Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.
Evidence from studies of disease risk in relation to the month of birth implicates early-life environmental factors in multiple sclerosis (MS) susceptibility
Migration data, and variability in disease onset and relapse rates, suggest that environmental factors might also act later in life and during the course of MS
Vitamin D is an attractive candidate factor implicated by the association of MS risk with latitude and month of birth, and is likely to act early in life
Epstein–Barr virus is also linked to MS and seems to act in adolescence or early adulthood to alter susceptibility
Smoking is associated with increased susceptibility to adult-onset MS when individuals are exposed later in life, and can alter the course of established MS
Strategies aimed at preventing or treating multiple sclerosis by manipulating environmental factors may provide a powerful way of reducing the prevalence of this often devastating disease
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Butyrate suppresses demyelination and enhances remyelination
Journal of Neuroinflammation Open Access 09 August 2019
A step beyond the hygiene hypothesis—immune-mediated classes determined in a population-based study
BMC Medicine Open Access 09 April 2019
Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study
Journal of Neurology Open Access 21 December 2018
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Hemmer, B., Archelos, J. J. & Hartung, H. P. New concepts in the immunopathogenesis of multiple sclerosis. Nat. Rev. Neurosci. 3, 291–301 (2002).
Ramagopalan, S. V. & Ebers, G. C. Genes for multiple sclerosis. Lancet 371, 283–285 (2008).
Pugliatti, M., Sotgiu, S. & Rosati, G. The worldwide prevalence of multiple sclerosis. Clin. Neurol. Neurosurg. 104, 182–191 (2002).
Willer, C. J., Dyment, D. A., Risch, N. J., Sadovnick, A. D. & Ebers, G. C. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc. Natl Acad. Sci. USA 100, 12877–12882 (2003).
Islam, T. et al. Differential twin concordance for multiple sclerosis by latitude of birthplace. Ann. Neurol. 60, 56–64 (2006).
Ebers, G. C. Environmental factors and multiple sclerosis. Lancet Neurol. 7, 268–277 (2008).
Ascherio, A. & Munger, K. L. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61, 288–299 (2007).
Ascherio, A. & Munger, K. L. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann. Neurol. 61, 504–513 (2007).
Yeh, E. A. et al. Pediatric multiple sclerosis. Nat. Rev. Neurol. 5, 621–631 (2009).
Sadovnick, A. D., Bulman, D. & Ebers, G. C. Parent–child concordance in multiple sclerosis. Ann. Neurol. 29, 252–255 (1991).
Hoppenbrouwers, I. A. et al. Maternal transmission of multiple sclerosis in a Dutch population. Arch. Neurol. 65, 345–348 (2008).
Ebers, G. C. et al. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 363, 1773–1774 (2004).
Herrera, B. M. et al. Parent-of-origin effects in MS: observations from avuncular pairs. Neurology 71, 799–803 (2008).
Ramagopalan, S. V. et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology 73, 602–605 (2009).
Willer, C. J. et al. Timing of birth and risk of multiple sclerosis: population based study. BMJ 330, 120 (2005).
Goodin, D. S. The causal cascade to multiple sclerosis: a model for MS pathogenesis. PLoS One 4, e4565 (2009).
Bulman, D. E., Sadovnick, A. D. & Ebers, G. C. Age of onset in siblings concordant for multiple sclerosis. Brain 114, 937–950 (1991).
Chao, M. J. et al. Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex. Hum. Mol. Genet. 18, 261–266 (2009).
Dean, G. & Elian, M. Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 63, 565–568 (1997).
Alter, M., Leibowitz, U. & Speer, J. Risk of multiple sclerosis related to age at immigration to Israel. Arch. Neurol. 15, 234–237 (1966).
Hammond, S. R., English, D. R. & McLeod, J. G. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 123, 968–974 (2000).
Orton, S. M. et al. Effect of immigration on multiple sclerosis sex ratio in Canada: the Canadian Collaborative Study. J. Neurol. Neurosurg. Psychiatry doi:10.1136/jnnp.2008.162784.
Ramagopalan, S. V. et al. Age of puberty and the risk of multiple sclerosis: a population based study. Eur. J. Neurol. 16, 342–347 (2009).
Ong, K. K. et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. doi:10.1038/ng.382.
Du, C. et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 10, 1252–1259 (2009).
Riise, T. et al. Clustering of residence of multiple sclerosis patients at age 13 to 20 years in Hordaland, Norway. Am. J. Epidemiol. 133, 932–939 (1991).
Pugliatti, M. et al. Evidence of early childhood as the susceptibility period in multiple sclerosis: space-time cluster analysis in a Sardinian population. Am. J. Epidemiol. 164, 326–333 (2006).
Confavreux, C. & Vukusic, S. Natural history of multiple sclerosis: a unifying concept. Brain 129, 606–616 (2006).
Cooper, G. S. & Stroehla, B. C. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119–125 (2003).
Tremlett, H. et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology 31, 271–279 (2008).
Embry, A. F., Snowdon, L. R. & Vieth, R. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann. Neurol. 48, 271–272 (2000).
Goldberg, P., Fleming, M. C. & Picard, E. H. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med. Hypotheses 21, 193–200 (1986).
Newhook, L. A. et al. Vitamin D insufficiency common in newborns, children and pregnant women living in Newfoundland and Labrador, Canada. Matern. Child Nutr. 5, 186–191 (2009).
Ramagopalan, S. V. et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 5, e1000369 (2009).
Ramagopalan, S. V. et al. HLA-DRB1 and month of birth in multiple sclerosis. Neurology 73, 2107–2111 (2009).
Gardener, H. et al. Prenatal and perinatal factors and risk of multiple sclerosis. Epidemiology 20, 611–618 (2009).
Ramagopalan, S. V., Dyment, D. A., Ebers, G. C. & Sadovnick, A. D. Gestational diabetes and multiple sclerosis. Epidemiology 20, 783–784 (2009).
Zhang, C. et al. Maternal plasma 25-hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLoS One 3, e3753 (2008).
Novakovic, B. et al. Placenta specific methylation of the vitamin D 24-hydroxylase gene: Implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface. J. Biol. Chem. 284, 14838–14848 (2009).
van der Mei, I. A. et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ 327, 316 (2003).
Kampman, M. T., Wilsgaard, T. & Mellgren, S. I. Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J. Neurol. 254, 471–477 (2007).
Antonovsky, A. et al. Epidemiologic study of multiple sclerosis in Israel. I. An overall review of methods and findings. Arch. Neurol. 13, 183–193 (1965).
Cendrowski, W. et al. Epidemiological study of multiple sclerosis in western Poland. Eur. Neurol. 2, 90–108 (1969).
Islam, T., Gauderman, W. J., Cozen, W. & Mack, T. M. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 69, 381–388 (2007).
Orton, S. M. et al. Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am. J. Clin. Nutr. 88, 441–447 (2008).
Munger, K. L., Levin, L. I., Hollis, B. W., Howard, N. S. & Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296, 2832–2838 (2006).
Correale, J., Ysrraelit, M. C. & Gaitán, M. I. Immunomodulatory effects of vitamin D in multiple sclerosis. Brain 132, 1146–1160 (2009).
Freedman, D. M., Dosemeci, M. & Alavanja, M. C. Mortality from multiple sclerosis and exposure to residential and occupational solar radiation: a case-control study based on death certificates. Occup. Environ. Med. 57, 418–421 (2000).
Westberg, M., Feychting, M., Jonsson, F., Nise, G. & Gustavsson, P. Occupational exposure to UV light and mortality from multiple sclerosis. Am. J. Ind. Med. 52, 353–357 (2009).
Munger, K. L. et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 62, 60–65 (2004).
Soilu-Hanninen, M. et al. A longitudinal study of serum 25–hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 79, 152–157 (2008).
Avgil, M. & Ornoy, A. Herpes simplex virus and Epstein–Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection. Reprod. Toxicol. 21, 436–445 (2006).
Sumaya, C. V., Myers, L. W. & Ellison, G. W. Epstein–Barr virus antibodies in multiple sclerosis. Arch. Neurol. 37, 94–96 (1980).
Bray, P. F., Bloomer, L. C., Salmon, V. C., Bagley, M. H. & Larsen, P. D. Epstein–Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch. Neurol. 40, 406–408 (1983).
Larsen, P. D., Bloomer, L. C. & Bray, P. F. Epstein–Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis. Neurology 35, 435–438 (1985).
Sumaya, C. V., Myers, L. W., Ellison, G. W. & Ench, Y. Increased prevalence and titer of Epstein–Barr virus antibodies in patients with multiple sclerosis. Ann. Neurol. 17, 371–377 (1985).
Shirodaria, P. V. et al. Viral antibody titers. Comparison in patients with multiple sclerosis and rheumatoid arthritis. Arch. Neurol. 44, 1237–1241 (1987).
Munch, M., Riisom, K., Christensen, T., Møller-Larsen, A. & Haahr, S. The significance of Epstein–Barr virus seropositivity in multiple sclerosis patients? Acta Neurol. Scand. 97, 171–174 (1998).
Myhr, K. M. et al. Altered antibody pattern to Epstein–Barr virus but not to other herpesviruses in multiple sclerosis: a population based case–control study from western Norway. J. Neurol. Neurosurg. Psychiatry 64, 539–542 (1998).
Wagner, H. J. et al. Altered prevalence and reactivity of anti-Epstein−Barr virus antibodies in patients with multiple sclerosis. Viral Immunol. 13, 497–502 (2000).
Ascherio, A. et al. Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286, 3083–3088 (2001).
Sundström, P. et al. An altered immune response to Epstein–Barr virus in multiple sclerosis: a prospective study. Neurology 62, 2277–2282 (2004).
Haahr, S., Plesner, A. M., Vestergaard, B. F. & Höllsberg, P. A role of late Epstein–Barr virus infection in multiple sclerosis. Acta Neurol. Scand. 109, 270–275 (2004).
Ponsonby, A. L. et al. Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 293, 463–469 (2005).
Levin, L. I. et al. Temporal relationship between elevation of Epstein–Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293, 2496–2500 (2005).
DeLorenze, G. N. et al. Epstein–Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch. Neurol. 63, 839–844 (2006).
Goldacre, M. J., Wotton, C. J., Seagroatt, V. & Yeates, D. Multiple sclerosis after infectious mononucleosis: record linkage study. J. Epidemiol. Community Health 58, 1032–1035 (2004).
Thacker, E. L., Mirzaei, F. & Ascherio, A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann. Neurol. 59, 499–503 (2006).
Nielsen, T. R. et al. Multiple sclerosis after infectious mononucleosis. Arch. Neurol. 64, 72–75 (2007).
Ramagopalan, S. V. et al. Association of infectious mononucleosis with multiple sclerosis. a population-based study. Neuroepidemiology 32, 257–262 (2009).
Zaadstra, B. M., Chorus, A. M., van Buuren, S., Kalsbeek, H. & van Noort, J. M. Selective association of multiple sclerosis with infectious mononucleosis. Mult. Scler. 14, 307–313 (2008).
Hernán, M. A., Zhang, S. M., Lipworth, L., Olek, M. J. & Ascherio, A. Multiple sclerosis and age at infection with common viruses. Epidemiology 12, 301–306 (2001).
De Jager, P. L. et al. Integrating risk factors: HLA-DRB1*1501 and Epstein–Barr virus in multiple sclerosis. Neurology 70, 1113–1118 (2008).
Marrie, R. A. et al. Multiple sclerosis and antecedent infections: a case–control study. Neurology 54, 2307–2310 (2000).
Kriesel, J. D. & Sibley, W. A. The case for rhinoviruses in the pathogenesis of multiple sclerosis. Mult. Scler. 11, 1–4 (2005).
Wandinger, K. et al. Association between clinical disease activity and Epstein–Barr virus reactivation in MS. Neurology 55, 178–184 (2000).
Lindsey, J. W., Hatfield, L. M., Crawford, M. P. & Patel, S. Quantitative PCR for Epstein–Barr virus DNA and RNA in multiple sclerosis. Mult. Scler. 15, 153–158 (2009).
Buljevac, D. et al. Epstein–Barr virus and disease activity in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76, 1377–1381 (2005).
Torkildsen, Ø., Nyland, H., Myrmel, H. & Myhr, K. M. Epstein–Barr virus reactivation and multiple sclerosis. Eur. J. Neurol. 15, 106–108 (2008).
Lünemann, J. D. et al. Elevated EBNA1 immune responses predict conversion to multiple sclerosis. Ann. Neurol. doi:10.1002/ana.21886.
Farrell, R. A. et al. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology 73, 32–38 (2009).
Edwards, S., Zvartau, M., Clarke, H., Irving, W. & Blumhardt, L. D. Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 64, 736–741 (1998).
Sibley, W. A., Bamford, C. R. & Clark, K. Clinical viral infections and multiple sclerosis. Lancet 325, 1313–1315 (1985).
Montgomery, S. M., Bahmanyar, S., Hillert, J., Ekbom, A. & Olsson, T. Maternal smoking during pregnancy and multiple sclerosis amongst offspring. Eur. J. Neurol. 15, 1395–1399 (2008).
Charlton, A. Children and smoking: the family circle. Br. Med. Bull. 52, 90–107 (1996).
Hedström, A. K., Bäärnhielm, M., Olsson, T. & Alfredsson, L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 73, 696–701 (2009).
Hernán, M. A. et al. Cigarette smoking and the progression of multiple sclerosis. Brain 128, 1461–1465 (2005).
Riise, T., Nortvedt, M. W. & Ascherio, A. Smoking is a risk factor for multiple sclerosis. Neurology 61, 1122–1124 (2003).
Villard-Mackintosh, L. & Vessey, M. P. Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception 47, 161–168 (1993).
Thorogood, M. & Hannaford, P. C. The influence of oral contraceptives on the risk of multiple sclerosis. Br. J. Obstet. Gynaecol. 105, 1296–1299 (1998).
Hernán, M. A., Olek, M. J. & Ascherio, A. Cigarette smoking and incidence of multiple sclerosis. Am. J. Epidemiol. 154, 69–74 (2001).
Di Pauli, F. et al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Mult. Scler. 14, 1026–1030 (2008).
Healy, B. C. et al. Smoking and disease progression in multiple sclerosis. Arch. Neurol. 66, 858–864 (2009).
Pittas, F. et al. Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis. J. Neurol. 256, 577–585 (2009).
Celius, E. G. & Vandvik, B. Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period. Eur. J. Neurol. 8, 463–469 (2001).
Hernán, M. A., Olek, M. J. & Ascherio, A. Geographic variation of MS incidence in two prospective studies of US women. Neurology 53, 1711–1718 (1999).
Alonso, A. & Hernán, M. A. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 71, 129–135 (2008).
Koch-Henriksen, N. The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult. Scler. 5, 293–296 (1999).
Barnett, M. H., Williams, D. B., Day, S., Macaskill, P. & McLeod, J. G. Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study. J. Neurol. Sci. 213, 1–6 (2003).
Sarasoja, T., Wikström, J., Paltamaa, J., Hakama, M. & Sumelahti, M. L. Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years. Acta Neurol. Scand. 110, 331–336 (2004).
Sundström, P., Nyström, L. & Forsgren, L. Incidence (1988–1997) and prevalence (1997). of multiple sclerosis in Vasterbotten County in northern Sweden. J. Neurol. Neurosurg. Psychiatry 74, 29–32 (2003).
Ranzato, F. et al. Increasing frequency of multiple sclerosis in Padova, Italy: a 30 year epidemiological survey. Mult. Scler. 9, 387–392 (2003).
Orton, S. M. et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 5, 932–936 (2006).
Vukusic, S. et al. Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse. Brain 127, 1353–1360 (2004).
Suarez, F., Rossignol, C. & Garabédian, M. Interactive effect of estradiol and vitamin D receptor gene polymorphisms as a possible determinant of growth in male and female infants. J. Clin. Endocrinol. Metab. 83, 3563–3568 (1998).
Spach, K. M. & Hayes, C. E. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J. Immunol. 175, 4119–4126 (2005).
Celius, E. G. et al. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. J. Neurol. Sci. 178, 132–135 (2000).
Hayes, C. E. & Donald Acheson, E. A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med. Hypotheses 71, 85–90 (2008).
Holmøy, T. Vitamin D status modulates the immune response to Epstein–Barr virus: Synergistic effect of risk factors in multiple sclerosis. Med. Hypotheses 70, 66–69 (2008).
Sadovnick, A. D., Duquette, P., Herrera, B., Yee, I. M. & Ebers, G. C. A timing-of-birth effect on multiple sclerosis clinical phenotype. Neurology 69, 60–62 (2007).
Vieth, R. et al. The urgent need to recommend an intake of vitamin D that is effective. Am. J. Clin. Nutr. 85, 649–650 (2007).
Wingerchuk, D. M., Lesaux, J., Rice, G. P., Kremenchutzky, M. & Ebers, G. C. A pilot study of oral calcitriol (1, 25-dihydroxyvitamin D3) for relapsing–remitting multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76, 1294–1296 (2005).
Kimball, S. M., Ursell, M. R., O'Connor, P. & Vieth, R. Safety of vitamin D3 in adults with multiple sclerosis. Am. J. Clin. Nutr. 86, 645–651 (2007).
Macsween, K. F. & Crawford, D. H. Epstein–Barr virus-recent advances. Lancet Infect. Dis. 3, 131–140 (2003).
Multiple Sclerosis International Federation Atlas of MS database [online], (2010).
Acheson, E. D., Bachrach, C. A. & Wright, F. M. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr. Scand. Suppl. 35, 132–147 (1960).
McGrath, J. J., Féron, F. P., Burne, T. H., Mackay-Sim, A. & Eyles, D. W. Vitamin D3—implications for brain development. J. Steroid Biochem. Mol. Biol. 89–90, 557–560 (2004).
Serafini, B. et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).
Jilek, S. et al. Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 131, 1712–1721 (2008).
Lang, H. L. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 3, 940–943 (2002).
Smith, K. J., Kapoor, R. & Felts, P. A. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol. 9, 69–92 (1999).
Scolding, N. & Franklin, R. Axon loss in multiple sclerosis. Lancet 352, 340–341 (1998).
Pembrey, M. E. et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2006).
Alonso, A. et al. Recent use of oral contraceptives and the risk of multiple sclerosis. Arch. Neurol. 62, 1362–1365 (2005).
Lee, M. & O'Brien, P. Pregnancy and multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 79, 1308–1311 (2008).
Hernán, M. A., Hohol, M. J., Olek, M. J., Spiegelman, D. & Ascherio, A. Oral contraceptives and the incidence of multiple sclerosis. Neurology 55, 848–854 (2000).
Zorgdrager, A. & De Keyser, J. Menstrually related worsening of symptoms in multiple sclerosis. J. Neurol. Sci. 149, 95–97 (1997).
Zorgdrager, A. & De Keyser, J. The premenstrual period and exacerbations in multiple sclerosis. Eur. Neurol. 48, 204–206 (2002).
Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777–780 (2001).
Hince, M. et al. The role of sex steroids and gonadectomy in the control of thymic involution. Cell. Immunol. 252, 122–138 (2008).
Walker, L. S. & Abbas, A. K. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat. Rev. Immunol. 2, 11–19 (2002).
Li, S., Hursting, S. D., Davis, B. J., McLachlan, J. A. & Barrett, J. C. Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann. NY Acad. Sci. 983, 161–169 (2003).
Warren, S., Greenhill, S. & Warren, K. G. Emotional stress and the development of multiple sclerosis: case-control evidence of a relationship. J. Chronic Dis. 35, 821–831 (1982).
Grant, I. et al. Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 52, 8–13 (1989).
Li, J. et al. The risk of multiple sclerosis in bereaved parents: A nationwide cohort study in Denmark. Neurology 62, 726–729 (2004).
Mohr, D. C., Hart, S. L., Julian, L., Cox, D. & Pelletier, D. Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ 328, 731 (2004).
Fassbender, K. et al. Mood disorders and dysfunction of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: association with cerebral inflammation. Arch. Neurol. 55, 66–72 (1998).
Souberbielle, B. E., Szawlowski, P. W. & Russell, W. C. Is there a case for a virus aetiology in multiple sclerosis? Scott. Med. J. 40, 55–62 (1995).
Landtblom, A. M., Flodin, U., Söderfeldt, B., Wolfson, C. & Axelson, O. Organic solvents and multiple sclerosis: a synthesis of the current evidence. Epidemiology 7, 429–433 (1996).
Mortensen, J. T., Brønnum-Hansen, H. & Rasmussen, K. Multiple sclerosis and organic solvents. Epidemiology 9, 168–171 (1998).
Riise, T., Moen, B. E. & Kyvik, K. R. Organic solvents and the risk of multiple sclerosis. Epidemiology 13, 718–720 (2002).
Juntunen, J., Taskinen, E., Luisto, M., Iivanainen, M. & Nurminen, M. Cerebrospinal fluid cells and proteins in patients occupationally exposed to organic solvents. J. Neurol. Sci. 54, 413–425 (1982).
Swank, R. L., Lerstad, O., Strøm, A. & Backer, J. Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N. Engl. J. Med. 246, 722–728 (1952).
Westlund, K. Distribution and mortality time trend of multiple sclerosis and some other diseases in Norway. Acta Neurol. Scand. 46, 455–483 (1970).
Brustad, M., Alsaker, E., Engelsen, O., Aksnes, L. & Lund, E. Vitamin D status of middle-aged women at 65–71 degrees N in relation to dietary intake and exposure to ultraviolet radiation. Public Health Nutr. 7, 327–335 (2004).
Brustad, M., Sandanger, T., Aksnes, L. & Lund, E. Vitamin D status in a rural population of northern Norway with high fish liver consumption. Public Health Nutr. 7, 783–789 (2004).
We would like to thank the Canadian Collaborative Study Group for many helpful discussions.
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Handel, A., Giovannoni, G., Ebers, G. et al. Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol 6, 156–166 (2010). https://doi.org/10.1038/nrneurol.2010.1
This article is cited by
Genetics and functional genomics of multiple sclerosis
Seminars in Immunopathology (2022)
Butyrate suppresses demyelination and enhances remyelination
Journal of Neuroinflammation (2019)
A step beyond the hygiene hypothesis—immune-mediated classes determined in a population-based study
BMC Medicine (2019)
Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study
Journal of Neurology (2019)
Astrocyte-derived tissue Transglutaminase affects fibronectin deposition, but not aggregation, during cuprizone-induced demyelination
Scientific Reports (2017)