Vol 54, No 6 (2020)
Review Article
Published online: 2020-09-17

open access

Page views 6311
Article views/downloads 4145
Get Citation

Connect on Social Media

Connect on Social Media

Pediatric multiple sclerosis – current status of epidemiology, diagnosis and treatment

Waldemar Brola1, Barbara Steinborn2
Pubmed: 32940341
Neurol Neurochir Pol 2020;54(6):508-517.


Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system that mostly affects younger adults. However, the first symptoms of MS can appear in children and adolescents before the age of 18, and we call this paediatric MS (PMS). It is estimated that paediatric MS accounts for 3-5% of the general population of patients with MS. Despite the fundamental si-milarities to adult MS, PMS has many distinctive features. Paediatric MS has a milder course compared to adults, but leads to sig-nificant disability at an early age. PMS is relapsing-remitting in 95-98% of cases; the primary progressive manifestation is much less common than in adults. The differential diagnosis of MS in children should include other childhood demyelinating diseases, mitochondrial and metabolic diseases, connective tissue diseases, and neuroborreliosis. Differentiating acute disseminated en-cephalomyelitis (ADEM) from the first onset of MS remains the biggest challenge. Over the past 10 years, understanding of the epidemiology, pathophysiology, diagnosis, and treatment of MS in children has significantly expanded. The diagnostic criteria leading to earlier diagnosis and initiation of disease-modifying therapy (DMT) have changed, and the number of drugs used in children has increased. However, many important issues require further research. This review discusses the current state of knowledge regarding the epidemiology, diagnosis, and treatment of multiple sclerosis in children.

Article available in PDF format

View PDF Download PDF file


  1. Fisher KS, Cuascut FX, Rivera VM, et al. Current Advances in Pediatric Onset Multiple Sclerosis. Biomedicines. 2020; 8(4).
  2. Krysko KM, Graves JS, Rensel M, et al. US Network of Pediatric MS Centers. Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis. Ann Neurol. 2020; 88(1): 42–55.
  3. Alroughani R, Boyko A. Pediatric multiple sclerosis: a review. BMC Neurol. 2018; 18(1): 27.
  4. Renoux C, Vukusic S, Confavreux C, et al. Adult Neurology Departments KIDMUS Study Group. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007; 356(25): 2603–2613.
  5. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group. 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): 1261–1267.
  6. Rensel M. Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies. Children (Basel). 2019; 6(6).
  7. Galardi MM, Gaudioso C, Ahmadi S, et al. Differential Diagnosis of Pediatric Multiple Sclerosis. Children (Basel). 2019; 6(6).
  8. An Q, Fan CH, Xu SM. Childhood multiple sclerosis: clinical features and recent developments on treatment choices and outcomes. Eur Rev Med Pharmacol Sci. 2018; 22(17): 5747–5754.
  9. Wong YuY, de Mol CL, van der Vuurst de Vries RM, et al. Real-world validation of the 2017 McDonald criteria for pediatric MS. Neurol Neuroimmunol Neuroinflamm. 2019; 6(2): e528.
  10. Jeong A, Oleske DM, Holman J. Epidemiology of Pediatric-Onset Multiple Sclerosis: A Systematic Review of the Literature. J Child Neurol. 2019; 34(12): 705–712.
  11. Boiko A, Vorobeychik G, Paty D, et al. University of British Columbia MS Clinic Neurologists. Early onset multiple sclerosis: a longitudinal study. Neurology. 2002; 59(7): 1006–1010.
  12. Bigi S, Banwell B. Pediatric multiple sclerosis. J Child Neurol. 2012; 27(11): 1378–1383.
  13. Gadoth N. Multiple sclerosis in children. Brain Dev. 2003; 25(4): 229–232.
  14. Wang CX, Greenberg BM. Pediatric Multiple Sclerosis: From Recognition to Practical Clinical Management. Neurol Clin. 2018; 36(1): 135–149.
  15. Huppke B, Ellenberger D, Rosewich H, et al. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol. 2014; 21(3): 441–446.
  16. Oksenberg JR, Baranzini SE, Sawcer S, et al. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet. 2008; 9(7): 516–526.
  17. Banwell BL. Pediatric multiple sclerosis. Curr Neurol Neurosci Rep. 2004; 4(3): 245–252.
  18. Ramagopalan SV, Knight JC, Ebers GC. Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol. 2009; 22(3): 219–225.
  19. 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(5): 436–445.
  20. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010; 67(5): 618–624.
  21. Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis. Epidemiology. 2000; 11(2): 220–224.
  22. Hedström AK, Olsson T, Alfredsson L. Smoking is a major preventable risk factor for multiple sclerosis. Mult Scler. 2016; 22(8): 1021–1026.
  23. Mikaeloff Y, Caridade G, Tardieu M, et al. KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007; 130(Pt 10): 2589–2595.
  24. Rotstein DL, Cortese M, Fung TT, et al. Body size and risk of MS in two cohorts of US women. Neurology. 2009; 73(19): 1543–1550.
  25. Langer-Gould A, Brara SM, Beaber BE, et al. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013; 80(6): 548–552.
  26. McDonald J, Graves J, Waldman A, et al. A case-control study of dietary salt intake in pediatric-onset multiple sclerosis. Mult Scler Relat Disord. 2016; 6: 87–92.
  27. Montgomery S, Hiyoshi A, Burkill S, et al. Concussion in adolescence and risk of multiple sclerosis. Ann Neurol. 2017; 82(4): 554–561.
  28. Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology. 2002; 59(12): 1922–1928.
  29. Mikaeloff Y, Suissa S, Vallée L, et al. KIDMUS Study Group. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr. 2004; 144(2): 246–252.
  30. Banwell B, Ghezzi A, Bar-Or A, et al. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 2007; 6(10): 887–902.
  31. Ruggieri M, Iannetti P, Polizzi A, et al. Italian Society of Paediatric Neurology Study Group on Childhood Multiple Sclerosis. Multiple sclerosis in children under 10 years of age. Neurol Sci. 2004; 25 Suppl 4: S326–S335.
  32. 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.
  33. McKay KA, Manouchehrinia A, Berrigan L, et al. Long-term Cognitive Outcomes in Patients With Pediatric-Onset vs Adult-Onset Multiple Sclerosis. JAMA Neurol. 2019 [Epub ahead of print].
  34. Gorman MP, Healy BC, Polgar-Turcsanyi M, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol. 2009; 66(1): 54–59.
  35. Benson LA, Healy BC, Gorman MP, et al. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord. 2014; 3(2): 186–193.
  36. Ness JM, Chabas D, Sadovnick AD, et al. International Pediatric MS Study Group. Clinical features of children and adolescents with multiple sclerosis. Neurology. 2007; 68(16 Suppl 2): S37–S45.
  37. Trojano M, Liguori M, Bosco Zimatore G, et al. Age-related disability in multiple sclerosis. Ann Neurol. 2002; 51(4): 475–480.
  38. Miller D, Leary S. Primary-progressive multiple sclerosis. The Lancet Neurology. 2007; 6(10): 903–912.
  39. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001; 50(1): 121–127.
  40. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005; 58(6): 840–846.
  41. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2): 292–302.
  42. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2): 162–173.
  43. Krupp LB, et al. B Banwell Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007; 68(16 ): S7–12.
  44. Hacohen Y, Mankad K, Chong WK, et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology. 2017; 89(3): 269–278.
  45. Jurkiewicz E, Kotulska K. [Neuroimaging of multiple sclerosis in children]. Neurol Neurochir Pol. 2011; 45(2): 152–160.
  46. Dębska J, Kotulska-Józwiak K, Pawliszak P, et al. Spinal cord lesions in children and adolescents with multiple sclerosis - Magnetic resonance imaging. Neurol Neurochir Pol. 2017; 51(1): 77–81.
  47. Hahn JS, Pohl D, Rensel M, et al. International Pediatric MS Study Group. Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology. 2007; 68(16 Suppl 2): S13–S22.
  48. Tenembaum S, Chitnis T, Ness J, et al. International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology. 2007; 68(16 Suppl 2): S23–S36.
  49. Alper G, Heyman R, Wang Li. Multiple sclerosis and acute disseminated encephalomyelitis diagnosed in children after long-term follow-up: comparison of presenting features. Dev Med Child Neurol. 2009; 51(6): 480–486.
  50. Dale RC, de Sousa C, Chong WK, et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000; 123 Pt 12: 2407–2422.
  51. Callen DJA, Shroff MM, Branson HM, et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology. 2009; 72(11): 968–973.
  52. Ketelslegers IA, Neuteboom RF, Boon M, et al. Dutch Pediatric MS Study Group. A comparison of MRI criteria for diagnosing pediatric ADEM and MS. Neurology. 2010; 74(18): 1412–1415.
  53. O'Mahony J, Bar-Or A, Arnold DL, et al. Canadian Pediatric Demyelinating Disease Network. Masquerades of acquired demyelination in children: experiences of a national demyelinating disease program. J Child Neurol. 2013; 28(2): 184–197.
  54. Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation. 2018; 15(1): 134–1399.
  55. Wynford-Thomas R, Jacob A, Tomassini V. Neurological update: MOG antibody disease. J Neurol. 2019; 266(5): 1280–1286.
  56. Ghezzi A, Banwell B, Boyko A, et al. The management of multiple sclerosis in children: a European view. Mult Scler. 2010; 16(10): 1258–1267.
  57. Lattanzi S, Cagnetti C, Danni M, et al. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017; 264(8): 1697–1704.
  58. Chitnis T, Ghezzi A, Bajer-Kornek B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016; 87(9 Suppl 2): S103–S109.
  59. Chitnis T, Arnold DL, Banwell B, et al. PARADIGMS Study Group. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018; 379(11): 1017–1027.
  60. Deiva K, Huppke P, Banwell B, et al. Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIG. J Neurol Neurosurg Psychiatry. 2020; 91(1): 58–66.
  61. Waubant E, Banwell B, Wassmer E, et al. IPMSSG. Clinical trials of disease-modifying agents in pediatric MS: Opportunities, challenges, and recommendations from the IPMSSG. Neurology. 2019; 92(22): e2538–e2549.
  62. https://clinicaltrials.gov.
  63. Ghezzi A, Amato MP, Makhani N, et al. Pediatric multiple sclerosis: Conventional first-line treatment and general management. Neurology. 2016; 87(9 Suppl 2): S97–S9S102.
  64. Narula S, Hopkins SE, Banwell B. Treatment of pediatric multiple sclerosis. Curr Treat Options Neurol. 2015; 17(3): 336.
  65. Banwell B, Reder AT, Krupp L, et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology. 2006; 66(4): 472–476.
  66. Tenembaum SN, Banwell B, Pohl D, et al. REPLAY Study Group. Subcutaneous interferon Beta-1a in pediatric multiple sclerosis: a retrospective study. J Child Neurol. 2013; 28(7): 849–856.
  67. Kornek B, Bernert G, Balassy C, et al. Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Neuropediatrics. 2003; 34(3): 120–126.
  68. Alroughani R, Das R, Penner N, et al. Safety and Efficacy of Delayed-Release Dimethyl Fumarate in Pediatric Patients With Relapsing Multiple Sclerosis (FOCUS). Pediatr Neurol. 2018; 83: 19–24.
  69. Kornek B, Aboul-Enein F, Rostasy K, et al. Natalizumab therapy for highly active pediatric multiple sclerosis. JAMA Neurol. 2013; 70(4): 469–475.
  70. Ghezzi A, Pozzilli C, Grimaldi LME, et al. Italian MS Study Group. Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases. Mult Scler. 2013; 19(8): 1106–1112.
  71. Ghezzi A, Moiola L, Pozzilli C, et al. MS Study Group-Italian Society of Neurology. Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. 2015; 15: 174.
  72. Alroughani R, Ahmed SF, Behbehani R, et al. The Use of Natalizumab in Pediatric Patients With Active Relapsing Multiple Sclerosis: A Prospective Study. Pediatr Neurol. 2017; 70: 56–60.
  73. Arnal-Garcia C, García-Montero MaR, Málaga I, et al. Natalizumab use in pediatric patients with relapsing-remitting multiple sclerosis. Eur J Paediatr Neurol. 2013; 17(1): 50–54.
  74. Salzer J, Lycke J, Wickström R, et al. Rituximab in paediatric onset multiple sclerosis: a case series. J Neurol. 2016; 263(2): 322–326.
  75. Beres SJ, Graves J, Waubant E. Rituximab use in pediatric central demyelinating disease. Pediatr Neurol. 2014; 51(1): 114–118.
  76. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014; 83(2): 142–150.
  77. Makhani N, Gorman MP, Branson HM, et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology. 2009; 72(24): 2076–2082.
  78. Gusev E, Boiko A, Bikova O, et al. The natural history of early onset multiple sclerosis: comparison of data from Moscow and Vancouver. Clin Neurol Neurosurg. 2002; 104(3): 203–207.
  79. Till C, Noguera A, Verhey LH, et al. Cognitive and Behavioral Functioning in Childhood Acquired Demyelinating Syndromes. J Int Neuropsychol Soc. 2016; 22(10): 1050–1060.
  80. Amato MP, Goretti B, Ghezzi A, et al. Multiple Sclerosis Study Group of the Italian Neurological Society. Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up. Neurology. 2010; 75(13): 1134–1140.
  81. Amato MP, Goretti B, Ghezzi A, et al. MS Study Group of the Italian Neurological Society. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology. 2014; 83(16): 1432–1438.
  82. Banwell BL, Anderson PE. The cognitive burden of multiple sclerosis in children. Neurology. 2005; 64(5): 891–894.
  83. Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997; 36(7): 980–988.
  84. Cardoso M, Olmo NR, Fragoso YD. Systematic Review of Cognitive Dysfunction in Pediatric and Juvenile Multiple Sclerosis. Pediatr Neurol. 2015; 53(4): 287–292.

Neurologia i Neurochirurgia Polska