Elsevier

The Lancet Neurology

Volume 3, Issue 12, December 2004, Pages 709-718
The Lancet Neurology

Review
Environmental risk factors in multiple sclerosis aetiology

https://doi.org/10.1016/S1474-4422(04)00933-0Get rights and content

Summary

The epidemiology of multiple sclerosis (MS) has been intensively studied. It is conceptualised as a complex disease in which genetic and environmental factors act together to cause disease. There are temporal and geographic variations in disease risk, and risk of disease may be affected by migration between regions of differing risk. Numerous potential causal factors including infection, immunisations, physical and emotional stressors, climate, diet, and occupational exposures have been studied using various observational study designs. Thus far, no single environmental exposure has been consistently identified as a causal factor in MS, but sufficient data have accumulated that causal pathways should be postulated and tested. This review will focus on the environmental epidemiology of MS.

Section snippets

Pathophysiology

MS is thought to be a cell-mediated autoimmune disease of the CNS.6 Evidence to support this concept of auto immunity includes (1) predominance of women affected, similar to autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus;7 (2) transient amelioration of disease activity during pregnancy, a relatively immunosuppressed state;8 (3) association with other autoimmune diseases both in affected individuals and their family members;9 (4) association with HLA type;10

A complex disease

MS is conceptualised as a complex disease, in which several environmental factors act together in a genetically susceptible individual to cause disease. Family members of affected individuals have a greater risk of disease than the general population.15, 16 Half-siblings of affected persons have roughly half the risk of full siblings of developing MS, and adopted siblings have no greater risk than the general population.16 This indicates that genetic factors do contribute to an individual's

Descriptive epidemiology

The geographic and temporal variations in the incidence and prevalence of MS have been intensively studied. However, it is important to note that several difficulties may arise when comparing incidence and prevalence studies from different areas or time intervals: (1) the populations studied may vary with respect to their size, age distribution, and ethnicity; (2) there may be differences between studies in the completeness of case ascertainment (affected by access to medical care, availability

Analytic epidemiology

Associations between putative environmental risk factors and disease are assessed using observational studies. Ecological studies look for associations at the population or group level. However, they are subject to the ecological fallacy if the association observed between variables at the group level is then applied to individuals.40 In a case-control study, individuals with and without disease are compared with respect to risk factors (exposures) of interest.41 This design is efficient for

Environmental risk factors

Potential risk factors that are commonly studied include infection, vaccinations, stress, occupation, climate, and diet. The roles of diet and sex hormones in the aetiology of MS are discussed elsewhere.45 The reason they are not discussed here is because the data are of insufficient quantity and quality to adequately assess whether diet and sex hormones play a causal role in MS.

Conclusion

Studying the role of environmental risk factors in the aetiology of MS is difficult for several reasons. Any given environmental agent may be only one of many factors capable of causing MS in a genetically susceptible individual, and these factors might be neither necessary or sufficient causes. The interaction of the components of cause may vary from study to study, producing inconsistent results.149 Exposure to putative agents is likely to be highly prevalent among individuals with and

Search strategy and selection criteria

Data for this review were identified by searches of MEDLINE (1965–2004) with the search terms “multiple sclerosis” and “case-control”, “cohort”, “ecologic”, “cluster”, “infection”, “measles”, “mumps”, “rubella”, “varicella”, “infectious mononucleosis”, “EBV”, “Chlamydia”, “vaccination”, “hepatitis B”, “organic solvents”, “trauma”, “stress”, “occupation”, “sunlight”, “vitamin D”, “risk factors”, “virus”, “dietary”, “fat”, “nutrition”, “hormones”, and “oral contraceptive pill”.

References (148)

  • A Miller et al.

    Multiple sclerosis

    Continuum

    (1999)
  • HL Weiner

    A 21 point unifying hypothesis on the etiology and treatment of multiple sclerosis

    Can J Neurol Sci

    (1998)
  • C Confavreux et al.

    Rate of pregnancy-related relapse in multiple sclerosis

    N Engl J Med

    (1998)
  • SA Broadley et al.

    Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey

    Brain

    (2000)
  • BD Trapp et al.

    Axonal transection in the lesions of multiple sclerosis

    N Engl J Med

    (1998)
  • BD Trapp et al.

    Neurodegeneration in multiple sclerosis: relationship to neurological disability

    Prog Clin Neurosci

    (1999)
  • C Lucchinetti et al.

    Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination

    Ann Neurol

    (2000)
  • GC Ebers et al.

    A genetic basis for familial aggregation in multiple sclerosis

    Nature

    (1995)
  • AD Sadovnick et al.

    A population-based study of multiple sclerosis in twins: update

    Ann Neurol

    (1993)
  • JF Kurtzke

    A reassessment of the distribution of multiple sclerosis. Part one

    Acta Neurol Scand

    (1975)
  • RB Forbes et al.

    The prevalence of multiple sclerosis in Tayside, Scotland: do latitudinal gradients really exist?

    J Neurol

    (1999)
  • R Zivadinov et al.

    The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. A meta-analysis study

    Neuroepidemiology

    (2003)
  • M-L Sumelahti et al.

    Multiple sclerosis in Finland: incidence trends and differences in relapsing remitting and primary progressive disease courses

    J Neurol Neurosurg Psychiatry

    (2003)
  • C McGuigan et al.

    Latitudinal variation in the prevalence of multiple sclerosis in Ireland, an effect of genetic diversity

    J Neurol Neurosurg Psychiatry

    (2003)
  • WF Page et al.

    Epidemiology of multiple sclerosis in U.S. Veterans: V. Ancestry and the risk of multiple sclerosis

    Ann Neurol

    (1993)
  • EG Celius et al.

    Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period

    Eur J Neurol

    (2001)
  • M Pugliatti et al.

    Multiple sclerosis epidemiology in Sardinia: evidence for a true increasing risk

    Acta Neurol Scand

    (2001)
  • G Dean et al.

    Multiple sclerosis among immigrants in Greater London

    BMJ

    (1976)
  • BR Visscher et al.

    Latitude, migration, and the prevalence of multiple sclerosis

    Am J Epidemiol

    (1977)
  • M Elian et al.

    Multiple sclerosis among United Kingdom-born children of immigrants from the Indian subcontinent, Africa and the West Indies

    J Neurol Neurosurg Psychiatry

    (1990)
  • M Alter et al.

    Risk of multiple sclerosis related to age at immigration to Israel

    Arch Neurol

    (1966)
  • R Detels et al.

    Multiple sclerosis and age at migration

    Am J Epidemiol

    (1978)
  • SR Hammond et al.

    The age-range of risk of developing multiple sclerosis. Evidence from a migrant population in Australia

    Brain

    (2000)
  • T Riise

    Cluster studies in multiple sclerosis

    Neurology

    (1997)
  • RB Schiffer et al.

    A multiple sclerosis cluster associated with a small, north-central Illinois community

    Arch Environ Health

    (2001)
  • JM Krebs et al.

    A neurological disease cluster at a manufacturing plant

    Arch Environ Health

    (1995)
  • JF Kurtzke et al.

    Multiple sclerosis in the Faroe Islands: I. clinical and epidemiological features

    Ann Neurol

    (1979)
  • CM Poser et al.

    Analysis of the ‘epidemic’ of multiple sclerosis in the Faroe Islands I. Clinical and epidemiological aspects

    Neuroepidemiology

    (1988)
  • CM Poser et al.

    Analysis of the ‘epidemic’ of multiple sclerosis in the Faroe Islands II. Biostatistical aspects

    Neuroepidemiology

    (1988)
  • K Lauer

    Ecologic studies of multiple sclerosis

    Neurology

    (1997)
  • C Wolfson et al.

    Case-control studies in multiple sclerosis

    Neurology

    (1997)
  • T Riise

    Historical cohort studies in multiple sclerosis

    Neurology

    (1997)
  • Smoking and health: report of the Advisory Committee to the Surgeon General

    (1964)
  • C Wolfson et al.

    The latent period of multiple sclerosis: a critical review

    Epidemiology

    (1993)
  • H Coo et al.

    A systematic review of several potential non-genetic risk factors for multiple sclerosis

    Neuroepidemiology

    (2004)
  • MR Hammerschlag et al.

    Is Chlamydia pneumoniae present in brain lesions of patients with multiple sclerosis?

    J Clin Microbiol

    (2000)
  • SL Cosby et al.

    Examination of eight cases of multiple sclerosis and 56 neurological and non-neurological controls for genomic sequences of measles virus, canine distemper virus, simian virus 5 and rubella virus

    J Gen Virol

    (1989)
  • AT Haase et al.

    Measles virus nucleotide sequences: detection by hybridization in situ

    Science

    (1981)
  • JG Stevens et al.

    No measles virus genetic information detected in multiple sclerosis-derived brains

    Ann Neurol

    (1980)
  • SD Cook et al.

    Multiple sclerosis and viruses: an overview

    Neurology

    (1980)
  • Cited by (270)

    • Protective role of natural products and bioactive compounds in multiple sclerosis

      2023, Treatments, Nutraceuticals, Supplements, and Herbal Medicine in Neurological Disorders
    • Immunological Tolerance

      2022, Encyclopedia of Infection and Immunity
    View all citing articles on Scopus
    View full text