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Journal of Neurology

, Volume 243, Issue 3, pp 214–224 | Cite as

Acyclovir treatment of relapsing-remitting multiple sclerosis

A randomized, placebo-controlled, double-blind study
  • Jan Lycke
  • Bo Svennerholm
  • Elisabeth Hjelmquist
  • Lars Frisén
  • Gaby Badr
  • Mats Andersson
  • Anders Vahlne
  • Oluf Andersen
Original Communication

Abstract

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on “intent-to-treat” data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0–2), medium (3–5) and high (6–8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.

Key words

Multiple sclerosis Clinical trial Acyclovir treatment Herpes virus 

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References

  1. 1.
    Andersen O (1980) Restricted dissemination of clinically defined attacks in an MS incidence material. Acta Neurol Scand 62:1–70PubMedGoogle Scholar
  2. 2.
    Andersen O (1984) Immunological and clinical aspects of multiple sclerosis. In: Gonsette RE, Delmotte P (eds) The proceedings of the XXV anniversary symposium of the Belgian research group for multiple sclerosis. MTP Press, Brussels, pp 110–118Google Scholar
  3. 3.
    Andersen O, Lygner P-E, Bergström T, Andersson M, Vahlne A (1993) Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. J Neurol 240:417–422PubMedGoogle Scholar
  4. 4.
    Beck A (1967) Depression: causes and treatment. University of Pennsylvania Press, PhiladelphiaGoogle Scholar
  5. 5.
    Bergström T, Andersen O, Vahlne A (1989) Isolation of herpes simplex virus type 1 during first attack of multiple sclerosis. Ann Neurol 26:283–285Google Scholar
  6. 6.
    Bray PF, Bloomer LC, Salmon VC, Bagley MH, Larsen PD (1983) Epstein-Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch Neurol 40:406–408PubMedGoogle Scholar
  7. 7.
    Broman T, Andersen O, Bergman L (1981) Clinical studies on MS. Acta Neurol Scand 63:6–33PubMedGoogle Scholar
  8. 8.
    Claesson LE, Dahl E (1971) CD-test. Psykologiförlaget, StockholmGoogle Scholar
  9. 9.
    Cronholm B, Molander L (1957) Memory disturbances after electroconvulsive therapy. Acta Psychiatr Neurol Scand 32:280–306PubMedGoogle Scholar
  10. 10.
    Durelli L, Bongioanni MR, Cavallo R, Ferrero B, Ferri R, Ferrio MF, Bradac GB, Riva A, Vai S, Geuna M, Bergamini L, Bergamasco B (1994) Chronic systemic high-dose recombinant interferon alpha-2a reduces exacerbation rate. MRI signs of disease activity and lymphocyte interferon gamma production in relapsing-remitting multiple sclerosis. Neurology 44:406–413PubMedGoogle Scholar
  11. 11.
    Forghani G, Schmidt NJ, Dennis J (1978) Antibody assays for varicellazoster virus: comparison of enzyme immunoassay with neutralization, immune adherence hemagglutination, and complement fixation. J Clin Microbiol 8:545–552PubMedGoogle Scholar
  12. 12.
    Frisén L (1987) A computer-graphics visual field screener using high-pass spatial frequency resolution targets and multiple feedback devices. In: Greve E, Heyl A (eds) Documenta Ophthalmologica Proceeding Series. Martinus Nijhoff/Dr W. Junk, Dordrecht, pp 441–446Google Scholar
  13. 13.
    Frisén L (1992) High-pass resolution perimetry: evidence for parvocellular channel dependence. Neuro-ophthalmology 12:257–264Google Scholar
  14. 14.
    Frisén L, Frisén M (1981) How good is normal visual acuity? A study of letter acuity thresholds as a function of age. Albrecht von Graefes Arch Klin Exp Ophthalmol 215:149–157PubMedGoogle Scholar
  15. 15.
    Haahr S, Sommerlund M, Christensen T, Jensen AW, Hansen HJ, Möl1er-Larsen A (1994) A putative new retrovirus associated with multiple sclerosis and the possible involvement of Epstein-Barr virus in this disease. Ann N Y Acad Sci 724:148–156PubMedGoogle Scholar
  16. 16.
    Haase AT, Stowring L, Ventura P, Burks J, Ebers G, Tourtellotte W, Warren K (1984) Detection by hybridization of viral infection of the human central nervous system. Ann N Y Acad Sci 436:103–108PubMedGoogle Scholar
  17. 17.
    IFNB Multiple Sclerosis Group (1993) Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661Google Scholar
  18. 18.
    Jeansson S, Forsgren M, Svennerholm B (1983) Evaluation of solubilized herpes simplex virus membrane antigen by enzyme-linked immunosorbent assay. J Clin Microbiol 18:1160–1166PubMedGoogle Scholar
  19. 19.
    Johnson RT (1985) Viral aspects of multiple scleross. In: Koetsier JC (ed) Demyelinating diseases. Elsevier, New York, pp 319–336Google Scholar
  20. 20.
    Krishna RV, Meurman OH, Ziegler T, Krech UH (1980) Solid-phase enzyme immunoassay for determination of antibodies to cytomegalovirus. J Clin Microbiol 12:46–51PubMedGoogle Scholar
  21. 21.
    Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452PubMedGoogle Scholar
  22. 22.
    Larsen PD, Bloomer LC, Bray PF (1985) Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis. Neurology 35:435–438PubMedGoogle Scholar
  23. 23.
    Laski RD, Troy FA (1984) Possible DNA-RNA tumor virus interaction in human lymphomas: expression of retroviral proteins in Ramos lymphoma lines is enhanced after conversion with Epstein-Barr virus. Proc Natl Acad Sci USA 81:33–37PubMedGoogle Scholar
  24. 24.
    Lennette E (1988) Laboratory diagnosis of infectious diseases. In: Lennette E, Halonen P, Murphy FA (eds) Viral, rickettsial and chlamydial diseases. Springer, Berlin Heidelberg New York, pp 230–266Google Scholar
  25. 25.
    Lezak M (1983) Neuropsychological assessment. Oxford University Press, New YorkGoogle Scholar
  26. 26.
    Lindberg C, Andersen O, Vahlne A, Dalton M, Runmarker B (1991) Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis. Neuroepidemiology 10:62–65PubMedGoogle Scholar
  27. 27.
    Luria A (1966) Higher cortical functions in man. Tavistock, LondonGoogle Scholar
  28. 28.
    Lycke J, Andersen O, Svennerholm B, Appelgren L, Dahlöf C (1989) Acyclovir concentrations in serum and cerebrospinal fluid at steady state. J Antimicrob Chemother 24:947–954PubMedGoogle Scholar
  29. 29.
    Molin L, Ruhnek-Forsbeck M, Svennerholm B (1991) One year acyclovir suppression of frequently recurring genital herpes: a study of efficacy, safety, virus sensitivity and antibody response. Scand J Infect Dis 78:33–39Google Scholar
  30. 30.
    Mosca JD; Bednarik DP, Raj NBK, Rosen CA, Sodroski JG, Haseltine WA, Haywards GS, Pitha PM (1987) Herpes simplex virus type-1 can reactivate transcription of latent human immunodeficiency virus. Nature 325:67–70PubMedGoogle Scholar
  31. 31.
    Operskalski EA, Visscher BR, Malmgren RM, Detels R (1989) A case-control study of multiple sclerosis. Neurology 39:825–829PubMedGoogle Scholar
  32. 32.
    Panitch HS (1994) Influence of infection on exacerbations of multiple sclerosis. Ann Neurol 36:S25-S28PubMedGoogle Scholar
  33. 33.
    Perron H, Suh M, Lalande B, Gratacap B, Laurent A, Stoebner P, Seigneurin JM (1993) Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis. J Gen Virol 74:65–72PubMedGoogle Scholar
  34. 34.
    Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines fro research protocols. Ann Neurol 13:227–231PubMedGoogle Scholar
  35. 35.
    Potvin AR, Tourtellotte WW (1985) Quantitative examination of neurologic functions. CRC Press, Boca RatonGoogle Scholar
  36. 36.
    Raven JC (1965) Guide to using the coloured progressive matrices. Lewis, LondonGoogle Scholar
  37. 37.
    Runmarker B, Andersen O (1993) Prognostic factors in a multiple sclerosis incidence cohort with 25 years of follow-up. Brain 116:117–134PubMedGoogle Scholar
  38. 38.
    Salmi A, Reunanen M, Ilonen J, Panelius M (1983) Intrathecal antibody synthesis to virus antigens in multiple sclerosis. Clin Exp Immunol 52:241–249PubMedGoogle Scholar
  39. 39.
    Sibley WA, Bamford C, Clark K (1985) Clinical viral infections and multiple sclerosis. Lancet II:1313–1315Google Scholar
  40. 40.
    Sola P, Merelli E, Marasca R, Poggi M, Luppi M, Montorsi M, Torelli G (1993) Human herpesvirus 6 and multiple sclerosis: survey of anti-HHV-6 antibodies by immunofluorescence analysis and of viral sequences by polymerase chain reaction. J Neurol Neurosurg Psychiatry 56:917–919PubMedGoogle Scholar
  41. 41.
    Sumaya CV, Lawrence WM, Ellison GW, Ench Y (1985) Increased prevalence and titer of Epstein-Barn virus antibodies in patients with multiple sclerosis. Ann Neurol 17:371–377PubMedGoogle Scholar
  42. 42.
    Svennerholm B, Olofsson S, Jeansson S, Vahlne A, Lycke E (1984) Herpes simplex virus type-selective enzyme-linked immunosorbent assay with helix pomatia lectin-purified antigens. J Clin Microbiol 19:235–239PubMedGoogle Scholar
  43. 43.
    Thin RN, Jeffries DJ, Taylor PK, Arya OP, Rodin P, Yeo J, Fiddian AP (1985) Recurrent genital herpes suppressed by oral acyclovir: a multicentre double-blind trial. J Antimicrob Chemother 16:219–226PubMedGoogle Scholar
  44. 44.
    Tyler KL (1994) Polymerase chain reaction and the diagnosis of viral central nervous system disease. Ann Neurol 36:809–811PubMedGoogle Scholar
  45. 45.
    Vahlne A, Edström S, Hanner P, Andersen O, Svennerholm B, Lycke E (1985) Possible association of herpes simplex virus infection with demyelinating disease. Scand J Infect Dis 47:16–21Google Scholar
  46. 46.
    Wagstaff A, Faulds D, Goa K (1994) Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 47:153–205PubMedGoogle Scholar
  47. 47.
    Wall M (1991) Resolution perimetry in optic neuritis. Invest Ophthalmol Vis Sci 32:2525–2529Google Scholar
  48. 48.
    Warren KG, Gilden DH, Brown SM, Devlin M, Wroblewska Z, Subak-Sharpe J, Koprowski H (1977) Isolation of herpes simplex virus from human trigeminal ganglia, including ganglia from one patient with multiple sclerosis. Lancet II:637–639Google Scholar
  49. 49.
    Wilborn F, Schmidt CA, Brinkmann V, Jendroska K, Oettle H, Siegert W (1994) A potential role for human herpesvirus type 6 in nervous system disease. J Neuroimmunol 49:213–214PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Jan Lycke
    • 1
  • Bo Svennerholm
    • 2
  • Elisabeth Hjelmquist
    • 1
  • Lars Frisén
    • 3
  • Gaby Badr
    • 4
  • Mats Andersson
    • 1
  • Anders Vahlne
    • 5
  • Oluf Andersen
    • 1
  1. 1.Department of NeurologyUniversity of Gothenburg, Sahlgren's HospitalGothenburgSweden
  2. 2.Department of VirologyUniversity of Gothenburg, Sahlgren's HospitalGothenburgSweden
  3. 3.Department of OphthalmologyUniversity of Gothenburg, Sahlgren's HospitalGothenburgSweden
  4. 4.Department of NeurophysiologyUniversity of Gothenburg, Sahlgren's HospitalGothenburgSweden
  5. 5.Department of Virology, Karolinska InstituteHuddinge HospitalHuddingeSweden

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