁷⁷	No; 16/16	48.0 (36–58)	1.Age between 18 and 65 years (both RRMS and SPMS) 2. Disease duration of at least 2 years 3.Evidence of active disease 4. Cardiac, pulmonary, renal and pulmonary function should be normal was required.	1 unit of PDA-0001(6) vs 4 units of PDA-0001(6) vs placebo (4)	4.8 (1.5 –6.5)	8.5 (1.0–31.8)	6 months with 6 months follow up	1. It was found safe to infuse mesenchymal like cells to patients with MS 2. No increments in EDSS score more than 0.5. 3.No worsening of MS noted.
Marc B. Rietberg⁷²	No; 48/44	46(9.25)	(1) ≥18 years, ambulatory. (2) Clinically diagnosed MS (3) Should have chronic fatigue fulfilling the MSCCPG definition	Multidisciplinary Rehabilitation (23) vs nurse consultations (25)	3.5(2.5) median (IQR)	7.5(6.35)	24 weeks	Within-group effects were found to be insignificant for both groups w.r.t the primary (0.57≤p≤0.97) and secondary (0.11≤p≤0.92) outcome measures from baseline to 12 (P = 0.39) or 24 weeks (P = 0.14)
S.Thomas⁶⁸	No; 164/131	49.05(9.65)	1.Clincally diagnosed MS. (2) Fatigue with FSS score >4 and (3) Ambulatory	FACETS plus CLP (84) vs CLP (80)	Not available	Different duration from < 1 year to >16 years	1 year	Statistically significant results were found in the reduction of fatigue severity in the intervention group at the end of 1 and 4 months of following up.no significant difference on MSIS scale at 4 months of follow up.
Peter W Thomas⁷⁰	No; 164/131	49.05(9.65)	1.Clinically proven MS diagnosis with FSS SCORE > 4 2. Should be ambulatory	FACETS plus CLP (84) vs CLP (80)	Not available	Different duration from < 1 year to >16 years	1 year	Improvements in self-efficacy and fatigue severity at 4-months of follow-up using FACETS were mostly sustained at 1 year. improvement on MSIS scale was seen which lacked previous assessments.
Vanessa Vermöhlen⁷⁸	No; 70/67	51 (46–55)	1.MS patients older than 18 years 2.Confirmed MS with spasticity of the lower limbs 3. EDSS score between 4-6.5	Hippotherapy plus standard care (32) vs standard care alone (38)	5.4 (0.9) (at inclusion) 21 (31%) = ≤5 46 (69%) = ≥5	17.3 (11–23)	12 weeks	The subgroup with EDSS score of ≥5 (5.1, p = 0.001) showed largest benefit with BBS. Fatigue (p = 0.02) and spasticity (p = 0.03) improved in the intervention group. The mean difference in change between groups was 12.0 (p<0.001) in physical health score and 14.4 (p<0.001) in mental health score of MSQoL-54.

Table 4. Summary of included observational studies.

Author number of patients (control/ experimental)	Age Of participants Mean ± SD	Characteristics of eligible participants intervention/ treatment	duration of treatment and treatment given	Duration of disease in control and experiment	EDSS scores± SD	Results
Adamczyk-Sowa et al.⁷⁹ n = 122 (20/102)	10 ± 11.6 (for controls) 86±10.28 (for RRMS pretreated group), 42±10.06(RRMS INF- beta), 15±7.01 (SP/PP MS Mitoxantrone) (41.90±7.13(RRMS Relapse)	All PwMS diagnosed, according to the McDonald criteria. Melatonin	90 days melatonin	Control= NA, Pretreated=1.85±1.21, RRMS INFβ=6.27±2. RRMS Mitoxantrone= 20.88±13.65 RRMS Relapse= 6.53±5.13	Control= 0, RRMS Pretreated= 1.85±095, RRMS INFβ=2.92±1.24, RRMS Mitoxantrone=5.68±1.51, RRMS Relapse =3.96±1.98	LHP (lipid hydroxy peroxides) and homocysteine concentration was higher in all studied MS groups vs. controls which decreased after melatonin usage. In the RRMS-relapse group levels of homocysteine were significantly higher compared to the RRMS-pre-treated group. The fatigue score was significantly lower in RRMS pre-treated group compared to RRMS-INF-beta and PP/SP MS- mitoxantrone treated patients.
Aydin, T.et al.80 n = 40	32.83 ± 3.64	1. acute exacerbation of MS symptoms. 2. An Ashworth spasticity score over 2 3. EDSS score over 4.	12 weeks of Calisthenic exercises	6.97 ±3.15	< 4.5, Hospital based group = 3.6 ± 1.3, Home based group= 3.4 ± 2.1	Significant improvements in terms of the BBS, HADS-A and Musi-QoL scores after 12 weeks of home and hospital-based exercises. The HADS-D score improved on the in hospital-based patients only. No significant difference in the FSS score (p < 0.05).
Baert, I.et al.⁸¹ n = 290 PwMS, 284 completed	49.7 ± 10.8	Included subjects had a definite diagnosis of MS, EDSS score ≤6.5	Single time experiment performed Physical rehabilitation exercises	11.9 ± 8.1	4.8 ± 1.5	Moderate to severely disabled pwMS performed well on MSWS-12, 2MWT, and 6MWT but not on 25MFWT.(MWT- minute walking test)
Burschka, J. M. et al.⁸² n= 32 PwMS, 15	TAU= 43.6± 8.0 Tai Chi= 42.6± 9.4	1.MS patients (any type) 2. EDSS < 5 3.Relapse free for a month prior study	6 months Tai chi	TAU*=7.8 ±(6.8) Tai Chi= 6.0±(4.7)	<5	Balance, coordination and life satisfaction had improved with Tai Chi treatment comparing to TAU. Fatigue and depression were found decreased with Tai Chi treatment.
Collett, J et al.⁸³ n = 23, PwMS=14, Control=9	MS= 52.4 ±8.1, Control= 49.6 ±8.6	1) Clinically definite MS, (2) Be the age of 18 years (3) have the adequate mental capacity to consent, (4) Clinically stable (5) Able to use a cycle ergometer.	Single time exercise test performed Multiple intensity exercises	14.1 SD 9.7	Not Provided	-Controls proved better on the exercise test (p < 0.05). -PwMS took longer to recover as the intensity of exercise increased (45% at 6 min; 60% at15 min; 90% at 35 min) and correlating with Tympanic temperature. MEParea was significantly depressed in both groups at 45% and 60% (p < 0.001), in the MS group which correlated well to recovery time measured by RPE. RPE= Borg’s ratings of perceived exertion. MEP=motor evoked potential
Fernandez-Munoz, J. J. et al.⁸⁴ n= 108 PwMS	44 ± 8	Definite MS according to the modified McDonald criteria.	NA	12.5±8.0	3.4±1.7	Fatigue score was associated with bodily pain (P<0.01), physical function (P<0.01) and mental health (P<0.01), and with positive association with depression (P<0.01). Depression had negative association with bodily pain (P<0.01) and mental health (P<0.01) Greater the body pain, greater were levels of depression.
Soysal Tomruk, M. et al.⁸⁵ n = 11 PwMS, 12 Control	Median values mentioned in the study MS=52 (35–66) control=50 (38–65)	Age :18 to 65 years, 2≥EDSS score ≤5,	Ten-week	-	3.5 (2.0–5.0)	Postural control and fatigue levels were significantly worse in PwMS w.r.t healthy controls (p<0.05) but improved sensory interactions were noted (p<0.05) and no effect on postural control (p>0.05).

TAU, treatment as usual.

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 [I²>58%] among the trails compared. A few studies showed exercise improved walking speed with 10-minute walking test showing mean difference [MD] reduction in walking time of 1.76 s; [95% (CI), 2.47 to 1.06; P<0.001]⁶⁶. Another study comes in support of the use of exercise which shows that pooled Effect size was 0.57 (95%CI: 0.10–1.04, P = 0.02)¹⁹. These findings suggest that exercise can help to reduce fatigue in MS patients. A study by Taylor et al. mentions a study showing exercise worsening fatigue in MS (P<0.05)¹⁷.

Amantadine^2,11 is 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 trial². 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 prognosis².

Cognitive behavioural therapy [CBT] can help reducing fatigue in MS (pooled SMD = −0.71, 95% CI: −1.05 to −0.37, P = 0.77) as compared to active controls¹. Supporting studies also show a positive effect [SMD] = −0.47;95% [CI] = −0.88; −0.06; I² = 73%]. A long-term positive effect of CBT [SMD = −0.30; CI −0.51; −0.08; I² = 0%] is also shown but had limited number of studies¹⁴. Thus, CBT shows a positive effect on fatigue in MS. Practices like yoga show some effect compared to usual care [SMD = 20.52; 95% CI = 21.02 to 20.02; p = 0.04] but fail to prove better than exercise therapy [SMD = 0.03; 95% CI = 20.24 to 0.30; p = 0.83]²³.

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)^68–70.

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.

Figure 3. Risk of bias graph.

Figure 4. Risk of bias summary.

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^69–71. 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 (pilates⁸⁵, calisthenics⁸⁰, Tai Chi⁸² 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 MS⁸⁴. 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 fatigue⁸⁴.

Fatigue in MS can be due to depression, which intercedes the association between neuronal issues and physical conditions⁸⁴. Pharmaceutical interventions like melatonin supplementation have been effective to treat the fatigue related to MS⁷⁹. 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 pathways⁷⁹.

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 disease⁸³.

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 signalling⁸⁶.

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.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Extended data

Open Science Framework: DIVERSE MECHANISMS AND TREATMENT STRATEGIES TO CONFRONT FATIGUE IN MULTIPLE SCLEROSIS -A SYSTEMATIC REVIEW. https://doi.org/10.17605/OSF.IO/W5DA4⁵⁰

This project contains references for all excluded studies.

Extended data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Reporting guidelines

Open Science Framework: PRISMA checklist for study “Diverse mechanisms and treatment strategies to confront fatigue in multiple sclerosis: A systematic review”. https://doi.org/10.17605/OSF.IO/W5DA4

Grant information

The author(s) declared that no grants were involved in supporting this work.

Faculty Opinions recommended

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¹ california institute of behavioral neurosciences and psychology, Fairfield, California, 94534, USA
² Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals, Pune, Maharashtra, 411011, India
³ Our Lady of Fatima University, Valenzuela, Manila, Philippines
⁴ Women University Multan, Multan, Punjab, Pakistan

Sumanth Khadke
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

tehmina siddique
Roles: Methodology, Writing – Original Draft Preparation

Competing interests

No competing interests were disclosed.

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The author(s) declared that no grants were involved in supporting this work.

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Khadke S and siddique t. Diverse mechanisms and treatment strategies to confront fatigue in multiple sclerosis: A systematic review [version 1; peer review: 2 not approved]. F1000Research 2019, 8:563 (https://doi.org/10.12688/f1000research.18247.1)

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Open Peer Review

Version 1

VERSION 1

PUBLISHED 26 Apr 2019

Views

21

Reviewer Report 18 Jun 2019

Tomas Kalincik, CORe, Department of Medicine, University of Melbourne, Melbourne, Vic, Australia

Not Approved

https://doi.org/10.5256/f1000research.19959.r48171

This article aims at providing a systematic review of literature on the treatment of fatigue in multiple sclerosis. This is an important topic, as management of MS-related fatigue is a difficult subject and the results achieved in clinical practice are ... Continue reading

This article aims at providing a systematic review of literature on the treatment of fatigue in multiple sclerosis. This is an important topic, as management of MS-related fatigue is a difficult subject and the results achieved in clinical practice are often frustrating to clinicians and patients alike. Unfortunately, the review falls short of its goal, providing only a superficial summary of the identified literature and a discussion based on a handful of selected anecdotes. The review would benefit from a more systematic approach to the topic.

Major comments:
The systematic review only included open access articles. This is potentially a significant limitation. How may otherwise eligible articles were excluded on these grounds?
The information summarised in the Introduction is selective and only remotely related to this article. The referencing style in the Introduction is suboptimal, with only limited number of indirect references cited. The summary given in the Introduction, paragraph 5 is unnecessary. Most of this information is not immediately relevant to this manuscript and the section is not appropriately referenced. Similarly, the information shown in paragraph 6 is patchy and poorly referenced.
The authors cite the old phenotypic classification of MS. Instead, the 2013 revisions of the classification of MS phenotypes (Lublin et al., Neurology 2014[Ref-1]) should be used.

During screening, the authors have excluded a large number of identified articles. This does not impact negatively on the quality of the systematic review but it highlights that the search terms employed were very broad.

The Results are hard to follow. The effect of different interventions on physical performance and fatigue are presented intermittently. In fact, the most of the section on the results of meta-analyses focuses on the effects of treatments on physical performance, with only a very brief mention of the reported effect on fatigue. The references of the individual results are scattered and often given without the appropriate context (for instance “6-month study in 2016, ECTRIMS showed no increase in mortality.” The summary of the safety issues mentioned for some of the presented interventions is not balanced. The authors erroneously state that there is no evidence of therapeutic effect in SPMS, whereas siponimod has in fact shown effect on slowing progression of disability in a phase 3 trial (EXPAND).
There is some duplication of the reported results, as some of the clinical trials were also included in the meta-analyses. This is unavoidable, but the amount of overlap between the meta-analyses and the trials reported individually in this review should be reported.
An improvement in 20-40% of patients treated with amantadine is referenced – it is unclear which domain and in what test this improvement involves. Similarly, it is unclear what is meant by the statement ‘The two most effective drugs in treatment are natalizumab and alemtuzumab…”. Does this relate to their effect on relapses/disability/MRI or fatigue?
The results of the individual randomised controlled trials should be summarised not only with p values but, most importantly, with the measures of effect size (both point and interval estimates).
The authors mention an issue of the efficacy of interventions in the context of the duration of the symptoms. This should be expanded upon and provided with more supporting evidence if this theme is to be retained within the article.

The manuscript would benefit from a stylistic review (a few examples – Introduction, paragraph 2, lines 6-7; Introduction, paragraph 3, lines 12-16; Introduction, paragraph 5, last line; Introduction, paragraph 5, lines 10-12; Methods, Inclusion/Exclusion criteria, lines 9-11; Figure 2 etc.). The authors should also use terminology more accurately – e.g. ’widespread MS investigation’, ‘disease burden’, ‘experimental studies’. The formulation “MS is affecting 2,000,000 people worldwide and 400,000 people in the United States per year” implies that the cited information represents incidence, whereas the numbers given are keeping with MS prevalence.
The Discussion is not systematically structured and would benefit from more thorough, systematic evaluation of the mentioned topics. These include the present anecdotes related to the link between depression and fatigue, use of melatonin, TMS and plasticity. An in-depth discussion of the summarised literature, including critical appraisal of the presented studies and meta-analyses, is needed.

The opening statement of the Discussion provides a perspective on relevant measurable outcomes in the tests of MS-related fatigue. This discussion should be linked to the results presented and the magnitude of the impact of the studied interventions on FSS should be evaluated.

The authors have phrased the conclusion in the fashion of an original study (“Our study has found a significant positive effect…”). However, it should be remembered that this article is a systematic review of literature, in which no novel results were generated. The Conclusion section should use the language of a review. In this context, references to ‘significant’ findings are not appropriate.

The following proposed conclusions are not supported by the results of the reported trials, including the following:

The suggestion that CBT and exercise-based therapies are not associated with better control of fatigue due to a more aggressive nature of PPMS and SPMS relative to RRMS
The proposed need for combination therapy for MS, which is also being implied as an accessible option (please note that combination immunotherapy is not approved for use in MS)

The sentence containing “…should focus on improving the quality of life of progressive forms of MS” objectifies patients and should be rephrased.

Minor comments:
Table 1: should provide explanation of the AMSTAR items in a footnote.
Table 2: Minor inconsistencies are present (such as n-acetyl carnitine vs. L-carnitine; the format of presenting control groups)

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?

No

References

1. Lublin FD, Reingold SC, Cohen JA, Cutter GR, et al.: Defining the clinical course of multiple sclerosis: the 2013 revisions.Neurology. 2014; 83 (3): 278-86 PubMed Abstract | Publisher Full Text

Competing Interests: Tomas Kalincik served on scientific advisory boards for Roche, Sanofi-Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi-Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Genzyme-Sanofi, Teva, BioCSL and Merck and received research support from Biogen. None of these disclosures is directly relevant to the presented article or its topic.

Reviewer Expertise: multiple sclerosis, neuroimmunology, biostatistics, clinical outcomes research

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Views

31

Reviewer Report 20 May 2019

Andrew Soundy, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK

Not Approved

https://doi.org/10.5256/f1000research.19959.r48607

Overall, I think more time is needed to explain what you did and show the reader that a quality process has been undertaken. Some points below are critical for me.

Abstract
As a reader I am ... Continue reading

Overall, I think more time is needed to explain what you did and show the reader that a quality process has been undertaken. Some points below are critical for me.

Abstract
As a reader I am not sure how you integrated and weighted findings from different designs e.g., you mention two random trials in the results EPOC and FACETS – yet review evidence would include more accurate results and you have identified 13 reviews?

Introduction
Does the reader need to know about the different drugs for treatments of MS or the main point which is fatigue remains
Not sure of the need for Figure – given the focus and aim of this work

There is no overview of why a review or what type of review is needed within this section?

Methods
There is no protocol
If you are using Cochrane then you would include systematic reviews in your synthesis – you would ideally aim to get a meta-analysis done of past empirical research. So the design is questionable. As your review is mixed methods review requiring aspects which are needed for mixed methods design including a decision around the point of integration of data.
If you used Cochrane as a basis your key words would have likely increased and the number of databases and search methods would be different from what you state
Your methods has no detail on synthesis as point in abstract is made

Results
Page 5 Think about the how you lay out the information – currently for me there is limited information which is hard to understand how and why you have presented it like this.
Think about how you integrate the quality assessment onto findings

Discussion
Without clarity from above – I can't assess the discussion currently

Are the rationale for, and objectives of, the Systematic Review clearly stated?

No
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

No
Are the conclusions drawn adequately supported by the results presented in the review?

No

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Methodology and publications in this area including one cited by the authors.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Version 1 26 Apr 19	read	read

Andrew Soundy, University of Birmingham, Birmingham, UK
Tomas Kalincik, University of Melbourne, Melbourne, Australia

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Reviewer Report

21 Views

18 Jun 2019 | for Version 1

Tomas Kalincik, CORe, Department of Medicine, University of Melbourne, Melbourne, Vic, Australia

21 Views Cite this report Responses(0)

Not Approved

This article aims at providing a systematic review of literature on the treatment of fatigue in multiple sclerosis. This is an important topic, as management of MS-related fatigue is a difficult subject and the results achieved in clinical practice are often frustrating to clinicians and patients alike. Unfortunately, the review falls short of its goal, providing only a superficial summary of the identified literature and a discussion based on a handful of selected anecdotes. The review would benefit from a more systematic approach to the topic.

Major comments:
The systematic review only included open access articles. This is potentially a significant limitation. How may otherwise eligible articles were excluded on these grounds?
The information summarised in the Introduction is selective and only remotely related to this article. The referencing style in the Introduction is suboptimal, with only limited number of indirect references cited. The summary given in the Introduction, paragraph 5 is unnecessary. Most of this information is not immediately relevant to this manuscript and the section is not appropriately referenced. Similarly, the information shown in paragraph 6 is patchy and poorly referenced.
The authors cite the old phenotypic classification of MS. Instead, the 2013 revisions of the classification of MS phenotypes (Lublin et al., Neurology 2014[Ref-1]) should be used.

During screening, the authors have excluded a large number of identified articles. This does not impact negatively on the quality of the systematic review but it highlights that the search terms employed were very broad.

The Results are hard to follow. The effect of different interventions on physical performance and fatigue are presented intermittently. In fact, the most of the section on the results of meta-analyses focuses on the effects of treatments on physical performance, with only a very brief mention of the reported effect on fatigue. The references of the individual results are scattered and often given without the appropriate context (for instance “6-month study in 2016, ECTRIMS showed no increase in mortality.” The summary of the safety issues mentioned for some of the presented interventions is not balanced. The authors erroneously state that there is no evidence of therapeutic effect in SPMS, whereas siponimod has in fact shown effect on slowing progression of disability in a phase 3 trial (EXPAND).
There is some duplication of the reported results, as some of the clinical trials were also included in the meta-analyses. This is unavoidable, but the amount of overlap between the meta-analyses and the trials reported individually in this review should be reported.
An improvement in 20-40% of patients treated with amantadine is referenced – it is unclear which domain and in what test this improvement involves. Similarly, it is unclear what is meant by the statement ‘The two most effective drugs in treatment are natalizumab and alemtuzumab…”. Does this relate to their effect on relapses/disability/MRI or fatigue?
The results of the individual randomised controlled trials should be summarised not only with p values but, most importantly, with the measures of effect size (both point and interval estimates).
The authors mention an issue of the efficacy of interventions in the context of the duration of the symptoms. This should be expanded upon and provided with more supporting evidence if this theme is to be retained within the article.

The manuscript would benefit from a stylistic review (a few examples – Introduction, paragraph 2, lines 6-7; Introduction, paragraph 3, lines 12-16; Introduction, paragraph 5, last line; Introduction, paragraph 5, lines 10-12; Methods, Inclusion/Exclusion criteria, lines 9-11; Figure 2 etc.). The authors should also use terminology more accurately – e.g. ’widespread MS investigation’, ‘disease burden’, ‘experimental studies’. The formulation “MS is affecting 2,000,000 people worldwide and 400,000 people in the United States per year” implies that the cited information represents incidence, whereas the numbers given are keeping with MS prevalence.
The Discussion is not systematically structured and would benefit from more thorough, systematic evaluation of the mentioned topics. These include the present anecdotes related to the link between depression and fatigue, use of melatonin, TMS and plasticity. An in-depth discussion of the summarised literature, including critical appraisal of the presented studies and meta-analyses, is needed.

The opening statement of the Discussion provides a perspective on relevant measurable outcomes in the tests of MS-related fatigue. This discussion should be linked to the results presented and the magnitude of the impact of the studied interventions on FSS should be evaluated.

The authors have phrased the conclusion in the fashion of an original study (“Our study has found a significant positive effect…”). However, it should be remembered that this article is a systematic review of literature, in which no novel results were generated. The Conclusion section should use the language of a review. In this context, references to ‘significant’ findings are not appropriate.

The following proposed conclusions are not supported by the results of the reported trials, including the following:

The suggestion that CBT and exercise-based therapies are not associated with better control of fatigue due to a more aggressive nature of PPMS and SPMS relative to RRMS
The proposed need for combination therapy for MS, which is also being implied as an accessible option (please note that combination immunotherapy is not approved for use in MS)

The sentence containing “…should focus on improving the quality of life of progressive forms of MS” objectifies patients and should be rephrased.

Minor comments:
Table 1: should provide explanation of the AMSTAR items in a footnote.
Table 2: Minor inconsistencies are present (such as n-acetyl carnitine vs. L-carnitine; the format of presenting control groups)

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?

No

References

1. Lublin FD, Reingold SC, Cohen JA, Cutter GR, et al.: Defining the clinical course of multiple sclerosis: the 2013 revisions.Neurology. 2014; 83 (3): 278-86 PubMed Abstract | Publisher Full Text

Competing Interests

Tomas Kalincik served on scientific advisory boards for Roche, Sanofi-Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi-Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Genzyme-Sanofi, Teva, BioCSL and Merck and received research support from Biogen. None of these disclosures is directly relevant to the presented article or its topic.

Reviewer Expertise

multiple sclerosis, neuroimmunology, biostatistics, clinical outcomes research

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

31 Views

20 May 2019 | for Version 1

Andrew Soundy, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK

31 Views Cite this report Responses(0)

Not Approved

Overall, I think more time is needed to explain what you did and show the reader that a quality process has been undertaken. Some points below are critical for me.

Abstract
As a reader I am not sure how you integrated and weighted findings from different designs e.g., you mention two random trials in the results EPOC and FACETS – yet review evidence would include more accurate results and you have identified 13 reviews?

Introduction
Does the reader need to know about the different drugs for treatments of MS or the main point which is fatigue remains
Not sure of the need for Figure – given the focus and aim of this work

There is no overview of why a review or what type of review is needed within this section?

Methods
There is no protocol
If you are using Cochrane then you would include systematic reviews in your synthesis – you would ideally aim to get a meta-analysis done of past empirical research. So the design is questionable. As your review is mixed methods review requiring aspects which are needed for mixed methods design including a decision around the point of integration of data.
If you used Cochrane as a basis your key words would have likely increased and the number of databases and search methods would be different from what you state
Your methods has no detail on synthesis as point in abstract is made

Results
Page 5 Think about the how you lay out the information – currently for me there is limited information which is hard to understand how and why you have presented it like this.
Think about how you integrate the quality assessment onto findings

Discussion
Without clarity from above – I can't assess the discussion currently

Are the rationale for, and objectives of, the Systematic Review clearly stated?

No
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

No
Are the conclusions drawn adequately supported by the results presented in the review?

No

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Methodology and publications in this area including one cited by the authors.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

Responses (0)

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

Abstract

Keywords

Introduction

Figure 1. Global prevalence of MS in 2013.

Methods

Data sources and search

Selection of studies

Data extraction

Table 1. Quality appraisal using AMSTAR guidelines.

Inclusion/exclusion criteria

Risk of bias assessment

Results

Studies identified

Figure 2. PRISMA flow diagram representing the selection process.

Study characteristics

Table 2. Summary of included systematic reviews.

Table 3. Summary of included randomized controlled trials.

Table 4. Summary of included observational studies.

Results observed in systematic reviews and meta-analysis

Effect of interventions in RCTs

Risk of bias analysis

Figure 3. Risk of bias graph.

Figure 4. Risk of bias summary.

Discussion

Conclusion

Data availability

Underlying data

Extended data

Reporting guidelines

Grant information

References

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