An update on multiple sclerosis in children: diagnosis, therapies, and prospects for the future

References

• Waldman A, Ghezzi A, Bar-Or A, et al. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014;13(9):936–948.
   PubMed Web of Science ®Google Scholar
• Gorman MP, Healy BC, Polgar-Turcsanyi M, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol [Internet]. 2009;66(1). DOI:10.1001/archneurol.2008.505
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Waldman AT, Stull LB, Galetta SL, et al. Pediatric optic neuritis and risk of multiple sclerosis: meta-analysis of observational studies. J Aapos. 2011;15(5):441–446.
   PubMed Web of Science ®Google Scholar
• Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–189.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59(4):499–505.
   PubMed Web of Science ®Google Scholar
• Krishnan C, Kaplin AI, Deshpande DM, et al. Transverse myelitis. Inflamm Disord Nervous Syst. 2005;217–236. Available from: https://link.springer.com/book/10.1385%2F1592599052
   Google Scholar
• Pidcock FS, Krishnan C, Crawford TO, et al. Acute transverse myelitis in childhood: center-based analysis of 47 cases. Neurology. 2007;68(18):1474–1480.
   PubMed Web of Science ®Google Scholar
• Thomas T, Branson HM, Verhey LH, et al. The demographic, clinical, and magnetic resonance imaging (MRI) features of transverse myelitis in children. J Child Neurol. 2012;27(1):11–21.
   PubMed Web of Science ®Google Scholar
• Deiva K, Absoud M, Hemingway C, et al. Acute idiopathic transverse myelitis in children: early predictors of relapse and disability. Neurology. 2015;84(4):341–349.
   PubMed Web of Science ®Google Scholar
• Krupp LB, Tardieu M, Amato MP, 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):1261–1267.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Iaffaldano P, Simone M, Lucisano G, et al. Prognostic indicators in pediatric clinically isolated syndrome. Ann Neurol. 2017;81(5):729–739.
   PubMed Web of Science ®Google Scholar
• Eichel R, Meiner Z, Abramsky O, et al. Acute disseminating encephalomyelitis in neuromyelitis optica: closing the floodgates. Arch Neurol. 2008;65(2):267–271.
   PubMedGoogle Scholar
• Collongues N, Marignier R, Zéphir H, et al. Long-term follow-up of neuromyelitis optica with a pediatric onset. Neurology. 2010;75(12):1084–1088.
   PubMed Web of Science ®Google Scholar
• Hacohen Y, Mankad K, Chong WK, et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology [Internet]. 2017. DOI:10.1212/WNL.0000000000004117
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Mikaeloff Y, Suissa S, Vallée L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr. 2004;144(2):246–252.
   PubMed Web of Science ®Google Scholar
• Mikaeloff Y, Caridade G, Husson B, et al. Acute disseminated encephalomyelitis cohort study: prognostic factors for relapse. Eur J Paediatr Neurol. 2007;11(2):90–95.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Tantsis EM, Prelog K, Brilot F, et al. Risk of multiple sclerosis after a first demyelinating syndrome in an Australian paediatric cohort: clinical, radiological features and application of the McDonald 2010 MRI criteria. Mult Scler. 2013;19(13):1749–1759.
   PubMed Web of Science ®Google Scholar
• Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain. 2004;127(Pt 9):1942–1947.
   PubMed Web of Science ®Google Scholar
• Chitnis T, Graves J, Weinstock-Guttman B, et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol. 2016;3(12):897–907.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• KIDSEP study group, Mikaeloff Y, Caridade G, Tardieu M, et al. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007;130(Pt 10):2589–2595.
   PubMed Web of Science ®Google Scholar
• Disanto G, Magalhaes S, Handel AE, et al. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology. 2011;76(9):781–786.
   PubMed Web of Science ®Google Scholar
• Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology. 2011;76(23):1989–1995.
   PubMed Web of Science ®Google Scholar
• Gianfrancesco MA, Stridh P, Rhead B, et al. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017;88(17):1623–1629.
   PubMed Web of Science ®Google Scholar
• Graves JS, Chitnis T, Weinstock-Guttman B, et al. Maternal and perinatal exposures are associated with risk for pediatric-onset multiple sclerosis. Pediatrics [Internet]. 2017;139(4). DOI:10.1542/peds.2016-2838
   Google Scholar
• Van Pelt ED, Mescheriakova JY, Makhani N, et al. Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination. Neurology. 2013;81(23):1996–2001.
   PubMed Web of Science ®Google Scholar
• Graves JS, Barcellos LF, Shao X, et al. Genetic predictors of relapse rate in pediatric MS. Mult Scler. 2016;22(12):1528–1535.
   PubMed Web of Science ®Google Scholar
• Waubant E, Ponsonby A-L, Pugliatti M, et al. Environmental and genetic factors in pediatric inflammatory demyelinating diseases. Neurology. 2016;87(9 Suppl 2):S20–7.
   PubMed Web of Science ®Google Scholar
• Hummel H-M, Brück W, Dreha-Kulaczewski S, et al. Pediatric onset multiple sclerosis: mcDonald criteria 2010 and the contribution of spinal cord MRI. Mult Scler. 2013;19(10):1330–1335.
   PubMed Web of Science ®Google Scholar
• Kornek B, Schmitl B, Vass K, et al. Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome. Mult Scler. 2012;18(12):1768–1774.
   PubMed Web of Science ®Google Scholar
• Sadaka Y, Verhey LH, Shroff MM, et al. 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. Ann Neurol. 2012;72(2):211–223.
   PubMed Web of Science ®Google Scholar
• Narula S, Banwell B. Pediatric demyelination. Continuum. 2016;22(3):897–915.
   PubMedGoogle Scholar
• Yeshokumar AK, Narula S, Banwell B. Pediatric multiple sclerosis. Curr Opin Neurol. 2017;30(3):216–221.
   PubMed Web of Science ®Google Scholar
• Rostasy K, Bajer-Kornek B, Venkateswaran S, et al. Differential diagnosis and evaluation in pediatric inflammatory demyelinating disorders. Neurology. 2016;87(9 Suppl 2):S28–37.
   PubMed Web of Science ®Google Scholar
• Kuntz NL, Strober J. Differential diagnosis of multiple sclerosis and acquired central nervous system demyelinating disorders in children and adolescents. Demyelinating Disord Cent Nervous Syst Childhood. 2011;58–74. Available from: http://www.cambridge.org/gb/academic/subjects/medicine/neurology-and-clinical-neuroscience/demyelinating-disorders-central-nervous-system-childhood?format=HB&isbn=9780521763493#iMs4lBgUF8eOhpeU.97
   Google Scholar
• International Pediatric MS Study Group, Hahn JS, Pohl D, Rensel M, et al. Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology. 2007;68(16 Suppl 2):S13–22.
   PubMed Web of Science ®Google Scholar
• Tenembaum S, Chitnis T, Nakashima I, et al. Neuromyelitis optica spectrum disorders in children and adolescents. Neurology. 2016;87(9 Suppl 2):S59–66.
   PubMed Web of Science ®Google Scholar
• Majed M, Fryer JP, McKeon A, et al. Clinical utility of testing AQP4-IgG in CSF. Neurology - Neuroimmunol Neuroinflamm. 2016;3(3):e231.
   PubMed Web of Science ®Google Scholar
• Banwell BL. Multiple sclerosis in children. Handb Clin Neurol. 2014;122:427–441.
   PubMedGoogle Scholar
• Benseler SM, Silverman E, Aviv RI, et al. Primary central nervous system vasculitis in children. Arthritis Rheum. 2006;54(4):1291–1297.
   PubMed Web of Science ®Google Scholar
• Cellucci T, Tyrrell PN, Twilt M, et al. Distinct phenotype clusters in childhood inflammatory brain diseases: implications for diagnostic evaluation. Arthritis Rheumatol. 2014;66(3):750–756.
   PubMed Web of Science ®Google Scholar
• Cellucci T, Benseler SM. Central nervous system vasculitis in children. Curr Opin Rheumatol. 2010;22(5):590–597.
   PubMed Web of Science ®Google Scholar
• Wolf NI, Toro C, Kister I, et al. DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder. Neurology. 2014;84(3):226–230.
   PubMed Web of Science ®Google Scholar
• Deretzi G, Kountouras J, Polyzos SA, et al. Polyautoimmunity in a Greek cohort of multiple sclerosis. Acta Neurol Scand. 2014;131(4):225–230.
   PubMed Web of Science ®Google Scholar
• Sahraian MA, Owji M, Naser Moghadasi A. Concomitant multiple sclerosis and another autoimmune disease: does the clinical course change? Clin Neurol Neurosurg. 2016;150:92–95.
   PubMed Web of Science ®Google Scholar
• Zéphir H, Gower-Rousseau C, Salleron J, et al. Milder multiple sclerosis course in patients with concomitant inflammatory bowel disease. Mult Scler. 2014;20(8):1135–1139.
   PubMed Web of Science ®Google Scholar
• Fanouriakis A, Mastorodemos V, Pamfil C, et al. Coexistence of systemic lupus erythematosus and multiple sclerosis: prevalence, clinical characteristics, and natural history. Semin Arthritis Rheum. 2014;43(6):751–758.
   PubMed Web of Science ®Google Scholar
• Kemanetzoglou E, Andreadou E. CNS demyelination with TNF-α blockers. Curr Neurol Neurosci Rep. 2017;17(4):36.
   PubMed Web of Science ®Google Scholar
• Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356(25):2603–2613.
   PubMed Web of Science ®Google Scholar
• O’Mahony J, Marrie RA, Laporte A, et al. Recovery from central nervous system acute demyelination in children. Pediatrics. 2015;136(1):e115–e123.
   PubMed Web of Science ®Google Scholar
• Gorman MP, Healy BC, Polgar-Turcsanyi M, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol [Internet]. 2009;66(1). DOI:10.1001/archneurol.2008.505
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Mult Scler. 2016;22(2):193–200.
   PubMed Web of Science ®Google Scholar
• Chitnis T. Role of puberty in multiple sclerosis risk and course. Clin Immunol. 2013;149(2):192–200.
   PubMed Web of Science ®Google Scholar
• Chabas D, Castillo-Trivino T, Mowry EM, et al. Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype? Neurology. 2008;71(14):1090–1093.
   PubMed Web of Science ®Google Scholar
• Till C, Ghassemi R, Aubert-Broche B, et al. MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. Neuropsychology. 2011;25(3):319–332.
   PubMed Web of Science ®Google Scholar
• Till C, Deotto A, Tipu V, et al. White matter integrity and math performance in pediatric multiple sclerosis. Neuroreport. 2011;22(18):1005–1009.
   PubMed Web of Science ®Google Scholar
• Amato MP, Ponziani G, Pracucci G, et al. Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up. Arch Neurol. 1995;52(2):168–172.
   PubMedGoogle Scholar
• Amato MP, Portaccio E, Goretti B, et al. Cognitive impairment in early stages of multiple sclerosis. Neurol Sci. 2010;31(S2):211–214.
   Web of Science ®Google Scholar
• Charvet LE, O’Donnell EH, Belman AL, et al. Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network. Mult Scler. 2014;20(11):1502–1510.
   PubMed Web of Science ®Google Scholar
• Julian L, Serafin D, Charvet L, et al. Cognitive impairment occurs in children and adolescents with multiple sclerosis: results from a United States network. J Child Neurol. 2013;28(1):102–107.
   PubMed Web of Science ®Google Scholar
• Akbar N, Till C, Sled JG, et al. Altered resting-state functional connectivity in cognitively preserved pediatric-onset MS patients and relationship to structural damage and cognitive performance. Mult Scler. 2016;22(6):792–800.
   PubMed Web of Science ®Google Scholar
• Rocca MA, Absinta M, Moiola L, et al. Functional and structural connectivity of the motor network in pediatric and adult-onset relapsing-remitting multiple sclerosis. Radiology. 2010;254(2):541–550.
   PubMed Web of Science ®Google Scholar
• Till C, Ho C, Dudani A, et al. Magnetic resonance imaging predictors of executive functioning in patients with pediatric-onset multiple sclerosis. Arch Clin Neuropsychol. 2012;27(5):495–509.
   PubMed Web of Science ®Google Scholar
• Ghezzi A, Goretti B, Portaccio E, et al. Cognitive impairment in pediatric multiple sclerosis. Neurol Sci. 2010;31(S2):215–218.
   Web of Science ®Google Scholar
• 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(8):967–971.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Kornek B, Schmitl B, Vass K, et al. Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome. Mult Scler. 2012;18(12):1768–1774.
   PubMed Web of Science ®Google Scholar
• Kerbrat A, Aubert-Broche B, Fonov V, et al. Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS. Neurology. 2012;78(3):194–201.
   PubMed Web of Science ®Google Scholar
• Aubert-Broche B, Fonov V, Narayanan S, et al. Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth. Neurology. 2014;83(23):2140–2146.
   PubMed Web of Science ®Google Scholar
• Weier K, Fonov V, Aubert-Broche B, et al. Impaired growth of the cerebellum in pediatric-onset acquired CNS demyelinating disease. Mult Scler. 2016;22(10):1266–1278.
   PubMed Web of Science ®Google Scholar
• Longoni G, Brown RA, MomayyezSiahkal P, et al. White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders. Brain [Internet]. 2017. DOI:10.1093/brain/awx041
   Google Scholar
• Rocca MA, Sonkin M, Copetti M, et al. Diffusion tensor magnetic resonance imaging in very early onset pediatric multiple sclerosis. Mult Scler. 2016;22(5):620–627.
   PubMed Web of Science ®Google Scholar
• Bhise V, Dhib-Jalbut S. Further understanding of the immunopathology of multiple sclerosis: impact on future treatments. Expert Rev Clin Immunol. 2016;12(10):1069–1089.
   PubMed Web of Science ®Google Scholar
• Chabas D, Ness J, Belman A, et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology. 2010;74(5):399–405.
   PubMed Web of Science ®Google Scholar
• Huppke B, Ellenberger D, Rosewich H, et al. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol. 2014;21(3):441–446.
   PubMed Web of Science ®Google Scholar
• Pohl D, Rostasy K, Reiber H, et al. CSF characteristics in early-onset multiple sclerosis. Neurology. 2004;63(10):1966–1967.
   PubMed Web of Science ®Google Scholar
• 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(3):363–370.
   PubMed Web of Science ®Google Scholar
• Huppke P, Stark W, Zürcher C, et al. Natalizumab use in pediatric multiple sclerosis. Arch Neurol. 2008;65(12):1655–1658.
   PubMedGoogle Scholar
• Martins TB, Rose JW, Jaskowski TD, et al. Analysis of proinflammatory and anti-inflammatory cytokine serum concentrations in patients with multiple sclerosis by using a multiplexed immunoassay. Am J Clin Pathol. 2011;136(5):696–704.
   PubMed Web of Science ®Google Scholar
• Farhadi N, Oryan S, Nabiuni M. Serum levels of melatonin and cytokines in multiple sclerosis. Biomed J. 2014;37(2):90–92.
   PubMedGoogle Scholar
• Palmer MT, Weaver CT. Autoimmunity: increasing suspects in the CD4+ T cell lineup. Nat Immunol. 2010;11(1):36–40.
   PubMed Web of Science ®Google Scholar
• Cala CM, Moseley CE, Steele C, et al. T cell cytokine signatures: biomarkers in pediatric multiple sclerosis. J Neuroimmunol. 2016;297:1–8.
   PubMed Web of Science ®Google Scholar
• Schwarz A, Balint B, Korporal-Kuhnke M, et al. B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(1):e309.
   PubMed Web of Science ®Google Scholar
• Rivas JR, Ireland SJ, Chkheidze R, et al. Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathol. 2017;133(1):43–60.
   PubMed Web of Science ®Google Scholar
• Dhaunchak AS, Becker C, Schulman H, et al. Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis. Ann Neurol. 2012;71(5):601–613.
   PubMed Web of Science ®Google Scholar
• Waters P, Woodhall M, O’Connor KC, et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e89.
   PubMed Web of Science ®Google Scholar
• Brilot F, Dale RC, Selter RC, et al. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol. 2009;66(6):833–842.
   PubMed Web of Science ®Google Scholar
• Fernandez-Carbonell C, Vargas-Lowy D, Musallam A, et al. Clinical and MRI phenotype of children with MOG antibodies. Mult Scler. 2016;22(2):174–184.
   PubMed Web of Science ®Google Scholar
• Probstel AK, Dornmair K, Bittner R, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology. 2011;77(6):580–588.
   PubMed Web of Science ®Google Scholar
• Ramanathan S, Dale RC, Brilot F. Anti-MOG antibody: the history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination. Autoimmun Rev. 2016;15(4):307–324.
   PubMed Web of Science ®Google Scholar
• Baumann M, Sahin K, Lechner C, et al. Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry. 2015;86(3):265–272.
   PubMed Web of Science ®Google Scholar
• Saadoun S, Waters P, Owens GP, et al. Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol Commun. 2014;2:35.
   PubMed Web of Science ®Google Scholar
• Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Practice guideline: disease-modifying therapies for multiple sclerosis 2 summary for comments from the public [Internet]. (2016). Available from: https://www.aan.com/uploadedFiles/Website_Library_Assets/Documents/2.Clinical_Guidelines/3.Browse_By_Status/4.Guidelines_Under_Development/MS%20DMT%20guideline%20public%20SUMMARY%20for%20public%20comment%202016-09-09.pdf.
   Google Scholar
• Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581–588.
   PubMed Web of Science ®Google Scholar
• Waldman AT, Gorman MP, Rensel MR, et al. Management of pediatric central nervous system demyelinating disorders: consensus of United States neurologists. J Child Neurol. 2011;26(6):675–682.
   PubMed Web of Science ®Google Scholar
• Apak RA, Anlar B, Saatci I. A case of relapsing acute disseminated encephalomyelitis with high dose corticosteroid treatment. Brain Dev. 1999;21(4):279–282.
   PubMed Web of Science ®Google Scholar
• Murthy SNK, Faden HS, Cohen ME, et al. Acute disseminated encephalomyelitis in children. Pediatrics. 2002;110(2 Pt 1):e21.
   PubMed Web of Science ®Google Scholar
• Pradhan S, Gupta RP, Shashank S, et al. Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis. J Neurol Sci. 1999;165(1):56–61.
   PubMed Web of Science ®Google Scholar
• Weinshenker B, Keegan B. Therapeutic plasma exchange for multiple sclerosis. Multiple Sclerosis Therapeutics, Third Edition. 2007;551–565. Available from: https://www.crcpress.com/Multiple-Sclerosis-Therapeutics-Third-Edition/Cohen-Rudick/p/book/9781841845258
   Google Scholar
• Dale R. Treatment choices in optic neuritis: corticosteroids, intravenous immunoglobulin, plasma exchange, or other? Neuropediatrics. 2016;47(03):137–138.
   PubMed Web of Science ®Google Scholar
• Yeshokumar AK, Banwell B, Philadelphia CH, et al. Management of children with multiple sclerosis. US Neurol. 2017;13(01):42. Available from: http://www.touchneurology.com/sites/www.touchneurology.com/files/ebooks/USNEURO131/files/44.html
   Google Scholar
• Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116–127.
   PubMed Web of Science ®Google Scholar
• Dahdaleh M, Alroughani R, Aljumah M, et al. Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet? Int J Neurosci. 2017;1–8.
   Web of Science ®Google Scholar
• Comi G, Radaelli M, Soelberg Sørensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet [Internet]. 2016. DOI:10.1016/S0140-6736(16)32388-1
   Web of Science ®Google Scholar
• On behalf of the Immunomodulatory Treatment of Early onset MS (ITEMS) Group, Ghezzi A. Immunomodulatory treatment of early onset multiple sclerosis: results of an Italian Co-operative Study. Neurol Sci. 2005;26(S4):s183–s186.
   PubMed Web of Science ®Google Scholar
• Tenembaum S, Segura M. Interferon beta-1A treatment in early-childhood and juvenile multiple sclerosis. Neuropediatrics [Internet]. 2006;37(S 1). DOI:10.1055/s-2006-945670
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Kornek B, Bernert G, Rostasy K, et al. Long-term follow-up of pediatric patients treated with mitoxantrone for multiple sclerosis. Neuropediatrics. 2011;42(01):7–12.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Salzer J, Lycke J, Wickström R, et al. Rituximab in paediatric onset multiple sclerosis: a case series. J Neurol. 2016;263(2):322–326.
   PubMed Web of Science ®Google Scholar
• Aharoni R. The mechanism of action of glatiramer acetate in multiple sclerosis and beyond. Autoimmun Rev. 2013;12(5):543–553.
   PubMed Web of Science ®Google Scholar
• Weinstock-Guttman B, Ransohoff RM, Kinkel RP, et al. The interferons: biological effects, mechanisms of action, and use in multiple sclerosis. Ann Neurol. 1995;37(1):7–15.
   PubMed Web of Science ®Google Scholar
• Chun J, Hartung H-P. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33(2):91–101.
   PubMed Web of Science ®Google Scholar
• Miller AE. Teriflunomide in multiple sclerosis: an update. Neurodegener Dis Manag. 2017;7(1):9–29.
   PubMed Web of Science ®Google Scholar
• Gross CC, Schulte-Mecklenbeck A, Klinsing S, et al. Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e183.
   PubMed Web of Science ®Google Scholar
• Rice GPA, Rice G PA, Hartung H-P, et al. Anti-4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64(8):1336–1342.
   PubMed Web of Science ®Google Scholar
• Milo R. Therapeutic strategies targeting B-cells in multiple sclerosis. Autoimmun Rev. 2016;15(7):714–718.
   PubMed Web of Science ®Google Scholar
• Salzer J, Svenningsson R, Alping P, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. Neurology. 2016;87(20):2074–2081.
   PubMed Web of Science ®Google Scholar
• Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–234.
   PubMed Web of Science ®Google Scholar
• The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43(4):655–655.
   PubMed Web of Science ®Google Scholar
• Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45(7):1268–1276.
   PubMed Web of Science ®Google Scholar
• Tenembaum SN, Banwell B, Pohl D, et al. Subcutaneous interferon beta-1a in pediatric multiple sclerosis: a retrospective study. J Child Neurol. 2013;28(7):849–856.
   PubMed Web of Science ®Google Scholar
• 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–S102.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016;13(1):280.
   PubMed Web of Science ®Google Scholar
• Perini P, Calabrese M, Rinaldi L, et al. The safety profile of cyclophosphamide in multiple sclerosis therapy. Expert Opin Drug Saf. 2007;6(2):183–190.
   PubMed Web of Science ®Google Scholar
• Pinkel D. Cyclophosphamide in children with cancer. Cancer. 1962;15(1):42–49.
   PubMed Web of Science ®Google Scholar
• Makhani N, Gorman MP, Branson HM, et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology. 2009;72(24):2076–2082.
   PubMed Web of Science ®Google Scholar
• Willis MD, Robertson NP. Alemtuzumab for multiple sclerosis. Curr Neurol Neurosci Rep [Internet]. 2016;16(9). DOI:10.1007/s11910-016-0685-y
   PubMed Web of Science ®Google Scholar
• Yeh EA, Waubant E, Krupp LB, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Arch Neurol. 2011;68(4):437–444.
   PubMedGoogle Scholar
• Schwartz CE, Grover SA, Powell VE, et al. Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis. Mult Scler. 2017. 1352458517695469
   PubMedGoogle Scholar
• Sormani MP, Muraro PA, Schiavetti I, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a meta-analysis. Neurology. 2017;88(22):2115–2122.
   PubMed Web of Science ®Google Scholar
• Atkins HL, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576–585.
   PubMed Web of Science ®Google Scholar
• Burman J, Kirgizov K, Carlson K, et al. Autologous hematopoietic stem cell transplantation for pediatric multiple sclerosis: a registry-based study of the Autoimmune Diseases Working Party (ADWP) and Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant [Internet]. 2017. DOI:10.1038/bmt.2017.40
   PubMed Web of Science ®Google Scholar
• Nourbakhsh B, Julian L, Waubant E. Fatigue and depression predict quality of life in patients with early multiple sclerosis: a longitudinal study. Eur J Neurol. 2016;23(9):1482–1486.
   PubMed Web of Science ®Google Scholar
• Skokou M, Soubasi E, Gourzis P. Depression in multiple sclerosis: a review of assessment and treatment approaches in adult and pediatric populations. ISRN Neurol. 2012;2012:1–6.
   Google Scholar
• Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol. 1989;46(6):676–680.
   PubMedGoogle Scholar
• Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72(2):179–183.
   PubMed Web of Science ®Google Scholar
• Narula S, Hopkins SE, Banwell B. Treatment of pediatric multiple sclerosis. Curr Treat Options Neurol. 2015;17(3):336.
   PubMed Web of Science ®Google Scholar
• Yadav V, Bever C Jr, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083–1092.
   PubMed Web of Science ®Google Scholar
• Yeh EA, Ann Yeh E, Kinnett-Hopkins D, et al. Physical activity and pediatric multiple sclerosis: developing a research agenda. Mult Scler J. 2015;21(13):1618–1625.
   PubMed Web of Science ®Google Scholar
• Weems CF, Costa NM. Developmental differences in the expression of childhood anxiety symptoms and fears. J Am Acad Child Adolesc Psychiatry. 2005;44(7):656–663.
   PubMed Web of Science ®Google Scholar
• Myers K, Troutman B. Developmental aspects of child and adolescent depression. J Pediatr. 1993;5(4):419–424.
   Google Scholar
• Parrish JB, Weinstock-Guttman B, Smerbeck A, et al. Fatigue and depression in children with demyelinating disorders. J Child Neurol. 2012;28(6):713–718.
   PubMed Web of Science ®Google Scholar
• Goretti B, Portaccio E, Ghezzi A, et al. Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis. Mult Scler. 2012;18(3):329–334.
   PubMed Web of Science ®Google Scholar
• The Council on Children with Disabilities and Council on School Health, Lipkin PH, Okamoto J. The Individuals With Disabilities Education Act (IDEA) for Children With Special Educational Needs. Pediatrics. 2015;136(6):e1650–e1662.
   PubMed Web of Science ®Google Scholar
• Shaughnessy L, Schuchman M, Ghumra M, et al. Sexual dysfunction in multiple sclerosis. Sex Reprod Neurorehabil. 1997;1:169–195.
   Google Scholar
• Lotstein DS. Transition planning for youth with special health care needs: results from the national survey of children with special health care needs. Pediatrics. 2005;115(6):1562–1568.
   PubMed Web of Science ®Google Scholar
• Scal P. Addressing transition to adult health care for adolescents with special health care needs. Pediatrics. 2005;115(6):1607–1612.
   PubMed Web of Science ®Google Scholar
• Wassmer E, Chitnis T, Pohl D, et al. International Pediatric MS Study Group Global Members Symposium report: table. Neurology. 2016;87(9 Supplement 2):S110–S116.
   PubMed Web of Science ®Google Scholar