1171047

research-article20232023
MSJ0010.1177/13524585231171047Multiple Sclerosis JournalB Banwell

MULTIPLE
SCLEROSIS MSJ
JOURNAL

Future Perspectives

Pediatric multiple sclerosis: The 2022 Multiple Sclerosis Journal

2023, Vol. 29(7) 772­–778

ECTRIMS lecture DOI: 10.1177/

https://doi.org/10.1177/13524585231171047
13524585231171047
https://doi.org/10.1177/13524585231171047

© The Author(s), 2023.

Article reuse guidelines:
Brenda Banwell sagepub.com/journals-
permissions

Abstract 
Correspondence to:
The 2022 ECTRIMS lecture focused on pediatric-onset multiple sclerosis (POMS), in recognition of the B Banwell
Children’s Hospital of
pivotal importance of prompt recognition and treatment of children and youth diagnosed with multiple Philadelphia, Grace E. Loeb
sclerosis (MS), enabled over the past decade by the formal inclusion of pediatric patients in the McDonald Chair in Neuroscience,
Perelman School of
diagnostic criteria. Epidemiologic, genetic and immunologic research has supported the concept that MS Medicine, University of
is a single disease across the age span and that clues to the inciting and early facets of MS pathobiology Pennsylvania, Philadelphia,
PA 19104, USA.
might be uniquely discerned through study of the youngest MS patients. Pediatric trials of pharmaceuti- banwellb@chop.edu
cal agents approved in adult-onset MS are emerging, although innovative study designs, alignment of Brenda Banwell
Children’s Hospital of
regulatory agency requirements for trial design, family-centric models for study visits and emphasis on Philadelphia, Grace E. Loeb
long-term safety and tolerability are essential. Evidence of safety and efficacy of key therapies is key Chair in Neuroscience,
Perelman School of
if POMS patients are to be availed of the full armamentarium of MS therapeutic options. Finally, the Medicine, University of
rarity of POMS necessitates an international community effort to advance care and research. Such col- Pennsylvania, Philadelphia,
PA, USA
laborations 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.

Keywords:  Pediatric, multiple sclerosis, ECTRIMS

Date received: 23 March 2023; revised: 4 April 2023; accepted: 4 April 2023

The 2022 invited ECTRIMS lecture focused on pedi-
atric-onset multiple sclerosis (POMS). The topic
selection honors the efforts of an international collec-
tive of pediatric and adult neurologists, researchers,
allied health providers, multiple sclerosis (MS) organ-
izations and most importantly, the international com-
munity of POMS children and their families. Several
milestones have marked the evolution of POMS care
and research to date: (i) recognition that POMS exists;
(ii) inclusion of POMS in international MS diagnostic
criteria; (iii) acceptance of MS as single disease across
the age span; (iv) insights into the impact of POMS on
physical and cognitive functioning and on brain tissue
integrity in children and adolescents; and (v) advance-
ment of clinical trials for POMS treatment. Attainment
of new milestones, such as global health equity for
access of persons living with POMS to appropriate
care, precision neuroimmunology as a guide to per-
sonalized therapeutic decision-making and monitor-
ing, and increased understanding and management of
mental health from POMS diagnosis and during emer-
gence into adulthood serve as an ongoing call to action.
POMS does exist
Recognition that MS onset can occur in childhood
has been increasingly appreciated over the past
20 years, although reports of MS in children date
back to the mid-19th century (reviewed by a pio-
neer in pediatric MS, Hanefeld1). In a national sur-
vey focused on knowledge and diagnosis of
acquired central nervous system (CNS) demyelina-
tion and POMS specifically, completed by over
2000 pediatric health care providers in Canada
between 2004 through 2007, provider awareness of
that MS can occur in the pediatric age group
increased from 65% to 85%.2 This increase in
awareness was achieved through a national educa-
tional effort supported by the Canadian Pediatric
Surveillance Program and highlights the impor-
tance of grassroots education. Given that children
and adolescents experiencing an incident MS attack
will present to pediatric care facilities, pediatric
health providers must consider POMS as a possible
diagnosis in order to refer to pediatric MS experts
for diagnostic confirmation.

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Diagnosis of POMS
Even with increased awareness, POMS is rare, with
estimated annual incidence rates across multiple
countries of approximately 1 per 100,000 children
(reviewed in Yan et al.3). Of all children manifesting
with a first CNS demyelinating attack, over 70% will
have a monophasic course, and fewer than 20% will
be diagnosed with POMS. The 20104 and 2017 ver-
sions5 of the McDonald MS diagnostic criteria detail
the requirements for confirmation of MS diagnosis at
the time of the presenting first attack. Both versions
include provision for pediatric-onset patients, with
the caveat that children manifesting with acute dis-
seminated encephalomyelitis (ADEM), defined by
polyfocal deficits and encephalopathy,6 must experi-
ence a non-ADEM attack plus evidence for dissemi-
nation in time and space prior to MS diagnosis.
Several studies confirm that these criteria perform
well in pediatric cohorts, with positive and negative
predictive values comparable to those seen in incident
attack adult patients.7–10 When considering specific
aspects of the current 2017 McDonald criteria in
POMS, the possibility to confirm dissemination time
through positivity of cerebrospinal fluid (CSF) oligo-
clonal bands led to increased diagnostic yield.11 It is
noteworthy that spinal lesions (while common) do not
improve diagnostic performance, owing to the high
frequency of supratentorial juxtacortical and periven-
tricular lesions.12 Since POMS patients often require
sedation for long magnetic resonance imaging (MRI)
sessions, more focused brain imaging without full
spinal cord imaging (in patients without spinal symp-
toms) is sufficient for diagnostic purposes.
MS is one disease across the age span
Strong support for the concept of MS as a single dis-
ease that manifests in both pediatric and adult popula-
tions comes from analyses of epidemiological and
genetic risk determinants (summarized in Figure 1).
With the ability to confirm MS promptly at onset, the
potential to study risk factors (particularly in close
proximity to POMS onset) was availed. While the pre-
cise biological underpinnings of MS remain elusive,
MS appears to be resultant of a complex interplay
between genetic predisposition, environmental expo-
sures, and aberrant host immune responses (reviewed
in Dobson and Giovannoni13 and Thompson et al.14).
POMS studies aimed to determine whether this inter-
play, and the factors felt to be most operative in adult
MS, were also contributory to POMS. Large adult-
onset MS studies have identified over 200 single-
nucleotide polymorphisms (SNPs), most in
immune-related genes, as well as the HLA locus (HLA
DRB1501 specifically) as contributing to MS risk.
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B Banwell
POMS patients have a greater number of MS risk SNPs
compared to both monophasic pediatric demyelination
and healthy controls.15 A recent study in POMS has
shown that specific but rare genetic variants linked to
adult-onset MS also contribute to increased MS risk in
pediatric patients.16 In several POMS studies, as well in
adult MS, the strongest genetic association is the pres-
ence of HLA-DR15 alleles, with a relative risk attribu-
tion between two- and six-fold.17 Relapse rates are
higher in POMS patients with at least one HLA-DRB15
allele and low serum vitamin D levels, implicating
gene–environment interactions as one component of
MS disease activity.18
Serological evidence of remote infection with Epstein–
Barr Virus (EBV) is highly associated with MS risk,
and seronegativity for EBV is rare in POMS and adult-
onset MS patients.19 Over 85% of POMS patients are
seropositive for EBV antibodies,17,20,21 and this propor-
tion will likely increase with the ability to exclude chil-
dren with revised diagnoses from POMS to myelin
oligodendrocyte glycoprotein antibody–associated dis-
ease (MOGAD).22 While the association between EBV
infection and MS is unquestionably strong, the mecha-
nisms whereby EBV influences MS risk and possibly
MS disease activity are less well understood.23 Analysis
of EBV viral shedding in saliva in a cohort of POMS
patients compared to EBV-positive age-matched com-
munity youth demonstrated that POMS patients shed
EBV in saliva over 60% of the year, while healthy con-
trols shed the virus only 20% of the months in a year—
raising the possibility that host failure to control EBV
latency might be relevant.24 The possible MS disease
specific role for EBV-immortalized B cells and EBV-
reactive T cells, particularly intrathecal presence of
these immune cells, had led to early phase 1 trials of
EBV-specific T cell therapy in adults with MS25 and to
considerations for EBV vaccines.26 The timing of EBV
vaccination, as a primary preventive strategy for MS,
would clearly require that the vaccine be administered
during early childhood, prior to the onset of POMS and
prior to natural community-based acquisition of EBV
infection.
Another strong environmental association exists
between low serum vitamin D concentrations and MS
risk in both POMS and adult MS cohorts. In a pediat-
ric cohort with incident acute CNS demyelination,
every 10 17 nmol/L decrease in serum 25(OH)D lev-
els associated with a 20% increased likelihood of an
MS diagnosis. Evidence that low vitamin D levels
lead to heighted pro-inflammatory immune responses
adds biological credence to this concept,14 as does
data showing low vitamin D levels being associated
with higher relapse rates in POMS.27
Multiple Sclerosis Journal 29(7)
Figure 1.  The interplay between genetic, environmental, and life-style risk determinants for pediatric-onset MS.
Lifetime MS risk is increased by childhood obesity
(reviewed in Alfredsson and Olsson28). Obesity is
linked with elevated serum adiponectin concentra-
tions in POMS patients.29 POMS patients have been
shown to have higher adiponectin concentrations,
particularly low molecular weight isoforms.
Moreover, serum from POMS patients induced an
adiponectin-driven pro-inflammatory response char-
acterized by activation of CD4 and CD8 T cells as
well as reduced microglial senescence.30
POMS risk is also increased by exposure to second-
hand smoke during childhood.31 In adults with MS,
smoking has also been linked to worse outcomes,
including greater disability. Given data suggesting
that children who grow up in a home with smokers are
more likely to smoke themselves,32 the potential for
worse outcomes in POMS patients is of concern,
although no data have yet explored this relationship.
Given the findings that POMS and adult-onset MS
share epidemiologic and genetic risk determinants,
studies then evaluated whether POMS shares the
same clinical features as seen in adults. Presenting
clinical features—such as optic neuritis, myelitis,
brainstem, and polyfocal attacks—is very similar
across all ages of MS onset.33 POMS follows a relaps-
ing-remitting course, with a higher relapse rate com-
pared to adult-onset disease.34 The higher relapse
rate in POMS patients age less than 10 years and in
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adolescents persists over the first 6 years, compared to
the same time frame in newly diagnosed adult MS
patients.35 In an analysis of serial MRI scans obtained
from untreated POMS patients, a mean of nine new
T2 bright lesions (standard deviation (SD) = 9.3) in
the first 6 months post-onset was observed,36 also
emphasizing the highly inflammatory nature of
POMS. Of note, primary progressive MS is excep-
tionally rare in the pediatric age group.
Impact of POMS
The natural history of POMS, prior to access to cur-
rent therapeutics, shows that accrual of physical dis-
ability and entry into secondary progressive disease
occurs after a median of 20 years post-onset and at a
young adult age (median age = 34 years).37 While
POMS patients rarely develop physical disability in
the first few years of disease, POMS is far from
benign. The negative experience of acute neurologi-
cal impairment during relapses, requirement for hos-
pitalization, missed schooling, and time for relapse
recovery clearly emphasize the need for prompt and
effective treatment for relapse prevention.
Importantly, POMS is characterized not only by clinical
and MRI evidence of active inflammation but also by
neurodegeneration. POMS patients have reduced
brain volume, evident at first attack, compared to age-
and sex-matched controls.38 Serial MRI analyses

demonstrate failure of age-expected brain growth,
reduced peak brain volumes (normally reached by age
15–17 years in typically developing youth), and pro-
gressive atrophy in late adolescence.39,40 More selective
atrophy of deep gray matter structures, particularly the
thalamus, is also notable.39–41 Even within gray matter
structures, specifically the thalamus, a gradient of pro-
gressive volume loss in the CSF-facing tissue occurs.41
Brain atrophy, and thalamic atrophy in particular, cor-
relates with cognitive impairment in POMS.42
Cognitive impairment occurs in 30%–50% of POMS
patients, with deficits in executive function, process-
ing speed, attention, and visuo-motor function
(reviewed in Portaccio et al.43). The onset of MS dur-
ing the years of formative education and over the
period of ongoing myelination through adolescence is
a major issue to address. Comprehensive neuropsy-
chological evaluations and academic enrichment
plans to maximize scholastic supports are essential.
Clinical trials in POMS
To date, a small number of clinical trials have been
completed in POMS, and as such, many of the thera-
pies approved for adults with MS are considered off-
label for POMS patients. Two POMS phase III studies
have been performed,44,45 leading to approval of fin-
golimod in North America and Europe and terifluno-
mide in Europe. Superiority of the oral therapy,
fingolimod over interferon beta-1a by intramuscular
injection, with over 80% relative risk reduction for
relapse was demonstrated.44 In a placebo-controlled
study, teriflunomide failed to meet the primary end-
point of time to first relapse, although a favorable
effect on MRI activity was shown.45 Both trials have
been instructive regarding the myriad of challenges
facing clinical trials in POMS.
Clinical trials for POMS are challenged by the rarity
of the disease, which invariably then leads to interna-
tional trials involving centers in numerous countries
in order to enroll and power the study. Clinical trial
designs involve frequent study visits, which is a major
issue for pediatric patients who are meant to be attend-
ing school and for their parents who have vocational
responsibilities. A detailed discussion regarding chal-
lenges facing POMS clinical trials was published by
the International Pediatric Multiple Sclerosis Study
Group.46
The real-world relevance, however, of access to prompt
diagnosis, early initiation of therapy, and access to
effective therapies was highlighted a four-decade
review of POMS patients in the Italian MS Registry.47
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B Banwell
Analysis of 3198 POMS patients (mean observa-
tion 
= 21.8 (11.7) years) demonstrated that risk of
reaching disability (defined as an Expanded Disability
Status Scale score of 4 or higher) decreased by over
50% over the 40-year interval. While many factors
contributed to this improvement in outcome, and
detailed information regarding specific therapies and
adherence is not possible to discern, the data are
compelling.
New horizons for POMS
Health care inequity
Access to pediatric neuroimmune specialists, and for-
mal pediatric MS clinics, is limited in most parts of
the world. Many pediatric health care facilities do not
have POMS expertise, leading pediatric patients to
seek care in adult MS programs. While adult MS cent-
ers have expertise in MS management, pediatric-spe-
cific care issues are often not addressed. To date, more
than 20 therapeutic agents have been approved for
adults living with MS, yet only one medication has
been fully approved for POMS in the United States,
two therapies are fully approved in most European
countries, and limited access to older therapies with
lower potency (interferons, glatiramer acetate) is
available in others.
Personalized precision care
Immunological studies of POMS patients have identi-
fied several interesting findings. POMS patients have
been shown to harbor increased numbers of myelin-
reactive T cells.48 POMS patients also have increased
CD4 T effector cells, which demonstrate features sug-
gestive of premature senescence.49 The presence of
increased pro-inflammatory cells may not be required,
and it may be that an imbalance between effector and
regulatory immune cell subsets may be a key feature
of POMS.50
Conceptually, defining the immune features of an
individual MS patient may not only shed light on their
disease activity but also may assist in the optimization
of individualized therapeutic interventions. Recent
studies in adults with MS have identified immune sig-
natures that predict likelihood of clinical response to
fingolimod51 (which as mentioned is the only MS
therapy approved for POMS in some countries).
Mental health and wellness
Depression is reported by 3%–40% of youth living
with POMS, and both fatigue and depression strongly
Multiple Sclerosis Journal 29(7)
impact patient-reported quality of life.52 In addition to
school supports, care of POMS patients also requires
focus on wellness. POMS engage in very limited
amounts of vigorous exercise,53 and are more seden-
tary than their peers. Care models that advocate exer-
cise, nutrition, healthy weight, avoidance of smoking
or smoke exposure, and proper sleep have a meaning-
ful contribution to the management of POMS
patients.54 Exercise interventions have the potential to
reduce fatigue and depression in youth with POMS.55
Summary
The past few decades have documented the key clini-
cal and MRI features of POMS, with confirmation
that genetic and environmental risks are shared across
the age span, and with the clear evidence that MS is
an inflammatory, neurodegenerative disease from
onset. Primary preventive strategies to reduce MS
incidence, such as EBV vaccination, universal vita-
min D supplementation, avoidance of smoke expo-
sures, and adherence to healthy body weight will be
initiatives that require partnerships with pediatric
health care providers and national advisories. Health
advocacy for all persons living with MS is crucial to
reduce the health care disparities facing children and
youth with MS, who are far too often restricted in
access to informed care, and for whom access to many
of the highly effective therapies proven for adult-
onset MS is unavailable. Strategies to provide holistic
management, inclusive of mental health, and a greater
appreciation of effective transition of POMS patient
into adult MS care are also new milestones to be
achieved.
Acknowledgements
This lecture would not have been possible without the
collaborations, wisdom, and incredible contributions
of many clinicians and researchers working in the
field of pediatric-onset MS. Regrettably, brevity lim-
ited the ability to acknowledge all of their seminal
observations. Inaugural and current Steering,
Research, Clinical and Education Committee mem-
bers of the International Pediatric Multiple Sclerosis
Study Group (IPMSSG), Drs Krupp, Chitnis, Banwell,
Belman, Tardieu, Amato, Ghezzi, Pohl, Tenenbaum,
Wassmer, Rostasy, Kornberg, Kornek, Waubant,
Hemingway, and the late Rogier Hintzen galvanized
collective awareness and advocacy for care, research,
and evidence-based therapeutics in pediatric MS, sup-
ported by the National MS Society, Multiple Sclerosis
International Federation, and by the Canadian and
Italian MS Societies. The Canadian Pediatric
Demyelinating Disease Network (PIs: Banwell,
Bar-Or, Arnold, Marrie, and Yeh), site investigators,
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and numerous trainees, funded through the generous
support of the Canadian MS Society and its
Foundation, provided the cornerstone upon which
much of the data shared in this manuscript rests.
However, it is the resilient children and adolescents
living with MS, and their families, who have inspired
us all.
Declaration of Conflicting Interests
The author declared the following potential conflicts
of interest with respect to the research, authorship,
and/or publication of this article: Dr B.B. serves as a
consultant to Novartis, Roche, UCB, Biogen-IDEC,
Teva Neurosciences, and Sanofi in regard to the con-
duct of pediatric MS trials.
Funding
The author received no financial support for the
research, authorship, and/or publication of this
article.
References
1. Hanefeld F. Pediatric multiple sclerosis: A short
history of a long story. Neurology 2007; 68(16 Suppl.
2): S3–S6.
2. Banwell B, Kennedy J, Sadovnick D, et al. Incidence
of acquired demyelination of the CNS in Canadian
children. Neurology 2009; 72(3): 232–239.
3. Yan K, Balijepalli C, Desai K, et al. Epidemiology of
pediatric multiple sclerosis: A systematic literature
review and meta-analysis. Mult Scler Relat Disord
2020; 44: 102260.
4. 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.
5. 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.
6. 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.
7. Sadaka Y, Verhey LH, Shroff MM, et al. 2010
McDonald criteria for diagnosing pediatric multiple
sclerosis. Ann Neurol 2012; 72(2): 211–223.
8. 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.

9. Bigi S, Marrie RA, Verhey L, et al. 2010 McDonald
criteria in a pediatric cohort: Is positivity at onset
associated with a more aggressive multiple sclerosis
course? Mult Scler 2013; 19(10): 1359–1362.
10. Wong YYM, 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.
11. Hacohen Y, Brownlee W, Mankad K, et al. Improved
performance of the 2017 McDonald criteria for
diagnosis of multiple sclerosis in children in a real-
life cohort. Mult Scler 2020; 26(11): 1372–1380.
12. Hummel HM, 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.
13. Dobson R and Giovannoni G. Multiple sclerosis—A
review. Eur J Neurol 2019; 26(1): 27–40.
14. Thompson AJ, Baranzini SE, Geurts J, et al. Multiple
sclerosis. Lancet 2018; 391(10130): 1622–1636.
15. 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.
16. Horton MK, Shim JE, Wallace A, et al. Rare and
low-frequency coding genetic variants contribute to
pediatric-onset multiple sclerosis. Mult Scler 2023;
2023: 1150736.
17. 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.
18. Gianfrancesco MA, Stridh P, Shao X, et al. Genetic
risk factors for pediatric-onset multiple sclerosis. Mult
Scler 2018; 24(14): 1825–1834.
19. Bjornevik K, Cortese M, Healy BC, et al.
Longitudinal analysis reveals high prevalence of
Epstein-Barr virus associated with multiple sclerosis.
Science 2022; 375(6578): 296–301.
20. Alotaibi S, Kennedy J, Tellier R, et al. Epstein-Barr
virus in pediatric multiple sclerosis. JAMA 2004;
291(15): 1875–1879.
21. 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(9): 773–781.
22. Banwell B, Bennett JL, Marignier R, et al. Diagnosis
of myelin oligodendrocyte glycoprotein antibody-
associated disease: International MOGAD Panel
proposed criteria. Lancet Neurol 2023; 22(3):
268–282.
journals.sagepub.com/home/msj 777
B Banwell
23. Bar-Or A, Banwell B, Berger JR, et al. Guilty by
association: Epstein-Barr virus in multiple sclerosis.
Nat Med 2022; 28(5): 904–906.
24. Yea C, Tellier R, Chong P, et al. Epstein-Barr virus
in oral shedding of children with multiple sclerosis.
Neurology 2013; 81(16): 1392–1399.
25. Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr
virus-specific T cell therapy for progressive multiple
sclerosis. JCI Insight 2020; 5(20): 144624.
26. Maple PA, Ascherio A, Cohen JI, et al. The potential
for EBV vaccines to prevent multiple sclerosis. Front
Neurol 2022; 13: 887794.
27. 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.
28. Alfredsson L and Olsson T. Lifestyle and
environmental factors in multiple sclerosis. Cold
Spring Harb Perspect Med 2019; 9(4): a028944.
29. Keyhanian K, Saxena S, Gombolay G, et al.
Adipokines are associated with pediatric multiple
sclerosis risk and course. Mult Scler Relat Disord
2019; 36: 101384.
30. Nyirenda MH, Fadda G, Healy LM, et al. Pro-
inflammatory adiponectin in pediatric-onset multiple
sclerosis. Mult Scler 2021; 27(12): 1948–1959.
31. Lavery AM, Waldman AT, Charles Casper T, et al.
Examining the contributions of environmental quality
to pediatric multiple sclerosis. Mult Scler Relat
Disord 2017; 18: 164–169.
32. Chen MY. The negative impact of parental smoking
on adolescents’ health-promoting behaviors: A
cross-sectional study. Int J Environ Res Public Health
2021; 18(5): 2514.
33. Belman AL, Krupp LB, Olsen CS, et al.
Characteristics of children and adolescents with
multiple sclerosis. Pediatrics 2016; 138(1):
e20160120.
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. Verhey LH, Signori A, Arnold DL, et al. Clinical
and MRI activity as determinants of sample size for
pediatric multiple sclerosis trials. Neurology 2013;
81(14): 1215–1221.
37. 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.
Multiple Sclerosis Journal 29(7)
38. 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.
39. 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.
40. 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.
41. Fadda G, Brown RA, Magliozzi R, et al. A surface-in
gradient of thalamic damage evolves in pediatric
multiple sclerosis. Ann Neurol 2019; 85(3): 340–351.
42. 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.
43. Portaccio E, De Meo E, Bellinvia A, et al. Cognitive
issues in pediatric multiple sclerosis. Brain Sci 2021;
11(4): 442.
44. Chitnis T, Arnold DL, Banwell B, et al. Trial of
fingolimod versus interferon beta-1a in pediatric
multiple sclerosis. N Engl J Med 2018; 379(11):
1017–1027.
45. Chitnis T, Banwell B, Kappos L, et al. Safety and
efficacy of teriflunomide in paediatric multiple
sclerosis (TERIKIDS): A multicentre, double-blind,
phase 3, randomised, placebo-controlled trial. Lancet
Neurol 2021; 20(12): 1001–1011.
Visit SAGE journals online 46. Waubant E, Banwell B, Wassmer E, et al. Clinical
journals.sagepub.com/ trials of disease-modifying agents in pediatric MS:
home/msj
Opportunities, challenges, and recommendations from
  journals the IPMSSG. Neurology 2019; 92(22): e2538–e2549.
778 journals.sagepub.com/home/msj
47. Baroncini D, Simone M, Iaffaldano P, et al. Risk
of persistent disability in patients with pediatric-
onset multiple sclerosis. JAMA Neurol 2021; 78(6):
726–735.
48. Vargas-Lowy D, Kivisäkk P, Gandhi R, et al.
Increased Th17 response to myelin peptides in
pediatric MS. Clin Immunol 2013; 146(3): 176–184.
49. Balint B, Haas J, Schwarz A, et al. T-cell homeostasis
in pediatric multiple sclerosis: Old cells in young
patients. Neurology 2013; 81(9): 784–792.
50. Mexhitaj I, Nyirenda MH, Li R, et al. Abnormal
effector and regulatory T cell subsets in paediatric-
onset multiple sclerosis. Brain 2019; 142(3):
617–632.
51. Mao-Draayer Y, Cohen JA, Bar-Or A, et al. Immune
cell subset profiling in multiple sclerosis after
fingolimod initiation and continued treatment: The
FLUENT study. Mult Scler J Exp Transl Clin 2022;
8(3): 1115023.
52. Storm Van’s Gravesande K, Blaschek A, Calabrese
P, et al. Fatigue and depression predict health-
related quality of life in patients with pediatric-onset
multiple sclerosis. Mult Scler Relat Disord 2019; 36:
101368.
53. Stephens S, Berenbaum T, Finlayson M, et al. Youth
with multiple sclerosis have low levels of fitness.
Mult Scler 2021; 27(10): 1597–1605.
54. Fernandez-Carbonell C, Charvet LE and Krupp LB.
Enhancing mood, cognition, and quality of life in
pediatric multiple sclerosis. Paediatr Drugs 2021;
23(4): 317–329.
55. Stephens S, Shams S, Lee J, et al. Benefits of physical
activity for depression and fatigue in multiple
sclerosis: A longitudinal analysis. J Pediatr 2019;
209: 226.e2–232.e2.