Hostname: page-component-7f64f4797f-p4db6 Total loading time: 0 Render date: 2025-11-04T00:12:44.855Z Has data issue: false hasContentIssue false
  • English
  • Français

Treatment Optimization in MS: Canadian MS Working Group Updated Recommendations

Published online by Cambridge University Press:  23 September 2014

Mark S. Freedman ,
Daniel Selchen ,
Douglas L. Arnold ,
Alexandre Prat ,
Brenda Banwell ,
Michael Yeung ,
David Morgenthau  and
Yves Lapierre
Mark S. Freedman*
Affiliation:
Ottawa Hospital Research Institute, University of Ottawa, Ottawa
Daniel Selchen
Affiliation:
St. Michael's Hospital, Toronto
Douglas L. Arnold
Affiliation:
Montreal Neurological Institute and Hospital
Alexandre Prat
Affiliation:
Centre hospitalier de l'Université de Montréal, Montreal, Quebec
Brenda Banwell
Affiliation:
The Hospital for Sick Children, Toronto, Ontario
Michael Yeung
Affiliation:
Foothills Medical Centre, Calgary, Alberta, Canada
David Morgenthau
Affiliation:
St. Michael's Hospital, Toronto
Yves Lapierre
Affiliation:
Montreal Neurological Institute and Hospital
*
University of Ottawa, Multiple Sclerosis Research Unit, The Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada. Email: mfreedman@toh.on.ca
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.

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.

Résumé:

Résumé:

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.

Information

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 40 , Issue 3 , May 2013 , pp. 307 - 323
Copyright
Copyright © The Canadian Journal of Neurological 2013

References

1. Freedman, MS, Patry, DG, Grand’Maison, F, et al. Treatment optimization in multiple sclerosis. Can J Neurol Sci. 2004;31: 157–68.CrossRefGoogle ScholarPubMed
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;343:898–904.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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;11:33–41.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
10. Polman, CH, Reingold, SC, Banwell, B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
16. Smestada, C, Sandvikb, L, Landrøc, NI, Celius, EG. Cognitive impairment after three decades of multiple sclerosis. Eur J Neurol. 2010;17:499–505.CrossRefGoogle Scholar
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;354:899–910.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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;362:387–401.Google Scholar
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.Google Scholar
22. Bashir, K, Buchwald, L, Coyle, PK, et al. MS patient management: optimizing the benefits of immunomodulatory therapy. Int J MS Care. 2002;(Suppl):1–7.Google Scholar
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.Google Scholar
24. Lublin, FD, Baier, M, Cutter, G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61: 1528–32.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
29. Freedman, MS. Improving long-term follow-up studies of immunomodulatory therapies. Neurology. 2011;76(1 Suppl 1): S35–8.Google ScholarPubMed
30. Thygesen, P. Evaluation of drug treatment of disseminated sclerosis. Ugeskr Laeger. 1965;127:1448–50.Google Scholar
31. Inusah, S, Sormani, MP, Cofield, SS, et al. Assessing changes in relapse rates in multiple sclerosis. Mult Scler. 2010;16:1414–21.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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;27:45–54.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
38. Bergamaschi, R, Berzuini, C, Romani, A, Cosi, V. Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis. J Neurol Sci. 2001;189:13–21.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
49. Kurtzke, JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33: 1444–52.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
55. Goodman, AD, Brown, TR, Edwards, KR, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68:494–502.CrossRefGoogle ScholarPubMed
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.Google Scholar
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;101:1–217.Google Scholar
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;52:63–70.Google Scholar
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.Google Scholar
60. Teunissen, CE, Khalil, M. Neurofilaments as biomarkers in multiple sclerosis. Mult Scler. 2012;18:552–6.Google Scholar
61. Bergamaschi, R, Quaglini, S, Tavazzi, E, et al. Immunomodulatory therapies delay disease progression in multiple sclerosis. Mult Scler. 2012; epublished May 31, 2012.Google ScholarPubMed
62. La Mantia, L, Munari, LM, Lovati, R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010 May 12;(5): CD004678.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
66. Rio, J, Comabella, M, Montalban, X. Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol. 2009;5:553–60.Google Scholar
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.Google Scholar
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.Google Scholar
69. Ebers, GC, Heigenhauser, L, Daumer, M, Lederer, C, Noseworthy, JH. Disability as an outcome in MS clinical trials. Neurology. 2008;71:624–31.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
82. Benedict, RHB, Zivadinov, R. Risk factors for and management of cognitive dysfunction in multiple sclerosis. Nat Rev Neurol. 2011;7:332–42.Google Scholar
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.Google Scholar
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.Google Scholar
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;231:29–34.Google Scholar
86. Smith, A. Symbol Digit Modalities Test: Manual. Western Psychological Services, Los Angeles CA, 1982.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
90. Heesen, C, Schulz, KH, Fiehler, J, et al. Correlates of cognitive dysfunction in multiple sclerosis. Brain Behav Immun. 2010;24:1148–55.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
100. Dean, G. A double-blind trial with an antidepressant drug, imipramine, in multiple sclerosis. S Afr Med J. 1969;43:86–7.Google Scholar
101. Schiffer, RB, Wineman, NM. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry. 1990;147:1493–7.Google Scholar
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: 68–77.CrossRefGoogle ScholarPubMed
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;255:57–63.Google Scholar
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.Google Scholar
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: 898–905.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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;15:9–15.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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;68:193–203.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
134. Hart, PH. Vitamin D supplementation, moderate sun exposure, and control of immune diseases. Discov Med. 2012;13:397–404.Google ScholarPubMed
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.Google Scholar
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.Google Scholar
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.Google Scholar
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;84:18–28.Google Scholar
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.Google Scholar
140. Kister, I, Chamot, E, Bacon, JH, et al. Rapid disease course in African Americans with multiple sclerosis. Neurology. 2010;75:217–23.Google Scholar
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.Google Scholar
142. Klineova, S, Nicholas, J, Walker, A. Response to disease modifying therapies in African Americans with multiple sclerosis. Ethn Dis. 2012;22:221–5.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
149. Prosperini, L, Gianni, C, Leonardi, L, et al. Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. Mult Scler. 2012;18:64–71.Google Scholar
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.Google Scholar
151. Krysko, KM, O’Connor, PW. The Toronto observational study of natalizumab in multiple sclerosis. Can J Neurol Sci. 2011;38:422–8.Google Scholar
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 3:299–302.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
155. Killestein, J, Vennegoor, A, Strijbis, EM, et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol. 2010;68:392–5.Google Scholar
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.CrossRefGoogle ScholarPubMed
157. West, TW, Cree, BA. Natalizumab dosage suspension: are we helping or hurting? Ann Neurol. 2010;68:395–9.Google Scholar
158. Schaaf, SM, Pitt, D, Racke, MK. What happens when natalizumab therapy is stopped? Expert Rev Neurother. 2011;11:1247–50.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
161. O’Rourke, KE, Hutchinson, M. Stopping beta-interferon therapy in multiple sclerosis: an analysis of stopping patterns. Mult Scler. 2005;11:46–50.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google Scholar
166. Wang, J, Xiao, Y, Luo, M, Luo, H. Statins for multiple sclerosis. Cochrane Database Syst Rev. 2011 Dec 7;(12):CD008386.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
174. Banwell, B, Kennedy, J, Sadovnick, D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology. 2009;72:232–9.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
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;6:887–902.Google Scholar
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.Google Scholar
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.Google Scholar
180. Tenembaum, SN, Segura, MJ. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology. 2006;67:511–3.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed