Semin Neurol 2008; 28(1): 017-028
DOI: 10.1055/s-2007-1019126
© Thieme Medical Publishers

Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention

Alberto Ascherio1 , Kassandra Munger2
  • 1Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
  • 2Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
Further Information

Publication History

Publication Date:
07 February 2008 (online)

ABSTRACT

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, infection with the Epstein-Barr virus, and cigarette smoking are emerging as the most consistent predictors of MS risk. In this article, we review the epidemiological data, critically discuss the evidence for causality of these associations, and briefly discuss the possibility of interventions to reduce MS risk.

REFERENCES

  • 1 Lassmann H, Bruck W, Lucchinetti C F. The immunopathology of multiple sclerosis: an overview.  Brain Pathol. 2007;  17 210-218
  • 2 Kurtzke J F. MS epidemiology world wide. One view of current status.  Acta Neurol Scand Suppl. 1995;  161 23-33
  • 3 Vukusic S, Van Bockstael V, Gosselin S, Confavreux C. Regional variations of multiple sclerosis prevalence in French farmers.  J Neurol Neurosurg Psychiatry. 2007;  78 707-709
  • 4 Koch-Henriksen N, Hyllested K. Epidemiology of multiple sclerosis: incidence and prevalence rates in Denmark 1948-64 based on the Danish Multiple Sclerosis Registry.  Acta Neurol Scand. 1988;  78 369-380
  • 5 Hernán M A, Olek M J, Ascherio A. Geographic variation of MS incidence in two prospective studies of US women.  Neurology. 1999;  53 1711-1718
  • 6 Orton S M, Herrera B M, Yee I M et al.. Sex ratio of multiple sclerosis in Canada: a longitudinal study.  Lancet Neurol. 2006;  5 932-936
  • 7 Koch-Henriksen N. The Danish Multiple Sclerosis Registry: a 50-year follow-up.  Mult Scler. 1999;  5 293-296
  • 8 Mayr W T, Pittock S J, McClelland R L et al.. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985-2000.  Neurology. 2003;  61 1373-1377
  • 9 Compston A, Coles A. Multiple sclerosis.  Lancet. 2002;  359 1221-1231
  • 10 Dyment D A, Ebers G C, Sadovnick A D. Genetics of multiple sclerosis.  Lancet Neurol. 2004;  3 104-110
  • 11 Sawcer S, Compston A. Multiple sclerosis: light at the end of the tunnel.  Eur J Hum Genet. 2006;  14 257-258
  • 12 Alter M, Kahana E, Loewenson R. Migration and risk of multiple sclerosis.  Neurology. 1978;  28 1089-1093
  • 13 Alter M, Leibowitz U, Speer J. Risk of multiple sclerosis related to age at immigration to Israel.  Arch Neurol. 1966;  15 234-237
  • 14 Dean G, Kurtzke J F. On the risk of multiple sclerosis according to age at immigration to South Africa.  BMJ. 1971;  3 725-729
  • 15 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. 2000;  123 968-974
  • 16 Kurtzke J F, Beebe G W, Norman J E. Epidemiology of multiple sclerosis in US veterans: III. Migration and the risk of MS.  Neurology. 1985;  35 672-678
  • 17 Gale C R, Martyn C N. Migrant studies in multiple sclerosis.  Prog Neurobiol. 1995;  47 425-448
  • 18 Compston A, Sawcer S. Genetic analysis of multiple sclerosis.  Curr Neurol Neurosci Rep. 2002;  2 259-266
  • 19 Wallin M T, Page W F, Kurtzke J F. Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography.  Ann Neurol. 2004;  55 65-71
  • 20 Norman J E, Kurtzke J F, Beebe G W. Epidemiology of multiple sclerosis in U.S. veterans: 2. Latitude, climate and the risk of multiple sclerosis.  J Chronic Dis. 1983;  36 551-559
  • 21 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. 1960;  35 132-147
  • 22 Sutherland J M, Tyrer J H, Eadie M J. The prevalence of multiple sclerosis in Australia.  Brain. 1962;  85 149-164
  • 23 Leibowitz U, Sharon D, Alter M. Geographical considerations in multiple sclerosis.  Brain. 1967;  90 871-886
  • 24 van der Mei I A, Ponsonby A L, Blizzard L, Dwyer T. Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation.  Neuroepidemiology. 2001;  20 168-174
  • 25 Kurtzke J F. On the fine structure of the distribution of multiple sclerosis.  Acta Neurol Scand. 1967;  43 257-282
  • 26 Goldberg P. Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence (a viewpoint) Part 1: Sunlight, dietary factors and epidemiology.  Intern J Environmental Studies. 1974;  6 19-27
  • 27 Holick M F. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.  Am J Clin Nutr. 2004;  80 1678S-1688S
  • 28 Webb A R, Kline L, Holick M F. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.  J Clin Endocrinol Metab. 1988;  67 373-378
  • 29 McKenna M J, Freaney R, Byrne P et al.. Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification.  QJM. 1995;  88 895-898
  • 30 Rockell J E, Skeaff C M, Williams S M, Green T J. Serum 25-hydroxyvitamin D concentrations of New Zealanders aged 15 years and older.  Osteoporos Int. 2006;  17 1382-1389
  • 31 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. 1952;  246 722-728
  • 32 Westlund K. Distribution and mortality time trend of multiple sclerosis and some other diseases in Norway.  Acta Neurol Scand. 1970;  46 455-483
  • 33 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. 2000;  57 418-421
  • 34 Goldacre M J, Seagroatt V, Yeates D, Acheson E D. Skin cancer in people with multiple sclerosis: a record linkage study.  J Epidemiol Community Health. 2004;  58 142-144
  • 35 Antonovsky A, Leibowitz U, Smith H A et al.. Epidemiologic study of multiple sclerosis in Israel.  Arch Neurol. 1965;  13 183-193
  • 36 Cendrowski W, Wender M, Dominik W et al.. Epidemiological study of multiple sclerosis in western Poland.  Eur Neurol. 1969;  2 90-108
  • 37 van der Mei I AF, Ponsonby A L, Dwyer T et al.. Past exposure to sun, skin phenotype and risk of multiple sclerosis: a case-control study.  BMJ. 2003;  327 316-321
  • 38 van der Mei I A, Blizzard L, Ponsonby A L, Dwyer T. Validity and reliability of adult recall of past sun exposure in a case-control study of multiple sclerosis.  Cancer Epidemiol Biomarkers Prev. 2006;  15 1538-1544
  • 39 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. 2007;  254 471-477
  • 40 Willett W C. Nutritional Epidemiology. 2nd ed. New York; Oxford University Press Inc 1998
  • 41 Munger K L, Zhang S M, O'Reilly E et al.. Vitamin D intake and incidence of multiple sclerosis.  Neurology. 2004;  62 60-65
  • 42 Willett W C, Sampson L, Browne M L et al.. The use of a self-administered questionnaire to assess diet four years in the past.  Am J Epidemiol. 1988;  127 188-199
  • 43 Salvini S, Hunter D J, Sampson L et al.. Food-based validation of a dietary questionnaire: the effects of week-to-week variation in food consumption.  Int J Epidemiol. 1989;  18 858-867
  • 44 Feskanich D, Willett W C, Colditz G A. Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women.  Am J Clin Nutr. 2003;  77 504-511
  • 45 Levin L I, Munger K L, Rubertone M V et al.. Temporal relationship between elevation of Epstein Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis.  JAMA. 2005;  293 2496-2500
  • 46 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. 2006;  296 2832-2838
  • 47 Lucas R M, Ponsonby A L. Considering the potential benefits as well as adverse effects of sun exposure: can all the potential benefits be provided by oral vitamin D supplementation?.  Prog Biophys Mol Biol. 2006;  92 140-149
  • 48 Lemire J M, Archer D C. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis.  J Clin Invest. 1991;  87 1103-1107
  • 49 Cantorna M T, Hayes C E, DeLuca H F. 1,25-dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.  Proc Natl Acad Sci U S A. 1996;  93 7861-7864
  • 50 Cantorna M T, Hayes C E, DeLuca H F. 1,25-dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.  Proc Natl Acad Sci U S A. 1996;  93 7861-7864
  • 51 Hayes C E, Nashold F E, Spach K M, Pedersen L B. The immunological functions of the vitamin D endocrine system.  Cell Mol Biol. 2003;  49 277-300
  • 52 Hayes C E, Cantorna M T, DeLuca H F. Vitamin D and multiple sclerosis.  Proc Soc Exp Biol Med. 1997;  216 21-27
  • 53 Meehan T F, DeLuca H F. The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice.  Arch Biochem Biophys. 2002;  408 200-204
  • 54 Spach K M, Hayes C E. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice.  J Immunol. 2005;  175 4119-4126
  • 55 Nashold F E, Hoag K A, Goverman J, Hayes C E. Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis.  J Neuroimmunol. 2001;  119 16-29
  • 56 Hayes C E, Nashold F E, Spach K M, Pedersen L B. The immunological functions of the vitamin D endocrine system.  Cell Mol Biol (Noisy-le-grand). 2003;  49 277-300
  • 57 Hollis B W. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D.  J Nutr. 2005;  135 317-322
  • 58 Dawson-Hughes B, Heaney R P, Holick M F et al.. Estimates of optimal vitamin D status.  Osteoporos Int. 2005;  16 713-716
  • 59 Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.  Am J Clin Nutr. 1999;  69 842-856
  • 60 Heaney R P, Davies K M, Chen T C, Holick M F, Barger-Lux M J. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.  Am J Clin Nutr. 2003;  77 204-210
  • 61 Standing Committee on the Scientific Evaluation of Dietary Reference Intakes FaNB, Institute of Medicine .Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC; National Academy Press 1997
  • 62 Bischoff-Ferrari H A, Giovannucci E, Willett W C, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes.  Am J Clin Nutr. 2006;  84 18-28
  • 63 Looker A C, Dawson-Hughes B, Calvo M S, Gunter E W, Sahyoun N R. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III.  Bone. 2002;  30 771-777
  • 64 Hypponen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors.  Am J Clin Nutr. 2007;  85 860-868
  • 65 Poskanzer D C, Schapira K, Miller H. Multiple sclerosis and poliomyelitis.  Lancet. 1963;  2 917-921
  • 66 Leibowitz U, Antonovsky A, Medalie J M et al.. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation.  J Neurol Neurosurg Psychiatry. 1966;  29 60-68
  • 67 Beebe G W, Kurtzke J F, Kurland L T, Auth T L, Nagler B. Studies on the natural history of multiple sclerosis. 3. Epidemiologic analysis of the Army experience in World War II.  Neurology. 1967;  17 1-17
  • 68 Russell W R. Multiple sclerosis: occupation and social group at onset.  Lancet. 1971;  2 832-834
  • 69 Sewell D L, Reinke E K, Hogan L H, Sandor M, Fabry Z. Immunoregulation of CNS autoimmunity by helminth and mycobacterial infections.  Immunol Lett. 2002;  82 101-110
  • 70 Bach J F. The effect of infections on susceptibility to autoimmune and allergic diseases.  N Engl J Med. 2002;  347 911-920
  • 71 Maizels R M, Bundy D A, Selkirk M E, Smith D F, Anderson R M. Immunological modulation and evasion by helminth parasites in human populations.  Nature. 1993;  365 797-805
  • 72 Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis.  Ann Neurol. 2007;  61 97-108
  • 73 Fleming J, Fabry Z. The hygiene hypothesis and multiple sclerosis.  Ann Neurol. 2007;  61 85-89
  • 74 Niederman J C, Evans A S. Epstein-Barr virus. In: Evans AS, Kaslow RA Viral Infections of Humans: Epidemiology and Control. 4th ed. New York; Plenum Medical Book Company 1997: 253-283
  • 75 Takeuchi K, Tanaka-Taya K, Kazuyama Y et al.. Prevalence of Epstein-Barr virus in Japan: trends and future prediction.  Pathol Int. 2006;  56 112-116
  • 76 Kurtzke J F. Multiple sclerosis in time and space: geographic clues to cause.  J Neurovirol. 2000;  6(suppl 2) S134-S140
  • 77 Warner H B, Carp R I. Multiple sclerosis and Epstein-Barr virus.  Lancet. 1981;  2 1290
  • 78 Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis.  Epidemiology. 2000;  11 220-224
  • 79 Ascherio A, Munger K L. Environmental risk factors for multiple sclerosis. Part I: The role of infection.  Ann Neurol. 2007;  61 288-299
  • 80 Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B. Epstein-Barr virus in pediatric multiple sclerosis.  JAMA. 2004;  291 1875-1879
  • 81 Pohl D, Krone B, Rostasy K et al.. High seroprevalence of Epstein-Barr virus in children with multiple sclerosis.  Neurology. 2006;  67 2063-2065
  • 82 Thacker E L, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis.  Ann Neurol. 2006;  59 499-503
  • 83 Nielsen T R, Rostgaard K, Nielsen N M et al.. Multiple sclerosis after infectious mononucleosis.  Arch Neurol. 2007;  64 72-75
  • 84 Cook S D. Does Epstein Barr virus cause multiple sclerosis?.  Rev Neurol Dis. 2004;  1 115-123
  • 85 James J A, Harley J B, Scofield R H. Epstein-Barr virus and systemic lupus erythematosus.  Curr Opin Rheumatol. 2006;  18 462-467
  • 86 Serafini B, Rosicarelli B, Franciotta D et al.. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain.  J Exp Med. 2007;  204 2899-2912
  • 87 Ascherio A, Munger K L, Lennette E T et al.. Epstein Barr virus antibodies and risk of multiple sclerosis: a prospective study.  JAMA. 2001;  286 3083-3088
  • 88 DeLorenze G N, Munger K L, Lennette E et al.. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up.  Arch Neurol. 2006;  63 839-844
  • 89 Sundstrom P, Juto P, Wadell G et al.. An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study.  Neurology. 2004;  62 2277-2282
  • 90 Lennette E T, Rymo L, Yadav M et al.. Disease-related differences in antibody patterns against EBV-encoded nuclear antigens EBNA 1, EBNA 2 and EBNA 6.  Eur J Cancer. 1993;  29A 1584-1589
  • 91 Kusunoki Y, Huang H, Fukuda Y et al.. A positive correlation between the precursor frequency of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and antibody titer level against Epstein-Barr virus-associated nuclear antigen in healthy seropositive individuals.  Microbiol Immunol. 1993;  37 461-469
  • 92 Lunemann J D, Edwards N, Muraro P A et al.. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis.  Brain. 2006;  129 1493-1506
  • 93 Cepok S, Zhou D, Srivastava R et al.. Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis.  J Clin Invest. 2005;  115 1352-1360
  • 94 Kurtzke J F, Heltberg A. Multiple sclerosis in the Faroe Islands: an epitome.  J Clin Epidemiol. 2001;  54 1-22
  • 95 Lycke J, Svennerholm B, Hjelmquist E et al.. Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study.  J Neurol. 1996;  243 214-224
  • 96 Friedman J E, Zabriskie J B, Plank C et al.. A randomized clinical trial of valacyclovir in multiple sclerosis.  Mult Scler. 2005;  11 286-295
  • 97 Ghadirian P, Dadgostar B, Azani R, Maisonneuve P. A case-control study of the association between socio-demographic, lifestyle and medical history factors and multiple sclerosis.  Can J Public Health. 2001;  92 281-285
  • 98 Zorzon M, Capus L, Pellegrino A, Cazzato G, Zivadinov R. Familial and environmental risk factors in Parkinson's disease: a case-control study in north-east Italy.  Acta Neurol Scand. 2002;  105 77-82
  • 99 Riise T, Nortvedt M W, Ascherio A. Smoking is a risk factor for multiple sclerosis.  Neurology. 2003;  61 1122-1124
  • 100 Villard-Mackintosh L, Vessey M P. Oral contraceptives and reproductive factors in multiple sclerosis incidence.  Contraception. 1993;  47 161-168
  • 101 Thorogood M, Hannaford P C. The influence of oral contraceptives on the risk of multiple sclerosis.  Br J Obstet Gynaecol. 1998;  105 1296-1299
  • 102 Hernán M A, Olek M J, Ascherio A. Cigarette smoking and incidence of multiple sclerosis.  Am J Epidemiol. 2001;  154 69-74
  • 103 Hernán M A, Jick S S, Logroscino G, Olek M J, Ascherio A, Jick H. Cigarette smoking and the progression of multiple sclerosis.  Brain. 2005;  128 1461-1465
  • 104 Ascherio A, Munger K L. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors.  Ann Neurol. 2007;  61 504-513
  • 105 Courville C B, Maschmeyer J E, DeLay C P. Effects of smoking on the acute exacerbations of multiple sclerosis.  Bull Los Angeles Neurol Soc. 1964;  29 1-6
  • 106 Emre M, de Decker C. Effects of cigarette smoking on motor functions in patients with multiple sclerosis.  Arch Neurol. 1992;  49 1243-1247
  • 107 Costenbader K H, Karlson E W. Cigarette smoking and autoimmune disease: what can we learn from epidemiology?.  Lupus. 2006;  15 737-745
  • 108 Hawkins B T, Brown R C, Davis T P. Smoking and ischemic stroke: a role for nicotine?.  Trends Pharmacol Sci. 2002;  23 78-82
  • 109 Vleeming W, Rambali B, Opperhuizen A. The role of nitric oxide in cigarette smoking and nicotine addiction.  Nicotine Tob Res. 2002;  4 341-348
  • 110 Hooper D C, Bagasra O, Marini J C et al.. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis.  Proc Natl Acad Sci U S A. 1997;  94 2528-2533
  • 111 Rejdak K, Eikelenboom M J, Petzold A et al.. CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis.  Neurology. 2004;  63 1439-1445
  • 112 Fryar C D, Hirsch R, Porter K S et al.. Smoking and alcohol behaviors reported by adults, United States, 1999-2002 [online]. Available at: http://www.cdc.gov/nchs/data/ad/ad378.pdf
  • 113 Rothman K, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia; Lippincott-Raven Publishers 1998

Alberto AscherioM.D. Dr.P.H. 

Departments of Nutrition and Epidemiology, Harvard School of Public Health

655 Huntington Avenue, Boston, MA 02115

Email: aascheri@hsph.harvard.edu

    >