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Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature



Patients with multiple sclerosis (MS) frequently have an intrathecal production of antibodies to different common viruses, which can be detected by elevated antiviral antibody indices (AIs). There is a strong and consistent association of MS and Epstein–Barr virus (EBV) infection.


To systematically compare the frequencies of intrathecal antibody production to EBV, measles virus, rubella virus, varicella zoster virus (VZV) and herpes simplex virus (HSV) in patients with MS.


Review of the English and German literature on the frequencies of intrathecal immunoglobulin (Ig)G antibody production, as defined by an elevated AI, to EBV, measles virus, rubella virus, VZV and HSV in adult and pediatric patients with MS.


In nine original studies identified, the frequencies of an intrathecal production of antibodies to Epstein–Barr nuclear antigen-1 (33/340, 9.7%), EBV viral capsid antigen (12/279, 4.3%) and antigens from EBV-infected cell lines (14/90, 15.6%) in adult patients with MS were clearly lower (p ≤ 0.03 for all pairwise comparisons) than the frequencies of an intrathecal production of antibodies to measles virus (612/922, 66.4%), rubella virus (521/922, 56.5%), VZV (470/922, 51%; data from 17 original studies) and HSV (78/291, 26.8%; data from 6 original studies). Though based on a lower number of original studies and patients, findings in children with MS were essentially similar. As in adults and children with MS the seroprevalence of EBV is higher than the seroprevalences of the other investigated viruses, the lower frequency of elevated EBV AIs became even more pronounced after correction of the frequencies of elevated antiviral AIs for the seroprevalences of the respective viruses.


Given the very high seroprevalence of EBV in MS, the frequency of intrathecally produced antibodies to EBV in patients with MS is paradoxically low compared to that of other common viruses. These findings are compatible with the recently proposed hypothesis that in individuals going on to develop MS antiviral antibody-producing cells may invade the brain predominantly at the time of and triggered by acute primary EBV infection, before anti-EBV IgG producing cells have yet occurred.

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  1. 1.

    Almohmeed YH, Avenell A, Aucott L, Vickers MA (2013) Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One 8:e61110

  2. 2.

    Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B (2004) Epstein–Barr virus in pediatric multiple sclerosis. JAMA 291:1875–1879

  3. 3.

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

  4. 4.

    Ascherio A, Munger KL (2016) Epidemiology of multiple sclerosis: from risk factors to prevention—an update. Semin Neurol 36:103–114

  5. 5.

    Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernan MA, Olek MJ, Hankinson SE, Hunter DJ (2001) Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286:3083–3088

  6. 6.

    Ascherio A, Munger KL, Lunemann JD (2012) The initiation and prevention of multiple sclerosis. Nat Rev Neurol 8:602–612

  7. 7.

    Balfour HH Jr, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, Vezina HE, Thomas W, Hogquist KA (2013) Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:80–88

  8. 8.

    Banwell B, Krupp L, Kennedy J, Tellier R, Tenembaum S, Ness J, Belman A, Boiko A, Bykova O, Waubant E, Mah JK, Stoian C, Kremenchutzky M, Bardini MR, Ruggieri M, Rensel M, Hahn J, Weinstock-Guttman B, Yeh EA, Farrell K, Freedman M, Iivanainen M, Sevon M, Bhan V, Dilenge ME, Stephens D, Bar-Or A (2007) Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 6:773–781

  9. 9.

    Bednarova J, Stourac P, Adam P (2005) Relevance of immunological variables in neuroborreliosis and multiple sclerosis. Acta Neurol Scand 112:97–102

  10. 10.

    Belbasis L, Bellou V, Evangelou E, Ioannidis JP, Tzoulaki I (2015) Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 14:263–273

  11. 11.

    Brettschneider J, Tumani H, Kiechle U, Muche R, Richards G, Lehmensiek V, Ludolph AC, Otto M (2009) IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One 4:e7638

  12. 12.

    Castellazzi M, Contini C, Tamborino C, Fasolo F, Roversi G, Seraceni S, Rizzo R, Baldi E, Tola MR, Bellini T, Granieri E, Fainardi E (2014) Epstein–Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies. J Neuroinflammation 11:188

  13. 13.

    Castellazzi M, Tamborino C, Cani A, Negri E, Baldi E, Seraceni S, Tola MR, Granieri E, Contini C, Fainardi E (2010) Epstein–Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis. Mult Scler 16:883–887

  14. 14.

    Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517

  15. 15.

    Delorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A (2006) Epstein–Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 63:839–844

  16. 16.

    Denne C, Kleines M, Dieckhofer A, Ritter K, Scheithauer S, Merz U, Hausler M (2007) Intrathecal synthesis of anti-viral antibodies in pediatric patients. Eur J Paediatr Neurol 11:29–34

  17. 17.

    Felgenhauer K, Reiber H (1992) The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system. Clin Investig 70:28–37

  18. 18.

    Goodin DS (2009) The causal cascade to multiple sclerosis: a model for MS pathogenesis. PLoS One 4:e4565

  19. 19.

    Graef IT, Henze T, Reiber H (1994) Polyspecific immune reaction in the central nervous system in autoimmune diseases with CNS involvement. Z Arztl Fortbild Jena 88:587–591

  20. 20.

    Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV (2010) An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 5:e12496

  21. 21.

    Hottenrott T, Dersch R, Berger B, Rauer S, Huzly D, Stich O (2017) The MRZ reaction in primary progressive multiple sclerosis. Fluids Barriers CNS 14:2

  22. 22.

    Jacobi C, Lange P, Reiber H (2007) Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol 187:139–146

  23. 23.

    Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B (2017) The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol 264:453–466

  24. 24.

    Jarius S, Franciotta D, Bergamaschi R, Rauer S, Wandinger KP, Petereit HF, Maurer M, Tumani H, Vincent A, Eichhorn P, Wildemann B, Wick M, Voltz R (2008) Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 79:1134–1136

  25. 25.

    Krone B, Pohl D, Rostasy K, Kahler E, Brunner E, Oeffner F, Grange JM, Gartner J, Hanefeld F (2008) Common infectious agents in multiple sclerosis: a case–control study in children. Mult Scler 14:136–139

  26. 26.

    Levin LI, Munger KL, O’Reilly EJ, Falk KI, Ascherio A (2010) Primary infection with the Epstein–Barr virus and risk of multiple sclerosis. Ann Neurol 67:824–830

  27. 27.

    Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Spiegelman D, Ascherio A (2005) Temporal relationship between elevation of Epstein–Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA 293:2496–2500

  28. 28.

    Makhani N, Banwell B, Tellier R, Yea C, McGovern S, O’Mahony J, Ahorro JM, Arnold D, Sadovnick AD, Marrie RA, Bar-Or A (2016) Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler 22:385–388

  29. 29.

    Munger KL, Levin LI, O’Reilly EJ, Falk KI, Ascherio A (2011) Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. Mult Scler 17:1185–1193

  30. 30.

    Otto C, Hofmann J, Ruprecht K (2016) Antibody producing B lineage cells invade the central nervous system predominantly at the time of and triggered by acute Epstein–Barr virus infection: a hypothesis on the origin of intrathecal immunoglobulin synthesis in multiple sclerosis. Med Hypotheses 91:109–113

  31. 31.

    Otto C, Oltmann A, Stein A, Frenzel K, Schroeter J, Habbel P, Gartner B, Hofmann J, Ruprecht K (2011) Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis. Neurology 76:1316–1321

  32. 32.

    Pakpoor J, Disanto G, Gerber JE, Dobson R, Meier UC, Giovannoni G, Ramagopalan SV (2012) The risk of developing multiple sclerosis in individuals seronegative for Epstein–Barr virus: a meta-analysis. Mult Scler 19:162–166

  33. 33.

    Pebody RG, Andrews N, Brown D, Gopal R, De Melker H, Francois G, Gatcheva N, Hellenbrand W, Jokinen S, Klavs I, Kojouharova M, Kortbeek T, Kriz B, Prosenc K, Roubalova K, Teocharov P, Thierfelder W, Valle M, Van Damme P, Vranckx R (2004) The seroepidemiology of herpes simplex virus type 1 and 2 in Europe. Sex Transm Infect 80:185–191

  34. 34.

    Petereit HF, Reske D (2005) Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients—follow-up and clinical implications. Cerebrospinal Fluid Res 2:3

  35. 35.

    Pfuhl C, Oechtering J, Rasche L, Giess RM, Behrens JR, Wakonig K, Freitag E, Pache FC, Otto C, Hofmann J, Eberspacher B, Bellmann-Strobl J, Paul F, Ruprecht K (2015) Association of serum Epstein–Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis. J Neuroimmunol 285:156–160

  36. 36.

    Poethko-Muller C, Mankertz A (2012) Seroprevalence of measles-, mumps- and rubella-specific IgG antibodies in German children and adolescents and predictors for seronegativity. PLoS One 7:e42867

  37. 37.

    Pohl D, Krone B, Rostasy K, Kahler E, Brunner E, Lehnert M, Wagner H-J, Gärtner J, Hanefeld F (2006) High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 67:2063–2065

  38. 38.

    Pohl D, Rostasy K, Jacobi C, Lange P, Nau R, Krone B, Hanefeld F (2009) Intrathecal antibody production against Epstein–Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis. J Neurol 257:212–216

  39. 39.

    Puccioni-Sohler M, Kitze B, Felgenhauer K, Graef IT, Lange P, Novis S, Reiber H, Vaz B (1995) The value of CSF analysis for the differential diagnosis of HTLV-I associated myelopathy and multiple sclerosis. Arq Neuropsiquiatr 53:760–765

  40. 40.

    Rand KH, Houck H, Denslow ND, Heilman KM (2000) Epstein–Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci 173:32–39

  41. 41.

    Reiber H (2017) Polyspecific antibodies without persisting antigen in multiple sclerosis, neurolupus and Guillain–Barre syndrome: immune network connectivity in chronic diseases. Arq Neuropsiquiatr 75:580–588

  42. 42.

    Reiber H, Kruse-Sauter H, Quentin CD (2015) Antibody patterns vary arbitrarily between cerebrospinal fluid and aqueous humor of the individual multiple sclerosis patient: specificity-independent pathological B cell function. J Neuroimmunol 278:247–254

  43. 43.

    Reiber H, Lange P (1991) Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 37:1153–1160

  44. 44.

    Reiber H, Peter JB (2001) Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 184:101–122

  45. 45.

    Reiber H, Teut M, Pohl D, Rostasy KM, Hanefeld F (2009) Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler 15:1466–1480

  46. 46.

    Reiber H, Ungefehr S, Jacobi C (1998) The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 4:111–117

  47. 47.

    Rickinson AB, Kieff E (2001) Epstein–Barr virus. In: Knipe DM, Howley PM (eds) Virology. Lippincott Williams and Wilkins, New York, pp 2575–2627

  48. 48.

    Robinson-Agramonte M, Reiber H, Cabrera-Gomez JA, Galvizu R (2007) Intrathecal polyspecific immune response to neurotropic viruses in multiple sclerosis: a comparative report from Cuban patients. Acta Neurol Scand 115:312–318

  49. 49.

    Rosche B, Laurent S, Conradi S, Hofmann J, Ruprecht K, Harms L (2012) Measles IgG antibody index correlates with T2 lesion load on MRI in patients with early multiple sclerosis. PLoS One 7:e28094

  50. 50.

    Rostasy K, Reiber H, Pohl D, Lange P, Ohlenbusch A, Eiffert H, Maass M, Hanefeld F (2003) Chlamydia pneumoniae in children with MS: frequency and quantity of intrathecal antibodies. Neurology 61:125–128

  51. 51.

    Sargsyan SA, Shearer AJ, Ritchie AM, Burgoon MP, Anderson S, Hemmer B, Stadelmann C, Gattenlohner S, Owens GP, Gilden D, Bennett JL (2010) Absence of Epstein–Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 74:1127–1135

  52. 52.

    Schubert J, Weissbrich B (2007) Detection of virus-specific intrathecally synthesised immunoglobulin G with a fully automated enzyme immunoassay system. BMC Neurol 7:12

  53. 53.

    Sindic CJ, Monteyne P, Laterre EC (1994) The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 54:75–80

  54. 54.

    Sisay S, Lopez-Lozano L, Mickunas M, Quiroga-Fernandez A, Palace J, Warnes G, Alvarez-Lafuente R, Dua P, Meier UC (2017) Untreated relapsing remitting multiple sclerosis patients show antibody production against latent Epstein Barr Virus (EBV) antigens mainly in the periphery and innate immune IL-8 responses preferentially in the CNS. J Neuroimmunol 306:40–45

  55. 55.

    Sundstrom P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nystrom L, Dillner J, Forsgren L (2004) An altered immune response to Epstein–Barr virus in multiple sclerosis: a prospective study. Neurology 62:2277–2282

  56. 56.

    Thorley-Lawson DA (2005) EBV persistence and latent infection in vivo. In: Robertson ES (ed) Epstein–Barr virus. Caister Academic Press, Wymondham, pp 309–358

  57. 57.

    Villegas E, Santiago O, Carrillo JA, Sorlozano A, Guerrero M, Fernandez O, Gutierrez J (2011) Low intrathecal immune response of anti-EBNA-1 antibodies and EBV DNA from multiple sclerosis patients. Diagn Microbiol Infect Dis 70:85–90

  58. 58.

    Waubant E, Mowry EM, Krupp L, Chitnis T, Yeh EA, Kuntz N, Ness J, Chabas D, Strober J, McDonald J, Belman A, Milazzo M, Gorman M, Weinstock-Guttman B, Rodriguez M, Oksenberg JR, James JA (2011) Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 76:1989–1995

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This work was supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and the Charité Research Fund. BW and SJ are thankful to the Dietmar Hopp Stiftung, Germany, and to Merck Serono, Germany, for funding research on the role of antibodies in the differential diagnosis of multiple sclerosis at the Department of Neurology, University Hospital Heidelberg, Germany.

Author information

KR conceived of the study, collected and analysed data, and wrote the manuscript. SJ and BW collected and analysed data and critically revised the manuscript. All authors read and approved the final manuscript.

Correspondence to Klemens Ruprecht.

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Conflicts of interest

KR was supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and has received research support from Novartis and Merck Serono as well as speaking fees or travel grants from Guthy Jackson Charitable Foundation, Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis/Genzyme, Teva Pharmaceuticals, Roche and Novartis. BW received grants from the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis), Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Biogen, Merck Serono, Sanofi Genzyme, Novartis pharmaceuticals, Teva Pharma and personal fees from Bayer Healthcare. SJ reports no conflicts of interest.

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Ruprecht, K., Wildemann, B. & Jarius, S. Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature. J Neurol 265, 239–252 (2018).

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  • Multiple sclerosis
  • Epstein–Barr virus
  • Measles virus
  • Rubella virus
  • Varicella zoster virus
  • Herpes simplex virus
  • Antibodies
  • Antibody index
  • Cerebrospinal fluid
  • Serum
  • Seroprevalence
  • Children