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Management Brief No. 111

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Management eBriefs
Issue 111April 2016

The report is a product of the VA/HSR Evidence Synthesis Program.

Systematic Review: Modifiable Risk Factors in the Progression of Multiple Sclerosis

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. MS disease presentation is very heterogeneous with variable clinical manifestations that evolve over time. In about 50 percent of patients the course of MS changes from relapsing-remitting to secondary progressive disease after ten years. Relapsing-remitting disease manifests in relapses followed by periods of partial or complete recovery (remissions). In secondary progressive MS, patients develop relapsing-remitting MS, but then begin progressing with or without relapses. Furthermore, 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 activities of daily living. Epidemiologic data suggest that rates of MS vary with demographic and environmental factors, which indicates 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.

Conducted by investigators with the VA Evidence-Based Synthesis Program (ESP) located at the West Los Angeles VA Medical Center, this systematic review focused on modifiable risk factors and exposures associated with MS progression, as well as on interventions directed at modifiable risk factors that might delay progression. ESP investigators reviewed the literature from inception of databases (i.e., PubMed, EMBASE, AMED, ProQuest Military Collection, etc.) to March 2015 and identified 94 publications that met inclusion criteria. Literature searches were not restricted to a narrow set of known risk factors, but were exploratory in nature.

Overall Findings

Risk factor studies:

  • There was great variation in assessment and prediction methods across 59 studies relevant to modifiable risk factors. More prospective studies are needed.
  • The most consistent results were shown for the correlation between EDSS (Expanded Disability Status Scale) and vitamin D levels, indicating that lower levels in vitamin D measures are associated with higher EDSS scores. Further, smoking was associated with a faster progression of MS in smokers compared to non-smokers across studies. The use of epidural analgesics in childbirth delivery was assessed in three studies, and none reported a statistically significant association between EDSS or DSS (Disability Status Scale) scores.
  • Results for sun exposure, sunscreen use, month of birth, diet, fish consumption, alcohol consumption, exercise, trauma, oral contraception, geographic region, and education were addressed in more than one study; however, differences in risk factor and outcome measures did not allow for concrete evidence statements.

Exposure prior or during military service:

  • Risk factors in Veterans and active military personnel were one of the key questions for this review, but only four studies targeted this subgroup. None of the studies assessed the same risk factors, and outcome measures varied.

Intervention studies:

  • This review did not identify interventions that showed a statistically significant effect of exercise, dietary, or vitamin D supplementation on EDSS scores across 36 identified randomized controlled trials (RCTs). However, studies were not designed to assess effects on MS progression, and more research is needed.

Future Research

This systematic review showed that more prospective research studies are needed to allow predictions and meaningful interpretation of MS progression risk factor analyses. Future studies should report more details and statistical analyses in order to facilitate evidence synthesis in meta-analyses. Specific areas that need more research are the consumption of alcohol and sun exposure and their potential effects on slowing progression of this disease. In addition, more research is needed on interventions for smoking cessation, adequately powered vitamin D supplementation RCTs, and studies that evaluate the effects of long-term exercise interventions. Finally, although this review addressed a broad research field, there are other potential risk factors of interest that were outside its scope, including the effect of treatable comorbidities of multiple sclerosis.

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.

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ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.


This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers – and to disseminate these reports throughout VA.

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