A systematic review of morbidities suggestive of the multiple sclerosis prodrome

ABSTRACT

Introduction

The identification of a prodromal phase in multiple sclerosis (MS) could have major implications for earlier recognition and management of MS. The authors conducted a systematic review assessing studies of morbidities before, or at, MS onset or diagnosis.Areas covered: Two independent reviewers searched Medline, Embase, Psycinfo and CINAHL from inception to February 8^th, 2019. To be eligible, studies had to be published in English and report the relative occurrence of at least one morbidity or symptom before, or at, MS onset or diagnosis among MS cases in comparison to a control group not known to have MS. Findings were narratively synthesized. Study quality was assessed using the Newcastle–Ottawa scale (NOS, maximum score 9).Expert opinion: Twenty-nine studies were included, which comprised 83,590 MS cases and 396,343 controls. Most were case-control studies (25/29), 8/29 were of high quality (NOS≥8) and 19/29 examined the period before MS symptom onset. Most studies assessing anxiety, depression, migraine and lower cognitive performance found these conditions to be more prevalent before MS onset or diagnosis relative to controls. There was limited evidence to implicate other conditions. Thus, there is evidence that anxiety, depression, migraine and lower cognitive performance form part of the MS prodrome.

KEYWORDS:

• Diagnosis
• multiple sclerosis
• onset
• prodrome
• review

Article Highlights

• Emerging evidence suggestions that combinations of vitamins and minerals may convey some general improvements.

• Eight of 11 studies in participants who were mentally or physically unwell were positive, demonstrating the benefit of micronutrient supplementation, particularly supplements that includes B vitamins. It was noted that only two studies of these 11 were conducted in adults with diagnosed psychiatric difficulties (Major Depressive Disorder).

• Evidence for supplementation in healthy adults is limited although may be better captured by using measures of resilience or general health and wellbeing.

• Higher-dose broad-spectrum micronutrient products appear to convey better treatment effects than lower-dose formulae.

• Compounds that include Vitamin B complex in doses above RDA appear to have benefit for reducing symptoms of anxiety, depression and/or stress.

• Including higher doses of minerals alongside vitamins in micronutrient formulas appears to add to a positive treatment effect.

• Future research needs to focus on replication of existing study lengths, formulas and extend to populations with diagnosed anxiety or depressive disorders.

• Appropriately powered studies that use consistent reporting of effect sizes would assist future reviews to make evidence-based recommendations.

Declaration of Interest

JMA Wijnands received research funding from the Michael Smith Foundation for Health Research/The Koehle Family Foundation. RA Marrie receives research funding from the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Research Manitoba, the Consortium of MS Centers, Crohn’s and Colitis Canada, the Waugh Family Chair in Multiple Sclerosis, and has conducted clinical trials funded by sanofi-aventis. H Tremlett is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. Current research support received from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation. In addition, in the last 5 years, has received research support from the UK MS Trust; travel expenses to present at CME conferences from the Consortium of MS Centres (2018), the National MS Society (2016, 2018), ECTRIMS/ACTRIMS (2016, 2017, 2018, 2019, 2020), American Academy of Neurology (2015, 2016, 2019). Speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by H Tremlett’s research group. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary Material

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Additional information

Funding

This paper was not funded.