Emerging disease modifying therapies for multiple sclerosis

Expert Opinion on Emerging Drugs

Volumn 8, Issue 1, 2003, Pages 145-161

  Waubant, Emmanuelle ^a  

^a UCSF Multiple Sclerosis Center   (United States)

Author keywords

Disease modifying therapy for MS; Immunomodulation; Immunosuppression; Multiple sclerosis; Neuroprotection

Indexed keywords

ALEFACEPT; ALEMTUZUMAB; ATORVASTATIN; AUTOANTIGEN; AZATHIOPRINE; BETA1A INTERFERON; CD40 LIGAND MONOCLONAL ANTIBODY; CYCLOPHOSPHAMIDE; CYCLOSPORIN A; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DACLIZUMAB; ESTROGEN; GLATIRAMER; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INTERFERON BETA SERINE; METHOTREXATE; METHYLPREDNISOLONE; MINOCYCLINE; MITOXANTRONE; NATALIZUMAB; PACLITAXEL; PHOSPHODIESTERASE IV INHIBITOR; RILUZOLE; RITUXIMAB; SELECTIVE ESTROGEN RECEPTOR MODULATOR; SIMVASTATIN; TACROLIMUS; TALAMPANEL; TAU INTERFERON; UNINDEXED DRUG;

ALOPECIA; AMENORRHEA; BALANCE DISORDER; BLOOD BRAIN BARRIER; BONE MARROW DEPRESSION; CARDIOTOXICITY; CYTOPENIA; DEMYELINATING DISEASE; DISABILITY; DRUG EFFICACY; DYSPNEA; EARLY MENOPAUSE; ENDOMETRIUM HYPERPLASIA; ENVIRONMENTAL FACTOR; FLU LIKE SYNDROME; GASTROINTESTINAL SYMPTOM; HEMORRHAGIC CYSTITIS; HEREDITY; HUMAN; HYPERSENSITIVITY REACTION; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; INFECTION; INFLAMMATION; INJECTION PAIN; INTERSTITIAL PNEUMONIA; LEUKEMIA; LEUKOPENIA; LIVER TOXICITY; MACROCYTIC ANEMIA; MULTIPLE SCLEROSIS; MUSCLE WEAKNESS; NAUSEA; NERVE REGENERATION; NEUROPROTECTION; OLIGOSPERMIA; PARESTHESIA; PRURITUS; RASH; REVIEW; SIDE EFFECT; SYMPTOMATOLOGY; T LYMPHOCYTE; THORAX PAIN; VISUAL DISORDER; VOMITING;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; HUMANS; MULTIPLE SCLEROSIS; NEUROPROTECTIVE AGENTS; TECHNOLOGY, PHARMACEUTICAL;

EID: 0037981307     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728214.8.1.145     Document Type: Review

References (96)

1. NOSEWORTHY JH, LUCCHINETTI C, RODRIGUEZ M, WEINSHENKER BG: Multiple sclerosis. N. Engl. J. Med. (2000) 343:938-952. Comprehensive review of MS and MS treatments.
2. WEINSHENKER BG, BASS B, RICE GP et al.: The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain (1989) 112:133-146.
3. LUBLIN FD, REINGOLD SC: Defining the clinical course of multiple sclerosis: results of an international survey. Neurology (1996) 46:907-911.
4. THOMPSON AJ, KERMODE AG, WICKS D et al.: Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann. Neurol. (1991) 29:533-562.
5. POSER CM, PATY DW, SCHEINBERG L et al.: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. (1983) 13:227-231.
6. 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) 50:121-127.
7. KERMODE AG, THOMPSON AJ, TOFTS P et al.: Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Brain (1990) 113:1477-1489.
8. OKSENBERG JR, BARANZINI SE, BARCELLOS LF, HAUSER SL: Multiple sclerosis: genomic rewards. J. Neuroimmunol. (2001) 113:171-184.
9. TRAPP BD, PETERSON J, RANSOHOFF RM, RUDICK R, MORK S, BO L: Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. (1998) 338:278-285.
10. LUCCHINETTI C, BRUCK W, PARISI J, SCHEITHAUER B, RODRIGUEZ M, LASSMANN H: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. (2000) 47(6):707-717.
11. ZAMVIL SS, STEINMAN L: The T lymphocyte in experimental allergic encephalomyelitis. (1990) Ann. Rev. Immunol. 8:579-621.
12. GENAIN CP, CANNELLA B, HAUSER SL, RAINE CS: Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat. Med. (1999) 5(2):170-175.
13. NO AUTHORS LISTED: Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. IFNB Multiple Sclerosis Study Group. Neurology (1993) 43:655-661.
14. JACOBS LD, COOKFAIR D, RUDICK R et al.: Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann. Neurol. (1996) 39:285-294.
15. 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. The Copolymer 1 Multiple Sclerosis Study Group. Neurology (1995) 45:1268-1276.
16. NO AUTHORS LISTED: Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing remitting multiple sclerosis. PRISMS Study Group. Lancet (1998) 352:1498-1504.
17. HARTUNG HP, GONSETTE R, KONIG N et al.: Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet (2002) 360(9350):2018-2025.
18. YONG VW: Differential mechanisms of action of interferon-beta and glatiramer acetate in MS. Neurology (2002) 59:802-808.
19. NO AUTHORS LISTED: Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Neurology (2001) 56:1496-1504.
20. COHEN JA, CUTTER GR, FISCHER JS et al.: Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology (2002) 59(5):679-687.
21. JACOBS L, BECK R, SIMON J et al.: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N. Engl. J. Med. (2000) 343:898-904.
22. COMI G, FILIPPI M, BARKHOF F et al.: Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Lancet (2001) 357:1576-1582.
23. COMI G, FILIPPI M, WOLINSKY JS et al.: European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effect of glatiramer acetate on magnetic resonance imaging- measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann. Neurol. (2001) 49:290-297.
24. ANDERSSON PB, GOODKIN DE: Glucocorticosteroid therapy for multiple sclerosis: a critical review. J. Neurol. Sci. (1998) 160(1):16-25.
25. GOODKIN DE, KINKEL RP, WEINSTOCK-GUTTMAN B et al.: A Phase II study of i.v. methylprednisolone in secondary-progressive multiple sclerosis. Neurology (1998) 51(1):239-245.
26. ZIVADINOV R, RUDICK RA, DE MASI R et al.: Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology (2001) 57(7):1239-1247.
27. RIDGE SC, SLOBODA AE, MCREYNOLDS RA et al.: Suppression of experimental allergic encephalomyelitis by mitoxantrone. Clin. Immunol. Immunopathol. (1985) 35:35-42.
28. HAUSER SL, DAWSON DM, LEHRICH JR et al.: Intensive immunosuppression in progressive multiple sclerosis; a randomised, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N. Engl. J. Med. (1983) 308:173-180.
29. NO AUTHORS LISTED: The Canadian co-operative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Canadian Cooperative Multiple Sclerosis Study Group. Lancet (1991) 337:441-446.
30. WEINER H, MACKIN G, ORAV E et al.: Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology (1993) 43:910-918.
31. SMITH DR, WEINSTOK-GUTTMAN B, COHEN J et al.: Randomized trial of pulse cyclophosphamide in IFNB resistant active MS. Neurology (2002) 58 (Suppl. 3):A455.
32. GOODKIN DE, BAILY RC, TEETZEN ML, HERTSGAARD D, BEATTY WW: The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology (1991) 41:20-25.
33. YUDKIN PL, ELLSION GW, GHEZZI A et al.: Overview of azathioprine treatment in multiple sclerosis. Lancet (1991) 338:1051-1055.
34. PALACE J, ROTHWELL P: New treatments and azathioprine in multiple sclerosis. Lancet (1997) 350:261.
35. CAVAZZUTI M, MERELLI E, TASSONE G, MAVILLA L: Lesion load quantification in serial MR of early relapsing multiple sclerosis patients in azathioprine treatment. A retrospective study. Eur. Neurol. (1997) 38(4):284-290.
36. GOODKIN DE, RUDICK RA, VANDERBRUG MEDENDORP S et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann. Neurol. (1995) 37(1):30-40.
37. GOODKIN DE, RUDICK RA, VANDERBRUG MEDENDORP S, DAUGHTRY MM, VAN DYKE CD: Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRI's. Neurology (1996) 47:1153-1157.
38. FAZEKAS F, DEISENHAMMER F, STRASSER-FUCHS S, NAHLER G, MAMOLI B: Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet (1997) 349:589-593.
39. ACHIRON A, GABBAY U, GILAD R et al.: Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology (1998) 50:398-402.
40. WEINSHENKER BG, O'BRIEN PC, PETTERSON PM et al.: A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann. Neurol. (1999) 46:878-886.
41. HOHLFELD R: Biotechnical agents for the immunotherapy of MS: principles, problems and perspectives. Brain (1997) 120:865-916. Comprehensive review of emerging therapies for MS.
42. SMITH T, GROOM A, ZHU B, TURSKI L: Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat. Med. (2000) 6:62-66.
43. PITT D, WERNER P, RAINE C: Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. (2000) 6:67-70.
44. WERNER P, PITT D, RAINE C: Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann. Neurol. (2001) 50:169-180.
45. CHANG A, TOURTELLOTTE WW, RUDICK R, TRAPP BD: Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. (2002) 346(3):165-173.
46. LEARY SM, MILLER DH, STEVENSON VL, BREX PA, CHARD DT, THOMPSON AJ: Interferon beta-1a in primary progressive MS. An exploratory, randomized, controlled trial. Neurology (2003) 60:44-51.
47. MANDALFINO P, RICE G, SMITH A, KLEIN JL, RYSTEDT L, EBERS GC: Bone marrow transplantation in multiple sclerosis. J. Neurol. (2000) 247(9):691-695.
48. FASSAS A, PASSWEG JR, ANAGNOSTOPOULOS A et al.: Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J. Neurol. (2002) 249(8):1088-1097.
49. CAO L, SUN D, CRUZ T, MOSCARELLO MA, LUDWIN SK, WHITAKER JN: Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel. J. Neuroimmunol. (2000) 108(1-2):103-111.
50. JACOBSOHN DA: Novel therapeutics for the treatment of graft-versus-host disease. Expert Opin. Investig. Drugs (2002) 11(9):1271-1280.
51. BIELEKOVA B, MARTIN R: Antigen-specific immunomodulation via altered peptide ligands. J. Mol. Med. (2001) 79(10):552-565.
52. GENAIN CP, ZAMVIL SS: Specific immunotherapy: one size does not fit all. Nat. Med. (2000) 6(10):1098-1100.
53. BIELEKOVA B, GOODWIN B, RICHERT N et al.: Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a Phase II clinical trial with an altered peptide ligand. Nat. Med. (2000) 6:1167-1175.
54. KAPPOS L, COMI G, PANITCH H et al.: Induction of a non-encephalitogenic Type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized Phase II trial. Nat. Med. (2000) 6:1176-1182.
55. KIM H, ANTEL J, DUQUETTE P, ALLEVA DG, CONLON PJ, BAR-OR A: Persistence of immune responses to altered and native myelin antigens in patients with multiple sclerosis treated with altered peptide ligand. Clin. Immunol. (2002) 104:105-114.
56. BEN-NUN A, WEKERLE H, COHEN IR: Vaccination against autoimmune encephalomyelitis with T-lymphocytes cell lines reactive against myelin basic protein. Nature (1981) 292:60-61.
57. ZHANG J, MEDAER R, STINISSEN P, HAFLER D, RAUS J: MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination. Science (1993) 261:1451-1454.
58. MEDAER R, STINISSEN P, TRUYEN L, RAUS J, ZHANG J: Depletion of myelin-basic-protein-autoreactive T cells by T-cell vaccination: pilot trial in multiple sclerosis. Lancet (1995) 346:807-808.
59. CORREALE J, LUND B, MCMILLAN M, KO DY, MCCARTHY K, WEINER LP: T cell vaccination in secondary progressive multiple sclerosis. J. Neuroimmunol. (2000) 107(2):130-139.
60. VANDENBARK AA, CHOU YK, WITHAM R et al. Treatment of multiple sclerosis with T-cell receptor peptides: results of a double-blind pilot trial. Nat. Med. (1996) 2:1109-1115.
61. BOURDETTE DN, CHOU YK, WHITHAM RH et al.: Immunity to T cell receptor peptides in multiple sclerosis. III. Preferential immunogenicity of complementarity-determining region 2 peptides from disease-associated T cell receptor BV genes. J. Immunol. (1998) 161(2):1034-1044.
62. MORGAN EE, NARDO CJ, DIVELEY JP et al.: Vaccination with a CDR2 BV6S2/6S5 peptide in adjuvant induces peptide-specific T-cell responses in patients with multiple sclerosis. J. Neurosci. Res. (2001) 64(3):298-301.
63. KOTZIN BL, KARUTURI S, CHOU YK et al.: Preferential T cell receptor β-chain variable gene use in myelin basic protein- reactive T cell clones from patients with multiple sclerosis. Proc. Natl. Acad. Sci. USA (1991) 88:9161-9165.
64. CROSS AH, GIRARD TJ, GIACOLETTO KS et al.: Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation. J. Clin. Invest. (1995) 95:2783-2789.
65. KHOURY SJ, AKALIN E, CHANDRAKER A et al.: CD28-B7 costimulatory blockade by CTLA-4 Ig prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spares Th2 cytokines in the central nervous system. J. Immunol. (1995) 155(10):4521-4524.
66. HOWARD LM, MIGA AJ, VANDERLUGT CL et al.: Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. Clin. Invest. (1999) 103(2):281-290
67. MOREAU T, THORPE J, MILLER D et al.: Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet (1994) 344:298-301.
68. MOREAU T, COLES A, WING M et al.: Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain (1996) 119:225-237.
69. ELLIS CN, KRUEGER GG: Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. (2001) 345(4):248-255.
70. TREBST C, SORENSEN TL, KIVISAKK P et al.: CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am. J. Pathol. (2001) 159:1701-1710.
71. ROTTMAN JB, SLAVIN AJ, SILVA R, WEINER HL, GERARD OG, HANCOCK WW: Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur. J. Immunol. (2000) 30(8):2372-2377.
72. KWAK B, MULHAUPT F, MYIT S, MACH F: Statins as a newly recognized type of immunomodulator. Nat. Med. (2000) 6(12):1399-1402.
73. WEITZ-SCHMIDT G, WELZENBACH K, BRINKMANN V et al.: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med. (2001) 7(6):687-692.
74. PAHAN K, SHEIKH FG, NAMBOODIRI AM, SINGH I: Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J. Clin. Invest. (1997) 100:2671-2679.
75. YOUSSEF S, STUVE O, PATARROYO JC et al.: The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in CNS autoimmune disease. Nature (2002) 420(6911):78-84.
76. VOLLMER T, DURKALSKI V, TYOR W et al.: An open-label, single arm study of simvastatin as a therapy for multiple sclerosis. Neurology (2003) 60(Suppl. 1)A84.
77. JANSSON L, OLSSON T, HOLMDAHL R: Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J. Neuroimmunol. (1994) 53:203-207.
78. BEBO BF, FYFE-JOHNSON A, ADLARD K, BEAM AG, VANDENBARK AA, OFFNER H: Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J. Immunol. (2001) 166:2080-2089.
79. SICOTTE N, PFIEFFER P, KLUTCH R et al.: Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann. Neurol. (2002) 52(4):421-428.
80. SOOS JM, SUBRAMIAN PS, HOBEIKA AC, SCHIFFENBAUER J, JOHNSON HM: The interferon pregnancy recognition hormone, interferon tau, blocks both development and superantigen reactivation of experimental allergic encephalomyelitis without associated toxicity. J. Immunol. (1995) 155:2747-2753.
81. SOOS JM, MUSTAFA GM, SUBRAMANIAN PS, STREIT WJ, JOHNSON HJ: Oral feeding of interferon τ can prevent acute and chronic relapsing forms of experimental allergic encephalomyelitis. J. Neuroimmunol. (1997) 75:43-50.
82. OLEK MJ, SMITH DJ, COOK SL, KHOURY SJ, WEINER HL: Phase I study of oral recombinant ovine interferon-tau in relapsing-remitting multiple sclerosis. Neurology (2001) 56(Suppl. 3):A76.
83. GENAIN CP, ROBERTS T, DAVIS RL et al.: Prevention of autoimmune demyelinarion in non-human primates by a cAMP-specific phosphodiesterase inhibitor. Proc. Natl. Acad. Sci. USA (1995) 92(8):3601-3605.
84. FOLCIK VA, SMITH T, O'BRYANT S et al.: Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of Type IV phosphodiesterase inhibitors. J. Neuroimmunol. (1999) 97(1-2):119-128.
85. LYONS JA, SAN M, HAPP MP, CROSS AH: B-cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur. J. Immunol. (1999) 29:3432-3439.
86. YEDNOCK TA, CANNON C, FRITZ LC, SANCHEZ-MADRID F, STEINMAN L, KARIN N: Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature (1992) 356:63-66.
87. MILLER DH, KHAN OA, SHEREMATA WA et al.: A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. (2003) 348(1):15-23.
88. CLEMENTS JM, COSSINS JA, WELLS GMA et al.: Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effect of a combined matrix metalloproteinase and tumor necrosis factor-alpha inhibitor. J. Neuroimmunol. (1997) 74:85-94.
89. MARRACCI GH, JONES RE, MCKEON GP, BOURDETTE DN: Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J. Neuroimmunol. (2002) 131(1-2):104-114.
90. BRUNDULA V, REWCASTLE NB, METZ LM, BERNARD CC, YONG VW: Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain (2002) 125:1297-1308.
91. POPOVIC N, SCHUBART A, GOETZ BD, ZHANG SC, LININGTON C, DUNCAN ID: Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann. Neurol. (2002) 51(2):215-223.
92. ZHU S, STAVROVSKAYA IG, DROZDA M et al.: Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature (2002) 417:74-78.
93. METZ LM, YONG VW, YEUNG M et al.: Open-label trial of minocycline in active relapsing-remitting multiple sclerosis. Neurology (2003) 60(Suppl. 1):A250.
94. GUO X, DILLMAN JF 3RD, DAWSON VL, DAWSON TM: Neuroimmunophilins: novel neuroprotective and neuroregenerative targets. Ann. Neurol. (2001) 50(1):6-16.
95. KURTZKE JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology (1983) 33:1444-1452.
96. KALKERS NF, BARKHOF F, BERGERS E, VAN SCHIJNDEL R, POLMAN CH: The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult. Scler. (2002) 8(6):532-533.