Elsevier

The Lancet Neurology

Volume 9, Issue 7, July 2010, Pages 727-739
The Lancet Neurology

Review
Multiple sclerosis: risk factors, prodromes, and potential causal pathways

https://doi.org/10.1016/S1474-4422(10)70094-6Get rights and content

Summary

Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.

Introduction

Multiple sclerosis (MS) is the most common disease of the CNS to cause permanent disability in young adults.1 On the basis of strong circumstantial evidence, MS is thought to be an organ-specific autoimmune disorder,1, 2 but much remains to be understood about the initiation of the disease. MS seems unlikely to result from a single causative event; instead, the disease seems to develop in genetically susceptible populations as a result of environmental exposures.

The concept of a prodrome is being studied intensively in neurological disease, and is defined as the time period between the onset of decline in a baseline level of functioning until criteria for disease diagnosis are met.3 The constellation of symptoms in a prodrome tends to be non-specific, particularly in the early stages. Thus, prodromal symptoms are not prospectively deterministic, and research is directed towards identifying which patients with prodromal symptoms will later develop disease.3 The findings of these studies will help us to understand the trajectory of changes in the disease process from genetic risk factors to clinical diagnosis.3

The question of whether there is a prodrome in MS has so far not been extensively studied. A diagnosis of MS is made after a historical review of events in a patient's life, findings observed on neurological examination, data acquired from diagnostic tests, and after the exclusion of other diseases that could account for the clinical and paraclinical findings.4 Patients with MS typically present with a clinically isolated syndrome (CIS), which is defined by a distinct first neurological event with observed demyelination involving the optic nerve, cerebrum, cerebellum, brainstem, or spinal cord.5 CIS has, until recently, been thought to be the first sign of MS. However, radiological abnormalities might be identified in the absence of clinical symptoms, leading to use of the term “radiologically isolated syndrome” (RIS) to specifically describe individuals who have structural anomalies in the CNS that are highly suggestive of demyelination.6 Individuals with RIS are at increased risk of developing MS.6 This observation, in conjunction with evidence for known MS risk factors that act many years before disease onset, renders unsurprising the notion that the disease develops subclinically. Thus, the existence of a prodrome in MS is compelling, but has so far received little attention. Endophenotypes, measurable components unseen by the unaided eye along the pathway of disease development, are also likely to exist in MS.7 In this Review, we summarise current understanding of disease susceptibility to elucidate potential causal pathways and endophenotypes, and suggest avenues for further study.

Section snippets

Genetic risk factors

The development of MS must start in individuals who are genetically susceptible. The importance of genetic factors in susceptibility to MS has been shown by genetic epidemiological studies.8 Family studies assessing risks to relatives of MS probands have revealed a marked familial aggregation of the disease.9, 10, 11, 12 First-degree relatives are generally at 10–25 times greater risk of developing MS than the general population. This risk correlates with degree of kinship (figure 1), with

Environmental risk factors

Although genes are needed for MS to develop, genetic epidemiological studies clearly illustrate a prominent role for the environment in determining MS risk. Factors with the strongest evidence for involvement in MS are Epstein-Barr virus (EBV), smoking, and latitude/vitamin D. Reports on other factors such as geographical region and data from migration studies suggest that the timing of exposure is a crucial determinant of risk for MS, particularly for some factors that operate very early in

Symptoms and signs before MS diagnosis

A substantial number of people who are diagnosed with MS recall earlier symptoms that could be attributable to a first demyelinating event. Individuals who later develop MS might also experience fatigue, depression, and/or cognitive impairment before the diagnosis of MS.82, 83 Many patients first present with CIS, but recent work has highlighted that radiological (RIS) and immunological changes might occur earlier.

Potential causal pathways

Our current understanding of MS development is that RIS leads to CIS and then eventually to MS. The associated risk factors for MS also seem to delineate a putative causal cascade (figure 3).130 Factors largely defined from birth (ie, sex, HLA status, place of birth) require the incitement of environmental factors (vitamin D deficiency, late EBV exposure) to develop the abnormalities required that subsequently lead to MS. The latitude effect (early life) and infectious-mononucleosis

Endophenotypes

An endophenotype is an intermediate phenotype that fills the gap in the causal chain between genes and clinical disease,136 and is typically defined by several traits and/or characteristics that in isolation might not be considered pathological. Endophenotypes are most commonly applied to psychiatric diseases, but can be applied to any complex disorder.7 The disease markers that are used to define the endophenotype are usually associated with disease in the population, might be heritable,

Conclusions and future perspectives

Modelling all known risk factors for MS (table 3) might enhance our ability to predict who will develop the disease and to select individuals in whom to intensively study the MS prodrome. This could help us to elucidate the steps leading to the development of MS and to identify robust and easily measurable biomarkers and endophenotypes.

Some attempts at combining risk factors have been made, leading to substantial improvements in the potential prediction of MS (table 4). The most comprehensive

Search strategy and selection criteria

A comprehensive search of the PubMed/Medline database was undertaken for all publications in English up to February, 2010. The following search terms were used in combination with “multiple sclerosis OR MS”: “vitamin D OR 25-hydroxyvitamin D”, “Epstein-Barr virus OR EBV”, “smoking”, “genet*”, “environment*”, “timing”, “exposure”, “clinically isolated syndrome OR CIS”, “radiologically isolated syndrome OR RIS”, “immunology”, and “migration”. Abstracts were manually searched for relevance,

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