Skip to main content

Advertisement

SpringerLink
Log in

Relation between Epstein-Barr virus and multiple sclerosis: analytic study of scientific production

  • Article
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Numerous studies have been carried out to determine whether infection by the Epstein-Barr virus (EBV) can be considered as a risk factor for multiple sclerosis (MS). This work is a meta-analysis of case–control observational studies published before January 2009 aimed at assessing the degree of association between EBV and MS infections. A Medline electronic database search was carried out using “Epstein-Barr virus” and “multiple sclerosis” as keywords, from which we selected 30 published studies that met our methodology criteria. We found an association between MS and an exposure to EBV, studied by determining the anti-VCA IgG antibodies (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 3.37–8.81; p < 0.0001), anti-complex EBNA IgG (OR = 5.4; 95% CI = 2.94–9.76; p < 0.0001) and anti-EBNA-1 IgG (OR = 12.1; 95% CI = 3.13–46.89; p < 0.0001). No significant association could be found when studying anti-EA IgG (OR = 1.3; 95% CI = 0.68–2.35; p = 0.457), EBV DNA in serum (OR = 1.8; 95% CI = 0.99–3.36; p = 0.051) and DNA in brain tissues and in cerebrospinal fluid (CSF) (OR = 0.9; 95% CI = 0.38–2.01; p = 0.768). This meta-analysis detected an association between infection by EBV and MS through the investigation of antibodies, mainly anti-EBNA-1, anti-complex EBNA and anti-VCA IgG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fernández O, Guerrero M, Fernández VE (2005) Esclerosis múltiple. McGraw-Hill-Interamericana, Madrid

    Google Scholar 

  2. Haahr S, Höllsberg P (2006) Multiple sclerosis is linked to Epstein-Barr virus infection. Rev Med Virol 16:297–310

    Article  CAS  PubMed  Google Scholar 

  3. Salvetti M, Giovannoni G, Aloisi F (2009) Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol 22:201–206

    Article  PubMed  Google Scholar 

  4. Haahr S, Plesner AM, Vestergaard BF et al (2004) A role of late Epstein-Barr virus infection in multiple sclerosis. Acta Neurol Scand 109:270–275

    Article  CAS  PubMed  Google Scholar 

  5. Haahr S, Koch-Henriksen N, Møller-Larsen A et al (1995) Increased risk of multiple sclerosis after late Epstein-Barr virus infection: a historical prospective study. Mult Scler 1:73–77

    CAS  PubMed  Google Scholar 

  6. Hernán MA, Zhang SM, Lipworth L et al (2001) Multiple sclerosis and age at infection with common viruses. Epidemiology 12:301–306

    Article  PubMed  Google Scholar 

  7. Nielsen TR, Rostgaard K, Nielsen NM et al (2007) Multiple sclerosis after infectious mononucleosis. Arch Neurol 64:72–75

    Article  PubMed  Google Scholar 

  8. Ascherio A, Munch M (2000) Epstein-Barr virus and multiple sclerosis. Epidemiology 11:220–224

    Article  CAS  PubMed  Google Scholar 

  9. DeLorenze GN, Munger KL, Lennette ET et al (2006) Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 63:839–844

    Article  PubMed  Google Scholar 

  10. Sundström P, Juto P, Wadell G et al (2004) An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology 62:2277–2282

    PubMed  Google Scholar 

  11. Serafini B, Rosicarelli B, Franciotta D et al (2007) Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 204:2899–2912

    Article  CAS  PubMed  Google Scholar 

  12. Thacker EL, Mirzaei F, Ascherio A (2006) Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 59:499–503

    Article  PubMed  Google Scholar 

  13. Ascherio A, Munger KL (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 61:288–299

    Article  PubMed  Google Scholar 

  14. Holmøy T (2008) Vitamin D status modulates the immune response to Epstein Barr virus: synergistic effect of risk factors in multiple sclerosis. Med Hypotheses 70:66–69

    Article  PubMed  CAS  Google Scholar 

  15. Lindberg C, Andersen O, Vahlne A et al (1991) Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis. Neuroepidemiology 10:62–65

    Article  CAS  PubMed  Google Scholar 

  16. Marrie RA, Wolfson C (2002) Multiple sclerosis and Epstein-Barr virus. Can J Infect Dis 13:111–118

    PubMed  Google Scholar 

  17. Alotaibi S, Kennedy J, Tellier R et al (2004) Epstein-Barr virus in pediatric multiple sclerosis. JAMA 291:1875–1879

    Article  CAS  PubMed  Google Scholar 

  18. Banwell B, Krupp L, Kennedy J et al (2007) Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 6:773–781

    Article  PubMed  Google Scholar 

  19. Pohl D, Krone B, Rostasy K et al (2006) High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 67:2063–2065

    Article  CAS  PubMed  Google Scholar 

  20. Alvarez R, Cour I, Kanaan A et al (2000) Detection of viral genomes of the Herpesviridae family in multiple sclerosis patients by means of the polymerase chain reaction (PCR). Enferm Infecc Microbiol Clin 18:223–228

    CAS  PubMed  Google Scholar 

  21. Alvarez-Lafuente R, García-Montojo M, De Las Heras V et al (2008) Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients. Mult Scler 14:595–601

    Article  CAS  PubMed  Google Scholar 

  22. Ascherio A, Munger KL, Lennette ET et al (2001) Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286:3083–3088

    Article  CAS  PubMed  Google Scholar 

  23. Bray PF, Luka J, Bray PF et al (1992) Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 42:1798–1804

    CAS  PubMed  Google Scholar 

  24. Bray PF, Bloomer LC, Salmon VC et al (1983) Epstein-Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch Neurol 40:406–408

    CAS  PubMed  Google Scholar 

  25. Buljevac D, van Doornum GJ, Flach HZ et al (2005) Epstein-Barr virus and disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 76:1377–1381

    Article  CAS  PubMed  Google Scholar 

  26. Denne C, Kleines M, Dieckhöfer A et al (2007) Intrathecal synthesis of anti-viral antibodies in pediatric patients. Eur J Paediatr Neurol 11:29–34

    Article  PubMed  Google Scholar 

  27. Ferrante P, Mancuso R, Pagani E et al (2000) Molecular evidences for a role of HSV-1 in multiple sclerosis clinical acute attack. J Neurovirol 6(Suppl 2):S109–S114

    CAS  PubMed  Google Scholar 

  28. Hay KA, Tenser RB (2000) Leukotropic herpesviruses in multiple sclerosis. Mult Scler 6:66–68

    CAS  PubMed  Google Scholar 

  29. Höllsberg P, Kusk M, Bech E et al (2005) Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity. Acta Neurol Scand 112:395–402

    Article  PubMed  CAS  Google Scholar 

  30. Morré SA, van Beek J, De Groot CJ et al (2001) Is Epstein-Barr virus present in the CNS of patients with MS. Neurology 56:692

    PubMed  Google Scholar 

  31. Munch M, Riisom K, Christensen T et al (1998) The significance of Epstein-Barr virus seropositivity in multiple sclerosis patients? Acta Neurol Scand 97:171–174

    Article  CAS  PubMed  Google Scholar 

  32. Mancuso R, Delbue S, Borghi E et al (2007) Increased prevalence of varicella zoster virus DNA in cerebrospinal fluid from patients with multiple sclerosis. J Med Virol 79:192–199

    Article  CAS  PubMed  Google Scholar 

  33. Martin C, Enbom M, Söderström M et al (1997) Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis. Acta Neurol Scand 95:280–283

    Article  CAS  PubMed  Google Scholar 

  34. Myhr KM, Riise T, Barrett-Connor E et al (1998) 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

    Article  CAS  PubMed  Google Scholar 

  35. Shirodaria PV, Haire M, Fleming E et al (1987) Viral antibody titers. Comparison in patients with multiple sclerosis and rheumatoid arthritis. Arch Neurol 44:1237–1241

    CAS  PubMed  Google Scholar 

  36. Ponsonby AL, van der Mei I, Dwyer T et al (2005) Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 293:463–469

    Article  CAS  PubMed  Google Scholar 

  37. Sumaya CV, Myers LW, Ellison GW (1980) Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol 37:94–96

    CAS  PubMed  Google Scholar 

  38. Sumaya CV, Myers LW, Ellison GW (1976) Epstein-Barr virus antibodies in multiple sclerosis. Trans Am Neurol Assoc 101:300–302

    CAS  PubMed  Google Scholar 

  39. Sanders VJ, Felisan S, Waddell A et al (1996) Detection of Herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J Neurovirol 2:249–258

    Article  CAS  PubMed  Google Scholar 

  40. Sotelo J, Ordoñez G, Pineda B (2007) Varicella-zoster virus at relapses of multiple sclerosis. J Neurol 254:493–500

    Article  PubMed  Google Scholar 

  41. Wagner HJ, Munger KL, Ascherio A (2004) Plasma viral load of Epstein-Barr virus and risk of multiple sclerosis. Eur J Neurol 11:833–834

    Article  PubMed  Google Scholar 

  42. Wandinger K, Jabs W, Siekhaus A et al (2000) Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 55:178–184

    CAS  PubMed  Google Scholar 

  43. Zivadinov R, Nasuelli D, Tommasi MA et al (2006) Positivity of cytomegalovirus antibodies predicts a better clinical and radiological outcome in multiple sclerosis patients. Neurol Res 28:262–269

    Article  CAS  PubMed  Google Scholar 

  44. Riverol M, Sepulcre J, Fernandez-Diez B et al (2007) Antibodies against Epstein-Barr virus and herpesvirus type 6 are associated with the early phases of multiple sclerosis. J Neuroimmunol 192:184–185

    Article  CAS  PubMed  Google Scholar 

  45. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  46. Egger M, Smith GD, Altman D (1995) Systematic reviews in health care: meta-analysis in context. BMJ Books, London

    Google Scholar 

  47. Wells GA, Shea B, O’Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available online at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm

  48. Levin LI, Munger KL, Rubertone MV et al (2005) Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293:2496–2500

    Article  CAS  PubMed  Google Scholar 

  49. Gutiérrez J, Sorlózano A, Soto MJ et al (2006) Microbiological diagnosis of infection by the Epstein-Barr virus: pathogenic basis. In: Umar CS (ed) New developments in Epstein-Barr virus research. Nova Science Publishers, New York, pp 277–299

    Google Scholar 

  50. Cepok S, Zhou D, Srivastava R et al (2005) Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115:1352–1360

    CAS  PubMed  Google Scholar 

  51. Lünemann JD, Edwards N, Muraro PA et al (2006) Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129:1493–1506

    Article  PubMed  Google Scholar 

  52. Holmøy T, Kvale EØ, Vartdal F (2004) Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein-Barr virus and myelin basic protein. J Neurovirol 10:278–283

    Article  PubMed  CAS  Google Scholar 

  53. van Noort JM, Bajramovic JJ, Plomp AC et al (2000) Mistaken self, a novel model that links microbial infections with myelin-directed autoimmunity in multiple sclerosis. J Neuroimmunol 105:46–57

    Article  PubMed  Google Scholar 

  54. Pender MP (2003) Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 24:584–588

    Article  CAS  PubMed  Google Scholar 

  55. Pender MP, Csurhes PA, Lenarczyk A et al (2009) Decreased T cell reactivity to Epstein-Barr virus infected lymphoblastoid cell lines in multiple sclerosis. J Neurol Neurosurg Psychiatry 80:498–505

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology, School of Medicine, University of Granada, Avenida de Madrid, 11, 18012, Granada, Spain

    O. Santiago, J. Gutierrez, A. Sorlozano & E. Villegas

  2. Department of Statistics and Operation Research, University of Granada, Granada, Spain

    J. de Dios Luna

  3. Neurology Service, Hospital Carlos Haya, Málaga, Spain

    O. Fernandez

Authors
  1. O. Santiago
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Sorlozano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. de Dios Luna
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Villegas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O. Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Gutierrez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santiago, O., Gutierrez, J., Sorlozano, A. et al. Relation between Epstein-Barr virus and multiple sclerosis: analytic study of scientific production. Eur J Clin Microbiol Infect Dis 29, 857–866 (2010). https://doi.org/10.1007/s10096-010-0940-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-010-0940-0

Keywords

Search

Navigation