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Treatment Optimization in MS: Canadian MS Working Group Updated Recommendations

  • Mark S. Freedman (a1), Daniel Selchen (a2), Douglas L. Arnold (a3), Alexandre Prat (a4), Brenda Banwell (a5), Michael Yeung (a6), David Morgenthau (a2) and Yves Lapierre (a3)...


The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.


Le Canadian Multiple Sclerosis Working Group (CMSWG) a élaboré des recommandations pratiques en 2004 pour aider les cliniciens à optimiser l'utilisation des traitements modificateurs de la maladie chez les patients atteints de sclérose en plaques récurrente-rémittente (SPRR). Le CMSWG s'est réuni pour réviser comment est évaluée l'activité de la maladie, pour actualiser l'évaluation d'une réponse sous-optimale et pour suggérer un plan de changement ou d'intensification du traitement. Des critères pratiques pour évaluer les épisodes de récurrence ainsi que la progression telle qu'évaluée par l'Expanded Disability Status Scale (EDSS) et l'IRM ont été développés pour classifier le niveau de préoccupation clinique comme étant faible, moyen ou élevé. Le groupe a conclu qu'un changement de traitement peut être envisagé chez tout patient atteint de SPRR s'il existe de vives préoccupations dans l'un ou l'autre domaine, soit les épisodes de récurrence, la progression ou l'IRM, un niveau de préoccupation modéré dans deux domaines, ou un faible niveau de préoccupation dans les trois domaines. Ces recommandations pour l'évaluation de la réponse au traitement devraient aider les cliniciens à faire des choix plus rationnels dans la gestion des patients atteints de SPRR.

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Corresponding author

University of Ottawa, Multiple Sclerosis Research Unit, The Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada. Email:


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1. Freedman, MS, Patry, DG, Grand’Maison, F, et al. Treatment optimization in multiple sclerosis. Can J Neurol Sci. 2004;31: 157–68.
2. Jacobs, LD, Beck, RW, Simon, JHS, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898904.
3. Comi, G, Filippi, M, Barkhof, F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576–82.
4. Kappos, L, Polman, CH, Freedman, MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242–9.
5. Comi, G, Martinelli, V, Rodegher, M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1503–11.
6. Comi, G, De Stefano, N, Freedman, MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012;11:3341.
7. Kinkel, RP, Dontchew, M, Kollman, C, et al. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance. Arch Neurol. 2012;69:183–90.
8. Kappos, L, Freedman, MS, Polman, CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8: 987–97.
9. Polman, CH, Reingold, SC, Edan, G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58:840–6.
10. Polman, CH, Reingold, SC, Banwell, B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292302.
11. Potagas, C, Giogkaraki, E, Koutsis, G, et al. Cognitive impairment in different MS subtypes and clinically isolated syndromes. J Neurol Sci. 2008;267:100–6.
12. Feuillet, L, Reuter, F, Audoin, B, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler. 2007;13:124–7.
13. Glanz, BI, Holland, CM, Gauthier, SA, et al. Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis. Mult Scler. 2007;13:1004–10.
14. Zipoli, V, Goretti, B, Hakiki, B, et al. Cognitive impairment predicts conversion to multiple sclerosis in clinically isolated syndromes. Mult Scler. 2010;16:62–7.
15. Amato, MP, Zipoli, V, Portaccio, E. Multiple sclerosis related cognitive changes: a review of cross-sectional and longitudinal studies. J Neurol Sci. 2006;245:41–6.
16. Smestada, C, Sandvikb, L, Landrøc, NI, Celius, EG. Cognitive impairment after three decades of multiple sclerosis. Eur J Neurol. 2010;17:499505.
17. Polman, CH, O’Connor, PW, Havrdova, E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899910.
18. Rudick, RA, Stuart, WH, Calabresi, PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–23.
19. Kappos, L, Bates, D, Edan, G, et al. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol. 2011;10:745–58.
20. Kappos, L, Radue, E-W, O’Connor, P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387401.
21. Cohen, JA, Barkhof, F, Comi, G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.
22. Bashir, K, Buchwald, L, Coyle, PK, et al. MS patient management: optimizing the benefits of immunomodulatory therapy. Int J MS Care. 2002;(Suppl):17.
23. 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;50:121–7.
24. Lublin, FD, Baier, M, Cutter, G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61: 1528–32.
25. Hirst, C, Ingram, G, Pearson, O, Pickersgill, T, Scolding, N, Robertson, N. Contribution of relapses to disability in multiple sclerosis. J Neurol. 2008;255:280–7.
26. Tremlett, H, Yousefi, M, Devonshire, V, Rieckmann, P, Zhao, Y, UBC Neurologists. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73:1616–23.
27. Confavreux, C, Vukusic, S, Moreau, T, Adeline, P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343:1430–8.
28. Scalfari, A, Neuhaus, A, Degenhardt, A, et al. The natural history of multiple sclerosis, a geographically based study 10: relapses and long-term disability. Brain. 2010;133:1914–29.
29. Freedman, MS. Improving long-term follow-up studies of immunomodulatory therapies. Neurology. 2011;76(1 Suppl 1): S358.
30. Thygesen, P. Evaluation of drug treatment of disseminated sclerosis. Ugeskr Laeger. 1965;127:1448–50.
31. Inusah, S, Sormani, MP, Cofield, SS, et al. Assessing changes in relapse rates in multiple sclerosis. Mult Scler. 2010;16:1414–21.
32. 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;43:655–61.
33. Nicholas, R, Straube, S, Schmidli, H, Schneider, S, Friede, T. Trends in annualized relapse rates in relapsing-remitting multiple sclerosis and consequences for clinical trial design. Mult Scler. 2011;17:1211–7.
34. Tremlett, H, Zhao, Y, Joseph, J, Devonshire, V, UBCMS Clinic Neurologists. Relapses in multiple sclerosis are age and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79:1368–74.
35. Binquet, C, Quantin, C, Le Teuff, G, Pagliano, JF, Abrahamowicz, M, Moreau, T. The prognostic value of initial relapses on the evolution of disability in patients with relapsing-remitting multiple sclerosis. Neuroepidemiology. 2006;27:4554.
36. Bosca, I, Coret, F, Valero, C, et al. Effect of relapses over early progression of disability in multiple sclerosis patients treated with beta-interferon. Mult Scler. 2008;14:636–9.
37. Sormani, MP, Rio, J, Tintore, M, et al. Scoring treatment response in patients with relapsing multiple sclerosis Mult Scler. 2012; published September 25, 2012.
38. Bergamaschi, R, Berzuini, C, Romani, A, Cosi, V. Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis. J Neurol Sci. 2001;189:1321.
39. Leone, MA, Bonissoni, S, Collimedaglia, L, et al. Factors predicting incomplete recovery from relapses in multiple sclerosis: a prospective study. Mult Scler. 2008;14:485–93.
40. Runmarker, B, Andersen, O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain. 1993;116:117–34.
41. Mowry, EM, Pesic, M, Grimes, B, Deen, S, Bacchetti, P, Waubant, E. Demyelinating events in early multiple sclerosis have inherent severity and recovery. Neurology. 2009;72:602–8.
42. Langer-Gould, A, Popat, RA, Huang, SM, et al. Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review. Arch Neurol. 2006;63:1686–91.
43. Vercellino, M, Romagnolo, A, Mattioda, A, et al. Multiple sclerosis relapses: a multivariable analysis of residual disability determinants. Acta Neurol Scand. 2009;119:126–30.
44. Scott, TF, Schramke, CJ. Poor recovery after the first two attacks of multiple sclerosis is associated with poor outcome five years later. J Neurol Sci. 2010;292:52–6.
45. Havrdova, E, Galetta, S, Hutchinson, M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8:254–60.
46. Khatri, B, Barkhof, F, Comi, G, et al. Fingolimod treatment increases the proportion of patients who are free from disease activity in multiple sclerosis compared to IFN-b1a: results from a phase 3, active-controlled study (TRANSFORMS). Presented at the 64th American Academy of Neurology annual meeting, New Orleans LA, April 21-28, 2012; abstract PD5.006.
47. Freedman, M, O’Connor, P, Wolinsky, J, et al. Teriflunomide increases the proportion of patients free from disease activity in the TEMSO phase III study. Presented at the 64th American Academy of Neurology annual meeting, New Orleans LA, April 21-28, 2012; abstract PD5.007.
48. Giovannoni, G, Gold, R, Kappos, L, et al. BG-12 increases the proportion of patients free of clinical and radiologic disease activity in relapsing-remitting multiple sclerosis: findings from the DEFINE study. Presented at the 64th American Academy of Neurology annual meeting, New Orleans LA, April 21-28, 2012; abstract PD5.005.
49. Kurtzke, JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33: 1444–52.
50. Fischer, JS, Rudick, RA, Cutter, GR, Reingold, SC. The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcomes assessment. Mult Scler. 1999; 5:244–50.
51. Kaufman, M, Moyer, D, Norton, J. The significant change for the Timed 25-foot Walk in the multiple sclerosis functional composite. Mult Scler. 2000;6:286–90.
52. Schwid, SR, Goodman, AD, McDermott, MP, Bever, CF, Cook, SD. Quantitative functional measures in MS: what is a reliable change? Neurology. 2002;58:1294–6.
53. Gijbels, D, Eijnde, BO, Feys, P. Comparison of the 2- and 6-minute walk test in multiple sclerosis. Mult Scler. 2011;17:1269–72.
54. Bosma, LVAE, Kragt, JJ, Knol, DL, Polman, CH, Uitdehaag, BM. Clinical scales in progressive MS: predicting long-term disability. Mult Scler. 2012;18:345–50.
55. Goodman, AD, Brown, TR, Edwards, KR, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68:494502.
56. Hobart, JC, Riazi, A, Lamping, DL, Fitzpatrick, R, Thompson, AJ. Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology. 2003;60:31–6.
57. International Federation of Multiple Sclerosis Societies. Symposium on a minimal record of disability for multiple sclerosis. Vancouver, Canada, September 11, 12, 1983. Acta Neurol Scand Suppl. 1984;101:1217.
58. Schwartz, CE, Vollmer, T, Lee, H. Reliability and validity of two self-report measures of impairment and disability for MS. North American Research Consortium on Multiple Sclerosis Outcomes Study Group. Neurology. 1999;52:6370.
59. Invernizzi, P, Bertolasi, L, Bianchi, MR, Turatti, M, Gajofatto, A, Benedetti, MD. Prognostic value of multimodal evoked potentials in multiple sclerosis: the EP score. J Neurol. 2011; 258:1933–9.
60. Teunissen, CE, Khalil, M. Neurofilaments as biomarkers in multiple sclerosis. Mult Scler. 2012;18:552–6.
61. Bergamaschi, R, Quaglini, S, Tavazzi, E, et al. Immunomodulatory therapies delay disease progression in multiple sclerosis. Mult Scler. 2012; epublished May 31, 2012.
62. La Mantia, L, Munari, LM, Lovati, R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010 May 12;(5): CD004678.
63. Shirani, A, Zhao, Y, Karim, ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308:247–56.
64. Goodin, DS, Ebers, GC, Cutter, G, et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study. BMJ Open. 2012;2: e001972.
65. Rio, J, Nos, C, Tintore, M, et al. Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon β: implications for clinical trials. Ann Neurol. 2002;52:400–6.
66. Rio, J, Comabella, M, Montalban, X. Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol. 2009;5:553–60.
67. Dayal, AS, Jensen, MA, Lledo, A, Arnason, BG. Interferon-gamma-secreting cells in multiple sclerosis patients treated with interferon beta-1b. Neurology. 1995;45:2173–7.
68. Rudick, RA, Lee, J-C, Cutter, GR, et al. Disability progression in a clinical trial of relapsing-remitting multiple sclerosis. Arch Neurol. 2010;67:1329–35.
69. Ebers, GC, Heigenhauser, L, Daumer, M, Lederer, C, Noseworthy, JH. Disability as an outcome in MS clinical trials. Neurology. 2008;71:624–31.
70. Rudick, RA, Lee, JC, Simon, J, Ransohoff, RM, Fisher, E. Defining interferon beta response status in multiple sclerosis patients. Ann Neurol. 2004;56:548–55.
71. Pozzilli, C, Prosperini, L, Sbardella, E, De Giglio, L, Onesti, E, Tomassini, V. Post-marketing survey on clinical response to interferon beta in relapsing multiple sclerosis: the Roman experience. Neurol Sci. 2005;26 Suppl 4:S174-8.
72. Tomassini, V, Paolillo, A, Russo, P, et al. Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis. J Neurol. 2006;253:287–93.
73. Prosperini, L, Gallo, V, Petsas, N, Borriello, G, Pozzilli, C. One-year MRI scan predicts clinical response to interferon beta in multiple sclerosis. Eur J Neurol. 2009;16:1202–9.
74. Rio, J, Rovira, A, Tintore, M, et al. Relationship between MRI lesion activity and response to IFN-beta in relapsing-remitting multiple sclerosis patients. Mult Scler. 2008;14:479–84.
75. Riddell, CA, Zhao, Y, Li, DK, et al. Evaluation of safety monitoring guidelines based on MRI lesion activity in multiple sclerosis. Neurology. 2011;77:2089–96.
76. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498–504.
77. Simon, JH, Li, D, Traboulsee, A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27:455–61.
78. Mikol, DD, Barkhof, F, Chang, P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7:903–14.
79. Gauthier, SA, Berger, AM, Liptak, Z, et al. Rate of brain atrophy in benign vs early multiple sclerosis. Arch Neurol. 2009;66:234–7.
80. Lukas, C, Minneboo, A, de Groot, V, et al. Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81:1351–6.
81. Prakash, RS, Snook, EM, Lewis, JM, Motl, RW, Kramer, AF. Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis. Mult Scler. 2008;14:1250–61.
82. Benedict, RHB, Zivadinov, R. Risk factors for and management of cognitive dysfunction in multiple sclerosis. Nat Rev Neurol. 2011;7:332–42.
83. Kalmar, JH, Gaudino, EA, Moore, NB, Halper, J, Deluca, J. The relationship between cognitive deficits and everyday functional activities in multiple sclerosis. Neuropsychology. 2008;22:442–9.
84. 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;41:692–6.
85. Benedict, RH, Wahlig, E, Bakshi, R, et al. Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change. J Neurol Sci. 2005;231:2934.
86. Smith, A. Symbol Digit Modalities Test: Manual. Western Psychological Services, Los Angeles CA, 1982.
87. Benedict, RHB, Duquin, JA, Jurgensen, S, et al. Repeated assessment of neuropsychological deficits in multiple sclerosis using the Symbol Digit Modalities Test and the MS Neuropsychological Screening Questionnaire. Mult Scler. 2008;14:940–6.
88. Morrow, SA, O’Connor, PW, Polman, CH, et al. Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumabtreated MS patients over 48 weeks. Mult Scler. 2010;16:1385–92.
89. Morrow, SA, Drake, A, Zivadinov, R, Munschauer, F, Weinstock-Guttman, B, Benedict, RH. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol. 2010;24:1131–45.
90. Heesen, C, Schulz, KH, Fiehler, J, et al. Correlates of cognitive dysfunction in multiple sclerosis. Brain Behav Immun. 2010;24:1148–55.
91. Carone, DA, Benedict, RHB, Munschauer, FE, Fishman, I, Weinstock-Guttman, B. Interpreting patient/informant discrepancies of reported cognitive symptoms in MS. J Int Neuropsychol Soc. 2005;11:574–83.
92. Deloire, MSA, Bonnet, MC, Salort, E, et al. How to detect cognitive dysfunction at early stages of multiple sclerosis? Mult Scler. 2006;12:445–52.
93. Arnett, PA, Higginson, CI, Voss, WD, et al. Depressed mood in multiple sclerosis: Relationship to capacity-demanding memory and attentional functioning. Neuropsychology. 1999;13:434–46.
94. Benedict, RHB, Fishman, I, McClellan, MM, Bakshi, R, Weinstock-Guttman, B. Validity of the Beck Depression Inventory - Fast Screen in multiple sclerosis. Mult Scler. 2003;9:393–6.
95. Fatigue guidelines development panel of the multiple sclerosis council for clinical practice guidelines. Fatigue and multiple sclerosis. Evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans of America, 1998.
96. Ehde, DM, Kraft, GH, Chwastiak, L, et al. Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis. Gen Hosp Psychiatry. 2008;30:40–8.
97. Benedetti, F, Campori, E, Colombo, C, Smeraldi, E. Fluvoxamine treatment of major depression associated with multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2004;16:364–6.
98. Mohr, DC, Boudewyn, AC, Goodkin, DE, Bostrom, A, Epstein, L. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol. 2001;69:942–9.
99. Barak, Y, Ur, E, Achiron, A. Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. J Neuropsychiatry Clin Neurosci. 1999;11:271–3.
100. Dean, G. A double-blind trial with an antidepressant drug, imipramine, in multiple sclerosis. S Afr Med J. 1969;43:86–7.
101. Schiffer, RB, Wineman, NM. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry. 1990;147:1493–7.
102. Patti, F, Amato, MP, Bastianello, S, et al. Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis. Mult Scler. 2010;16: 6877.
103. Schwid, SR, Goodman, AD, Weinstein, A, McDermott, MP, Johnson, KP; for the Copaxone Study Group. Cognitive function in relapsing multiple sclerosis: Minimal changes in a 10-year clinical trial. J Neurol Sci. 2007;255:5763.
104. Fischer, JS, Priore, RL, Jacobs, LD, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol. 2000;48:885–92.
105. Weinstock-Guttman, B, Galetta, SL, Giovannoni, G, et al. Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS. J Neurol. 2012; 259: 898905.
106. Fox, EJ, Sullivan, HC, Gazda, SK, et al. A single-arm, open-label study of alemtuzumab in treatment-refractory patients with multiple sclerosis. Eur J Neurol. 2012;19:307–11.
107. He, D, Zhou, H, Guo, D, Hao, Z, Wu, B. Pharmacologic treatment for memory disorder in multiple sclerosis. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD008876.
108. Morrow, SA, Jurgensen, S, Forrestal, F, Munchauer, FE, Benedict, RH. Effects of acute relapses on neuropsychological status in multiple sclerosis patients. J Neurol. 2011;258:1603–8.
109. Jungedal, R, Lundkvist, M, Engdahl, E, et al. Prevalence of anti-drug antibodies against interferon beta has decreased since routine analysis of neutralizing antibodies became clinical practice. Mult Scler. 2012;18:1775–81.
110. Hegen, H, Schleiser, M, Gneiss, C, et al. Persistency of neutralizing antibodies depends on titer and interferon-beta preparation. Mult Scler. 2012;18:610–5.
111. Boz, C, Oger, J, Gibbs, E, Grossberg, SE, Neurologists of the UBC MS Clinic. Reduced effectiveness of long-term interferon-beta treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study. Mult Scler. 2007;13:1127–37.
112. Hartung, HP, Freedman, MS, Polman, CH, et al. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome. Neurology. 2011;77:835–43.
113. Farrell, RA, Espasandin, M, Lakdawala, N, Creeke, PI, Worthington, V, Giovannoni, G. Incorporation of an interferon-β neutralizing antibody assay into routine clinical practice. Mult Scler. 2011;17:1333–40.
114. Calabresi, PA, Giovannoni, G, Confavreux, C, et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology. 2007;69:1391–403.
115. Deisenhammer, F. Neutralizing antibodies to interferon-beta and other immunological treatments for multiple sclerosis: prevalence and impact on outcomes. CNS Drugs. 2009;23:379–96.
116. Teitelbaum, D, Brenner, T, Abramsky, O, Aharoni, R, Sela, M, Arnon, R. Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy. Mult Scler. 2003;9:592–9.
117. Acheson, ED, Bachrach, CA, Wright, FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr Scand Suppl. 1960;35:132–47.
118. Munger, KL, Levin, LI, Hollis, BW, Howard, NS, Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832–8.
119. Kragt, J, van Amerongen, B, Killestein, J, et al. Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult Scler. 2009;15:915.
120. Bhalla, AK, Amento, EP, Clemens, TL, Holick, MF, Krane, SM. Specific high affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983;57:1308–10.
121. Vedman, CM, Cantorna, MT, DeLuca, HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys. 2000;374:334–8.
122. Chen, S, Sims, GP, Chen, XX, Gu, YY, Chen, S, Lipsky, PE. Modulatory effect of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179:1634–47.
123. Rucker, D, Allan, JA, Fick, GH, Hanley, DA. Vitamin D insufficiency in a population of healthy western Canadians. Can Med Assoc J. 2002;166:1517–24.
124. Webb, AR, Kline, L, Holick, MF. Influence of season and latitude on the cutaneous synthesis of vitamin-D3 - exposure to winter sunlight in Boston and Edmonton will not promote vitamin-D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67:373–8.
125. Tremlett, H, van der Mei, IA, Pittas, F, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31:271–9.
126. D’hooghe, M, Haentjens, P, Nagels, G, Garmyn, M, De Keyser, J. Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis. Mult Scler. 2012;18:451–9.
127. Smolders, J, Menheere, P, Kessels, A, Damoiseaux, J, Hupperts, R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008;14:1220–4.
128. Simpson, S, Taylor, B, Blizzard, L, et al. Higher levels of serum 25-hydroxyvitamin D3 are associated with a reduced risk of relapse in multiple sclerosis. Ann Neurol. 2010;68:193203.
129. Mowry, EM, Waubant, E, McCulloch, CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72:234–40.
130. Soilu-Hanninen, M, Aivo, J, Lindstrom, BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:565–71.
131. Stein, MS, Liu, Y, Gray, OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77:1611–8.
132. Mosayebi, G, Ghazavi, A, Ghasami, K, Jand, Y, Kokhaei, P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest. 2011;40:627–39.
133. Lucas, RM, Ponsonby, AL, Dear, K, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76:540–8.
134. Hart, PH. Vitamin D supplementation, moderate sun exposure, and control of immune diseases. Discov Med. 2012;13:397404.
135. Smolders, J, Hupperts, R, Barkhof, F, et al. Efficacy of vitamin D(3) as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: a Phase II, multicenter, double-blind, randomized, placebo-controlled trial. J Neurol Sci. 2011;311:44–9.
136. Dorr, J, Ohlraun, S, Skarabis, H, Paul, F. Efficacy of vitamin D supplementation in multiple sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial. Trials. 2012 Feb 8;13:15.
137. Burton, JM, Kimball, S, Vieth, R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010;74:1852–9.
138. Bischoff-Ferrari, HA, Giovannucci, E, Willett, WC, Dietrich, T, Dawson-Hughes, B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:1828.
139. O’Connor, P, Filippi, M, Arnason, B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8:889–97.
140. Kister, I, Chamot, E, Bacon, JH, et al. Rapid disease course in African Americans with multiple sclerosis. Neurology. 2010;75:217–23.
141. Naismith, RT, Trinkaus, K, Cross, AH. Phenotype and prognosis in African-Americans with multiple sclerosis: a retrospective chart review. Mult Scler. 2006;12:775–81.
142. Klineova, S, Nicholas, J, Walker, A. Response to disease modifying therapies in African Americans with multiple sclerosis. Ethn Dis. 2012;22:221–5.
143. Cree, BA, Al-Sabbagh, A, Bennett, R, Goodin, D. Response to interferon beta-1a treatment in African American multiple sclerosis patients. Arch Neurol. 2005;62:1681–3.
144. Cree, BA, Stuart, WH, Tornatore, CS, et al. Efficacy of natalizumab therapy in patients of African descent with relapsing multiple sclerosis: analysis of AFFIRM and SENTINEL data. Arch Neurol. 2011;68:464–8.
145. O’Connor, P, Wolinsky, JS, Confavreux, C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293–303.
146. Gold, R, Kappos, L, Arnold, DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–107.
147. Comi, G, Jeffery, D, Kappos, L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366:1000–9.
148. Putzki, N, Yaldizli, O, Buhler, R, Schwegler, G, Curtius, D, Tettenborn, B. Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity: results from a multicenter study in Switzerland. Eur Neurol. 2010;63:101–6.
149. Prosperini, L, Gianni, C, Leonardi, L, et al. Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. Mult Scler. 2012;18:6471.
150. Castillo-Trivino, T, Mowry, EM, Gajofatto, A, et al. Switching multiple sclerosis patients with breakthrough disease to second-line therapy. PLoS One. 2011;6:e16664.
151. Krysko, KM, O’Connor, PW. The Toronto observational study of natalizumab in multiple sclerosis. Can J Neurol Sci. 2011;38:422–8.
152. Sangalli, F, Moiola, L, Bucello, S, et al. Efficacy and tolerability of natalizumab in relapsing-remitting multiple sclerosis patients: a post-marketing observational study. Neurol Sci. 2011;31 Suppl 3:299302.
153. Sorensen, PS, Bertolotto, A, Edan, G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18:143–52.
154. Khatri, B, Barkhof, F, Comi, G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol. 2011;10:520–9.
155. Killestein, J, Vennegoor, A, Strijbis, EM, et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol. 2010;68:392–5.
156. Miravalle, A, Jensen, R, Kinkel, RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. 2011;68:186–91.
157. West, TW, Cree, BA. Natalizumab dosage suspension: are we helping or hurting? Ann Neurol. 2010;68:395–9.
158. Schaaf, SM, Pitt, D, Racke, MK. What happens when natalizumab therapy is stopped? Expert Rev Neurother. 2011;11:1247–50.
159. Siger, M, Durko, A, Nicpan, A, Konarska, M, Grudziecka, M, Selmaj, K. Discontinuation of interferon beta therapy in multiple sclerosis patients with high pre-treatment disease activity leads to prompt return to previous disease activity. J Neurol Sci. 2011;303:50–2.
160. Lonergan, R, Kinsella, K, Duggan, M, Jordan, S, Hutchinson, M, Tubridy, N. Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started? Mult Scler. 2009;15:1528–31.
161. O’Rourke, KE, Hutchinson, M. Stopping beta-interferon therapy in multiple sclerosis: an analysis of stopping patterns. Mult Scler. 2005;11:4650.
162. Cohen, JA, Imrey, PB, Calabresi, PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology. 2009;72: 535–41.
163. Sorensen, PS, Mellgren, SI, Svenningsson, A, et al. NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol. 2009;8:519–29.
164. Ravnborg, M, Sorensen, PS, Andersson, M, et al. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial. Lancet Neurol. 2010;9:672–80.
165. Havrdova, E, Zivadinov, R, Krasensky, J, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler. 2009;15:965–76.
166. Wang, J, Xiao, Y, Luo, M, Luo, H. Statins for multiple sclerosis. Cochrane Database Syst Rev. 2011 Dec 7;(12):CD008386.
167. Metz, LM, Li, D, Traboulsee, A, et al. Glatiramer acetate in combination with minocycline in patients with relapsing-remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler. 2009;15:1183–94.
168. Lindsey, J, Scott, T, Lynch, S, et al. The CombiRx trial of combined therapy with interferon and glatiramer cetate in relapsing remitting MS: Design and baseline characteristics. Mult Scler. Relat Disord 2012;1:81–6.
169. Goodman, AD, Rossman, H, Bar-Or, A, et al. GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology. 2009;72:806–12.
170. Naismith, RT, Piccio, L, Lyons, JA, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology. 2010;74:1860–7.
171. Freedman, MS, Wolinsky, JS, Wamil, B, et al. Teriflunomide added to interferon-β in relapsing multiple sclerosis: A randomized phase II trial. Neurology. 2012;78:1877–85.
172. Coles, AJ, Twyman, CL, Arnold, DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829–39.
173. Kappos, L, Li, D, Calabresi, PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378:1779–87.
174. Banwell, B, Kennedy, J, Sadovnick, D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology. 2009;72:232–9.
175. Pohl, D, Hennemuth, I, von Kries, R, Hanefeld, F. Paediatric multiple sclerosis and acute disseminated encephalomyelitis in Germany: results of a nationwide survey. Eur J Pediatr. 2007;166:405–12.
176. Langer-Gould, A, Zhang, JL, Chung, J, Yeung, Y, Waubant, E, Yao, J. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology. 2011;77:1143–8.
177. Banwell, B, Ghezzi, A, Bar-Or, A, Mikaeloff, Y, Tardieu, M. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 2007;6:887902.
178. Chitnis, T, Tenembaum, S, Banwell, B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18:116–27.
179. Ghezzi, A, Amato, MP, Capobianco, M, et al. Disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study. Mult Scler. 2005;11:420–4.
180. Tenembaum, SN, Segura, MJ. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology. 2006;67:511–3.
181. Banwell, B, Reder, AT, Krupp, L, et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology. 2006;66:472–6.
182. Kornek, B, Bernert, G, Balassy, C, Geldner, J, Prayer, D, Feucht, M. Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Neuropediatrics. 2003;34:120–6.
183. Banwell, B, Bar-Or, A, Giovannoni, G, Dale, RC, Tardieu, M. Therapies for multiple sclerosis: considerations in the pediatric patient. Nat Rev Neurol. 2011;7:109–22.
184. Yeh, EA, Waubant, E, Krupp, LB, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol. 2011;68:437–44.


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