4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

Modifiable Risk Factors in 

the Progression of Multiple 

Sclerosis: A Systematic 

Review of the Epidemiology 

and Treatment

December 2015

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

West Los Angeles VA Medical Center

Los Angeles, CA

Paul G. Shekelle, MD, PhD, Director 

Investigators:

Principal Investigator: 

Susanne Hempel, PhD

Paul Shekelle, MD, PhD

Co-investigators: 

Ning Fu, PhDc

Elena Estrada, BS, BA, MS

Annie Chen, BS, BA

Research Associates: 

Isomi Miake-Lye, PhDc

Jessica Beroes, BS

Roberta Shanman, MS

Jeremy Miles, PhD
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice

guidelines and performance measures; and

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations. 

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov. 

Recommended citation: Hempel S, Fu, N, Estrada E, Chen A, Miake-Lye I, Beroes J, Miles JNV, 

Shanman R, Shekelle P. Risk Factors for Multiple Sclerosis Progression: A Systematic Review. VA 

ESP Project #05-226; 2015.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the West Los Angeles VA Medical Center, Los Angeles, CA, funded by the Department of Veterans Affairs, 

Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. 

The findings and conclusions in this document are those of the author(s) who are responsible for its contents; the 

findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the 

United States government. Therefore, no statement in this article should be construed as an official position of the 

Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, 

consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or 

royalties) that conflict with material presented in the report. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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TABLE OF CONTENTS 

Executive Summary ..................................................................................................................1

Introduction .............................................................................................................................1

Methods..................................................................................................................................1

Data Sources and Searches..................................................................................................1

Study Selection....................................................................................................................1

Data Abstraction and Quality Assessment ...........................................................................2

Data Synthesis and Analysis................................................................................................2

Results ....................................................................................................................................3

Results of Literature Search.................................................................................................3

Summary of Results for Key Questions...............................................................................3

Discussion...............................................................................................................................4

Key Findings and Strength of Evidence ...............................................................................4

Applicability .......................................................................................................................5

Research Gaps/Future Research...........................................................................................5

Conclusions.........................................................................................................................6

Abbreviations..........................................................................................................................7

Introduction...............................................................................................................................8

Methods................................................................................................................................... 10

Topic Development............................................................................................................... 10

Search Strategy ..................................................................................................................... 10

Study Selection ..................................................................................................................... 11

Data Abstraction ................................................................................................................... 13

Quality Assessment............................................................................................................... 14

Data Synthesis and Analysis.................................................................................................. 14

Rating the Body of Evidence ................................................................................................. 15

Technical Expert Panel.......................................................................................................... 16

Peer Review .......................................................................................................................... 16

Results ..................................................................................................................................... 17

Literature Flow...................................................................................................................... 17

Key Question 1: What modifiable epidemiologic factors are related to multiple sclerosis 

progression following diagnosis?........................................................................................... 19
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Key Question 2: What environmental exposures prior to or during military service 

are related to multiple sclerosis progression following onset symptoms? ............................... 65

Key Question 3: Among identified risk factors for progression, what treatment/risk factor 

modification therapies have been shown to delay or hasten the progression of MS once 

it has initiated? ...................................................................................................................... 67

Summary and Discussion........................................................................................................ 88

Summary of Evidence by Key Question ................................................................................ 88

Limitations............................................................................................................................ 91

Applicability of Findings to the VA Population ................................................................. 91

Research Gaps/Future Research ............................................................................................ 91

Conclusions........................................................................................................................... 93

References ................................................................................................................................ 94

TABLES

Table 1. Evidence for KQ1 (MS Progression Risk Factors): Vitamin D 

or Sunshine Exposure............................................................................................................ 20

Table 2. Evidence for KQ1 (MS Progression Risk Factors): Smoking ................................... 28

Table 3. Evidence for KQ1 (MS Progression Risk Factors): Childbirth-associated Factors.... 37

Table 4. Evidence for KQ1 (MS Progression Risk Factors): Diet........................................... 40

Table 5. Evidence for KQ1 (MS Progression Risk Factors): Exercise .................................... 43

Table 6. Evidence for KQ1 (MS Progression Risk Factors): Other......................................... 46

Table 7. Evidence for KQ1 (MS Progression Risk Factors): Multiple .................................... 49

Table 8. Summary of Findings for KQ1................................................................................. 64

Table 9. Summary of Findings for KQ2................................................................................. 66

Table 10: Evidence for KQ3: Effects of Exercise Interventions on MS Progression............... 68

Table 11: Evidence for KQ3: Effects of Dietary Interventions on MS Progression................. 74

Table 12. Evidence for KQ3: Effects of Vitamin D Supplementation Interventions 

on MS Progression ................................................................................................................ 80

Table 13. Summary of Findings for KQ3............................................................................... 87

FIGURES

Figure 1: Literature Flow Chart ............................................................................................. 18

Figure 2: Correlation between EDSS Score and Vitamin D Level.......................................... 58

Figure 3: Time to Progression and Smoking .......................................................................... 60

Figure 4: Effect of Exercise Interventions on EDSS Scores................................................... 83

Figure 5: Effect of Fatty Acid Supplementation Interventions on the Relative Risk of 

Progression ........................................................................................................................... 84
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Figure 6: Effect of Dietary Interventions on EDSS Scores..................................................... 85

Figure 7: Effect of Vitamin D Interventions on EDSS Scores................................................ 86

Appendix A. Search Strategies............................................................................................... 104

Appendix B. Study Selection and List of Excluded Studies .................................................... 109

Appendix C. Criteria Used in Quality Assessment.................................................................. 126

Appendix D. Peer Review Comments/Author Responses ....................................................... 132
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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EXECUTIVE SUMMARY

INTRODUCTION

Multiple sclerosis (MS) is the most common progressive disease of the central nervous system in 

young adults and the cause of serious physical disability in adults of working age. Epidemiologic 

data suggest that rates of MS vary with demographic and environmental factors. The disease 

presentation is very heterogeneous with diverse clinical manifestations. Progression of MS may

vary with modifiable risk factors. 

This systematic review focused on modifiable risk factors and exposures that are associated with

MS progression, and interventions that are directed at modifiable risk factors to delay

progression.

The Key Questions (KQs) were: 

KQ1: What modifiable epidemiologic factors are related to multiple sclerosis progression 

following diagnosis? 

KQ2: What environmental exposures prior to or during military service are related to multiple 

sclerosis progression following onset symptoms? 

KQ3: Among identified risk factors for progression, what treatment/risk factor modification 

therapies have been shown to delay or hasten the progression of multiple sclerosis once it has 

initiated? 

The review will be used by the VA Multiple Sclerosis Centers of Excellence to initiate new 

research studies, refine clinical guidelines, and plan for targeted disease-modifying and diseaseprevention strategies.

METHODS

Data Sources and Searches

We searched the databases PubMed, EMBASE, AMED, Web of Science, SCOPUS, GreenFILE, 

ProQuest Military Collection, and DTIC to March 2015; reference-mined reviews and included 

studies; and consulted with experts to identify pertinent studies. Literature searches were not 

restricted to a narrow set of known risk factors but were exploratory in nature.

Study Selection

The review focused on patient-modifiable risk factors, such as food intake or health behaviors of 

patients with MS. Studies meeting the following criteria were eligible for inclusion in the review: 

Population: Adults with MS (KQ1, KQ3), military personnel/Veterans with MS (KQ2)

Interventions/exposure: Potential MS progression risk factors (KQ1, KQ2; eg, smoking, 

nutrition) and interventions targeting risk factors (KQ3; eg, smoking cessation programs, dietary 

interventions)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Comparators (study design): Observational and experimental studies analyzing factors 

associated with MS progression (KQ1, KQ2), randomized controlled trials (RCTs) regardless of 

the comparator (KQ3)

Outcomes: Progression of MS, primary outcome measure Expanded Disability Status Scale 

(EDSS)

Timing: not restricted

Setting: No restriction but planned subgroup analyses for Veteran population.

Data Abstraction and Quality Assessment

For KQ1 we extracted sample characteristics, geographical region, and number of participants;

study design, analysis, and assessment timing (eg, prospective); the predicted outcome, assessed 

potential risk factors, and controlled variables; EDSS results and other MS progression results. 

For studies relevant to KQ2, we extracted study details and MS progression results associated 

with prior military service exposure and exposure during military service. For intervention 

studies (KQ3) we extracted methodological characteristics; number and characteristics of 

participants; intervention and comparator content and duration; EDSS results and other MS 

progression outcomes together with the follow-up point, and adverse events.

For KQ1 and KQ2 we distinguished concurrent, retrospective, and prospective studies. 

Prospective studies were assessed with QUIPS, a critical appraisal tool for prognostic studies. 

The RCTs informing KQ3 were assessed with the Cochrane risk of bias tool.

Data Synthesis and Analysis

All included studies were presented in evidence tables, grouped by key question, to allow a 

comprehensive overview. We differentiated results based on standardized and common measures

of disease status, the EDSS, and other results. Where possible, variables were pooled using a 

restricted maximum-likelihood estimator and the Hartung-Knapp-Sidik-Jonkman standard error 

method for random-effects models to identify reliable and valid effects across studies. 

Continuous outcomes were reported as standardized mean differences (SMD), dichotomous 

outcomes as relative risks (RR), time to event data as hazard ratios (HR), and correlations were 

transformed to z statistics (using the Fisher transformation) to pool across studies. Point 

estimates were reported with the 95 percent confidence interval (CI). Heterogeneity was assessed 

with the I

2 statistic, publication bias with the Egger and Begg test, and we used the trim-and-fill 

method in the presence of publication bias.

KQ1 studies were grouped by evaluated risk factors. A summary of findings table documented 

the number of available studies for all risk factors that had been addressed in more than one 

study, the strength of association with MS progression, and our confidence in the finding. For 

studies in military personnel and Veterans relevant to KQ2, we differentiated assessed variables 

and statistically significant effects across studies documented in a summary of findings table. 

Intervention studies (KQ3) were stratified by intervention category and summarized across 

studies in a summary of findings table. The quality of evidence assessment followed the standard 

GRADE approach for RCTs and an adaptation for prognostic factor research for KQ1 and KQ2.

The quality of evidence indicates the confidence in the results that are drawn from the literature,

and we distinguished high, moderate, low, and very low quality of evidence.
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RESULTS

Results of Literature Search

The search identified 8,594 citations. In total, 94 studies met inclusion criteria. 

Summary of Results for Key Questions

Fifty-nine studies contributed to KQ1, 4 studies contributed to KQ2 (all also relevant to KQ1), 

and 36 RCTs addressed KQ3.

KQ1: Modifiable Risk Factors

Studies assessed a number of risk factors and used a variety of progression measures, including 

EDSS scores, time to conversion from remitting relapsing to secondary progressive MS, and 

odds of reaching EDSS 6 (requiring a cane for walking). Thirteen studies were prospective 

studies, assessing risk factors and subsequent outcome measures at 2 different time points.

Vitamin D has been addressed in a large number of studies. Across studies, there was a negative 

correlation of -0.22 (CI -0.32, -0.12; 11 studies; I2 66%) indicating that lower Vitamin D levels

are associated with higher EDSS scores. The result is primarily based on concurrent predictor 

studies (measuring Vitamin D level and disability status at the same time). 

Across studies, we identified an increased risk of faster progression in smokers than nonsmokers 

(HR 1.55; CI 1.10, 2.19; I

2 72%; 7 studies, 8 datasets). The result is primarily based on 

retrospective studies. 

The use of epidural analgesics during childbirth delivery has been assessed in 3 studies and none 

reported a statistically significant association with EDSS or DSS scores.

Results for sun exposure, sunscreen use, month of birth, diet, fish consumption, alcohol 

consumption, exercise, trauma, oral contraception, geographic region, and education have been 

addressed in more than one study, but the differences in risk factor operationalizations and 

outcome measures did not allow concrete evidence statements to be made.

All other investigated factors have been addressed in only one of the included studies and have 

not been replicated. These include effects of cesarean delivery; breast feeding; having been 

breast fed; obstetrical and spinal anesthesia; childhood maltreatment; working outdoors;

individual health-promoting lifestyle domains; meditation practice; insurance coverage; medical 

care satisfaction variables; exposure to different types of animals; coal heating; wood heating;

humid living space; no sewage system; no piped water; type of environment (eg, farm); specific 

diet factors such as coffee consumption, liver consumption, vitamin supplementation, fortified 

foods, vegetarian diet; cod liver oil intake; occupational status; deployment to a war theater;

being a Veteran; and earthquake experience.

KQ2: Exposures Prior to or During Military Service

We identified 4 studies that reported on exposures prior to and during military services 

associated with MS progression (KQ2) in active military personnel or Veterans. Assessed risk 

factors were geographic location at entry to the military, occupational status at entry to the 

military, average fall/winter sun exposures before MS onset, cod liver oil intake at ages 6-15, 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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fish consumption at ages 6-15, deployment, being a Veteran, and dietary treatment. None of the 

studies assessed the same risk factors and outcome measures varied across studies.

KQ3: Risk Factor Modification Therapies

Despite the inclusive and extensive systematic search, all identified risk factor modification 

interventions targeted either physical exercise, dietary interventions, or vitamin D 

supplementation. Across the 36 predominantly small RCTs, we did not detect interventions with

statistically significant treatment effects compared to passive control groups on MS progression.

The pooled effect of exercise interventions on EDSS scores was not different from untreated 

control groups (SMD 0.02; CI -0.40, 0.44; I

2 0%; 7 RCTs). However, using baseline-adjusted 

data for a sensitivity analysis, the result favored the exercise intervention (SMD -0.19; CI -0.34, 

-0.03).

The 12 identified dietary intervention evaluations primarily assessed the effects of fatty acid 

supplements. We did not identify a statistically significant effect on the relative risk of 

progression (RR 0.86; CI 0.67, 1.05; I

2 0%; 4 RCTs) or EDSS scores (SMD -0.13; -0.83, 0.45; I2

5%; 3 RCTs) compared to placebo.

Vitamin D supplementation showed a trend for improved EDSS scores but the pooled 

standardized mean difference was not statistically significant from placebo groups (SMD -0.15; 

CI -0.33, 0.02; I

2 0; 5 RCTs). However, the weighted mean difference favored vitamin D 

supplementation and showed that supplements were associated with a 0.22-point difference in 

EDSS scores (WMD -0.22; CI -0.39, -0.05).

DISCUSSION

Key Findings and Strength of Evidence

Our systematic review and meta-analysis focused on modifiable risk factors. We systematically 

searched for, documented, and synthesized evidence available in the research literature on MS 

progression. A large number of relevant studies is available to contribute to the evidence base but 

the research area is very complex.

We did not identify factors that were shown to be significant risk factors in epidemiological 

studies and published evidence that shows their amenability to intervention and their effects on 

MS progression.

KQ1

There was great variation in assessment and prediction details across studies relevant to KQ1 and 

only 13 prospective studies were identified, limiting the conclusions that can be drawn from the 

literature. There is moderate-quality evidence of a correlation between vitamin D levels and 

EDSS scores. Our confidence in the result was downgraded to moderate quality of evidence due 

to indirectness. The correlation does not allow causal inferences and prospective studies are 

needed linking vitamin D intake to MS progression. There is moderate-quality evidence 

(downgraded due to unexplained heterogeneity) suggesting an association between the time to 

progression and smoking. There is low-quality evidence (due to study design limitation and lack 

of point estimates) suggesting that epidural analgesia during childbirth is not associated with 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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EDSS scores. A large number of potential risk factors have been reported in the literature;

however, the existing evidence is insufficient for providing concrete evidence statements for 

individual outcomes.

KQ2

The quality of the evidence for research on environmental exposures during military service was 

determined to be insufficient for evidence statements because all factors were reported in only 

one included study without replication in another participant sample.

KQ3

Despite substantially more available literature on risk factor modification therapies, we 

confirmed earlier reviews showing that currently no statistically significant evidence exists to

supports specific interventions for MS progression and more research is needed. 

The quality of the evidence for the result of no difference between exercise interventions and 

untreated control groups on EDSS scores was downgraded due to severe study limitations and 

conflicting results in a sensitivity analysis (imprecision). Our confidence in the evidence 

summary is limited because studies were not designed to assess EDSS changes, study sample 

sizes were very small, there were baseline imbalances, and the interventions may have been too 

short to achieve and detect changes with standard diagnostic criteria. Nonetheless, any treatment 

effect is likely to be very small; adjusting for baseline imbalances, the estimate was 0.20 points 

on the EDSS scale.

The quality of evidence for the dietary intervention results showing the absence of an effect on 

MS progression measured as deterioration or EDSS scores were both downgraded to moderate 

due to study limitations. The early studies lack reporting detail while the more recently published 

studies were small and did not report statistical power calculations to determine whether studies 

could detect an effect of the intervention on MS progression.

The quality of evidence for a non-significant effect of vitamin D supplementation on EDSS 

scores was downgraded due to study limitations and imprecision. The included studies were 

small and the lack of reported power calculations makes it unclear whether the studies were 

sufficiently powered to be able to detect small treatment effects. The statistical significance was

dependent on the effect measure, showing that the effect estimate is not very robust.

Nonetheless, any potential treatment effects are likely to be small with an estimated difference of 

0.22 points in EDSS scores between intervention and control groups.

Applicability

Very few studies reported specifically on VA samples. However, there is no indication that risk 

factor results and treatment effects are not applicable to the VA population.

Research Gaps/Future Research

Our systematic review showed that more prospective research studies are needed to allow 

predictions and meaningful interpretation of risk factor analyses. Furthermore, future studies 

should report more details and statistical analyses in order to facilitate evidence synthesis in 
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meta-analyses. Specific areas that need more research are the consumption of alcohol and sun 

exposure and their potential effects in slowing progression.

The existing intervention studies testing the effect on MS progression should determine the 

statistical power needed to detect a difference between treatment groups, in particular for vitamin 

D supplementation trials. Effects of smoking cessation should be investigated given the 

association between smoking and MS progression. Based on sensitivity analyses we found that 

more studies evaluating the effects of long-term exercise interventions are warranted.

Finally, although our review addressed a broad research field, there are other, potential risk 

factors of interest that are outside the scope of this review, including the effect of treatable 

comorbidities of MS.

Conclusions

A large number of studies is available to contribute to the growing research literature on 

modifiable risk factors and MS progression, but the research field is very complex. 

Risk factor studies used diverse operationalizations of risk factors and different outcome 

measures, and more prospective studies are needed. Most consistent results were shown for the 

association between EDSS scores and Vitamin D levels. Smoking was associated with a faster 

progression of MS in smokers compared to nonsmokers.

Risk factors in Veterans and active military personnel were one of the key questions for this 

review but very few studies are available to inform on this participant subgroup. 

We did not identify interventions that showed a statistically significant effect of exercise, dietary, 

or vitamin D supplementation on EDSS scores across studies. However, studies were not 

designed to assess effects on MS progression. More research is, in particular, needed on 

interventions for smoking cessation, adequately powered vitamin D supplementation RCTs, and 

RCTs testing the effects of long-term exercise interventions.
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ABBREVIATIONS

EDSS Expanded Disability Status Scale

HR Hazard ratio

OR Odds ratio

KQ Key question

MS Multiple sclerosis

r Correlation

RR Relative risk
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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EVIDENCE REPORT

INTRODUCTION

Multiple sclerosis (MS) is the most common progressive disease of the central nervous system in

young adults and the most common cause of serious physical disability in adults of working age.1 

,2 The estimated incidence is 7 per 100,000 per year and the median age of onset is 30 years.

3 For 

the military it is a significant neurological disease burden in terms of diagnosis, management, 

and disability retirement. 

MS is characterized pathologically by focal areas of inflammation, demyelination, gliosis, and 

axonal damage throughout the central nervous system.4,5 The course of MS is characterized by 

clinical relapses and disease progression. Relapse, exacerbations, or attacks, are acute, 

inflammatory events that occur episodically within the central nervous system. They can 

correspond to either the development of new focal inflammatory lesions or the reactivation of old 

lesions, and after an exacerbation, symptoms spontaneously remit, either partially or completely. 

Progression describes a steady deterioration in neurologic function associated with new 

symptoms and continuously worsening disability which takes place over a period of at least 6

(Poser criteria) or 12 months (McDonald criteria).6,7 Once progression has developed, the course

is continuous despite occasional plateaus and temporary minor improvements.8

MS disease presentation is very heterogeneous with variable clinical manifestations that evolve 

over time. About 80% of patients present with relapsing-remitting disease which manifests in 

relapses followed by periods of partial or complete recovery (remissions). Other subtypes of MS 

include secondary progressive MS (patients develop relapsing-remitting MS but then begin 

progressing with or without relapses). In about 50% of patients the course of MS changes from 

relapsing-remitting to secondary progressive disease after 10 years.

9 Active progressive MS 

shows a slow progression of disability from onset with periods of stability and occasional 

relapses, while patients with primary progressive MS show progressive worsening in disability 

from onset without exacerbations. It is estimated that while 15% of patients with MS will

become severely disabled within a short time, for 25% of patients MS will never affect daily life. 

10

Epidemiologic data show that rates of MS appear to vary with environmental factors. 10 This 

suggests a role of potentially modifiable risk factors associated with the onset and phenotypic 

manifestation of the disease. Similarly, the course of MS varies with demographic variables and

possibly other factors. Furthermore, the mechanism that changes the disease pattern from 

relapsing-remitting to secondary progressive MS is largely unknown.

9 Factors that may explain 

the diversity in clinical presentation, help predict the course of the disease, and identify potential 

triggers of disease progression are of great interest to patients and clinicians, in particular 

modifiable risk factors.

11

Disease-modifying therapies for relapsing forms of MS are only partially effective in slowing 

short-term morbidity and there are no effective medication options for progressive MS.12

Additional MS treatment and management options are needed to support patients with a 

diagnosis of MS. Some risk factors associated with the onset or progression of MS may be 

translatable into interventions, such as in the case of the potential risk factor vitamin D 
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deficiency, which can be tested in effectiveness trials by treating MS patients with a vitamin D

supplement.

13

This project focuses on empirical evidence on modifiable exposures and risk factors that are 

related to MS progression and approaches to reduce progression that are directed at modifiable 

risk factors. This review will be used by the VA Multiple Sclerosis Centers of Excellence to 

initiate new research studies, refine clinical guidelines, and plan for targeted disease-modifying 

and disease-prevention strategies.
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METHODS

TOPIC DEVELOPMENT

This topic was developed in response to a nomination by the VA Multiple Sclerosis Center of 

Excellence-East, for an evidence review to examine the role of modifiable risk factors and 

military exposures in the progression of MS, as well as methods to reduce progression that are 

directed at modifiable risk factors.

The Key Questions (KQ) were: 

(1) What modifiable epidemiologic factors are related to multiple sclerosis progression following 

diagnosis? 

(2) What environmental exposures prior to or during military service are related to multiple 

sclerosis progression following onset symptoms? 

(3) Among identified risk factors for progression, what treatment/risk factor modification 

therapies have been shown to delay or hasten the progression of multiple sclerosis once it has 

initiated? 

SEARCH STRATEGY

We searched the electronic databases PubMed (medical literature); EMBASE (biomedical 

literature); AMED (Allied and Complementary Medicine Database); SCOPUS and Web of 

Science (broad research databases indexing conference papers and innovations); GreenFILE 

(environmental factors); DTIC (Defense Technical Information Center), and ProQuest Military 

Collection (databases for military research) for primary research studies published in English to 

March 2015 without date restriction. Dates of database inception varied; for example, PubMed 

systematically indexes research published since 1966, with some earlier publications. 

For KQ1, we employed a search strategy that combined known presumed risk factors, and a 

more general search for prognostic study designs based on a published search filter14 applied to

PubMed, SCOPUS, Web of Science, and GreenFILE.

The KQ2 search strategy used search terms for military populations to identify MS studies 

without further study restrictions in the databases PubMed, EMBASE, AMED, SCOPUS, Web 

of Science, GreenFILE, DTIC, and ProQuest Military Collection. 

For KQ3 we applied a search filter for randomized controlled trials (RCTs) to search the 

databases PubMed, AMED, SCOPUS, and Web of Science, to target eligible studies. The 

PubMed search encompassed all indexed RCTs in MS patients and was not restricted to a set of 

pre-defined interventions, to avoid missing relevant studies targeting uniquely-named or novel 

interventions.

Furthermore, we screened references of pertinent reviews and consulted with topic experts to 

ensure that all relevant studies were identified.
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STUDY SELECTION

Two independent reviewers screened titles and abstracts of retrieved citations and recorded

decisions in an electronic database. Citations deemed potentially relevant by at least one of the

reviewers were obtained as full text. The full-text publications were screened against the 

specified inclusion criteria by 2 independent literature reviewers; disagreements were resolved 

through discussion within the review team. The literature flow was documented in an electronic 

database and reasons for exclusion of full text publications were recorded. 

To be included in the systematic review, studies had to meet the following criteria, organized in 

the PICOTS framework.

Participants: Studies in human adult participants with a clinical diagnosis of MS were eligible 

for inclusion for KQ1 and KQ3. KQ2 was limited to active military personnel and Veterans with 

MS. Studies exclusively focusing on pediatric MS in children and adolescents were excluded.

Studies targeting a range of clinical conditions were included as long as data on MS progression 

was reported separately. The sample composition of MS populations was not restricted but risk 

factor studies excluding all progressive forms and not reporting on MS progression were 

excluded (eg, studies describing disease severity in explicitly non-progressive forms).

Intervention: Studies reporting on modifiable epidemiologic factors and environmental 

exposures potentially associated with MS progression (“risk factors”) were eligible for inclusion 

for KQ1 and KQ2. Eligible risk factors included (but were not limited to) the geographic region

of residence, sun exposure, vitamin D intake, polyunsaturated fatty acid intake, diet, smoking, 

alcohol, exercise behavior, vaccinations, anesthesia exposure, radiation therapy exposure, use of 

oral contraception, fertility treatment, childbirth delivery variables, breastfeeding, salt intake, use 

of milk products, water sources intake, trace elements intake, mercury exposure, trauma

exposure, military service/deployment, and military exposures. Non-modifiable risk factors such 

as genetic predispositions, physiological correlates, or demographic characteristics at MS onset 

were excluded. Descriptive factors such as quality of life or vitality with unclear modifiability,

comorbidities, and concurrent psychological correlates of disability status that are more likely to 

be a reaction to than a predictor of MS (eg, coping strategies and perceptions of body image)

were excluded. Factors directly associated with known MS medication, such as the use of 

disease-modifying treatment, type of medication, medication combinations, dosing schemes, 

adherence, and timing of therapy onset were also excluded.

Intervention studies evaluating the effect of modifying the intake or exposure to potential risk 

factors (eg, smoking cessation, weight loss, or exercise programs; nutritional interventions 

targeting vitamin D or Omega-3), alone or in combination with other therapies, were eligible for 

KQ3. Treatment studies testing potential risk factors were eligible for inclusion regardless of the 

current strength of association in empirical studies, but studies evaluating unspecific 

interventions not associated with potential or identified MS risk factors (eg, acupuncture) were

excluded. Treatment studies evaluating the effect of existing, FDA-approved MS medications 

that aim to modify the disease course of MS (eg, interferon beta-1a), or aim to manage MS 

relapses (eg, prednisone), other suggested medication for MS (eg, laquinimod), treatments for 

autoimmune and immunodeficiency diseases (eg, corticosteroids), and medication given for their 

immunomodulatory properties (eg, statins) or tested for their use in MS (eg, lithium) were

excluded regardless of any underlying risk factor hypotheses (eg, infection, hygiene hypothesis).
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

12

Comparator (design): Observational studies (eg, case-control, cohort studies comparing 2 

cohorts, or cross-sectional studies including surveys), and experimental studies analyzing factors 

associated with MS progression were eligible for KQ1 and KQ2. Non-randomized experimental 

studies had to have a non-treated concurrent control group to identify standard progression rates 

and provide a power calculation to determine a priori whether differences between experimental 

groups could be identified. Risk factor studies had to report data on 10 or more participants with 

MS. Case studies speculating about associations were excluded.

RCTs in adults regardless of the comparator were eligible for KQ3. Only primary research 

studies were eligible for inclusion. Pertinent reviews and secondary data analyses were retained 

as background paper for reference mining. 

Outcome: Studies reporting on the progression of MS were eligible for inclusion in the review. 

The primary outcome was Expanded Disability Status Scale (EDSS) scores or progression 

classifications based on EDSS score cut-offs. Studies reporting on earlier versions of the EDSS 

scale; other global patient-centered, clinical MS progression measures (eg, Multiple Sclerosis 

Functional Composite [MSFC], multiple domain assessments of the Functional System Score 

[FSS], Patient Determined Disability Scale [PDDS]); the clinical course of MS (eg, progression 

defined by clinical judgment, time to secondary progression); or comparing MS subgroups 

relevant to progression (eg, relapsing-remitting versus secondary-progressive stage) were eligible 

for inclusion. Studies reporting on disability measures focusing on the general ability to walk 

(eg, MS Progression: Disease Steps [DS]) were included. Studies only reporting on individual 

characteristics of walking (eg, gait, muscle strength, speed) were excluded. Studies reporting on 

other individual symptoms (eg, fatigue or depression) or individual diagnostic markers (eg, 

lesions shown with imaging techniques) without reporting on patient outcomes of MS 

progression were excluded. Studies reporting disability measures not specific to MS (eg, 

receiving a disability pension) were excluded. Studies reporting on MS-associated mortality were

included if the endpoint was part of a continuum of progression and not an incidence measure of 

MS. Studies reporting on all-cause mortality in MS patient samples, for example investigating 

whether associations between epidemiologic factors and mortality found in the general 

population (‘smoking predicts mortality’) also apply to the MS population, were excluded. 

Studies exclusively reporting on the onset, rather than the progression of MS, and studies only 

reporting on the prevalence and incidence of MS without differentiating MS subtypes relevant to 

MS progression (eg, primary progressive MS) were excluded.

Timing: Risk factor studies were not limited by exposure duration and timing (eg, childhood 

exposure) and any follow-up points were eligible for inclusion in KQ1, but investigator-initiated 

exposures (ie, interventions) were restricted to long-term interventions if they did not report a 

statistical power calculation indicating that the study had sufficient power to show a difference 

between exposed groups. We included prospective (measuring the exposure before the outcome), 

retrospective (measuring the exposure of a past event retrospectively at the time of measuring the 

outcome), and concurrent (measuring the exposure status and the outcome at the same time 

point) studies. Studies eligible for KQ2 were limited to exposures prior to or during military 

service. Intervention RCTs including any intervention duration, regardless of the intervention 

timing, and any follow-up points were eligible for inclusion for KQ3.

Setting: Studies of any settings were eligible for inclusion in the review. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Other limiters: English-language studies were included. 

The review was registered in PROSPERO, the international registry for systematic reviews 

PROSPERO http://www.crd.york.ac.uk/PROSPERO/. (PROSPERO 2015:CRD42015016461)

Protocol Deviations

Due to the overwhelming size of the literature identified through our literature searches that 

exceeded the available time and resources needed to complete the project, we removed comorbidities such as stress, anxiety, depression, infections, sleep problems, or obesity regardless 

of their treatability and modifiability status from the eligibility criteria. We also excluded the 

large body of literature on pregnancy and parity given that the decision to have children may be 

directly associated with disease severity and anticipated progression (reverse causality is 

discussed in more detail in the discussion section). Finally, we excluded studies that reported on 

the physiological or clinical status of patients, such as body weight or serum fatty acid levels, 

without information on the intake or patient behavior (eg, diet regime) other than vitamin D. In 

sum, we excluded factors that could either be a reaction to, an independent comorbidity, or a 

predictor of MS progression, and concentrated primarily on behavior and choices or exposures 

somewhat under the control of the patient or their families.

DATA ABSTRACTION

Studies underwent standardized abstraction of study-level data in an electronic database. Data 

collection forms were designed by the project lead and discussed in the review team.

For KQ1 (risk factors) studies, we extracted information on the MS population (eg, proportion of 

patients with relapsing-remitting, secondary progressive, or primary progressive MS; age; %

male; race/ethnicity distribution). We documented the number of participants in the study sample 

and the number of cases (ie, patients with progressive MS). We recorded the geographic region 

of the sample. We documented the study design (eg, cohort study), methods used to analyze the

results (eg, linear mixed effects model, partial correlations), and the predictive timeframe 

(concurrent, retrospective, prospective data). We extracted analyzed, potential, modifiable risk 

factors of interest together with the time of exposure (eg, alcohol consumption in last 2 years). 

We recorded all independent variables entering the prediction model. We extracted the point 

estimate of effects and statistical significance of risk factors on MS progression. The evidence 

table differentiates predictions for EDSS scores and other clinical course characteristics relevant 

to MS progression.

Concurrent studies were defined as measuring the exposure status and the outcome at the same 

time point, such as current alcohol intake. Retrospective studies assessed at least some outcomes 

retrospectively (eg, cod liver oil consumption during childhood). Prospective studies had to 

report on at least 2 different points in time assessing the risk factor prior to the MS progression 

outcome to be classified as prospective.

For studies relevant to KQ2 (military service exposures), we extracted the information on the 

study population including: MS characteristics and military service status; number of study 

participants and cases, geographic region; study design; analytic method; assessed prior or post 

military service exposures; assessed military service exposures; other analyzed independent 

variables; predictive time frame; EDSS score results; and other clinical course results.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

14

For intervention studies (KQ3, risk factor modification therapies), we extracted the study design 

and methodological characteristics, number of randomized participants per intervention group

and proportion of participants with progressive MS, characteristics of participants, intervention 

components and co-interventions, comparator details, outcomes, followup points, statistical 

power analysis, EDSS results, other disease progression results, and adverse events.

Some studies were reported on in more than one publication. Studies, defined by the included 

participants, were only counted once, regardless of the number of publications the results were 

published in. The data extraction considered data from all publications available for the study.

QUALITY ASSESSMENT

For KQ1 and KQ2 we distinguished concurrent, retrospective, and prospective studies. 

Prospective studies were assessed with QUIPS (Quality In Prognosis Studies), a critical appraisal 

tool for prognostic studies.15

Intervention studies (KQ3) were assessed with the Cochrane risk of bias tool assessing selection 

bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias

(where appropriate). 

Quality criteria definitions and scoring guidelines for all domains are documented in Appendix C 

together with the assessment results.

DATA SYNTHESIS AND ANALYSIS

The evidence tables provide information on each included study to allow a comprehensive 

overview. Summary of findings tables summarize results for analyzed modifiable risk factor in 

the general population (KQ1) and military samples (KQ2), and results for individual 

interventions (KQ3) across all identified studies.

The evidence tables and summary of findings tables differentiated results based on EDSS scores, 

the primary outcome of the review, and other MS progression results. The EDSS16 is widely used 

to assess the disability and the progression of MS. Scores range from 1 (no disability) to 10 

(death due to MS). A milestone often used in research is EDSS 6, characterized by the need for a 

cane or other constant assistance to walk 100 meters.

Where possible, variables were pooled across studies in meta-analyses to identify reliable and 

valid effects across studies. We pooled studies where at least 3 studies were available for the risk 

factor of interest and the effect measure of interest (eg, correlations, time to event data, count

data). Continuous outcomes were reported as standardized mean differences (SMD) to facilitate 

the comparison of effect sizes across outcome measures. We calculated weighted mean 

differences (WMD) to determine the clinical importance of the effect for studies reporting on the 

primary outcome EDSS scores. Dichotomous data were presented as relative risks (RR). For 

time to event data we computed hazard ratios (HR). Correlations (r) transformed to z statistics 

(using the Fisher transformation) to pool across studies. Point estimates were calculated together 

with the 95 percent confidence interval (CI). We used a restricted maximum-likelihood estimator 

and the Hartung-Knapp-Sidik-Jonkman method for random-effects models to pool across 

studies.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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All studies relevant to KQ1 were summarized narratively. When at least 3 studies were available 

that reported on the same risk factor and the same outcome measure, we performed metaanalysis. The synthesis differentiated variables assessed as potential risk factors, and results 

indicating a statistically significant association with MS disability and progression. The synthesis 

addressed negative and positive associations indicating worsening of progression status or 

protective factors. In addition, it also documented the absence of associations. 

Due to the diversity in study designs, analytic methods, and effect measures, and the small 

number of studies, studies in military personnel and Veterans relevant to KQ2 were summarized 

narratively. We differentiated assessed variables and statistically significant effects. The 

narrative synthesis emphasizes risk factors identified in more than one individual study. 

Intervention studies (KQ3) were summarized narratively, grouped by intervention category. 

When at least 3 studies were available for the same intervention group and outcome measure (eg, 

EDSS scores, number of patients progressing, time to progression), we performed meta-analysis. 

Data were based on intention-to-treat results, where available. For continuous outcomes results 

were based on unadjusted post-intervention scores. Results of studies in military personnel and 

Veterans were an a priori planned subgroup analysis.

RATING THE BODY OF EVIDENCE

We rated the quality of the evidence for individual risk factors across all identified studies 

(KQ1), in military and Veteran populations (KQ2), and for individual interventions (KQ3) across 

all identified pertinent studies. Based on GRADE guidelines17 the quality of the evidence was

categorized as follows:

High: We are very confident that the true effect lies close to that of the estimate of the effect.

Moderate: We are moderately confident in the effect estimate: The true effect is likely to be 

close to the estimate of the effect, but there is a possibility that it is substantially different.

Low: Our confidence in the effect estimate is limited: The true effect may be substantially 

different from the estimate of the effect.

Very low: We have very little confidence in the effect estimate: The true effect is likely to be 

substantially different from the estimate of effect.

Given the complexity of epidemiological data collection and interpretation, the synthesis focused 

on factors that have been assessed in more than one study. Other, unique assessment results were 

reported in evidence tables but not further documented in the summary of findings tables for 

KQ1 and KQ3 to provide a concise overview. Given the relevance to the VA, all available 

evidence was documented for KQ2.

For KQ1 and KQ2 we took the following criteria into account to determine the level of evidence 

quality. These are based on an adaptation of the GRADE framework for prognostic factor 

research.

18 The “phase of investigation” criterion was used as a starting point (high or moderate 

quality of evidence). The criteria “study limitations,” “inconsistency,” “indirectness,”

“imprecision,” and “publication bias” were used to decrease the quality of evidence. The criteria 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

16

“moderate / large effect size” and “exposure-response gradient” were used to increase the 

evidence grade where applicable.

For KQ3 we took the number of identified studies and the criteria “risk of bias,” “inconsistency,”

“imprecision,” and “publication bias” into account. The starting point was high evidence because 

the data are based on RCTs.17

Publication bias was assessed with the regression test (Egger test) and the rank test (Begg test).

Results indicating evidence of publication bias were reanalyzed using the trim-and-fill method to 

adjust for potentially missing studies.

TECHNICAL EXPERT PANEL

The technical expert panel (TEP) for the project included Mitchell T. Wallin MD, MPH, Clinical 

Associate Director, VA MS Center of Excellence-East; Glenn D. Graham, MD PhD, Deputy 

National Director for Neurology, Specialty Care Services, VA Central Office, Christopher 

Bever, Jr., MD, MBA, Director of the MS Center of Excellence-East, Professor, Departments of 

Neurology, Pharmacology and Physical Therapy, University of Maryland School of Medicine; 

Jodie Haselkorn, MD, MPH, Director, MS Center of Excellence-West, Professor, Rehabilitation 

Medicine, VA Puget Sound Health Care System; W. Joel Culpepper, MA, PhD, Associate 

Director of Epidemiology and Outcomes for the MS Center of Excellence-East; John W. Rose, 

M.D., Chief, Division of Neuroimmunology, VA Salt Lake City Health Care System; Gary M. 

Franklin, MD, MPH, Research Professor, Department of Environmental and Occupational 

Health Sciences Medicine (Neurology) and Health Services, University of Washington; 

Vijayshree Yadav, MBBS, MCR, Associate Professor, Neurology, Clinical Director, MS Center, 

Oregon Health & Science University; John F Kurtzke MD, FACP, FAAN, Professor Emeritus of 

Neurology, Georgetown University, Consultant in Neurology and Neuroepidemiology, Veterans 

Affairs Medical Center, Washington, DC; and Aaron Turner, PhD, Mental/Behavioral Health 

Psychology, VA Puget Sound Health Care System.

PEER REVIEW

A draft version of the report was reviewed by technical experts, clinical leadership, and 

additional peer reviewers where appropriate. Reviewer comments and how we have addressed 

them is documented in Appendix D.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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RESULTS

LITERATURE FLOW

The literature search identified a large number of citations (N = 8,594). We selected 455

potentially relevant publications to be obtained as full text in order to screen them against the 

predetermined inclusion criteria. 

We obtained a large number of publications as full text and checked studies for the outcome of 

interest after piloting the inclusion criteria in the first set of citations. Publications did not 

systematically mention progression in the title or abstract of the publication; hence, a large 

number of studies was obtained as full text and results sections were carefully screened for data 

relevant to MS progression. 

In total, 300 publications were excluded because they did not meet one or more of the inclusion 

criteria. The list of excluded studies and the reasons for exclusion are documented in Appendix 

B. A large proportion of the studies was excluded because the full-text review showed that the

study did not report on MS progression. The second-largest reason for exclusion was associated 

with studies not reporting on modifiable risk factors (Exclude-Intervention/Exposure).

In total, 95 studies19-112 met inclusion criteria and contributed to answering the review questions. 

Of these, 59 studies contributed to KQ1. Despite the extensive search in general and specialist 

databases for military research, we only identified 4 studies that provided data for KQ2. In total, 

36 RCTs were identified that contributed to KQ3.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Figure 1: Literature Flow Chart

Note: Some included studies contributed to more than one KQ. 

Search results: 

8,594 references

Retrieved for full text 

review: N = 453

Included studies:

N = 95

Excluded = 8,2139 references

Not MS, not progression, not empirical 

study, not English language

Could not be obtained 

2 references

Excluded references

Participants (not MS): 2

Intervention or exposure: 105

Study design: 32

Outcome: 159

Language: 1

Duplicate: 1

Retained as background = 58 references

More information on included studies or 

source of potential includes

KQ1 (progression 

risk factors):

N = 59

KQ2 (military 

specific):

N = 4

KQ3 

(interventions):

N = 36
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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KEY QUESTION 1: What modifiable epidemiologic factors are related 

to multiple sclerosis progression following diagnosis?

Risk factor studies meeting inclusion criteria were published between 1973 and 2015, with a 

large proportion of studies having been published in the last 3 years. Of note, no study was 

excluded due to the publication year for this review and all databases were searched without date 

restriction.

Studies were conducted in the US, Canada, Australia, Japan, Iran, Italy, Belgium, UK, the 

Netherlands, France, Sweden, Germany, Turkey, and Finland, and some were international 

samples based on online surveys. Studies identified participants through hospital records or 

surveyed members of MS registries. Most studies used unselected samples that included a range 

of MS forms. 

Studies assessed a large variety of modifiable epidemiological factors and used different 

operationalizations of potential risk factors (eg, average number of cigarettes smoked per day, 

exercise / physical activities assessed with the revised Health Promoting Lifestyle Profile 

[HPLP-II]). Some studies assessed the current status while others assessed lifetime prevalence 

(eg, ever smokers).

Included studies used a broad range of outcome measures such as EDSS scores, other patientreported scale scores, correlations with EDSS scores or other measures of disease status, time to 

EDSS 6, time to EDSS 4, time to secondary progression, or time to wheelchair dependency.

Some studies used standardized scales such as the EDSS while others reported on cliniciandefined outcomes (eg, clinical deterioration).

The research study pool included 13 prospective studies.20,30,35,69,72,76,87,91,96-98,112,113 These studies 

assessed participants at 2 or more different points in time and are better suited to make 

predictions (rather than establish concurrent associations, or relying on retrospective assessments 

from memory about factors experienced in the past).

Details of all included studies are presented in the evidence tables. We grouped studies 

exclusively reporting on vitamin D or sun exposure, studies reporting on childbirth-related 

factors, studies investigating the role of smoking, studies reporting on diet and nutrition, and 

studies reporting on unique factors such as childhood trauma. The last evidence table 

summarizes studies that investigated more than one risk factor of interest for this review. 

Of the single-factor studies, the largest group addressed vitamin D. Vitamin D can be absorbed 

from exposure from sunlight, from diet, or from dietary supplements. The first evidence table for 

KQ1 documents how published studies have operationalized this potential risk factor for MS 

progression.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Table 1. Evidence for KQ1 (MS Progression Risk Factors): Vitamin D or Sunshine Exposure

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Ascherio, 

201420

prospective

18 

European 

countries, 

Israel, and 

Canada

Sample from BENEFIT 

trial, presenting with first 

episode of neurological 

dysfunction suggestive of 

MS 

Form N/A; Poser criteria, 

McDonald 2001 criteria

EDSS 

changes

465 Time series

Multivariate 

analysis

25(OH)D level Sex, age at 

baseline, 

treatment 

group, 

baseline T2 

lesion score, 

type of 

clinically 

isolated 

syndrome 

(BMI and 

steroid use 

explored)

A 50-nmol/L 

increase in 25(OR)D 

levels was 

associated with a 

reduction of 0.16 

steps in EDSS 

scores (p = 0.11); 

25(OH)D 

concentrations >/= 

50nmol/L predicted 

lower EDSS during 

subsequent 4 years 

(p = 0.004)

Dastagir, 

201333

concurrent

US MS center patients

Relapsing MS patients 

(R-R or SP); criteria N/A

EDSS score 100 Crosssectional 

Multiple 

regression

Vitamin D 

levels

Race, age, 

disease 

duration, 

time of 

onsite of Rx

Vitamin D level 

showed significant 

inverse correlation 

with EDSS (data 

N/A)

Fragoso, 

201239

retrospective

South 

America 

Patients with MS from 

Argentina, Brazil, Chile, 

and Peru, mean age 40.8 

(SD 12.6) years, mean 

disease duration 8.2 (SD 

15.5) years, 29.1% 

female

Form N/A, mean EDSS 

2.48 (SD 2.34); Poser 

criteria, McDonald 2005 

criteria, McDonald 2001 

criteria 

Progression 

to EDSS 6

1207 cases, 

1207 

controls

Casecontrol

ANOVA, 

chi-square 

test, linear 

regression, 

correlation

Month of birth 

in different 

latitudes of 

South America

Latitude, 

age, disease 

duration, 

gender

No difference in 

disease progression 

in relation to the 

month or season of 

birth (numerical data 

N/A) 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Gelfand, 

201141

concurrent

US African Americans with 

MS, mean age 21.9 (SD 

11.2) years, 55.9% 

female, 18.7% European 

genetic ancestry 

Form N/A, MSSS 6.1(CI 

4.8, 8.1); McDonald 2001 

criteria 

MSSS score 339 cases, 

342 

controls

Crosssectional 

Correlation

25(OH)D

levels

Age, gender, 

HLADRB1*15 

status, 

latitude

No linear 

association 

between MSSS 

and vitamin D 

status (p = 

0.57), no 

association 

between low vs 

high MSSS and 

deseasonalized 

or unadjusted 

vitamin D (OR 

0.79, p = 0.86; 

OR 1.01, p = 

0.97)

Hatamian, 

201345

concurrent

Iran Patients of MS Society 

with R-R confirmed by 

clinical findings and MRI, 

mean age 28.4 yrs, 70% 

female

R-R with EDSS score < 

5.5 and in remission; 

criteria N/A

EDSS score 52 MS 

patients, 52 

healthy 

participants

Casecontrol 

Multiple 

linear 

regression 

analysis

25(OH)D level Duration of 

disease, sex, 

age

Vitamin D was not 

associated with 

EDSS (beta = -0.01, 

p = 0.34) in 

univariate analysis; 

in adjusted model 

duration of disease 

was the only 

significant 

contributor to EDSS

Lucenti, 

201458

retrospective

Italy MS patients, mean age 

32 (SD 10.4) years, 

mean disease duration of 

8.8 (SD 7.8) years, 65% 

female, 

84% R-R and SP, 16% 

PP, median MSSS 3.86 

(CI 3.55, 4.14); criteria 

N/A 

MSSS score 1782 Crosssectional 

Quantile 

regression

Month of birth Gender, age 

at onset, 

clinical form

Month of birth 

had no impact 

on disease 

progression

Knippenberg

, 201150

concurrent

The

Netherlands

Outpatients with MS, 

73% female, mean age 

44.2

R-R, SP, PP; criteria N/A

EDSS score 59 Crosssectional 

Correlation

25(OH)D 

serum level

N/A Vitamin D did not 

reach statistical 

significance (r = -

0.198)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Koch, 200851

retrospective

Canada,The

Netherlands

Canadian MS database 

29.6% males, mean age 

at onset 30.6, mean 

disease duration 20.1 

years (SD 9.9); Dutch 

database 33.3% males, 

mean age at onset 32.9, 

mean disease duration 

17.98 years ( SD 10.4)

Canadian: 12.4% PP, 

87.2% R-R; Dutch 29.4% 

PP, 87.6% R-R; Poser 

criteria 

Time to 

EDSS 6, 

time from 

MS onset to 

secondary 

progression, 

age at 

secondary 

progression

N = 2837; 

N = 810

Crosssectional 

KaplanMeier 

survival 

analysis

Month of birth N/A No association 

between the month 

or season of birth 

and disease 

progression could be 

found that was 

reproducible in both 

cohorts

Kragt, 

200953

concurrent

Europe, The 

Netherlands

MS patients 68% female, 

98% Caucasian, and 

mean 11.2 years 

duration, 98% born in the 

Netherlands, 64% of 

women premenopausal

Definitive MS; Poser 

criteria 

EDSS score 103 MS and 

110 healthy 

controls

Casecontrol 

Correlation

Summer and 

winter serum 

25(OH)D 

concentrations

N/A No significant 

correlation between 

summer and winter 

vitamin D and 

summer and winter 

EDSS in sample; but 

in women r = -0.25 

(summer, p = 0.044) 

and r = -0.29 (winter, 

p = 0.020)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Niino, 201370

concurrent

Japan MS patients from Medical 

Center and Neurology 

Clinic, 90% female, mean 

age 40.8, mean age 

onset 30.1 years, mean 

and median age of 

disease duration 10.8 

and 10.5 years

69% remitting phase, 

33% relapsing phrase, 

21% SP; McDonald 2010 

criteria 

Decreasing 

EDSS score 

and MSSS

43 cases, 

34 controls

Casecontrol 

ANOVA 

1,25(OH)2D, 

25(OH)D, 

Vitamin Dbinding protein

N/A Negative correlation 

between 25(OH)D 

and EDSS (r = -

0.53, p < 0.01)

25(OH)D levels 

in SPMS 

patients were 

decreased 

compared with 

R-R patients at 

remitting phase 

(p < 0.01); 

serum 

25(OH)D 

correlates 

negatively with 

disease 

severity in R-R 

in the remitting 

phase and SP

MS

Shahbeigi, 

201386

concurrent

Iran Neurology clinic patients, 

76% women, mean age 

34 (SD 9.1), mean 

disease duration 6 years 

(5.14)

Mild (73%), moderate 

(11%), and severe (16%) 

MS; mean EDSS score 

2.76 (SD 1.93); 

McDonald 2005 criteria

EDSS score 98 Crosssectional 

Correlation

25(OH) 

Vitamin D3 

concentration

N/A Significant inverse 

correlation between 

EDSS and vitamin D 

level (r = -0.168, p = 

0.049)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Smolders, 

200890

concurrent

The

Netherlands

Outpatient clinic patients, 

75% female

R-R 47%, SP 32%, PP 

18%, unknown 3%; 

McDonald 2001 criteria

EDSS score 267 Crosssectional 

T test, 

MannWhitney U 

test, linear 

regression 

model, 

poisson 

regression 

model

25(OH)D 

serum levels, 

1,25(OH)2D

Sex, age, 

disease 

course 

(years) 

Raw 25(OH)D levels 

correlated negatively 

with EDSS, there 

was no association 

between EDSS 

score and raw 

1,25(OH)2D levels 

(p = 0.065); when 

vitamin D 

levels were tested 

as predictors of 

EDSS score, only 

the adjusted 

25(OH)D level was 

an independent 

predictor, when the 

levels were 

considered as 

dependents of 

disability, only 

25(OH)D was 

independently 

predicted by EDSS 

score (OR−3.155, CI 

-4.936, -1.374); 

1,25(OH)2D level 

was not dependent 

upon disability

SoiluHanninen, 

200891

prospective

Finland MS patients, mean age 

34.1 (SD 1.5 years), 

mean time from the 

diagnosis of definite MS 

5.6 years (range 6-15 

years); healthy laboratory 

personnel living in the 

same area

Form N/A, Mean EDSS 

2.4 (range 0-5); criteria 

N/A

EDSS 

progression 

during 1 

year

Treatment 

23, Control 

23

Casecontrol 

Logitudinal 

analysis

Vitamin D 

(25(OH)D) 

level

Grouped by 

winter, 

spring, 

summer, and 

autumn 

serum 

25(OH)D 

levels

No correlation 

between vitamin D 

nutrition and EDSS 

progression (p = 

0.07)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Sternberg, 

201395

retrospective

US MS patients: 75.7% 

female, mean age 55.6 

(SD 11.5) years, mean 

disease duration 19.0 

(SD 9.8) years

61% R-R, 31.6% SP, 

7.4% PP; EDSS 4.1 (SD 

2.2); criteria N/A

EDSS, 

MSSS score

206 Case 

control

Regression 

analyses

Vitamin D3 

plasma level

Cardiovascul

ar drugs, 

smoking

Vitamin D level was 

inversely associated 

with EDSS (p = 

0.05) and MSSS (p

= 0.04)

Thouvenot, 

2014100

concurrent

France Files from MS clinic, age 

45.3, 12.1 average years 

of disease, 72% women

PP, SP, R-R; McDonald 

2005 criteria

EDSS score 181 Other

retrospectiv

e cohort 

analysis

KruskalWallis to 

compare 

vitamin D 

levels 

between 

MS types, 

Wilcoxon 

test 

comparing 

vitamin D 

levels in 

different 

origins

25(OH)D 

plasma level

N/A Vitamin D level 

associated with 

EDSS score in 

bivariate model OR

= 2.87 (p = 0.0012)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

26

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Van der Mei, 

2007103

concurrent, 

retrospective

Australia Recruitment at local MS 

societies, eligible cases 

had cerebral MRI 

abnormalities and 

clinically definite MS

RRMS, SPMS, PPMS; 

Poser criteria

EDSS score 136 MS 

patients, 

272 

matched 

community 

controls

Case

control

ANOVA F 

test

Linear 

regression

25(OH)D 

status, time in 

the sun in 

summer and 

winter on 

leisure days in 

last 3 years, 

time in the sun 

in summer 

during work 

hours in the 

last year, past 

sun exposure, 

dietary intake 

last 12 months

Month serum 

sample was 

taken, 

duration of 

MS since 

first 

symptom

EDSS and 25(OH)D 

level correlation r = -

0.38 (p < 0.0001); 

recent sun exposure 

was significantly 

associated with high 

EDSS (leisure r = 

0.39, p < 0.01; 

during work hours r

= 0.40, p < 0.01); no 

statistically 

significant 

correlation with past 

sun exposure or 

dietary intake

WeinstockGuttman, 

2011108

concurrent

US MS patients mean age 

46.6 (SD 10.6) years, 

disease duration 13.8 

(SD 10.3) years, 71.9% 

female, 15.2% statin use

85.4% R-R, 11.8% SP, 

2.8% PP; median EDSS 

2.5, MSSS 3.5 (SD 5.43); 

McDonald 2010 criteria

EDSS and 

MSSS 

score, 

EDSS 4 or 

greater

178 Crosssectional 

Stepwise 

regression 

Vitamin D 

levels

Age, gender, 

race, statin 

use, lipid 

indicator 

variables

Deseasonalized 25-

hydroxy vitamin D3 

associated with 

MSSS (p = 0.021) 

but not included in 

EDSS prediction

Note: N/A not available, R-R relapsing-remitting, PP primary progressive, SP secondary progressive, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

27

The 17 identified studies provided data on patients in different European countries, the US, 

Canada, Iran, Japan, Israel, and Australia. Several studies recruited patients through MS 

registries. Total sample sizes ranged from 46 and 2,837. The majority of studies were concurrent 

studies, measuring the current status of the proposed risk factor and the outcome of interest 

simultaneously. Four studies assessed retrospective data (ie, predicted outcomes from exposures 

in the past).

39,51,58,95 Two studies were prospective studies20,114 reporting on the risk factor and 

outcome sequentially, with the exposure preceding the outcome measure.

Assessed potential risk factors (as reported) were serum or plasma 25(OH)D levels at the time of 

assessment, 25(OH)D levels in the summer and winter, 1,25(OH)2D, vitamin D-binding protein, 

vitamin D levels not further specified, dietary vitamin D intake, sun exposure in the summer, sun 

exposure in the winter, time in the sun on leisure and on work days, and the month of birth.

Several studies reported on the correlation between 25(OH)D levels and EDSS scores, either 

reporting the correlation coefficient, the p-value, or paraphrasing the association. No other 

specific risk factor (eg, sun exposure) and specific outcome (eg, MSSS score) combination was 

assessed in more than one study. Only one study reported on the change between relapsingremitting MS to secondary progressive MS. Koch et al51 analyzed the month of birth and the 

time from MS onset to secondary progression in sample of patients with primary progressive or 

relapsing-remitting MS. Half the studies adjusted for potential confounders, such as age and 

duration of disease.

One of the prospective studies reported that 25(OH)D levels of 50nmol/L at up to 12 months 

predicted lower disability during the subsequent 4 years.20 The other prospective study reported a 

statistically non-significant correlation between vitamin D nutrition and EDSS progression, but it 

was unclear whether the study had sufficient power to detect an effect.

91 The quality assessment 

of the two prospective studies is shown in the appendix. The study by Ascherio et al was a 

clinical trial sample,20 rather than derived from a large and broader in scope MS registry sample. 

The study by Soilu-Hanninen was very small (23 patients with MS) and may also not be a good 

representation of the population of interest.114

Another large group of studies reported on smoking and effects on disease progression, as 

documented in the next evidence table.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

28

Table 2. Evidence for KQ1 (MS Progression Risk Factors): Smoking

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Healy, 200946

retrospective

US 1465 out of 1745 

patients who 

completed 

questionnaire at 

MS center

R-R (N = 1020), 

SP (N = 212), 

primary 

progressive (PP) 

(N = 63), 

progressive 

relapsing (PR) (N 

= 24), CIS (N =

106), unspecified 

demyelinating 

disease (N = 39), 

or suspected MS 

(N = 1); 

McDonald 2005 

criteria 

EDSS score, 

MSSS, time 

to conversion 

from R-R to 

SP, 

proportion of 

patients who 

progressed 

on EDSS 

after 2 years/ 

after 5 years 

(increase in 

EDSS score)

1465 Crosssectional

KruskalWallis, 

Wilcoxon, chisquare test, 

Cox 

proportional 

hazard model

Smoking history 

(smoking status, 

age of starting 

and quitting, 

average number 

of cigarettes 

smoked per day)

Age, disease 

duration from 

first symptom, 

gender

EDSS was 

significantly higher 

in current smokers 

(p < 0.0001) but 

not significantly 

different in exsmokers (p = 

0.22) compared to 

never smokers; 

EDSS was 

significantly lower 

in the light 

smoking group 

compared to the 

moderate smoking 

group (p = 0.040) 

and compared to 

the heavy 

smoking group (p

= 0.025)

Conversion from 

R-R to SP 

occurred at 

faster rate in 

current smokers 

than never 

smokers (HR 

2.50, CI 1.42, 

4.41) but was 

similar in exsmokers and in 

never smokers 

(HR 1.05, CI 

0.59, 1.84); 

MSSS was 

significantly 

higher in the 

heavy smoking 

group compared 

to the light 

smoking group 

(p = 0.038) and 

the moderate 

smoking group 

(p = 0.048); 

probability of a 

PP course was 

higher among 

current smokers 

(OR 2.42; CI 

1.09, 5.35) or exsmokers (OR 

1.91; 95% CI 

1.02, 3.58) than 

never smokers
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

29

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Hernán, 

200547

retrospective

UK Individuals with a 

confirmed 

diagnosis of MS 

and 2 years or 

more of medical 

history prior to 

diagnosis

available

R-R; Poser 

criteria 

R-R 

converting to 

progressive 

course 

(continuously 

worsening 

disability 

lasting 6 

months or 

more as 

determined 

by 2 

independent 

reviewers) 

201 Case-control

Cox 

proportional 

hazards 

regression

Current, past or 

never smokers; 

ever vs never 

smokers; 

according to 

medical records

Age at first 

symptoms, sex, 

first symptoms 

including motor 

deficits

Incidence rate 

ratio of 

secondary 

progression was 

3.6 (CI 1.3, 9.9) 

for ever smokers 

compared with 

never smokers; 

80% of 

progression 

occurred by 4.6 

years of followup in smokers 

and by 5.3 years 

in nonsmokers

Jansons, 

201148

retrospective

US Patients with 

progressive MS

Established 

progressive MS; 

criteria N/A

Time to 

progression 

from onset of 

MS in 

patients with 

relapsingremitting MS; 

age at 

progression 

onset; time to 

EDSS 6 after 

progression 

onset

756 Crosssectional

Cox 

regression

Smoking (ever 

vs never; current 

vs previous; 

higher vs lower 

than mean packyears) 

Gender, age, 

number of 1st 

two year 

relapses,

immunetherapy, PPMS 

vs SAPMS vs 

SPMS, postprogression 

relapses, 

symptoms at 

MS onset, CSF 

positivity

More than 19 

pack-years of 

smoking was 

independently 

associated with 

shorter time to 

progression (p = 

0.015); smokers 

reached EDSS 6 

~5 years earlier 

than never 

smokers (p < 

0.001); smoking 

alone very 

strongly predicts 

an earlier onset 

of progression 

and disability 

after progression 

in MS
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

30

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Koch, 200752

retrospective

The 

Netherlands

Patients in MS 

database, 

definitive MS 

meeting Poser 

criteria 

Benign relapsingremitting, R-R, 

SPMS, PPMS; 

Poser criteria

Benign 

relapsingremitting, RR, SPMS, 

PPMS; age at 

onset of SP, 

age at onset 

of PP 

disease; time 

from disease 

onset to 

EDSS 4, time 

from disease 

onset to 

EDSS 6; 

EDSS score

364 Case-control

Conditional 

logistic 

regression 

and Cox 

hazard ratio

Smoking history: 

current status, 

starting and 

quitting dates, 

nonsmoking 

periods, number 

of cigarettes 

smoked, number 

of smoked packyears before 

and after onset

Gender No significant 

differences in the 

time to EDSS 

scores 4 and 6; 

total pack-years 

were not 

significantly 

correlated with 

EDSS in the total 

sample but in 

women (r = -0.16, 

p = 0.01)

In patients with 

PPMS, none of 

the variables had 

a significant 

effect on the age 

of progression

Maghzi, 

201159

retrospective

Iran Patients from MS 

registry; smoking 

group: 78.5% 

female, mean age 

32.75 (SD 8,68) 

years, mean age 

at onset 27.42 

(SD 7.91) years; 

control group: 

46.5% female, 

mean age 32.86 

(SD 9.65)

83.2% R-R, 2.9% 

PP, 13.9% SP 

course in the 

smoking group; 

McDonald 2005 

criteria, McDonald 

2001 criteria

Progression 

(EDSS/ 

disease 

duration)

516 Crosssectional

Conditional 

logistic 

regression

Ever/never 

smoker, 

smoking history, 

smoking 

duration, packyears smoked

Age, gender No difference in 

disease 

progression 

(EDSS/ disease 

duration) between 

smokers and 

nonsmokers 

(0.54, SD 0.42 vs 

0.49, SD 0.48) in 

male patients
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

31

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Manoucherhri

nia, 201361

retrospective

UK Patients 

registered in MS 

specialist clinic 

database, 270 

male, 625 female, 

mean age 49 

years, mean 

duration of illness 

17 years

CIS, suspected 

MS, R-R, SP, PP; 

Lublin & Reingold 

criteria 

Reaching 

EDSS 4, 

reaching 

EDSS 6

895 Crosssectional 

Linear 

regression, 

Cox 

proportional 

hazard 

regression 

model

Smoking status 

(nonsmoker, 

stopped before 

onset, stopped 

after onset, 

current smoker)

Sex, onset age, 

use of DMT, 

initial course 

(R-R, PP)

RR of reaching 

EDSS 6 was 

higher in smokers 

compared to 

nonsmokers; risk 

of reaching EDSS 

4 and 6 in eversmokers vs neversmokers was 1.34 

(CI 1.12,1.60) and 

1.25 (CI 1.02, 

1.51); current 

smokers showed 

1.64 (CI 1.33, 

2.02) and 1.49 (CI 

1.18, 1.86) times 

higher risk of 

reaching EDSS 4 

and 6 compared 

with nonsmokers; 

ex-smokers had a 

significantly lower 

risk of reaching 

EDSS 4 (HR 0.65, 

CI 0.50, 0.83) and 

6 (HR 0.69, CI 

0.53, 0.90) than 

current smokers, 

and there was no 

significant 

difference 

between exsmokers and 

nonsmokers in 

terms of time to 

EDSS 4 or 6

No association 

between 

smoking status 

and PP vs R-R 

type at onset
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

32

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Pittas, 200976

prospective

Australia Patients with MS, 

female 69.2%, 

mean age 48.2 

years (SD 11.4), 

median age of MS 

onset 33.5 years, 

mean disease 

duration 14.1 (SD 

10.3) years

R-R at cohort 

entry 75%; mean 

EDSS 3.7 (SD 

2.3); Poser 

criteria, McDonald 

criteria 

MS 

progression 

(MS Severity 

Scale 

[MSSS]) 

203 Experimental

Mixed effects 

linear 

regression

Pack-years

smoked in the 

past 6 months at 

entry, ever 

smoker, total 

pack-years prior 

to MS, packyears from 

onset, current 

smoker

Entry MSSS 

and EDSS, 

age, gender, 

IMT use, 

education level,

and month of 

review

Cumulative 

pack-year 

smoked after 

cohort entry was 

associated with 

an increase in 

longitudinal 

MSSS (p < 

0.001)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

33

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Roudbari, 

2013115

retrospective

Iran Patients 

registered in the 

MS Society 

(Guilan, Iran) 

database; mean 

age 34.8 (SD 9.5) 

years, 74% 

female, mean age 

at disease onset 

1.7 (SD 2.3) 

years, 14% 

smokers, 86% 

nonsmokers

R-R 64%, SP 

36%; McDonald 

2005 criteria

Risk of 

progression

524 

included, 

400 

responded

Crosssectional 

Cox 

regression

Smoking (packyears smoked; 

20 cigarettes 

smoked per day 

for 1 year = 

pack-year; 

nonsmokers vs 

< 10 pack-years

vs > 10 packyears) 

Age on disease 

onset, number 

of relapses per 

year, gender

Compared with 

nonsmokers, 

current smokers 

who continued 

smoking after 

MS diagnosis 

and patients who 

started smoking 

after MS 

diagnosis 

showed a RR of 

2.43 (CI 1.2, 4.8; 

p < 0.001) and 

RR 3.55 (CI 1.3, 

9.2; p = 0.007) 

for MS 

progression; HR 

for smokers vs 

nonsmokers was 

2.25 (CI 1.3, 

3.99; p = 0.004); 

risk of SP was 

2.43 times higher 

(CI 1.28, 4.6; p = 

0.007) for 

greater numbers 

of cigarettes 

smoked per day 

vs nonsmokers
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

34

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Sundström, 

200897

prospective

Sweden Respondents MS 

epidemiological 

survey and 

interviews, 64% 

female

R-R, SP, 

progressive from 

onset; criteria N/A

Progressive 

disease (PP, 

SP, or 

progressive 

relapsing) 

determined 

during 

interview, 

neurological 

exam, and 

medical 

records; 

progressive 

disease from 

onset, 

conversion to 

progressive 

disease (R-R, 

SP), time to 

progressive 

disease 

based on 

EDSS 

122 Crosssectional 

Multivariate 

Cox 

regression

Self-reported 

smoking habits; 

ever smoker 

(had to have 

started before 

MS onset to be 

included), never 

smoker; early 

start (15 or 

younger) or later 

start

Gender, age at 

disease onset, 

relapsingremitting MS 

cases

After a median of 

6 years disease 

duration, 

progressive 

disease was 

significantly 

more likely to

occur in ever 

smokers 

compared to 

never smokers 

(p = 0.006); 

progression was 

most likely in 

patients who 

started smoking 

early compared 

to later (p = 

0.005) or never 

smokers (p < 

0.001); cases 

with late disease 

onset had 3x 

higher risk and 

ever smokers 

had 2x as high a 

risk for 

progression

Tepavcevic, 

2010112

prospective

Serbia Patients with MS, 

age 18-60 years 

EDSS < 8; 

McDonald criteria

EDSS score 98 Prospective 

followup

T-test, linear 

regression

Cigarette 

smoking status 

at baseline

Baseline 

EDSS, gender

The baseline 

smoking status 

showed 

independent 

predictive value 

on development of 

physical disability 

(p = 0.001)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

35

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Zivadinov, 

2009111

retrospective

US Patients with MS 

at MS center with 

MRI exam, age 

18-80 years, 

mean age 44 (SD 

10.2), mean 

disease duration 

12.1 years (SD 

9.1), 93% white, 

6% black; 79% 

female

R-R: 68.6%, CIS: 

5.7%, SP: 22.9%, 

PP: 2.8%; criteria 

N/A

EDSS score 368 Crosssectional 

Polytomous 

universal 

model ordinal 

regression 

method

Smoking: neversmoker, eversmoker, active 

smoker; mean 

duration; 

average number 

of packs per day

Age, disease 

duration, 

treatment 

duration

Median EDSS for 

the ever-smokers 

was 3.0 compared 

with 2.5 for the 

never-smokers; 

association of 

EDSS score with 

neversmoker/eversmoker status (p = 

0.004)

Notes: N number of participants, N/A not available, SD standard deviation, R-R relapsing-remitting, PP primary progressive, SP secondary progressive, RR relative risk, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

36

We identified 11 studies that exclusively evaluated the effect of smoking on disease progression. 

Studies from the US, different European countries, Iran, and Tasmania contributed research. All 

but 3 studies were retrospective analyses. Participants were recruited at MS centers and 

registries. The number of included participants ranged from 98 to 1,465.

Specific assessed risk factors were: current smoking status; smoking status as baseline; age of 

starting and quitting; early (15 years or younger) or later smoking start; number of cigarettes 

smoked per day; current, past, or never smokers; ever versus never smokers; number of cigarette 

pack-years in total; pack-years smoked in past 6 months; smoking status before and after onset of 

MS; nonsmoking periods; and smoking duration in years. Information came from self-reported 

survey data or medical records. All studies used multivariate methods controlling for 

demographic and disease characteristics. 

Studies used a range of outcome predictors, assessing continuous outcomes, dichotomous status 

variables, and time to event data. The individual measures were EDSS scores, MSSS scores 

(measure of rate of disease progression, standardized for disease duration), EDSS score divided 

by disease duration, time to conversion to secondary progression from onset, time from disease 

onset to EDSS 4, time to EDSS 6, reaching EDSS 4 during study period, reaching EDSS 6, 

experiencing progression, age at onset of secondary progression, and proportion of patients who 

progressed on EDSS after 2 years/ after 5 years (increase in EDSS score).

Three prospective studies were identified. All reported a statistically significant effect of 

smoking on MS but reported on different outcome measures.

76,97,112 The detailed quality 

assessment of the prospective studies is shown in Appendix C. Two of the studies did not 

indicate major flaws. One was published as an abstract only and lacked detail.

The following evidence table shows studies that investigated childbirth-related factors such as 

the use of epidural analgesia during childbirth. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

37

Table 3. Evidence for KQ1 (MS Progression Risk Factors): Childbirth-associated Factors

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Confavreux, 

199830,116

prospective

Europe, 

multiple 

countries

Women had MS before 

pregnancy and were 

pregnant, referred by 

European neurologist; 

duration of MS before 

pregnancy 6 years, age 

at beginning of 

pregnancy 30

96.6% R-R, 3.14% SP; 

mean EDSS at baseline 

1.32; Poser criteria

EDSS or 

DSS

254 Time series

Logistic 

regression

Epidural 

analgesia, 

breast feeding

Age, duration 

of disease, 

occurrence of 

relapses before 

and during 

pregnancy

No acceleration 

of the 

progression 

according to use 

of epidural 

analgesia (p = 

0.66) or breastfeeding (p = 

0.27); same 

finding 2 years 

post-partum

Gava, 201440

retrospective

Italy Women with MS at an 

academic medical center

SP and R-R; McDonald 

2010 criteria 

EDSS 

score 

174 Crosssectional 

Logistic 

regression 

analysis

Oral 

contraceptives 

use

Age, duration 

of disease, age 

of menarche, 

use of DMT, 

parity

Ever users of 

combined oral 

contraceptives 

had lower EDSS 

scores compared 

to never users (p

= 0.044)

Lu, 201357

retrospective

Canada Female MS patients with 

live births, British 

Columbia Perinatal 

Database Registry, 

mean age 32 years

99% relapsing-onset, 

1% PP; Poser criteria, 

McDonald 2005 criteria

EDSS 1-

1.5 vs 2-

2.5 vs 3 or 

higher

431 Crosssectional

Multivariate 

models

Obstetrical 

epidural and 

spinal 

anesthesia use 

during delivery

Age, parity, 

comorbidities, 

mode of 

delivery, birth 

weight, 

gestational age 

in weeks 

EDSS was not 

associated with 

use of either type 

of anesthesia (p > 

0.1)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

38

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Pastò, 201272

prospective

Italy Women with 

pregnancies between 

2002 and 2008 in 21 MS 

centers, mean age at 

conception 31.8, mean 

age at onset 24.7, mean 

disease duration at 

conception 7.1 years

Form N/A, mean EDSS 

at conception 1.5 (SD 

1.0); McDonald 2010 

criteria 

Progressio

n on EDSS

415 Crosssectional

Multivariate 

analysis

Epidural 

analgesia 

delivery, 

cesarean 

delivery

Age at MS 

onset, age, 

disease 

duration, EDSS 

at conception, 

DMT before 

pregnancy, 

number of 

relapses in 

year before 

pregnancy / 

during 

pregnancy, 

exclusive 

breastfeeding

Epidural analgesia 

delivery and 

cesarean delivery 

were not 

associated with 

disability 

progression after 

delivery

Sena, 201285

retrospective

Europe Female MS patients 

registered with 

hospital,with R-R MS, 

median disease duration 

6.2 (SD 5.1) years, 

never-users vs pastusers vs after-users: 

mean age 37.3 (SD 

10.2) vs 38.6 (SD6.8) vs 

32 (SD6.6) years, mean 

age at disease onset 

29.9 (SD 9.8) vs 34.6 

(SD 

R-R; McDonald 2005 

criteria 

EDSS, 

MSSS 

scores; 

benign 

course 

(MSSS < 

2.5)

132 (53 

neverusers, 26 

post-users, 

54 afterusers) 

Crosssectional

Multivariate 

linear and 

logistic 

regression 

Oral 

contraceptive 

use

Age, gender, 

smoking, 

childbirths, age 

at disease 

onset, disease 

duration, 

relapse rate, 

age of 

menarche, age 

at onset of OC 

use, OC use 

duration

After-user patients 

had lower EDSS 

and MSSS scores 

than never users 

(p < 0.001, p = 

0.002) and past 

users (p = 0.015 

and p = 0.002)

Patients who 

took oral 

contraceptives 

after disease 

onset were more 

likely to have a 

more benign 

disease course 

(MSSS < 2.5) 

than never / past 

users (OR: 2.97; 

CI 1.24, 6.54; p = 

0.011)

Notes: DMT disease modifying treatment, N number of participants, N/A not available, SD standard deviation, R-R relapsing-remitting, PP primary progressive, SP secondary 

progressive, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

39

We identified 5 studies reporting on pertinent risk factors. Study sample sizes in the studies 

varied widely, ranging from 174 to 2,105 included women. Studies used different outcomes

measures: EDSS, DSS, or MSSS scores. One study included only patients with relapsingremitting MS. It predicted EDSS and MSSS scores and reported on the odds ratio of having a 

more benign disease course defined as MSSS below 2.5.85

The studies evaluated a number of potential risk factors that may be associated with MS 

progression: epidural and/or spinal analgesia during delivery, breast feeding, use of oral 

contraceptives, and cesarean delivery. All studies adjusted for covariates in the analyses, in 

particular the age at the time of the first child and age at MS onset.

Three studies were retrospective analyses but 2 studies assessed women at the time of pregnancy 

and followed them for a number of years.30,72 The quality assessment of the prospective studies 

are shown in the appendix. The main source of potential bias was confounding due to selection 

bias. It is possible that participants self-selected the exposure or intervention, such as breast 

feeding, because of their EDSS scores. Hence studies may show reverse causality with EDSS 

scores (the outcome) influencing the variable assessed as the risk factor.

We also identified studies that exclusively reported on diet and its effects on disability and 

progression of MS, as documented in the following evidence table.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

40

Table 4. Evidence for KQ1 (MS Progression Risk Factors): Diet

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Aupperle, 

200521

concurrent

US Patients with MS, 

84% female

R-R; criteria N/A

EDSS 38 Case-control

Analysis N/A

Red blood cell 

fatty acids, 

dietary fatty 

acids intake

N/A None of the 

fatty acids were 

related to 

disability

Foster, 

201238

retrospective

US MS patients, mean 

age 47.8 (SD 12.5) 

years, mean disease 

duration 15.2 (SD 

10.5) years, median 

EDSS 3.0 (SD 4.0) 

93.5% Caucasian

American, 4.5%

African American, 

and 5% other races, 

76% female

66.2% R-R, 22.4% 

SP, 7% relapsing 

SP, 4.4% PP or 

primary relapsing; 

McDonald 2001 

criteria 

EDSS and 

MSSS 

scores 

272 

cases, 

151 

controls

Cross-sectional

Regression analyses

Duration of 

alcohol 

consumption 

after MS 

diagnosis 15 

years or fewer

(compared to no 

consumption of 

alcohol or 

consumption for 

> 15 years) 

Age, age of 

onset, sex, 

disease 

duration

EDSS scores 

were lower in 

patients who

had consumed 

for 15 years or 

fewer after MS 

onset compared 

those who did 

not consume 

alcohol or 

consumed it for

> 15 years; 

pattern of nonlinear 

dependence 

suggests that 

moderate 

duration of 

alcohol use 

does not have 

adverse effects

Kurtzke, 

197354

retrospective

US Men first diagnosed 

with MS in US Army 

hospitals during 

World War II

Form N/A; 

Schumacher criteria

DSS score 

change 

(better, 

same, 

worse after 

hospitalizati

on)

517 Other

Count comparison

Diet N/A Diet: 28% better, 

56% the same, 16% 

worse; patients with 

hospital routine 

without specific 

treatments: 19% 

better, 74% same, 

8% worse.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

41

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Plow, 201277

concurrent

US N/ARCOMS registry, 

292 respondents out 

of 1000 randomly 

selected surveyed 

patients, 79.7% 

female, average 

duration since

diagnosis 15 (SD 

8.30) years

63% R-R, 20% SP, 

8.1% PP, 6.6% 

progressive

relapsing MS; 

criteria N/A

Type of MS 

(R-R, 

progressive, 

unknown)

292 Cross-sectional

Logistic regression

Healthy 

nutritional 

behavior 

indicator defined 

by whether 

participants 

answered 4 out 

of 5 questions 

with the 

response of 

"often": 1) make 

good food 

choices, 2) eat 5 

servings of fruits 

and vegetables 

a day, 3) limit fat 

intake, 4) read 

labels, 5) eat 

regularly

Gender, 

optimism/

pessimism, 

BMI, physical 

activity, 

emotional 

selfmanagement, 

communicatio

n with 

physician

Nonsignificant 

correlation type of 

MS-nutritional 

behavior (p = 0.38)

Swank, 

199098,117

prospective

US,

Canada

Patients who 

maintained contact 

with MS clinic

Form N/A, minimum, 

moderate, and 

severe disability; 

other criteria

Average 

worsening 

in disability 

grade, 

percentage 

of deaths 

due to MS 

144 Case series

t-test

Good dieters 

(fat 

consumption = 

< 20 g/day) vs 

poor dieters 

(consumption > 

20 g/day), 

period checks of 

eating habits 

(presumably) 

self-reported

N/A In each of the 

disability groups the 

average worsening 

in disability grade 

and the percentage 

of deaths of the poor 

dieters significantly 

exceeded those of 

the good dieters; 

greatest difference 

occurred for 

minimum disability 

at study entry (p < 

0.0001)

Notes: N number of participants, N/A not available, N/ARCOMS North American Research Committee on Multiple Sclerosis, SD standard deviation, R-R relapsing-remitting, PP 

primary progressive, SP secondary progressive, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

42

We identified 4 studies that exclusively looked at dietary behavior. All studies were conducted in 

the US or the US and Canada.

One study reported concurrent data, meaning current dietary fatty acid intake, in patients with 

relapsing-remitting MS. The study, published as a conference abstract, lacked detail but stated 

that none of the assessed fatty acids were related to disability.21

Two studies were retrospective analyses.38,54 One reported on the duration of alcohol 

consumption after MS diagnosis. The other focused on men on active duty in the US Army and 

reported on the disease course for patients that were put on a specific diet in the hospital, 

compared to patients without administration of a specific therapy.54 The study did not report a 

statistical analysis but, applying Fisher’s exact test to the raw data, we find that the difference 

between groups was not statistically significant. No information was available on the specific 

diet and approaches may have varied across patients and hospitals.

A fourth study reported on the Swank diet in multiple publications.

98,118,119 The prospective study 

compared “good dieters,” meaning people with fat consumption of 20g per day or less, and “poor 

dieters” who exceeded the fat consumption limit. Patients who were given the diet advice were 

followed for 34 years. The study reported that in each of the disability groups, the average 

worsening in disability grade and the percentage of deaths of the poor dieters significantly 

exceeded those of the good dieters. The detailed quality assessment of the study is shown in 

Appendix C. The main concern is the ascertainment of the risk factor, which in this case is the 

compliance of the participants with the diet and self-reports that determined the classification 

into good or poor dieters.

A small group of studies exclusively reported on exercise behavior as shown in the following 

evidence table.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

43

Table 5. Evidence for KQ1 (MS Progression Risk Factors): Exercise

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Marrie, 200962

retrospective

US,

Canada

N/ARCOMS 

questionnaire 

respondents, 94.5% 

white, 75.8% women, 

mean age 52.7; mean 

age at onset 31.2, mean 

age of diagnosis 31.2, 

mean disease duration 

21.5

Form N/A, PDDS mild 

disability 35.4%, 

moderate disability 11.95, 

severe disability 52.7%; 

criteria N/A

PDDS 

category

8983 Crosssectional 

Multivariate 

regression

Physical activity, 

leisure-time 

activity (scale 

from 1 = inactive 

to 4 = heavy 

activity) in the 

last year

Smoking 

status, physical 

activity level

Physical activity 

decreased steadily 

with increasing 

disability

Milivojevic, 

201364

retrospective

US MS patients, 65.1% 

female, mean age 38 

(range 21-58), mean 

disease duration 5.4 

years (range 1-16) 

Form N/A, mean EDSS 

1.7 (range 0-5.5); 

neurological evaluation

EDSS 

score 

63 Crosssectional 

T-tests

Use of physical 

rehabilitation

N/A Patients who used 

inpatient, 

outpatient, and 

home-based 

rehabilitation had 

higher levels of 

impairment 

compared to 

patients who were 

not rehabilitated (p

= 0.002, p = 

0.004, p = 0.0021)

Motl, 201268

prospective,

retrospective

US MS patients recruited 

through National MS 

Society, mean age 45.9 

(SD 9.6) years, mean 

disease duration 8.8 

years (SD 7.0), median 

PDDS 2, 86.6% female, 

91% Caucasian, welleducated

R-R; criteria N/A

Progression 

in PDDS

269 Time series

Latent growth 

curve 

modeling

Premorbid 

physical activity

Gender, age 

disease 

duration since 

diagnosis, 

diseasemodifying 

therapies

Premorbid physical 

activity predicts the 

linear change in 

disability scores 

(PDDS) (p < 

0.005)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

44

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS results Other results

Shammas, 

201487

prospective

German

y 

Patients with definite MS

and EDSS < 5, 64% 

female, mean age 41 

years (SD 9.3), mean 

disease duration 12.18 

years (SD 10.67), 

recruited in MS clinic

8/11 R-R, 1/11 PP, 2/11 

SP, mean EDSS 3.6 (SD 

1.66); McDonald 2010 

criteria 

EDSS 

score 

11 Other

Correlation

Total number of 

steps taken 

during study 

period

Age, gender, 

weight, height, 

shoe sizes

Number of steps 

negatively 

correlated with 

EDSS score (r = 

-0.54, p = 0.01)

Stuifbergen, 

200696

prospective

US Patients from MS Society 

patients and 

advertisments in rural 

newspapers, mean age 

49.4 years, 83% women

R-R, PP, SP, PR; criteria 

N/A

Incapacity 

Status 

Scale (ISS) 

scores 

611 Time series

Multivariate 

latent curve 

modeling

Exercise 

behavior (HPLPII exercise/

physical activity 

subscale)

Age, sex, years 

since 

diagnosis, 

residency type, 

attrition

Exercise behaviors 

and functional 

limitations were 

negatively 

correlated (r = 

-0.34); time 1 

exercise scores 

were negatively 

correlated with 

annual change rate 

in functional 

limitations (r = 

-0.17); increasing 

rates of change in 

functional 

limitations 

correlated with 

decreasing rates of 

change in exercise 

behavior (r = -0.25)

Notes: N number of participants, N/A not available, N/ARCOMS North American Research Committee on Multiple Sclerosis, SD standard deviation, R-R relapsing-remitting, PP 

primary progressive, SP secondary progressive, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

45

The 5 studies addressing exercise were conducted in the US, US and Canada, and Germany. The 

number of included participants ranged from 11 to 8,983. The studies included retrospective and 

prospective analyses.

A large retrospective study used data from 8,983 survey respondents.

62 It reported an association 

between self-reported physical activity in the last 12 months and disability measured with the 

Patient Determined Disease Steps (PDDS), indicating that physical activity decreased steadily 

with increasing disability. The PDDS is a self-report measure of disability using a scale of 0 

(normal) through 8 (bedridden), developed as a surrogate for the EDSS. Another retrospective 

study assessed the use of physical rehabilitation and reported that patients who had used 

inpatient, outpatient, or home-based rehabilitation had higher levels of impairment compared to 

patients who were not rehabilitated.64

A very small, prospective study in 11 participants reported a negative correlation between 

objectively measured physical activity over one year and EDSS scores.87 No other data were 

reported that may inform the temporal association between the 2 variables, such as the effect of 

physical activity at baseline on MS progression.

A prospective study by Stuifbergen et al, on the other hand, assessed exercise behavior in a 

sample followed for 5 years. Exercise scores at the first assessment time point were negatively 

correlated (r = -0.17) with annual change rate in functional limitations due to MS (Incapacity 

Status Scale, ISS; self-reported degree of impairment).

96 A prospective study by Motl et al68

reported that participants with higher premorbid physical activity levels reported less change in 

disability over time (PDDS scores) compared with those who reported lower premorbid physical 

activity. 

The risk of bias evaluation for the prospective studies is shown in the Appendix C. The 

objectively measured study only included 11 patients and data were not prospectively analyzed.

87

The other prospective studies were higher quality but neither reported on EDSS scores, the 

primary outcome of this review.

The next evidence table summarizes studies that addressed other exposures not captured in 

previous evidence tables, such as exposure to trauma.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

46

Table 6. Evidence for KQ1 (MS Progression Risk Factors): Other

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS 

results

Other results

Baghizadeh, 

201322

retrospective

Iran Neurology and MS clinicattending patients, 78% 

female, mean age 34 yrs, 

mean age of onset 24 yrs 

R-R, SP, PP; McDonald 

criteria 

MSSS scores 

(chronic, mildmoderate, 

advancedaccelerated, 

aggressivemalignant 

disease 

severity)

338 Cross-sectional

Ordinal logistic 

regression 

Education Unclear Education did 

not predict 

getting worse (p

= 0.074)

Detels, 

198235

prospective

US MS onset between Jan 1, 

1960 and Dec 31, 1969, 

born in the US, white, 

residents in 1970 in either 

a low-prevalence (Los 

Angeles County, CA) or in 

a high-prevalence area 

(King and Pierce Counties, 

WA); LA: 67.7% female, 

WA: 74.8% female; mean 

age at onset 33.4 yrs

Form N/A; Schumacher 

criteria 

3-point scale: 

1) walking 

without aids; 2) 

walking with 

aids such as 

braces, 

crutches, or 

canes; and 3) 

restricted to 

wheelchair or 

to bed (selfreported)

560 cases 

in LA, 326 

cases in 

WA

Cross-sectional

Multivariate 

regression

Geographic 

regions (high- vs 

low-prevalence 

area)

Age at 

onset, 

residence, 

sex, 

disability 

status at 

intake

Progression to a 

non-ambulatory 

status or death 

was significantly 

greater among 

patients who 

lived in LA 

county (lowprevalence area)

Sibley, 

199089

retrospective

US Patients in the community 

with clinically definitive MS, 

mean age 43 years, 

female to male ratio 1.6 to 

1 

Form N/A; Schumacher 

criteria 

Mean increase 

in DSS/year

170 MS 

patients

Other design

Chi-square test

Trauma, different 

subtypes (dental 

procedures, minor 

surgery, major 

surgery, fractures, 

sprains, burns, 

head injuries, 

abrasions/

lacerations/

contusions)

N/A Peripheral 

trauma is not a 

risk factor for MS 

progression
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

47

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Covariates EDSS 

results

Other results

Spitzer, 

201293

retrospective

Germany Patients with definite MS 

attending a MS outpatient 

clinic, age 18-50 years, 

mean age 39.7, 73% 

women, mean MS onset 

29.2 years, mean MS 

duration 10.5 years, mean 

relapse rate 0.66% 

70% R-R, 7% PP, 23% 

SP, mean EDSS score 3.2; 

McDonald 2001 criteria, 

McDonald 2005 criteria

EDSS score, 

disease 

progression

(EDSS scores 

divided by 

years of 

disease 

duration)

234 with 

MS 

Case-control

Logistic and 

multiple linear 

regression

Self-reported 

childhood 

maltreatment 

(CTQ total score, 

emotional abuse, 

physical abuse, 

sexual abuse, 

emotional neglect 

and physical 

neglect)

Age, sex, 

education, 

current 

depression

Childhood 

trauma was not 

associated with 

disease 

progression or 

EDSS 

Tuzun, 

2010102

retrospective

Turkey MS patients with R-R or 

SP MS; earthquake victim 

vs control: 66.7% vs 58.8% 

female, mean age of onset 

26.8 (SE 1.3) vs 24.8 (SE 

1.2), 

68.6% R-R, 31.2% SP, 

EDSS 3.09 (SE 0.3) 

(earthquake); 64.7% R-R, 

35.3% SP, 3.01 (SE 0.4) 

(control); McDonal criteria

EDSS score 82 Cross-sectional

Logistic 

regression

Earthquake

experience

N/A Comparable 

EDSS 

scores 

between 

groups after 

the 

earthquake

Vollmer, 

2002104

retrospective

US US Veterans and nonveterans from NARCOMS 

patient registry

Relapsing, PP; criteria N/A

PDDS score 2150 

Veterans, 

2107 nonVHA 

Veterans, 

16119 

nonveterans

Matched 

controls

Paired t-test

VHA Veteran, 

non-VHA 

Veteran, nonveteran

N/A PDDS scores 5.0 

in VHA, 4 in nonVHA Veterans, 

3.6 in nonveterans (p < 

0.001 VHA 

Veteran vs nonveteran)

Note: N number of participants, N/A not available, N/ARCOMS North American Research Committee on Multiple Sclerosis, R-R relapsing-remitting, PP primary progressive, SP 

secondary progressive, SD standard deviation, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

48

We identified 6 studies that reported on unique risk factors of interest. Three were US studies, 

one was conducted in Iran, one in Turkey, and one in Germany. All but one were retrospective 

studies; one followed patients prospectively.

35 Where reported, studies included a range of MS 

subtypes. The largest study compared 2,150 VHA Veterans with 2,107 non-VHA Veterans and 

16,119 non-veterans.

In terms of risk factors, studies reported on education, peripheral trauma (eg, surgery, head 

injuries), childhood maltreatment, geographic regions with high or low MS prevalence, recent 

earthquake exposure, and being a VHA Veteran.

A prospective study reported that progression to a non-ambulatory status or death was 

significantly greater among patients who lived in LA county, a low-prevalence area for MS.35

The detailed risk of bias assessment for this study is shown in the appendix. Of note, the study 

measured disability status at follow-up by a self-administered mailed questionnaire; hence, the 

progression data are not based on physician assessments.

One study used a VA-relevant dataset and reported that VHA Veterans had higher PDDS scores 

than non-veterans.104

The other studies reported no associations between assessed predictors and outcome measures.

The last KQ1 evidence table summarizes all those studies that reported on more than one group 

of risk factor of interest for this review, for example studies reporting the effect of smoking and

exercise.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

49

Table 7. Evidence for KQ1 (MS Progression Risk Factors): Multiple

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

Bombardier,

200427

concurrent

US Survey 

respondents with 

diagnosis of MS 

by MRI, 77% 

female, mean 

age 48.7 years, 

mean EDSS 5.7, 

mean disease 

duration 11.8 

years

Form N/A; 

criteria N/A

EDSS 

score 

739 

respondents 

(out of 1374 

surveyed)

Crosssectional

T-test

Possible, current 

alcohol problems 

during preceeding 

month (4 items) 

vs no alcohol 

problems; drug or 

medication 

misuse during the 

past month (1 

item) vs not

N/A Respondents with

possible alcoholrelated problems (p

= 0.001) and 

respondents with 

drug misuse (p < 

0.05) had lower 

EDSS scores
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

50

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

D'hooghe, 

201236,120-122

retrospective

Belgium Flemish MS 

Registry, 

relapsing vs 

progressive 

onset patients: 

mean age 50.3 

vs 58.6, mean 

age onset 31.5 

vs 37.3, mean 

disease duration 

18.8 vs 21.4, 

female 75.6% vs 

62.2%, 

33.3% relapsing 

onset, 34.9% 

progressive 

onset, EDSS >= 

6 35.9% vs 80%; 

Poser criteria

Time from 

onset or 

from birth to 

sustained 

EDSS 6

1431 

respondents 

(out of 3320 

invited); 704 

with EDSS 6 

or more

Crosssectional 

KaplanMeier 

survival 

and Cox 

proportion

al hazard 

regression

Alcohol, coffee, 

and fish 

consumption

(compared to no 

consumption); 

smoking; sun 

exposure in 

summer (hours 

daily), sun 

exposure in 

winter, sun 

exposure 

compared to 

peers, 

sunscreen/protect

ion, working place 

(inside, both, 

outdoors); age at 

starting oral 

contraception, 

duration of oral 

contraceptive 

intake; health 

promoting 

lifestyles profile II 

(HPLP total 

score, health 

responsibility, 

physical activity, 

nutrition, spiritual 

growth, 

interpersonal 

relationships, 

stress 

management)

Gender, age at 

MS onset, IMT 

use

In relapsing MS, 

alcohol, wine,

coffee, and fish 

consumption were 

associated with a 

reduced risk to 

reach EDSS 6; in 

progressive onset 

MS, all n.s. 

Smoking was 

associated with an 

increased risk to 

reach EDSS 6 in 

relapsing onset MS; 

in progressive onset 

MS, all n.s. except 

for type of fish (fatty 

fish associated with 

increased risk to 

reach EDSS 6 

compared to lean 

fish). In relapsing 

onset MS, 

respondents 

reporting equal or 

higher levels of sun 

exposure than 

peers had a 

decreased risk of 

reaching EDSS 6

In progressive 

onset MS, the use 

of oral 

contraceptives was 

related to an 

increased risk. 

For relapsing onset, 

HPLP (p = 0.030), 

health responsibility 

(p = 0.218), 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

51

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

physical activity (p

< 0.001), and 

nutrition (p < 0.001) 

were predictive of 

time from onset to 

EDSS 6 but not 

spiritual growth (p = 

0,048); time from 

birth analyses 

showed physical 

activity and nutrition 

to be significant (p

< 0.001); for 

progressive onset, 

all n.s.

Goodin, 

199943

concurrent

US Survey 

respondent with 

definite MS, 

78.6% female, 

92.5% 

Caucasian, 2% 

African 

American, 2.5% 

Asian, 3.0% 

Hispanic, mean 

age 48.1, mean 

age at MS onset 

31.1, mean 

duration of 

symptoms 17.1 

years 

57.8% R-R, 

22.6% SP, 

20.1% PP; mean 

EDSS 4.8 (SD 

2.3); diagnosed 

by a physician, 

any criteria

EDSS 

score 

168 Crosssectional 

Multiple 

regression

Exercise, 

consumption of 

alcohol (5-point 

scale from never 

to daily), 

insurance 

coverage, 

physical therapy, 

getting a 2nd 

opinion, being 

happy with 

medical care or 

coverage, being 

denied medical 

coverage or 

treatment, other 

dietary factors

unclear Exercising (p = 

0.001) and 

consumption of 

alcohol (p < 0.001) 

associated with 

lower EDSS scores; 

medical insurance 

coverage (p < 

0.001) and physical 

therapy (p < 0.001) 

associated with 

higher EDSS

scores; getting a 

second opinion, 

being happy with or 

being denied 

medical coverage, 

other dietary factors 

not associated with 

EDSS (p > 0.05)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

52

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

Lauer, 199255

retrospective

Germany MS patients, 

64.1% female

64.2% benign, 

35.8% malignant

MS 

MS patients 

with benign 

(DSS = < 

2.0 after 11 

or more 

years' 

duration) vs 

malignant 

(DSS > = 

7.0 after 

less than 16 

years' 

duration) 

course

81 (52 

benign, 29 

malignant)

Crosssectional

Logistic 

regression

Ether anesthesia, 

brain trauma, 

vaccination 

(poliomyelitis, 

diphtheria, 

tetanus, 

influenza), 

childhood diet 

breast fed, diet 

rich in animal fat, 

predominantly 

butter, domestic 

slaughtering, milk 

daily, 

unpasteurized 

milk, 3 or more 

eggs per week, 

animal brain, 

often brain 

sausage; 

childhood animal 

exposures (dog, 

cat, bird, pig , 

rats, mice, other 

rodents, cattle); 

animal exposure 

within 5 years 

before onset 

(dog, cat, bird, 

domestic rodents, 

cattle, pigs); 

childhood coal 

heating, wood 

heating, humid 

flats, no sewage 

system, no piped 

water; frequent 

environments 

(farm, industrial 

plant, fields, 

Covariates Associated with 

benign course: milk 

daily (OR 3.03, p = 

0.03), grew up with 

chickens (OR 2.77, 

p = 0.03), frequent 

environment 

meadows/pastures 

(OR 3.88, p = 

0.007), close 

contact to wood 

(OR 3.31, p = 

0.017); not 

associated with 

ether anesthesia, 

vaccination 

(poliomyelitis, 

diphtheria, tetanus, 

influenza), brain 

trauma, childhood 

diet breast fed, diet 

rich in animal fat, 

predominantly 

butter, domestic 

slaughtering, 

unpasteurized milk, 

3 or more eggs per 

week, animal brain, 

often brain 

sausage, dog, cat, 

bird, pig , rats, 

mice, other rodents, 

cattle, within 5 

years before onset 

dog, cat, bird, 

domestic rodents, 

cattle, pigs, 

childhood coal 

heating, wood 

heating, humid flats, 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

53

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

meadows/pasture

s, natural waters, 

forest, close to 

wood)

no sewage system, 

no piped water, 

other frequent 

environments (farm, 

industrial plant, 

fields, natural 

waters, forest)

Mandia, 

201460

retrospective

Italy MS patients 

mean age 45 

(SD 11.0 ) years, 

disease duration 

13.6 (SD 9.1) 

years 

Form N/A, mean 

EDSS 3.0 (SD 

2.4), MSSS 3.2 

(SD 2.6); 

McDonald 2001 

criteria 

MSSS 

score, 

MSSS 1 or 

less (mild) 

vs MSSS 6 

or more 

(severe)

131 Crosssectional

Multiple 

linear 

regression

Smoking (ever, 

never, ex, current 

smoker, 

active/passive 

exposure), 

sunlight exposure 

(frequent vs rare,

> 2h/day vs < 

2h/day, 

sunscreen use), 

diet (vegetarian, 

egg consumption, 

fish consumption, 

consumption of 

dairy products, 

liver consumption, 

vitamin 

supplementation, 

fortified foods) in 

previous 2 years

Age, sex, 

covariates

Severe MS was 

predicted by vitamin 

D (p = 0.001) and sun 

exposure (p = 0.005)

but not smoking or 

diet
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

54

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

McDowell, 

201163

retrospective

US Patients with 

progressive MS, 

mean age 61 

(SD 9.6), 

between 18 and 

65 years old at 

time of onset, 

77% male, born 

and raised in the 

USA, registered 

in the VHA 

Multiple 

Sclerosis 

Surveillance 

Registry

Progressive MS 

(progressively 

worsening from 

symptom onset 

with or without 

any recovery 

from symptoms 

later in the 

course), PP, and 

progressive 

relapsing MS; 

McDonald 

criteria 2001

Time to 

PDDS 8

219 Other

KaplanMeier 

analysis,

log rank 

tests, Cox 

proportion

al hazards 

models

Average 

fall/winter sun 

exposure before 

MS onset, cod 

liver oil intake at 

ages 6-15, fish 

consumption at 

ages 6-15

Age at 

symptom 

onset, MS 

subtype, onset 

symptoms, 

demographics, 

mononucleosis 

before 

symptom 

onset, smoking 

before disease 

onset, type of 

skin

Median time from 

disease onset to 

PDDS 8 was 20 years 

(CI 16, 29) for low 

average fall/winter 

sun exposure 

compared to 29 years

(CI 14, 42) for higher 

exposure; fall/winter 

sun exposure HR 

2.13 (CI 1.20, 3.78, p

= 0.01), cod liver 

intake HR 0.44 (CI 

0.20, 0.96; p = 0.04), 

fish consumption HR 

0.79 (CI 0.45, 1.41; p

= 0.43)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

55

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

Mowry,

201269

prospective

US EPIC cohort (5-

year longitudinal 

MS cohort), 

white MS 

patients over 18, 

with EDSS score

< 8 from MS 

center

MS or CIS; 

McDonald 2001 

criteria,

McDonald 2005 

criteria 

EDSS 

score 

469 Time

series

Multivariat

e 

regression

25 hydoxyvitamin 

D level, smoker at 

baseline (5 years 

earlier)

Age, sex, 

ethnicity, DMT

EDSS was not 

associated with 

smoking at baseline 

(IRR 0.09, p = 0.49) 

but each 10 ng/mL 

higher vitamin D 

level was 

associated with 

lower subsequent 

disability (IRR -

0.047, CI -0.091, -

0.003; p = 0.037)

Teter, 200899

retrospective

US Female MS 

patients age 45 

and older, 

NYSMSC 

registry, mean 

age 54.2 (SD 

7.3), mean 

disease duration 

18 (SD 10.8) 

years

48% progressive 

disease at 

enrolment; 

criteria N/A

EDSS > 6 2935 Crosssectional

Logistic 

regression

Educational 

attainment, sun 

exposure

Age, disease 

duration, MS 

type

Lower educational 

attainment (OR 1.5, 

95% CI 1.2, 2.8) 

and less sun 

exposure (OR 1.8, 

95% CI 1.2, 2.8) 

predict EDSS > 6 

Wallin,

2015105

retrospective

US Gulf War-era MS 

cohort with US 

military service 

between 1990-

2007

Form N/A; 

criteria N/A

Progression 

to DSS 6 

and DSS 7

2691 Crosssectional 

Cox 

proportion

al hazard 

model

Geographic 

location and

occupational 

status at entry to 

the military, 

deployment to a 

war theater

Deployment to a war 

theater , geographic 

location and 

occupational status at 

entry to the military 

were not predictors of 

progression to DSS 6 

and DSS 7
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

56

ID

Assessment 

timing

Region Sample

MS form

Predicted 

outcome

N Design

Analysis

Risk factors Co-variates EDSS results Other results

Weiland, 

2014106,123,124

retrospective, 

concurrent

Australia, 

US, 

Europe

Internet survey, 

adults diagnosed 

with MS by a 

physician

Form N/A, 

physician 

diagnosis

PDDS 

converted 

to normal/

some 

disability, 

gait/ cane 

disability, 

major 

mobility 

support 

2469 Crosssectional 

Multiple 

regression

Alcohol 

(frequency of 

alcohol use, 

amount; nondrinker, low level 

vs high level of 

consumption, 

binge drinking; 

moderate drinking 

[up to 30g/day for 

women, up to 

45g/day for men] 

vs low or no 

alcohol 

consumption);

smoking (current, 

former, or never 

smoker; 

frequency, time

since quitting; 

physical activity; 

meditation 

practice, 

frequency

Gender, age Disability associated 

with moderate alcohol 

consumption (p < 

0.001) and smoking 

status (p < 0.001); 

being a current 

smoker increased 

odds of requiring 

major mobility support 

(OR1.9, CI 1.44, 2.5;

p < 0.001), being a 

former smoker 

associated with 

increased odds of 

1.24 (CI 1.0, 1.5, p = 

0.23) compared with 

never smokers. 

Those with higher 

disability had a lower 

level of physical 

activity and vice versa 

(p < 0.001)

No association 

between those who 

did and did not 

meditate in PDDS 

scores but significant 

association with 

frequency of 

meditation and PDDS 

(more-disabled 

respondents were 

more likely to 

meditate, p < .001)

Note: IRR incidence rate ratio, N/A not available, n.s. not statistically significant, NYSMSC New York State Multiple Sclerosis Consortium, R-R relapsing-remitting, PP primary 

progressive, SP secondary progressive, RR relative risk, vs versus
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

57

The 10 studies that each addressed multiple risk factors of interest were 6 US studies, one which

included the data from the Flemish MS registry, one study which was conducted in Germany, 

one in Italy, and one study which reported on an internet survey which international responders. 

The studies addressed a wide range of potential risk factors such as alcohol, wine, coffee, fish, 

cod liver oil, and fat consumption. Studies also addressed health-promoting nutrition and other 

dietary factors; alcohol-related problems, drug misuse, smoking; vitamin D levels, sun exposure; 

oral contraceptive intake; physical activity; meditation practices, spiritual growth; interpersonal 

relationships; and stress management behaviors. Some studies associated MS progression with 

insurance coverage and treatment-associated factors; latitude and geographic location; and 

deployment to a war theater.

Three studies primarily reported on concurrent data27,43,106 (that is, linking current behavior such 

as current alcohol intake to EDSS scores). Most studies assessed the effects of prior events, 

exposures, or behaviors in retrospective studies.

36,55,63,105,106 60,99 The retrospective study by 

D’hooghe was based on a 2009 survey of people registered in the Flemish MS society, and the 

data were reported in multiple publications focusing on the effects of alcohol, coffee, fish, and 

smoking;36 sunlight exposure;120 and menarche, oral contraceptives, and self-reported health 

promotion behaviors.

122 A German study assessed a catalogue of potential risk factors, ranging 

from exposure to vaccines, childhood diet, exposures to pets and livestock, and environmental 

factors such as living near an industrial plant.55

One prospective study addressed vitamin D levels and smoking. The longitudinal US study 

reported that EDSS scores were not associated with smoking at baseline but each 10ng/mL 

higher vitamin D level was associated with lower subsequent disability.69 The detailed risk of 

bias assessment for this high-quality study is documented in Appendix C.

Summary of Findings and Quality of Evidence

We identified a large number of studies reporting on potential modifiable risk factors for MS 

progression. However, studies assessed very specific risk factors (eg, vitamin D serum level, sun 

exposure in the summer 2 hours or more daily, etc) and predicted very specific outcomes (eg, 

EDSS scores, time to reach EDSS 6, etc). The following summarizes the available evidence for 

individual risk factors across all identified risk factor studies. 

Vitamin D 

Vitamin D and sun exposure-associated variables have been addressed in a large number of 

studies; however, the risk factor analyses used many different approaches, as documented in the 

evidence tables (see Table 1 and Table 7). The following figure summarizes the correlation 

between EDSS scores and the physiological vitamin D level of participants. The figure shows a 

risk factor and outcome measure that was reported in multiple studies that all reported a 

correlation as the measure of association or allowed computing a correlation from the reported 

data. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

58

Figure 2: Correlation between EDSS Score and Vitamin D Level 

Eleven included studies reported a correlation between vitamin D levels and EDSS scores. 

Across all available data, there was a weak negative correlation of -0.22 (CI -0.32, -0.12; 11 

studies) indicating that lower vitamin D levels are associated with higher EDSS scores. All 

individual studies suggested the same direction of effects but not all were statistically significant 

and there was evidence of heterogeneity (I2 66%). We also identified evidence of publication 

bias (regression test p = 0.045, rank test p = 0.087). Using the trim-and-fill method of correcting 

for potentially missing studies, the estimate was slightly lower but still statistically significant (r

= -0.20; CI -0.29, -0.11).

Eight data points in the meta-analysis came from concurrent data analyses, assessing current 

vitamin D level and EDSS scores at the time of data assessment. One retrospective chart review 

also reported an association.95 Of the 2 included prospective studies, one highlighted that there 

was not a statistically significant negative correlation between vitamin D nutrition and EDSS 

progression.

91 However, the finding is likely to be linked to the small sample size; the reported 

correlation is in range with other reported results seen in the forest plot. The other prospective 

study showed higher vitamin D levels to be associated with lower subsequent disability in a 

multivariate analysis.69

An additional prospective study assessing on vitamin D was identified that could not be added to 

the meta-analysis because it reported on other measures of association. The study reported that 

values greater than or equal to 50nmol/L at up to 12 months predicted lower EDSS scores (p = 

0.004).20 

The evidence suggesting a correlation between vitamin D levels and EDSS scores was 

downgraded to only moderate quality of evidence due to indirectness. For this systematic review, 

the correlation between the physiological measures of vitamin D serum or plasma level is an 

indirect outcome. The review evaluated patient-modifiable risk factors, such as exposure, intake, 

or behavioral risk factors. The meta-analysis shows a correlation between the physiological level

and a progression measure and whether the physiological levels can be directly influenced by the 

participant is an unresolved question. We did not identify more than one study reporting on

intake of vitamin D and a measure of MS progression. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

59

Sun Exposure

Five studies reported on sun exposure and MS progression.36,60,63,99,103 All were retrospective 

studies. Four reported a negative association of sun exposure and MS progression or a positive 

association of increasing disability and reduced sun exposure. One reported an association in 

patients with relapsing onset MS but not in progressive onset MS. However, all studies used 

different assessment tools (EDSS, PDDS, and MSSS) and different predictors (time to sustained 

EDSS 6, time to PDDS 8, a score of MSSS 6 or above, odds of reaching an EDSS score greater 

than 6, EDSS scores). Hence it was not possible to estimate the size of the potentially protective 

effect across studies and the quality of the evidence base is currently insufficient for concrete 

effect estimates. 

Sunscreen Use 

Sunscreen use has been addressed in 2 studies.36,60 Both reported no association with MS 

progression but both used different outcome measures (reaching EDSS 6, MSSS scores), 

precluding concrete evidence statements.

Month of Birth

Three studies assessed whether the month of birth was associated with disease progression, often 

hypothesizing this affects the amount of sunshine a newborn is exposed to.39 51,58 One study 

reported on the time from onset to secondary progression, one on progression to EDSS 6, and 

one on MSSS scores. All reported no impact on disease progression but studies did not report on 

the same outcome measure and did not report numerical results other than the statistical 

significance of the association that would allow further analyses. The quality of the evidence 

base was determined to be insufficient for specific evidence statements. 

Smoking

A large number of studies reported on smoking but studies used a variety of operationalizations 

of the risk factor and a range of different outcome measures. The forest plot summarizes the 

studies that reported on disease progression, either operationalized as time to reach EDSS 6, time 

to conversion to secondary progression, or time to progressive disease. The studies compared 

current and/or ever smokers with nonsmokers and/or never smokers. Data are primarily based on 

retrospective data collections.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

60

Figure 3: Time to Progression and Smoking

Across studies we identified an increased risk of faster progression in smokers than nonsmokers 

(HR 1.55; CI 1.10, 2.19; I

2

 72%; 7 studies, 8 datasets). However, there was evidence of 

substantial heterogeneity (that is, unexplained variation in results across studies). A subgroup 

analysis restricting to studies predicting time to secondary progressive MS (rather than 

progression to EDSS 6 or progression in all samples) showed a larger effect estimate, but the 

pooled effect was not statistically significant in this subset and substantial heterogeneity 

remained (HR 1.90; CI 0.73, 4.94; I2 77%; 4 RCTs). There was also evidence of publication bias

(rank test p = 0.179, regression test p = 0.038). A sensitivity analysis computing the trim-and-fill 

method to account for potentially missing studies estimated a smaller effect (HR 1.33, CIs 1.05, 

1.85; 2 estimated missing studies), but nonetheless a still statistically significant effect.

The forest plot includes one out of 4 identified prospective studies.97 The other prospective 

studies could not be added to the meta-analysis because they reported on different measures. 

These studies reported conflicting results: one found no association between smoking status at 

baseline and EDSS scores over a period of 5 years (incidence rate ratio [IRR] 0.09; -0.17, 0.36)69

while another one found baseline smoking status to be a predictor of physical disability after 6 

years.112 The third reported that the cumulative cigarette pack-years smoked after cohort entry 

was associated with an increase in longitudinal MSSS scores (p < 0.001).76

The body of evidence regarding an effect of smoking on the risk of progression was downgraded 

to moderate evidence quality due to unexplained heterogeneity in effect estimates across studies 

(inconsistency). 

Diet

Evidence on dietary regimen was sparse and lacked detail.21,36,38,54,60,63,98 We did not identify 

more than one study reporting on the same diet or diet variable except fish consumption (see 

below). Studies addressing fat consumption did not report on the same outcome measure. Results 

across individual studies varied, with some studies showing associations with MS progression, 

others not; and results also varied within studies (comparing relapsing and progressive onset 

MS).36
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

61

The only identified prospective study reported on the Swank diet for MS patients and showed 

that for poor dieters, operationalized as participants with an intake of more than 20g fat per day, 

the average worsening significantly exceeded those of the good dieters, but the size of the effect 

was not reported.98 The quality of the evidence base was judged to be insufficient overall.

Fish Consumption

Fish consumption specifically, which is associated with vitamin D as well as fatty acid intake, 

has been evaluated in 3 studies: the Flemish registry survey, a study in patients with progressive 

MS registered in the VHA Multiple Sclerosis Surveillance Registry, and an Italian cohort.

36,60,63

The studies differed in risk factor timing (current; in the last 2 years; intake as a child) and used 

different outcome measures. The existing retrospective studies reported conflicting results with 

regard to the presence or absence of a negative association with MS progression. The quality of

evidence was determined to be insufficient for specific evidence statements.

Alcohol 

Alcohol consumption or alcohol misuse has been addressed in 5 studies in total.

27,36,38,43,106

Possible alcohol-related problems,27 moderate duration of alcohol use after MS onset (15 years 

or less as compared to those who did not consume alcohol or consumed it for more than 15 

years),38 higher levels of alcohol consumption (using a 5-point scale ranging from never to 

daily)43 have been associated with lower EDSS score categories, that is less disability in 

participants consuming alcohol, in 3 identified studies. One study found an association of alcohol 

consumption (compared to no consumption) with a reduced risk to reach EDSS 6 in relapsing 

MS patients but not in patients with progressive onset MS.36 One study found that engaging in 

moderate alcohol consumption (up to 30g/day for women, up to 45g/day for men) compared to 

low or no alcohol consumption was associated with reduced odds of increased disability based 

on the PDDS (OR 0.59, p < 0.001).

No prospective study exists, and the identified studies reported predominantly on concurrent 

associations (measuring current intake and current disability status). We did not identify more 

than one study reporting on the same operationalization of alcohol consumption and the same 

progression or disability measure; hence, the quality of evidence was insufficient for effect 

estimates across studies.

Exercise

Although a handful of studies on physical exercise is available, we did not identify more than 

one study reporting on the same specific exercise variable and the same measure of MS 

progression.

36,43,62,64,68,87,96,123 All identified studies reported an association between exercise and 

EDSS score or another measure of progression or disability, but the direction of effects varied by 

study design.

Only 2 identified studies were prospectively analyzed, predicting later progression from baseline 

physical activity.68,96 Both highlighted the possible role of premorbid or baseline physical 

activity on future progression. Neither reported on the primary outcome of the review. One 

reported that premorbid physical activity statistically significantly predicted the linear change in 

PDDS scores in patients with relapsing-remitting MS and emphasized the possible role of 

physical activity for lessening disability progression.

68 The other reported that baseline exercise 

scores were negatively correlated with the annual change rate in functional limitations assessed 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

62

with a self-reported incapacity status scale and discussed the potential positive impact of exercise 

on MS progression.

96 The overall quality of evidence was determined to be insufficient for 

concrete evidence statements, given the differences in outcome and predictor measures.

Trauma

Two studies addressed exposure to brain trauma.

55,89 Both reported that it is not a risk factor for

MS progression, but studies used different outcome measures (mean increase in DSS per year, 

benign MS defined as DSS equal or lower than 2 after 11 or more years of MS duration). No 

concrete evidence statement could be formulated for an individual outcome that has been shown 

in more than one study.

Epidural Analgesia

The association with MS progression and epidural analgesia has been addressed in 3 studies, 

including 2 prospective and one retrospective study.

30,57,72 None reported a statistically 

significant association with EDSS or DSS scores. We did not identify studies that reported on the 

change to secondary progression.

The quality of the evidence for the statement that epidural analgesia does not affect progression 

was downgraded due to phase of investigation and imprecision. The risk factor was identified in 

exploratory, not confirmatory, studies and the point estimate of the association was not reported 

in either study. Hence, the strength of association is not known (studies only reported the 

statistically significance of the association).

Oral Contraception

Three studies reported on oral contraceptive use with conflicting results within and across 

studies.

36,40,57 The Flemish registry survey reported that use of oral contraceptives was related to 

an increased risk of reaching EDSS 6 in progressive but not in relapsing onset MS.36 A second 

study reported that patients who had used combined oral contraceptives continuously for at least 

one year had lower EDSS scores compared to never users, indicating a protective effect.

40 A 

third study reported that women who started oral contraceptives after disease onset had lower 

EDSS scores than both never users and past users. A benign disease course was predicted by 

current oral contraceptive use compared to never or past users.85 Given that none of the studies 

compared an identical combination of risk factor and outcome measure operationalization, the 

quality of evidence was determined insufficient for concrete evidence statements.

Geographic Region

Two studies addressed geographic regions but in different operationalizations (eg, high vs low 

MS prevalence areas; geographic region of military personnel at entry to the military) and studies 

used different outcome measures (3-point scale differentiating walking without aids, walking 

with aids, and restricted to wheelchair; progression to DSS 6 and DSS7).35,105 Only one of the 

studies reported an association; progression to a non-ambulatory status or death was significantly 

greater among patients who lived in Los Angeles County (a low-prevalence area). The different 

outcome measures, risk factor operationalizations, and conflicting results cannot be combined to 

a concrete evidence statement.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

63

Education 

Two studies investigated an association between education and MS progression.22,99 Both studies 

were retrospective analyses, they reported on EDSS greater than 6 or MSSS scores, and they 

reported conflicting results. One study assessing MSSS did not find that education predicted 

getting statistically significantly worse in a sample of 338 patients, the other one reported that 

lower educational attainment predicted EDSS scores above 6 (OR 1.5; CI 1.2, 2.8). Given the 

lack of replication on outcome measures and the conflicting results, the quality of evidence was 

rated insufficient.

Other Factors

All other factors have been addressed in only one of the included studies and have not been 

replicated yet. The study details together with the results are shown in the evidence tables. 

KQ1 Summary

The summary of findings table documents the available evidence for specific risk factors and 

specific outcome measures that were reported in more than one study. We did not include results 

that were based on a single study without replication by another, independent author group, 

given the complexity of epidemiological data collection. 

Results (strength and statistical significance of the association) for EDSS scores and for other 

MS progression-relevant findings were summarized across studies. For each outcome, the 

GRADE summary is documented. The summary of findings tables is organized by outcome and 

where outcomes were not identical or not compatible across studies, no effect estimate could be 

determined and the evidence was consequently graded as insufficient for concrete evidence 

statements. The table shows the presence and the absence of associations, and factors delaying as 

well as hastening progression have been considered.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

64

Table 8. Summary of Findings for KQ1 

Risk factor and 

Outcome 

measure

Study Design, 

# of Studies

EDSS Findings: 

Direction, Magnitude of 

Effect

Other Progression 

Findings: Direction, 

Magnitude of Effect 

GRADE 

Vitamin D

Correlation 

25(OH)D level 

and EDSS

8 concurrent, 1 

retrospective, 1 

prospective 

study 

Weak correlation (r -0.22; 

CI -0.28, -0.10) indicating 

lower levels of vitamin D 

are associated with higher 

EDSS scores

Moderate

(indirect)* 

Sun Exposure

No outcome 

assessed in > 1 

study

5 retrospective 

studies

N/A (see text) N/A Insufficient

Sunscreen Use

No outcome 

assessed in > 1 

study

2 retrospective 

studies

N/A (see text) N/A Insufficient

Month of Birth

No outcome 

assessed in > 1 

study

3 retrospective 

studies

N/A (see text) N/A Insufficient

Smoking

Risk of 

progression 

comparing 

smokers and 

nonsmokers

6 retrospective, 

1 prospective 

study 

N/A Smoking is associated 

with an increased risk 

of progression (HR 

1.55; CI 1.10, 2.19) 

Moderate

(heterogeneity)*

Diet

No outcome 

assessed in > 1 

study

2 concurrent, 4 

retrospective, 1 

prospective 

study

N/A (see text) N/A Insufficient

Fish Consumption

No outcome 

assessed in > 1 

study

3 retrospective 

studies

N/A (see text) N/A Insufficient

Alcohol-related Variables

No outcome 

assessed in > 1 

study reporting on 

the same 

operationalization

3 concurrent, 2 

retrospective 

studies

N/A (see text) N/A Insufficient

Exercise

No outcome 

assessed in > 1 

study

2 retrospective, 

3 prospective 

studies

N/A (see text) N/A Insufficient

Trauma

No outcome 

assessed in > 1 

study

2 retrospective 

studies

N/A (see text) N/A Insufficient

Epidural Analgesia
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

65

EDSS scores 2 prospective 

studies, 1 

retrospective 

study 

2 studies showed no 

association with EDSS 

scores (sign. N/A) or 3 

EDSS score categories (p

> 0.1)

One study showed no 

statistically significant 

association with EDSS 

or DSS (p = 0.66)

Low

(exploratory, no 

point 

estimate)**

Oral Contraception

No outcome 

assessed in > 1 

study

3 retrospective 

studies

N/A (see text) N/A Insufficient

Geographic Region

No outcome 

assessed in > 1 

study

1 retrospective, 

1 prospective 

study

N/A (see text) N/A Insufficient

Education

No outcome 

assessed in > 1 

study

2 retrospective 

studies

N/A (see text) N/A Insufficient

Note: The table only shows risk factors that were reported in more than one study; * quality of evidence downgraded 

by 1 level, ** quality of evidence downgraded by 2 levels

KEY QUESTION 2: What environmental exposures prior to or during 

military service are related to multiple sclerosis progression following 

onset symptoms?

Despite the extensive search, very few relevant studies were identified. In addition, only some of 

the studies addressed environmental exposures during military service. The remaining studies 

addressed other factors in samples of Veterans.

One of the studies has been presented in the context of diet risk factors (evidence table 4). The 

study evaluated MS in men on active duty in the US Army. It reported on the disease course for 

patients that were put on a specific diet in the hospital, compared to patients without 

administration of a specific therapy.54 The reported data were not statistically significantly 

different between groups. However, no information was available on the specific diet and 

approaches may have varied across patients and hospitals. 

A second study focused on disability and treatment patterns of MS patients in Veterans and nonveterans. The concurrent study reported that VHA Veterans had statistically significantly higher 

PDDS scores than non-veterans.104 More information is presented in table 6, the evidence table 

summarizing “other” MS progression risk factors. 

Two additional studies reported on multiple risk factors of interest and are shown in more detail 

in evidence table 7. One study reported on a Gulf War-era MS cohort which includes 2,631 

patients.105 The study reported that deployment to a war theater, geographic location, and 

occupational status at entry to the military were not predictors of progression to DSS 6 and DSS

7. The study was reported in a conference abstract and data on the exact point estimate and 

measure of dispersion were not available.

The fourth study addressed vitamin D exposure and reported on the average fall/winter sun 

exposure before MS onset, cod liver oil intake as a child (ages 6 to 15), and fish consumption 

between the age of 6 and 15.63 The study reported on 219 Veterans with progressive MS 

registered in the Multiple Sclerosis Surveillance Registry. The study used the PDDS to assess 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

66

progression and predicted hazard ratios for the time to reach a PDDS score of 8 from disease 

symptom onset. This stage indicates that a wheelchair or scooter is the main form of mobility. 

The study reported low average sun exposure in the fall/winter before disease onset was 

associated with an increased risk of progression (HR 2.13; CI 1.20, 3.78) and cod liver oil during 

childhood and adolescence was associated with a reduced risk (HR 0.44; CI 0.20, 0.96). Fish 

consumption was not statistically significantly associated with PDDS progression in this sample. 

The study concluded that exposure to vitamin D before MS onset may slow disease-related 

neurodegeneration and thus delay progression to disability in patients with progressive MS.

Summary of Findings and Quality of Evidence for Key Question 2

The summary of findings table showing KQ2 evidence is grouped by exposures prior to or post 

military service and exposures during military service. All studies relevant to KQ2 also 

contribute to KQ1 and were already included in KQ1 evidence statements.

Table 9. Summary of Findings for KQ2

Risk Factor Study Design, # 

of Studies

EDSS Findings: 

Direction, 

Magnitude of 

Effect

Other Progression Findings: 

Direction, Magnitude of Effect GRADE 

Prior or Post Military Service in Veterans

Geographic 

location at entry 

to the military

1 retrospective 

study, N = 2631

N/A Geographic location was not a 

predictor of progression to DSS 6 

and DSS 7 (magnitude of effect N/A)

Insufficient

Occupational 

status at entry 

to the military

1 retrospective 

study, N = 2631

N/A Status was not a predictor of 

progression to DSS 6 and DSS 7 

(magnitude of effect N/A)

Insufficient

Average 

fall/winter sun 

exposure before 

MS onset

1 retrospective 

study, N = 219

N/A Low sun exposure was associated 

with faster progression (HR 2.13; CI 

1.20, 3.13)

Insufficient

Cod liver oil 

intake at ages 

6-15

1 retrospective 

study, N = 219

N/A Cod liver oil intake was associated 

with slower progression (HR 0.44; CI 

0.20, 0.96)

Insufficient

Fish 

consumption at 

ages 6-15

1 retrospective 

study, N = 219

N/A No statistically significant association 

with progression (HR 0.79; CI 0.45, 

1.41)

Insufficient

Exposure During Military Service

Deployment to 

a war theater

1 retrospective 

study, N = 2631

N/A Deployment to a war theater was not 

a predictor of progression to DSS 6 

and DSS 7 (magnitude of effect N/A)

Insufficient

Being a Veteran 1 concurrent 

study; N = 2150

N/A VHA Veterans had higher PDDS 

scores than non-veterans (p < 0.001)

Insufficient

Diet in hospital 1 retrospective 

study, N = 517

N/A Diet group: 28% better, 56% the 

same, 16% worse; patients with 

hospital routine without specific 

treatments: 19% better, 74% same, 

8% worse (p = 0.131)

Insufficient

Note: N/A not reported, not available

None of the identified studies were prospective studies, which allow more confident 

interpretations of associations. In addition, all associations were based on only one study, and 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

67

without any replication in independent studies, the available evidence was graded as insufficient.

Some of the factors shown in this summary of findings table were uniquely addressed in the 

KQ2-relevant studies, such as deployment. Other investigated factors, such as sun exposure,

have been addressed in other studies documented in the KQ1 evidence synthesis; however, the 

exact operationalization of the factors, for example sun exposure during childhood and teenage 

years, also has not been replicated in other available studies by independent author groups.

KEY QUESTION 3: Among identified risk factors for progression, what 

treatment/risk factor modification therapies have been shown to delay 

or hasten the progression of MS once it has initiated?

We identified a substantial number of intervention evaluations; however, they addressed only a 

small range of interventions. Despite the comprehensive search and inclusive inclusion criteria, 

all identified studies evaluated either vitamin D supplementation, exercise interventions, or 

dietary interventions.

Details of included studies contributing to KQ3 are presented in 3 evidence tables in the 

following text.

The largest group of interventions addressed physical exercise. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Table 10: Evidence for KQ3: Effects of Exercise Interventions on MS Progression

ID, Trial 

type§

N

Power

Participants Intervention Co Comparator EDSS results Other results AE

Armutlu, 

200119

26

No power 

calculation

Patients with ataxic MS, 

intervention group mean age 

32.61 (23-44), 9 female, 4 male, 

EDSS 4.53 (3.5-5.5); control 

group mean age 34.61, (range 

26-45), 7 female, 6 male; PP and 

SP; Poser criteria

Neuromuscular 

rehabilitation with 

pressure splints, 3x /

week for 4 weeks

Neuromuscular 

rehabilitation 

alone

Significant 

improvements in 

EDSS scores in both 

groups, no difference 

between groups (p > 

0.05)

N/A

Bjarnadott

ir, 200726

16 (6 

treatment, 

10 control)

No power

calculation

Patients with mild MS aged 18-

50 years with definite MS and 

EDSS < 4, and with the ability to 

ride a stationary bicycle; mean

age 38.7 vs 36.1, mean EDSS 

2.1 vs 1.8, mean duration of MS 

8.7 vs 8.3 years; Poser criteria

Training 3x / week 

for 5 weeks or a total 

of 15 hours; aerobic 

exercise, resistance 

exercise and 

stretching and 

relaxation

No treatment No change in EDSS 

was detected and 

groups did not differ 

in pre-post difference 

(-0.07, CI -0.7, 0.61)

1 patient in each 

group developed 

a relapse and 

was withdrawn, 

transient increase 

in symptoms was 

not observed

Carter, 

2013125

28

No power

calculation

Patients with MS, mean age 40 

years (24-49) with mild to 

moderate EDSS = < 5.5; 

treatment vs usual care: female 

87.5% vs 85.7%, mean age 39.5 

(SD 6.5) vs 40.9 (SD 8.7), mean 

EDSS 3.0 (SD 1.1) vs 3.1 (SD 

1.7); McDonald 2010 criteria

10 week pragmatic 

exercise intervention 

(2 supervised and 1 

home-based session

/ week) 

TAU Lower EDSS scores 

in intervention group 

after 10 weeks (p = 

0.07) and 3 months 

post-intervention (p = 

0.48) compared to 

control

N/A

Conklyn, 

201031

10

No power 

calculation

Adult MS patients with gait 

disturbance, able to walk 100 

feet without physical assistance; 

treatment vs control: mean age 

47 (SD 10.51) vs 50.2 (SD 5.45), 

60% vs 80% female, relapsingremitting 80% vs 60%, SP 0% vs 

40%, primary progressive 20% 

vs 0%; criteria N/A

2 week Rhythmic 

Auditory Stimulation

No treatment No statistically 

significant 

changes in 

PDDS scores

N/A
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID, Trial 

type§

N

Power

Participants Intervention Co Comparator EDSS results Other results AE

Dalgas, 

200932

cross-over

38

Power

unclear

Moderately impaired patients 

with MS, treatment vs control: 

female 10/16 vs 10/15, mean age 

49.1 vs 47.7, mean EDSS 3.9 vs 

3.7, mean time since diagnosis 

8.1 vs 6.6; McDonald 2001 

criteria 

Biweekly 12-week 

lower extremity 

progressive 

resistance training 

program, 

participants 

encouraged to 

continue training 

afterwards

No treatment EDSS remained 

unchanged in both 

groups

N/A

DeBolt, 

200434

36 (19 

treatment, 

17 control)

No power 

calculation

Healthy adults with MS and the 

ability to walk (with or without 

assistive devices) at least 20m 

without rest, EDSS scores 

ranged from 2 to 6, 29 women 

(mean age, 50.3, SD 8.5) and 8 

men (mean age 51.1, SD 7.1); 

criteria N/A

Home-based 

resistance exercise 

(8-week)

No treatment No significant 

differences between 

groups after 

intervention (p = 

0..552)

N/A

Fimland, 

201037

14

No power 

calculation

Maximal strength training vs 

control group: female 75% vs 

75%, mean age 53 vs 54, mean 

EDSS 4.6 vs 3.5, years since 

diagnosed 8 vs 8; criteria N/A

A rehabilitation 

program, maximal 

strength training 

using high loads and 

few repetitions, 5 

days/wk for 3 wks

No treatment No changes were 

observed for the 

EDSS between 

groups.,scores 

remained unchanged 

in all participants

No adverse 

effects

Golzari, 

201042

20

No power 

calculation

Women from MS society and 

clinic, age 20-50, with clinically 

diagnosed R-R and EDSS 0-4; 

exercise vs control: mean age 

32.5 (SD 7.57) vs 33.75 (SD 

8.18), mean EDSS 2.14 (SD 

1.06) vs 1.96 (SD 1.06); criteria 

N/A

Combined exercises

for 24 sessions 

during 8 wks; 1-hour 

session with warmup, stretch, aerobic, 

endurance, and 

resistance training, 

and relaxation

No treatment Score was decreased 

in intervention group 

8 weeks after training 

(p < 0.43) but not 

control group

N/A

Lo, 200856

cross-over

13

No power 

calculation

R-R, SP, and PP MS patients, 

mean age 49.8 (SD 11.1), EDSS 

4.9 (SD 1.2), female 6/13, R-R 

8/13, PP 5/13; McDonald 2001 

criteria 

Body weight 

supported treadmill 

training with or 

without robotic 

assistance training 

sessions, 2/week for 

3 weeks, a total of 6 

sessions of 40 mins

Reversed 

treatment order

Significant 

improvement in EDSS 

scores in both groups: 

-0.83 (SD 0.61, p = 

0.06) and -1.1 (SD 

0.7, p = 0.03)

No adverse 

events occurred
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

70

ID, Trial 

type§

N

Power

Participants Intervention Co Comparator EDSS results Other results AE

Miller, 

201166

30

Insufficient 

power

Patients with PP or SP MS and 

EDSS scores 6.5-8; intervention 

vs control: 26.7% vs 46.7% 

female, mean age 56.3 vs 52.9, 

time since diagnosis 13 vs 18.7, 

EDSS 7 vs 7.1; definitive 

diagnosis, criteria N/A

8 week 

physiotherapy

TAU EDSS: no interaction 

effect over time (p = 

0.803) or group effect 

(p = 0.074) 

None

Petajan, 

1996126

46

No power 

calculation

Ambulatory MS patients recruited 

through MS society and 

physician referrals, exercise vs 

non-exercise: female 71.4% vs 

76%, mean age 41.4 (SD 2) vs 

39 (SD 1.7), EDSS 3.8 (SD 0.3) 

vs 2.9 (SD 0.3), years since first 

symptoms 11.6 (SD 1.7) vs 10.5 

(SD 1.6), years since diagnosis 

9.3 (SD 1.6) vs 6.2 (SD 1.1); 

Poser criteria

15 weeks aerobic 

training with 3 

supervised training 

sessions per week 

(5 minute warm-up, 

30 mins at 60% 

maximum aerobic 

capacity, 5 min 

cooldown)

No treatment Overall EDSS scores 

did not change (-0.1 

in exercise group, -

0.1 in nonexercise 

group)

N/A

Pfalzer, 

201175

39

No power 

calculation

Ambulatory patients with 

clinically diagnosed MS; 22 with 

R-R, 5 SP, 5 PP, 3 PR, 4 

unknown; clinically diagnosed, 

criteria N/A

Home-based 

exercise training (10 

weeks)

No treatment Intervention: EDSS 

mean 4.3 (SD 1.9, 

improvement pretestposttest 0.2 (0.7)), 

Control: 3.7 (SD 1.6); 

pre-post 0.5 (SD 1.2) 

post-intervention

2 dropped out 

due to medical 

illness unrelated 

to MS

Rampello, 

200779

cross-over

19

No power 

calculation

Patients aged 20-55 years with 

MS on waiting list for 

rehabilitation program with EDSS 

< 7; treatment vs control: mean 

age 44 vs37, female 8/11 vs 6/8, 

mean disease duration 6 vs 10 

years, mean EDSS 3.5 vs 3.25; 

Poser criteria

Aerobic training (8 

weeks)

Other: 

neurological 

rehabilitation

No change over time 

was found in EDSS (p

= 1.0)

2 dropped out

due to perception 

of breathlessness 

and fatigue
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID, Trial 

type§

N

Power

Participants Intervention Co Comparator EDSS results Other results AE

Romberg, 

200481

cross-over

114

Sufficient 

power

Patients aged 30-55 with definite 

MS and EDSS -5.5; exercise vs 

control: female 30/47 vs 41/48, 

mean age 43.8 vs 43.9, mean 

years after 1st symptoms 9.7 vs 

9.6, mean years after diagnosis 

6.0 vs 5.5, mean EDSS 2.0 vs

2.5; Poser criteria

Strength and aerobic 

training initiated 

during 3-week 

inpatient 

rehabilitation and 

continued for 23 

weeks at home

TAU No change (p = 0.93) 

over time in EDSS

No exerciserelated injuries; 5 

relapses in 

intervention 

group and 6 in 

control group in 9 

patients

Sangelaji, 

201483

147

Power

unclear

MS patients, EDSS score 0-4; 

criteria N/A

Aerobic, 

strengthening, 

balancing, and 

stretching exercises 

(10 weeks)

No treatment No significant 

changes in EDSS at 

any follow-up, but 

both control and 

intervention increased 

EDSS scores at 1-

year follow-up 

(intervention: 0.5 

points, p = 0.001; 

control: 0.72 points, p

= 0.001)

1 dropped out 

due to muscular 

pain in cuff 

muscles, 1 due to 

new attack and 

nonresponding 

symptoms

Schwartz, 

201284

32

Insufficient 

power

MS patients with chronic 

progressive pattern or relapsingprogressive with no relapse for 3 

months (RP, SP, and PP); robotassisted vs conventional: female 

41% vs 43%, mean age 50.5 (SD 

11.5) vs 46.8 (SD 11.5), disease 

duration 14.9 (SD 8.1) vs 11.3 

(SD 6.7), EDSS 6 (SD 0.6) vs 6.2 

(SD 0.5); McDonald 2001 criteria

12 sessions of robotassisted gait training 

(gait orthosis) or 

conventional walking 

treatment 2-3 times 

a week (30 min net 

treatment) for 4 

weeks

Conventional

walking 

treatment

EDSS scores 

improved significantly 

post-treatment with 

no difference between 

the groups; mean 

changes in EDSS 

robot-assisted vs 

conventional postintervention: -0.29 

(SD 0.4) vs -0.31 (SD 

0.3); at 3 months 

-0.22 (SD 0.4) vs 

-0.27 (SD 0.3); at 6 

months -0.21 (SD 0.4) 

vs -0.25 (SD 0.4)

N/A
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID, Trial 

type§

N

Power

Participants Intervention Co Comparator EDSS results Other results AE

Solari, 

199992

50

Sufficient

power

MS patients aged 18-65, EDSS 

3-6.5, mean EDSS 5.5; treatment 

vs control: 63 vs 48% female, 

mean age 44.6 (SD 10.2) vs 44.9 

(SD 10.9), R-R 22.2 vs 21.7%, 

PP 14.8 vs 17.4%, SP 63 vs 

60.9%; clinically definite or 

laboratory-supported MS

3 week inpatient 

physical therapy

Exercise at 

home

No changes in 

impairment occurred 

in either group (EDSS 

scores)

N/A

Wiles, 

2011109

cross-over

42

Power

unclear

MS patients with walking 

difficulties, able to walk 5 meters 

without any physical assistance, 

mean age 47.2 (28.2-68.8), 

35.7% female, mean duration of 

disease onset 4.4 (SD4.6); Poser 

criteria 

Allocation to one of 

6 permutations of 

three 8-week 

treatment periods 

separated by 8-week 

intervals: 

physiotherapy at 

home or no therapy

No treatment Effects favored 

hospital- or 

home-based 

therapy over no 

therapy

N/A

Notes: AE adverse events, Co co-intervention, N/A not available, TAU treatment as usual, R-R relapsing-remitting, PP primary progressive, SP secondary progressive, vs versus

§ All studies are RCTs unless otherwise noted.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

73

The 18 studies tested a range of physical interventions, including aerobic exercise, resistance 

training, physiotherapy, or rehabilitation with maximal strength training. Settings were homebased or rehabilitation centers. The majority of studies compared the program to no treatment; 3

studies compared to treatment as usual.

29,66,81 Two studies assessed the comparative effectiveness 

of a robot-assisted intervention84,56 and one the effect of adding pressure splints to the training.19

The training duration ranged from 2 to 26 weeks. 

Studies enrolled between 10 and 147 participants. The majority of included studies was small 

and did not report a statistical power calculation. Four studies reported a power calculation but 

for a different outcome than MS progression or disability scores.32,81,83,109 Two studies reported 

that power was insufficient even for the primary outcome.66,84 Only one study took EDSS scores 

into account for the power calculation; the study reported no changes in impairment occurred in 

either group after 3-week inpatient physical therapy or exercise training at home.92

The identified studies were primarily in patients with mild MS who were ambulatory. However, 

2 of the included studies were specifically designed to test the comparative effectiveness of 

robot-assisted gait training compared to conventional walking treatment or adding pressure 

splints to the training in patients with progressive MS; EDSS scores improved in both 

intervention arms.

19,84

All included studies reported on disability of MS measured by the primary outcome of this 

review – EDSS scores. However, in none of the studies was MS progression a primary outcome,

and only selected studies reported EDSS assessments to be a secondary outcome42,74,75,83,84 to 

evaluate the intervention. Given the short duration of the intervention, many studies reported no 

substantial changes in EDSS levels after the intervention. 

Half the studies did not report on adverse events. Reported adverse events were relapses,26,81,83

breathlessness and fatigue,79 muscular pain,83 and unrelated illnesses.75 Two studies assessed 

adverse events and reported that none occurred.37,56

The risk of bias assessment for the identified studies is shown in Appendix C. Performance bias 

was a prominent source of bias in the identified interventions because blinding of participants 

and personnel was not possible given the nature of the intervention. In addition, only selected 

studies ensured that the outcome assessors were blind to the treatment condition. Two studies, 

Fimland et al and Petajan et al, had noticeable imbalanced samples at baseline, with intervention 

patients that had higher EDSS scores than the control group.37,127 While the internal validity of 

included studies varied, several studies were not particularly suitable to assess the outcome of 

interest due to the short duration of the intervention. Only 11 out of 18 studies reported on an 

intervention with a duration of 2 months or more.29,32,34,42,66,74,75,79,81,83,109

The second group of intervention studies reported on dietary interventions. The details of 

included RCTs are shown in the following evidence table.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Table 11: Evidence for KQ3: Effects of Dietary Interventions on MS Progression

ID, Trial 

type§

N

Power

Participants Intervention Co Compara

tor 

EDSS results Other results AE

Bates, 

197724

152

No power

calculation

Patients with chronic 

progressive nonrelapsing MS; criteria 

N/A

Group A: 8 capsules of 

360mg linolenic and 3-

42 g of linoleic acid 

daily; group B: placebo 

capsules (oleic acid 

oil); group C received 

11.5 g/day of linoleic 

acid spread; group D 

placebo spread (oleic 

acid) for [presumably] 

24 months

Placebo No statistically 

significant difference 

between groups in 

the number of 

patients who 

improved, 

deteriorated, or 

remained unchanged

N/A

Bates, 

197825

cross-over

116 (29 for 

each of 4 

groups)

No power 

calculation

Patients with remitting 

MS; Group A vs B, C 

vs D: female 19/29 vs 

19/29, 24/29 vs 18/29; 

mean age 35 vs 32, 34 

vs 33; mean duration 

of disease 7 vs 6, 7 vs 

6; criteria N/A

Group A: 8 capsules 

daily (2 92g linoleic 

acid, 0 34g gammalinolenic acid); Group 

B: 8 similar capsules 

(4 g oleic acid, 

control); Group C: 23g 

linoleic acid daily in a 

spread; Group D: 16g 

oleic acid in a spread 

(control) for 

[presumably] 24 

months

Placebo After 2 years, the 

number of patients 

who had deteriorated 

(DSS and additional 

assessment) in 

intervention group A 

was significantly 

greater than that in 

the control group B 

(p < 0.05)

N/A

Bates,

198923

multicenter

312

No power 

calculation

Patients aged 16-45 

years with definite MS, 

suffered at least 2 

relapses with 1 during 

last 24 months, EDSS

=< 6.0, treatment vs 

control: female 

102/155 vs 109/157, 

mean age 34 vs 33, 

mean duration of 

disease 6.5 vs 6.6; 

McDonald & Halliday 

criteria

20 capsules of 0.5 g of 

omega-3 fatty acid 

(1.71 g C20:5 and 1.14 

g C22:6 per day) for 

[presumably] 24 

months

Placebo Intervention: 51% better, 

43% worse, 1 patient 

died; placebo (olive oil): 

41% better, 52% worse, 

no deaths (difference p = 

0.07)

1 patient died
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID, Trial 

type§

N

Power

Participants Intervention Co Compara

tor 

EDSS results Other results AE

Harbige, 

200744

36

No power 

calculation

Patients with active 

MS; international MS 

criteria 

High or low dose of 

gamma-liolenic acid 

(18:3n-6)-rich borage 

oil (high in sn-2 GLA, 

low in monoenes, 

natural levels of 

vitamin E) for 18 

months

Placebo High-dose treatment 

significantly reduced 

disability progression 

(EDSS) compared with 

placebo and low dose 

treatment (no numerical 

results) 

N/A

Millar, 

197365 87 (36 treatment, 

39 control)

No power 

calculation

MS patients, treatment 

vs control: mean age 

37.8 vs 35.5, female 

56% vs 64%, average 

age at onset 38 vs 36, 

mean duration of 

symptoms before entry 

7.7 vs 9.2, mean 

disability score 2.9 vs 

2.7; criteria N/A

Linoleate 

supplementation (30 

ml sunflower seed oil, 

8-6g of linoleic acid, 

2/day) for 2 years

Placebo Placebo (olive oil) 

deteriorated from 2.7 

to 3.3 at the end of 

the trial, treatment 

group from 2.9 to 3.1 

(n.s.)

N/A

Pantzaris, 

201371

80 (20 each 

in 4 groups)

No power 

calculation

R-R patients aged 18-

65 years, EDSS 0-5, 

with at least 1 

documented clinical 

relapse; McDonald 

criteria 

Intervention A: omega3 and omega-6 

polyunsaturated fatty 

acids at 1:1 wt/wt; 

Intervention B: 

combination of A and 

gamma-tocopherol; 

intervention C: 

gamma-tocopherol; 

Control: placebo (olive 

oil).; 19.5 ml / day for 

30 months

Placebo The cumulative 

probability of progression 

of EDSS with 1 point 

increase at 2 years was 

10% in the combination 

group and 35% in the 

placebo group (p = 

0.052), adjusted HR 

0.22 (CI 0.04, 1.07; p = 

0.06))

No significant AE, 

nausea N = 2, no 

abnormal values 

in biochemical 

and blood tests, 

no allergic 

reactions
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

76

ID, Trial 

type§

N

Power

Participants Intervention Co Compara

tor 

EDSS results Other results AE

Paty, 

197873

96

No power 

calculation

Patients with definite 

MS, ambulatory (either 

on their own or with 

ambulatory aids); 

treatment vs control: 

mean age 45 for both, 

mean age onset 32 vs 

30, duration of disease 

13 vs 16, mean DSS 

4.24 vs 4.26; 

Schumacher criteria

Linoleic acid (1 oz, 

2/day, sun flower seed 

oil, 66.2% linoleic acid) 

for 30 months

Placebo Final disability scale 

score for intervention 

vs placebo (olive oil): 

3.52 vs 3.85, 

changes from 

baseline: -0.72 vs -

0.41 (n.s.)

N/A

RamirezRamirez, 

201378

50

Power

unclear

Patients with R-R, at 

least 1 relapse in year 

before, EDSS score 0-

5, treated with 

interferon beta-1b; 

intervention vs 

placebo: female 17% 

vs 18%, mean age 35 

(SD 7.6) vs 35 (SD 

7.8), mean EDSS 2.1 

(SD 0.98) vs 2.06 (SD 

0.84), years with 

disease 7.1 (SD 4.8) 

vs 6.7 (SD 6.7); 

McDonald 2005 

criteria

Fish oil (4 g/day, 0.8g 

EPA, 1.6g DHA, and 

excipient) for 12 

months

Interferon 

beta-1b

Placebo EDSS changes from 

baseline to 12 months: 

0.1 in intervention, 0.2 in 

placebo group (group 

differences n.s.)

No serious 

adverse effects; 

no changes in 

liver and renal 

tests, platelets, 

blood count, 

bleeding; fishy 

taste; < 5% 

reported nausea, 

stomach pain, 

diarrhea
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID, Trial 

type§

N

Power

Participants Intervention Co Compara

tor 

EDSS results Other results AE

RezapourFirouzi, 

201380

100

No power 

calculation

R-R; group A vs B vs 

C: mean age 34.2 (SD 

7.5) vs 35.9 (SD 7.8) 

vs 33.7 (SD 7.8); 

average age at onset 

25 (SD 7.5) vs 30.3 

(SD 8.1) vs 27.6 (SD 

6.4); disease duration 

6.23 (SD 3.9) vs 7.55 

(SD 5.08) vs 6.6 (SD 

4.0); female 69.6% vs 

50% vs 75%; baseline 

EDSS 2.76 (SD 1.39) 

vs 3.45 (SD 1.41) vs 

3.25 (SD 1.9); criteria 

N/A

Group A: hemp seed 

and evening primrose 

oils with Hot nature 

diet (foods with Hot 

nature; low intake of 

cholesterol, 

hydrogenated / trans 

fatty acids and 

saturated fats (fried 

food), olive / grape 

seed oil, fresh fruit and 

vegetables, nuts and 

seeds, fish and 

seafood, unrefined 

carbohydrates, plenty 

of water, cutting down 

sugar and refined 

starch, dairy products 

with honey or date, 

removing foods with 

Cold nature); Group B: 

hemp seed and 

evening primrose oils

for 6 months

Placebo Significant improvements 

in EDSS in intervention 

groups, significant 

increase in EDSS score 

in control group (olive oil)

No serious 

adverse effects in 

any of the 

patients

Torkildsen, 

2012101

multicenter

92

Power

unclear

R-R patients, 18-55 

years, EDSS = > 5.0; 

fatty acids vs placebo: 

female 30/46 vs 29/45, 

mean age 28.8 vs 

28.3, mean EDSS at 

baseline, 1.94 vs 1.86, 

mean disease duration 

5.4 vs 5.8 years, mean 

relapses the year prior 

1.7 vs 1.6, mean time 

since diagnosis 2.2 vs 

1.7; McDonald 2001 

criteria

Oral omega-3 fatty 

acids (270mg EPA, 

170mg DHA) and 4 

units of alphatocopherol per gram 

for 18 months

Interferon 

beta-1a 

Placebo After 24 months, EDSS 

increased to 2.22 (1.34) 

in the fatty acids group 

and 2.19 (1.34) in 

placebo group (p = 0.63); 

30% in the fatty acids 

group vs 30% in the 

placebo group had 

experienced disease 

progression (p > 0.99)

No differences in 

changes of MS 

Functional 

Composite scores 

after 6 (p = 0.53) or 

24 (p = 0.57) months

74% intervention, 

63% placebo 

experienced AE 

(eg, influenza-like 

symptoms, 

injection site 

reaction), n.s. 

between groups; 

1 intervention 

patient (nausea) 

and 2 placebo 

patients (allergic 

reaction) 

withdrew
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

78

ID, Trial 

type§

N

Power

Participants Intervention Co Compara

tor 

EDSS results Other results AE

WeinstockGuttman, 

2005107

cross-over

31

No power 

calculation 

MS patients, 18-60 

years; intervention vs 

placebo: female 85.7% 

vs 84.6%, mean age 

45.1 vs 39.9, mean 

disease duration 6.9 

vs 4.6, mean EDSS 

1.9 vs 2.0; Poser 

criteria 

Very low-fat diet 

dietary advice (not to 

exceed 15% of total 

daily calories) plus fish

oil supplement (6 

capsules / day, 1.98g 

EPA, 1.32 DHA); 

control group received 

AHA diet advice (30% 

fat) plus placebo

Other Weak trend towards an 

increase in EDSS 

(+0.35) in the control 

group vs a decrease of 

0.07 points in the 

intervention group after 1 

year

2 could not 

tolerate the diet 

(1 per group)

Yadav, 

2014110

61

No power 

calculation

R-R (mean EDSS 2.5; 

mean age 41, range 

24-55); criteria N/A

Low-fat plant-based 

diet (1 year)

Waitlist After baseline difference 

adjustment, the groups 

showed no siginificant 

change in EDSS

"study 

demonstrated 

safety"

Notes: AE adverse events; Co co-intervention, N/A not available, n.s. not statistically significant, R-R relapsing-remitting, PP primary progressive, SP secondary progressive, vs 

versus

§ All studies are RTCs unless otherwise noted.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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The majority of the 12 dietary intervention studies addressed effects of fatty acid 

supplementation. Three studies evaluated the effects of advice for a diet of foods with “Hot 

nature” according to traditional Chinese medicine, a very low-fat diet plus fish oil, and a low-fat 

plant-based diet.80,107,110 Studies compared interventions primarily to placebo. One study 

compared to patients assigned to waitlist (patients will receive the intervention eventually).110

Another compared to different, not very low-fat diet advice plus placebo instead of fish oil 

supplementation.107 All studies tested long-term interventions; the duration ranged from 6 to 30 

months. 

Studies enrolled between 31 and 312 patients. Studies either reported no power calculation to 

determine the sample size necessary to detect a statistically significant difference between 

treatment groups, or it was computed for a different outcome than MS progression or disability 

scores. One of the included studies tested the intervention specifically in chronic progressive 

non-relapsing MS,

24 while other studies used unrestricted MS samples or did not report on the 

form and stage.

Several studies reported on EDSS results but not all reported EDSS endpoint values to allow a 

comparison between intervention and control groups. Some studies only stated the statistical 

significance of the difference, reported the statistical significance of the difference between 

baseline and endpoint for each group, or reported no specific numbers. Four included studies 

were published before the development of the EDSS and reported on the number of patients who 

deteriorated.24,25,65,73 The adverse event assessment was sparse; 5 included studies did not report

on adverse events at all, 3 reported adverse events but did not specify the treatment group 

patients were assigned to, and 2 gave no details on the experienced events. Only 2 studies 

reported on adverse events by intervention group and reported that one or 2 patients withdrew 

from the study.

The risk of bias assessment for the identified studies is shown in Appendix C. There was 

insufficient detail to assess the risk of bias in a number of dietary intervention studies, in 

particular the studies that were published 40 years ago, presumably due to differences in 

reporting standards.

24,25,65,73 Compliance in diet advice studies was judged to be a source of other 

bias, given the long duration of the intervention that required the participants to adhere to a 

demanding dietary schedule.80,107,110 

Studies reporting on vitamin D supplementation are shown in the following, final evidence table. 

Studies exclusively gave dietary supplements to patients, rather than addressing more complex 

nutritional changes or dietary habits. 
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Table 12. Evidence for KQ3: Effects of Vitamin D Supplementation Interventions on MS Progression

ID, Trial type§ N

Power

Participants Intervention Co Comparator EDSS results AE

Burton, 201028

multi-center

49

Power 

unclear

MS clinic patients, mean age 40.5 

years, EDSS 1.34, and 25(OH)D 78 

nmol/L; treatment vs control: female 

84% vs 70%, R-R/SP 23/2 vs 22/2, 

mean disease duration 8.2 vs 7.4; 

patients already taking > 4,000 

IU/day were excluded; McDonald 

2001 criteria

Escalating vitamin D 

doses up to 40,000 

IU/day over 28 weeks 

followed by 10,000

IU/day, and further 

downtitrated to 0 

IU/day; calcium 1,200 

mg/day; for 52 weeks

Placebo Treatment vs control 

EDSS (p > 0.5), % 

change in EDSS -

0.23 vs 0.30 (p > 

0.5), proportion 

completing with 

increased EDSS 

0.88 vs 0.375 (p = 

0.019) at end of trial

No adverse events 

observed

Kampman, 

201249

68 (35 

treatment, 

33 

placebo)

No power 

calculation

Patients aged 18-50 with clinically

definite MS and EDSS = < 4.5; 

vitamin D vs placebo: female 69% 

vs 73%, mean age 40 vs 41, mean 

duration from first symptom (range) 

11 (1-27) vs 10 (2-26) years, mean 

EDSS 2.5 vs 2.0, mean MSSS 3.6 

vs 3.2; McDonald 2001 criteria

20,000 IU vitamin D3 

once a week in capsule 

for 96 weeks

Placebo No significant 

difference in EDSS 

between treatment 

and placebo groups 

(absolute difference 

-0.01, CI -0.35, 

-0.35, p = 0.091)

1 placebo patient 

dropped out due to 

nephrolithiasis

Mosayebi, 

201167

62 (28 

treatment, 

34 

placebo)

No power 

calculation

MS patients, 18-60 years, at least 1 

relapse in the previous 12 months; 

> 3 lesions on spinal or brain-MRI or 

both; EDSS 0-3.5; vitamin D vs 

placebo: female 17/26 vs 25/33, 

mean age 37 vs 35, mean duration 

of disease 4.15 vs 6.4 years; 

patients with progressive MS were 

excluded; McDonald 2001 criteria

300,000 IU vitamin D3 

as intra-muscular 

injections every month 

for 6 months

Placebo EDSS increased by 

0.21 from 2.10 after 

6 month intervention 

and by 0.17 from 2.5 

in placebo group

N/A

Shaygannejad, 

201288

50

Sufficient 

power

MRI, clinical, or laboratorysupported R-R, EDSS < 7, average 

age 38.6; PP and SP MS excluded; 

McDonald 2005 criteria

Low-dose vitamin D 

(calcitriol) for 1 year

DMT Placebo Intervention: EDSS 

1.63 (SD 0.70, 

difference pre-post 

0, CI -0.15, 0.15); 

Placebo: 1.94 (SD 

1.41, difference prepost -0.24, CI -0.40,

-0.08; p < 0.01) at 

12-month follow-up

Vitamin D was welltolerated; most AE were 

mild. Most common in 

intervention vs placebo 

group: constipation (N =

6 vs 4), dyspepsia (N = 6 

vs 2), fatigue (N = 4 vs 

5), headache (N = 2 vs 

1)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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ID, Trial type§ N

Power

Participants Intervention Co Comparator EDSS results AE

SoiluHanninen, 

2012128

multi-center

66 (34 

treatment, 

32 

placebo)

Power 

unclear

R-R patients age 18-55 years with 

IFNB-1b use for at least 1 month 

and EDSS = < 5.0; vitamin D vs 

placebo: female 21/34 vs 20/32, 

mean age 39 vs 35, mean EDSS 

2.0 vs 2.4, mean disease duration 

3.0 vs 2.4, mean annual relapse 

rate from the 2 years before the 

study onset 0.49 vs 0.52, patients 

with relapses during the year 

preceding baseline 12/34 vs 13/32; 

McDonald 2005 criteria

Vitamin D3 (20,000 IU 

or 0.5 mg of vitamin D3 

in capsule, once 

weekly) for 1 year

Placebo EDSS score 

decreased in the 

vitamin D group by -

0.2 from 1.8 and 

remained the same 

in the placebo group 

(-0.02) after the 12 

months intervention 

(p = 0.071)

No hypercalcaemia or 

significant differences in 

any clinical chemistry 

parameters or AE 

between groups; 

diarrhea (intervention N 

= 5 vs control 2), fever (2 

vs 5); SAE: 1 case of 

erysipelas treated with 

antibiotics in 

intervention, 2 

hospitalizations in control 

group (elective hip 

surgery, elbow fracture)

Stein, 201194 23

No power 

calculation

Patients with R-R older than 18 

years, relapse within the preceding 

24 months; intervention vs placebo, 

mean age 34 (29.5-49) vs 44.5 

939.5 -47), female 63% vs 75%, 

duration of MS, 6 (1.5-10.5) vs 6 (2-

12), EDSS 2.5 (2-4) vs 2 (1-3); PP 

and SP excluded; McDonald 2001 

criteria

High-dose D2 group 

received 1,000 IU 

vitamin D2 daily plus a 

high-dose vitamin D2 

supplement for 6 

months

Other: lowdose D2 

received 1000

IU vitamin D2 

daily plus a 

placebo

OR for lower exit 

EDSS comparing 

high-dose with lowdose: 0.16 (CI 0.02, 

1.34, p = 0.09)

N/A

Notes: AE adverse events, Co co-intervention, DMT disease-modifying therapy, N/A not available, R-R relapsing-remitting, PP primary progressive, SP secondary progressive, vs 

versus

§All studies are RCTs unless otherwise noted.
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We identified 6 RCTs addressing vitamin D supplementation. Studies provided patients with 

different doses, and some studies explicitly tested high- or low-dose supplementation. Most 

studies administered vitamin D as a capsule. One study provided intramuscular injections. One 

study provided vitamin D and calcium.28 All but one study compared intervention effects to 

placebo; 1 study provided the control group with a low-dose supplement.94 The duration of 

interventions ranged from 6 to 24 months. 

Samples were small and ranged from 23 to 68 randomized patients. One study88 reported a power 

calculation for EDSS score differences. Two studies reported a power calculation, but for a 

different outcome, and 3 reported no power calculation; hence, it is unclear whether studies were 

adequately powered to detect a difference in MS progression. Only one study explicitly reported 

that the sample included 4 (out of 49) patients in secondary progression28 and patients with 

progressive MS were excluded in 3 of the identified studies. 67,88,94

All but one of the identified studies reported mean EDSS scores at the end of the trial for both 

experimental groups, some together with a statistical significance test for differences between 

groups. One study reported the proportion of patients completing the trial with increased EDSS, 

but none of the studies reported on the number of patients who entered progression, or reported 

on the time to progression. Adverse events were addressed in 4 out of 6 studies: one RCT 

reported no adverse events; one reported nephrolithiasis but did not specify the group; and 2 

studies reported on minor adverse events.

The risk of bias assessment for the individual studies is shown in Appendix C. Studies gave 

supplements with matching placebos or injections with matching placebo injections, thereby 

reducing the risk of performance bias.

Summary of Findings and Quality of Evidence for Key Question 3

Results for KQ3 studies (risk factor modification therapies) are grouped by identified 

intervention type: exercise, diverse dietary interventions, and vitamin D supplementation.

Exercise

Across all identified physical exercise intervention studies, 7 reported post-intervention EDSS 

scores for both treatment arms. The results are shown in the following forest plot.
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Figure 4: Effect of Exercise Interventions on EDSS Scores

None of the individual studies reported a statistically significant effect, and the pooled result also 

did not provide evidence of statistically significant improvements in EDSS scores for exercise

relative to an untreated control group (SMD 0.02; CI -0.40, 0.44; I2

 0%; 7 RCTs). However, 

several studies showed baseline imbalances, where intervention participants had higher EDSS 

scores than the control group. Using baseline-adjusted data for a sensitivity analysis, the result 

favored the exercise intervention (SMD -0.19; CI -0.34, -0.03; I2 0; 7 RCTs). There was no 

indication of publication bias (rank test p = 0.562, regression test p = 0.850).

The quality of the evidence for the result of no difference between exercise interventions and 

untreated control groups on EDSS scores was downgraded by 2 due to severe study limitations

and by 1 due to conflicting results in a sensitivity analysis (imprecision). Our confidence in the 

evidence summary showing the absence of an effect is limited because most studies were not 

designed to assess EDSS changes, study sample sizes were very small which could only detect a 

large treatment effect, and there were baseline imbalances. The intervention duration was not 

long-term but ranged between 4 weeks and 3 months, which may be too short to achieve, and to 

detect changes with standard diagnostic criteria. In addition, the difference between intervention 

and control groups was statistically significant when adjusting for baseline scores; hence an 

intervention effect in better-designed studies cannot be ruled out. Nonetheless, any treatment 

effect is likely to be very small; even adjusting for baseline imbalances, the estimate was an 

average of 0.20 points of improvement on the EDSS scale.

None of the studies reported on other outcome measures such as the change from relapsingremitting to secondary progressive MS.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Dietary Interventions

Across studies, 4 dietary intervention studies reported on the number of patients deteriorating 

and entering progression in each group. The figure shows that none of the included studies 

reported a statistically significant effect between fatty acids supplementation compared to 

placebo. The intervention duration ranged from 18 to 24 months. 

Figure 5: Effect of Fatty Acid Supplementation Interventions on the Relative Risk of 

Progression

The pooled relative risk of experiencing progression was not statistically significantly lower in 

intervention groups (RR 0.86; CI 0.67, 1.05; I

2

 0; 4 RCTs). Of note, Bates et al (1977)

exclusively addressed patients with chronic progression.24

A similar result was shown for differences in EDSS scores between treatment and control groups 

across 3 dietary intervention studies testing fatty acids supplementation or Hot nature diet advice. 
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Figure 6: Effect of Dietary Interventions on EDSS Scores

None of the individual interventions demonstrated a statistically significant effect on EDSS 

scores. Across studies, the difference in EDSS scores was not systematically different between 

intervention and control groups (SMD -0.13, -83, 0.56; I

2 5%; 3 RCTs). 

One identified dietary intervention study reported a significant intervention effect, but this study 

could not be included in the meta-analysis. The study concluded that high-dose treatment of 

gamma-linolenic acid significantly reduced disability progression compared with placebo and 

low-dose treatment, but it did not report numerical data.44

The quality of evidence for the dietary intervention results showing the absence of an effect on 

MS progression (measured as the relative risk of progression [see figure 5] or based on EDSS 

scores [see figure 6]) were both downgraded to moderate due to study limitations. The early 

studies lack reporting detail while the more recently published studies were small and did not 

report statistical power calculations to determine whether studies were designed to detect an 

effect of the intervention on MS progression. 

We did not identify studies reporting on other MS progression outcomes such as the time to 

secondary progression.

Vitamin D

The 5 RCTs comparing vitamin D supplementation to placebo and reporting on the same 

outcome measure are shown in the figure. All reported on EDSS scores.
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Figure 7: Effect of Vitamin D Interventions on EDSS Scores

None of the individual studies reported a statistically significant effect of the specific 

intervention under evaluation. While the pooled result indicated a positive trend, we also could 

not show a significant difference in EDSS scores between intervention and control group across 

all studies using standardized mean differences (SMD -0.15; CI -0.33, 0.02; I2 0; 5 RCTs). 

However, analyzing weighted mean differences to determine the clinical importance of the 

difference showed a statistically significant effect of vitamin D supplementation on EDSS scores 

(WMD -0.22; CI -0.39, -0.05; I2 0; 5 RCTs). The result indicates a difference in EDSS scores of 

0.22 between intervention and control groups. There was no evidence of publication bias for this 

result (rank test p = 0.82, regression test p = 0.99). 

The quality of evidence for a non-significant effect of vitamin D supplementation on EDSS 

scores was downgraded by 2 due to study limitations and by 1 due to imprecision. The included 

studies were small and the lack of reported power calculations makes it unclear whether the 

studies were sufficiently powered to be able to detect small treatment effects. The statistical 

significance is dependent on the effect measure, showing that the effect estimate is not very 

robust.

Studies on vitamin D did not report on other MS progression-relevant outcomes.

Summary for KQ3

The following summary of findings table documents the results for all interventions or class of 

interventions for outcomes that were reported in at least 2 studies. 
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Table 13. Summary of Findings for KQ3

Intervention

Outcome

# of 

RCTs Findings: Direction, Magnitude of Effect GRADE 

Exercise Interventions

EDSS score

differences

7 

RCTs

No statistically significant difference between exercise 

intervention and control group (SMD 0.02; CI -0.40, 0.44) 

Very low

(study limitations,**

imprecision*)

Dietary Interventions

Number of 

patients 

progressing

4 

RCTs

No statistically significant difference between fatty acids 

supplementation intervention and control group (RR 0.86; 

CI 0.67, 1.05)

Moderate

(study limitations*) 

EDSS score 

differences

3 

RCTs

No statistically significant difference between dietary 

intervention (fatty acids or Hot nature diet) and control 

group (SMD -0.13; CI -0.83, 0.56)

Moderate 

(study limitations*) 

Vitamin D Supplements

EDSS score 

differences

5 

RCTs

No statistically significant difference between vitamin D 

supplementation and placebo (SMD -0.15; CI -0.33, 0.02) 

Very low

(study limitations,** 

imprecision*)

Note: * quality of evidence downgraded by 1 level, ** quality of evidence downgraded by 2 levels

VA Subgroup Analysis 

The participants in Lo et al were recruited either from the MS clinic at the VA Connecticut

Healthcare System or through chapters of the National Multiple Sclerosis Society.56 The study 

compared body weight supported treadmill training, with or without robot assistance, and found 

an improvement in EDSS scales for both groups across the 13 participants.

The author affiliation of the study by Yadav et al110 suggests that the participants were US 

Veterans. Patients were assigned to a one year low-fat, plant-based diet. The study reported no 

significant changes in EDSS scores in the groups after baseline difference adjustment. Only few 

study details were available; the study was published as a conference abstract.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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SUMMARY AND DISCUSSION

Our systematic review focused on modifiable risk factors, such as health behaviors of patients 

with MS. We systematically searched for, documented, and synthesized studies available in the 

international literature on modifiable risk factors and the effect of modification therapies. 

The review addressed a broad and very complex research field and a large number of studies 

contributed to this review. Literature searches were comprehensive and exploratory in nature and 

were not limited to a narrow set of known risk factors. Few prospective studies were identified to 

inform the association between modifiable risk factors and MS progression, limiting the 

conclusions that can be drawn from the existing literature for KQ1. Furthermore, while the 

review made every effort to locate studies relevant to KQ2 (exposure during military service), 

only a very small number of studies was identified. Although a number of interventions have 

been tested in RCTs, many were not designed to assess the effect on MS progression, also 

limiting the conclusions that can be drawn from the intervention literature addressed in KQ3.

We did not find variables that were identified as valid risk factors of MS progression and that 

have been shown in intervention studies to improve MS progression. However, the review

systematically explores and catalogues what is currently known in this research field, highlights 

promising areas, and identifies future research needs to address the progression of MS.

SUMMARY OF EVIDENCE FOR KQ1: What modifiable epidemiologic 

factors are related to multiple sclerosis progression following 

diagnosis?

Our literature review identified a large number of modifiable epidemiologic factors that have

been assessed in the context of MS progression. However, study designs, operationalizations of 

risk factors, and outcome assessment measures varied widely.

A substantial amount of research has been dedicated to the role of vitamin D in MS progression. 

Our synthesis shows a weak but consistent negative correlation between 25(OH)D levels and 

EDSS scores across studies. Evidence comes primarily from concurrent studies which assess the 

physiological level and the disability status at the same time. Hence, this result should be 

interpreted as an association without causal interpretation. Low vitamin D levels may be the 

cause, the effect, or a covariate of EDSS levels. In addition, whether the physiological levels can 

be directly influenced by patients is an unresolved question. The association has also been shown 

in 2 prospective studies that reported on this outcome and although there was some evidence of 

publication bias, an adjusted analysis found a very similar effect. We did not find studies 

reporting on other operationalizations of the role of vitamin D, such as sun exposure or use of 

supplements, that could be combined, and we did not find studies reporting on the effect of 

vitamin D on the change from relapsing-remitting to secondary progressive MS. The 

international literature has linked MS to vitamin D deficiency and suggests additional functions

outlining why high levels of vitamin D may be beneficial for MS patients (eg, anti-inflammatory 

aspects of vitamin D).

4,129

Smoking has also been addressed in a large number of studies and was associated with an 

increased risk of progression in MS patients. The association was shown in studies predicting 

time to EDSS scores of 6 (use of cane, crutch, or brace) as well as conversion to secondary 
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progression. Our confidence in the exact size of effect is somewhat limited due to unexplained 

heterogeneity (moderate quality of evidence). Our pooled estimate was statistically significant 

but lower than that reported by a 2011 meta-analysis. The earlier existing meta-analysis was 

based on fewer studies and did not find a statistically significant effect, and concluded at the time 

that smoking is important in determining MS susceptibility but the effect on the progression of 

disease is less certain.130 The now available literature suggests that smoking is an important 

modifiable risk factor for MS progression. This is of particular importance as it is a risk factor 

that can be directly influenced by MS patients.

There is low quality of evidence that epidural analgesics during childbirth are associated with

EDSS scores. This outcome has been addressed in retrospective as well as prospective studies 

but all existing studies report on disability levels across study samples, not direct measures of 

progression in individuals such as time to secondary progression.

The risk factors sun exposure, month of birth, diet, fish consumption, alcohol-related predictors, 

exercise, oral contraception, and education have been addressed in more than one study and were 

documented in detail in the summary of findings section. It was not possible to derive specific 

evidence statements due to the unique operationalization of risk factors and outcome measures;

however, in particular the role of sun exposure and alcohol-related variables should be 

investigated further.

The evidence tables document a large range of potential risk factors such as: cesarean delivery;

breast feeding; having been breast fed; obstetrical and spinal anesthesia; childhood maltreatment;

working outdoors; individual health promoting lifestyle domains; meditation practice; insurance 

coverage; medical care satisfaction variables; exposure to different types of animals; coal 

heating; wood heating; humid living space; no sewage system; no piped water; type of 

environment (eg, farm); specific diet factors such as coffee consumption, liver consumption, 

vitamin supplementation, fortified foods, vegetarian diet; cod liver oil intake; occupational 

status; deployment to a war theater; being a Veteran; and earthquake experience. These were 

addressed in single studies and have not been replicated in other studies.

The review explored a large number of potential risk factors but shows that in many cases, the 

existing evidence base investigating an association is insufficient to make evidence statements 

for specific outcomes and results. This is illustrated by the following examples. Our systematic 

review showed that the evidence for an association between progression of MS and dietary 

factors is sparse. We did not identify more than one study reporting on the same diet and 

reporting on the same outcome measure. Similarly, a Cochrane review on dietary interventions in 

MS highlighted that a number of diets for MS (eg, Swank Diet) have been proposed; however,

dietary habits in MS patients have not been extensively studied or reported.12 Furthermore, 

physical exercise has been addressed in a number of published studies, both as a correlate of 

disability and its predictive validity for MS progression. Study results varied by analytic design. 

Lower physical exercise can be the cause, the effect, or a covariate of higher EDSS scores. We 

did not identify more than one study reporting on the same risk factor operationalization and MS 

progression outcome measure. Hence, the existing evidence base is still very limited. 

Approaches to offer physical exercise to MS patients are traditionally based on optimizing daily 

functioning, but whether exercise has a role in slowing progression of MS has also been raised as 

a research question.131-133
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SUMMARY OF EVIDENCE KQ2: What environmental exposures prior 

to or during military service are related to multiple sclerosis 

progression following onset symptoms?

Only very few studies were identified that reported on exposures prior to and during military 

services associated with MS progression (KQ2) in active military personnel or Veterans. 

Evaluated risk factors in existing studies include only a small number of potentially relevant 

exposures such as deployment. 

The quality of the evidence across studies was determined to be insufficient for evidence 

statements. None of the studies employed a prospective study design and risk factors were 

addressed in single studies without replication in other studies. All potential risk factors were 

reported in only one included study without replication in another participant sample. Hence, the 

available evidence is not suitable to answer the review question.

SUMMARY OF EVIDENCE KQ3: Among identified risk factors for 

progression, what treatment / risk factor modification therapies have 

been shown to delay or hasten the progression of MS once it has 

initiated?

Our literature searches identified a substantial number of studies that have addressed modifiable 

risk factors; however, all addressed exercise programs, dietary interventions, or vitamin D 

supplementation. 

Exercise interventions did not demonstrate a statistically significant effect on EDSS scores 

comparing intervention and untreated control groups across all studies reporting on this outcome. 

However, sensitivity analyses indicated that, adjusting for baseline imbalances, small effects on 

EDSS become apparent (0.20 point difference between treatment groups). Studies were not 

designed to assess EDSS changes or other measures of progression, study sample sizes were very 

small with indications of baseline imbalances, and the interventions may have been too short to 

achieve and to detect changes with standard diagnostic criteria. The negative results should not 

be interpreted as exercise not being beneficial in MS in general. Exercise in MS patients may 

have many positive effects132 and a recent systematic review134 addressing a range of outcomes 

concluded that exercise may be recommended for rehabilitation. Our review aimed to detect an 

effect for a very specific outcome – progression of MS.

The identified data did not indicate a statistically significant positive effect of dietary 

interventions that affected the progression of MS. This result mirrors the conclusion of an 

existing Cochrane review on dietary interventions for MS that included studies published to 

November 2011.12 The review reported that polyunsaturated fatty acids seem to have no major 

effect on disease progression but cautioned also that evidence statements are limited due to 

uncertain quality of the studies.

Individual studies and the pooled result showed a trend for an effect favoring vitamin D 

supplementation in MS patients but the statistical significance depended on the effect measure. 

Our confidence in the evidence for the absence of an effect is limited given that the existing 

studies were small and they may lack statistical power to detect small treatment effects. A 

Cochrane review that searched for intervention studies in May 2010 identified only one study; all 
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91

additional studies shown in our meta-analysis were published after this date. The review 

concluded that the level of evidence for the effectiveness of vitamin D supplementation does not 

allow confident decision-making about the use of vitamin D in MS.4 Any potential treatment 

effects are likely to be small, with an estimated difference of 0.22 points in EDSS scores between 

intervention and control groups.

Finally, smoking, a risk factor for progression with a stronger evidence base, has not been 

addressed in RCTs to assess the effects of smoking cessation interventions on progression in MS 

patients. This is unfortunate because some risk factor studies suggested that negative 

consequences of smoking can be reversed in ex-smokers, suggesting that this risk factor could be 

amenable to intervention.46

LIMITATIONS

It should be noted that this review was restricted to patient-reported measures of MS progression 

and disability. Other progression measures such as MRI results are also of interest to clinicians 

and can make additional contributions to this complex research field.

Furthermore, due to resource constraints, this review was limited to English-language 

publications. Although we included several international studies, the language restriction will 

have missed some studies, in particular older studies contributing to research on MS progression.

This review identified a large number of studies contributing to the evidence base on modifiable 

risk factors associated with MS progression. However, the evidence base is limited due to the 

small number of prognostic studies and the small number of studies reporting on direct measures 

of progression (eg, conversion to secondary progressive MS) rather than proxies such as MS 

disability status.

We converted statistics to the extent possible for this review. Nonetheless we were often not able 

to summarize results across studies due to lack of reporting of key variables, such as point 

estimates and measures of dispersion, in addition to the statistical significance of the presence or 

absence of associations. Due to the timeframe and lack of resources the review is entirely based 

on published literature and did not contact authors for missing information or additional data;

furthermore, several included studies have been published decades ago, making it unlikely that 

additional data is still available.

Applicability of Findings to the VA Population

We found no indication that risk factor results and treatment effects are not applicable to the VA 

population. However, the existing evidence does not permit analyses to test this hypothesis by 

identifying moderator effects linking study populations to differential effects. There are very few 

risk factor or intervention studies reporting specifically on VA samples.

RESEARCH GAPS/FUTURE RESEARCH

Our systematic review showed that more prospective research studies are needed to allow 

predictions and meaningful interpretation of risk factor analyses. Furthermore, it is imperative 

that risk factor studies report more details (eg, mean EDSS scores and a measure of dispersion),

more measures of progression, and/or more analyses (eg, reporting on EDSS scores means as 

well as time to progression to specific EDSS benchmarks). While many individual studies do not 
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92

have sufficient statistical power to detect small effects of risk factors on progression, studies may 

contribute to future meta-analyses. We identified a number of areas with published research on a 

risk factor of interest, but due to the unique operationalization of predictor and outcome measure, 

it was not possible to adequately synthesize results across studies.

Although our review addressed a broad research field, there are other potential risk factors that 

were outside the scope of this review, such as comorbidities.

11 There is a growing literature on 

MS comorbidities, including obesity and the associations of body weight and MS progression,

which warrants an individual systematic review.

135,136 Future reviews should in particular address 

the role of treatable comorbidities in MS progression. Scoping searches also identified a large 

literature base evaluating the effect of pregnancies. However, any association needs to be 

interpreted with caution. While the data may suggest a protective effect, reverse causality cannot 

be ruled out – a MS diagnosis and perceived progression may affect reproductive decision 

making.137

Furthermore, this review did not target psychological variables, such as depression, anxiety, 

coping strategies, social functioning, distress, anger, and other emotions and cognitive styles,

which may be reactions to MS progression and/or contributing factors to MS progression. 

Although variables have been assessed in the literature, very often, these have been studied as 

correlates of the disease, and while many studies have tried to predict psychological variables 

with MS progression, some have used the psychological variables as predictors for MS 

progression. These variables should be assessed in prospective risk factor studies to establish the 

temporal chain of events in order to establish a prognostic link between these variables and MS 

progression. However, even if a link can be established, it is a different matter to show that the 

psychological variables can a) be modified and b) the modification has an effect on progression; 

hence, intervention studies testing the modification therapy will be subsequently needed.

Generally, more prospective risk factor studies are needed that allow determining a temporal 

sequence of events and that address the direction of associations. For example, a number of 

studies have reported on alcohol-related measures and showed better outcomes associated with 

specific operationalizations of alcohol use or misuse, but the available studies used primarily 

concurrent data (correlating current alcohol intake and current disability) and an alternative 

interpretation of this “protective” effect of alcohol is that more disabled people drink less alcohol

because of their disability. Sun exposure should also be evaluated further in order to replicate 

identified associations of specific operationalizations of the predictor variable and MS disability 

and progression measures. Prospective studies are needed to provide more information on the 

role of sun exposure and alcohol consumption (and the optimum amount) in MS progression.

11

Finally, intervention studies testing the effect of interventions on MS progression should 

determine the statistical power needed to detect a difference between treatment groups. This is in 

particular needed for vitamin D supplementation trials. In addition, more research on exercise 

interventions is warranted with studies that are adequately powered and interventions of 

sufficient duration to potentially influence MS progression. Effects of smoking cessation 

interventions should be determined in intervention studies given the association between 

smoking and MS progression. Furthermore, while a substantial number of intervention studies 

exist that have reported on disease status and disability measures, larger studies reporting on 

direct progression measures are urgently needed.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

93

CONCLUSIONS

A large number of studies is available to contribute to the growing research literature on 

modifiable risk factors and MS progression but the research field is very complex. 

Risk factor studies used diverse operationalizations of risk factors and different outcome 

measures, and more prospective studies are needed. Most consistent results were shown for the 

association between EDSS scores and vitamin D levels. Smoking was associated with a faster 

progression of MS in smokers compared to nonsmokers.

Risk factors in Veterans and active military personnel were one of the key questions for this 

review but very few studies are available to inform on this participant subgroup. 

We did not identify interventions that showed a statistically significant effect of exercise, diet, or 

vitamin D supplementation on EDSS scores across studies. However, studies were not designed 

to assess effects on MS progression. More research is needed, in particular, on interventions for 

smoking cessation, adequately powered vitamin D supplementation RCTs, and RCTs testing the 

effects of long-term exercise interventions.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

94

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114. Brandes DW, Bigley K, Hornstein W, Cohen H, Au W, Shubin R. Alleviating flu-like 

symptoms with dose titration and analgesics in MS patients on intramuscular interferon 

beta-1a therapy: a pilot study. Curr Med Res Opin. Jul 2007;23(7):1667-1672.

115. Maciejek Z, Wojcik-Draczkowska H, Wawrzyniak S, Niezgodzinska-Maciejek A. 

Evaluation of efficacy, safety and tolerability of fingolimod in patients with the relapsing 

form of multiple sclerosis - 12-month observation. A preliminary report. Neurologia i 

Neurochirurgia Polska. Mar-Apr 2013;47(2):145-151.

116. Vukusic S, Hutchinson M, Hours M, et al. Pregnancy and multiple sclerosis (the PRIMS 

study): clinical predictors of post-partum relapse. Brain: A Journal of Neurology. Jun 

2004;127(Pt 6):1353-1360.

117. Tavee J, Rensel M, Planchon SM, Butler RS, Stone L. Effects of meditation on pain and 

quality of life in multiple sclerosis and peripheral neuropathy: a pilot study. International 

Journal of MS Care. Winter 2011;13(4):163-168.
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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118. Swank RL, Goodwin J. Review of MS patient survival on a Swank low saturated fat diet. 

Nutrition. Feb 2003;19(2):161-162.

119. Swank RL. Multiple sclerosis: fat-oil relationship. Nutrition. Sep-Oct 1991;7(5):368-376.

120. D'Hooghe M B, Haentjens P, Nagels G, Garmyn M, De Keyser J. Sunlight exposure and 

sun sensitivity associated with disability progression in multiple sclerosis. Multiple 

Sclerosis (Houndmills, Basingstoke, England). Apr 2012;18(4):451-459.

121. D'Hooghe M B, Haentjens P, Nagels G, D'Hooghe T, De Keyser J. Menarche, oral

contraceptives, pregnancy and progression of disability in relapsing onset and progressive 

onset multiple sclerosis. Journal of Neurology. May 2012;259(5):855-861.

122. D'Hooghe M B, Nagels G, De Keyser J, Haentjens P. Self-reported health promotion and 

disability progression in multiple sclerosis. Journal of the Neurological Sciences. Feb 15 

2013;325(1-2):120-126.

123. Marck CH, Hadgkiss EJ, Weiland TJ, van der Meer DM, Pereira NG, Jelinek GA. 

Physical activity and associated levels of disability and quality of life in people with 

multiple sclerosis: a large international survey. BMC Neurol. 2014;14:143.

124. Levin AB, Hadgkiss EJ, Weiland TJ, et al. Can meditation influence quality of life, 

depression, and disease outcome in multiple sclerosis? Findings from a large international 

web-based study. Behavioural Neurology. 2014;2014:916519.

125. Thomas S, Thomas PW, Kersten P, et al. A pragmatic parallel arm multi-centre 

randomised controlled trial to assess the effectiveness and cost-effectiveness of a groupbased fatigue management programme (FACETS) for people with multiple sclerosis. 

Journal of Neurology, Neurosurgery, and Psychiatry. Oct 2013;84(10):1092-1099.

126. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other 

symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebocontrolled trial. Lancet. Nov 8 2003;362(9395):1517-1526.

127. Solari A, Motta A, Mendozzi L, et al. Computer-aided retraining of memory and 

attention in people with multiple sclerosis: a randomized, double-blind controlled trial. 

Journal of the Neurological Sciences. Jul 15 2004;222(1-2):99-104.

128. Soilu-Hanninen M, Aivo J, Lindstrom BM, et al. A randomised, double blind, placebo 

controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients 

with multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry. May 

2012;83(5):565-571.

129. Pozuelo-Moyano B, Benito-Leon J, Mitchell AJ, Hernandez-Gallego J. A systematic 

review of randomized, double-blind, placebo-controlled trials examining the clinical 

efficacy of vitamin D in multiple sclerosis. Neuroepidemiology. 2013;40(3):147-153.

130. Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G, Ramagopalan SV. 

Smoking and multiple sclerosis: an updated meta-analysis. PloS One. 2011;6(1):e16149.

131. Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G. Exercise therapy for multiple 

sclerosis - art. no. CD003980.pub2. Cochrane Database Syst Rev. 2005(1).

132. Feinstein A, Dalgas U. The benefits of exercise in progressive MS: some cautious 

optimism. Multiple Sclerosis (Houndmills, Basingstoke, England). Mar 2014;20(3):269-

270.
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133. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can 

exercise slow down the progression of multiple sclerosis? Therapeutic Advances in 

Neurological Disorders. Mar 2012;5(2):81-95.

134. Sa MJ. Exercise therapy and multiple sclerosis: a systematic review. Journal of 

Neurology. Sep 2014;261(9):1651-1661.

135. Marrie RA, Hanwell H. General health issues in multiple sclerosis: comorbidities, 

secondary conditions, and health behaviors. Continuum (Minneapolis, Minn.). Aug 

2013;19(4 Multiple Sclerosis):1046-1057.

136. Overs S, Hughes CM, Haselkorn JK, Turner AP. Modifiable comorbidities and disability 

in multiple sclerosis. Current Neurology and Neuroscience reports. Oct 2012;12(5):610-

617.

137. Miller DH, Fazekas F, Montalban X, Reingold SC, Trojano M. Pregnancy, sex and 

hormonal factors in multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, 

England). Apr 2014;20(5):527-536.
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APPENDIX A. SEARCH STRATEGIES

This appendix documents the exact search strings for all searched electronic databases. We 

designed a search strategy for each key question in order to maximize relevance and retrieval 

success.

SEARCH METHODOLOGY KQ1

DATABASE SEARCHED & TIME PERIOD COVERED:

PubMed – ~1946-2/27/2015 

LANGUAGE:

 English

SEARCH STRATEGY #1 (Study Design Filter):

multiple sclerosis[tiab] OR multiple sclerosis[majr] 

AND

progression[tiab] OR progressive[tiab] OR progressing[tiab] OR mortality[tiab] OR disease course[tiab] 

OR disability[tiab] 

AND

"cohort studies”[mh] OR “follow-up studies”[mh] OR prognos*[tiab] OR predict*[tiab] OR 

multivariate[tiab]

NOT

(animal OR animals) NOT (human OR humans)

SEARCH STRATEGY #2 (Risk Factor Filter):

multiple sclerosis[tiab] OR multiple sclerosis[majr] 

AND

progression[tiab] OR progressive[tiab] OR progressing[tiab] OR mortality[tiab] OR disease course[tiab] 

OR disability[tiab] 

AND

geographic[tiab] OR sun exposure[tiab] OR vitamin D[tiab] OR fatty acid[tiab] OR diet[tiab] OR 

dietary[tiab] OR nutrition*[tiab] OR obesity[tiab] OR smoking[tiab] OR tobacco[tiab] OR alcohol[tiab] 

OR exercise[tiab] OR physical activity[tiab] OR stress[tiab] OR anesthesia[tiab] OR radiation 

therapy[tiab] OR oral contraception[tiab] OR fertility treatment[tiab] OR pregnan*[tiab] OR 

delivery[tiab] OR breastfeeding[tiab] OR salt intake[tiab] OR milk[tiab] OR water[tiab] OR trace 

elements[tiab] OR trauma[tiab] OR traumatic[tiab] OR Epstein–Barr virus[tiab]

NOT

(animal OR animals) NOT (human OR humans)

DATABASE SEARCHED & TIME PERIOD COVERED:

Web of Science– Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH - 1980-2/27/2015 

LANGUAGE:

 English

SEARCH STRATEGY #1:

TS = (multiple sclerosis) 

AND 

TS = (progression OR progressive OR progressing)

AND 

TS = (cohort OR prognos*OR predict* OR multivariate)

SEARCH STRATEGY #2:

TS = (multiple sclerosis) 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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AND 

TS = (progression OR progressive OR progressing) 

AND 

TS = (geographic OR sun OR sunlight OR vitamin D OR fatty acid OR diet OR dietary OR nutrition* OR 

obesity OR obese OR smoking OR tobacco OR alcohol OR exercise OR physical activity OR stress* OR 

anesthesia OR radiation therapy OR oral contracepti* OR fertility treatment OR pregnan* OR breastfeed* 

OR salt OR milk OR water OR trace elements OR trauma OR traumatic OR Epstein–Barr OR "Epstein 

barr")

DATABASE SEARCHED & TIME PERIOD COVERED:

SCOPUS – ~1800’s-3/2/2015 

LANGUAGE:

 English

SEARCH STRATEGY #1:

TITLE-ABS-KEY("multiple sclerosis")

AND

TITLE-ABS-KEY(progression OR progressive OR progressing) 

AND

TITLE-ABS-KEY(cohort OR prognos*OR predict* OR multivariate) 

SEARCH STRATEGY #2:

TITLE-ABS-KEY ( "multiple sclerosis") 

AND 

TITLE-ABS-KEY ( progression OR progressive OR progressing ) 

AND

vitamin d OR fatty acid OR diet OR dietary OR nutrition* OR obesity OR obese OR smoking 

OR tobacco OR alcohol ) OR ( geographic OR sun OR sunlight OR exercise OR physical 

activity OR stress* OR anesthesia OR radiation therapy OR oral contracepti* ) OR ( fertility 

treatment OR pregnan* OR breastfeed* OR salt OR milk OR water OR trace elements OR 

trauma OR traumatic OR epstein--barr OR "Epstein barr" 

DATABASE SEARCHED & TIME PERIOD COVERED:

GreenFILE - ~1970’s- 3/2/2015 

SEARCH STRATEGY:

"multiple sclerosis"

SEARCH METHODOLOGY KQ2

DATABASE SEARCHED & TIME PERIOD COVERED:

 PubMed – Earliest-3/16/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

multiple sclerosis

AND

United States Department of Veterans Affairs[mh] OR Veterans Health[mh] OR Hospitals, Veterans[mh] 

OR Veterans Disability Claims[mh] OR Veterans[mh] OR military personnel[mh] OR military 

medicine[mh] OR veteran* or military or army or navy or naval or air force or marines or coast guard or 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

106

national guard or soldier* or guardsmen or reservist* or troops or infantry* or armed forces or armed 

service* or war or wars or war-related or combat* or battle* or service-member*

DATABASE SEARCHED & TIME PERIOD COVERED:

Embase – Earliest-3/23/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

'multiple sclerosis'

AND

military OR army OR navy OR naval OR 'air force' OR marines OR 'coast guard' OR 'national guard' OR 

soldier* OR guardsmen OR reservist* OR troops OR infantry* OR 'armed forces' OR 'armed services' OR 

war OR wars OR 'war related' OR combat* OR battle* OR 'service member' OR 'service members' OR 

'veteran'/exp OR 'veteran' OR veteran*:ti OR 'veterans health'/de OR 'veterans health'

DATABASE SEARCHED & TIME PERIOD COVERED:

Web of Science Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH– 1/1/1980-3/23/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

TOPIC: ("multiple sclerosis") 

AND

TOPIC: (veteran* OR military OR army OR navy OR naval OR 'air force' OR marines OR 'coast guard' 

OR 'national guard' OR soldier* OR guardsmen OR reservist* OR troops OR infantry* OR 'armed forces' 

OR 'armed services' OR war OR wars OR 'war related' OR combat* OR battle* OR 'service member' OR 

'service members')

DATABASE SEARCHED & TIME PERIOD COVERED:

SCOPUS– Earliest-3/23/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

TITLE-ABS-KEY("multiple sclerosis") 

AND

ALL(veteran* OR military OR army OR navy OR naval OR 'air force' OR marines OR 'coast guard' OR 

'national guard' OR soldier* OR guardsmen OR reservist* OR troops OR infantry* OR 'armed forces' OR 

'armed services' OR war OR wars OR 'war related' OR combat* OR battle OR 'service member' OR 

'service members' )

DATABASE SEARCHED & TIME PERIOD COVERED:

AMED– Earliest-3/23/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

ti("multiple sclerosis") OR su("multiple sclerosis")

AND

ab(veteran* OR military OR army OR navy OR naval OR 'air force' OR marines OR 'coast guard' OR 

'national guard' OR soldier* OR guardsmen OR reservist* OR troops OR infantry* OR 'armed forces' OR 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

107

'armed services' OR war OR wars OR 'war related' OR combat* OR battle* OR 'service member' OR 

'service members') OR ti(veteran* OR military OR army OR navy OR naval OR 'air force' OR marines 

OR 'coast guard' OR 'national guard' OR soldier* OR guardsmen OR reservist* OR troops OR infantry* 

OR 'armed forces' OR 'armed services' OR war OR wars OR 'war related' OR combat* OR battle* OR 

'service member' OR 'service members') OR su(veteran* OR military OR army OR navy OR naval OR 

'air force' OR marines OR 'coast guard' OR 'national guard' OR soldier* OR guardsmen OR reservist* OR 

troops OR infantry* OR 'armed forces' OR 'armed services' OR war OR wars OR 'war related' OR 

combat* OR battle* OR 'service member' OR 'service members')

DATABASE SEARCHED & TIME PERIOD COVERED:

GreenFILE– Earliest-3/23/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

multiple sclerosis 

NUMBER OF RESULTS: 49

DATABASE SEARCHED & TIME PERIOD COVERED:

Proquest Military Collection – Earliest-3/23/2015 

LANGUAGE:

 English

SEARCH STRATEGY:

(ti("multiple sclerosis") OR ab("multiple sclerosis") OR su("multiple sclerosis"))

AND 

(ab(veteran* OR military OR army OR navy OR naval OR 'air force' OR marines OR 'coast guard' OR 

'national guard' OR soldier* OR guardsmen OR reservist* OR troops OR infantry* OR 'armed forces' OR 

'armed services' OR war OR wars OR 'war related' OR combat* OR battle* OR 'service member' OR 

'service members') OR ti(veteran* OR military OR army OR navy OR naval OR 'air force' OR marines 

OR 'coast guard' OR 'national guard' OR soldier* OR guardsmen OR reservist* OR troops OR infantry* 

OR 'armed forces' OR 'armed services' OR war OR wars OR 'war related' OR combat* OR battle* OR 

'service member' OR 'service members') OR su(veteran* OR military OR army OR navy OR naval OR 

'air force' OR marines OR 'coast guard' OR 'national guard' OR soldier* OR guardsmen OR reservist* OR 

troops OR infantry* OR 'armed forces' OR 'armed services' OR war OR wars OR 'war related' OR 

combat* OR battle* OR 'service member' OR 'service members'))

DATABASE SEARCHED & TIME PERIOD COVERED:

DTIC Technical Reports Collections – Earliest-3/17/2015 

SEARCH STRATEGY:

exact phrase: Multiple sclerosis

AND

Veterans
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

108

SEARCH METHODOLOGY KQ3

This section documents the exact search strings used to identify studies relevant for KQ3.

DATABASE SEARCHED & TIME PERIOD COVERED:

 PubMed – Earliest-1/13/2015 

FILTERS: 

 English, Randomized Controlled Trial

SEARCH STRATEGY:

“multiple sclerosis” 

DATABASE SEARCHED & TIME PERIOD COVERED:

AMED – Earliest-3/3/2015 

SEARCH STRATEGY:

"multiple sclerosis" AND interven* AND (random* OR rct*)

DATABASE SEARCHED & TIME PERIOD COVERED:

Web of Science – Earliest-3/3/2015 

SEARCH STRATEGY:

TS = (multiple sclerosis)

AND

TS = (geographic OR sun OR sunlight OR vitamin D OR fatty acid OR diet OR dietary OR 

nutrition* OR obesity OR obese OR smoking OR tobacco OR alcohol OR exercise OR physical 

activity OR stress* OR anesthesia OR radiation therapy OR oral contracepti* OR fertility

treatment OR pregnan* OR breastfeed* OR salt OR milk OR water OR trace elements OR 

trauma OR traumatic OR Epstein–Barr OR "Epstein barr")) 

AND

ts = (intervention* OR intervene*) 

AND 

LANGUAGE: (English)
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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APPENDIX B. STUDY SELECTION AND LIST OF EXCLUDED 

STUDIES

The search yield, title and abstract screening results; full text decisions, and the data extraction

are documented in electronic databases which can be obtained from the authors, in compliance 

with standard data sharing requirements. 

This appendix lists the citation of publications obtained as full text but not meeting inclusion 

criteria together with the reason for excluding the publication. 

EXCLUDE: OUTCOME

Excluded publications not reporting on MS progression:

1. Acheson ED, Bachrach CA. The distribution of multiple sclerosis in U. S. veterans by birthplace. American 

Journal of Hygiene. Jul 1960;72:88-99.

2. Ackerman KD, Stover A, Heyman R, et al. Relationship of cardiovascular reactivity, stressful life events, 

and multiple sclerosis disease activity. Brain Behav. Immun. Jun 2003;17(3):141-151. 

3. Amato MP, Ponziani G, Rossi F, Liedl CL, Stefanile C, Rossi L. Quality of life in multiple sclerosis: the 

impact of depression, fatigue and disability. Multiple Sclerosis (Houndmills, Basingstoke, England). Oct 

2001;7(5):340-344. 

4. Ayatollahi P, Nafissi S, Eshraghian MR, Kaviani H, Tarazi A. Impact of depression and disability on 

quality of life in Iranian patients with multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, 

England). Mar 2007;13(2):275-277. 

5. Bansi J, Bloch W, Gamper U, Kesselring J. Training in MS: influence of two different endurance training 

protocols (aquatic versus overland) on cytokine and neurotrophin concentrations during three week 

randomized controlled trial. Multiple Sclerosis (Houndmills, Basingstoke, England). Apr 2013;19(5):613-

621. 

6. Barth SK, Kang HK, Bullman TA, Wallin MT. Neurological mortality among U.S. veterans of the Persian 

Gulf War: 13-year follow-up. American Journal of Industrial Medicine. Sep 2009;52(9):663-670. 

7. Basak T, Unver V, Demirkaya S. Activities of Daily Living and Self-Care Agency in Patients with Multiple 

Sclerosis for the First 10 Years. Rehabilitation Nursing: The Official Journal of the Association of 

Rehabilitation Nurses. Mar 25 2014.

8. Baumstarck K, Pelletier J, Boucekine M, Auquier P. Predictors of quality of life in patients with relapsingremitting multiple sclerosis: A 2-year longitudinal study. Rev Neurol (Paris). Feb 2015;171(2):173-180. 

9. Bayraktar D, Guclu-Gunduz A, Yazici G, et al. Effects of Ai-Chi on balance, functional mobility, strength 

and fatigue in patients with multiple sclerosis: a pilot study. NeuroRehabilitation. 2013;33(3):431-437. 

10. Bee YS, Lin MC, Wang CC, Sheu SJ. Optic neuritis: clinical analysis of 27 cases. The Kaohsiung Journal 

of Medical Sciences. Mar 2003;19(3):105-112. 

11. Beebe GW, Kurtzke JF. Herpes zoster and multiple sclerosis. British Medical Journal. Nov 1 

1969;4(5678):303. 

12. Beebe GW, Kurtzke JF, Kurland LT, Auth TL, Nagler B. Studies on the natural history of multiple 

sclerosis. 3. Epidemiologic analysis of the army experience in World War II. Neurology. Jan 1967;17(1):1-

17. 

13. Beer S, Aschbacher B, Manoglou D, Gamper E, Kool J, Kesselring J. Robot-assisted gait training in 

multiple sclerosis: a pilot randomized trial. Multiple Sclerosis (Houndmills, Basingstoke, England). Mar 

2008;14(2):231-236. 

14. Beier M, D'Orio V, Spat J, Shuman M, Foley FW. Alcohol and substance use in multiple sclerosis. Journal 

of the Neurological Sciences. Mar 15 2014;338(1-2):122-127. 

15. Bobowick AR, Kurtzke JF, Brody JA, Hrubec Z, Gillespie M. Twin study of multiple sclerosis: an 

epidemiologic inquiry. Neurology. Oct 1978;28(10):978-987. 

16. Bombardier CH, Cunniffe M, Wadhwani R, Gibbons LE, Blake KD, Kraft GH. The efficacy of telephone 

counseling for health promotion in people with multiple sclerosis: a randomized controlled trial. Archives 

of Physical Medicine and Rehabilitation. Oct 2008;89(10):1849-1856. 

17. Bombardier CH, Ehde DM, Gibbons LE, et al. Telephone-based physical activity counseling for major 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

110

depression in people with multiple sclerosis. Journal of Consulting and Clinical Psychology. Feb 

2013;81(1):89-99.

18. Briken S, Gold SM, Patra S, et al. Effects of exercise on fitness and cognition in progressive MS: a 

randomized, controlled pilot trial. Multiple Sclerosis (Houndmills, Basingstoke, England). Mar 

2014;20(3):382-390. 

19. Broekmans T, Roelants M, Alders G, Feys P, Thijs H, Eijnde BO. Exploring the effects of a 20-week 

whole-body vibration training programme on leg muscle performance and function in persons with multiple 

sclerosis. J Rehabil Med. Oct 2010;42(9):866-872. 

20. Broekmans T, Roelants M, Feys P, et al. Effects of long-term resistance training and simultaneous electrostimulation on muscle strength and functional mobility in multiple sclerosis. Multiple Sclerosis 

(Houndmills, Basingstoke, England). Apr 2011;17(4):468-477. 

21. Brown JS, Jr. Correlation of mollicutes and their viruses with multiple sclerosis and other demyelinating 

diseases. Medical Hypotheses. Feb 2003;60(2):298-303. 

22. Buljevac D, Hop WC, Reedeker W, et al. Self reported stressful life events and exacerbations in multiple 

sclerosis: prospective study. BMJ. Sep 20 2003;327(7416):646.

23. Burschka JM, Keune PM, Oy UH, Oschmann P, Kuhn P. Mindfulness-based interventions in multiple 

sclerosis: beneficial effects of Tai Chi on balance, coordination, fatigue and depression. BMC Neurol. 

2014;14:165. 

24. Cakt BD, Nacir B, Genc H, et al. Cycling progressive resistance training for people with multiple sclerosis: 

a randomized controlled study. American Journal of Physical Medicine & Rehabilitation / Association of 

Academic Physiatrists. Jun 2010;89(6):446-457. 

25. Carter A, Daley A, Humphreys L, et al. Pragmatic intervention for increasing self-directed exercise 

behaviour and improving important health outcomes in people with multiple sclerosis: a randomised 

controlled trial. Multiple Sclerosis (Houndmills, Basingstoke, England). Jan 13 2014;20(8):1112-1122. 

26. Carvalho AT, Veiga A, Morgado J, et al. Multiple sclerosis and motherhood choice: an observational study 

in Portuguese women patients. Revista de Neurologia. Dec 16 2014;59(12):537-542. 

27. Castro-Sanchez AM, Mataran-Penarrocha GA, Lara-Palomo I, Saavedra-Hernandez M, Arroyo-Morales M, 

Moreno-Lorenzo C. Hydrotherapy for the treatment of pain in people with multiple sclerosis: a randomized 

controlled trial. Evidence-based Complementary and Alternative Medicine: eCAM. 2012;2012:473963. 

28. Cattaneo D, Jonsdottir J, Zocchi M, Regola A. Effects of balance exercises on people with multiple 

sclerosis: a pilot study. Clin Rehabil. Sep 2007;21(9):771-781.

29. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability 

in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. 

Lancet. Jun 28 2014;383(9936):2213-2221. 

30. Chruzander C, Johansson S, Gottberg K, et al. A 10-year follow-up of a population-based study of people 

with multiple sclerosis in Stockholm, Sweden: changes in disability and the value of different factors in 

predicting disability and mortality. Journal of the Neurological Sciences. Sep 15 2013;332(1-2):121-127. 

31. Cioncoloni D, Innocenti I, Bartalini S, et al. Individual factors enhance poor health-related quality of life 

outcome in multiple sclerosis patients. Significance of predictive determinants. Journal of the Neurological 

Sciences. Oct 15 2014;345(1-2):213-219. 

32. Claerbout M, Gebara B, Ilsbroukx S, et al. Effects of 3 weeks' whole body vibration training on muscle 

strength and functional mobility in hospitalized persons with multiple sclerosis. Multiple Sclerosis 

(Houndmills, Basingstoke, England). Apr 2012;18(4):498-505. 

33. Collett J, Dawes H, Meaney A, et al. Exercise for multiple sclerosis: a single-blind randomized trial 

comparing three exercise intensities. Multiple Sclerosis (Houndmills, Basingstoke, England). May 

2011;17(5):594-603. 

34. Coote S, Hughes L, Rainsford G, Minogue C, Donnelly A. Pilot randomized trial of progressive resistance 

exercise augmented by neuromuscular electrical stimulation for people with multiple sclerosis who use 

walking AIDS. Archives of Physical Medicine and Rehabilitation. Feb 2015;96(2):197-204. 

35. Dalgas U, Stenager E, Jakobsen J, et al. Fatigue, mood and quality of life improve in MS patients after 

progressive resistance training. Multiple Sclerosis (Houndmills, Basingstoke, England). Apr 

2010;16(4):480-490. 

36. Dettmers C, Sulzmann M, Ruchay-Plossl A, Gutler R, Vieten M. Endurance exercise improves walking 

distance in MS patients with fatigue. Acta Neurologica Scandinavica. Oct 2009;120(4):251-257. 

37. D'Hooghe M B, Feys P, Deltour S, et al. Impact of a 5-day expedition to machu picchu on persons with 

multiple sclerosis. Multiple Sclerosis International. 2014;2014:761210. 

38. Dlugonski D, Motl RW, Mohr DC, Sandroff BM. Internet-delivered behavioral intervention to increase 
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physical activity in persons with multiple sclerosis: sustainability and secondary outcomes. Psychology, 

Health & Medicine. 2012;17(6):636-651. 

39. Dodd KJ, Taylor NF, Shields N, Prasad D, McDonald E, Gillon A. Progressive resistance training did not 

improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple 

sclerosis: a randomized controlled trial. Multiple Sclerosis (Houndmills, Basingstoke, England). Nov 

2011;17(11):1362-1374.

40. Eftekhari E, Mostahfezian M, Etemadifar M, Zafari A. Resistance training and vibration improve muscle 

strength and functional capacity in female patients with multiple sclerosis. Asian Journal of Sports 

Medicine. Dec 2012;3(4):279-284. 

41. Ennis M, Thain J, Boggild M, Baker GA, Young CA. A randomized controlled trial of a health promotion 

education programme for people with multiple sclerosis. Clin Rehabil. Sep 2006;20(9):783-792. 

42. Fernandez-Jimenez E, Arnett PA. Impact of neurological impairment, depression, cognitive function and 

coping on quality of life of people with multiple sclerosis: A relative importance analysis. Multiple 

Sclerosis (Houndmills, Basingstoke, England). Dec 22 2014.

43. Fryze W, Mirowska-Guzel D, Wiszniewska M, Darda-Ledzion L, Czlonkowska A, Czlonkowska A. 

Alternative methods of treatment used by multiple sclerosis patients in Poland. Neurologia i 

Neurochirurgia Polska. 2006;40(5):386-390. 

44. Garrett M, Hogan N, Larkin A, Saunders J, Jakeman P, Coote S. Exercise in the community for people with 

multiple sclerosis - a follow-up of people with minimal gait impairment. Mult. Scler. J. May 

2013;19(6):790-798. 

45. Glad SB, Aarseth JH, Nyland H, Riise T, Myhr KM. Benign multiple sclerosis: a need for a consensus. 

Acta Neurologica Scandinavica. Supplementum. 2010(190):44-50. 

46. Golan D, Somer E, Dishon S, Cuzin-Disegni L, Miller A. Impact of exposure to war stress on 

exacerbations of multiple sclerosis. Annals of Neurology. Aug 2008;64(2):143-148. 

47. Golan D, Staun-Ram E, Glass-Marmor L, et al. The influence of vitamin D supplementation on melatonin 

status in patients with multiple sclerosis. Brain Behav Immun. Aug 2013;32:180-185. 

48. Harrison T, Stuifbergen A, Adachi E, Becker H. Marriage, impairment, and acceptance in persons with 

multiple sclerosis. Western Journal of Nursing Research. Apr 2004;26(3):266-285; discussion 286-292. 

49. Hart S, Fonareva I, Merluzzi N, Mohr DC. Treatment for depression and its relationship to improvement in 

quality of life and psychological well-being in multiple sclerosis patients. Quality of Life Research: An 

International Journal of Quality of Life Aspects of Treatment, Care and Rehabilitation. Apr 

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74. Roullet E, Verdier-Taillefer MH, Amarenco P, Gharbi G, Alperovitch A, Marteau R. Pregnancy and 

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84. Stroud N, Minahan C, Sabapathy S. The perceived benefits and barriers to exercise participation in persons 
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98. Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive 

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EXCLUDE: DESIGN

Publications not meeting study design inclusion criteria: 

1. Amezcua L, Chung RH, Conti DV, Langer-Gould AM. Vitamin D levels in Hispanics with multiple 

sclerosis. Journal of Neurology. Dec 2012;259(12):2565-2570.

2. Anens E, Emtner M, Zetterberg L, Hellstrom K. Physical activity in subjects with multiple sclerosis with 

focus on gender differences: a survey. BMC Neurol. 2014;14:47. 

3. Bamford CR, Sibley WA, Laguna JF. Swine influenza vaccination in patients with multiple sclerosis. 

Archives of Neurology. Apr 1978;35(4):242-243. 

4. Bhargava P, Cassard S, Steele SU, et al. The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: 

study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. 

Contemporary Clinical Trials. Nov 2014;39(2):288-293. 

5. Brichetto G, Rinaldi S, Spallarossa P, Battaglia MA, de Carvalho ML. Efficacy of physical therapy in 

multiple sclerosis as measured with the modified fatigue impact scale and ambulation index: a retrospective 

study. NeuroRehabilitation. 2013;33(1):107-112. 

6. D'Hooghe MB, De Keyser J. Multiparity in women with multiple sclerosis causes less long-term disability: 

Yes. Mult. Scler. J. Oct 2014;20(11):1432-1434. 

7. Esparza ML, Sasaki S, Kesteloot H. Nutrition, latitude, and multiple sclerosis mortality: an ecologic study. 

American Journal of Epidemiology. Oct 1 1995;142(7):733-737. 

8. Farinotti M, Simi S, Di Pietrantonj C, et al. Dietary interventions for multiple sclerosis. Cochrane 

Database Syst Rev. 2007(1):Cd004192. 

9. Freedman DM, Dosemeci H, Alavanja MCR. Mortality from multiple sclerosis and exposure to residential 

and occupational solar radiation: a case-control study based on death certificates. Occup. Environ. Med. Jun 

2000;57(6):418-421. 

10. Goodin DS. The impact of war-stress on MS exacerbations. Annals of neurology. Aug 2008;64(2):114-115. 

11. Grant WB. Epidemiology of disease risks in relation to vitamin D insufficiency. Prog. Biophys. Mol. Biol. 

Sep 2006;92(1):65-79.

12. Griffith G, Klaren RE, Motl RW, Baynard T, Fernhall B. Experimental protocol of a randomized controlled 

clinical trial investigating exercise, subclinical atherosclerosis, and walking mobility in persons with 

multiple sclerosis. Contemporary Clinical Trials. Feb 14 2015.

13. Heine M, Hoogervorst EL, Hacking HG, Verschuren O, Kwakkel G. Validity of maximal exercise testing 

in people with multiple sclerosis and low to moderate levels of disability. Physical Therapy. Aug 

2014;94(8):1168-1175. 

14. Holmoy T, Kampman MT. Alaska, multiple sclerosis, and the vitamin D hypothesis. Journal of Neurology. 

Feb 2010;257(2):305-306. 

15. Kileff J, Ashburn A. A pilot study of the effect of aerobic exercise on people with moderate disability 

multiple sclerosis. Clin Rehabil. Mar 2005;19(2):165-169.

16. Kurtzke JF. Some contributions of the Department of Veterans Affairs to the epidemiology of multiple 

sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England). Sep 2008;14(8):1007-1012. 

17. Mason RR, Cochrane DJ, Denny GJ, Firth EC, Stannard SR. Is 8 weeks of side-alternating whole-body 

vibration a safe and acceptable modality to improve functional performance in multiple sclerosis? 

Disability and Rehabilitation. 2012;34(8):647-654. 

18. McCombe PA, Callaway LK. Multiparity in women with multiple sclerosis causes less long-term 

disability: No. Mult. Scler. J. Oct 2014;20(11):1435-1436. 

19. Munoz-Lasa S, Ferriero G, Valero R, Gomez-Muniz F, Rabini A, Varela E. Effect of therapeutic horseback 

riding on balance and gait of people with multiple sclerosis. Giornale Italiano di Medicina del Lavoro ed 

Ergonomia. Oct-Dec 2011;33(4):462-467. 

20. Namaka M, Turcotte D, Leong C, Grossberndt A, Klassen D. Multiple sclerosis: Etiology and treatment 

strategies. Consultant Pharmacist. 2008;23(11):886-896. 

21. Nordvik I, Myhr KM, Nyland H, Bjerve KS. Effect of dietary advice and n-3 supplementation in newly 

diagnosed MS patients. Acta Neurologica Scandinavica. Sep 2000;102(3):143-149. 

22. Ozgocmen S, Bulut S, Ilhan N, Gulkesen A, Ardicoglu O, Ozkan Y. Vitamin D deficiency and reduced 

bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacity. Journal of 

Bone and Mineral Metabolism. 2005;23(4):309-313. 

23. Pariser G, Madras D, Weiss E. Outcomes of an aquatic exercise program including aerobic capacity, lactate 

threshold, and fatigue in two individuals with multiple sclerosis. Journal of neurologic physical therapy: 
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122

JNPT. Jun 2006;30(2):82-90.

24. Pimentel ML. Multiple sclerosis in the Southern and Northern hemispheres: the month of birth at different 

latitudes has the same influence on the prevalence and progression of the disease in the Northern and 

Southern hemispheres? Arq Neuropsiquiatr. Sep 2013;71(9A):569-570. 

25. Poser S, Wikstrom J, Bauer HJ. Clinical data and the identification of special forms of multiple sclerosis in 

1271 cases studied with a standardized documentation system. Journal of the Neurological Sciences. Feb 

1979;40(2-3):159-168. 

26. Singh V, Hintzen RQ, Luider TM, Stoop MP. Proteomics technologies for biomarker discovery in multiple 

sclerosis. Journal of Neuroimmunology. Jul 15 2012;248(1-2):40-47.

27. Smolders J, Hupperts R, Barkhof F, et al. Efficacy of vitamin D3 as add-on therapy in patients with 

relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: a Phase II, multicenter, 

double-blind, randomized, placebo-controlled trial. Journal of the Neurological Sciences. Dec 15 

2011;311(1-2):44-49.

28. Torkildsen O, Grytten N, Aarseth J, Myhr KM, Kampman MT. Month of birth as a risk factor for multiple 

sclerosis: an update. Acta Neurologica Scandinavica. Supplementum. 2012(195):58-62.

29. Vukusic S, Confavreux C. Pregnancy and multiple sclerosis: the children of PRIMS. Clinical Neurology 

and Neurosurgery. Mar 2006;108(3):266-270. 

30. Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-

dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. Journal of Neurology, Neurosurgery, and 

Psychiatry. Sep 2005;76(9):1294-1296. 

31. Wojcicki TR, Roberts SA, Learmonth YC, et al. Improving physical functional and quality of life in older 

adults with multiple sclerosis via a DVD-delivered exercise intervention: a study protocol. BMJ Open. 

2014;4(12):e006250. 

32. Yadav V, Bever C, Jr., Bowen J, et al. Summary of evidence-based guideline: complementary and 

alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the 

American Academy of Neurology. Neurology. Mar 25 2014;82(12):1083-1092. 

EXCLUDE: PARTICIPANTS

Excluded publications not reporting on participants with MS and risk factor studies excluding 

progressive MS: 

1. Harandi AA, Shahbeigi S, Pakdaman H, Fereshtehnejad SM, Nikravesh E, Jalilzadeh R. Association of 

serum 25(OH) vitamin D3 concentration with severity of multiple sclerosis. Iranian Journal of Neurology. 

2012;11(2):54-58.

2. Henderson VW. Alzheimer's disease and other neurological disorders. Climacteric. Oct 2007;10 Suppl 

2:92-96.

EXCLUDE: LANGUAGE

Excluded non-English language publications: 

1. Ragonese P, Castiglia G, Cusimano V, Battaglieri F, Salemi G. Cigarette smoking, coffee consumption and 

multiple sclerosis risk: A case - Control study. Acta Medica Mediterranea. 2007;23(3):133-140. 

EXCLUDE: DUPLICATE

Duplicate publications: 

1. Sandroff BM, Klaren RE, Pilutti LA, Dlugonski D, Benedict RHB, Motl RW. Randomized controlled trial 

of physical activity, cognition, and walking in multiple sclerosis. Journal of Neurology. Feb 

2014;261(2):363-372. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

123

BACKGROUND

Reviews screened for additional references and multiple publications of included studies: 

1. Multiple sclerosis - management of multiple sclerosis in primary and secondary care. October 2014.

2. Ascherio A. Environmental factors in multiple sclerosis. Expert Review of Neurotherapeutics. Dec 

2013;13(12 Suppl):3-9.

3. Ascherio A, Munger K, White R, et al. Vitamin D as a predictor of multiple sclerosis activity and 

progression. Mult. Scler. J. Oct 2013;19(11):23-24.

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APPENDIX C. CRITERIA USED IN QUALITY ASSESSMENT

This appendix documents the individual risk of bias criteria used to assess included studies. In 

addition, it documents the criteria used to rate the quality of evidence across studies.

RISK OF BIAS ASSESSMENT OF KQ1 AND KQ2 STUDIES

A large number of diverse studies contributed to the review. We broadly categorized risk factor 

studies into concurrent, retrospective, and prospective studies. Concurrent and retrospective 

studies can provide only limited information on questions of progression, regardless of their 

methodological quality, and these studies were not further differentiated. 

The identified prospective studies relevant to KQ1 and KQ2 were assessed with QUIPS (QUality 

In Prognosis Studies), a critical appraisal tool for prognostic studies. QUIPS assesses the 

domains study participation, study attrition, prognostic factor measurement, outcome 

measurement, study confounding, and statistical analysis and reporting.15 For each domain we 

determined whether the study indicates high risk of bias, moderate risk of bias, or low risk of 

bias.

Appendix Table 1. Risk of Bias: KQ1 and KQ2 Prospective Studies

Author, year Study 

Participation

Study 

Attrition 

Prognostic 

Factor 

Measurement

Outcome 

Measurement

Study 

Confounding

Statistical 

Analysis and 

Reporting

KQ1 and 

KQ2

Ascherio, 

201420

High Moderate Low Low Moderate Low

Confavreux, 

199830

Low Low Low Low High Low

Detels, 

198235

Low Moderate Moderate High Moderate Moderate

Mowry, 

201269

Low Low Low Low Low Low

Pasto, 201272 Low Low Low Low High Low

Pittas, 200976 Moderate Low Low Low Low Low

Runmarker, 

1995113

Moderate Low Low Low High Moderate

Shammas, 

201487

High Low Low Low Moderate High

SoiluHanninen, 

200791

High Low Low Low Moderate High

Stuifbergen, 

200696

Low Low Low Low Low Low

Sundstom, 

200897

Moderate Low Moderate Low Low Moderate

Swank, 

199098

Low Low High Low Low Moderate

Tepavcevic, 

2010112

Moderate Moderate High Low Moderate High
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Legend: 

Study participation: Prompting items: a. Adequate participation in the study by eligible persons, b. Description of 

the source population or population of interest, c. Description of the baseline study sample, d. Adequate description 

of the sampling frame, and recruitment, e. Adequate description of the period and place of recruitment, f. Adequate 

description of inclusion and exclusion criteria. Ratings: High risk: The relationship between the PF and outcome is 

very likely to be different for participants and eligible nonparticipants; Moderate bias: The relationship between the

PF and outcome may be different for participants and eligible nonparticipants; Low bias: The relationship between 

the PF and outcome is unlikely to be different for participants and eligible nonparticipants

Study attrition: a. Adequate response rate for study participants, b. Description of attempts to collect information 

on participants who dropped out, c. Reasons for loss to follow-up are provided, d. Adequate description of 

participants lost to follow-up, e. There are no important differences between participants who completed the study 

and those who did not. Ratings: High bias: The relationship between the PF and outcome is very likely to be 

different for completing and non-completing participants; Moderate bias: The relationship between the PF and 

outcome may be different for completing and non-completing participants; Low bias: The relationship between the 

PF and outcome is unlikely to be different for completing and non-completing participants

Prognostic Factor Measurement: Prompting items: a. A clear definition or description of the PF is provided, b. 

Method of PF measurement is adequately valid and reliable, c. Continuous variables are reported or appropriate cut 

points are used, d. The method and setting of measurement of PF is the same for all study participants, e. Adequate 

proportion of the study sample has complete data for the PF, f. Appropriate methods of imputation are used for 

missing PF data. Ratings: High bias: The measurement of the PF is very likely to be different for different levels of 

the outcome of interest, Moderate bias: The measurement of the PF may be different for different levels of the 

outcome of interest, Low bias: The measurement of the PF is unlikely to be different for different levels of the 

outcome of interest

Outcome Measurement: Prompting items: a. clear definition of the outcome is provided, b. Method of outcome 

measurement used is adequately valid and reliable, c. The method and setting of outcome measurement is the same 

for all study participants. Ratings: High bias: The measurement of the outcome is very likely to be different related

to the baseline level of the PF, Moderate bias: The measurement of the outcome may be different related to the 

baseline level of the PF, Low bias: The measurement of the outcome is unlikely to be different related to the 

baseline level of the PF

Study Confounding: Prompting items: a. All important confounders are measured, b. Clear definitions of the 

important confounders measured are provided, c. Measurement of all important confounders is adequately valid and 

reliable, d. The method and setting of confounding measurement are the same for all study participants, e. 

Appropriate methods are used if imputation is used for missing confounder data, f. Important potential confounders 

are accounted for in the study design, g. Important potential confounders are accounted for in the analysis. Ratings: 

High bias: The observed effect of the PF on the outcome is very likely to be distorted by another factor related to PF 

and outcome, Moderate bias: The observed effect of the PF on outcome may be distorted by another factor related to 

PF and outcome, Low bias: The observed effect of the PF on outcome is unlikely to be distorted by another factor 

related to PF and outcome

Statistical Analysis and Reporting: Prompting items: a. Sufficient presentation of data to assess the adequacy of 

the analytic strategy, b. Strategy for model building is appropriate and is based on a conceptual framework or model, 

c. The selected statistical model is adequate for the design of the study, d. There is no selective reporting of results. 

Ratings: High bias: The reported results are very likely to be spurious or biased related to analysis or reporting, 

Moderate bias: The reported results may be spurious or biased related to analysis or reporting, Low bias: The 

reported results are unlikely to be spurious or biased related to analysis or reporting 

RISK OF BIAS ASSESSMENT OF KQ3 STUDIES

Studies relevant to KQ3 were assessed with the Cochrane risk of bias tool. The tool assesses 

random sequence generation (selection bias), allocation concealment (selection bias), blinding of 

participants and providers (performance bias), blinding of outcome assessors (detection bias), 

completeness of reporting outcome data (attrition bias), selective outcome reporting (reporting 

bias), and other sources of bias (if appropriate) for each of the included studies. For each domain
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we determined whether the study indicates a high risk of bias, a low risk of bias, or an unclear 

risk of bias.

Appendix Table 2. Risk of Bias: KQ3 Studies

Author, year Random 

sequence 

generation

Allocation 

concealment

Blinding of 

participants/

providers

Blinding of 

outcome 

assessors

Incomplete 

outcome 

data

Selective 

reporting

Other bias

Armutlu, 200119 Unclear Unclear High risk Low risk Low risk Low risk Low risk

Bates, 197724 Unclear Unclear Low risk Low risk Low risk High risk Low risk

Bates, 197825 Unclear Unclear Low risk Low risk Unclear Unclear Unclear

Bates, 198923 Unclear Unclear Low risk Low risk Unclear Unclear Unclear

Bjarnadottir, 

200726

Unclear Low risk High risk High risk Unclear Unclear High risk

Burton, 201028 Low risk Low risk Low risk Low risk High risk Low risk Low risk

Carter, 201329 Low risk Low risk High risk Low risk Low risk Low risk Low risk

Conklyn, 201031 Unclear Unclear High risk High risk Low risk Low risk High risk

Dalgas, 200932 Unclear Low risk High risk Low risk Low risk Low risk Low risk

DeBolt, 200434 Unclear Unclear High risk High risk Unclear Unclear Unclear

Fimland, 201037 Unclear Unclear Unclear Unclear Low risk Low risk High risk

Golzari, 201042 Unclear Unclear High risk Low risk Unclear Unclear High risk

Harbige, 200744 Unclear Unclear Low risk Low risk Unclear Unclear High risk

Kampman, 

201249

Low risk Low risk Low risk Low risk Low risk Low risk Low risk

Lo, 200856 Unclear Unclear High risk Low risk Low risk Low risk High risk

Millar, 197365 Low risk Low risk Low risk Low risk High risk Low risk Low risk

Miller, 201166 Unclear Unclear High risk Unclear Low risk Low risk Unclear

Mosayebi, 

201167

Unclear Low risk Low risk Low risk High risk Low risk Unclear

Pantzaris, 

201371

Low risk Low risk Low risk Low risk Low risk Unclear Unclear

Paty, 197873 Unclear Unclear Low risk Low risk High risk Unclear Unclear

Petajan, 199674 Unclear Unclear High risk Low risk High risk Low risk High risk

Pfalzer, 201175 Unclear Unclear High risk Unclear Unclear Low risk Low risk

RamirezRamirez, 

201378

Low risk Low risk Low risk Low risk High risk Low risk Low risk

Rampello, 

200779

Low risk Low risk Unclear Unclear High risk Unclear Unclear

RezapourFirouzi, 201380Low risk Low risk Low risk Low risk High risk Low risk High risk

Romberg, 

200481

Unclear Unclear High risk High risk Low risk Unclear Unclear

Sangelaji, 

201483

Unclear Low risk High risk Unclear High risk Low risk Low risk

Schwartz, 

201284

Low risk Low risk High risk Low risk High risk Low risk High risk

Shaygannejad, 

201288

Low risk Low risk Low risk Low risk Low risk Low risk Low risk

Soilu-Hanninen, 

2012128

Low risk Low risk Low risk Low risk High risk Unclear High risk

Solari, 199992 Low risk Low risk High risk Low risk Low risk Low risk Low risk
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Stein, 201194 Low risk Low risk High risk Low risk Low risk High risk High risk

Torkildsen, 

2012101

Low risk Low risk Low risk Low risk Unclear Low risk Unclear

WeinstockGuttman, 

2005107

Unclear Unclear Low risk Low risk High risk Low risk High risk

Wiles, 2001109 Unclear Unclear High risk Low risk Low risk Low risk Low risk

Yadav, 2014110 Unclear Unclear High risk Low risk High risk Low risk High risk

Legend:

Random sequence generation: Low risk: The investigators describe a random component in the sequence 

generation process such as: Referring to a random number table, Using a computer random number generator; Coin 

tossing; Shuffling cards or envelopes; Throwing dice; Drawing of lots; Minimization; High risk: The investigators 

describe a non-random component in the sequence generation process. Usually, the description would involve some 

systematic, non-random approach, for example: Sequence generated by odd or even date of birth; Sequence 

generated by some rule based on date (or day) of admission; Sequence generated by some rule based on hospital or 

clinic record number; Allocation by judgment of the clinician; Allocation by preference of the participant;

Allocation based on the results of a laboratory test or a series of tests; Allocation by availability of the intervention.

Unclear: Insufficient information about the sequence generation process to permit judgment of ‘Low risk’ or ‘High 

risk’. 

Allocation concealment: Low risk: Participants and investigators enrolling participants could not foresee 

assignment because one of the following, or an equivalent method, was used to conceal allocation: Central 

allocation (including telephone, web-based and pharmacy-controlled randomization); Sequentially numbered drug 

containers of identical appearance; Sequentially numbered, opaque, sealed envelopes. High risk: Participants or 

investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as 

allocation based on: Using an open random allocation schedule (eg, a list of random numbers); Assignment 

envelopes were used without appropriate safeguards (eg, if envelopes were unsealed or non-opaque or not 

sequentially numbered); Alternation or rotation; Date of birth; Case record number; Any other explicitly 

unconcealed procedure. Unclear: Insufficient information to permit judgment of ‘Low risk’ or ‘High risk’. This is 

usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite 

judgment – for example if the use of assignment envelopes is described, but it remains unclear whether envelopes 

were sequentially numbered, opaque and sealed.

Blinding of participants and personnel: Low risk: No blinding or incomplete blinding, but the review authors 

judge that the outcome is not likely to be influenced by lack of blinding; Blinding of participants and key study 

personnel ensured, and unlikely that the blinding could have been broken. High risk: No blinding or incomplete 

blinding, and the outcome is likely to be influenced by lack of blinding; Blinding of key study participants and 

personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced 

by lack of blinding. Unclear: Insufficient information to permit judgment of ‘Low risk’ or ‘High risk’; The study did 

not address this outcome.

Blinding of outcome assessment: Low risk: No blinding of outcome assessment, but the review authors judge that 

the outcome measurement is not likely to be influenced by lack of blinding; Blinding of outcome assessment 

ensured, and unlikely that the blinding could have been broken. High risk: No blinding of outcome assessment, and 

the outcome measurement is likely to be influenced by lack of blinding; Blinding of outcome assessment, but likely 

that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of 

blinding. Unclear: Insufficient information to permit judgment of ‘Low risk’ or ‘High risk’; The study did not 

address this outcome.

Incomplete outcome data: Low risk: No missing outcome data; Reasons for missing outcome data unlikely to be 

related to true outcome (for survival data, censoring unlikely to be introducing bias); Missing outcome data balanced 

in numbers across intervention groups, with similar reasons for missing data across groups; For dichotomous 

outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a 

clinically relevant impact on the intervention effect estimate; For continuous outcome data, plausible effect size 

(difference in means or standardized difference in means) among missing outcomes not enough to have a clinically 

relevant impact on observed effect size; Missing data have been imputed using appropriate methods. High risk: 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

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Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons 

for missing data across intervention groups; For dichotomous outcome data, the proportion of missing outcomes 

compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; For 

continuous outcome data, plausible effect size (difference in means or standardized difference in means) among 

missing outcomes enough to induce clinically relevant bias in observed effect size; ‘As-treated’ analysis done with 

substantial departure of the intervention received from that assigned at randomization; Potentially inappropriate 

application of simple imputation. Unclear: Insufficient reporting of attrition/exclusions to permit judgment of ‘Low 

risk’ or ‘High risk’ (eg, number randomized not stated, no reasons for missing data provided); The study did not 

address this outcome.

Selective reporting: Low risk: The study protocol is available and all of the study’s pre-specified (primary and 

secondary) outcomes that are of interest in the review have been reported in the pre-specified way; The study 

protocol is not available but it is clear that the published reports include all expected outcomes, including those that 

were pre-specified (convincing text of this nature may be uncommon). High risk: Not all of the study’s pre-specified 

primary outcomes have been reported; One or more primary outcomes is reported using measurements, analysis 

methods or subsets of the data (eg, subscales) that were not pre-specified; One or more reported primary outcomes 

were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse 

effect); One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a 

meta-analysis; The study report fails to include results for a key outcome that would be expected to have been 

reported for such a study. Unclear: Insufficient information to permit judgment of ‘Low risk’ or ‘High risk’. It is 

likely that the majority of studies will fall into this category.

Other bias: Low risk: The study appears to be free of other sources of bias. High risk: There is at least one 

important risk of bias. For example the study had a potential source of bias related to the specific study design used; 

has been claimed to have been fraudulent; or had some other problem. Unclear: There may be a risk of bias, but 

there is either: Insufficient information to assess whether an important risk of bias exists; or insufficient rationale or 

evidence that an identified problem will introduce bias.

CRITERIA TO RATE THE BODY OF EVIDENCE FOR KQ1 AND KQ2

The GRADE framework for prognostic factor research18 differentiates 8 criteria that are used to 

evaluate the quality of the evidence across all identified studies:

The phase of investigation differentiates whether the risk factor evidence is primarily based on a 

study that aimed to identify potential prognostic factors (moderate quality) rather than based on 

studies aiming to confirm identified associations or explanatory research aiming to understand 

prognostic pathways (high quality). 

Study limitations took the assessment frame into account by differentiating whether the risk 

factor status and the outcome variable were assessed at the same time (concurrently), 

retrospectively, or prospectively. Prospective studies were further differentiated by the risk of 

bias based on the QUIPS scores.

Inconsistency assessed whether the identified association was consistently present across studies

and across study designs (eg, present in concurrent and prospective studies). 

Indirectness took into account whether the available research studies does not accurately reflect 

the review question. Examples are cases where the only available research studies reported on 

vitamin D status, rather than a directly patient-modifiable risk factor such as vitamin D intake.

Evidence was downgraded for imprecision if the sample size was insufficient, the confidence 

interval was wide and overlapped the value of no effect, there were less than 10 outcome events 

for each prognostic variable, or there were less than 100 cases reaching endpoints. 
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Evidence was downgraded for publication bias unless the value of the risk or protective factor in 

predicting the outcome has been repetitively investigated. 

Evidence for individual risk factors may be upgraded if effects are moderate or large or there is 

evidence of exposure-gradient response for factors measured at different doses.

CRITERIA TO RATE THE BODY OF EVIDENCE FOR KQ3

For KQ3 we took the criteria risk of bias, inconsistency, indirectness, imprecision, publication 

bias, large effect, dose response, and all plausible residual confounding would reduce a 

demonstrated effect and/or would suggest a spurious effect if no effect was observed into 

account. The starting point was high evidence because the data are based on RCTs. 

Risk of bias, inconsistency, indirectness, imprecision, and publication bias can lower the quality. 

Large effect, dose response, and all plausible residual confounding can upgrade the quality of the 

body of evidence. 17 

Risk of bias evaluations were based on the above documented Cochrane Risk of Bias tool 

assessments. Inconsistency took the direction and the size of effects across studies into account. 

Indirectness may assess whether comparative effects are based on head-to-head trial evidence or 

was obtained from meta-regressions and subgroup analyses. Imprecision takes the confidence 

interval around the point estimate into account. Publication bias was assessed to determine 

whether there is evidence that pertinent studies, in this case negative effect studies are missing. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

132

APPENDIX D. PEER REVIEW COMMENTS/AUTHOR RESPONSES

Comment Response

Studies missing - Yes - Studies evaluating geography itself as a risk factor, studies prior 

to 1973, studies involving co-morbidity

The identified studies on associations between geography and 

progression are shown in the “other” and the “multiple” risk factor 

section.

Studies published prior to 1973 were eligible for inclusion in the review 

and all databases were searched without date restriction. We have 

added the eligibility criteria after the description of the included studies 

in the result section to avoid ambiguity. In addition, we have 

emphasized that databases were searched from inception.

Co-morbidities were outside the scope of this review but we have 

expanded the future research section to indicate that sufficient 

literature exists for systematic reviews on several individual comorbidities. 

It would have been useful to add obesity related studies in the review as it appears to be 

an important co-morbid condition and related information would have been of great 

research as well as clinical significance. 

See above. In particular there is a growing literature on weight and MS 

progression; we have expanded on this issue in the future research 

section.

Several typographical errors are present in the draft, that I assume will be reviewed 

carefully towards the final draft.

Typographical errors will be correct before publication

Pg 1/Line 8: Traumatic brain injury is more common than MS in younger adults but is not 

progressive. I’d reword this sentence as follows: Multiple sclerosis (MS) is the most 

common progressive disease of the central nervous system in young adults and the 

cause of serious physical disability in adults of working age.

Revised as suggested

Pg 1/Line 21: Use “MS” throughout the manuscript after it’s defined. We have revised the text accordingly but left the key questions as is to 

avoid ambiguity

Pg 1/Line 49: Is this a preliminary report vs. final? The draft report is subjected to peer review

Pg 3/Line 16: “Concurrent” is not commonly used and is confusing. It should be replaced 

with retrospective. 

To address this point, we have added a definition to avoid confusion 

(measuring the exposure status and the outcome at the same time 

point, eg, current alcohol intake)

Pg 5/Line 5: Change “Out” to Our. Changed

Pg 5/Line 25: There are several redundant and inaccurate statements in the conclusion. 

The association between MS progression and vitamin D supplementation is not 

significant but the conclusions imply it is related. The conclusion should be modified to 

something like the following: 

Our systematic review documents the available evidence on modifiable risk factors for MS 

progression. Associations with MS progression are strongest for smoking. None of the 

intervention studies examining exercise, dietary, and vitamin D supplementation reported 

a statistically significant effect on MS disability. Other than smoking cessation, there are 

no other modifiable risk factors that can be given support from this review as an 

intervention worthy of slowing MS progression. 

To address the perceived redundancy we have divided the conclusions 

into multiple paragraphs: one characterizes the overall evidence base, 

one summarizes the risk factor studies, one summarizes the 

intervention RCTs, and the last one describes the evidence for factors 

that were addressed in both, risk factor and in intervention studies. The 

correlation between EDSS scores and vitamin D level was statistically 

significant. We have revised the sentence to avoid the perceived 

inaccuracy. 
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

133

Pg 8/Line 3: There are several reviews of MS risk factors published in the literature. 

Some are comprehensive in scope. The statement below is confusing in implying there 

are multiple reviews of risk factors translated into treatment options. Is this referring to 

dietary or exercise treatments? 

There is an emerging body of research that evaluates risk factors translated into 

treatment options but no systematic review has to date comprehensively synthesized the 

available evidence.

We have deleted the sentence

Pg 18/Line 8: Why was 1973 used as the starting year (vs. 1970)? See above 

Pg 51/Line 5: There is no figure in the box. Unfortunately the conversion to PDF in the online editorial manager 

system did not display the figure; this will be corrected in the final 

report.

Forest plots: There is no confidence interval represented on the summary measure of risk 

in the diagram. This should be included.

We were not sure how this perception came about, confidence 

intervals are shown for individual studies and the pooled effect in all 

forest plots

Please see editorial suggestions and comments in the uploaded document. Thank you for your careful review; we have accepted all editorial 

changes 

p. 10: So if I understand correctly, a study on solely Relapsing Remitting MS (RR MS), 

the most common disease type, would have been excluded - even though patients with 

RR MS often progress over time?

We have revised the sentence to avoid confusion

p. 24: Sentence is unclear. Which of the studies does this phrase refer to? Author name added to avoid ambiguity

p. 50: awkward wording Revised to clarify that the individually assessed risk factors as well as 

predicted outcomes were very specific

p. 51: Figure missing from draft See above

p. 51: I assume you mean since the Vit D values were dichotomized, rather than reported 

as a continuous variable? The statement is unclear as written, since the study did in fact 

use the EDSS.

The studies did not report on a correlation, hence they could not be 

added to the meta-analysis; we have clarified this in the text

p. 52: Graphs have a diagonal line, which should be deleted. Formatting changes are due to converting to PDF and will be corrected 

in the final report

p. 54: Which - any alcohol consumption, or heavy drinking, or both? Clarified

p. 56: Explain the "downgrades" (or refer to the text in the legend) Added

p. 69: Unclear in this context We have added more explanation regarding the waitlist condition

p. 78: Would this be better expressed as "pregnancy" rather than "children"? See above

p. 82: Unclear. Do you mean "for which the published evidence demonstrates their 

amenability...". Need a clear statement to conclude the review!

We have revised the draft conclusions

Did any study examine the impact of moving to a different region/climate/latitude during 

childhood or early adulthood?

We did not identify such a study

I have a general concern that there may be confusion in discussion of studies between 

change from Relapsing-Remitting MS (RR MS) to Secondary Progressive MS (SP MS), 

and progression of disability caused by MS, which can occur both in RR MS and SP MS.

Yes, several studies did not restrict to RR MS and studies used a 

variety of outcome measures. To address this concern, we have 

highlighted those studies in the summary of findings section that 

specifically reported on the change from RR to SP MS and those that 

only included patients with RR MS at baseline
Modifiable Risk Factors in the Progression of Multiple Sclerosis Evidence-based Synthesis Program

134

Was the post-partum period also analyzed separate from pregnancy itself? It is commonly 

held that MS is likely to be quiescent during pregnancy, but the risk for relapses or 

progression is increased from baseline during the immediate post-partum interval.

Given the complexity of the topic and the diversity across the large 

number of studies that should be addressed in a separate systematic 

review we have added this topic to the list of suggested future research 

studies.

Page 5, line 5: Change "Out" to "Our" See above

Page 7, line 16: Change "described" to "characterized pathologically" and add "focal 

areas of" before "inflammation..."

Changed as suggested

Page 7, lines 35 to 37: Change "Progressive relapsing MS" to "Active progressive MS" 

The classification system for MS subtypes was revised in 2014 to remove the 

classification of "progressive relapsing" and replace it with the classification of "active 

progressive" This is given in Reference 8.

Changed as suggested

Page 10, line 60: Azathioprine is listed as a medication specifically designed for MS, 

which . Azathioprine was originally developed as an antineoplastic agent it is now used 

for immunosuppression in autoimmune diseases and organ transplantation. Other drugs 

in this class that were omitted from the list include methotrexate and cyclophosphamide. 

Cladribine, listed later, probably belongs in the same list.

We have removed the specific examples and reduced the text to one 

example per medication type to address this point

Page 13, line 54: Move "presented" to after "statistics" We have revised the sentence

Page 15, line 14: After "East" add ", Professor, Departments of Neurology, Pharmacology 

and Physical Therapy, University of Maryland School of Medicine"

Added

Page 15, line 14: After "MPH" add ", Director, MS Center of Excellence - West" Added

Page 15, line 26: Change,"PHD" to "PhD" Changed

Tables 1 to 7: I may not be reading the tables correctly but I did not see a column 

indicating the rating of the quality of the evidence in each study. I believe that Appendix C 

deals with that issue in detail but should some summary indication be included on these 

tables?

The studies were assessed with a number of individual risk of bias 

criteria which exceeded the available space in the evidence tables. To 

address this point we have systematically added information on the risk 

of bias to the result sections following the evidence tables

Tables 1 to 7, case definition: I may not be understanding what is being reported here. I 

am used to this column being used to report whether an acceptable case definition was 

used by the study in question. In most cases this would involve a diagnosis of MS based 

on published criteria such as the Poser, McDonald or modified McDonald criteria. Cases 

might be further restricted based on disability range using a scale like the EDSS score. 

The entries in this column don't seem to fit this so I am unclear on what is being displayed 

here. I am also not clear on whether publications were reviewed to ensure that accepted 

case definitions were used.

We have revised the term to “predicted variable” to avoid confusion 

with MS diagnostic criteria. In addition, we have added the diagnostic 

criteria for prospective studies to the evidence tables.