Estrategias de tratamiento basadas en la evidencia para el tratamiento de la esclerosis múltiple

(Traducción de la guía del Consejo de Esclerosis Múltiple para el Desarrollo de Guías de Práctica Clínicas)



1. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: I. clinical course and disability. Brain 1989;112:133–146.

2. Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: II. predictive value of the early clinical course. Brain 1989;112:133–146.

3. Weinshenker BG. The epidemiology of multiple sclerosis Neurologic Clinics 1996;14:29192-308.

4. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393–9.

5. Compston, DA. McAlpine’s Multiple Sclerosis, 3rd ed., New York, Churchill Livingstone, 1998.

6. Trapp BD, Peterson JP, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–285.

7. Bar-Or A, Oliviera EML, Anderson DE, Hafler DA. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999;100:252–9.

8. Conlon P, Oksenberg JR, Zhang J. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol Dis 6;1999:149–166

9. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis. Neurology 1996;46:907–911.

10. Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatr, 1999;67:148–52.

11. Rodriguez M, Siva A, Cross S, et al. Optic neuritis: a population based study in Olmsted county, Minnesota. Neurology 1994;44:A374.

12. O’Riordan JI, Thompson DP, Kingsley DP, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain 1998;121:495–503.

13. Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1720–1725.

14. Sharief MK, Thompson EJ. The predictive value of intrathecal immunoglobulin synthesis and magnetic resonance imaging in acute isolated syndromes for subsequent development of multiple sclerosis. Ann Neurol 1991;29:147–151.

15. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: Guidelines for Research Protocols. Ann Neurol 1983;13:227–231.

16. McDonald WI, Compston DAS, 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.

17. 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;43:655–661.

18. Paty DW, Li DKB, the UBC MS/MRI Study Group, the IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in remitting and relapsing multiple sclerosis: II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:662–667.

19. The IFNB Multiple Sclerosis Study Group and the UBC MS/MRI Analysis Group. Interferon Beta-1b in the Treatment of MS: Final Outcome of the Randomized Controlled Trial. Neurology 1995;45:1277–1285.

20. PRISMS Study Group. Randomized double-blind placebo- controlled study of interferon ß-1a in relapsing/ remitting multiple sclerosis. Lancet 1998;352:1498–1504.

21. The Once Weekly Interferon for MS Study Group. Evidence of interferon beta-1a dose response in relapsingremitting MS: the OWIMS Study. Neurology, 1999;53:679–86.

22. 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.

23. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 1998;50:701–708.

24. Li DK, Paty DW, UBC MS/MRI Analysis Research Group, PRISMS Study Group. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferonbeta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multiple Sclerosis. Ann Neurol 1999;46: 197–206.

25. Comi G, Fillippi M, The Copaxone MRI Study Group. The effect of glatiramer acetate (Copaxone) on disease activity as measured by Cerebral MRI in patients with remitting-relapsing multiple sclerosis (RRMS): a multicenter, randomized, double-blind, placebo-controlled study extended by open label treatment. Neurology 1999;52(Suppl 2):A289.

26. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in exacerbating- remitting multiple sclerosis. Ann Neurol 1996;39:285–294.

27. European Study Group on Interferon beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomized trial of interferon â-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491–1497.

28. Gonon O, Catalaa I, Babb JS, et al. Total brain Nacetylaspartate: a new measure of disease load in MS. Neurology 2000;54:15–19.

29. International Federation of Multiple Sclerosis Societies. Symposium on a minimal record of disability in multiple sclerosis. Acta Neurol Scand 1984;70 (Suppl 101):176–181.

30. Amato MP, Fratiglioni L, Groppi C, et al. Interrater reliability in assessing functional systems and disability on the Kurtzke scale in multiple sclerosis. Arch Neurol 1988;45:746–748.

31. Noseworthy JH, Vandervort MK, Wong CJ, et al. Canadian Cooperative MS Study Group. Interrater variability with the expanded disability status scale (EDSS) and functional systems (FS) in a multiple sclerosis clinical trial. Neurology 1990;40:971–975.

32. Francis DA, Bain P, Swan AV, Hughes RAC. An assessment of disability scales used in multiple sclerosis. Arch Neurol 1991;48:299–301

33. Cohen RA, Kessler HR, Fischer M. The expanded disability status scale (EDSS) as a predictor of impairments of functional activities of daily living in multiple sclerosis. J Neurol Sci 1993;115:132–135.

34. Liu C , Blumhardt LD. Disability outcome measures in therapeutic trials of relapsing- remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts. J Neurol Neurosurg Psychiatr 2000;68:450–7.

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

36. Sipe JC, Knobler RL, Braheny SL, et al. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology 1988;34:1368–1372.

37. Goodin DS. A questionnaire to assess neurological impairment in multiple sclerosis. Multiple Sclerosis 1998;4:444–451.

38. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41:685–691.

39. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis II. Impact on employment and social functioning. Neurology 1991;41:692–696.

40. Rudick RA, Antel J, Confavreux C, et al. Recommendations from the National Multiple Sclerosis Society clinical outcomes assessment task force. Ann Neurol 1997;42:379–382

41. Cutter GR, Baier MS, Rudick, et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999;122:101–112

42. Goodkin DE, Rudick RA, VanderBrug-Medendorp S, et al. Low-dose (7.5mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995;37:30–40.

43. Amato MP, Ponziani G, Bartolozzi ML, Siracusa G. A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci, 1999;168:96–106.

44. Kappos L, Moeri D, Radue EW, et al. Predictive value of gadolinium enhanced magnetic resonance imaging for relapse rate and changes in disability and impairment in multiple sclerosis: a meta-analysis. Lancet 1999;353:964–969.

45. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. New Engl J Med, 2000; 343:1430–8.

46. Lublin FD, Cutter GR, Baier M. Exacerbation recovery and the progression of multiple sclerosis Neurology 2000;54(Suppl3):A216–217.

47. Goodman SN. Reviews and Commentary: p values, Hypothesis Tests, and Likelihood: Implications for Epidemiology of a Neglected Historical Debate. Am J Epidemiol 1993:137:485–496.

48. Bellhouse DR. Invited Commentary: p Values, Hypothesis Tests, and Likelihood. Am J Epidemiol 1993;137:497–499.

49. Goodman SN. Author’s Response to: Invited Commentary: p Values, Hypothesis Tests, and Likelihood. Am J Epidemiol 1993;137:500–501.

50. Goodin DS. Perils and pitfalls in the interpretation of clinical trials: A reflection on the recent experience in multiple sclerosis. Neuroepidemiol 1999;18:53–63.

51. O’Brien PC. Procedures for comparing samples with multiple endpoints. Biometrics 1984;40:1079–1087.

52. Thomas DC, Siemiatycki J, Dewar R, et al. The problem of multiple inference in studies designed to generate hypotheses. Am J Epidemiol 1985;122:1080–1095.

53. Rothman KJ. Significance questing. Ann Int Med 1986;105:445–447. 54. Tandon PK. Applications of global statistics in analyzing quality of life data. Statistics in Medicine 1990;9:819-827.

55. Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Statistics in Medicine 1990;9:811–818

56. Cohen J. Statistical power analysis for the behavioral sciences; Second Edition. (1988) Lawrence Erlbaum Associates, Hillsdale, New Jersey.

57. Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo-final report. Neurology 1970;20:1–59.

58. Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology 1989;39:969–971.

59. Milanese C, LaManita L, Salmaggi A, et al. Doubleblind, randomized trial of ACTH versus dexamethasone versus methylprednisolone in multiple sclerosis bouts. Clinical, cerebrospinal fluid, and neurophysiological results. European Neurol 1989;29:10–14.

60. Beck RW. The optic neuritis treatment trial. Arch Opthalmol 1988;106:1051–1053.

61. Beck RW, Cleary PA, Anderson MM Jr., et al. A randomized, controlled, trial of corticosteroids in the treatment of acute optic neuritis. New Engl J Med 1992;326:581–588.

62. Beck RW. Corticosteroid treatment of optic neuritis: a need to change treatment practices. The Optic Neuritis Study Group. Neurology 1992;42:1133–1135.

63. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. New Engl J Med 1995;35:193–198.

64. Beck RW, Cleary PA. Optic neuritis treatment trial. One-year follow-up results. Arch Opthalmol 1993; 111:773–775.

65. Beck RW, Clearly PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993; 329:1764-1769.

66. Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis: the experience of the optic neuritis treatment trial. Neurology 1997;49:1404–1413.

67. Achiron A, Djaldetti R, Ziv I. Corticosteroids in the treatment of optic neuritis. N Engl J Med 1992; 327:281–282.

68. Silberberg DH. Corticosteroids and optic neuritis. N Engl J Med 1993;329:1808–1810.

69. Olek MJ, Kahn OA. Corticosteroids, optic neuritis, and multiple sclerosis. N Engl J Med 1994;330:1238.

70. Herishanu YO, Badarna S, Sarov B, Abarbanel JM, Segal S, Bearman JE. A possible harmful late effect of methylprednisolone therapy on a time cluster of optic neuritis. Acta Neurol Scand 1989;80:569–574.

71. Milligan NM, Newcombe R, Compston DA. A doubleblind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatr 1987;50:511–516.

72. Durelli L, Cocito D, Riccio A, et al. High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations. Neurology 1986;36:238–243.

73. Barkhof F, Hommes OR, Scheltens P, Valk J. Quantitative MRI changes in gadolinium-DPTA enhancement after high-dose intravenous methylprednisolone in multiple sclerosis. Neurology 1991;41:1219–1222.

74. Barkhof F, Scheltens P, Frequin ST, et al. Relapsingremitting multiple sclerosis: sequential enhanced MR imaging vs clinical findings in determining disease activity. Am J Roentgeonol 1992;159:1041–1047.

75. Kappos L, Staedt D, Rohrbach E, et al. Time course of gadolinium enhancement in MRI of patients with multiple sclerosis: effects of corticosteroid treatment. J Neurol 1988;235:10.

76. Burnham JA, Wright RR, Dreisbach J, Murray RS. The effect of high-dose steroids on MRI gadolinium enhancement in acute demyelinating lesions. Neurology 1991;41:1349–1354.

77. Oliveri RL, Valentino P, Russo C, et al. Randomized trial comparing two different high doses of methylprednisolone in MS. Neurology 1998;50:1833–1836.

78. Miller, D.H., Thompson, A.J., Morrissey, S.P., et al. High dose steroids in acute relapses of multiple sclerosis: MRI evidence for a possible mechanism of therapeutic effect. J Neurol Neurosurg Psychiatry 1992; 55:450–453.

79. Barkhof F, Tas MW, Frequin STFM, et al. Limited duration of the effect of methylprednisolone on changes on MRI in multiple sclerosis. Neuroradiology 1994; 36:382–387.

80. Smith ME, Stone LA, Albert PS, et al. Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentate dimeglumine-enhancing magnetic resonance imaging lesions. Ann Neurol 1993;33:480–489.

81. Reder AT, Thapar M, Jensen MA. A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: implications for treatment of inflammatory brain disease. Neurology 1994;44:2289–2294.

82. Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatr 1993;56: 1219–1220.

83. Barnes MP, Hughes RA, Morris RW, et al. Randomized trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 1997; 349:902–906.

84. Sellebjerg F, Frederiksen JL, Nielsen PM, Olesen J. Double- blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 1998;51:529–534.

85. Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen J. A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis. Neurology 1999;52:1479-1484.

86. Goodkin DE, Kinkel RP, Weinstock-Guttman B, et al. A phase II study of i.v. methylprednisolone in secondary- progressive multiple sclerosis. Neurology 1998;51:239–245.

87. Kumpfel T, Schuman E, Bergh FT, et al. Monthly highdose methylprednisolone pulse therapy in patients with multiple sclerosis: an MRI controlled study with single crossover design. Neurology 2001;56(suppl 3):A76.

88. Zivadinov R, Rudick RA, DeMasi R, et al. Effect of intravenous methylprednisolone on brain atrophy in relapsing- remitting multiple sclerosis. Neurology 56;2001 (suppl 3):A192.

89. Rudick RA, Goodkin DE, Jacobs LD, et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Neurology 1997;49:358¨C363.

90. Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon (-1a for relapsing multiple sclerosis. Ann Neurol 1996;43:79¨C87.

91. Biogen Inc., 1995. Summary Basis of Approval. FDA official document for license of interferon beta-1a (Avonex), Cambridge, MA. On file at:

92. PRISMS Study Group. Randomized double-blind placebo- controlled study of interferon b-1a in relapsingremitting multiple sclerosis. Lancet 1998;352:1498¨C1504.

93. Rudick RA, Fisher E, Lee JC, et al. and the Multiple Sclerosis Collaborative Research Group. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999;53:1698¨C704.

94. Goodkin DE and the North American SPMS Study Group. The North American Study of Interferon beta- 1b in Secondary Progressive Multiple Sclerosis. 52nd Annual Meeting of the American Academy of Neurology (2000), San Diego, CA. Abstract # LBN.002.

95. SPECTRIMS Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001;56:1496¨C1504.

96. Li DKB, Zhao GJ, Paty DW, et al. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology 2001;56:1505¨C1513.

97. Cohen JA, Goodman AD, Heidenreich FR, et al. Results of IMPACT, a phase 3 trial of interferon beta-1a in secondary progressive MS. Neurology 2001;56(suppl 3):A148¨C149.

98. Jacobs LD, Beck RW, Simon JH, et al., and the CHAMPS Study Group. Intramuscular interferon beta- 1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med, 2000;343:898¨C904.

99. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576¨C1582.

100. St¨¹rzebecher S, Maibauer R, Heuner A, Beckmann K, Aufdembrincke B. Pharmacodynamic comparison of single doses of IFN-b1a and IFNb-1b in healthy volunteers. J Interferon Cytokine Res 1999;19:1257¨C64.

101. Borden E, Paulnock D, Spear G, et al. Biological response modification in man: measurement of interferon induced proteins. In: The interferon system: a current review. Baron S, Dianzani F, Stanton JC, Fleischman WR (editors). 1986 Austin: University of Texas, pp:1¨C7.

102. Deisenhammer F, Mayringer I, Harvey J, et al. A comparative study of the relative bioavailability of different interferon beta preparations. Neurology 2000;54:2055¨C60.

103. Alam J, Goelz S, Rioux P, et al. Comparative pharmacokinetics and pharmacodynamics of two recombinant human interferon beta-1a (IFNâ-1a) products administered intramuscularly in healthy male and female volunteers. Pharmaceut Res 1997;14(4):546–549.

104. Salmon P, Le Cotonnee JY, Galazka A, Abduhl-Ahad A, Darragh A. Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers. J Interferon Cytokine Res 1996;16:759–764.

105. Munafo A, Trinchard-Lugan I, Nguyen TXQ, Buraglio M. Comparative pharmicokinetics and pharmicodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol 1998;5:1–7.

106. PRISMS Study Group. PRISMS-4: Long-term efficacy of interferon-b-1a in relapsing MS. Neurology 2001;56:1628–1636.

107. Clanet M, Kappos L, Radue EW, et al. Results of the European interferon beta-1a (Avonex) dose-comparison study. J Neurol 2001;248(supple 2):II/63.

108. Durelli L, Ferrero T, Ghezzi G, et al. The independent comparison of interferon (INCOMIN) Trial: a multicenter randomized trial comparing clinical and MRI efficacy of IFN btea-1a and beta-1b in multiple sclerosis. Neurology 2001;56(suppl 3):A148. 109. Coyle P. Results of comparative efficacy trial using two formulations of interferon beta-1a in RRMS. J Neurol Sci 2001;187(suppl 1):S436.

110. The IFNB Multiple Sclerosis Study Group. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b. Neurology 1996;47:889–894

. 111. Khan QA, Xia Q, Bever CT, et al. Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration. Neurology 1996; 46:1639–1643.

112. Pachner AR. Anticytokine antibodies in beta interferontreated MS patients and the need for testing: plight of the practicing neurologist. Neurology 1997; 49:647–650.

113. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Neurology 1998; 50:1266–1272.

114. Ross C, Clemmesen KM, Svenson M, et al. Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Ann Neurol. 2000;48:706–712.

115. Runkel L, Werner M, Blake R, et al. Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-â (IFN-â). Pharmaceut Res 1998;15:641–649. 116. Hochuli E. Interferon immunogenicity: technical evaluation of interferon-alpha 2a. J Interferon Cytokine Res 1997;17:S15–S21.

117. Wang C, Eufemi M, Turano C, Giartosio A. Influences of the carbohydrate moiety on the stability of glycoproteins. Biochem 1996;35:7299–7307.

118. Teitelbaum D, Aharoni R, Sela M, Arnon R. Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer- 1. Proc Natl Acad Sci USA 1991;88:9528–9532.

119. Teitelbaum D, Milo R, Arnon R, Sela M. Synthetic copolymer-1 inhibits human T-cell lines specific for myelin basic protein. Proc Natl Acad Sci USA 1992;89:137–141.

120. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 2001;56:702–708.

121. Comi G, Filippi M, Wolinsky JS. 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 multiple sclerosis. Ann Neurol 2001;49:290–297.

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

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

124. Johnson KP, Brooks BR, Ford CC, et al. and the Copolymer 1 Multiple Sclerosis Study Group. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Multiple Sclerosis, 2000;6:255–66.

125. Wolinsky JS, Narayana PA, Johnson KP, et al. United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates. Multiple Sclerosis 2001;7:33–41.

126. Khan OA, Tselis AC, Kamholz JA, et al. A prospective, open-label treatment trial to compare the effect of IFN beta-1a (Avonex), IFN beta-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis. Eur J Neurol. 2001;8:141–8.

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

128. Goodkin DE, Plencer S, Palmer-Saxreud J, et al. Cyclophosphamide in chronic progressive multiple sclerosis. Neurology 1985;44:823-827.

129. Likosky WH, Fireman B. Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. J Neurol Neurosurg Psychiatry 1991;54:1055–1060.

130. Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991;337:441–446.

131. 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.

132. Currier RD, Haerer AF, Meydrech EF. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatr 1993;56:1217–1218.

133. Goodkin DE, Rudick RA, VanderBrug Meendorp S, et al. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analysis of serial MRIs. Neurology 1996;47:1153–1157.

134. Witte AS, Cornblath DR, Schatz NJ, Lisak RP. Monitoring azathioprine therapy in myasthenia gravis. Neurology 1986;36:1533–1534.

135. Confavreux C, Saddier P, Grimaud J, et al. Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology 1996;46:1607–1612. 136. Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 1991;338:1051–1055.

137. Palace J, Rothwell P. New treatments and azathioprine in multiple sclerosis. Lancet 1997;350:261. 138. British and Dutch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis. Lancet, 1988;2:179–83.

139. Ellison GW, Myers LW, Mickey MR, et al. A placebocontrolled, randomized, double-masked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in multiple sclerosis. Neurology 1989;39:1018–1026.

140. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344:9–13.

141. Beutler E , Sipe J, Romine JS, et al. Treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 1996;93:1716–1720

. 142. Romine JS, Sipe JC, Koziol JA, Beutler E. A doubleblind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999;111:35–44.

143. Rice GP, Filippi M, Comi G, and the Cladribine Study Group. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology 2000;54:1145–1155.

144. Rudge P, Koester JC, Mertin J, et al. Randomized double blind controlled trial of cyclosporin in multiple sclerosis. J Neurol Neurosurg Psychiatry 1989;52:559–565.

145. The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded placebo-controlled trial. Ann Neurol 1990;27:591–605.

146. DeCastro S, Cartoni D, Millefiorni E, et al. Noninvasive assessment of mitoxantrone cardiotoxicity in relapsing remitting multiple sclerosis. J Clin Pharmacol 1995;35:627–632.

147. Chaplain G, Milan C, Sigro C, et al. Increased risk of acute leukemia after chemotherapy for breast cancer: a population-based study. J Clin Oncol 2000;18:2836–2842.

148. Bastianello S, Pozzilli C, D’Andrea F, et al. A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year. Can J Neurol Sci 1994;21: 266–270.

149. Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomized multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatr 1997;62:112–118.

150. Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing- remitting multiple sclerosis:24-month clinical and MRI outcome. J Neurol 1997;244:153–159.

151. Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Austrian immunoglobulin in Multiple Sclerosis Study Group. Lancet 1997;349:589–593.

152. Sorensen PS, Wanscher B, Schreiber K, et al. A double- blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: preliminary results. Multiple Sclerosis 1997;3:145-–148.

153. Achiron A, Gabbay U, Gilad R, et al. Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 1998;50:398–402.

154. Gadoth N, Melamed E, Miller A, et al. Intravenous immunoglobulin treatment in multiple sclerosis Neurology 1999;52:214–5.

155. Gordon PA, Carroll DJ, Etches WS, et al. A doubleblind controlled pilot study of plasma exchange versus sham pharesis in chronic progressive multiple sclerosis. Can J Neurol Sci 1985;12:39–44.

156. Khatri BO, McQuillen MP, Harrington GJ, et al. Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 1985;35:312–319.

157. 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.

158. Weinshenker BG, O’Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999;46:878–86.

159. Noseworthy JH, O’Brien P, Erickson BJ, et al. The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis. Neurology 1998;51:1342–52.

160. Shekelle PG. Are Appropriateness Criteria Ready for Use in Clinical Practice? New Engl J Med 2001; 344:677–678.

161. Konkle-Parker DJ. Evidence-based practice: A motivational intervention to improve adherence to treatment of chronic disease. J Am Acad Nurse Practicioners 2001;13:61–68.