Skip to main content
SpringerLink
Log in

Improving Outcomes in Pediatric Multiple Sclerosis: Current and Emerging Treatments

  • Review Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Pediatric-onset multiple sclerosis (MS) comprises 2–5% of MS cases, and is known to be associated with high disease activity and the accumulation of disability at an earlier age than their adult-onset counterparts. Appropriate therapy leading to disease control has the potential to alter the known trajectory of adverse long-term physical, cognitive, and psychosocial outcomes in this population. Thus, optimizing treatment for children and adolescents with MS is of paramount importance. The last decade has seen a growing number of disease-modifying therapies approved for relapsing MS in adults, and available agents now include oral, injectable, and infusion therapies. Recently, the development of randomized controlled MS trials in youth has led to the first agent approved by the US FDA for the treatment of pediatric MS—fingolimod. With this, we have entered a new era of knowledge and treatment in this population and ongoing pediatric trials are expected to further inform clinical management. With the emergence of highly effective therapies targeting the inflammatory component of the disease, there has been increased interest in identifying treatment strategies that instead target mechanisms such as remyelination/repair, neuroprotection, or rehabilitation. The potential role for such emerging therapies in the treatment of pediatric MS remains an important area of study. In this review, we discuss current evidence for MS therapies in children including the treatment of acute relapses, disease-modifying therapies, and symptomatic management. We will also discuss evidence for emerging therapies, including remyelinating and neuroprotective agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D. University of British Columbia MS Clinic Neurologists. Early onset multiple sclerosis: a longitudinal study. Neurology. 2002;59:1006–10.

    Article  CAS  PubMed  Google Scholar 

  2. Renoux C, Vukusic S, Mikaeloff Y, Edan G, Clanet M, Dubois B, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356:2603–13.

    Article  CAS  PubMed  Google Scholar 

  3. Aubert-Broche B, Fonov V, Narayanan S, Arnold DL, Araujo D, Fetco D, et al. Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth. Neurology. 2014;83:2140–6.

    Article  PubMed  PubMed Central  Google Scholar 

  4. MacAllister WS, Belman AL, Milazzo M, Weisbrot DM, Christodoulou C, Scherl WF, et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology. 2005;64:1422–5.

    Article  CAS  PubMed  Google Scholar 

  5. Amato MP, Goretti B, Ghezzi A, Hakiki B, Niccolai C, Lori S, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: 5-year follow-up. Neurology. 2014;83:1432–8.

    Article  PubMed  Google Scholar 

  6. Pediatric research equity act of 2003. 2003. https://www.congress.gov/108/plaws/publ155/PLAW-108publ155.pdf. Accessed 15 Dec 2018.

  7. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006. 2006. https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. Accessed 15 Dec 2018.

  8. Chitnis T, Arnold DL, Banwell B, Bruck W, Ghezzi A, Giovannoni G, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. 2018;379:1017–27.

    Article  CAS  PubMed  Google Scholar 

  9. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–73.

    Article  PubMed  Google Scholar 

  10. Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19:1261–7.

    Article  PubMed  Google Scholar 

  11. Fadda G, Brown RA, Longoni G, Castro DA, O’Mahony J, Verhey LH, et al. MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study. Lancet Child Adolesc Health. 2018;2:191–204.

    Article  PubMed  Google Scholar 

  12. Belman AL, Krupp LB, Olsen CS, Rose JW, Aaen G, Benson L, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138:e20160120.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Harding KE, Liang K, Cossburn MD, Ingram G, Hirst CL, Pickersgill TP, et al. Long-term outcome of paediatric-onset multiple sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2013;84:141–7.

    Article  PubMed  Google Scholar 

  14. Iaffaldano P, Simone M, Lucisano G, Ghezzi A, Coniglio G, Brescia-Morra V, et al. Prognostic indicators in pediatric clinically isolated syndrome. Ann Neurol. 2017;81:729–39.

    Article  PubMed  Google Scholar 

  15. Benson LA, Healy BC, Gorman MP, Baruch NF, Gholipour T, Musallam A, et al. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord. 2014;3:186–93.

    Article  CAS  PubMed  Google Scholar 

  16. Simone IL, Carrara D, Tortorella C, Liguori M, Lepore V, Pellegrini F, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology. 2002;59:1922–8.

    Article  CAS  PubMed  Google Scholar 

  17. Amato MP, Goretti B, Ghezzi A, Lori S, Zipoli V, Portaccio E, et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology. 2008;70:1891–7.

    Article  CAS  PubMed  Google Scholar 

  18. Julian L, Serafin D, Charvet L, Ackerson J, Benedict R, Braaten E, et al. Cognitive impairment occurs in children and adolescents with multiple sclerosis: results from a United States network. J Child Neurol. 2013;28:102–7.

    Article  PubMed  Google Scholar 

  19. MacAllister WS, Christodoulou C, Troxell R, Milazzo M, Block P, Preston TE, et al. Fatigue and quality of life in pediatric multiple sclerosis. Mult Scler. 2009;15:1502–8.

    Article  PubMed  Google Scholar 

  20. Goretti B, Portaccio E, Ghezzi A, Lori S, Moiola L, Falautano M, et al. Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis. Mult Scler. 2012;18:329–34.

    Article  CAS  PubMed  Google Scholar 

  21. Weisbrot DM, Ettinger AB, Gadow KD, Belman AL, MacAllister WS, Milazzo M, et al. Psychiatric comorbidity in pediatric patients with demyelinating disorders. J Child Neurol. 2010;25:192–202.

    Article  PubMed  Google Scholar 

  22. Mowry EM, Julian LJ, Im-Wang S, Chabas D, Galvin AJ, Strober JB, et al. Health-related quality of life is reduced in pediatric multiple sclerosis. Pediatr Neurol. 2010;43:97–102.

    Article  PubMed  Google Scholar 

  23. Citterio A, La Mantia L, Ciucci G, Candelise L, Brusaferri F, Midgard R, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;4:CD001331.

    Google Scholar 

  24. Beck RW, Cleary PA, Anderson MM, Keltner JL, Shults WT, Kaufman DI, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326:581–8.

    Article  CAS  PubMed  Google Scholar 

  25. Waldman AT, Gorman MP, Rensel MR, Austin TE, Hertz DP, Kuntz NL, et al. Management of pediatric central nervous system demyelinating disorders: consensus of United States neurologists. J Child Neurol. 2011;26:675–82.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Martinelli V, Rocca MA, Annovazzi P, Pulizzi A, Rodegher M, Boneschi FM, et al. A short-term randomized MRI study of high-dose oral vs intravenous methylprednisolone in MS. Neurology. 2009;73:1842–8.

    Article  CAS  PubMed  Google Scholar 

  27. Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386:974–81.

    Article  CAS  PubMed  Google Scholar 

  28. Perumal JS, Caon C, Hreha S, Zabad R, Tselis A, Lisak R, et al. Oral prednisone taper following intravenous steroids fails to improve disability or recovery from relapses in multiple sclerosis. Eur J Neurol. 2008;15:677–80.

    Article  CAS  PubMed  Google Scholar 

  29. Bigi S, Banwell B, Yeh EA. Outcomes after early administration of plasma exchange in pediatric central nervous system inflammatory demyelination. J Child Neurol. 2015;30:874–80.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76:294–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for apheresis: the seventh special issue. J Clin Apher. 2016;31:149–62.

    PubMed  Google Scholar 

  33. Visser LH, Beekman R, Tijssen CC, Uitdehaag BMJ, Lee ML, Movig KLL, et al. A randomized, double-blind, placebo-controlled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS. Mult Scler. 2004;10:89–91.

    Article  CAS  PubMed  Google Scholar 

  34. Sorensen PS, Haas J, Sellebjerg F, Olsson T, Ravnborg M, TARIMS Study Group. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology. 2004;63:2028–33.

    Article  CAS  PubMed  Google Scholar 

  35. Feasby T, Banwell B, Benstead T, Bril V, Brouwers M, Freedman M, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. 2007;21:S57–107.

    Article  PubMed  Google Scholar 

  36. Elovaara I, Apostolski S, van Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J, et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 2008;15:893–908.

    Article  CAS  PubMed  Google Scholar 

  37. Pitteri M, Magliozzi R, Bajrami A, Camera V, Calabrese M. Potential neuroprotective effect of fingolimod in multiple sclerosis and its association with clinical variables. Expert Opin Pharmacother. 2018;19:387–95.

    Article  CAS  PubMed  Google Scholar 

  38. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    Article  CAS  PubMed  Google Scholar 

  39. Kappos L, Radue E-W, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

    Article  CAS  PubMed  Google Scholar 

  40. Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–56.

    Article  CAS  PubMed  Google Scholar 

  41. Tully T, Barkley A, Silber E. Kaposi sarcoma in a patient with relapsing–remitting multiple sclerosis receiving fingolimod. Neurology. 2015;84:1999–2001.

    Article  PubMed  Google Scholar 

  42. Berger JR, Cree BA, Greenberg B, Hemmer B, Ward BJ, Dong VM, et al. Progressive multifocal leukoencephalopathy after fingolimod treatment. Neurology. 2018;90:e1815–21.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Oshima Y, Tanimoto T, Yuji K, Tojo A. Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients. Mult Scler. 2018. https://doi.org/10.1177/1352458518786075.

    Article  PubMed  Google Scholar 

  44. Dubey D, Kieseier BC, Hartung HP, Hemmer B, Warnke C, Menge T, et al. Dimethyl fumarate in relapsing–remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother. 2015;15:339–46.

    Article  CAS  PubMed  Google Scholar 

  45. Alroughani R, Das R, Penner N, Pultz J, Taylor C, Eraly S. Safety and efficacy of delayed-release dimethyl fumarate in pediatric patients with relapsing multiple sclerosis (FOCUS). Pediatr Neurol. 2018;83:19–24.

    Article  PubMed  Google Scholar 

  46. Makhani N, Schreiner T. Oral dimethyl fumarate in children with multiple sclerosis: a dual-center study. Pediatr Neurol. 2016;57:101–4.

    Article  PubMed  Google Scholar 

  47. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–97.

    Article  CAS  PubMed  Google Scholar 

  48. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–107.

    Article  CAS  PubMed  Google Scholar 

  49. EMA. Updated recommendations to minimise the risk of the rare brain infection PML with Tecfidera. 2015. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500196017&mid=WC0b01ac058009a3dc. Accessed 24 Sept 2018.

  50. Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74:659–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Krysko KM, Graves J, Rensel M, Weinstock-Guttman B, Aaen G, Benson L, et al. Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US. Neurology. 2018;91:e1778–87.

    Article  PubMed  Google Scholar 

  52. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:247–56.

    Article  CAS  PubMed  Google Scholar 

  53. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293–303.

    Article  PubMed  Google Scholar 

  54. Vermersch P, Czlonkowska A, Grimaldi LME, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20:705–16.

    Article  CAS  PubMed  Google Scholar 

  55. Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:977–86.

    Article  CAS  PubMed  Google Scholar 

  56. Jacobs BM, Ammoscato F, Giovannoni G, Baker D, Schmierer K. Cladribine: mechanisms and mysteries in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2018;89:1266–71.

    Article  PubMed  Google Scholar 

  57. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sorensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416–26.

    Article  CAS  PubMed  Google Scholar 

  58. Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, et al. Safety and efficacy of cladribine tablets in patients with relapsing–remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler. 2018;24:1594–604.

    Article  CAS  PubMed  Google Scholar 

  59. Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, et al. Cladribine tablets added to IFN-β in active relapsing MS. Neurol Neuroimmunol Neuroinflamm. 2018;5:e477-11.

    Article  Google Scholar 

  60. Leist TP, Comi G, Cree BAC, Coyle PK, Freedman MS, Hartung HP, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014;13:257–67.

    Article  CAS  PubMed  Google Scholar 

  61. Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011;25:491–502.

    Article  CAS  PubMed  Google Scholar 

  62. Pohl D, Rostásy K, Gärtner J, Hanefeld F. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology. 2005;64:888–90.

    Article  CAS  PubMed  Google Scholar 

  63. Ghezzi A, Amato MP, Annovazzi P, Capobianco M, Gallo P, La Mantia L, et al. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci. 2009;30:193–9.

    Article  PubMed  Google Scholar 

  64. Tenembaum SN, Banwell B, Pohl D, Krupp LB, Boyko A, Meinel M, et al. Subcutaneous interferon beta-1a in pediatric multiple sclerosis: a retrospective study. J Child Neurol. 2013;28:849–56.

    Article  PubMed  Google Scholar 

  65. Gärtner J, Bruck W, Weddige A, Hummel H, Norenberg C, Bugge J-P, et al. Interferon beta-1b in treatment-naïve paediatric patients with relapsing–remitting multiple sclerosis: 2-year results from the BETAPAEDIC study. Mult Scler J Exp Transl Clin. 2017;3:2055217317747623.

    PubMed  PubMed Central  Google Scholar 

  66. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285–94.

    Article  CAS  PubMed  Google Scholar 

  67. PRISMS (prevention of relapses and disability by interferon beta-1a subcutaneously in multiple sclerosis) Study Group. Randomised doubleblind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498–504.

    Article  Google Scholar 

  68. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. Pegylated interferon β-1a for relapsing–remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13:657–65.

    Article  CAS  PubMed  Google Scholar 

  69. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:1277–85.

    Article  Google Scholar 

  70. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898–904.

    Article  CAS  PubMed  Google Scholar 

  71. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576–82.

    Article  CAS  Google Scholar 

  72. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007;370:389–97.

    Article  CAS  PubMed  Google Scholar 

  73. Scott LJ. Glatiramer acetate: a review of its use in patients with relapsing–remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. CNS Drugs. 2013;27:971–88.

    Article  CAS  PubMed  Google Scholar 

  74. 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.

    Article  CAS  PubMed  Google Scholar 

  75. Yeh EA, Waubant E, Krupp LB, Ness J, Chitnis T, Kuntz N, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol. 2011;68:437–44.

    Article  PubMed  Google Scholar 

  76. Makhani N, Ngan B-Y, Kamath BM, Yeh EA. Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS. Neurology. 2013;81:850–2.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268–76.

    Article  CAS  PubMed  Google Scholar 

  78. 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. European/Canadian Glatiramer Acetate Study Group. Ann Neurol. 2001;49:290–7.

    Article  CAS  PubMed  Google Scholar 

  79. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, 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.

    Article  CAS  PubMed  Google Scholar 

  80. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing–remitting multiple sclerosis. Ann Neurol. 2013;73:705–13.

    Article  CAS  PubMed  Google Scholar 

  81. Wolinsky JS, Borresen TE, Dietrich DW, Wynn D, Sidi Y, Steinerman JR, et al. GLACIER: an open-label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg three-times weekly versus 20 mg daily in patients with relapsing–remitting multiple sclerosis. Mult Scler Relat Disord. 2015;4:370–6.

    Article  PubMed  Google Scholar 

  82. Cohen J, Belova A, Selmaj K, Wolf C, Sormani MP, Oberyé J, et al. Equivalence of generic glatiramer acetate in multiple sclerosis. JAMA Neurol. 2015;72:1433–9.

    Article  PubMed  Google Scholar 

  83. Selmaj K, Barkhof F, Belova AN, Wolf C, van den Tweel ER, Oberyé JJ, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23:1909–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992;356:63–6.

    Article  CAS  PubMed  Google Scholar 

  85. Alroughani R, Ahmed SF, Behbehani R, Al-Hashel J. The use of natalizumab in pediatric patients with active relapsing multiple sclerosis: a prospective study. Pediatr Neurol. 2017;70:56–60.

    Article  PubMed  Google Scholar 

  86. Ghezzi A, Moiola L, Pozzilli C, Brescia-Morra V, Gallo P, Grimaldi LME, et al. Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. 2015;15:174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Huppke P, Huppke B, Ellenberger D, Rostásy K, Hummel H, Stark W, et al. Therapy of highly active pediatric multiple sclerosis. Mult Scler. 2019;25:72–80.

    Article  PubMed  Google Scholar 

  88. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.

    Article  CAS  PubMed  Google Scholar 

  89. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–23.

    Article  CAS  PubMed  Google Scholar 

  90. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–80.

    Article  CAS  PubMed  Google Scholar 

  91. McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, Molyneux P, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry. 2016;87:117–25.

    Article  CAS  PubMed  Google Scholar 

  92. Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87:885–9.

    Article  CAS  PubMed  Google Scholar 

  93. Yamout BI, Sahraian MA, Ayoubi NE, Tamim H, Nicolas J, Khoury SJ, et al. Efficacy and safety of natalizumab extended interval dosing. Mult Scler Relat Disord. 2018;24:113–6.

    Article  PubMed  Google Scholar 

  94. Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:298–304.

    Article  PubMed  Google Scholar 

  95. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing–remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819–28.

    Article  CAS  PubMed  Google Scholar 

  96. CAMMS223 Trial Investigators, Coles AJ, Compston DAS, Selmaj KW, Lake SL, Moran S, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359:1786–801.

    Article  Google Scholar 

  97. Coles AJ, Cohen JA, Fox EJ, Giovannoni G, Hartung HP, Havrdova E, et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology. 2017;89:1117–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. United States Food and Drug Administration. FDA Drug Safety Communication. 2018. https://www.fda.gov/media/119052/download. Accessed 9 May 2019.

  99. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376:221–34.

    Article  CAS  PubMed  Google Scholar 

  100. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–45.

    CAS  PubMed  Google Scholar 

  101. Beres SJ, Graves J, Waubant E. Rituximab use in pediatric central demyelinating disease. Pediatr Neurol. 2014;51:114–8.

    Article  PubMed  Google Scholar 

  102. Salzer J, Lycke J, Wickström R, Naver H, Piehl F, Svenningsson A. Rituximab in paediatric onset multiple sclerosis: a case series. J Neurol. 2016;263:322–6.

    Article  CAS  PubMed  Google Scholar 

  103. Dale RC, Brilot F, Duffy LV, Twilt M, Waldman AT, Narula S, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83:142–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med. 2008;358:676–88.

    Article  CAS  PubMed  Google Scholar 

  105. Granqvist M, Boremalm M, Poorghobad A, Svenningsson A, Salzer J, Frisell T, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018;75:320–8.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Spelman T, Frisell T, Piehl F, Hillert J. Comparative effectiveness of rituximab relative to IFN-β or glatiramer acetate in relapsing–remitting MS from the Swedish MS registry. Mult Scler. 2018;24:1087–95.

    Article  CAS  PubMed  Google Scholar 

  107. Makhani N, Gorman MP, Branson HM, Stazzone L, Banwell BL, Chitnis T. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology. 2009;72:2076–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Smith DR, Weinstock-Guttman B, Cohen JA, Wei X, Gutmann C, Bakshi R, et al. A randomized blinded trial of combination therapy with cyclophosphamide in patients-with active multiple sclerosis on interferon beta. Mult Scler. 2005;11:573–82.

    Article  CAS  PubMed  Google Scholar 

  109. Yilmaz N, Emmungil H, Gucenmez S, Ozen G, Yildiz F, Balkarli A, et al. Incidence of cyclophosphamide-induced urotoxicity and protective effect of mesna in rheumatic diseases. J Rheumatol. 2015;42:1661–6.

    Article  CAS  PubMed  Google Scholar 

  110. Chemaitilly W, Li Z, Krasin MJ, Brooke RJ, Wilson CL, Green DM, et al. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude lifetime cohort. J Clin Endocrinol Metab. 2017;102:2242–50.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Burman J, Kirgizov K, Carlson K, Badoglio M, Mancardi GL, De Luca G, et al. Autologous hematopoietic stem cell transplantation for pediatric multiple sclerosis: a registry-based study of the Autoimmune Diseases Working Party (ADWP) and Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2017;52:1133–7.

    Article  CAS  PubMed  Google Scholar 

  112. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388:576–85.

    Article  PubMed  Google Scholar 

  113. Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Griffith LM, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing–remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. 2015;72:159–69.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a meta-analysis. Neurology. 2017;88:2115–22.

    Article  PubMed  Google Scholar 

  115. Multiple Sclerosis Society of Canada. Vitamin D and Multiple Sclerosis Recommendations. 2018. https://mssociety.ca/library/document/Vka6RXcnOizNm9sIwuWvroxejlhLqTJ8/original.pdf. Accessed 16 Nov 2018.

  116. Pétrin J, Fiander M, Doss PMIA, Yeh EA. A scoping review of modifiable risk factors in pediatric onset multiple sclerosis: building for the future. Children. 2018;5:e146.

    Article  PubMed  Google Scholar 

  117. Evans E, Piccio L, Cross AH. Use of vitamins and dietary supplements by patients with multiple sclerosis. JAMA Neurol. 2018;75:1013–9.

    Article  PubMed  Google Scholar 

  118. Mische LJ, Mowry EM. The evidence for dietary interventions and nutritional supplements as treatment options in multiple sclerosis: a review. Curr Treat Options Neurol. 2018;20:8.

    Article  PubMed  Google Scholar 

  119. Chitnis T, Tenembaum S, Banwell B, Krupp L, Pohl D, Rostasy K, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18:116–27.

    Article  CAS  PubMed  Google Scholar 

  120. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D, et al. ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler. 2017;24:96–120.

    Article  Google Scholar 

  121. Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90:777–88.

    Article  PubMed  Google Scholar 

  122. Naismith RT. Multiple sclerosis should be treated using a step-down strategy rather than a step-up strategy-NO. Mult Scler. 2016;22:1400–2.

    Article  PubMed  Google Scholar 

  123. Baroncini D, Zaffaroni M, Moiola L, Lorefice L, Fenu G, Iaffaldano P, et al. Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: a multicentre, Italian, retrospective, observational study. Mult Scler. 2019;25:399–407.

    Article  CAS  PubMed  Google Scholar 

  124. Giovannoni G. Multiple sclerosis should be treated using a step-down strategy rather than a step-up strategy-YES. Mult Scler. 2016;22:1397–400.

    Article  PubMed  Google Scholar 

  125. Mikaeloff Y, Caridade G, Assi S, Suissa S, Tardieu M. Prognostic factors for early severity in a childhood multiple sclerosis cohort. Pediatrics. 2006;118:1133–9.

    Article  PubMed  Google Scholar 

  126. Akhtar S, Alroughani R, Ahmed SF, Al-Hashel JY. Prognostic indicators of secondary progression in a paediatric-onset multiple sclerosis cohort in Kuwait. Mult Scler. 2016;22:1086–93.

    Article  PubMed  Google Scholar 

  127. Giovannoni G, Turner B, Gnanapavan S, Offiah C, Schmierer K, Marta M. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4:329–33.

    Article  PubMed  Google Scholar 

  128. Kappos L, De Stefano N, Freedman MS, Cree BA, Radue E-W, Sprenger T, et al. Inclusion of brain volume loss in a revised measure of “no evidence of disease activity” (NEDA-4) in relapsing–remitting multiple sclerosis. Mult Scler. 2016;22:1297–305.

    Article  PubMed  Google Scholar 

  129. Parks NE, Pittock SJ, Mandrekar J, Kantarci OH, Lucchinetti CF, Weinshenker BG, et al. Population-based study of “no evident disease activity” in MS. Neurol Neuroimmunol Neuroinflamm. 2018;5:e495–6.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Gasperini C, Prosperini L, Tintore M, Sormani MP, Filippi M, Río J, et al. Unraveling treatment response in multiple sclerosis: a clinical and MRI challenge. Neurology. 2019;92:180–92.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1075–84.

    Article  CAS  PubMed  Google Scholar 

  133. Panitch H, Miller A, Paty D, Weinshenker B. North American Study Group on interferon beta-1b in secondary progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology. 2004;63:1788–95.

    Article  CAS  PubMed  Google Scholar 

  134. Vollmer T, Signorovitch J, Huynh L, Galebach P, Kelley C, DiBernardo A, et al. The natural history of brain volume loss among patients with multiple sclerosis: a systematic literature review and meta-analysis. J Neurol Sci. 2015;357:8–18.

    Article  PubMed  Google Scholar 

  135. Azevedo CJ, Cen SY, Khadka S, Liu S, Kornak J, Shi Y, et al. Thalamic atrophy in multiple sclerosis: a magnetic resonance imaging marker of neurodegeneration throughout disease. Ann Neurol. 2018;83:223–34.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390:2481–9.

    Article  CAS  PubMed  Google Scholar 

  137. Cadavid D, Balcer L, Galetta S, Aktas O, Ziemssen T, Vanopdenbosch L, et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16:189–99.

    Article  CAS  PubMed  Google Scholar 

  138. Tourbah A, Lebrun-Frenay C, Edan G, Clanet M, Papeix C, Vukusic S, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mult Scler. 2016;22:1719–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sühs K-W, Hein K, Sättler MB, Görlitz A, Ciupka C, Scholz K, et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol. 2012;72:199–210.

    Article  CAS  PubMed  Google Scholar 

  140. Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:259–69.

    Article  CAS  PubMed  Google Scholar 

  141. Esfahani MR, Harandi ZA, Movasat M, Nikdel M, Adelpour M, Momeni A, et al. Memantine for axonal loss of optic neuritis. Graefes Arch Clin Exp Ophthalmol. 2012;250:863–9.

    Article  CAS  PubMed  Google Scholar 

  142. Najmi Varzaneh F, Najmi Varzaneh F, Azimi AR, Rezaei N, Sahraian MA. Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis. Acta Neurol Belg. 2014;114:273–8.

    Article  PubMed  Google Scholar 

  143. Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383:2213–21.

    Article  CAS  PubMed  Google Scholar 

  144. Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med. 2018;379:846–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Spain R, Powers K, Murchison C, Heriza E, Winges K, Yadav V, et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017;4:e374.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Connick P, De Angelis F, Parker RA, Plantone D, Doshi A, John N, et al. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open. 2018;8:e021944-16.

    Article  Google Scholar 

  147. Shangyan H, Kuiqing L, Yumin X, Jie C, Weixiong L. Meta-analysis of the efficacy of modafinil versus placebo in the treatment of multiple sclerosis fatigue. Mult Scler Relat Disord. 2018;19:85–9.

    Article  PubMed  Google Scholar 

  148. The Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci. 1987;14:273–8.

    Article  Google Scholar 

  149. Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45:1956–61.

    Article  CAS  PubMed  Google Scholar 

  150. van den Akker LE, Beckerman H, Collette EH, Twisk JW, Bleijenberg G, Dekker J, et al. Cognitive behavioral therapy positively affects fatigue in patients with multiple sclerosis: results of a randomized controlled trial. Mult Scler. 2017;23:1542–53.

    Article  PubMed  Google Scholar 

  151. Pilutti LA, Greenlee TA, Motl RW, Nickrent MS, Petruzzello SJ. Effects of exercise training on fatigue in multiple sclerosis: a meta-analysis. Psychosom Med. 2013;75:575–80.

    Article  CAS  PubMed  Google Scholar 

  152. Grossman P, Kappos L, Gensicke H, D’Souza M, Mohr DC, Penner IK, et al. MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology. 2010;75:1141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Connolly SD, Bernstein GA, Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46:267–83.

    Article  PubMed  Google Scholar 

  154. National Collaborating Centre for Mental Health (UK). Depression in children and young people: identification and management in primary, community and secondary care. Leicester: British Psychological Society; 2005.

    Google Scholar 

  155. Kalb R, Beier M, Benedict RH, Charvet L, Costello K, Feinstein A, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler. 2018;24:1665–80.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Charvet LE, Yang J, Shaw MT, Sherman K, Haider L, Xu J, et al. Cognitive function in multiple sclerosis improves with telerehabilitation: results from a randomized controlled trial. PLoS One. 2017;12:e0177177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Messinis L, Nasios G, Kosmidis MH, Zampakis P, Malefaki S, Ntoskou K, et al. Efficacy of a computer-assisted cognitive rehabilitation intervention in relapsing–remitting multiple sclerosis patients: a multicenter randomized controlled trial. Behav Neurol. 2017;2017:5919841-17.

    Article  Google Scholar 

  158. Mattioli F, Bellomi F, Stampatori C, Provinciali L, Compagnucci L, Uccelli A, et al. Two years follow up of domain specific cognitive training in relapsing remitting multiple sclerosis: a randomized clinical trial. Front Behav Neurosci. 2016;10:28.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Simone M, Viterbo RG, Margari L, Iaffaldano P. Computer-assisted rehabilitation of attention in pediatric multiple sclerosis and ADHD patients: a pilot trial. BMC Neurol. 2018;18:82.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Till C, Kuni B, De Somma E, Yeh EA, Banwell B. A feasibility study of working memory training for individuals with paediatric-onset multiple sclerosis. Neuropsychol Rehabil. 2017. https://doi.org/10.1080/09602011.2017.1372786.

    Article  PubMed  Google Scholar 

  161. Coghill D, Banaschewski T, Lecendreux M, Soutullo C, Johnson M, Zuddas A, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol. 2013;23:1208–18.

    Article  CAS  PubMed  Google Scholar 

  162. Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, et al. The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial. J Neurol. 2009;256:1095–102.

    Article  CAS  PubMed  Google Scholar 

  163. Morrow SA, Smerbeck A, Patrick K, Cookfair D, Weinstock-Guttman B, Benedict RHB. Lisdexamfetamine dimesylate improves processing speed and memory in cognitively impaired MS patients: a phase II study. J Neurol. 2013;260:489–97.

    Article  CAS  PubMed  Google Scholar 

  164. Thannhauser JE, Mah JK, Metz LM. Adherence of adolescents to multiple sclerosis disease-modifying therapy. Pediatr Neurol. 2009;41:119–23.

    Article  PubMed  Google Scholar 

  165. Lulu S, Julian L, Shapiro E, Hudson K, Waubant E. Treatment adherence and transitioning youth in pediatric multiple sclerosis. Mult Scler Relat Disord. 2014;3:689–95.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Schwartz CE, Grover SA, Powell VE, Noguera A, Mah JK, Mar S, et al. Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis. Mult Scler. 2017;24:175–85.

    Article  PubMed  Google Scholar 

  167. Yeh EA, Chiang N, Darshan B, Nejati N, Grover SA, Schwartz CE, et al. Adherence in youth with multiple sclerosis: a qualitative assessment of habit formation, barriers, and facilitators. Qual Health Res. 2018. https://doi.org/10.1177/1049732318779039.

    Article  PubMed  Google Scholar 

  168. Yeh EA, Powell VE, Edwards K, Graves J, Lotze TE, Obadia M, et al. Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial. Qual Life Res. 2017;26:2333–49.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine and Dentistry, Women and Children’s Health Research Institute, University of Alberta, Edmonton, AB, Canada

    Colin Wilbur

  2. Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada

    E. Ann Yeh

  3. Division of Neurosciences and Mental Health, SickKids Research Institute, Toronto, ON, Canada

    E. Ann Yeh

  4. Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    E. Ann Yeh

Authors
  1. Colin Wilbur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Ann Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Ann Yeh.

Ethics declarations

Funding

No direct funding was received in support of this work.

Conflict of interest

CW has no conflicts of interest to declare in relation to this work. EAY has received research funds from Biogen for an investigator-initiated research project and has received unrestricted educational funds from Teva.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wilbur, C., Yeh, E.A. Improving Outcomes in Pediatric Multiple Sclerosis: Current and Emerging Treatments. Pediatr Drugs 21, 137–152 (2019). https://doi.org/10.1007/s40272-019-00338-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-019-00338-6

Search

Navigation