Skip to main content
SpringerLink
Log in

Disease-Modifying Therapy of Pediatric Multiple Sclerosis

  • Review
  • Published:
Neurotherapeutics

Abstract

Multiple sclerosis (MS) is increasingly recognized in children and adolescents. Improved awareness, access to care, and subspecialty training in pediatric MS has allowed for better access to treatment. Children with MS present with an overwhelmingly relapsing form of the disease and have more frequent relapses than their adult counterparts during the early phases of disease. Cognitive deficits are prominent in pediatric MS, as opposed to locomotor disability. Beta interferons and glatiramer acetate are frequently used off-label drugs. Additional second-line therapies have occasionally been used in treatment failures. No randomized clinical trials have been performed to date in pediatric MS; however, recent legislation necessitates pediatric studies for new agents, which will allow for better defined pharmacokinetic, dosing, and efficacy data to guide the treating neurologist.

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. Chitnis T. Pediatric multiple sclerosis. Neurologist 2006;12:299-310.

    Article  PubMed  Google Scholar 

  2. Duquette P, Murray TJ, Pleines J, et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr 1987;111:359-363.

    Article  PubMed  CAS  Google Scholar 

  3. Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D. Early onset multiple sclerosis: a longitudinal study. Neurology 2002;59:1006-1010.

    Article  PubMed  CAS  Google Scholar 

  4. Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 1997;3:43-46.

    Article  PubMed  CAS  Google Scholar 

  5. Sindern E, Haas J, Stark E, Wurster U. Early onset MS under the age of 16: clinical and paraclinical features. Acta Neurol Scand 1992;86:280-284.

    Article  PubMed  CAS  Google Scholar 

  6. Chitnis T, Glanz B, Jaffin S, Healy B. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler 2009;15:627-631.

    Article  PubMed  CAS  Google Scholar 

  7. Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 2002;59:1922-1928.

    Article  PubMed  CAS  Google Scholar 

  8. 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;77:1143-1148.

    Article  PubMed  CAS  Google Scholar 

  9. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 2009;72:232-239.

    Article  PubMed  CAS  Google Scholar 

  10. 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;166:405-412.

    Article  PubMed  Google Scholar 

  11. Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007;356:2603-2613.

    Article  PubMed  CAS  Google Scholar 

  12. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002;59:1224-1231.

    Article  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. Chabas D, Castillo-Trivino T, Mowry EM, Strober JB, Glenn OA, Waubant E. Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype? Neurology 2008;71:1090-1093.

    Article  PubMed  CAS  Google Scholar 

  15. Atzori M, Battistella PA, Perini P, et al. Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Mult Scler 2009;15:363-370.

    Article  PubMed  CAS  Google Scholar 

  16. Gorman MP, Healy BC, Polgar-Turcsanyi M, Chitnis T. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 2009;66:54-59.

    Article  PubMed  Google Scholar 

  17. Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol 2011;10:436-445.

    Article  PubMed  CAS  Google Scholar 

  18. Mikaeloff Y, Suissa S, Vallee L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr 2004;144:246-252.

    Article  PubMed  Google Scholar 

  19. Ghezzi A, Pozzilli C, Liguori M, et al. Prospective study of multiple sclerosis with early onset. Mult Scler 2002;8:115-118.

    Article  PubMed  CAS  Google Scholar 

  20. Ruggieri M, Iannetti P, Polizzi A, Pavone L, Grimaldi LM. Multiple sclerosis in children under 10 years of age. Neurol Sci 2004;25(suppl 4):S326-S335.

    Article  PubMed  Google Scholar 

  21. Fay AJ, Mowry EM, Strober J, Waubant E. Relapse severity and recovery in early pediatric multiple sclerosis. Mult Scler 2012;18:1008-1012.

    Article  PubMed  Google Scholar 

  22. Banwell BL, Anderson PE. The cognitive burden of multiple sclerosis in children. Neurology 2005;64:891-894.

    Article  PubMed  Google Scholar 

  23. MacAllister WS, Belman AL, Milazzo M, et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology 2005;64:1422-1425.

    Article  PubMed  CAS  Google Scholar 

  24. MacAllister WS, Christodoulou C, Milazzo M, Krupp LB. Longitudinal neuropsychological assessment in pediatric multiple sclerosis. Dev Neuropsychol 2007;32:625-644.

    Article  PubMed  Google Scholar 

  25. Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology 2008;70:1891-1897.

    Article  PubMed  CAS  Google Scholar 

  26. Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up. Neurology 2010;75:1134-1140.

    Article  PubMed  CAS  Google Scholar 

  27. Portaccio E, Goretti B, Zipoli V, et al. Cognitive rehabilitation in children and adolescents with multiple sclerosis. Neurol Sci 2011;32(6):1043-1046.

    Google Scholar 

  28. Waubant E, Chabas D, Okuda DT, et al. Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol 2009;66:967-971.

    Article  PubMed  Google Scholar 

  29. Yeh EA, Weinstock-Guttman B, Ramanathan M, et al. Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. Brain 2009;132(pt 12):3392-3400.

    Article  PubMed  CAS  Google Scholar 

  30. Absinta M, Rocca MA, Moiola L, et al. Cortical lesions in children with multiple sclerosis. Neurology 2011;76:910-913.

    Article  PubMed  CAS  Google Scholar 

  31. Vishwas MS, Chitnis T, Pienaar R, Healy BC, Grant PE. Tract-based analysis of callosal, projection, and association pathways in pediatric patients with multiple sclerosis: a preliminary study. AJNR Am J Neuroradiol 2010;31:121-128.

    Article  PubMed  CAS  Google Scholar 

  32. Vishwas MS, Healy BC, Pienaar R, Gorman MP, Grant PE, Chitnis T. Diffusion tensor analysis of pediatric multiple sclerosis and clinically isolated syndromes. AJNR Am J Neuroradiol 2012. doi:10.3174/ajnr.A3216

  33. Hahn CD, Shroff MM, Blaser SI, Banwell BL. MRI criteria for multiple sclerosis: Evaluation in a pediatric cohort. Neurology 2004;62:806-808.

    Article  PubMed  Google Scholar 

  34. Sadaka Y, Verhey LH, Shroff MM, et al. 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. Ann Neurol 2012;72:211-223.

    Article  PubMed  Google Scholar 

  35. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler 2012;18:116-127.

    Article  PubMed  CAS  Google Scholar 

  36. Waldman AT, Gorman MP, Rensel MR, Austin TE, Hertz DP, Kuntz NL. Management of pediatric central nervous system demyelinating disorders: consensus of United States neurologists. Journal of child neurology. 2011;26:675-682.

    Article  PubMed  Google Scholar 

  37. Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology 2010;74(suppl 1):S17-S24.

    Article  PubMed  CAS  Google Scholar 

  38. Group IMSS. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I Clinical results of a multicenter, randomized, double blind, placebo-controlled trial. Neurology 1993:655-661.

  39. Jacobs L, Cookfair D, Rudick R, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39:285-294.

    Article  PubMed  CAS  Google Scholar 

  40. Group PRISMS. Randomised, double-blind, placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498-1504.

    Google Scholar 

  41. Mikaeloff Y, Moreau T, Debouverie M, et al. Interferon-beta treatment in patients with childhood-onset multiple sclerosis. J Pediatr 2001;139:443-446.

    Article  PubMed  CAS  Google Scholar 

  42. Banwell B, Reder AT, Krupp L, et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology 2006;66:472-476.

    Article  PubMed  CAS  Google Scholar 

  43. Bykova OV, Kuzenkova LM, Maslova OI. [The use of beta-interferon-1b in children and adolescents with multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova 2006;106(9):29-33.

    PubMed  CAS  Google Scholar 

  44. Pohl D, Rostasy K, Gartner J, Hanefeld F. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology 2005;64:888-890.

    Article  PubMed  CAS  Google Scholar 

  45. Bergamaschi R, Rezzani C, Minguzzi S, et al. Validation of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis. Funct Neurol 2009;24:159-162.

    PubMed  Google Scholar 

  46. 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;11:420-424.

    Article  PubMed  CAS  Google Scholar 

  47. Ghezzi A, Amato MP, Capobianco M, et al. Treatment of early-onset multiple sclerosis with intramuscular interferonbeta-1a: long-term results. Neurol Sci 2007;28:127-132.

    Article  PubMed  CAS  Google Scholar 

  48. Tenembaum SN, Segura MJ. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology 2006;67:511-513.

    Article  PubMed  CAS  Google Scholar 

  49. Waubant E, Hietpas J, Stewart T, et al. Interferon beta-1a in children with multiple sclerosis is well tolerated. Neuropediatrics 2001;32:211-213.

    Article  PubMed  CAS  Google Scholar 

  50. Mikaeloff Y, Caridade G, Tardieu M, Suissa S. Effectiveness of early beta interferon on the first attack after confirmed multiple sclerosis: a comparative cohort study. Eur J Paediatr Neurol 2008;12:205-209.

    Article  PubMed  Google Scholar 

  51. Yeh E, Heim R, Karpinski M, Ray J, Weinstock-Guttman B. Neutralizing antibodies to interferon in children with MS on interferon treatment. Presented at the Annual Meeting of the Child Neurology Society; October 14-17, 2009; Louisville, KY.

  52. Dhib-Jalbut S. Sustained immunological effects of Glatiramer acetate in patients with multiple sclerosis treated for over 6 years. J Neurol Sci 2002;201:71-77.

    Article  PubMed  Google Scholar 

  53. Johnson K, Brooks B, Cohen J, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276.

    Article  PubMed  CAS  Google Scholar 

  54. 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;34:120-126.

    Article  PubMed  CAS  Google Scholar 

  55. Cohen BA, Khan O, Jeffery DR, et al. Identifying and treating patients with suboptimal responses. Neurology 2004;63(12 suppl 6):S33-S40.

    Article  PubMed  CAS  Google Scholar 

  56. Freedman MS, Cohen B, Dhib-Jalbut S, et al. Recognizing and treating suboptimally controlled multiple sclerosis: steps toward regaining command. Curr Med Res Opin 2009;(10):2459-2470.

  57. 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 beta: implications for clinical trials. Ann Neurol 2002;52:400-406.

    Article  PubMed  CAS  Google Scholar 

  58. Ghezzi A, Pozzilli C, Grimaldi LM, et al. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology 2010;75(10):912-917.

    Google Scholar 

  59. Yeh EA, Waubant E, Krupp LB, et al. Multiple Sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol 2010;68(4):437-444.

    Google Scholar 

  60. 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.

    Article  PubMed  CAS  Google Scholar 

  61. Huppke P, Stark W, Zurcher C, Huppke B, Bruck W, Gartner J. Natalizumab use in pediatric multiple sclerosis. Arch Neurol 2008;65:1655-1658.

    Article  PubMed  Google Scholar 

  62. Borriello G, Prosperini L, Luchetti A, Pozzilli C. Natalizumab treatment in pediatric multiple sclerosis: a case report. Eur J Paediatr Neurol 2009;13:67-71.

    Article  PubMed  Google Scholar 

  63. Ghezzi A, Pozzilli C, Grimaldi LM, et al. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology 2010;75:912-917.

    Article  PubMed  CAS  Google Scholar 

  64. Hyams JS, Wilson DC, Thomas A, et al. Natalizumab therapy for moderate to severe Crohn disease in adolescents. J Pediatr Gastroenterol Nutr 2007;44:185-191.

    Article  PubMed  CAS  Google Scholar 

  65. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010;68:295-303.

    Article  PubMed  Google Scholar 

  66. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870-1880.

    Article  PubMed  CAS  Google Scholar 

  67. Sorensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012;18:143-152.

    Article  PubMed  Google Scholar 

  68. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog 2009;5:e1000363.

    Article  PubMed  Google Scholar 

  69. Knowles WA, Pipkin P, Andrews N, et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 2003;71:115-123.

    Article  PubMed  Google Scholar 

  70. Comi G, O'Connor P, Montalban X, Antel J, et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler 2010;16(2):197-207.

    Google Scholar 

  71. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-415.

    Google Scholar 

  72. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2006;355(11):1124-1140.

    Google Scholar 

  73. Mehling M, Lindberg R, Raulf F, et al. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 2010;75:403-410.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Weiner HL, Mackin GA, Orav EJ, et al. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993;43:910-918.

    Article  PubMed  CAS  Google Scholar 

  76. Makhani N, Gorman MP, Branson HM, Stazzone L, Banwell BL, Chitnis T. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology 2009;72:2076-2082.

    Article  PubMed  CAS  Google Scholar 

  77. Baca V, Lavalle C, Garcia R, et al. Favorable response to intravenous methylprednisolone and cyclophosphamide in children with severe neuropsychiatric lupus. J Rheumatol 1999;26:432-439.

    PubMed  CAS  Google Scholar 

  78. Yildirim-Toruner C, Diamond B. Current and novel therapeutics in the treatment of systemic lupus erythematosus. J Allergy Clin Immunol 2011;127:303-314.

    Article  PubMed  CAS  Google Scholar 

  79. Adams A, MacDermott EJ, Lehman TJ. Pharmacotherapy of lupus nephritis in children: a recommended treatment approach. Drugs 2006;66:1191-1207.

    Article  PubMed  CAS  Google Scholar 

  80. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358:676-688.

    Article  PubMed  CAS  Google Scholar 

  81. Tzaribachev N, Koetter I, Kuemmerle-Deschner JB, Schedel J. Rituximab for the treatment of refractory pediatric autoimmune diseases: a case series. Cases J 2009;2:6609.

    Article  PubMed  Google Scholar 

  82. Carson KR, Focosi D, Major EO, et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009;10:816-824.

    Article  PubMed  CAS  Google Scholar 

  83. Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006;103:5941-5946.

    Article  PubMed  CAS  Google Scholar 

  84. Bielekova B, Richert N, Howard T, et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U S A 2004;101:8705-8708.

    Article  PubMed  CAS  Google Scholar 

  85. Rose JW, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 2004;56:864-867.

    Article  PubMed  CAS  Google Scholar 

  86. Ali EN, Healy BC, Stazzone LA, Brown BA, Weiner HL, Khoury SJ. Daclizumab in treatment of multiple sclerosis patients. Mult Scler 2009;15:272-274.

    Article  PubMed  CAS  Google Scholar 

  87. Sheridan C. Abbott outbids Biogen for Facet's multiple sclerosis antibody. Nat Biotechnol 2010;28:387-389.

    Article  PubMed  CAS  Google Scholar 

  88. Fernandez-Fernandez O, Alvarez-Cermeno JC, Arbizu-Urdiain T, et al. [Review of the novelties presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II)]. Rev Neurol 2011;52:289-299.

    PubMed  CAS  Google Scholar 

  89. Gorman MP, Tillema JM, Ciliax AM, Guttmann CR, Chitnis T. Daclizumab use in patients with pediatric multiple sclerosis. Arch Neurol 2012;69:78-81.

    Article  PubMed  Google Scholar 

  90. Di Filippo S. Anti-IL-2 receptor antibody vs. polyclonal anti-lymphocyte antibody as induction therapy in pediatric transplantation. Pediatr Transplant 2005;9:373-380.

    Article  PubMed  Google Scholar 

  91. Gallagher M, Quinones K, Cervantes-Castaneda RA, Yilmaz T, Foster CS. Biological response modifier therapy for refractory childhood uveitis. Br J Ophthalmol 2007;91:1341-1344.

    Article  PubMed  Google Scholar 

Download references

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Authors and Affiliations

  1. Harvard Medical School, Boston, MA, 02115, USA

    Tanuja Chitnis

  2. Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, 02114, USA

    Tanuja Chitnis

Authors
  1. Tanuja Chitnis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tanuja Chitnis.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 510 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chitnis, T. Disease-Modifying Therapy of Pediatric Multiple Sclerosis. Neurotherapeutics 10, 89–96 (2013). https://doi.org/10.1007/s13311-012-0158-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13311-012-0158-1

Keywords

Search

Navigation