Early Treatment in Multiple Sclerosis with Intravenous Immunoglobulin: Rationale and Study Design

  • A. Achiron
  • Y. Barak
  • M. Faibel
  • S. Miron
  • I. Kishner
  • M. Chen
  • Y. Stern
  • I. Sarova-Pinhas
Part of the Topics in Neuroscience book series (TOPNEURO)


Multiple sclerosis (MS) is a chronic debilitating disease that will cause significant disability to the majority of patients overtime [1]. Previous studies of the natural course of the disease showed that disability will accumulate in more that 90% of patients and additional relapses may result in significant handicap [2]. Assessment of patients with a diagnosis of probable MS with positive brain magnetic resonance imaging (MRI) demonstrated that the risk of relapsing within 1 year is 57.6% [3]. Treating patients early means treating patients with less disability. We describe the rationale for early treatment in patients with the first episode of neurological symptomatology suggestive of clinically probable MS, and the design of a randomized, double-blind, placebo-controlled trial of early treatment with intravenous immunoglobulin (IVIg, Omrix, Israel) in these patients. The primary objective of this study was to investigate the efficacy of IVIg treatment, administered at 0.4 g/kg per day for 5 consecutive days, as a loading dose, and 0.4 g/kg per day every 6 weeks thereafter as a booster dose, for a 1-year period, on the risk of patients with clinically probable MS and positive brain MRI to convert to clinically definite MS.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Intravenous Immunoglobulin Axonal Loss Relapse Remit Multiple Sclerosis Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weinshenker BG (1994) Natural history of multiple sclerosis. Ann Neurol 36 [Suppl]: S6–S11PubMedCrossRefGoogle Scholar
  2. 2.
    Amato MP, Ponziani G, Bartolozzi ML, Siracusa G (1999) A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci 168:96–106PubMedCrossRefGoogle Scholar
  3. 3.
    Achiron A, Barak Y (2000) Multiple sclerosis — from probable to definite diagnosis: a prospective study over 7 years. Arch Neurol 57:974–979PubMedCrossRefGoogle Scholar
  4. 4.
    Lublin FD, Whitaker JN, Eidelman BH, Miller AE, Arnason BG, Burks JS (1996) Management of patients receiving interferon beta-lb for multiple sclerosis: report of a consensus conference. Neurology 46:12–18PubMedCrossRefGoogle Scholar
  5. 5.
    Simon JH, Jacobs LD, Campion M, Wende K, Simonian N, Cookfair DL et al (1998) Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 43:79–87PubMedCrossRefGoogle Scholar
  6. 6.
    Wolinsky JS (1995) Copolymer 1: a most reasonable alternative therapy for early relapsing-remitting multiple sclerosis with mild disability. Neurology 45:1245–1247PubMedCrossRefGoogle Scholar
  7. 7.
    Achiron A, Gabbay U, Gilad R, Hassin-Baer S, Barak Y, Gornish M, Elizur A, Goldhammer Y, Sarova-Pinhas I (1998) Intravenous immunoglobulin treatment in multiple sclerosis: effect on relapses. Neurology 50:398–402PubMedCrossRefGoogle Scholar
  8. 8.
    Miller A (1998) Diagnosis of multiple sclerosis. Semin Neurol 18:309–316PubMedCrossRefGoogle Scholar
  9. 9.
    Bourdette D, Antel J, McFarland H, Montgomery E (1999) Monitoring relapsing remitting MS patients. J Neuroimmunol 98:16–21PubMedCrossRefGoogle Scholar
  10. 10.
    Thompson AJ, Noseworthy JH (1996) New treatments for multiple sclerosis: a clinical perspective. Curr Opin Neurol 9:187–198PubMedCrossRefGoogle Scholar
  11. 11.
    Trials ECFWGfT (1995) Guidelines for early treatment trials in patients presenting with clinical and paraclinical abnormalities which put them at high risk for conversion to multiple sclerosis. European Charcot Foundation Working Group for Treatment Trials. Mult Scler 1 [Suppl 1]:S55–S59Google Scholar
  12. 12.
    Comi G, Barkhof F, Durelli L, Edan G, Fernandez O, Filippi M, Hartung HP, Hommes OR, Seeldrayers P, Soelberg-Sorensen P (1995) Early treatment of multiple sclerosis with Rebif (recombinant human interferon beta): design of the study. Mult Scler 1 [Suppl 1]:S24–S27PubMedGoogle Scholar
  13. 13.
    Munschauer FE, Stuart WH (1997) Rationale for early treatment with interferon beta-la in relapsing-remitting multiple sclerosis. Clin Ther 19:868–882PubMedCrossRefGoogle Scholar
  14. 14.
    Rudick RA, Goodman A, Herndon RM, Panitch HS (1999) Selecting relapsing remitting multiple sclerosis patients for treatment: the case for early treatment. J Neuroimmunol 98:22–28PubMedCrossRefGoogle Scholar
  15. 15.
    Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta-la therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898–904PubMedCrossRefGoogle Scholar
  16. 16.
    Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR (2001) Effect ofearly interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582PubMedCrossRefGoogle Scholar
  17. 17.
    Vanderlugt CL, Neville KL, Nikcevich KM, Eagar TN, Bluestone JA, Miller SD (2000) Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. J Immunol 164:670–678PubMedGoogle Scholar
  18. 18.
    Miller SD, McRae BL, Vanderlugt CL, Nikcevich KM, Pope JG, Pope L, Karpus WI (1995) Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol Rev 144:225–244PubMedCrossRefGoogle Scholar
  19. 19.
    Tuohy VK, Yu M, Yin L, Kawczak JA, Kinkel RP (1999) Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis. J Exp Med 189:1033–1042PubMedCrossRefGoogle Scholar
  20. 20.
    Barkhof F, van Walderveen M (1999) Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance. Philos Trans R Soc Lond B Biol Sci 354:1675–1686PubMedCrossRefGoogle Scholar
  21. 21.
    Matthews PM, De Stefano N, Narayanan S, Francis GS, Wolinsky JS, Antel JP, Arnold DL (1998) Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Semin Neurol 18:327–336PubMedCrossRefGoogle Scholar
  22. 22.
    Miller DH, Grossman RI, Reingold SC, McFarland HF (1998) The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 121:3–1224PubMedCrossRefGoogle Scholar
  23. 23.
    Davie CA, Silver NC, Barker GJ, Tofts PS, Thompson AJ, McDonald WI, Miller DH (1999) Does the extent of axonal loss and demyelination from chronic lesions in multiple sclerosis correlate with the clinical subgroup? J Neurol Neurosurg Psychiatry 67:710–715PubMedCrossRefGoogle Scholar
  24. 24.
    Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53:1698–1704PubMedCrossRefGoogle Scholar
  25. 25.
    Zivadinov R, Sepcic J, Nasuelli D, De Masi R, Bragadin LM, Tommasi MA, Zambito-Marsala S, Moretti R, Bratina A, Ukmar M, Pozzi-Mucelli RS, Grop A, Cazzato G, Zorzon M (2001) A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 70:773–780PubMedCrossRefGoogle Scholar
  26. 26.
    Achiron A, Barak Y (2003) Cognitive impairment in probable multiple sclerosis. J Neurol Neurosurg Psychiatry 74:443–446PubMedCrossRefGoogle Scholar
  27. 27.
    Lassmann H, Bruck W, Lucchinetti C, Rodriguez M (1997) Remyelination in multiple sclerosis. Mult Scler 3:133–136PubMedCrossRefGoogle Scholar
  28. 28.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl I Med 339:278–285CrossRefGoogle Scholar
  29. 29.
    Trapp BD, Bo L, Mork S, Chang A (1999) Pathogenesis of tissue injury in MS lesions. J Neuroimmunol 98:49–56PubMedCrossRefGoogle Scholar
  30. 30.
    Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B (1997) Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian Immunoglobulin in Multiple Sclerosis Study Group. Lancet 349:589–593PubMedCrossRefGoogle Scholar
  31. 31.
    Sorensen PS, Wanscher B, Jensen CV, Schreiber K, Blinkenberg M, Ravnborg M, Kirsmeier H, Larsen VA, Lee ML (1998) Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 50:1273PubMedCrossRefGoogle Scholar
  32. 32.
    Achiron A, Gabbay U, Gilad R, Hassin-Baer S, Barak Y, Gornish M, Elizur A, Goldhammer Y, Sarova-Pinhas I (1998) Intravenous immunoglobulin treatment in multiple sclerosis: effect on relapses. Neurology 50:398–402PubMedCrossRefGoogle Scholar
  33. 33.
    Achiron A (1997) Complications of intravenous immune globulin treatment in neurologic disease. Neurology 49:899–900PubMedCrossRefGoogle Scholar
  34. 34.
    Achiron A, Rotstein Z, Noy S, Mashiach S, Dulitzky M, Achiron R (1996) Intravenous immunoglobulin treatment in the prevention of childbirth-associated acute exacerbations in multiple sclerosis: a pilot study. J Neurol 243:25–28PubMedCrossRefGoogle Scholar
  35. 35.
    Orvieto R, Achiron R, Rotstein Z, Noy S, Bar-Hava I, Achiron A (1999) Pregnancy and multiple sclerosis: a 2-year experience. Eur J Obstet Gynecol Reprod Biol 82:191–194PubMedCrossRefGoogle Scholar
  36. 36.
    Sorensen PS, Fazekas F, Lee M (2002) Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 9:557–563PubMedCrossRefGoogle Scholar
  37. 37.
    Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Eber GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231PubMedCrossRefGoogle Scholar
  38. 38.
    Fazekas F, Barkhof F, Filippi M, Grossman RI, Li DK, McDonald WI, McFarland HF, Paty DW, Simon JH, Wolinsky JS, Miller DH (1999) The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 53:448–456PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2004

Authors and Affiliations

  • A. Achiron
  • Y. Barak
  • M. Faibel
  • S. Miron
  • I. Kishner
  • M. Chen
  • Y. Stern
  • I. Sarova-Pinhas

There are no affiliations available

Personalised recommendations