Primary Progressive Multiple Sclerosis

Siobhan M. Leary; Alan J. Thompson

doi:10.2165/00023210-200519050-00001

CNS Drugs

May 2005, Volume 19, Issue 5, pp 369–376

Primary Progressive Multiple Sclerosis

Current and Future Treatment Options

Authors
Authors and affiliations

Siobhan M. Leary
Alan J. Thompson

Leading Article

First Online:: 29 August 2012

Abstract

Approximately 10% of patients with multiple sclerosis (MS) run a primary progressive course characterised by an accumulation of neurological deficits without relapse or remission. Designing therapeutic trials in primary progressive MS (PPMS) has presented several problems. Patient recruitment may be difficult because of the relative rarity of PPMS and historically has been hindered by the lack of specific diagnostic criteria. There has been a limited choice of validated outcome measures, although, in recent studies, the MS functional composite measure and magnetic resonance imaging measures of lesion load and atrophy have been widely used.

Despite these problems, several trials have been designed specifically for PPMS, including exploratory randomised controlled trials of interferon-β-1a and interferon-β-1b and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in randomised controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide, and open-label studies of haematopoietic stem cell transplantation and pirfenidone in progressive MS. However, no treatment has been proven definitively to modify the course of the disease. Looking to the future, therapeutic agents should aim to target the underlying pathogenic mechanisms in PPMS. As a result of the relative lack of inflammation in PPMS, neuroprotective agents that target neuronal loss directly, rather than inflammation, may be more worthwhile. However, further investigation into the pathogenic mechanisms in PPMS is required to guide the development of future therapeutic agents.

References

1.
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–11PubMedCrossRefGoogle Scholar
2.
Thompson AJ, Polman CH, Miller DH, et al. Primary progressive multiple sclerosis. Brain 1997; 120: 1085–96PubMedCrossRefGoogle Scholar
3.
Stevenson VL, Miller DH, Rovaris M, et al. Primary and transitional progressive multiple sclerosis: a clinical and MRI cross sectional study. Neurology 1999; 52: 839–45PubMedCrossRefGoogle Scholar
4.
Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980; 103: 281–300PubMedCrossRefGoogle Scholar
5.
Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: 5. the clinical features and natural history of primary progressive multiple sclerosis. Brain 1999; 122: 625–39Google Scholar
6.
McDonnell GV, Hawkins SA. Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK. J Neurol Neurosurg Psychiatry 1998; 64: 451–4PubMedCrossRefGoogle Scholar
7.
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116: 117–34PubMedCrossRefGoogle Scholar
8.
Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: 1. clinical course and disability. Brain 1989; 112: 133–46Google Scholar
9.
Confavreux C, Vukusoc S, Moreau T, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000; 343: 1430–8PubMedCrossRefGoogle Scholar
10.
Minderhoud JM, van der Hoeven JH, Prange AJ. Course and prognosis of chronic progressive multiple sclerosis: results of an epidemiological study. Acta Neurol Scand 1988; 78: 10–5PubMedCrossRefGoogle Scholar
11.
Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ 1990; 300: 631–4PubMedCrossRefGoogle Scholar
12.
Thompson AJ, Kermode AG, Wicks D, et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991; 29: 53–62PubMedCrossRefGoogle Scholar
13.
Revesz T, Kidd D, Thompson AJ, et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 1994; 117: 759–65PubMedCrossRefGoogle Scholar
14.
Lassman H, Brack W, Lucchinetti C, et al. Remyelination in multiple sclerosis. Mult Scler 1997; 3: 133–6CrossRefGoogle Scholar
15.
Lucchinetti C, Bruck W, Parisi J, et al. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions: a study of 113 cases. Brain 1999; 122: 2279–95PubMedCrossRefGoogle Scholar
16.
Neuhaus O, Hartung HP. In search of a disease marker: the cytokine profile of primary progressive multiple sclerosis. Mult Scler 2001; 7: 143–4PubMedGoogle Scholar
17.
Hillert J. Genetics of primary progressive MS [abstract]. Rev Neurol 2000; 156 Suppl. 3: S14Google Scholar
18.
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–31PubMedCrossRefGoogle Scholar
19.
Leary SM, Stevenson VL, Miller DH, et al. Problems in designing and recruiting to therapeutic trials in primary progressive multiple sclerosis. J Neurol 1999; 246: 562–8PubMedCrossRefGoogle Scholar
20.
Thompson AJ, Montalban X, Barkhof F, et al. Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann Neurol 2000; 47: 831–5PubMedCrossRefGoogle Scholar
21.
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–7PubMedCrossRefGoogle Scholar
22.
Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: 6. applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis. Brain 1999; 122: 641–7Google Scholar
23.
Wolinsky JS, on behalf of the PROMiSe trial Study Group. The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 2003; 206: 145–52PubMedCrossRefGoogle Scholar
24.
Whitaker JN, McFarland HF, Rudge P, et al. Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Mult Scler 1995; 1: 37–47PubMedGoogle Scholar
25.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–52PubMedCrossRefGoogle Scholar
26.
Willoughby EW, Paty DW. Scales for rating impairment in multiple sclerosis: a critique. Neurology 1988; 38: 1793–8PubMedCrossRefGoogle Scholar
27.
Noseworthy JH, Vandervoort MK, Wong CJ, et al. Interrater variability with the expanded disability status scale (EDSS) and functional systems (FS) in a multiple sclerosis clinical trial. Neurology 1990; 40: 971–5PubMedCrossRefGoogle Scholar
28.
Hobart J, Freeman J, Thompson A. Kurtzke scales revisited: the application of psychometric methods to clinical intuition. Brain 2000; 123: 1027–40PubMedCrossRefGoogle Scholar
29.
Cutter GR, Baier ML, Rudick RA, et al. Development of a multiple sclerosis composite as a clinical trial outcome measure. Brain 1999; 122: 871–82PubMedCrossRefGoogle Scholar
30.
Kalkers NF, de Groot V, Lazeron RHC, et al. MS functional composite: relation to disease phenotype and disability strata. Neurology 2000; 54: 1233–9PubMedCrossRefGoogle Scholar
31.
Cohen JA, Cutter GR, Fischer JS, et al. Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Arch Neurol 2001; 58: 961–7PubMedCrossRefGoogle Scholar
32.
Ciccarelli O, Brex PA, Thompson AJ, et al. Disability and lesion load in MS: a reassessment with MS functional composite score and 3D fast FLAIR. J Neurol 2002; 249: 18–24PubMedCrossRefGoogle Scholar
33.
Miller DH, Albert PS, Barkhof F, et al. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. Ann Neurol 1996; 39: 6–16PubMedCrossRefGoogle Scholar
34.
Ingle GT, Stevenson VL, Miller DH, et al. Primary progressive multiple sclerosis: a 5-year clinical and MR study. Brain 2003; 126: 2528–36PubMedCrossRefGoogle Scholar
35.
Losseff NA, Webb SL, O’Riordan JI, et al. Spinal cord atrophy and disability in multiple sclerosis: a new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 1996; 119: 701–8PubMedCrossRefGoogle Scholar
36.
Losseff NA, Wang L, Lai HM, et al. Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain 1999; 119: 2009–19CrossRefGoogle Scholar
37.
Rovaris M, Bozzali M, Santuccio G, et al. In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain 2001; 124: 2540–9PubMedCrossRefGoogle Scholar
38.
Miller DH, Grossman RI, Reingold SC, et al. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998; 121: 3–24PubMedCrossRefGoogle Scholar
39.
Thompson AJ. Symptomatic management and rehabilitation in multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 71 Suppl. 2: 22–7Google Scholar
40.
Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85PubMedCrossRefGoogle Scholar
41.
Ferguson B, Matysak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9PubMedCrossRefGoogle Scholar
42.
Nijeholt GJ, van Walderveen AA, Castelijns JA, et al. Brain and spinal cord abnormalities in multiple sclerosis: correlation between MRI parameters, clinical subtypes and symptoms. Brain 1998; 121: 687–97PubMedCrossRefGoogle Scholar
43.
Weinstock-Guttman B, Ransohoff RM, Kinkel RP, et al. The interferons: biological effects, mechanisms of action, and use in multiple sclerosis. Ann Neurol 1995; 37: 7–15PubMedCrossRefGoogle Scholar
44.
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–61Google Scholar
45.
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94PubMedCrossRefGoogle Scholar
46.
PRISMS (Prevention of Relapses and Disability by Interferon beta-la Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498–504CrossRefGoogle Scholar
47.
European Study Group on Interferon β-1b in Secondary Progressive Multiple Sclerosis. Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491–7CrossRefGoogle Scholar
48.
Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of recombinant interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001; 56: 1496–504CrossRefGoogle Scholar
49.
Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-la on MSFC progression in secondary progressive MS. Neurology 2002; 59: 679–87PubMedCrossRefGoogle Scholar
50.
Paty DW. MRI data from the North American Study of interferon beta 1b in secondary progressive multiple sclerosis [abstract]. Rev Neurol 2000; 156Suppl. 3: S39Google Scholar
51.
Leary SM, Miller DH, Stevenson VL, et al. Interferon beta-1a in primary progressive MS: an exploratory randomized controlled trial. Neurology 2003; 60: 44–51PubMedCrossRefGoogle Scholar
52.
Montalban X. Overview of European pilot study of interferon beta-1b in primary progressive multiple sclerosis. Mult Scler 2004; 10Suppl. 1: S62PubMedCrossRefGoogle Scholar
53.
Aharoni R, Teitelbaum D, Arnon R, et al. Copolymer 1 acts against the immunodominant epitope 82–100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci U S A 1999; 96: 634–9PubMedCrossRefGoogle Scholar
54.
Ziemssen T, Kumpfel T, Klinkert WE, et al. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 2002; 125: 2381–91Google Scholar
55.
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 1995; 45: 1268–76PubMedCrossRefGoogle Scholar
56.
Wolinsky JS. New insights in primary progressive multiple sclerosis [abstract]. Mult Scler 2004; 10Suppl. 2: SI 10Google Scholar
57.
Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, multicentre trial. Lancet 2002; 360: 2018–25PubMedCrossRefGoogle Scholar
58.
Kita M, Cohen JA, Fox RJ, et al. A phase II trial of mitoxantrone in patients with primary progressive multiple sclerosis [abstract]. Neurology 2004; 62 Suppl. 5: A99Google Scholar
59.
Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000; 6: 67–70PubMedCrossRefGoogle Scholar
60.
Kalkers NF, Barkhof F, Bergers E, et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler 2002; 8: 532–3PubMedCrossRefGoogle Scholar
61.
British and Dutch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988; II: 179–83Google Scholar
62.
Goodkin DE, Rudick RA, Vander Brug Medendorp S, et al. Low dose (7.5mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995; 37: 30–40PubMedCrossRefGoogle Scholar
63.
Rice GPA, Filippi M, Comi G, et al. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology 2000; 54: 1145–55PubMedCrossRefGoogle Scholar
64.
Poehlau D, Federlein J, Postert T, et al. Intravenous immunoglobulin (IVIG) treatment for patients with primary or secondary progressive multiple sclerosis: outline of a double-blind randomized, placebo-controlled trial. Mult Scler 1997; 3: 149–52PubMedCrossRefGoogle Scholar
65.
Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomized placebo-controlled trial. Lancet 2004; 364: 1149–56PubMedCrossRefGoogle Scholar
66.
Zephir H, de Seze J, Duhamel A, et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients. J Neurol Sci 2004; 218: 73–7PubMedCrossRefGoogle Scholar
67.
Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 2002; 8: 142–54PubMedCrossRefGoogle Scholar
68.
Fassas A, Passweg JR, Anagnostopoulos A, et al. Hematopoietic stem cell transplantation for multiple sclerosis: a retrospective multicenter study. J Neurol 2002; 249: 1088–97PubMedCrossRefGoogle Scholar
69.
Bowen JD, Maravilla K, Margolin SB. Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis. Mult Scler 2003; 9: 280–3PubMedCrossRefGoogle Scholar
70.
Noseworthy JH. Management of multiple sclerosis: current trials and future options. Curr Opin Neurol 2003; 16: 289–97PubMedCrossRefGoogle Scholar
71.
Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23PubMedCrossRefGoogle Scholar
72.
Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999; 46: 296–304PubMedCrossRefGoogle Scholar
73.
Stangel M, Hartung HP. Despair of repair. J Neurol Neurosurg Psychiatry 2002; 72: 1–4PubMedCrossRefGoogle Scholar

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Authors and Affiliations

Siobhan M. Leary
- 1
Alan J. Thompson
- 1

1.Institute of NeurologyUniversity College LondonLondonUK

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Cite this article as:: Leary, S.M. & Thompson, A.J. CNS Drugs (2005) 19: 369. https://doi.org/10.2165/00023210-200519050-00001

Primary Progressive Multiple Sclerosis

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