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Pediatric Multiple Sclerosis: an Update

  • Pediatric Neurology (W Kaufmann, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Diagnostic criteria for pediatric-onset multiple sclerosis (POMS) and related demyelinating disorders have been updated, neuroimaging studies have revealed new insights, biological assays identify patients with specific antibodies that influence both diagnosis and treatment, clinical trials are informing on treatment efficacy and safety, and longitudinal studies of neurological, cognitive and quality of life outcomes are informing on the impact of these diseases. We provide updates to assist providers caring for these children.

Recent Findings

The recent 2017 McDonald Criteria for MS provide a simplified means to confirm diagnosis at onset and over time, and have been shown to be equally applicable for POMS. MRI analyses demonstrate that brain volume is reduced at onset, and that both volumetric and tissue integrity measures decline over time, indicating that POMS shares the degenerative aspects that also characterize adult-onset disease. The presence of myelin oligodendrocyte glycoprotein (MOG) antibodies at onset is detected in more than 50% of children with acute disseminated encephalomyelitis. When persistent over time, they are associated with relapsing disease. The first randomized clinical trials of disease supports superiority of fingolimod over subcutaneous interferon beta 1a, and demonstrated a favorable safety profile. Finally, while Expanded Disability Status Scale (EDSS) scores remain low in the first 10 years post-onset, POMS is associated with high rates of patient-reported fatigue and reduced engagement in exercise and carries a risk for cognitive impairment.

Summary

The past 15 years have borne witness to a marked expansion in recognition and research in POMS. There are now more specific diagnostic criteria, antibodies to CNS proteins appear to define diagnostically distinct disorders, clinical trials have successfully launched and one has completed, and we are gaining increasing appreciation of the impact of MS and related disorders on the lived experience of children and adolescents.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D. University of British Columbia MSCN. Early onset multiple sclerosis: a longitudinal study. Neurology. 2002;59(7):1006–10.

    Article  CAS  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(25):2603–13. https://doi.org/10.1056/NEJMoa067597.

    Article  CAS  PubMed  Google Scholar 

  3. Waldman A, Ness J, Pohl D, Simone IL, Anlar B, Amato MP, et al. Pediatric multiple sclerosis: clinical features and outcome. Neurology. 2016;87(9 Suppl 2):S74–81. https://doi.org/10.1212/WNL.0000000000003028.

    Article  PubMed  Google Scholar 

  4. Krajnc N, Orazem J, Rener-Primec Z, Krzan MJ. Multiple sclerosis in pediatric patients in Slovenia. Mult Scler Relat Disord. 2018;20:194–8. https://doi.org/10.1016/j.msard.2018.01.026.

    Article  CAS  PubMed  Google Scholar 

  5. Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai Y, Sanefuji M, et al. A nationwide survey of pediatric acquired demyelinating syndromes in Japan. Neurology. 2016;87(19):2006–15. https://doi.org/10.1212/WNL.0000000000003318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gudbjornsson BT, Haraldsson A, Einarsdottir H, Thorarensen O. Nationwide incidence of acquired central nervous system demyelination in Icelandic children. Pediatr Neurol. 2015;53(6):503–7. https://doi.org/10.1016/j.pediatrneurol.2015.08.020.

    Article  PubMed  Google Scholar 

  7. Reinhardt K, Weiss S, Rosenbauer J, Gartner J, von Kries R. Multiple sclerosis in children and adolescents: incidence and clinical picture - new insights from the nationwide German surveillance (2009-2011). Eur J Neurol. 2014;21(4):654–9. https://doi.org/10.1111/ene.12371.

    Article  CAS  PubMed  Google Scholar 

  8. Achiron A, Garty BZ, Menascu S, Magalashvili D, Dolev M, Ben-Zeev B, et al. Multiple sclerosis in Israeli children: incidence, an clinical, cerebrospinal fluid and magnetic resonance imaging findings. Isr Med Assoc J. 2012;14(4):234–9.

    PubMed  Google Scholar 

  9. Dell’Avvento S, Sotgiu MA, Manca S, Sotgiu G, Sotgiu S. Epidemiology of multiple sclerosis in the pediatric population of Sardinia, Italy. Eur J Pediatr. 2016;175(1):19–29. https://doi.org/10.1007/s00431-015-2588-3.

    Article  PubMed  Google Scholar 

  10. Simpson S Jr, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(10):1132–41. https://doi.org/10.1136/jnnp.2011.240432.

    Article  PubMed  Google Scholar 

  11. Tao C, Simpson S Jr, van der Mei I, Blizzard L, Havrdova E, Horakova D, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(12):1343–9. https://doi.org/10.1136/jnnp-2016-314013.

    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(1). https://doi.org/10.1542/peds.2016-0120.

    Article  Google Scholar 

  13. Renoux C, Vukusic S, Confavreux C. The natural history of multiple sclerosis with childhood onset. Clin Neurol Neurosurg. 2008;110(9):897–904. https://doi.org/10.1016/j.clineuro.2008.04.009.

    Article  PubMed  Google Scholar 

  14. Rhead B, Baarnhielm M, Gianfrancesco M, Mok A, Shao X, Quach H, et al. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. Neurol Genet. 2016;2(5):e97. https://doi.org/10.1212/NXG.0000000000000097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gomez C, et al. Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis. Am J Hum Genet. 2017;101(2):227–38. https://doi.org/10.1016/j.ajhg.2017.06.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67(5):618–24. https://doi.org/10.1002/ana.21972.

    Article  CAS  PubMed  Google Scholar 

  17. Gianfrancesco MA, Stridh P, Rhead B, Shao X, Xu E, Graves JS, et al. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017;88(17):1623–9. https://doi.org/10.1212/WNL.0000000000003849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hedstrom AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler. 2012;18(9):1334–6. https://doi.org/10.1177/1352458512436596.

    Article  PubMed  Google Scholar 

  19. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80(6):548–52. https://doi.org/10.1212/WNL.0b013e31828154f3.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Huitema MJD, Schenk GJ. Insights into the mechanisms that may clarify obesity as a risk factor for multiple sclerosis. Curr Neurol Neurosci Rep. 2018;18(4):18. https://doi.org/10.1007/s11910-018-0827-5.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cook DG, Mendall MA, Whincup PH, Carey IM, Ballam L, Morris JE, et al. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors. Atherosclerosis. 2000;149(1):139–50.

    Article  CAS  Google Scholar 

  22. Valle M, Martos R, Gascon F, Canete R, Zafra MA, Morales R. Low-grade systemic inflammation, hypoadiponectinemia and a high concentration of leptin are present in very young obese children, and correlate with metabolic syndrome. Diabetes Metab. 2005;31(1):55–62.

    Article  CAS  Google Scholar 

  23. Hypponen E, Boucher BJ. Adiposity, vitamin D requirements, and clinical implications for obesity-related metabolic abnormalities. Nutr Rev. 2018;76:678–92. https://doi.org/10.1093/nutrit/nuy034.

    Article  PubMed  Google Scholar 

  24. Lavery AM, Collins BN, Waldman AT, Hart CN, Bar-Or A, Marrie RA, et al. The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk. Mult Scler. 2018;1352458518757089:135245851875708. https://doi.org/10.1177/1352458518757089.

    Article  Google Scholar 

  25. Disanto G, Magalhaes S, Handel AE, Morrison KM, Sadovnick AD, Ebers GC, et al. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology. 2011;76(9):781–6. https://doi.org/10.1212/WNL.0b013e31820ee1cd.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. van Pelt ED, Mescheriakova JY, Makhani N, Ketelslegers IA, Neuteboom RF, Kundu S, et al. Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination. Neurology. 2013;81(23):1996–2001. https://doi.org/10.1212/01.wnl.0000436934.40034eb.

    Article  CAS  PubMed  Google Scholar 

  27. Gianfrancesco MA, Stridh P, Shao X, Rhead B, Graves JS, Chitnis T, et al. Genetic risk factors for pediatric-onset multiple sclerosis. Mult Scler. 2017;1352458517733551:135245851773355. https://doi.org/10.1177/1352458517733551.

    Article  Google Scholar 

  28. Graves JS, Barcellos LF, Simpson S, Belman A, Lin R, Taylor BV, et al. The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults. Mult Scler Relat Disord. 2018;19:161–5. https://doi.org/10.1016/j.msard.2017.10.008.

    Article  PubMed  Google Scholar 

  29. Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol. 2016;23(8):1308–21. https://doi.org/10.1111/ene.13026.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tremlett H, Waubant E. Gut microbiome and pediatric multiple sclerosis. Mult Scler. 2018;24(1):64–8. https://doi.org/10.1177/1352458517737369.

    Article  PubMed  Google Scholar 

  31. Tremlett H, Fadrosh DW, Faruqi AA, Hart J, Roalstad S, Graves J, et al. Gut microbiota composition and relapse risk in pediatric MS: a pilot study. J Neurol Sci. 2016;363:153–7. https://doi.org/10.1016/j.jns.2016.02.042.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Waubant E, Ponsonby AL, Pugliatti M, Hanwell H, Mowry EM, Hintzen RQ. Environmental and genetic factors in pediatric inflammatory demyelinating diseases. Neurology. 2016;87(9 Suppl 2):S20–7. https://doi.org/10.1212/WNL.0000000000003029.

    Article  CAS  PubMed  Google Scholar 

  33. Leibovitch EC, Lin CM, Billioux BJ, Graves J, Waubant E, Jacobson S. Prevalence of salivary human herpesviruses in pediatric multiple sclerosis cases and controls. Mult Scler. 2018;1352458518765654:135245851876565. https://doi.org/10.1177/1352458518765654.

    Article  Google Scholar 

  34. Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B. Epstein-Barr virus in pediatric multiple sclerosis. JAMA. 2004;291(15):1875–9. https://doi.org/10.1001/jama.291.15.1875.

    Article  CAS  PubMed  Google Scholar 

  35. Banwell B, Krupp L, Kennedy J, Tellier R, Tenembaum S, Ness J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol. 2007;6(9):773–81. https://doi.org/10.1016/S1474-4422(07)70196-5.

    Article  PubMed  Google Scholar 

  36. Sundqvist E, Bergstrom T, Daialhosein H, Nystrom M, Sundstrom P, Hillert J, et al. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult Scler. 2014;20(2):165–73. https://doi.org/10.1177/1352458513494489.

    Article  CAS  PubMed  Google Scholar 

  37. • 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(2):162–73. https://doi.org/10.1016/S1474-4422(17)30470-2 The most recent update to the primary diagnostic criteria for multiple sclerosis.

    Article  PubMed  Google Scholar 

  38. • Fadda G, Longoni G, Banwell B, 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. The Lancet Child & Adolescent Health. 2018;2(3):191–204 Confirmation that the new criteria are applicable to POMS.

    Article  Google Scholar 

  39. 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(10):1261–7. https://doi.org/10.1177/1352458513484547.

    Article  PubMed  Google Scholar 

  40. Verhey LH, Branson HM, Shroff MM, Callen DJ, Sled JG, Narayanan S, et al. MRI parameters for prediction of multiple sclerosis diagnosis in children with acute CNS demyelination: a prospective national cohort study. Lancet Neurol. 2011;10(12):1065–73. https://doi.org/10.1016/S1474-4422(11)70250-2.

    Article  PubMed  Google Scholar 

  41. • Hennes EM, Baumann M, Schanda K, Anlar B, Bajer-Kornek B, Blaschek A, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017;89(9):900–8. https://doi.org/10.1212/WNL.0000000000004312 Recent cohort better defining the clinical spectrum of relapsing MOG-ab patients.

    Article  CAS  PubMed  Google Scholar 

  42. • Duignan S, Wright S, Rossor T, Cazabon J, Gilmour K, Ciccarelli O, et al. Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes. Dev Med Child Neurol. 2018. https://doi.org/10.1111/dmcn.13703. Recent cohort better defining the spectrum of relapsing MOG-ab patients.

    Article  Google Scholar 

  43. Huppke P, Rostasy K, Karenfort M, Huppke B, Seidl R, Leiz S, et al. Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients. Mult Scler. 2013;19(7):941–6. https://doi.org/10.1177/1352458512466317.

    Article  PubMed  Google Scholar 

  44. Ramanathan S, Mohammad S, Tantsis E, Nguyen TK, Merheb V, Fung VSC, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry. 2018;89(2):127–37. https://doi.org/10.1136/jnnp-2017-316880.

    Article  PubMed  Google Scholar 

  45. •• Hacohen Y, Wong YY, Lechner C, Jurynczyk M, Wright S, Konuskan B, et al. Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol. 2018;75(4):478–87. https://doi.org/10.1001/jamaneurol.2017.4601 Recent cohort providing preliminary evidence on treatment efficacy in relapsing MOG-ab patients.

    Article  PubMed  Google Scholar 

  46. Winter M, Baksmeier C, Steckel J, Barman S, Malviya M, Harrer-Kuster M, et al. Dose-dependent inhibition of demyelination and microglia activation by IVIG. Ann Clin Transl Neurol. 2016;3(11):828–43. https://doi.org/10.1002/acn3.326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee-Kirsch MA. The type I interferonopathies. Annu Rev Med. 2017;68:297–315. https://doi.org/10.1146/annurev-med-050715-104506.

    Article  CAS  PubMed  Google Scholar 

  48. Wolf NI, Toro C, Kister I, Latif KA, Leventer R, Pizzino A, et al. DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder. Neurology. 2015;84(3):226–30. https://doi.org/10.1212/WNL.0000000000001157.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Schiffmann R, Elroy-Stein O. Childhood ataxia with CNS hypomyelination/vanishing white matter disease--a common leukodystrophy caused by abnormal control of protein synthesis. Mol Genet Metab. 2006;88(1):7–15. https://doi.org/10.1016/j.ymgme.2005.10.019.

    Article  CAS  PubMed  Google Scholar 

  50. Rodriguez-Fernandez C, Lopez-Marin L, Lopez-Pino MA, Gutierrez-Solana LG, Soto-Insuga V, Conejo-Moreno D. Analysis of a series of cases with an initial diagnosis of acute disseminated encephalomyelitis over the period 2000-2010. Rev Neurol. 2013;57(7):297–305.

    PubMed  Google Scholar 

  51. Harris MO, Walsh LE, Hattab EM, Golomb MR. Is it ADEM, POLG, or both? Arch Neurol. 2010;67(4):493–6. https://doi.org/10.1001/archneurol.2010.36.

    Article  PubMed  Google Scholar 

  52. Hacohen Y, Rossor T, Mankad K, Chong W, Lux A, Wassmer E, et al. ‘Leukodystrophy-like’ phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease. Dev Med Child Neurol. 2018;60(4):417–23. https://doi.org/10.1111/dmcn.13649.

    Article  PubMed  Google Scholar 

  53. Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum. 2011;41(1):1–11. https://doi.org/10.1016/j.semarthrit.2010.08.001.

    Article  PubMed  Google Scholar 

  54. Pittock SJ, Lennon VA, de Seze J, Vermersch P, Homburger HA, Wingerchuk DM, et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol. 2008;65(1):78–83. https://doi.org/10.1001/archneurol.2007.17.

    Article  PubMed  Google Scholar 

  55. Kemanetzoglou E, Andreadou E. CNS demyelination with TNF-alpha blockers. Curr Neurol Neurosci Rep. 2017;17(4):36. https://doi.org/10.1007/s11910-017-0742-1.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Pfeifenbring S, Bunyan RF, Metz I, Rover C, Huppke P, Gartner J, et al. Extensive acute axonal damage in pediatric multiple sclerosis lesions. Ann Neurol. 2015;77(4):655–67. https://doi.org/10.1002/ana.24364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Banwell B, Bar-Or A, Cheung R, Kennedy J, Krupp LB, Becker DJ, et al. Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann Neurol. 2008;63(1):98–111. https://doi.org/10.1002/ana.21244.

    Article  PubMed  Google Scholar 

  58. Dhaunchak AS, Becker C, Schulman H, De Faria O Jr, Rajasekharan S, Banwell B, et al. Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann Neurol. 2012;71(5):601–13. https://doi.org/10.1002/ana.22693.

    Article  PubMed  Google Scholar 

  59. Balint B, Haas J, Schwarz A, Jarius S, Furwentsches A, Engelhardt K, et al. T-cell homeostasis in pediatric multiple sclerosis: old cells in young patients. Neurology. 2013;81(9):784–92. https://doi.org/10.1212/WNL.0b013e3182a2ce0e.

    Article  PubMed  Google Scholar 

  60. Vargas-Lowy D, Kivisakk P, Gandhi R, Raddassi K, Soltany P, Gorman MP, et al. Increased Th17 response to myelin peptides in pediatric MS. Clin Immunol. 2013;146(3):176–84. https://doi.org/10.1016/j.clim.2012.12.008.

    Article  CAS  PubMed  Google Scholar 

  61. 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(1):54–9. https://doi.org/10.1001/archneurol.2008.505.

    Article  PubMed  Google Scholar 

  62. Pohl D, Rostasy K, Gartner J, Hanefeld F. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology. 2005;64(5):888–90. https://doi.org/10.1212/01.WNL.0000153570.33845.6A.

    Article  CAS  PubMed  Google Scholar 

  63. 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(2):186–93. https://doi.org/10.1016/j.msard.2013.06.004.

    Article  CAS  PubMed  Google Scholar 

  64. Mikaeloff Y, Suissa S, Vallee L, Lubetzki C, Ponsot G, Confavreux C, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr. 2004;144(2):246–52. https://doi.org/10.1016/j.jpeds.2003.10.056.

    Article  PubMed  Google Scholar 

  65. Amato MP, Krupp LB, Charvet LE, Penner I, Till C. Pediatric multiple sclerosis: cognition and mood. Neurology. 2016;87(9 Suppl 2):S82–7. https://doi.org/10.1212/WNL.0000000000002883.

    Article  PubMed  Google Scholar 

  66. Amato MP, Goretti B, Ghezzi A, Hakiki B, Niccolai C, Lori S, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology. 2014;83(16):1432–8. https://doi.org/10.1212/WNL.0000000000000885.

    Article  PubMed  Google Scholar 

  67. Till C, Udler E, Ghassemi R, Narayanan S, Arnold DL, Banwell BL. Factors associated with emotional and behavioral outcomes in adolescents with multiple sclerosis. Mult Scler. 2012;18(8):1170–80. https://doi.org/10.1177/1352458511433918.

    Article  CAS  PubMed  Google Scholar 

  68. 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(3):329–34. https://doi.org/10.1177/1352458511420846.

    Article  CAS  PubMed  Google Scholar 

  69. Self MM, Fobian A, Cutitta K, Wallace A, Lotze TE. Health-related quality of life in pediatric patients with demyelinating diseases: relevance of disability, relapsing presentation, and fatigue. J Pediatr Psychol. 2018;43(2):133–42. https://doi.org/10.1093/jpepsy/jsx093.

    Article  PubMed  Google Scholar 

  70. Grover SA, Sawicki CP, Kinnett-Hopkins D, Finlayson M, Schneiderman JE, Banwell B, et al. Physical activity and its correlates in youth with multiple sclerosis. J Pediatr. 2016;179:197–203 e2. https://doi.org/10.1016/j.jpeds.2016.08.104.

    Article  PubMed  Google Scholar 

  71. Sikes EM, Motl RW, Ness JM. Pediatric multiple sclerosis: current perspectives on health behaviors. Pediatric Health Med Ther. 2018;9:17–25. https://doi.org/10.2147/PHMT.S140765.

    Article  PubMed  PubMed Central  Google Scholar 

  72. • Makhani N, Lebrun C, Siva A, Brassat D, Carra Dalliere C, de Seze J, et al. Radiologically isolated syndrome in children: clinical and radiologic outcomes. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e395. https://doi.org/10.1212/NXI.0000000000000395 Recent data on outcomes after radiologically isolated syndromes in pediatric patients.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Sastre-Garriga J, Pareto D, Rovira A. Brain atrophy in multiple sclerosis: clinical relevance and technical aspects. Neuroimaging Clin N Am. 2017;27(2):289–300. https://doi.org/10.1016/j.nic.2017.01.002.

    Article  PubMed  Google Scholar 

  74. 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(23):2140–6. https://doi.org/10.1212/WNL.0000000000001045.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kerbrat A, Aubert-Broche B, Fonov V, Narayanan S, Sled JG, Arnold DA, et al. Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS. Neurology. 2012;78(3):194–201. https://doi.org/10.1212/WNL.0b013e318240799a.

    Article  CAS  PubMed  Google Scholar 

  76. • Aubert-Broche B, Weier K, Longoni G, Fonov VS, Bar-Or A, Marrie RA, et al. Monophasic demyelination reduces brain growth in children. Neurology. 2017;88(18):1744–50. https://doi.org/10.1212/WNL.0000000000003884 A suprising recent finding that monophasic demyeination reduces subsequent brain growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Aubert-Broche B, Fonov V, Ghassemi R, Narayanan S, Arnold DL, Banwell B, et al. Regional brain atrophy in children with multiple sclerosis. NeuroImage. 2011;58(2):409–15. https://doi.org/10.1016/j.neuroimage.2011.03.025.

    Article  CAS  PubMed  Google Scholar 

  78. Longoni G, Brown RA, MomayyezSiahkal P, Elliott C, Narayanan S, Bar-Or A, et al. White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders. Brain. 2017;140(5):1300–15. https://doi.org/10.1093/brain/awx041.

    Article  PubMed  Google Scholar 

  79. Banwell B, Reder AT, Krupp L, Tenembaum S, Eraksoy M, Alexey B, et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology. 2006;66(4):472–6. https://doi.org/10.1212/01.wnl.0000198257.52512.1a.

    Article  CAS  PubMed  Google Scholar 

  80. 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(7):849–56. https://doi.org/10.1177/0883073813488828.

    Article  PubMed  Google Scholar 

  81. Ghezzi A, Amato MP, Capobianco M, Gallo P, Marrosu G, Martinelli V, et al. Disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study. Mult Scler. 2005;11(4):420–4. https://doi.org/10.1191/1352458505ms1206oa.

    Article  CAS  PubMed  Google Scholar 

  82. Waubant E, Hietpas J, Stewart T, Dyme Z, Herbert J, Lacy J, et al. Interferon beta-1a in children with multiple sclerosis is well tolerated. Neuropediatrics. 2001;32(4):211–3. https://doi.org/10.1055/s-2001-17370.

    Article  CAS  PubMed  Google Scholar 

  83. 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(3):120–6. https://doi.org/10.1055/s-2003-41274.

    Article  CAS  PubMed  Google Scholar 

  84. 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. 2018;1352458518754364:135245851875436. https://doi.org/10.1177/1352458518754364.

    Article  Google Scholar 

  85. Huppke P, Huppke B, Ellenberger D, Rostasy K, Hummel H, Stark W, et al. Therapy of highly active pediatric multiple sclerosis. Mult Scler. 2017;1352458517732843:135245851773284. https://doi.org/10.1177/1352458517732843.

    Article  Google Scholar 

  86. •• Chitnis T, et al. PARADIGMS: a randomised double-blind study of fingolimod versus interferon β-1a in paediatric multiple sclerosis. ECTRIMS. 2017. Preliminary data from the PARADIGMS trial. The full details are anticipated.

  87. FDA expands approval of Gilenya to treat multiple sclerosis in pediatric patients. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607501.htm?utm_campaign=05112018_FDA%20approves%20Galenya&utm_medium=email&utm_source=Eloqua.

  88. • 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. https://doi.org/10.1016/j.pediatrneurol.2018.03.007. Phase 2 data on dimethyl fumarate safety.

    Article  Google Scholar 

  89. Phase 3 efficacy and safety study of BG00012 in pediatric subjects with relapsing-remitting multiple sclerosis (RRMS) (CONNECT). https://www.clinicaltrials.gov/ct2/show/NCT02283853?cond=pediatric+multiple+sclerosis&draw=4&rank=21. Accessed June 20 2018.

  90. Chitnis T, Ghezzi A, Bajer-Kornek B, Boyko A, Giovannoni G, Pohl D. Pediatric multiple sclerosis: escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S103–9. https://doi.org/10.1212/WNL.0000000000002884.

    Article  PubMed  Google Scholar 

  91. Efficacy, safety and pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis (TERIKIDS). https://www.clinicaltrials.gov/ct2/show/NCT02201108?cond=pediatric+multiple+sclerosis&draw=2&rank=16. Accessed 6/20/ 2018.

  92. A study to evaluate efficacy, safety, and tolerability of alemtuzumab in pediatric patients with RRMS with disease activity on prior DMT (LemKids). https://clinicaltrials.gov/ct2/show/NCT03368664. Accessed June 20 2018.

  93. Dubey D, Forsthuber T, Flanagan EP, Pittock SJ, Stuve O. B-cell-targeted therapies in relapsing forms of MS. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e405. https://doi.org/10.1212/NXI.0000000000000405.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A, Ghorayeb C, et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann Neurol. 2010;67(4):452–61. https://doi.org/10.1002/ana.21939.

    Article  CAS  PubMed  Google Scholar 

  95. Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015;7(310):310ra166. https://doi.org/10.1126/scitranslmed.aab4176.

    Article  CAS  PubMed  Google Scholar 

  96. Kavcic M, Fisher BT, Seif AE, Li Y, Huang YS, Walker D, et al. Leveraging administrative data to monitor rituximab use in 2875 patients at 42 freestanding children’s hospitals across the United States. J Pediatr. 2013;162(6):1252–8, 8 e1. https://doi.org/10.1016/j.jpeds.2012.11.038.

    Article  CAS  PubMed  Google Scholar 

  97. 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(2):142–50. https://doi.org/10.1212/WNL.0000000000000570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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(3):221–34. https://doi.org/10.1056/NEJMoa1601277.

    Article  CAS  PubMed  Google Scholar 

  99. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209–20. https://doi.org/10.1056/NEJMoa1606468.

    Article  CAS  PubMed  Google Scholar 

  100. Ghezzi A, Moiola L, Pozzilli C, Brescia-Morra V, Gallo P, Grimaldi LM, et al. Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. 2015;15:174. https://doi.org/10.1186/s12883-015-0433-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pardo G, Jones DE. The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. J Neurol. 2017;264(12):2351–74. https://doi.org/10.1007/s00415-017-8594-9.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Torkildsen O, Myhr KM, Bo L. Disease-modifying treatments for multiple sclerosis - a review of approved medications. Eur J Neurol. 2016;23(Suppl 1):18–27. https://doi.org/10.1111/ene.12883.

    Article  PubMed  Google Scholar 

  103. Salzer J, Svenningsson R, Alping P, Novakova L, Bjorck A, Fink K, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. Neurology. 2016;87(20):2074–81. https://doi.org/10.1212/WNL.0000000000003331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Pediatric Multiple Sclerosis and Demyelinating Disorders Clinic, Division of Pediatric Neurology, Department of Neurology, Wake Forest University/Brenner Children’s Hospital, Medical Center Boulevard, JT9, Winston Salem, NC, 27157, USA

    Scott Otallah

  2. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Brenda Banwell

  3. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Brenda Banwell

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  1. Scott Otallah
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Correspondence to Scott Otallah.

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Brenda Banwell has served as a central MRI reviewer for Novartis for the PARADIGMS trial. This study is referenced in the review.

Scott Otallah declares no potential conflict of interest.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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This article is part of the Topical Collection on Pediatric Neurology

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Otallah, S., Banwell, B. Pediatric Multiple Sclerosis: an Update. Curr Neurol Neurosci Rep 18, 76 (2018). https://doi.org/10.1007/s11910-018-0886-7

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