The 2022 ECTRIMS lecture focused on pediatric-onset multiple sclerosis (POMS), in recognition of the pivotal importance of prompt recognition and treatment of children and youth diagnosed with multiple sclerosis (MS), enabled over the past decade by the formal inclusion of pediatric patients in the McDonald diagnostic criteria. Epidemiologic, genetic and immunologic research has supported the concept that MS is a single disease across the age span and that clues to the inciting and early facets of MS pathobiology might be uniquely discerned through study of the youngest MS patients. Pediatric trials of pharmaceutical agents approved in adult-onset MS are emerging, although innovative study designs, alignment of regulatory agency requirements for trial design, family-centric models for study visits and emphasis on long-term safety and tolerability are essential. Evidence of safety and efficacy of key therapies is key if POMS patients are to be availed of the full armamentarium of MS therapeutic options. Finally, the rarity of POMS necessitates an international community effort to advance care and research. Such collaborations have been facilitated through the International Pediatric Multiple Sclerosis Group, Multiple Sclerosis International Federation, and by national multiple sclerosis societies. International efforts and priorities for the next decade will be highlighted.
HanefeldF. Pediatric multiple sclerosis: A short history of a long story. Neurology2007; 68(16Suppl. 2): S3–S6.
2.
BanwellBKennedyJSadovnickD, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology2009; 72(3): 232–239.
3.
YanKBalijepalliCDesaiK, et al. Epidemiology of pediatric multiple sclerosis: A systematic literature review and meta-analysis. Mult Scler Relat Disord2020; 44: 102260.
4.
PolmanCHReingoldSCBanwellB, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol2011; 69(2): 292–302.
5.
ThompsonAJBanwellBLBarkhofF, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol2018; 17(2): 162–173.
6.
KruppLBTardieuMAmatoMP, 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 Scler2013; 19(10): 1261–1267.
7.
SadakaYVerheyLHShroffMM, et al. 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. Ann Neurol2012; 72(2): 211–223.
8.
KornekBSchmitlBVassK, et al. Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome. Mult Scler2012; 18(12): 1768–1774.
9.
BigiSMarrieRAVerheyL, et al. 2010 McDonald criteria in a pediatric cohort: Is positivity at onset associated with a more aggressive multiple sclerosis course?Mult Scler2013; 19(10): 1359–1362.
10.
WongYYMde MolCLvan der Vuurst de VriesRM, et al. Real-world validation of the 2017 McDonald criteria for pediatric MS. Neurol Neuroimmunol Neuroinflamm2019; 6(2): e528.
11.
HacohenYBrownleeWMankadK, et al. Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort. Mult Scler2020; 26(11): 1372–1380.
12.
HummelHMBrückWDreha-KulaczewskiS, et al. Pediatric onset multiple sclerosis: McDonald criteria 2010 and the contribution of spinal cord MRI. Mult Scler2013; 19(10): 1330–1335.
ThompsonAJBaranziniSEGeurtsJ, et al. Multiple sclerosis. Lancet2018; 391(10130): 1622–1636.
15.
Van PeltEDMescheriakovaJYMakhaniN, et al. Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination. Neurology2013; 81(23): 1996–2001.
16.
HortonMKShimJEWallaceA, et al. Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis. Mult Scler2023; 2023: 1150736.
17.
BanwellBBar-OrAArnoldDL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: A prospective national cohort study. Lancet Neurol2011; 10(5): 436–445.
18.
GianfrancescoMAStridhPShaoX, et al. Genetic risk factors for pediatric-onset multiple sclerosis. Mult Scler2018; 24(14): 1825–1834.
19.
BjornevikKCorteseMHealyBC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science2022; 375(6578): 296–301.
20.
AlotaibiSKennedyJTellierR, et al. Epstein-Barr virus in pediatric multiple sclerosis. JAMA2004; 291(15): 1875–1879.
21.
BanwellBKruppLKennedyJ, et al. Clinical features and viral serologies in children with multiple sclerosis: A multinational observational study. Lancet Neurol2007; 6(9): 773–781.
22.
BanwellBBennettJLMarignierR, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol2023; 22(3): 268–282.
23.
Bar-OrABanwellBBergerJR, et al. Guilty by association: Epstein-Barr virus in multiple sclerosis. Nat Med2022; 28(5): 904–906.
24.
YeaCTellierRChongP, et al. Epstein-Barr virus in oral shedding of children with multiple sclerosis. Neurology2013; 81(16): 1392–1399.
25.
PenderMPCsurhesPASmithC, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight2020; 5(20): 144624.
26.
MaplePAAscherioACohenJI, et al. The potential for EBV vaccines to prevent multiple sclerosis. Front Neurol2022; 13: 887794.
27.
MowryEMKruppLBMilazzoM, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol2010; 67(5): 618–624.
28.
AlfredssonLOlssonT. Lifestyle and environmental factors in multiple sclerosis. Cold Spring Harb Perspect Med2019; 9(4): a028944.
29.
KeyhanianKSaxenaSGombolayG, et al. Adipokines are associated with pediatric multiple sclerosis risk and course. Mult Scler Relat Disord2019; 36: 101384.
30.
NyirendaMHFaddaGHealyLM, et al. Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis. Mult Scler2021; 27(12): 1948–1959.
31.
LaveryAMWaldmanATCharles CasperT, et al. Examining the contributions of environmental quality to pediatric multiple sclerosis. Mult Scler Relat Disord2017; 18: 164–169.
32.
ChenMY. The negative impact of parental smoking on adolescents’ health-promoting behaviors: A cross-sectional study. Int J Environ Res Public Health2021; 18(5): 2514.
33.
BelmanALKruppLBOlsenCS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics2016; 138(1): e20160120.
34.
GormanMPHealyBCPolgar-TurcsanyiM, et al. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol2009; 66(1): 54–59.
35.
BensonLAHealyBCGormanMP, et al. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord2014; 3(2): 186–193.
36.
VerheyLHSignoriAArnoldDL, et al. Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials. Neurology2013; 81(14): 1215–1221.
37.
RenouxCVukusicSMikaeloffY, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med2007; 356(25): 2603–2613.
38.
KerbratAAubert-BrocheBFonovV, et al. Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS. Neurology2012; 78(3): 194–201.
39.
Aubert-BrocheBFonovVNarayananS, et al. Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth. Neurology2014; 83(23): 2140–2146.
40.
De MeoEMeaniAMoiolaL, et al. Dynamic gray matter volume changes in pediatric multiple sclerosis: A 3.5 year MRI study. Neurology2019; 92(15): e1709–e1723.
41.
FaddaGBrownRAMagliozziR, et al. A surface-in gradient of thalamic damage evolves in pediatric multiple sclerosis. Ann Neurol2019; 85(3): 340–351.
42.
TillCGhassemiRAubert-BrocheB, et al. MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. Neuropsychology2011; 25(3): 319–332.
43.
PortaccioEDe MeoEBellinviaA, et al. Cognitive issues in pediatric multiple sclerosis. Brain Sci2021; 11(4): 442.
44.
ChitnisTArnoldDLBanwellB, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med2018; 379(11): 1017–1027.
45.
ChitnisTBanwellBKapposL, et al. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): A multicentre, double-blind, phase 3, randomised, placebo-controlled trial. Lancet Neurol2021; 20(12): 1001–1011.
46.
WaubantEBanwellBWassmerE, et al. Clinical trials of disease-modifying agents in pediatric MS: Opportunities, challenges, and recommendations from the IPMSSG. Neurology2019; 92(22): e2538–e2549.
47.
BaronciniDSimoneMIaffaldanoP, et al. Risk of persistent disability in patients with pediatric-onset multiple sclerosis. JAMA Neurol2021; 78(6): 726–735.
48.
Vargas-LowyDKivisäkkPGandhiR, et al. Increased Th17 response to myelin peptides in pediatric MS. Clin Immunol2013; 146(3): 176–184.
49.
BalintBHaasJSchwarzA, et al. T-cell homeostasis in pediatric multiple sclerosis: Old cells in young patients. Neurology2013; 81(9): 784–792.
50.
MexhitajINyirendaMHLiR, et al. Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis. Brain2019; 142(3): 617–632.
51.
Mao-DraayerYCohenJABar-OrA, et al. Immune cell subset profiling in multiple sclerosis after fingolimod initiation and continued treatment: The FLUENT study. Mult Scler J Exp Transl Clin2022; 8(3): 1115023.
52.
Storm Van’s GravesandeKBlaschekACalabreseP, et al. Fatigue and depression predict health-related quality of life in patients with pediatric-onset multiple sclerosis. Mult Scler Relat Disord2019; 36: 101368.
53.
StephensSBerenbaumTFinlaysonM, et al. Youth with multiple sclerosis have low levels of fitness. Mult Scler2021; 27(10): 1597–1605.
54.
Fernandez-CarbonellCCharvetLEKruppLB. Enhancing mood, cognition, and quality of life in pediatric multiple sclerosis. Paediatr Drugs2021; 23(4): 317–329.
55.
StephensSShamsSLeeJ, et al. Benefits of physical activity for depression and fatigue in multiple sclerosis: A longitudinal analysis. J Pediatr2019; 209: 226.e2–232.e2.
