Multiple Sclerosis in Children: Current and Emerging Concepts

J. Nicholas Brenton; Ryan Kammeyer; Lauren Gluck; Teri Schreiner; Naila Makhani

doi:10.1055/s-0040-1703000

Seminars in Neurology, Table of Contents

Semin Neurol 2020; 40(02): 192-200
DOI: 10.1055/s-0040-1703000

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Multiple Sclerosis in Children: Current and Emerging Concepts

Authors

J. Nicholas Brenton

¹Department of Neurology, University of Virginia, Charlottesville, Virginia
Ryan Kammeyer

²Department of Pediatrics, University of Colorado, Aurora, Colorado

³Department of Neurology, University of Colorado, Aurora, Colorado
Lauren Gluck

⁴Department of Pediatrics, Yale University, New Haven, Connecticut
Teri Schreiner

²Department of Pediatrics, University of Colorado, Aurora, Colorado

³Department of Neurology, University of Colorado, Aurora, Colorado
Naila Makhani

⁴Department of Pediatrics, Yale University, New Haven, Connecticut

⁵Department of Neurology, Yale University, New Haven, Connecticut

Abstract

Multiple sclerosis is being increasingly recognized and diagnosed in children. In the past several years, advances have been made in diagnosing multiple sclerosis in children, identifying new genetic and environmental risk factors, delineating underlying immunobiology, characterizing imaging findings, and implementing new treatment strategies. In this review, we discuss these advances. Future research into the determinants of multiple sclerosis in children and into new treatment options will be aided by continued international collaboration.

Keywords

multiple sclerosis - children - pediatric

Full Text

References

References
1 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
2 Chitnis T, Glanz B, Jaffin S, Healy B. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler 2009; 15 (05) 627-631
3 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 (01) 54-59
4 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 (02) 186-193
5 Ghassemi R, Narayanan S, Banwell B, Sled JG, Shroff M, Arnold DL. ; Canadian Pediatric Demyelinating Disease Network. Quantitative determination of regional lesion volume and distribution in children and adults with relapsing-remitting multiple sclerosis. PLoS One 2014; 9 (02) e85741
6 Alroughani R, Akhtar S, Ahmed SF, Behbehani R, Al-Abkal J, Al-Hashel J. Incidence and prevalence of pediatric onset multiple sclerosis in Kuwait: 1994-2013. J Neurol Sci 2015; 353 (1-2): 107-110
7 de Mol CL, Wong YYM, van Pelt ED. , et al. Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study. J Neurol 2018; 265 (06) 1310-1319
8 Bizjak N, Osredkar D, Perković Benedik M, Šega Jazbec S. Epidemiological and clinical characteristics of multiple sclerosis in paediatric population in Slovenia: a descriptive nation-wide study. Mult Scler Relat Disord 2017; 18: 56-59
9 Gudbjornsson BT, Haraldsson Á, Einarsdóttir H, Thorarensen Ó. Nationwide incidence of acquired central nervous system demyelination in Icelandic children. Pediatr Neurol 2015; 53 (06) 503-507
10 Boesen MS, Magyari M, Koch-Henriksen N. , et al. Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: a nationwide population-based incidence study. Mult Scler 2018; 24 (08) 1077-1086
11 Marrie RA, O'Mahony J, Maxwell C. , et al; Canadian Pediatric Demyelinating Disease Network. Incidence and prevalence of MS in children: a population-based study in Ontario, Canada. Neurology 2018; 91 (17) e1579-e1590
12 Cappa R, Theroux L, Brenton JN. Pediatric multiple sclerosis: genes, environment, and a comprehensive therapeutic approach. Pediatr Neurol 2017; 75: 17-28
13 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 (05) 436-445
14 Banwell B, Krupp L, Kennedy J. , et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6 (09) 773-781
15 Yea C, Tellier R, Chong P. , et al; Canadian Pediatric Demyelinating Disease Network. Epstein-Barr virus in oral shedding of children with multiple sclerosis. Neurology 2013; 81 (16) 1392-1399
16 Makhani N, Banwell B, Tellier R. , et al; Canadian Pediatric Demyelinating Disease Network. Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler 2016; 22 (03) 385-388
17 Waubant E, Mowry EM, Krupp L. , et al; US Pediatric MS Network. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011; 76 (23) 1989-1995
18 Waubant E, Mowry EM, Krupp L. , et al. Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis. Mult Scler 2013; 19 (07) 891-895
19 Nourbakhsh B, Rutatangwa A, Waltz M. , et al; US Network of Pediatric MS Centers. Heterogeneity in association of remote herpesvirus infections and pediatric MS. Ann Clin Transl Neurol 2018; 5 (10) 1222-1228
20 Mikaeloff Y, Caridade G, Tardieu M, Suissa S. ; KIDSEP Study Group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 2007; 130 (Pt 10): 2589-2595
21 Lavery AM, Collins BN, Waldman AT. , et al. The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk. Mult Scler 2019; 25 (04) 515-522
22 Graves JS, Chitnis T, Weinstock-Guttman B. , et al; Network of Pediatric Multiple Sclerosis Centers. Maternal and perinatal exposures are associated with risk for pediatric-onset multiple sclerosis. Pediatrics 2017; 139 (04) e20162838
23 Lavery AM, Waubant E, Casper TC. , et al. Urban air quality and associations with pediatric multiple sclerosis. Ann Clin Transl Neurol 2018; 5 (10) 1146-1153
24 Brenton JN, Engel CE, Sohn M-W, Goldman MD. Breastfeeding during infancy is associated with a lower future risk of pediatric multiple sclerosis. Pediatr Neurol 2017; 77: 67-72
25 Huppke B, Ellenberger D, Rosewich H, Friede T, Gärtner J, Huppke P. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol 2014; 21 (03) 441-446
26 Ahn JJ, O'Mahony J, Moshkova M. , et al. Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice. Mult Scler 2015; 21 (06) 735-748
27 Chitnis T, Graves J, Weinstock-Guttman B. , et al; U.S. Network of Pediatric MS Centers. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol 2016; 3 (12) 897-907
28 Young B, Waubant E, Lulu S, Graves J. Puberty onset and pediatric multiple sclerosis activity in boys. Mult Scler Relat Disord 2019; 27: 184-187
29 Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Mult Scler 2016; 22 (02) 193-200
30 Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80 (06) 548-552
31 Brenton JN, Woolbright E, Briscoe-Abath C, Qureshi A, Conaway M, Goldman MD. Body mass index trajectories in pediatric multiple sclerosis. Dev Med Child Neurol 2019; 61 (11) 1289-1294
32 Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev 2014; 13 (09) 981-1000
33 Brenton JN, Koenig S, Goldman MD. Vitamin D status and age of onset of demyelinating disease. Mult Scler Relat Disord 2014; 3 (06) 684-688
34 Pakpoor J, Seminatore B, Graves JS. , et al; US Network of Pediatric Multiple Sclerosis Centers. Dietary factors and pediatric multiple sclerosis: a case-control study. Mult Scler 2018; 24 (08) 1067-1076
35 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
36 Disanto G, Magalhaes S, Handel AE. , et al; Canadian Pediatric Demyelinating Disease Network. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 2011; 76 (09) 781-786
37 Chi C, Shao X, Rhead B. , et al. Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry. PLoS Genet 2019; 15 (01) e1007808
38 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
39 Ramagopalan SV, Maugeri NJ, Handunnetthi L. , et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009; 5 (02) e1000369
40 Gianfrancesco MA, Stridh P, Rhead B. , et al; Network of Pediatric Multiple Sclerosis Centers. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology 2017; 88 (17) 1623-1629
41 Thompson AJ, Banwell BL, Barkhof F. , et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17 (02) 162-173
42 Fadda G, Brown RA, Longoni G. , et al; Canadian Pediatric Demyelinating Disease Network. MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study. Lancet Child Adolesc Health 2018; 2 (03) 191-204
43 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
44 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 (08) 967-971
45 Bartels F, Nobis K, Cooper G. , et al. Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure. Mult Scler 2019; 25 (07) 927-936
46 Aubert-Broche B, Fonov V, Narayanan S. , et al; Canadian Pediatric Demyelinating Disease Network. Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth. Neurology 2014; 83 (23) 2140-2146
47 De Meo E, Meani A, Moiola L. , et al. Dynamic gray matter volume changes in pediatric multiple sclerosis: a 3.5 year MRI study. Neurology 2019; 92 (15) e1709-e1723
48 Datta R, Sethi V, Ly S. , et al. 7T MRI visualization of cortical lesions in adolescents and young adults with pediatric-onset multiple sclerosis. J Neuroimaging 2017; 27 (05) 447-452
49 Maranzano J, Till C, Assemlal HE. , et al. Detection and clinical correlation of leukocortical lesions in pediatric-onset multiple sclerosis on multi-contrast MRI. Mult Scler 2019; 25 (07) 980-986
50 Rocca MA, De Meo E, Amato MP. , et al. Cognitive impairment in paediatric multiple sclerosis patients is not related to cortical lesions. Mult Scler 2015; 21 (07) 956-959
51 Tillema JM, Leach J, Pirko I. Non-lesional white matter changes in pediatric multiple sclerosis and monophasic demyelinating disorders. Mult Scler 2012; 18 (12) 1754-1759
52 Blaschek A, Keeser D, Müller S. , et al. Early white matter changes in childhood multiple sclerosis: a diffusion tensor imaging study. AJNR Am J Neuroradiol 2013; 34 (10) 2015-2020
53 Akbar N, Giorgio A, Till C. , et al. Alterations in functional and structural connectivity in pediatric-onset multiple sclerosis. PLoS One 2016; 11 (01) e0145906
54 Aung WY, Massoumzadeh P, Najmi S. , et al. Diffusion tensor imaging as a biomarker to differentiate acute disseminated encephalomyelitis from multiple sclerosis at first demyelination. Pediatr Neurol 2018; 78: 70-74
55 Hintzen RQ, Dale RC, Neuteboom RF, Mar S, Banwell B. Pediatric acquired CNS demyelinating syndromes: features associated with multiple sclerosis. Neurology 2016; 87 (09) (Suppl. 02) S67-S73
56 Brown RA, Narayanan S, Banwell B, Arnold DL. ; Canadian Pediatric Demyelinating Disease Network. Magnetization transfer ratio recovery in new lesions decreases during adolescence in pediatric-onset multiple sclerosis patients. Neuroimage Clin 2014; 6: 237-242
57 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 (02) 541-550
58 Rocca MA, De Meo E, Filippi M. Functional MRI in investigating cognitive impairment in multiple sclerosis. Acta Neurol Scand 2016; 134 (Suppl. 200) 39-46
59 Balint B, Haas J, Schwarz A. , et al. T-cell homeostasis in pediatric multiple sclerosis: old cells in young patients. Neurology 2013; 81 (09) 784-792
60 Vargas-Lowy D, Kivisäkk P, Gandhi R. , et al. Increased Th17 response to myelin peptides in pediatric MS. Clin Immunol 2013; 146 (03) 176-184
61 Cala CM, Moseley CE, Steele C. , et al. T cell cytokine signatures: biomarkers in pediatric multiple sclerosis. J Neuroimmunol 2016; 297: 1-8
62 O'Connor KC, Lopez-Amaya C, Gagne D. , et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J Neuroimmunol 2010; 223 (1-2): 92-99
63 Hennes EM, Baumann M, Schanda K. , et al; BIOMARKER Study Group. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology 2017; 89 (09) 900-908
64 Kraus V, Srivastava R, Kalluri SR. , et al. Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease. Neurology 2014; 82 (06) 470-473
65 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
66 Thannhauser JE, Mah JK, Metz LM. Adherence of adolescents to multiple sclerosis disease-modifying therapy. Pediatr Neurol 2009; 41 (02) 119-123
67 McGinley M, Rossman IT. Bringing the HEET: the argument for high-efficacy early treatment for pediatric-onset multiple sclerosis. Neurotherapeutics 2017; 14 (04) 985-998
68 Rensel M, Rossman I, Moodley M. NEDA in pediatric MS, is it attainable?. Neurology 2016; 86 (16 Suppl): P2.128
69 Krysko KM, Graves J, Rensel M. , et al; US Network of Pediatric MS Centers. Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US. Neurology 2018; 91 (19) e1778-e1787
70 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 (05) 618-624
71 Azary S, Schreiner T, Graves J. , et al. Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry 2018; 89 (01) 28-33
72 Grover SA, Aubert-Broche B, Fetco D. , et al. Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis. Neurology 2015; 85 (19) 1663-1669
73 Torkildsen Ø, Myhr KM, Bø L. Disease-modifying treatments for multiple sclerosis - a review of approved medications. Eur J Neurol 2016; 23 (Suppl. 01) 18-27
74 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 (07) 849-856
75 Krupp LB, Pohl D, Ghezzi A. , et al; REPLAY Study Group. Subcutaneous interferon β-1a in pediatric patients with multiple sclerosis: regional differences in clinical features, disease management, and treatment outcomes in an international retrospective study. J Neurol Sci 2016; 363: 33-38
76 Fragomeni MO, Bichuetti DB, Oliveira EML. Pediatric-onset multiple sclerosis in Brazilian patients: clinical features, treatment response and comparison to pediatric neuromyelitis optica spectrum disorders. Mult Scler Relat Disord 2018; 25 (June): 138-142
77 Ghezzi A, Amato MP, Annovazzi P. , et al; ITEMS (Immunomodulatory Treatment of Early-onset MS) Group. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci 2009; 30 (03) 193-199
78 Banwell B, Reder AT, Krupp L. , et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology 2006; 66 (04) 472-476
79 Khan O, Rieckmann P, Boyko A. , et al. Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study. Mult Scler 2017; 23 (06) 818-829
80 Gärtner J, Chitnis T, Ghezzi A. , et al. Relapse rate and MRI activity in young adult patients with multiple sclerosis: a post hoc analysis of phase 3 fingolimod trials. Mult Scler J Exp Transl Clin 2018; 4 (02) 2055217318778610
81 Makhani N, Schreiner T. Oral dimethyl fumarate in children with multiple sclerosis: a dual-center study. Pediatr Neurol 2016; 57: 101-104
82 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; 83: 19-24
83 Comi G, Cohen JA, Arnold DL, Wynn D, Filippi M. ; FORTE Study Group. Phase III dose-comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol 2011; 69 (01) 75-82
84 Wolinsky JS, Narayana PA, Nelson F. , et al; Teriflunomide Multiple Sclerosis Oral (TEMSO) Trial Group. Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. Mult Scler 2013; 19 (10) 1310-1319
85 Etemadifar M, Afzali P, Abtahi S-H. , et al. Safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis. Eur J Paediatr Neurol 2014; 18 (02) 119-125
86 Alroughani R, Ahmed SF, Behbehani R, Al-Hashel J. The use of natalizumab in pediatric patients with active relapsing multiple sclerosis: a prospective study. Pediatr Neurol 2017; 70: 56-60
87 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) 174
88 Arnal-Garcia C, García-Montero MR, Málaga I. , et al. Natalizumab use in pediatric patients with relapsing-remitting multiple sclerosis. Eur J Paediatr Neurol 2013; 17 (01) 50-54
89 Kornek B, Aboul-Enein F, Rostasy K. , et al. Natalizumab therapy for highly active pediatric multiple sclerosis. JAMA Neurol 2013; 70 (04) 469-475
90 Dale RC, Brilot F, Duffy LV. , et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014; 83 (02) 142-150
91 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
92 Makhani N, Gorman MP, Branson HM, Stazzone L, Banwell BL, Chitnis T. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology 2009; 72 (24) 2076-2082