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Critical Review of Existing Trials

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Neurodegeneration in Multiple Sclerosis

Part of the book series: Topics in Neuroscience ((TOPNEURO))

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Abstract

Epidemiological studies indicate that about 90% of multiple sclerosis (MS) patients experience a progression of the disease at some time during their life [1, 2]. In about 15% of patients, the disease starts with an insidious onset followed by a progressive phase, with or without phases of stability; the so-called primary progressive (PP) MS. In all other patients, the early phase of MS is marked by acute attacks characterized by unifocal (2/3 of patients) or multifocal white matter disease [3]. Attacks are usually followed by complete or almost complete recovery; however, pathological studies demonstrate the presence of an axonal transection inside the lesion [4–6]. Axonal loss is predominant in lesions appearing in the early phases of the disease [7] and decreases over time. A large amount of damage occurs in areas with a considerable infiltration of T lymphocytes (especially CD8+ T cells) and macrophages [7], indicating a correlation between inflammation and axonal damage - a relationship which has also been shown by magnetic resonance imaging (MRI) studies. The acute axonal damage also occurs because of the products of inflammation, such as nitric oxide and tumor necrosis factor [8]. Recent studies indicate that a high level of electrical activity may increase the axonal degeneration of partially or completely demyelinated lesions at the nodes of Ranvier, as a consequence of the activation of glutamate receptors increasing the entry of calcium into the axon [9]. Recent studies suggest that axonal damage may also be independent of demyelination [10] and may be caused by antibodies against axonal antigens [11].

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References

  1. Weinshenker BG, Bass B, Rice GHPA et al (1989) The natural history of multiple sclerosis: a geographical based study 1. Clinical course and disability. Brain 112:133–146

    Article  PubMed  Google Scholar 

  2. Runmarker B, Andersen O (1993) Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 116:117–134

    Article  PubMed  Google Scholar 

  3. Wingerchuk DM, Weinshenker BG (2000) Multiple sclerosis: epidemiology, genetic, classification, natural history and clinical outcome measures. Neuroimaging Clin N Am 10:611–623

    PubMed  CAS  Google Scholar 

  4. Ferguson B, Matyszak MK, Esiri MM, Perry VH ( 1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399

    Article  PubMed  Google Scholar 

  5. Trapp BD, Peterson J, Ransohoff RM et al (1998) Axonal transection in the lesions of multiple sclerosis. New Engl J Med 338:278–285

    Article  PubMed  CAS  Google Scholar 

  6. Kornek B, Storech MK, Weissert R et al (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis. Am J Pathol 157:267–276

    PubMed  CAS  Google Scholar 

  7. Kuhlmann T, Lingfeld G, Bitsch A et al (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212

    Article  PubMed  Google Scholar 

  8. Smith KJ, Kapoor R, Felts PA (2001) Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 49:470–476

    Article  PubMed  CAS  Google Scholar 

  9. Kapoor R, Davied M, Blaker PA et al (2003) Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol 53:174–180

    Article  PubMed  CAS  Google Scholar 

  10. Bitsch A, Schuchardt J, Bunkowski S et al (2000) Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 123:1174–1183

    Article  PubMed  Google Scholar 

  11. Raine C, Cannella B, Hauser S, Genain C (1999) Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: a case for antigen-specific antibody mediation. Ann Neurol 46:144–160

    Article  PubMed  CAS  Google Scholar 

  12. Filippi M, Inglese M, Rovaris M et al (2000) Magnetization transfer imaging to monitor the evolution of MS: a 1-year follow-up study. Neurology 55:940–946

    PubMed  CAS  Google Scholar 

  13. Iannucci G, Tortorella C, Rovaris M et al (2001) Prognostic value of MR and magnetization transfer imaging findings in patients with clinically isolated syndromes suggestive of multiple sclerosis at presentation. Am J Neuroradiol 21:1034–1038

    Google Scholar 

  14. Sater RA, Rostami AM, Galetta S et al (1999) Serial evoked potential studies and MRI imaging in chronic progressive multiple sclerosis. J Neurol Sci 171(2):79–83

    Article  PubMed  CAS  Google Scholar 

  15. Leocani L, Comi G (2000) Neurophysiological investigations in multiple sclerosis. Curr Opin Neurol 13:255–261

    Article  PubMed  CAS  Google Scholar 

  16. Rocca MA, Mastronardo G, Rodegher M et al (1999) Long-term changes of magnetization transfer-derived measures from patients with relapsing-remitting and secondary progressive multiple sclerosis. Am J Neuroradiol 20:821–827

    PubMed  CAS  Google Scholar 

  17. Linington C, Engelhardt B, Kapocs G, Lassmann H (1992) Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibody. J Neuroimmunol 40:219–224

    Article  PubMed  CAS  Google Scholar 

  18. Lucchinetti C, Bruck W, Parisi J et al (1999) A quantitative analysis of oligodendrocytes in multiple sclerosis lesions: a study of 113 cases. Brain 122:2279–2295

    Article  PubMed  Google Scholar 

  19. European Study Group on Interferon β-1b in Secondary Progressive MS (1998) Placebo-controlled multicentre randomised trial of interferon β-lb in treatment of secondary progressive multiple sclerosis. Lancet 352:1491–1497

    Article  Google Scholar 

  20. Miller DH, Molyneux PD, Barker GJ et al (1999) Effect of interferon β-lb on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multicenter, randomized, double-blind, placebo-controlled trial. Ann Neurol 46:850–859

    Article  PubMed  CAS  Google Scholar 

  21. North American Study Group on Interferon beta-1b in Secondary Progressive MS (2004) Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 63:1788–1795

    Google Scholar 

  22. Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group (2001) Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 56:1496–1504

    Google Scholar 

  23. Li DKB, Zhao GJ, Paty DW (2001) Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology 56:1505–1513

    PubMed  CAS  Google Scholar 

  24. Cohen JA, Cutter GR, Fischer JS et al (2002) Benefit of interferon β-la on MSFC progression in secondary progressive MS. Neurology 59:679–687

    PubMed  CAS  Google Scholar 

  25. Andersen O, Elovaara I, Färkkilä M et al (2004) Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiat 75:706–710

    Article  PubMed  CAS  Google Scholar 

  26. The Once Weekly Interferon for MS Study Group (OWIMS) (1999) Evidence of interferon β-la dose response in relapsing-remitting MS: The OWIMS Study. Neurology 53:679–686

    Google Scholar 

  27. Kappos L, Weinshenker B, Pozzilli C et al (2004) Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 63:1779–1787

    PubMed  CAS  Google Scholar 

  28. Leary SM, Thomson AJ (2003) Interferon beta-1a in primary progressive multiple sclerosis. J Neurol Sci 206:215–216

    Article  PubMed  CAS  Google Scholar 

  29. Montalban X, Thomson AJ (2002) Workshop on primary progressive multiple sclerosis: meeting summary. Mult Scler 8:177–178

    Article  PubMed  CAS  Google Scholar 

  30. Bornstein MB, Miller A, Teitelbaum D et al (1982) Multiple sclerosis: trial of a synthetic polypeptide. Ann Neurol 11:317–319

    Article  PubMed  CAS  Google Scholar 

  31. Bornstein MB, Miller A, Slagle S et al (1987) A pilot trial of COP 1 in exacerbating-remitting multiple sclerosis. New Engl J Med 317:408–414

    Article  PubMed  CAS  Google Scholar 

  32. Johnson KP, Brooks BR, Cohen JA et al and Copolymer 1 Multiple Sclerosis Study Group (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of the phase III multicenter, double-blind placebo-controlled trial. Neurology 45:1296–1276

    Google Scholar 

  33. Comi G, Filippi M, Wolinsky JS and the European-Canadian Glatiramer Acetate Study Group (2001) The European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing-remitting multiple sclerosis. Ann Neurol 49:290–297

    Article  PubMed  CAS  Google Scholar 

  34. Bornstein MB, Miller A, Slagle S et al (1991) A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 41:533–539

    PubMed  CAS  Google Scholar 

  35. Sorensen PS, Fazekas F, Lee M (2002) Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 9:557–563

    Article  PubMed  CAS  Google Scholar 

  36. Hommes OR, Sorensen PS, Fazekas F et al (2004) Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 364:1149–1156

    Article  PubMed  CAS  Google Scholar 

  37. Fazekas F, Sorensen PS, Filippi M et al (2005) MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler 11:433–440

    Article  PubMed  CAS  Google Scholar 

  38. Filippi M, Rocca MA, Pagani E et al (2004) European study on intravenous immunoglobulin in multiple sclerosis: results of magnetization transfer magnetic resonance imaging analysis. Arch Neurol 61:1409–1412

    Article  PubMed  Google Scholar 

  39. Hommes OR, Prick JJG, Lamers KJB (1975) Treatment of the chronic progressive form of multiple sclerosis with a combination of cyclophosphamide and prednisone. Clin Neurol Neurosurg 78:59–73

    Article  PubMed  CAS  Google Scholar 

  40. Gonsette R, Demonty L, Delmotte P (1977) Intensive immunosuppression with cyclophosphamide in remittent forms of multiple sclerosis: follow up of 110 patients for 2–6 years. J Neuroimmunol 214:173–181

    CAS  Google Scholar 

  41. Hauser SL, Dawson DM, Lehrich JR et al (1983) Intensive immunosuppression in progressive multiple sclerosis: a randomized three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 308:173–180

    Article  PubMed  CAS  Google Scholar 

  42. Canadian Cooperative Study Group (1991) The Canadian Cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 337:441–446

    Google Scholar 

  43. Likowsky VH, Fireman B, Elmore R et al (1991) Intensive immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. J Neurol Neurosurg Psychiat 54:1055–1060

    Article  Google Scholar 

  44. Weiner HL, Mackin GA, Orav EJ et al (1993) Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 43:910–918

    PubMed  CAS  Google Scholar 

  45. Gobbini MI, Smith ME, Richert ND et al (1999) Effect of open-label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing-remitting multiple sclerosis. J Neuroimmunol 99:142–149

    Article  PubMed  CAS  Google Scholar 

  46. Perini P, Gallo P (2003) Cyclophosphamide is effective in stabilizing rapidly deteriorating SPMS. J Neurol 250:834–838

    Article  PubMed  CAS  Google Scholar 

  47. Smith DR, Weinstock-Guttman B, Cohen JA et al (2005) A randomized blinded trial of combination therapy with cyclophosphamide in patients with active multiple sclerosis on interferon beta. Mult Scler 11:573–582

    Article  PubMed  CAS  Google Scholar 

  48. Fidler JM, Dejoy SQ, Gibbons JJ Jr (1986) Selective immunomodulation by the antineoplastic agent mitoxantrone I. Suppression of B lymphocyte function. J Immunol 137:727–732

    PubMed  CAS  Google Scholar 

  49. Fidler JM, Dejoy SQ, Smith FR 3rd, Gibbons JJ Jr (1986) Selective immunomodulation by the antineoplastic agent mitoxantrone II. Nonspecific adherent suppressor cells derived from mitoxantrone. J Immunol 136:2747–2754

    PubMed  CAS  Google Scholar 

  50. Millefiorini E, Gasperini C, Pozzilli C et al (1997) Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24 month clinical and MRI outcome. J Neurol 244:153–59

    Article  PubMed  CAS  Google Scholar 

  51. Edan G, Miller D et al (1995) Evaluation of the efficacy of mitoxantrone by use of MRI: a multicenter randomized study in multiple sclerosis. Neurology 242(Suppl 2): S38 [abstract]

    Google Scholar 

  52. Hartung HP, Gonsette R, Kwiecinski H et al (2002) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 360(9350):2018–2025

    Article  PubMed  Google Scholar 

  53. van de Wyngaert FA, Beguin C, D’Hooghe MB et al (2001) A double blind clinical trial of mitoxantrone versus methylprednisolone in relapsing secondary progressive multiple sclerosis. Acta Neurol Belg 244:153–159

    Google Scholar 

  54. Krapf H, Morrissey SP, Zenker O et al (2005) Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology 65:690–695

    Article  PubMed  CAS  Google Scholar 

  55. Martinelli Boneschi F, Rovaris M, Capra R, Comi G (2005) Mitoxantrone for multiple sclerosis. Cochrane Database of Systematic Reviews 4:CD002127

    Google Scholar 

  56. Fox EJ (2006) Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Therapeut 28:461–474

    Article  CAS  Google Scholar 

  57. Jammohammed R, Milligan DW (1989) Mitoxantrone induced congestive heart failure in patients previously treated with anthracyclines. Br J Haematol 71:292–293

    Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy

    G. Comi

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  1. G. Comi
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Editors and Affiliations

  1. Neuroimaging Research Unit Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy

    Massimo Filippi  & Marco Rovaris  & 

  2. Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy

    Giancarlo Comi

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© 2007 Springer-Verlag Italia

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Comi, G. (2007). Critical Review of Existing Trials. In: Filippi, M., Rovaris, M., Comi, G. (eds) Neurodegeneration in Multiple Sclerosis. Topics in Neuroscience. Springer, Milano. https://doi.org/10.1007/978-88-470-0391-0_16

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  • DOI: https://doi.org/10.1007/978-88-470-0391-0_16

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-0390-3

  • Online ISBN: 978-88-470-0391-0

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