Semin Neurol 2016; 36(02): 103-114
DOI: 10.1055/s-0036-1579693
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention—An Update

Alberto Ascherio
1   Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
2   Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
,
Kassandra L. Munger
1   Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

Publication Date:
26 April 2016 (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, obesity in early life, infection with the Epstein-Barr virus, and cigarette smoking are the most consistent environmental predictors of MS risk. The authors review the epidemiological data, critically discuss the evidence for causality of these and other associations, and briefly review the possibility of interventions to reduce MS risk.

 
  • References

  • 1 Lassmann H, Brück W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007; 17 (2) 210-218
  • 2 Kurtzke JF. MS epidemiology world wide. One view of current status. Acta Neurol Scand Suppl 1995; 161 (Suppl): 23-33
  • 3 Vukusic S, Van Bockstael V, Gosselin S, Confavreux C. Regional variations in the prevalence of multiple sclerosis in French farmers. J Neurol Neurosurg Psychiatry 2007; 78 (7) 707-709
  • 4 Koch-Henriksen N, Sorensen PS. Why does the north-south gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere?. J Neurol Sci 2011; 311 (1–2) 58-63
  • 5 Hernán MA, Olek MJ, Ascherio A. Geographic variation of MS incidence in two prospective studies of US women. Neurology 1999; 53 (8) 1711-1718
  • 6 Wallin MT, Page WF, Kurtzke JF. Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann Neurol 2004; 55 (1) 65-71
  • 7 Orton SM, Herrera BM, Yee IM , et al; Canadian Collaborative Study Group. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 2006; 5 (11) 932-936
  • 8 Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9 (5) 520-532
  • 9 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 (5) 369-380
  • 10 Koch-Henriksen N. The Danish Multiple Sclerosis Registry: a 50-year follow-up. Mult Scler 1999; 5 (4) 293-296
  • 11 Mayr WT, Pittock SJ, McClelland RL, Jorgensen NW, Noseworthy JH, Rodriguez M. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985-2000. Neurology 2003; 61 (10) 1373-1377
  • 12 Wallin MT, Culpepper WJ, Coffman P , et al; Veterans Affairs Multiple Sclerosis Centres of Excellence Epidemiology Group. The Gulf war era multiple sclerosis cohort: age and incidence rates by race, sex and service. Brain 2012; 135 (Pt 6) 1778-1785
  • 13 Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80 (6) 548-552
  • 14 Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr 2008; 88 (6) 1519-1527
  • 15 Sawcer S, Franklin RJ, Ban M. Multiple sclerosis genetics. Lancet Neurol 2014; 13 (7) 700-709
  • 16 Alter M, Kahana E, Loewenson R. Migration and risk of multiple sclerosis. Neurology 1978; 28 (11) 1089-1093
  • 17 Alter M, Leibowitz U, Speer J. Risk of multiple sclerosis related to age at immigration to Israel. Arch Neurol 1966; 15 (3) 234-237
  • 18 Dean G, Kurtzke JF. On the risk of multiple sclerosis according to age at immigration to South Africa. BMJ 1971; 3 (5777) 725-729
  • 19 Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000; 123 (Pt 5) 968-974
  • 20 Gale CR, Martyn CN. Migrant studies in multiple sclerosis. Prog Neurobiol 1995; 47 (4–5) 425-448
  • 21 Kurtzke JF, Beebe GW, Norman Jr JE. Epidemiology of multiple sclerosis in US veterans: III. Migration and the risk of MS. Neurology 1985; 35 (5) 672-678
  • 22 Compston A, Sawcer S. Genetic analysis of multiple sclerosis. Curr Neurol Neurosci Rep 2002; 2 (3) 259-266
  • 23 Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004; 80 (6, Suppl) 1678S-1688S
  • 24 Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr Scand Suppl 1960; 35 (147, Suppl) 132-147
  • 25 Sutherland JM, Tyrer JH, Eadie MJ. The prevalence of multiple sclerosis in Australia. Brain 1962; 85: 149-164
  • 26 Leibowitz U, Sharon D, Alter M. Geographical considerations in multiple sclerosis. Brain 1967; 90 (4) 871-886
  • 27 Kurtzke JF. On the fine structure of the distribution of multiple sclerosis. Acta Neurol Scand 1967; 43 (3) 257-282
  • 28 Goldberg P. Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence (A viewpoint) Part 1: sunlight, dietary factors and epidemiology. Int J Environ Stud 1974; 6: 19-27
  • 29 Swank RL, 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 (19) 722-728
  • 30 Westlund K. Distribution and mortality time trend of multiple sclerosis and some other diseases in Norway. Acta Neurol Scand 1970; 46 (4) 455-483
  • 31 Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296 (23) 2832-2838
  • 32 Munger KL, Levin LI, Massa J, Horst R, Orban T, Ascherio A. Preclinical serum 25-hydroxyvitamin D levels and risk of type 1 diabetes in a cohort of US military personnel. Am J Epidemiol 2013; 177 (5) 411-419
  • 33 Salzer J, Hallmans G, Nyström M, Stenlund H, Wadell G, Sundström P. Vitamin D as a protective factor in multiple sclerosis. Neurology 2012; 79 (21) 2140-2145
  • 34 Munger KL, Zhang SM, O'Reilly E , et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62 (1) 60-65
  • 35 Willett WC, Sampson L, Browne ML , et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 1988; 127 (1) 188-199
  • 36 Salvini S, Hunter DJ, 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 (4) 858-867
  • 37 Willett WC. Nutritional Epidemiology. 3rd ed. New York: Oxford University Press; 2012: 552
  • 38 Giovannucci E, Stampfer MJ, Colditz GA , et al. A comparison of prospective and retrospective assessments of diet in the study of breast cancer. Am J Epidemiol 1993; 137 (5) 502-511
  • 39 Kampman MT, Wilsgaard T, Mellgren SI. Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J Neurol 2007; 254 (4) 471-477
  • 40 Bäärnhielm M, Olsson T, Alfredsson L. Fatty fish intake is associated with decreased occurrence of multiple sclerosis. Mult Scler 2014; 20 (6) 726-732
  • 41 Cortese M, Riise T, Bjørnevik K , et al. Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study. Mult Scler 2015; 21 (14) 1856-1864
  • 42 Ascherio A, Munger K. Epidemiology of multiple sclerosis: from risk factors to prevention. Semin Neurol 2008; 28 (1) 17-28
  • 43 Antonovsky A, Leibowitz U, Smith HA , et al. Epidemiologic study of multiple sclerosis in Israel. I. An overall review of methods and findings. . Arch Neurol 1965; 13: 183-193
  • 44 Cendrowski W, Wender M, Dominik W, Flejsierowicz Z, Owsianowski M, Popiel M. Epidemiological study of multiple sclerosis in western Poland. Eur Neurol 1969; 2 (2) 90-108
  • 45 van der Mei IAF, Ponsonby AL, Dwyer T , et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ 2003; 327 (7410) 316-321
  • 46 Lucas RM, Ponsonby AL, Dear K , et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology 2011; 76 (6) 540-548
  • 47 Bäärnhielm M, Hedström AK, Kockum I , et al. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15. Eur J Neurol 2012; 19 (7) 955-962
  • 48 Bjørnevik K, Riise T, Casetta I , et al. Sun exposure and multiple sclerosis risk in Norway and Italy: The EnvIMS study. Mult Scler 2014; 20 (8) 1042-1049
  • 49 Ponsonby AL, Lucas RM, van der Mei IA. UVR, vitamin D and three autoimmune diseases—multiple sclerosis, type 1 diabetes, rheumatoid arthritis. Photochem Photobiol 2005; 81 (6) 1267-1275
  • 50 Mirzaei F, Michels KB, Munger K , et al. Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann Neurol 2011; 70 (1) 30-40
  • 51 Ueda P, Rafatnia F, Bäärnhielm M , et al. Neonatal vitamin D status and risk of multiple sclerosis. Ann Neurol 2014; 76 (3) 338-346
  • 52 Ascherio A, Munger KL. Not too late to take vitamin D supplements. Ann Neurol 2014; 76 (3) 321-322
  • 53 Mokry LE, Ross S, Ahmad OS , et al. Vitamin D and risk of multiple sclerosis: a Mendelian randomization study. PLoS Med 2015; 12 (8) e1001866
  • 54 Wang TJ, Zhang F, Richards JB , et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010; 376 (9736) 180-188
  • 55 Lucas RM, Ponsonby AL. 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 (1) 140-149
  • 56 van der Mei IA, Ponsonby AL, Dwyer T , et al. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol 2007; 254 (5) 581-590
  • 57 Simpson Jr S, Taylor B, Blizzard L , et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010; 68 (2) 193-203
  • 58 Runia TF, Hop WCJ, de Rijke YB, Buljevac D, Hintzen RQ. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology 2012; 79 (3) 261-266
  • 59 Mowry EM, Krupp LB, Milazzo M , et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010; 67 (5) 618-624
  • 60 Ascherio A, Munger KL, White R , et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol 2014; 71 (3) 306-314
  • 61 Martinelli V, Dalla Costa G, Colombo B , et al. Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes. Mult Scler 2014; 20 (2) 147-155
  • 62 Kuhle J, Disanto G, Dobson R , et al. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler 2015; 21 (8) 1013-1024
  • 63 Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler 2012; 18 (8) 1144-1151
  • 64 Stein MS, Liu Y, Gray OM , et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 2011; 77 (17) 1611-1618
  • 65 Soilu-Hänninen M, Aivo J, Lindström BM , et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83 (5) 565-571
  • 66 Smolders J, Hupperts R, Barkhof F , et al; SOLAR study group. Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a: a phase II, multicenter, double-blind, randomized, placebo-controlled trial. J Neurol Sci 2011; 311 (1–2) 44-49
  • 67 Dörr J, Ohlraun S, Skarabis H, Paul F. Efficacy of vitamin D supplementation in multiple sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial. Trials 2012; 13 (1) 15
  • 68 Bhargava P, Cassard S, Steele SU , et al. The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. Contemp Clin Trials 2014; 39 (2) 288-293
  • 69 Hayes CE, Hubler SL, Moore JR, Barta LE, Praska CE, Nashold FE. Vitamin D actions on CD4(+) T cells in autoimmune disease. Front Immunol 2015; 6: 100
  • 70 Cantorna MT, Snyder L, Lin YD, Yang L. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients 2015; 7 (4) 3011-3021
  • 71 Hollis BW. 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 (2) 317-322
  • 72 Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 2005; 16 (7) 713-716
  • 73 Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999; 69 (5) 842-856
  • 74 Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77 (1) 204-210
  • 75 Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 2002; 30 (5) 771-777
  • 76 Hyppönen 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 (3) 860-868
  • 77 Cooper JD, Smyth DJ, Walker NM , et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 2011; 60 (5) 1624-1631
  • 78 Pereira-Santos M, Costa PR, Assis AM, Santos CA, Santos DB. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev 2015; 16 (4) 341-349
  • 79 Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology 2009; 73 (19) 1543-1550
  • 80 Munger KL, Bentzen J, Laursen B , et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler 2013; 19 (10) 1323-1329
  • 81 Hedström AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler 2012; 18 (9) 1334-1336
  • 82 Wesnes K, Riise T, Casetta I , et al. Body size and the risk of multiple sclerosis in Norway and Italy: the EnvIMS study. Mult Scler 2015; 21 (4) 388-395
  • 83 Gianfrancesco MA, Acuna B, Shen L , et al. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors. Obes Res Clin Pract 2014; 8 (5) e435-e447
  • 84 Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311 (8) 806-814
  • 85 Sewell DL, Reinke EK, Hogan LH, Sandor M, Fabry Z. Immunoregulation of CNS autoimmunity by helminth and mycobacterial infections. Immunol Lett 2002; 82 (1–2) 101-110
  • 86 Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347 (12) 911-920
  • 87 Niederman JC, Evans AS. Epstein-Barr virus. In: Evans AS, Kaslow RA, , eds. Viral Infections of Humans: Epidemiology and Control. 4th ed. New York: Plenum; 1997: 253-283
  • 88 Warner HB, Carp RI. Multiple sclerosis and Epstein-Barr virus. Lancet 1981; 2 (8258) 1290
  • 89 Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis. Epidemiology 2000; 11 (2) 220-224
  • 90 Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 2007; 61 (4) 288-299
  • 91 Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B. Epstein-Barr virus in pediatric multiple sclerosis. JAMA 2004; 291 (15) 1875-1879
  • 92 Pohl D, Krone B, Rostasy K , et al. High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 2006; 67 (11) 2063-2065
  • 93 Banwell B, Krupp L, Kennedy J , et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6 (9) 773-781
  • 94 Thacker EL, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006; 59 (3) 499-503
  • 95 Nielsen TR, Rostgaard K, Nielsen NM , et al. Multiple sclerosis after infectious mononucleosis. Arch Neurol 2007; 64 (1) 72-75
  • 96 Ascherio A, Munger KL, Lennette ET , et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001; 286 (24) 3083-3088
  • 97 Levin LI, Munger KL, Rubertone MV , et al. Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 2005; 293 (20) 2496-2500
  • 98 DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 2006; 63 (6) 839-844
  • 99 Sundström P, Juto P, Wadell G , et al. An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology 2004; 62 (12) 2277-2282
  • 100 Munger KL, Levin LI, O'Reilly EJ, Falk KI, Ascherio A. Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult Scler 2011; 17 (10) 1185-1193
  • 101 Levin LI, Munger KL, O'Reilly EJ, Falk KI, Ascherio A. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol 2010; 67 (6) 824-830
  • 102 Ascherio A, Munger KL, Lünemann JD. The initiation and prevention of multiple sclerosis. Nat Rev Neurol 2012; 8 (11) 602-612
  • 103 James JA, Harley JB, Scofield RH. Epstein-Barr virus and systemic lupus erythematosus. Curr Opin Rheumatol 2006; 18 (5) 462-467
  • 104 Lang HL, Jacobsen H, Ikemizu S , et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002; 3 (10) 940-943
  • 105 Höllsberg P, Hansen HJ, Haahr S. Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis. Clin Exp Immunol 2003; 132 (1) 137-143
  • 106 Holmøy T, Vartdal F. Cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus-transformed B cells. J Neurovirol 2004; 10 (1) 52-56
  • 107 Rand KH, Houck H, Denslow ND, Heilman KM. Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 2000; 173 (1) 32-39
  • 108 Lennette ET, 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 (11) 1584-1589
  • 109 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 (6) 461-469
  • 110 Lünemann JD, Edwards N, Muraro PA , et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 2006; 129 (Pt 6) 1493-1506
  • 111 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 (5) 1352-1360
  • 112 Lossius A, Johansen JN, Vartdal F , et al. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol 2014; 44 (11) 3439-3452
  • 113 van Nierop GP, Mautner J, Mitterreiter JG, Hintzen RQ, Verjans GM. Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins. Mult Scler 2015;
  • 114 Mechelli R, Manzari C, Policano C , et al. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology 2015; 84 (13) 1362-1368
  • 115 Hilton DA, Love S, Fletcher A, Pringle JH. Absence of Epstein-Barr virus RNA in multiple sclerosis as assessed by in situ hybridisation. J Neurol Neurosurg Psychiatry 1994; 57 (8) 975-976
  • 116 Sanders VJ, Felisan S, Waddell A, Tourtellotte WW. Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J Neurovirol 1996; 2 (4) 249-258
  • 117 Opsahl ML, Kennedy PG. An attempt to investigate the presence of Epstein Barr virus in multiple sclerosis and normal control brain tissue. J Neurol 2007; 254 (4) 425-430
  • 118 Serafini B, Rosicarelli B, Franciotta D , et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 2007; 204 (12) 2899-2912
  • 119 Magliozzi R, Serafini B, Rosicarelli B , et al. B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J Neuropathol Exp Neurol 2013; 72 (1) 29-41
  • 120 Willis SN, Stadelmann C, Rodig SJ , et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 2009; 132 (Pt 12) 3318-3328
  • 121 Sargsyan SA, Shearer AJ, Ritchie AM , et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 2010; 74 (14) 1127-1135
  • 122 Peferoen LA, Lamers F, Lodder LN , et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain 2010; 133 (Pt 5) e137
  • 123 Torkildsen Ø, Stansberg C, Angelskår SM , et al. Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol 2010; 20 (4) 720-729
  • 124 Ascherio A, Bar-Or A. EBV and brain matter(s)?. Neurology 2010; 74 (14) 1092-1095
  • 125 Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM ; NeuroproMiSe EBV Working Group. Epstein-Barr virus in the multiple sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain 2011; 134 (Pt 9) 2772-2786
  • 126 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 (3) 214-224
  • 127 Friedman JE, Zabriskie JB, Plank C , et al. A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler 2005; 11 (3) 286-295
  • 128 Villard-Mackintosh L, Vessey MP. Oral contraceptives and reproductive factors in multiple sclerosis incidence. Contraception 1993; 47 (2) 161-168
  • 129 Thorogood M, Hannaford PC. The influence of oral contraceptives on the risk of multiple sclerosis. Br J Obstet Gynaecol 1998; 105 (12) 1296-1299
  • 130 Hernán MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol 2001; 154 (1) 69-74
  • 131 Hernán MA, Jick SS, Logroscino G, Olek MJ, Ascherio A, Jick H. Cigarette smoking and the progression of multiple sclerosis. Brain 2005; 128 (Pt 6) 1461-1465
  • 132 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 (4) 281-285
  • 133 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 (2) 77-82
  • 134 Sundström P, Nyström L. Smoking worsens the prognosis in multiple sclerosis. Mult Scler 2008; 14 (8) 1031-1035
  • 135 Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009; 73 (9) 696-701
  • 136 Ramagopalan SV, Lee JD, Yee IM , et al. Association of smoking with risk of multiple sclerosis: a population-based study. J Neurol 2013; 260 (7) 1778-1781
  • 137 Briggs FB, Acuna B, Shen L , et al. Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants. Epidemiology 2014; 25 (4) 605-614
  • 138 Riise T, Nortvedt MW, Ascherio A. Smoking is a risk factor for multiple sclerosis. Neurology 2003; 61 (8) 1122-1124
  • 139 Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007; 61 (6) 504-513
  • 140 Sundström P, Nyström L, Hallmans G. Smoke exposure increases the risk for multiple sclerosis. Eur J Neurol 2008; 15 (6) 579-583
  • 141 Hedström AK, Sundqvist E, Bäärnhielm M , et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 2011; 134 (Pt 3) 653-664
  • 142 Simon KC, van der Mei IA, Munger KL , et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. Neurology 2010; 74 (17) 1365-1371
  • 143 Palacios N, Alonso A, Brønnum-Hansen H, Ascherio A. Smoking and increased risk of multiple sclerosis: parallel trends in the sex ratio reinforce the evidence. Ann Epidemiol 2011; 21 (7) 536-542
  • 144 Courville CB, Maschmeyer JE, Delay CP. Effects of smoking on the acute exacerbations of multiple sclerosis. Bull Los Angel Neuro Soc 1964; 29: 1-6
  • 145 Emre M, de Decker C. Effects of cigarette smoking on motor functions in patients with multiple sclerosis. Arch Neurol 1992; 49 (12) 1243-1247
  • 146 Healy BC, Ali EN, Guttmann CR , et al. Smoking and disease progression in multiple sclerosis. Arch Neurol 2009; 66 (7) 858-864
  • 147 Di Pauli F, Reindl M, Ehling R , et al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Mult Scler 2008; 14 (8) 1026-1030
  • 148 Munger KL, Fitzgerald KC, Freedman MS , et al. No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT. Neurology 2015; 85 (19) 1694-1701
  • 149 Hawkins BT, Brown RC, Davis TP. Smoking and ischemic stroke: a role for nicotine?. Trends Pharmacol Sci 2002; 23 (2) 78-82
  • 150 Costenbader KH, Karlson EW. Cigarette smoking and autoimmune disease: what can we learn from epidemiology?. Lupus 2006; 15 (11) 737-745
  • 151 Hedström AK, Hillert J, Olsson T, Alfredsson L. Nicotine might have a protective effect in the etiology of multiple sclerosis. Mult Scler 2013; 19 (8) 1009-1013
  • 152 Gao Z, Nissen JC, Ji K, Tsirka SE. The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components. PLoS ONE 2014; 9 (9) e107979
  • 153 Gao Z, Nissen JC, Legakis L, Tsirka SE. Nicotine modulates neurogenesis in the central canal during experimental autoimmune encephalomyelitis. Neuroscience 2015; 297: 11-21
  • 154 Odoardi F, Sie C, Streyl K , et al. T cells become licensed in the lung to enter the central nervous system. Nature 2012; 488 (7413) 675-679
  • 155 Jamal A, Agaku IT, O'Connor E, King BA, Kenemer JB, Neff L. Current cigarette smoking among adults—United States, 2005-2013. MMWR Morb Mortal Wkly Rep 2014; 63 (47) 1108-1112
  • 156 Rothman K, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia: Lippincott-Raven; 1998
  • 157 Farez MF, Fiol MP, Gaitán MI, Quintana FJ, Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 2015; 86 (1) 26-31
  • 158 Massa J, O'Reilly EJ, Munger KL, Ascherio A. Caffeine and alcohol intakes have no association with risk of multiple sclerosis. Mult Scler 2013; 19 (1) 53-58
  • 159 D'hooghe MB, Haentjens P, Nagels G, De Keyser J. Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis. Eur J Neurol 2012; 19 (4) 616-624
  • 160 Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol 2014; 71 (3) 300-305
  • 161 Pekmezovic T, Drulovic J, Milenkovic M , et al. Lifestyle factors and multiple sclerosis: a case-control study in Belgrade. Neuroepidemiology 2006; 27 (4) 212-216