Hostname: page-component-8448b6f56d-sxzjt Total loading time: 0 Render date: 2024-04-23T10:10:06.667Z Has data issue: false hasContentIssue false
  • English
  • Français

A 21 Point Unifying Hypothesis on the Etiology and Treatment of Multiple Sclerosis

Published online by Cambridge University Press:  18 September 2015

Howard L. Weiner
Howard L. Weiner*
Affiliation:
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston.
*
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, HIM 730, Boston, Massachusetts, USA 02115
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Multiple sclerosis (MS) is postulated to be a cell mediated autoimmune disease directed against central nervous system myelin components. Our understanding of the disease has been enhanced by a number of factors: 1) advances in our understanding of the immune system; 2) clinical trials which are beginning to identify treatments which can affect MS; 3) a better understanding of the clinical features of MS; and 4) advances in MRI imaging of the brain. Based on the current state of knowledge, this paper proposes a 21 point unifying hypothesis on the etiology and treatment of the disease. This hypothesis makes a series of assumptions, many of which are unproven, and is presented as a framework from which to investigate and treat the disease, not as a established biology. It is hypothesized that the underlying pathogenesis of MS is related to an inappropriate class of immune response against myelin antigens favoring proinflammatory Th1 versus anti-inflammatory Th2 or Th3 type responses. Environmental and genetic factors predispose toward MS by affecting the class of response and effectiveness of treatment is also related to how it impacts on this common final pathway. Because of epitope spreading, there is not one autoantigen involved in MS and the progressive form of MS differs immunologically from the relapsing remitting form. Viruses trigger and perpetuate MS, although MS is not related to a persistent viral infection. Because MS is a multifactorial disease, there are clinical and perhaps immunological subtypes of MS and a single type of treatment is unlikely to control the disease in all patients. Thus, there will be responders and non-responders to each effective therapy and ultimately combination therapy will be required to cure the disease.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 25 , Issue 2 , February 1998 , pp. 93 - 101
Copyright
Copyright © Canadian Neurological Sciences Federation 1998

References

REFERENCES

1.Martin, R, McFarland, HF and McFarlin, DE. Immunological aspects of demyelinating diseases. Annu Rev Immunol 1992; 10: 153–187.CrossRefGoogle ScholarPubMed
2.Raine, CS. The Dale McFarlin memorial lecture. The immunology of the MS lesion. Ann Neurol 1994; 36: S61-S72.CrossRefGoogle Scholar
3.Prineas, JW. Pathology of Multiple Sclerosis. In: Cook, S.D. eds. Handbook of Multiple Sclerosis. Newark: Marcel Dekker, Inc., 1996: 223–255.Google Scholar
4.Lassmann, H. Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis, eds. Berlin: Springer-VerlaG, 1983.CrossRefGoogle ScholarPubMed
5.Windhagen, A, Newcombe, J, Dangond, F, et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 1995; 182: 1985–1996.CrossRefGoogle ScholarPubMed
6.Olsson, T, Wang, W-Z, Höjeberg, B, et al. Autoreactive T-lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. J Clin Invest 1990; 86: 981–985.CrossRefGoogle ScholarPubMed
7.Allegretta, M, Nicklas, J, Sriram, S, Albertini, R. T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 1990; 247: 718.CrossRefGoogle ScholarPubMed
8.Zhang, J, Markovic, S, Raus, J, et al. Increased frequency of IL-2 responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1993; 179: 973–984.CrossRefGoogle Scholar
9.Bieganowska, KD, Ausubel, LJ, Modabber, Y, et al. Direct ex vivo analysis of activated, fas-sensitive autoreactive T cells in human autoimmune disease. J Exp Med 1997; 185: 1585–1594.CrossRefGoogle ScholarPubMed
10.Warren, KG, Catz, I, Johnson, E, Mielke, B. Anti-myelin basic protein and anti-proteolipid protein specific forms of multiple sclerosis. Ann of Neurol 1994; 35: 280–289.CrossRefGoogle ScholarPubMed
11.Linington, C, Bradi, M, Lassmann, H, Brunner, C, Vass, K. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 1988; 130: 443–454.Google Scholar
12.Schluesener, H, Sobel, R, Linington, C, Weiner, HL. A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in CNS autoimmune disease. J Immunol 1987; 139: 4016–4021.CrossRefGoogle Scholar
13.Lehmann, P, Forsthuber, T, Miller, A, Sercarz, E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992; 358: 155.CrossRefGoogle ScholarPubMed
14.McCarron, R, Fallis, R, McFarlin, D. Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephlomyelitis. J Neuroimmunol 1990; 29: 73–79.CrossRefGoogle Scholar
15.Cross, AH, Tuohy, VK, Raine, CS. Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell Immunol 1993; 146: 261–270.CrossRefGoogle ScholarPubMed
16.Kaufman, DI, Clare-Salzler, M, Tian, , et al. Spontaneous loss of Tcell tolerance to glutamic acid decarboxylase in murine insulindependent diabetes. Nature 1993; 366: 69–72.CrossRefGoogle Scholar
17.Tisch, R, Yang, X-D, Singer, SM, et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993; 366: 72–75.CrossRefGoogle ScholarPubMed
18.Kerlero de Rosbo, N, Milo, R, Lees, MB, et al. Reactivity to myelin antigens in multiple sclerosis: peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest 1993; 92: 2602–2608.CrossRefGoogle ScholarPubMed
19.Harrison, LC. Islet cell antigens in insulin-dependent diabetes: Pandora’s box revisited. Immunol Today 1992; 13: 348–352.CrossRefGoogle ScholarPubMed
20.Shimonkevitz, R, Colburn, C, Burnham, J, Murray, RS, Kotzin, BL. Clonal expansion of activated gamma/delta T cells in recent onset multiple sclerosis. Proc Natl Acad Sci U S A 1993; 90: 923–927.CrossRefGoogle ScholarPubMed
21.Wucherpfennig, KW, Newcombe, J, Kebby, C, Cuzner, ML, Hafler, DA. Gamma/delta T cell receptor repertoire in acute demyelinating multiple sclerosis lesions. Proc Natl Acad Sci U S A 1992; 89: 4588–4592.CrossRefGoogle ScholarPubMed
22.Panitch, HS, Hirsch, RL, Haley, AS, Johnson, KP. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1987; 1: 893–895.CrossRefGoogle ScholarPubMed
23.Seder, RA, Paul, WE. Lymphocyte responses and cytokines. Cell 1994; 76: 241–251.Google Scholar
24.Racke, MK, Bonomo, A, Scott, DE, et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 1994; 180: 1961–1966.CrossRefGoogle ScholarPubMed
25.Groux, H, O’Garra, A, Bigler, M, et al. A CD4‣ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389: 737–742.CrossRefGoogle ScholarPubMed
26.Chen, Y, Kuchroo, VK, Inobe, J-I, Hafler, DA, Weiner, HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994; 265: 1237–1240.CrossRefGoogle ScholarPubMed
27.Khoury, SJ, Hancock, WW, Weiner, HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis as associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β interleukin 4, and prostaglandin E expression in the brain. J Exp Med 1992; 176: 1355–1364.CrossRefGoogle ScholarPubMed
28.Karpus, W, Swanborg, R. CD4‣ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor beta. J Immunol 1991; 146: 1163–1168.CrossRefGoogle ScholarPubMed
29.Steinman, L. Multiple sclerosis and its animal models: the role of the major histocompatibility complex and the T cell receptor repertoire. Semin Immunopathol 1992; 14: 79–93.Google ScholarPubMed
30.Zipp, F, Weber, F, Huber, S, et al. Genetic control of multiple sclerosis: increased production of lymphotoxin and tumor necrosis factor-α by HLA-DR2‣ T cells. Ann Neurol 1995; 38: 723–730.CrossRefGoogle ScholarPubMed
31.Segal, BM, Shevach, EM. IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med 1996; 184: 771–775.CrossRefGoogle ScholarPubMed
32.Maron, R, Hancock, W, Slavin, A, et al. Genetic susceptibility or resistance to EAE in MHC identical mice is linked to differential cytokine production. FASEB 1997; LB60 (Abst):Google Scholar
33.Mussener, A, Lorentzen, JC, Kleinau, S, Klareskog, L. Altered Thl/Th2 balance associated with non-major histocompatibility complex genes in collagen-induced arthritis in resistant rat strains. Eur J Immunol 1997; 27: 695–699.CrossRefGoogle Scholar
34.Kuchroo, V, Prabhu Das, M, Brown, JA, et al. B7-1 and B7-2 costimulatory molecules differentially activate the Thl/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995; 80: 707–718.Google Scholar
35.Oro, AS, Guarino, TJ, Driver, R, Steinman, L, Umetsu, DT. Regulation of disease susceptibility: decreased prevalence of IgE- mediated allergic disease in patients with multiple sclerosis. J Allergy Clin Immunol 1996; 97: 1402–1408.CrossRefGoogle ScholarPubMed
36.Sadovnick, AD, Rice, GP, Armstrong, H. A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33: 281–285.CrossRefGoogle ScholarPubMed
37.Kurtzke, JF. Epidemiology of multiple sclerosis. In: Vinken, PJ, Bruyn, GW, Klawans, HL, et al., eds. Handbook of Clinical Neurology. New York: Elsevier Science Publishers, 1985: 259–287.Google Scholar
38.Bamford, CR, Sibley, WA, Thies, C. Seasonal variation of multiple sclerosis exacerbations in Arizona. Neurology 1983; 33: 897–701.CrossRefGoogle ScholarPubMed
39.Balashov, KE, Olek, MJ, Khoury, SJ, Weiner, HL. Seasonal variation of IFN-γ production in progressive multiple sclerosis. AAN 1998 Scientific Program: Neurology (Abst) 1998.Google ScholarPubMed
40.Cook, SD, Rohowsky-Kochan, C, Bansil, S, Dowling, PC. Evidence for a viral etiology of multiple sclerosis. In: Cook, SD, eds. Handbook of Multiple Sclerosis. Newark: Marcel Dekker, Inc., 1996: 97–118.Google Scholar
41.Antel, J, Arnason, B, Medof, M. Suppressor cell function in multiple sclerosis: correlation with clinical disease activity. Ann Neurol 1978; 5: 338–342.CrossRefGoogle Scholar
42.Hafler, DA, Weiner, HL. Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev 1995; 144: 75–107.CrossRefGoogle ScholarPubMed
43.Hafler, DA, Weiner, HL. In vivo labeling of peripheral blood T-cells using monoclonal antibodies: rapid traffic into cerebrospinal fluid in multiple sclerosis. Ann Neurol 1987; 22: 90–93.CrossRefGoogle ScholarPubMed
44.Bongioanni, P, Meucci, G. T-cell tumor necrosis factor-alpha receptor binding in patients with multiple sclerosis. Neurology 1997; 48: 826–831.CrossRefGoogle ScholarPubMed
45.Noronha, A, Toscas, A, Jensen, MA. Interferon beta augments suppressor cell function in multiple sclerosis. Ann Neurol 1990; 27: 207–210.CrossRefGoogle ScholarPubMed
46.Hafler, D, Fox, D, Manning, M, et al. In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. N Engl J Med 1985; 312: 1405–1411.CrossRefGoogle ScholarPubMed
47.Berger, T, Weerth, S, Kojima, K, et al. Experimental autoimmune encephalomyelitis: The antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. Laboratory Investigation 1997; 76: 355–364.Google ScholarPubMed
48.Revesz, T, Kidd, D, Thompson, AJ, et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 1994; 117: 759–765.CrossRefGoogle ScholarPubMed
49.Schmied, M, Breitschopf, H, Gold, R, et al. Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. Am J Pathol 1993; 143: 446–452.Google ScholarPubMed
50.Kennedy, MK, Torrance, DS, Picha, KS, Mohler, KM. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J Immunol 1992; 149: 2496–2505.CrossRefGoogle ScholarPubMed
51.Chen, Y, Hancock, WW, Marks, R, Gonnella, PA, Weiner, HL. Mechanisms of recovery from experimental allergic encephalomyelitis: T cell deletion and immune deviation in myelin basic protein receptor transgenic mice. J Neuroimmunol 1998; in press.CrossRefGoogle ScholarPubMed
52.Correale, J, Gilmore, W, McMillan, M, et al. Patterns of cytokine secretion by autoreactive proteolipid protein-specific T cell clones during the course of multiple sclerosis. J Immunol 1995; 154: 2959–2968.CrossRefGoogle ScholarPubMed
53.Balashov, KE, Smith, DR, Khoury, SJ, Hafler, DA, Weiner, HL. Increased IL-12 production in progressive multiple sclerosis: Induction by activated CD4‣ T cells via CD40 ligand. Proc Natl Acad Sci U S A 1997; 94: 599–603.CrossRefGoogle ScholarPubMed
54.Comabella, M, Balashov, K, Smith, D, Weiner, HL, Khoury, SJ. Cyclophosphamide treatment normalizes the increased IL-12 production in patients with chronic progressive MS and induces a Th2 cytokine switch. AAN Scientific Program: Neurology (Abst) 1998.Google Scholar
55.Miller, DH, Grossman, RI, Reingold, SC, McFarland, HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain (1998); 121: 3–24.CrossRefGoogle ScholarPubMed
56.Khoury, SJ, Guttman, CRG, Orav, EJ, et al. Longitudinal MRI imaging in multiple sclerosis: correlation between disability and lesion burden. Neurology 1994; 44: 2120–2124.CrossRefGoogle Scholar
57.Filippi, M, Horsfield, MA, Morrissey, SP. Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis. Neurology 1994; 44: 635–641.CrossRefGoogle ScholarPubMed
58.Weiner, HL, Khoury, SJ, Guttmann, C, et al. Magnetic resonance imaging correlates with clinical disability and attacks in multiple sclerosis. AAN Scientific Program: Neurology (Abst) 1998.Google Scholar
59.Losseff, NA, et al. Spinal cord atrophy and disability in multiple sclerosis: A new reproducible and sensitive MRI technique with potential to monitor disease progression. Brain 1996; 119: 101–108.CrossRefGoogle ScholarPubMed
60.van Walderveen, MA, Barkhof, F, Hommes, OR, et al. Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short-TR/short-TE (Tl-weighted) spin-echo images. Neurology 1995; 45: 1684–1690.CrossRefGoogle Scholar
61.Martin, R, McFarland, HF. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 1995; 32: 121–182.CrossRefGoogle ScholarPubMed
62.Lublin, FD, Knobler, RL, Kalman, B, et al. Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 1993; 16: 267–274.CrossRefGoogle ScholarPubMed
63.Ferber, IA, Brocke, S, Taylor-Edwards, C, et al. Mice with disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunology 1996; 156: 5–7.CrossRefGoogle Scholar
64.Billiau, A, Heremans, H, Vandekerckhove, F, et al. Enhancement of experimental allergic encephalomyelitis by antibodies against IFN-γ. J Immunol 1988; 140: 1506–1510.CrossRefGoogle ScholarPubMed
65.Weiner, H, Hohol, M, Khoury, S, Dawson, D, Hafler, D. Therapy for MS. Neurologic Clinics 1995; 13: 173–196.CrossRefGoogle Scholar
66.Hohol, MJ, Olek, MJ, Orav, EJ, et al. Treatment of progressive multiple sclerosis with pulse cyclophosphamide/methylprednisolone: response to therapy is linked to duration of progressive disease. AAN Scientific Program: Neurology (Abst) 1998.Google Scholar
67.Weiner, HL. Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 1997; 18: 335–343.CrossRefGoogle ScholarPubMed
68.Fukaura, H, Kent, SC, Pietrusewicz, MJ, et al. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta 1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 1996; 98; 70–77.CrossRefGoogle Scholar
69.Nicholson, L, Greer, J, Sobel, R, Lees, M, Kuchroo, V. An altered peptide ligand mediates immune deviation and prevents EAE. Immunity 1995; 3: 397–405.CrossRefGoogle Scholar
70.Miller, A, Lider, O, Weiner, HL. Antigen-driven bystander suppression following oral administration of antigens. J Exp Med 1991; 174: 791–798.CrossRefGoogle Scholar
71.Al-Sabbagh, A, Miller, A, Santos, LMB, Weiner, HL. Antigen-driven tissue-specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid induced experimental autoimmune encephalomyelitis in the SJL mouse. Eur J Immunol 1994; 24: 2104–2109.CrossRefGoogle ScholarPubMed
72.von Herrath, MG, Dyrberg, T, Oldstone, MBA. Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice. J Clin Invest 1996; 98: 1324–1331.CrossRefGoogle ScholarPubMed
73.Becker, KJ, McCarron, RM, Ruetzler, C, et al. Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. Proc Natl Acad Sci U S A 1997; 94: 10873–10878.CrossRefGoogle ScholarPubMed
74.Aharoni, R, Teitelbaum, D, Sela, M, Arnon, R. Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Science, USA 1997; 94: 10821–10826.CrossRefGoogle Scholar
75.Smith, D, Balshov, K, Hafler, D, Khoury, S, Weiner, H. Immune deviation following cyclophosphamide/ methylprednisolone treatment of multiple sclerosis: Increased IL-4 and associated eosinophilia. Ann Neurol 1997; 42: 313–318.CrossRefGoogle ScholarPubMed
76.Rudick, R, Ransohoff, R, Peppier, R. Interferon beta induces 1L-10 expression: relevance to multiple sclerosis. Ann Neurol 1996; 40: 618–627.CrossRefGoogle Scholar
77.Takashima, H, Smith, DR, Fukaura, H, et al. Cyclophosphamide induces myelin antigen specific IL-4 secreting T cells in multiple sclerosis patients. Clin Immunol Immunopath 1998: in press.CrossRefGoogle ScholarPubMed
78.Gene, K, Dona, D, Reder, AT. Increased CD80‣ B cells in active multiple sclerosis and reversal by interferon β-lb therapy. J Clin Invest 1997; 99: 2664–2671.Google Scholar
79.Trapp, BD, Peterson, J, Ransohoff, RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338; 278–285.CrossRefGoogle ScholarPubMed
80.Sriram, S, Rodriguez, M. Indictment of the microglia as the villain in multiple sclerosis. Neurology 1997; 48: 464–470.CrossRefGoogle ScholarPubMed
81.Yudkin, PL, Ellison, GW, Ghezzi, A, et al. Overview of azathioprine treatment in multiple sclerosis. The Lancet 1991; 338: 1051–1055.CrossRefGoogle ScholarPubMed
82.Durelli, L, Bongioanni, MR, Ferrero, B, et al. Interferon alpha-2a treatment of relapsing-remitting multiple sclerosis: disease activity resumes after stopping treatment. Neurology 1996; 47: 123–129.CrossRefGoogle ScholarPubMed
83.Jacobs, L, Cookfair, D, Rudick, R, et al. Results of a phase III trial of intramuscular recombinant beta interferon as treatment for multiple sclerosis. Ann Neurol 1994; 36: 259.Google Scholar
84.The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-lb in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. Neurology 1995; 45: 1277–1285.CrossRefGoogle Scholar
85.Beutler, E, Sipe, JC, Romine, JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996; 93: 1716–1720.CrossRefGoogle ScholarPubMed
86.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: 1268–1276.CrossRefGoogle ScholarPubMed
87.Beck, RW, Cleary, PA, Trobe, JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. NEJM 1993; 239: 1764–1769.CrossRefGoogle Scholar
88.Weiner, HL, Mackin, GA, Orav, EJ, 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.CrossRefGoogle ScholarPubMed
89.Hommes, OR, Lamers, KJB, Reekers, P. Effect of intensive immunosuppression on the course of chronic progressive multiple sclerosis. J Neurol 1980; 223: 177–190.CrossRefGoogle Scholar
90.Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990; 27: 591–605.CrossRefGoogle Scholar
91.Fazekas, F, Deisenhammer, F, Strasser-Fuchs, S, Nahler, G, Mamoli, B. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349: 589–593.CrossRefGoogle ScholarPubMed
92.Anderson, O, Lycke, J, Tollesson, PO, et al. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology 1996; 47: 895–900.CrossRefGoogle Scholar
93.Karussis, DM, Meiner, Z, Lehmann, D, et al. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology 1996; 47: 341–346.CrossRefGoogle ScholarPubMed
94.Goodkin, DE, Rudick, RA, VanderBrug Medendorp, S. Low-dose (7.5mg) oral methotrexate reduces the rate if progression in chronic progressive multiple sclerosis. Ann Neurol 1995; 37: 30–40.CrossRefGoogle Scholar
95.Edan, G, Miller, D, Clanet, M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicenter study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997; 62: 112–118.CrossRefGoogle ScholarPubMed
96.Weiner, HL, Dau, PC, Khatri, BO, et al. Double-blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis. Neurology 1989; 39: 1143–1149.CrossRefGoogle ScholarPubMed
97.Rodriguez, M, Karnes, WE, Bartleson, JD, Pineda, AA. Plasmpheresis in acute episodes of fulminant CNS inflammatory demyelination. Neurology 1993; 43: 1100–1104.CrossRefGoogle ScholarPubMed
98.Cook, SD, Devereux, C, Troiano, R, et al. Total lymphoid irradiation in multiple sclerosis. In: Rudick, RA, Goodkin, DE, eds. Treatment of multiple sclerosis: trial design, results, and future perspectives. New York: Springer-Verlag, 1992: 267–280.CrossRefGoogle Scholar