Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapies for multiple sclerosis: considerations in the pediatric patient

Nature Reviews Neurology volume 7, pages 109–122 (2011)Cite this article

Subjects

Abstract

Current and emerging therapies for multiple sclerosis (MS) offer promise for improved disease control and long-term clinical outcome. To date, these therapies have been evaluated solely in the context of adult MS. However, onset of MS in children is being increasingly recognized, and recent studies have identified a significant impact of MS onset during childhood on cognitive and physical functioning. Optimization of pediatric MS care requires that promising new therapies be made available to children and adolescents, but also that safety and tolerability and potential influence of therapies on the developing immune and neural networks of pediatric patients be closely considered. We propose care algorithms illustrating models for therapy that detail careful monitoring of pediatric patients with MS, provide definitions for inadequate treatment response and treatment escalation, and foster multinational collaboration in future therapeutic trials.

Key Points

  • Currently approved immunomodulatory therapies for multiple sclerosis (MS) in adults appear to be safe and efficacious in children, but ≈30% of pediatric MS patients will relapse despite treatment

  • Maturation of the fundamental components of the immune system occurs in utero and in early infancy, well before the typical clinical onset of childhood MS

  • Similar risk factors and immune mechanisms seem to contribute to MS pathophysiology in children and adults, so the relevant mechanisms of action of therapies are also likely to be similar

  • The impact of emerging therapies—particularly those that access the CNS—on disease neurobiology and the still-maturing CNS warrants further investigation

  • Evidence-based decisions are urgently needed to define 'adequate' and 'inadequate' treatment responses—a key issue in pediatric MS patients owing to concerns regarding rapid escalation to more-powerful therapies with greater potential toxicities

  • Shared models of care across multiple centers worldwide are essential to meaningfully optimize and monitor care for children and adolescents with MS

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Treatment models for pediatric multiple sclerosis: start low and escalate if needed.
Figure 2: Treatment models for pediatric multiple sclerosis: start strong, maintain remission.
Figure 3: MS attack frequency in pediatric patients.

Similar content being viewed by others

References

  1. Gorman, M. P., Healy, B. C., Polgar-Turcsanyi, M. & Chitnis, T. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch. Neurol. 66, 54–59 (2009).

    Article  PubMed  Google Scholar 

  2. Ghezzi, A. et al. The management of multiple sclerosis in children: a European view. Mult. Scler. 16, 1258–1267 (2010).

    Article  PubMed  Google Scholar 

  3. Pohl, D. et al. Treatment of pediatric multiple sclerosis and variants. Neurology 68 (16 Suppl. 2), S54–S65 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Chabas, D., Strober, J. & Waubant, E. Pediatric multiple sclerosis. Curr. Neurol. Neurosci. Rep. 8, 434–441 (2008).

    Article  PubMed  Google Scholar 

  5. Dale, R. C., Brilot, F. & Banwell, B. Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis. Curr. Opin. Neurol. 22, 233–240 (2009).

    Article  PubMed  Google Scholar 

  6. Rostásy, K. et al. Clinical outcome of children presenting with a severe manifestation of acute disseminated encephalomyelitis. Neuropediatrics 40, 211–217 (2009).

    Article  PubMed  Google Scholar 

  7. Venkateswaran, S. & Banwell, B. Pediatric multiple sclerosis. Neurologist 16, 92–105 (2010).

    Article  PubMed  Google Scholar 

  8. Waubant, E. & Chabas, D. Pediatric multiple sclerosis. Curr. Treat. Options Neurol. 11, 203–210 (2009).

    Article  PubMed  Google Scholar 

  9. Yeh, E. A. et al. Pediatric multiple sclerosis. Nat. Rev. Neurol. 5, 621–631 (2009).

    Article  PubMed  Google Scholar 

  10. Banwell, B., Ghezzi, A., Bar-Or, A., Mikaeloff, Y. & Tardieu, M. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 6, 887–902 (2007).

    Article  PubMed  Google Scholar 

  11. Banwell, B. et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol. 6, 773–781 (2007).

    Article  PubMed  Google Scholar 

  12. Deryck, O., Ketelaer, P. & Dubois, B. Clinical characteristics and long term prognosis in early onset multiple sclerosis. J. Neurol. 253, 720–723 (2006).

    Article  PubMed  Google Scholar 

  13. Ghassemi, R. et al. Lesion distribution in children with clinically isolated syndromes. Ann. Neurol. 63, 401–405 (2008).

    Article  PubMed  Google Scholar 

  14. Ghezzi, A. et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult. Scler. 3, 43–46 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Ghezzi, A. et al. Prospective study of multiple sclerosis with early onset. Mult. Scler. 8, 115–118 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Mikaeloff, Y., Caridade, G., Assi, S., Suissa, S. & Tardieu, M. Prognostic factors for early severity in a childhood multiple sclerosis cohort. Pediatrics 118, 1133–1139 (2006).

    Article  PubMed  Google Scholar 

  17. Renoux, C. et al. Natural history of multiple sclerosis with childhood onset. N. Engl. J. Med. 356, 2603–2613 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Waubant, E. 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. 66, 967–971 (2009).

    Article  PubMed  Google Scholar 

  19. Krupp, L. et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology 68 (16 Suppl. 2), S7–S12 (2007).

    Article  PubMed  Google Scholar 

  20. Alotaibi, S., Kennedy, J., Tellier, R., Stephens, D. & Banwell, B. Epstein–Barr virus in pediatric multiple sclerosis. JAMA 291, 1875–1879 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Ascherio, A. & Munger, K. L. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61, 288–299 (2007).

    Article  PubMed  Google Scholar 

  22. Bar-Or, A. The immunology of multiple sclerosis. Semin. Neurol. 28, 29–45 (2008).

    Article  PubMed  Google Scholar 

  23. Ebers, G. C. et al. A full genome search in multiple sclerosis. Nat. Genet. 13, 472–476 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Hafler, D. A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Trapp, B. D., Ransohoff, R., Fisher, E. & Rudick, R. Neurodegeneration in multiple sclerosis: relationship to neurological disability. Neuroscientist 5, 48–57 (1999).

    Article  Google Scholar 

  26. Yeh, E. A. et al. Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. Brain 132, 3392–3400 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Callen, D. J. et al. MRI in the diagnosis of pediatric multiple sclerosis. Neurology 72, 961–967 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Chabas, D. et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology 74, 399–405 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pohl, D., Rostasy, K., Reiber, H. & Hanefeld, F. CSF characteristics in early-onset multiple sclerosis. Neurology 63, 1966–1967 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Banwell, B. et al. T-cell proliferation against myelin, pancreatic, and dietary antigens in children: autoimmunity is detectable early in CNS demyelination and type I diabetes [abstract S42.001]. Neurology 66 (Suppl. 2), A310 (2006).

    Google Scholar 

  31. McLaughlin, K. A. et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J. Immunol. 183, 4067–4076 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Disanto, G. et al. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology (in press).

  33. Mowry, E. M. et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann. Neurol. 67, 618–624 (2010).

    CAS  PubMed  Google Scholar 

  34. Pohl, D. et al. High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 67, 2063–2065 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Mikaeloff, Y. et al. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 130, 2589–2595 (2007).

    Article  PubMed  Google Scholar 

  36. Giovannoni, G. & Ebers, G. Multiple sclerosis: the environment and causation. Curr. Opin. Neurol. 20, 261–268 (2007).

    Article  PubMed  Google Scholar 

  37. Abraham, C. M. & Ownby, D. R. Ontogeny of the allergic inflammatory response. Immunol. Allergy Clin. North Am. 25, 215–229 (2005).

    Article  PubMed  Google Scholar 

  38. Cunningham-Rundles, S. et al. Human immune development: implications for congenital HIV infection. Ann. N. Y. Acad. Sci. 693, 20–34 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Bartlett, B. L., Pellicane, A. J. & Tyring, S. K. Vaccine immunology. Dermatol. Ther. 22, 104–109 (2009).

    Article  PubMed  Google Scholar 

  40. Decaminada, N. et al. Familial hemophagocytic lymphohistiocytosis: clinical and neuroradiological findings and review of the literature. Childs Nerv. Syst. 26, 121–127 (2010).

    Article  PubMed  Google Scholar 

  41. Crow, Y. J. & Rehwinkel, J. Aicardi–Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum. Mol. Genet. 18, R130–R136 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Krug, P. et al. Opsoclonus–myoclonus in children associated or not with neuroblastoma. Eur. J. Paediatr. Neurol. 14, 400–409 (2010).

    Article  PubMed  Google Scholar 

  43. Dale, R. C. et al. N-methyl-D-aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann. Neurol. 66, 704–709 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Girard, S. et al. Role of perinatal inflammation in cerebral palsy. Pediatr. Neurol. 40, 168–174 (2009).

    Article  PubMed  Google Scholar 

  45. Adkins, B., Leclerc, C. & Marshall-Clarke, S. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Banwell, B. et al. Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann. Neurol. 63, 98–111 (2008).

    Article  PubMed  Google Scholar 

  48. O'Connor, K. C. et al. Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. J. Neuroimmunol. 136, 140–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. O'Connor, K. C. et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J. Neuroimmunol. 223, 92–99 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. O'Connor, K. C. et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 13, 211–217 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Afifi, A., Raja, S. G., Pennington, D. J. & Tsang, V. T. For neonates undergoing cardiac surgery does thymectomy as opposed to thymic preservation have any adverse immunological consequences? Interact. Cardiovasc. Thorac. Surg. 11, 287–291 (2010).

    Article  PubMed  Google Scholar 

  52. Agarwal, S. & Busse, P. J. Innate and adaptive immunosenescence. Ann. Allergy Asthma Immunol. 104, 183–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Duzova, A. & Bakkaloglu, A. Central nervous system involvement in pediatric rheumatic diseases: current concepts in treatment. Curr. Pharm. Des. 14, 1295–1301 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Ramanan, A. V. et al. The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis Rheum. 52, 3570–3578 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Ranchin, B. & Fargue, S. New treatment strategies for proliferative lupus nephritis: keep children in mind! Lupus 16, 684–691 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Tintoré, M. et al. Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. AJNR Am. J. Neuroradiol. 21, 702–706 (2000).

    PubMed  PubMed Central  Google Scholar 

  57. Mikaeloff, Y. et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J. Pediatr. 144, 246–252 (2004).

    Article  PubMed  Google Scholar 

  58. Scalfari, A. et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 133, 1914–1929 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. McFarland, H. F. Examination of the role of magnetic resonance imaging in multiple sclerosis: a problem-orientated approach. Ann. Indian Acad. Neurol. 12, 254–263 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Rudick, R. A. et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 49, 358–363 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Ascherio, A. & Munger, K. L. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann. Neurol. 61, 504–513 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. van der Mei, I. A. et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case–control study. BMJ 327, 316 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kimball, S. M., Ursell, M. R., O'Connor, P. & Vieth, R. Safety of vitamin D3 in adults with multiple sclerosis. Am. J. Clin. Nutr. 86, 645–651 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. van der Mei, I. A. et al. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J. Neurol. 254, 581–590 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Burton, J. M. et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 74, 1852–1859 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. El Hajj Fuleihan, G. et al. Hypovitaminosis D in healthy schoolchildren. Pediatrics 107, E53 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Maalouf, J. et al. Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children. J. Clin. Endocrinol. Metab. 93, 2693–2701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Vieth, R., Cole, D. E., Hawker, G., Trang, H. M. & Rubin, L. A. Wintertime vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it. Eur. J. Clin. Nutr. 55, 1091–1097 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Hanwell, H. E. & Banwell, B. Assessment of evidence for a protective role of vitamin D in multiple sclerosis. Biochim. Biophys. Acta doi:10.1016/j.bbadis.2010.07.017.

  70. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. [No authors listed] Vitamin D supplementation: recommendations for Canadian mothers and infants. Pediatr. Child Health 12, 583–598 (2007).

  72. Dawson-Hughes, B. et al. Estimates of optimal vitamin D status. Osteoporos. Int. 16, 713–716 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Baker, S. S. et al. American Academy of Pediatrics. Committee on Nutrition. Calcium requirements of infants, children, and adolescents. Pediatrics 104, 1152–1157 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Expert Group on Vitamins and Minerals. Safe upper levels for vitamins and minerals. Food Standards Agency, London, UK [online], (2003).

  75. Ghazi, A. A. et al. Effects of different doses of oral cholecalciferol on serum 25(OH)D, PTH, calcium and bone markers during fall and winter in schoolchildren. Eur. J. Clin. Nutr. doi:10.1038/ejcn.2010.169.

  76. Filippini, G. et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database of Systematic Reviews, Issue 4, Art. No.: CD001331. doi:10.1002/14651858.CD001331 (2000).

  77. Hahn, J. S., Siegler, D. J. & Enzmann, D. Intravenous gammaglobulin therapy in recurrent acute disseminated encephalomyelitis. Neurology 46, 1173–1174 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Nishikawa, M., Ichiyama, T., Hayashi, T., Ouchi, K. & Furukawa, S. Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis. Pediatr. Neurol. 21, 583–586 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Boyd, J. R. & MacMillan, L. J. Experiences of children and adolescents living with multiple sclerosis. J. Neurosci. Nurs. 37, 334–342 (2005).

    Article  PubMed  Google Scholar 

  80. Tenembaum, S. N. & Segura, M. J. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology 67, 511–513 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Banwell, B. et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology 66, 472–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Ghezzi, A. et al. Immunomodulatory treatment of early onset multiple sclerosis: results of an Italian Co-operative Study. Neurol. Sci. 26 (Suppl. 4), S183–S186 (2005).

    Article  PubMed  Google Scholar 

  83. Ghezzi, A. et al. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol. Sci. 30, 193–199 (2009).

    Article  PubMed  Google Scholar 

  84. Ghezzi, A. et al. Disease-modifying drugs in childhood–juvenile multiple sclerosis: results of an Italian co-operative study. Mult. Scler. 11, 420–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Mikaeloff, Y. et al. Effectiveness of early beta interferon on the first attack after confirmed multiple sclerosis: a comparative cohort study. Eur. J. Paediatr. Neurol. 12, 205–209 (2008).

    Article  PubMed  Google Scholar 

  86. Pohl, D. Rostasy, K., Hanefeld, F. & Gartner, J. The use of interferon-beta-1a (Rebif) in children and adolescents with multiple sclerosis. Mult. Scler. 10 (Suppl. 2), S250 (2004).

    Google Scholar 

  87. Waubant, E. et al. Interferon beta-1a in children with multiple sclerosis is well tolerated. Neuropediatrics 32, 211–213 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Polman, C. H. et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol. 9, 740–750 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. O'Connor, P. Key issues in the diagnosis and treatment of multiple sclerosis. An overview. Neurology 59 (6 Suppl. 3), S1–S33 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Boiko, A. et al. Early onset multiple sclerosis: a longitudinal study. Neurology 59, 1006–1010 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Huppke, P. et al. Natalizumab use in pediatric multiple sclerosis. Arch. Neurol. 65, 1655–1658 (2008).

    Article  PubMed  Google Scholar 

  93. Ghezzi, A. et al. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology 75, 912–917 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Borriello, G., Prosperini, L., Luchetti, A. & Pozzilli, C. Natalizumab treatment in pediatric multiple sclerosis: a case report. Eur. J. Paediatr. Neurol. 13, 67–71 (2009).

    Article  PubMed  Google Scholar 

  95. Clifford, D. B. et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 9, 438–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. TYSABRI. Biogen Idec[online], (2010).

  97. Gorelik, L. et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann. Neurol. 68, 295–303 (2010).

    Article  PubMed  Google Scholar 

  98. Martinelli, V., Radaelli, M., Straffi, L., Rodegher, M. & Comi, G. Mitoxantrone: benefits and risks in multiple sclerosis patients. Neurol. Sci. 30 (Suppl. 2), S167–S170 (2009).

    Article  PubMed  Google Scholar 

  99. Pascual, A. M. et al. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult. Scler. 15, 1303–1310 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. [No authors listed] The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. The Canadian Cooperative Multiple Sclerosis Study Group. Lancet 337, 441–446 (1991).

  101. Makhani, N. et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology 72, 2076–2082 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ginsberg, J. P. et al. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum. Reprod. 25, 37–41 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Casetta, I. Iuliano, G. & Filippini, G. Azathioprine for multiple sclerosis. Cochrane Database of Systematic Reviews, Issue 4, Art. No.: CD003982. doi:10.1002/14651858.CD003982.pub2 (2007).

  104. La Mantia, L., Mascoli, N. & Milanese, C. Azathioprine. Safety profile in multiple sclerosis patients. Neurol. Sci. 28, 299–303 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Bar-Or, A. et al. Serial combination therapy: is immune modulation in multiple sclerosis enhanced by initial immune suppression? Mult. Scler. 15, 959–964 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Giacomini, P. S., Arnold, D. L., Bar-Or, A. & Antel, J. P. Defining multiple sclerosis treatment response with magnetic resonance imaging: how much activity is too much? Arch. Neurol. 66, 19–20 (2009).

    Article  PubMed  Google Scholar 

  107. Rieckmann, P. Concepts of induction and escalation therapy in multiple sclerosis. J. Neurol. Sci. 277 (Suppl. 1), S42–S45 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Coyle, P. K. Disease-modifying agents in multiple sclerosis. Ann. Indian Acad. Neurol. 12, 273–282 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cox, A. L. et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur. J Immunol. 35, 3332–3342 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Freedman, M. S. Bone marrow transplantation: does it stop MS progression? J. Neurol. Sci. 259, 85–89 (2007).

    Article  PubMed  Google Scholar 

  111. Fagius, J., Lundgren, J. & Oberg, G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult. Scler. 15, 229–237 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Bar-Or, A. et al. Rituximab in relapsing–remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann. Neurol. 63, 395–400 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Hauser, S. L. et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Barun, B. & Bar-Or, A. Treatment of multiple sclerosis with anti-CD20 antibodies. Clin. Immunol. (in press).

  115. Marks, S. D. & Tullus, K. Modern therapeutic strategies for paediatric systemic lupus erythematosus and lupus nephritis. Acta Paediatr. 99, 967–974 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Calabrese, L. H. & Molloy, E. S. Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies. Ann. Rheum. Dis. 67 (Suppl. 3), iii64–iii65 (2008).

    PubMed  Google Scholar 

  117. Carson, K. R. et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113, 4834–4840 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wynn, D. et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 9, 381–390 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Durafourt, B. A. et al. Differential responses of human microglia and blood-derived myeloid cells to FTY720. J. Neuroimmunol. doi:10.1016/j.jneuroim.2010.08.006.

  120. Miron, V. E. et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann. Neurol. 63, 61–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Drennan, M. B., Elewaut, D. & Hogquist, K. A. Thymic emigration: sphingosine-1-phosphate receptor-1-dependent models and beyond. Eur. J. Immunol. 39, 925–930 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Cohen, J. A. et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362, 402–415 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387–401 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Johnson, T. A., Lapierre, Y., Bar-Or, A. & Antel, J. P. Distinct properties of circulating CD8+ T cells in FTY720-treated patients with multiple sclerosis. Arch. Neurol. 67, 1449–1455 (2010).

    Article  PubMed  Google Scholar 

  125. Johnson, T. A. et al. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin. Immunol. 137, 15–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Giacomini, P. S. & Bar-Or, A. Antigen-specific therapies in multiple sclerosis. Expert Opin. Emerg. Drugs 14, 551–560 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Zeyda, M. et al. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheum. 52, 2730–2739 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Bar-Or, A. et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch. Neurol. 64, 1407–1415 (2007).

    Article  PubMed  Google Scholar 

  129. Correale, J. & Fiol, M. BHT-3009, a myelin basic protein-encoding plasmid for the treatment of multiple sclerosis. Curr. Opin. Mol. Ther. 11, 463–470 (2009).

    CAS  PubMed  Google Scholar 

  130. Marriott, J. J. & O'Connor, P. W. Emerging therapies in relapsing–remitting multiple sclerosis. Rev. Recent Clin. Trials 5, 179–188 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Gawronski, K. M., Rainka, M. M., Patel, M. J. & Gengo, F. M. Treatment options for multiple sclerosis: current and emerging therapies. Pharmacotherapy 30, 916–927 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Cohen, E. et al. Child vs adult randomized controlled trials in specialist journals: a citation analysis of trends, 1985–2005. Arch. Pediatr. Adolesc. Med. 164, 283–288 (2010).

    Article  PubMed  Google Scholar 

  133. Budetti, P. P. Ensuring safe and effective medications for children. JAMA 290, 950–951 (2003).

    Article  PubMed  Google Scholar 

  134. Roberts, R., Rodriguez, W., Murphy, D. & Crescenzi, T. Pediatric drug labeling: improving the safety and efficacy of pediatric therapies. JAMA 290, 905–911 (2003).

    Article  PubMed  Google Scholar 

  135. Rivara, F. P. & Alexander, D. Randomized controlled trials and pediatric research. Arch. Pediatr. Adolesc. Med. 164, 296–297 (2010).

    Article  PubMed  Google Scholar 

  136. Chessells, J. M. Treatment of childhood acute lymphoblastic leukaemia: present issues and future prospects. Blood Rev. 6, 193–203 (1992).

    Article  CAS  PubMed  Google Scholar 

  137. Kurtzke, J. F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33, 1444–1452 (1983).

    Article  CAS  PubMed  Google Scholar 

  138. Amato, M. P. et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology 70, 1891–1897 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Banwell, B. L. & Anderson, P. E. The cognitive burden of multiple sclerosis in children. Neurology 64, 891–894 (2005).

    Article  PubMed  Google Scholar 

  140. MacAllister, W. S. et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology 64, 1422–1425 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Banwell, B. & Tremlett, H. Coming of age: the use of immunomodulatory therapy in children with multiple sclerosis. Neurology 64, 778–779 (2005).

    Article  PubMed  Google Scholar 

  142. Mikaeloff, Y., Caridade, G., Billard, C., Bouyer, J. & Tardieu, M. School performance in a cohort of children with CNS inflammatory demyelination. Eur. J. Paediatr. Neurol. 14, 418–424 (2010).

    Article  PubMed  Google Scholar 

  143. Sormani, M. P. et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann. Neurol. 65, 268–275 (2009).

    Article  PubMed  Google Scholar 

  144. Rudick, R. A., Lee, J. C., Simon, J., Ransohoff, R. M. & Fisher, E. Defining interferon β response status in multiple sclerosis patients. Ann. Neurol. 56, 548–555 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Río, J. et al. Relationship between MRI lesion activity and response to IFN-β in relapsing–remitting multiple sclerosis patients. Mult. Scler. 14, 479–484 (2008).

    Article  PubMed  Google Scholar 

  146. Benedict, R. H. et al. Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. Arch. Neurol. 61, 226–230 (2004).

    Article  PubMed  Google Scholar 

  147. Sicotte, N. L. et al. Regional hippocampal atrophy in multiple sclerosis. Brain 131, 1134–1141 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Till, C. et al. MRI correlates of cognitive impairment in childhood onset multiple sclerosis. Neuropsychology (in press).

  149. International Pediatric MS Study Group [online], (2007).

  150. Polman, C. H. et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 58, 840–846 (2005).

    Article  PubMed  Google Scholar 

  151. The Consortium of Multiple Sclerosis Centers [online], (2010).

  152. Killestein, J. et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann. Neurol. 68, 392–395 (2010).

    Article  PubMed  Google Scholar 

  153. Mikaeloff, Y. et al. Interferon-β treatment in patients with childhood-onset multiple sclerosis. J. Pediatr. 139, 443–446 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Ghezzi, A. Clinical characteristics of multiple sclerosis with early onset. Neurol. Sci. 25 (Suppl. 4), S336–S339 (2004).

    Article  PubMed  Google Scholar 

  155. Pohl, D., Rostasy, K., Gärtner, J. & Hanefeld, F. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology 64, 888–890 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Kornek, B. et al. Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Neuropediatrics 34, 120–126 (2003).

    Article  CAS  PubMed  Google Scholar 

  157. Sevon, M, Sumelhati, M. L., Tienari, P., Haltia, M. & Iivanainen, M. Multiple sclerosis in childhood and its prognosis. Int. MS J. 8, 28–33 (2001).

    Google Scholar 

  158. Shiraishi, K., Higuchi, Y., Ozawa, K., Hao, Q. & Saida, T. Clinical course and prognosis of 27 patients with childhood onset multiple sclerosis in Japan. Brain Dev. 27, 224–227 (2005).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

B. Banwell and A. Bar-Or are supported by the Multiple Sclerosis Society of Canada (MSSC) and the Canadian Multiple Sclerosis Scientific Research Foundation, and by a New Emerging Team Grant in Autoimmunity supported by the Canadian Institutes of Health Research and MSSC. G. Giovannoni is supported by the National MS Society, the MS Society of Great Britain and Northern Ireland, AIMS2CURE and the Medical Research Council. R. C. Dale has received funding through Multiple Sclerosis Research Australia, and M. Tardieu is supported by the Institut National de la Recherche Médicale (INSERM U1012), Université Paris Sud 11, Assistance Publique-Hôpitaux de Paris.

Author information

Authors and Affiliations

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

    Brenda Banwell

  2. Department of Neurology and Neurosurgery, Montreal Neurological Institute, 3801 University, Room 111, Montreal, H3A 2B4, QC, Canada

    Amit Bar-Or

  3. Queen Mary University of London, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, E1 2AT, London, UK

    Gavin Giovannoni

  4. Clinical School, Locked Bag 4001, The Children's Hospital at Westmead, Sydney, 2145, NSW, Australia

    Russell C. Dale

  5. Neurologie Pediatrique, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275, Le Kremlin Bicêtre Cedex, France

    Marc Tardieu

Authors
  1. Brenda Banwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amit Bar-Or
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gavin Giovannoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Russell C. Dale
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marc Tardieu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B. Banwell and M. Tardieu designed and contributed to the entire content of the manuscript. A. Bar-Or, G. Giovannoni, and R. C. Dale assisted in the design of the manuscript and contributed to the core text. All authors provided edits to the final manuscript.

Corresponding author

Correspondence to Brenda Banwell.

Ethics declarations

Competing interests

None of the authors report a conflict of interest related to the present work. B. Banwell has received speaker's honoraria from Merck-Serono, Biogen-IDEC, Bayer Healthcare, and Teva Neuroscience, and serves as an advisor on pediatric therapies for Biogen-IDEC, Merck-Serono and Genzyme. A. Bar-Or has received honoraria for speaking at meetings supported by, or consulting for: Bayer, Bayhill Therapeutics, Berlex, Biogen-Idec, BioMS, Diogenix, Eli-Lilly, GlaxoSmithKline, Merck-Serono, Novartis, Roche/Genentech, Sanofi-Aventis, Serono, Teva Neuroscience and Wyeth. G. Giovannoni reports having received consulting fees from Bayer-Schering Healthcare, Biogen-Idec, Genzyme, GlaxoSmithKline, Merck-Serono, Novartis, Protein Discovery Laboratories, Teva-Aventis and UCB Pharma; lecture fees from Bayer-Schering Healthcare, Biogen-Idec, Pfizer, Teva-Aventis and Vertex; and grant support from Bayer-Schering Healthcare, Biogen-Idec, Merck-Serono, Merz, Novartis, Teva-Aventis and UCB Pharma. R. C. Dale has received honoraria for speaking at meetings for Biogen-Idec. M. Tardieu has received speaker's honoraria from LFB and Sanofi, and has received travel support to serve as an advisor on pediatric therapies for Biogen-IDEC and Genzyme.

Supplementary information

Supplementary Table 1

Established and emerging therapies in phase II or III development for MS (DOC 96 kb)

Supplementary Table 2

Attacks experienced in first 2 years of multiple sclerosis in 106 pediatric patients (DOC 54 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Banwell, B., Bar-Or, A., Giovannoni, G. et al. Therapies for multiple sclerosis: considerations in the pediatric patient. Nat Rev Neurol 7, 109–122 (2011). https://doi.org/10.1038/nrneurol.2010.198

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2010.198

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing