http://neurology.thelancet.com Vol 6 October 2007 887
Multiple sclerosis in children: clinical diagnosis, therapeutic
strategies, and future directions
Brenda Banwell, Angelo Ghezzi, Amit Bar-Or, Yann Mikaeloff , Marc Tardieu
The onset of multiple sclerosis (MS) in childhood poses diagnostic and therapeutic challenges, particularly if the
symptoms of the fi rst demyelinating event resemble acute disseminated encephalomyelitis (ADEM). MRI is an
invaluable diagnostic tool but it lacks the specifi city to distinguish ADEM from the fi rst attack of MS. Advanced MRI
techniques might have the required specifi city to reveal whether the loss of integrity in non-lesional tissue occurs as
a fundamental feature of MS. Although the onset of MS in childhood typically predicts a favourable short-term
prognosis, some children are severely disabled, either physically or cognitively, and more than 50% are predicted to
enter the secondary-progressive phase of the disease by the age of 30 years. Immunomodulatory therapies for MS and
their safe application in children can improve long-term prognosis. Genetic and environmental factors, such as viral
infection, might be uniquely amenable to study in paediatric patients with MS. Understanding the immunological
consequences of these putative exposures will shed light on the early pathological changes in MS.
Multiple sclerosis (MS) in children and adolescents is
increasingly recognised worldwide. The disorder presents
almost exclusively as a relapsing-remitting disease in
children, and most recover from the initial attacks. The
accumulation of disabilities and the development of
secondary-progressive MS most commonly occur more
than 15 years after the fi rst attack. MRI has contributed
substantially to the increasing recognition of and certainty
in the diagnosis of MS in children. The potential for
advanced MRI techniques to visualise fundamental
features of myelin integrity and repair provides exciting
opportunities for future research. Treatment is currently
based on strategies optimised for adult-onset MS and
seems to be safe and well tolerated, although prospective
therapeutic trials in paediatric MS have not been done.
We describe the clinical, radiographic, and biological
characteristics of MS and the other disorders considered
in the diff erential diagnosis in children. We also describe
current therapeutic practice and discuss avenues of
Acute demyelination of the CNS
The fi rst acute demyelinating event, termed a clinically
isolated syndrome, can manifest with signs and
symptoms caused by a single lesion (monofocal clinically
isolated syndrome) or with polyfocal features, implicating
multiple lesions. There are published clinical defi nitions
for these various clinical demyelinating presentations
(fi gure 1).1–23
In a prospective study of 296 children with acute
demyelination, 81 presented with focal involvement, 119
with acute disseminated encephalomyelitis (ADEM), and
96 with symptoms that suggest already established MS
(defi ned as MRI features of well-defi ned lesions or lesions
perpendicular to the corpus callosum combined with
appropriate clinical features). Long-tract (motor, sensory, or
sphincter) dysfunction was the commonest fi nding in
226 children (76%), followed by symptoms localised to the
brainstem in 121 children (41%), optic neuritis in 67 children
(22%), and transverse myelitis in 42 children (14%).24
Monofocal presentation was more common in adolescents.
Recovery from acute demyelination is variable: 85% of
children with optic neuritis recover full visual acuity.25–27 In
published reports of 250 children with transverse myelitis,
80% were paraplegic or tetraplegic and had incontinence or
severe urinary symptoms at onset, and 5% died.28–40 More
than 30% of survivors remain wheelchair dependent, and
70% have residual bladder control problems.29
Published reports of neuromyelitis optica in children
are scarce.41–43 In one study of nine children, none had
relapsing neuromyelitis optica, and visual and motor
recovery was excellent43 compared with adults with
relapsing neuromyelitis optica, of whom 50% developed
paraplegia, 60% developed severe visual loss, and 32%
Recovery from ADEM can take several months,18,19,22
and residual physical defi cits, although mild, were noted
in 11–43% of children.18,22 Furthermore, mild cognitive
sequelae can be detected in children with full physical
Risk of subsequent attacks after a demyelinating event
A prospective study of 296 children with acute
demyelination led to the diagnosis of MS in 168, after a
mean observation of 2·9±3 years (mean±SD), in 38 (47%)
of 81 patients with initial focal involvement, and in 34
(29%) of 119 patients with an initial diagnosis of ADEM.24
Several features were highly predictive of MS outcome:
being older than 10 years at the fi rst demyelinating event;
the absence of mental-state change at onset; and a family
history of optic neuritis or MS. None of these predictors
was absolute, as shown by the fact that of the 168 children
diagnosed with MS, some were as young as 2 years old,
34 had encephalopathy and were initially diagnosed with
ADEM, and there was a family history of MS in only 7%.24
Of the children with relapsing disease, being younger
than 10 years old predicted a longer time from fi rst to
second attack (median 6 years), compared with that in
older children (median 1 year).
Lancet Neurol 2007; 6: 887–902
Department of Paediatrics,
Division of Neurology, The
Hospital for Sick Children,
University of Toronto, Toronto,
Canada (B Banwell MD);
Ospedale di Gallarate, Centro
Studi Sclerosi Multipla,
Gallarate, Italy (A Ghezzi MD);
Department of Neurology and
Neurological Institute, McGill
University, Montreal, Canada
(A Bar-Or MD); Service de
Hôpital Bicêtre, Assistance
Publique—Hôpitaux de Paris,
INSERM U802, Paris, France
(Y Mikaeloff MD, M Tardieu MD)
Brenda Banwell, Research
Institute, The Hospital for Sick
Children, University of Toronto,
555 University Avenue, Toronto,
Ontario, Canada M5G 1X8
http://neurology.thelancet.com Vol 6 October 2007
In a prospective study of 36 children with optic neuritis,
13 children were diagnosed with MS after a mean
observation of 2·4 years (range 0·3–8·3 years).25 The risk
of developing MS after childhood optic neuritis, reported
in retrospective series, varied from 15% to 42%.26,45 A
second attack that would confi rm MS might occur many
years after childhood optic neuritis, as shown in a
longitudinal study in which MS was diagnosed in 15
patients (19%) during the period of observation. Kaplan-
Meier analysis showed a probability of a diagnosis of MS
of 13% at 10 years and 22% at 23 years after optic neuritis.9
Bilateral optic neuritis is associated with a greater
likelihood of MS outcome.25,27 Recurrent optic neuritis,
and optic neuritis in the context of opticospinal MS or
neuromyelitis optica, might be more common in Asian
children.27,46 MRI evidence of at least one demyelinating
lesion separate from the optic nerves at onset of optic
neuritis is strongly associated with a diagnosis of MS
within 2 years.25 Ocular coherence tomography, a non-
invasive technique that uses near-infrared light to
measure retinal nerve fi bre layer thickness, provides a
quantitative measure of axonal loss.47 This is a promising
technique with potential implications for visual prognosis
and estimation of the risk of MS in adults.48 There are no
published studies of ocular coherence tomography in
paediatric optic neuritis.
In contrast to optic neuritis, MS is rarely diagnosed
after acute isolated transverse myelitis in children.35 Of
168 children diagnosed with MS in a prospective study,
only 13 (8%) had isolated transverse myelitis as the fi rst
occurence of MS.24
In children with ADEM, the risk of recurrent or
multiphasic forms of the disorder is less than 10%.18,49
Recurrent and multiphasic ADEM are thought of as
restricted illnesses not associated with chronic relapsing
demyelination. At least 20% of children initially diagnosed
Symptoms localise to
multiple CNS sites
First attack of demyelination
Symptoms localise to
Other Isolated transverse
Symptoms localise to
spinal cord and optic
Isolated optic neuritis
Polyfocal with encephalopathy
(no new areas of involvement)
Polyfocal with encephalopathy
(new areas of involvement)
Further demyelinating attacks
Restricted to spinal cord
and optic nerve
Disseminated in space and time,
two or more non-ADEM events (in a
child with initial ADEM)
Figure 1: Classifi cation of acquired infl ammatory CNS demyelination in children
When the diagnosis of acute infl ammatory demyelination of the CNS is made, the description of the clinical presentation is delineated on the basis of clinical features
and whether the patient has a single or relapsing disease course. Optic neuritis is defi ned by acute or sub-acute visual loss, relative aff erent pupillary defect, restricted
visual fi elds, and pain with ocular movement.9 Diagnostic criteria for transverse myelitis have been developed.10 The currently proposed defi nition for ADEM requires
polyfocal defi cits accompanied by encephalopathy.1 Neuromyelitis optica, or Devic’s disease, is characterised by optic neuritis and transverse myelitis that occur
simultaneously or in close succession.11–13 Spinal MRI typically has lesions that extend over more than three vertebral segments (longitudinally extensive transverse
myelitis). Brain MRI is typically healthy, or shows cerebral lesions in regions of the brainstem and hypothalamic structures, in a pattern atypical for MS.2,3 ADEM is
characterised by polyfocal clinical defi cits, alterations in consciousness (irritability, somnolence, encephalopathy, or coma), can follow recent infection, and is
commonly associated with fever, seizures, or meningism.14–23 MRI typically shows ill-defi ned, bilateral lesions in the deep grey nuclei and cortical grey matter, and
diff use supratentorial and infratentorial white matter involvement.4,18,22 Further demyelinating events can occur as a recurrence of the same features, as seen in the
initial event of ADEM (recurrent ADEM), or rarely can occur as a second, distinct episode of ADEM (new neurological defi cits with encephalopathy, termed multiphasic
ADEM).1 Relapsing symptoms in new areas of involvement in the CNS, separated by more than 1 month, are the hallmark of relapsing-remitting MS.6,7 Patients with
neuromyelitis optica can continue to have recurrent attacks in the optic nerves or spinal cord, leading to a diagnosis of relapsing neuromyelitis optica.5,8 Primary-
progressive MS is exceptionally rare in children; thus it is not shown.
http://neurology.thelancet.com Vol 6 October 2007 889
with ADEM have further demyelinating events that are
atypical for ADEM, which leads to a diagnosis of
In the proposed diagnostic criteria for paediatric MS,1 the
consensus was that the diagnosis of MS in a child with
an initial diagnosis of ADEM should be made only after
two subsequent non-ADEM events (demyelinating events
that do not include encephalopathy), a criterion that is
deliberately conservative, and future multinational
collaborations will establish whether such a restriction
ensures or delays an appropriate diagnosis of MS.
Confi rmation of the diagnosis
Diff erential diagnosis
A cornerstone of the diagnosis of MS in adults and
children rests on showing lesion dissemination in space
and time and the exclusion of other disorders.7 One
approach to discount disorders in the diff erential
diagnosis of acute CNS demyelination was set out in a
recent consensus article (fi gure 2 and webfi gure).50 CNS
infection and intracerebral malignancy must always be
considered. Although CNS lymphoma is rare in children,
intracallosal involvement can be similar to the white-
matter lesions seen in MS.51
Primary small-vessel vasculitis of the CNS is one of the
most diffi cult disorders to distinguish from acquired
demyelination. Vasculitis of the CNS in children can
occur as systemic vasculitis, such as systemic lupus
erythematosus, or as a CNS-restricted angiitis.52–54 Serum
vasculitic markers and features of systemic disease are
completely absent in isolated CNS angiitis. The results of
CNS angiography can show vascular disease in children
with moderate-vessel to large-vessel involvement but can
seem healthy in patients with small-vessel infl ammation.55
Multifocal areas of increased signal of the CNS white
matter, deep grey nuclei, optic nerves, and spinal cord
appear in a pattern that is diffi cult to distinguish from
infl ammatory demyelination. Persistent headache and
malaise, and recurrence of symptoms with corticosteroid
taper, should prompt the consideration of CNS vasculitis;
however, brain biopsy is essential for diagnosis.54
The symptoms of macrophage-activation syndrome can
initially resemble ADEM or MS.56–58 Although macrophage-
activation syndrome is typically a multisystem illness—
with hepatomegaly, splenomegaly, adenopathy, fever, and
signs of intravascular
symptoms might be the only features at onset. Treatment
with corticosteroids will alleviate the symptoms, but the
malaise, headache, and polyfocal neurological defi cits will
recur when patients are weaned off the corticosteroid
therapy. Clues to the diagnosis of macrophage-activation
syndrome include the young age of the patient (usually
less than 2 years but cases in adolescents have been
reported), parental consanguinity or death of a sibling,
the presence of acute necrotic lesions seen on MRI, and
the development of multisystemic involvement.59,60 The
diagnosis is confi rmed by haemophagocytosis of cells in
cerebrospinal fl uid or in bone marrow aspirates, elevated
concentrations of serum ferritin and triglycerides, low
concentrations of serum fi brin, indirect signs of
lymphocyte activation (including high expression of DR
antigen), lack of perforin expression in lymphocytes, and
evidence of lymphocyte cytotoxicity. Mutations in the
genes encoding perforin 1, Munc 13-4, and syntaxin 11
result in haemophagocytic
mutations in LYST cause Chediak–Higashi syndrome;
mutations in RAB27A cause Griscelli syndrome; and
mutations in SH2D1A result in the X-linked proliferative
syndrome.59 Prompt diagnosis is essential to enable early
bone marrow transplantation, which is the only eff ective
long-term treatment for
The clinical and radiographic delineation of inherited
white-matter leukodystrophies are described in detail.63
Children with metachromatic leukodystrophy present
with progressive psychomotor slowing, ataxia, spasticity,
peripheral neuropathy, and MRI evidence of bilateral,
all the familial
Acquired CNS deficit
Acute or subacute onset†
• CNS inflammatory
• infectious aetiologies§
• vasculopathies or
• malignancy or macrophage-
Exclusion of other aetiologies
Imaging and laboratory
CSF oligoclonal bands
serial MRI imaging
Diagnosis: acquired inflammatory
• vascular aetiologies
• toxins or infectious aetiologies
• acute demyelination
• inherited metabolic disorders
• nutritional deficiencies (B12)
• vasculitis or vasculopathies
Figure 2: Approach to the diagnosis of acute demyelination in children
Diseases in the diff erential of infl ammatory demyelination. The fi gure is not meant to be exhaustive but instead
provides an overview of common disorders included in the diff erential and rare disorders that should not be
missed. *Maximal neurological defi cit reached within hours of onset. †Neurological defi cits that fl uctuate or reach
maximum intensity over a period of several days to about 3 months. ‡Clinical examination localised the
neurological signs and symptoms within the CNS. §Causes of infections include viruses such a herpes, HIV,
Mycoplasma pneumoniae, and other viruses relevant to specifi c geographical regions. ¶Accrual of defi cits over the
course of 6 months or more. PPMS=primary-progressive multiple sclerosis. VEPs=visual evoked potentials.
SSEPs=somatosensory evoked potentials. A fuller version of this fi gure is available (webfi gure).
See Online for webfi gure
http://neurology.thelancet.com Vol 6 October 2007
arylsulfatase A defi ciency is a diagnostic fi nding. Episodic
neurological defi cits occur in Fabry’s disease, which is
diagnosed by the presence of dermal angiokeratomata,
corneal dystrophy, MRI evidence of a vascular
distribution of the disease,
evidence of leucocyte α-galactosidase defi ciency.65
progressive behavioural and cognitive decline in late
childhood, followed by progressive spasticity. MRI shows
bilateral, anterior-predominant increased signal in white
matter with gadolinium enhancement in the border
between visibly healthy and abnormal white matter.66,67
Occasionally, patients present with relapsing-remitting
symptoms, which precede the inevitable progressive
deterioration;64 thus, X-linked adrenoleukodystrophy
should be considered in male adolescents, particularly if
the features seen on MRI are atypical for MS. High
serum concentrations of very-long-chain fatty acids are
diagnostic for adrenoleukodystrophy. In general, the
leukodystrophies enables them to be distinguished
readily from MS, particularly because primary-progressive
MS is exceptionally rare in children.68
increased signal in white matter;64
nature of inherited
CSF analysis has a key role in the exclusion of acute
infection and malignancy from the diagnosis of MS. The
CSF white-cell count in children presenting with the fi rst
attack of MS typically ranges from 0–30 leucocytes/mm,3
although cell counts of up to 60 leucocytes/mm3 are seen
in about 8% of children;69 higher CSF cell counts are more
characteristic of infection, vasculitis, or neuromyelitis
optica.53,70 Oligoclonal bands in spinal fl uid analysed with
isoelectric focusing are reported in about 90% of children
with MS;69,71–73 however, CSF oligoclonal bands develop
over the course of the disease, and not all children have
positive results at fi rst.69,71 Although the results of previous
studies suggested that CSF oligoclonal bands were rare in
young patients with MS,74 a recent study detected CSF
oligoclonal bands in 24 of 25 children under the age of
10 years with MS.69 CSF oligoclonal bands were absent in
a study of 84 children with ADEM.18 Similarly, CSF
oligoclonal bands are rarely detected in patients with
neuromyelitis optica and, if detected, they tend to be
transient.70 Serum antibodies against aquaporin 4 (NMO-
IgG) distinguish adults with neuromyelitis optica from
those with relapsing-remitting MS, with 73% sensitivity
and 91% specifi city.75 Aquaporin 4 is an active astrocytic
water channel implicated in cellular electrolyte infl ux,
particularly at the blood–brain barrier.76 Serum NMO-IgG
was seen in a case report of a child with clinical
neuromyelitis optica.77 The prognostic role of NMO-IgG
in children with demyelination is an area for further
Multimodal evoked potential testing can confi rm the
involvement of or detect clinically silent defi cits in the
visual evoked potential, brainstem auditory evoked
potential, or somatosensory
pathways.78,79 In a study of 156 children with MS,
85 children had visual evoked potentials tested at the
time of the fi rst attack. Visual evoked potentials were
abnormal in 48 children (56%), 29 of whom had no
clinical evidence of optic nerve disease.80 However,
investigation of brainstem auditory evoked potentials
and somatosensory evoked potentials rarely detected
abnormalities not apparent on clinical examination,
which is consistent with other reports.79,80 Visual evoked
potentials were abnormal in 26 of 27 participants in a
study of children with optic neuritis,25 confi rming the
usefulenss of visual evoked potential testing in the
assessment of demyelination of the optic pathways.
MRI has a pivotal role in confi rming the presence
of CNS lesions consistent with infl ammatory
demyelination and in the exclusion of other CNS
disorders (fi gure 3).81 Ill-defi ned lesions that include the
deep grey nuclei in MS are more commonly seen in
young children.24 Ill-defi ned lesion borders, large
lesions, and lesions in the central grey-matter regions
are also characteristic of ADEM.16,19 Several studies of
both children and adults have shown that MRI is not
suffi cient to distinguish between ADEM and MS.82–84
MRI of children with ADEM should not show the
accrual of clinically silent lesions, in contrast to MS.18
Spinal cord imaging of patients with MS typically shows
lesions in only a portion of the diameter and only a
short longitudinal expanse of the spinal cord.85 However,
some children with MS have longitudinally extensive
transverse myelitis.86 Demyelination in children with
MS might be associated with a greater degree of oedema
or with a greater propensity for widespread white-
matter involvement during acute relapses than is
typically seen in adults with the disorder.
The diagnostic criteria for MS in adults include MRI
evidence of dissemination of the disease both in space
(within the CNS) and over time.6,87 These criteria have a
sensitivity of only 52–54% when applied to images
obtained in children at the time of the fi rst MS attack,82,88
and a sensitivity of 67% at the time of the second MS-
defi ning event.88 Low sensitivity (37%) was particularly
notable when the MRI criteria were applied to images
from children who were less than 10 years old when they
had the fi rst attack of MS.82
Mikaeloff and co-workers82 used standardised methods
to identify MRI features predictive of MS outcome in a
group of 116 children imaged at an initial acute
demyelinating event. After a mean observation period of
4·9±3 years (mean±SD), 45% of the children had a
second demyelinating event and were diagnosed with
MS. MRI features predictive of such an outcome included
lesions located perpendicular to the long axis of the
corpus callosum and the sole presence of well-defi ned
http://neurology.thelancet.com Vol 6 October 2007 891
lesions in the brain. The presence of both these features
was 100% specifi c for MS outcome, although the
sensitivity was only 21%.82 The presence of only one of
these criteria (55% of patients) increased the sensitivity
to 79%, whereas specifi city decreased to only 63%.
MRI-based techniques can also be used to investigate
tissue integrity (magnetisation transfer imaging or
diff usion tensor imaging) and tissue biochemistry
(magnetic resonance spectroscopy). The mean diff usivity
—an index of the loss of tissue integrity and thus an
increased capacity for protons to move—of brain tissue that
looks otherwise healthy was only slightly higher in
13 children with MS than in healthy children,89 suggestive
of limited damage early in the disease. The results of
another study of 23 children with MS also showed no
diff erence between children with MS and healthy children
on magnestisation transfer imaging and diff usion measures
in the grey matter.90 MRI in eight children with MS revealed
decreased N-acetylaspartate and creatine concentrations
and increased concentrations of choline and lipids within
lesions and the adjacent cortical grey matter.91 Magnetic
resonance spectroscopy spectra in healthy-looking tissue
did not diff er from those in healthy controls, which suggests
that the widespread abnormalities in tissue that looks
healthy in adults with MS might not be detectable in
children with the disorder. A single study of magnestisation
transfer imaging in 15 children with ADEM identifi ed a
citrulline peak in the healthy-looking white matter in
seven patients and in one control.92 Post-translational
citrullination of myelin is an age-dependent process, with a
high degree of citrullination seen only in immature myelin
(<2 years).93 Myelin in adults with MS might be
developmentally immature93 and thus might be more prone
to degradation, in turn leading to increased myelin debris,
which might then incite an immunological reaction.
Detailed magnetic resonance spectroscopy studies
specifi cally looking for citrulline spectra in children with
relapsing-remitting MS would be of interest.
Diligent exclusion of other diseases by use of a
standardised approach and the application of the
Figure 3: MRI of MS in children
A: Axial FLAIR image of a 12-year-old boy with MS with multiple lesions. B: Sagittal T2-weighted image of a 14-year-old girl with MS; numerous lesions emanating
from the corpus callosum (Dawson’s fi ngers) are highlighted. C: Axial T1-weighted image with gadolinium that shows several enhancing lesions in a 15-year-old
boy with MS. D: Axial FLAIR image of a 7-year-old girl with a fi rst demyelinating event, who was subsequently diagnosed with MS on the basis of numerous
further attacks. As can be seen in younger children with MS, the involvement of the deep grey-nuclei is prominent. E: Axial FLAIR image of an 8-year-old boy with
MS that shows the prominent involvement of the posterior fossa white matter. F: Axial T1-weighted image of a 14-year-old boy with severe MS with multiple
http://neurology.thelancet.com Vol 6 October 2007
proposed criteria for paediatric MS1 will enable an
accurate diagnosis in most aff ected children. Furthermore,
investigation of oligoclonal bands with advanced
techniques is almost as sensitive in children with MS as
it is in adults. MRI evidence of the accrual of clinically
silent lesions is particularly important in the assessment
of children with an initial ADEM-like event, and MRI of
young patients with initial lesions that are atypical for
adult-onset MS might change over time into a pattern
similar to that seen in adults.
Characteristics of child-onset MS
An estimated 3–10% of all patients with MS have onset
before the age of 18 years.71,94–97 The true frequency of
paediatric MS will be determined only from prospective
studies from both paediatric and adult clinical centres.
MS in childhood has been reported in numerous countries
(table 1).94–118 The ethnic diversity of children with MS in a
Canadian study closely mirrored the diverse cultures of
recent immigrants to that region, even when the parental
countries of origin had low prevalence of MS.119 The results
of migration studies of adult-onset MS show that people
who emigrate during childhood to areas of high risk have
the risk of MS associated with their adopted home.120
Gender ratios in paediatric MS diff er with age at onset
(fi gure 4). Whether the substantial increase in female
DetailsN† Mean observation (years)‡PPMS (N)SPMS (%)
Belopitova and co-workers98
Boiko and co-workers94
Boutin and co-workers99
Bye and co-workers100
Chiemchanya and Visudhiphan 46
Cole and Stuart101
Dale and co-workers22
Deryck and co-workers102
Duquette and co-workers95
Gall and co-workers103
Ghezzi and co-workers97
Ghezzi and co-workers73
Glasier and co-workers86
Guilloto and co-workers104
Gusev and co-workers105
Hanefeld and co-workers106
Iannetti and co-workers108
Mattyus and Veres109
Mikaeloff and co-workers82
Mikaeloff and co-workers24
Mikaeloff and co-workers68
Millner and co-workers110
Ozakbas and co-workers72
Perniola and co-workers111
Pinhas-Hamiel and co-workers112
Ruggieri and co-workers113
Selcen and co-workers114
Shiraishi and co-workers115
Simone and co-workers96
Sindern and co-workers71
Trojano and co-workers116
Weng and co-workers117
Zelnik and co-workers118
Bulgaria, single centre*
Canada, single centre
France, single centre
UK, single centre
Scotland, single centre
UK, single centre
Belgium, single centre
USA, single centre
Italy, national programme*
Italy, national programme*
USA, single centre
Brazil, single centre
Russia and Canada, two-centre comparison
Germany, single centre*
Canada, single centre
Italy, single centre
Hungary, single centre
France, national programme*
France, national programme*
France, national programme*
Austria, single centre
Turkey, single centre
Italy, single centre
Israel, single centre
Italy, preliminary results of a national programme
Turkey, single centre
Japan, single centre
Italy, national programme
Germany, single centre
Italy, national programme*
Taiwan, single centre
USA, single centre
*Prospective studies. †Each article was carefully reviewed, and only patients with confi rmed multiple sclerosis and age less than 18 years were included. ‡Mean follow-up was
either provided directly by the authors in the text, or was calculated from the clinical information on patients described in tables or text format. A=adult centre. NR=not
recorded. P=paediatric centre. PPMS=primary-progressive MS. SPMS=secondary-progressive MS.
Table 1: Studies of the clinical features of multiple sclerosis in children
http://neurology.thelancet.com Vol 6 October 2007 893
preponderance in adolescence is indicative of a hormonal
infl uence on risk of MS, a gender-specifi c genetic
infl uence on immunological reactivity, or some other age-
related factor is unknown.
A family history of MS is reported by 6–8% of children
and adolescents with MS,24,72,96,121 although retrospective
studies with longer observation periods report a familial
prevalence of about 20%.95,102 The diff erence is probably
due to suffi cient time having elapsed for a diagnosis of
MS in parents, relatives, or siblings who, at the time of
diagnosis in a pediatric relative, might not have
manifested the disorder.
Of 1540 children (table 1), 96% were diagnosed initially
with relapsing-remitting MS, and only 57 (3·7%) were
diagnosed with primary-progressive MS.
Variable descriptions in the literature and inconsistent
use of the term polysymptomatic (which might imply
multiple lesions or multiple symptoms from a single
lesion) versus polyfocal (which implies multiple lesions)
hampers recognition of the frequencies of diff erent
presenting features of the fi rst attack of MS. Overall, about
50–70% of children will have a polyfocal or polysymptomatic
presentation,24,72,96 whereas 30–50% of children will have a
monofocal presentation: of the latter presentation, 10–22%
of children present with optic neuritis, 30% have motor
dysfunction, 15–30% have sensory symptoms, 5–15%
present with ataxia, and 25% have brainstem
symptoms.72,73,96,105 Optic neuritis as the fi rst presentation of
MS is more commonly reported in studies from Asia,27,115
which is consistent with the higher representation of optic
neuritis in adults with MS from these regions. Isolated
transverse myelitis as the presenting symptom of MS
occurs in less than 10% of children.24,71,95 Symptoms
consistent with ADEM were noted in prospective studies
at presentation in 20–28% of children.24,49
Fatigue that is severe enough to limit scholastic or
recreational activities is reported by 40% of children with
MS. Seizures occur in about 5% of children with MS105,107
but are much more common in children under the age of
The onset of MS in childhood occurs during the key
formative academic years, which might restrict school
attendance and has the potential to aff ect negatively the
developing neural connections implicated in learning and
higher-order information processing. Defi cits in general
cognition, visuomotor integration, and memory have
been documented in at least 30% of children with MS.122–124
The most common impairments were in complex
attention (eg, shifting attention from one idea to another),
visuomotor integration, confrontation naming, receptive
language, and executive function, whereas verbal fl uency
was intact in all patients.122,124 Academic test scores were
relatively spared and, when combined with preserved
verbal fl uency, might serve to mask the depth of cognitive
defi cits present in these children. Furthermore, the
defi cits in attention, executive functions, and memory are
likely to have greater importance as children enter
secondary and postsecondary education, when these skills
are paramount. The severity of cognitive impairment also
increases with longer disease duration and is of greater
severity in patients who are young at disease onset.122,125
Larger studies are clearly needed to document more fully
the morbidity of MS on cognitive functioning and to
understand better the consequences of impaired cognitive
processing on academic and future vocational success.
MS in young children
Of 1540 participants (table 1), 263 (17%) were under the
age of 10 years at the time of their fi rst attack. Clinical
information is available on 87 of these children
Ataxia is particularly common (53%) as a presenting
feature in this age group, whereas brainstem features
were not always clearly described. Fever was reported in
26% of patients, which is a rare feature of relapses in older
patients or adults. Cognitive functioning was specifi cally
mentioned for 30 patients, and was impaired in 20 (66%),
which supports concerns regarding the cognitive morbidity
of MS in young children.
The time from the initial acute attack to the second,
MS-defi ning event is highly variable. Younger children
tend to have a longer interval from fi rst to second
attack (median 6 years), in contrast to most adolescent
patients with MS, who have their second attack within
12 months.24 The relapse rate reported in retrospective
studies with long observation periods ranges from
0·38 a year102 to 1·0 a year.105
The clinical features of MS in children vary as a
function of age at fi rst attack. Younger children are
All <6 6–10 >10
Figure 4: Age and gender relationships in paediatric MS
Data on gender from demographic information on the 1384 children with MS listed in table 1 and table 2, which is
summarised as a proportion of children of each sex as a function of the total number of children (fi rst bars) and
subdivided into age at fi rst attack.
http://neurology.thelancet.com Vol 6 October 2007
more likely to present with widespread demyelination
seen on MRI, polyfocal clinical features, and
manifestations of acute demyelination are the response
of an immature brain to immunological insult,
the heightened infl ammatory
immature or developing immune system, age-related
immunogenicity of myelin proteins, or another age-
related factor is unknown. Future immunological
studies and the application of advanced MRI analyses
might provide further insights.
capacity of an
Disability and outcome
Kurtzke’s expanded disability status scale (EDSS) is the
most common measure of physical neurological sequelae
in adults and children with MS (table 3),68,73,94,96,105 although
the measure has several key limitations (non-linear
ordinals, wide intraobserver and interobserver variability,
and, essentially, exclusive weighting of motor dysfunction
at the higher range of the scale).
In a prospective study of 54 children or adolescents
with MS disease duration of 8 years or longer, 36 had an
EDSS of less than 4, fi ve had scores between 4 and 6, and
13 had signifi cant physical disability, with scores greater
than 6.73 After 10 years of follow-up, the mean EDSS score
was 3·8. The proportion of children with substantial
disability increases with disease duration, as shown by a
mean EDSS score of 5·8 in a group of 28 patients with
disease duration of 29 years.102 The mean time to reach an
EDSS score of 4 was 10·8 years (range 2–24 years), and it
took a mean time of 18·2 years (range 5–48 years) to reach
a score of 6. Of 197 children followed from fi rst attack in
a prospective study, an EDSS score of 4 was reached by
15% of the children after a mean observation of 7·8 years.68
Survival analysis in a retrospective group of 83 patients
with paediatric-onset MS showed that the median time to
an EDSS score of 4 was 14 years, and such an outcome
occurred in 25%.96 Overall, 15–25% of these patients will
accrue fi xed disabilities 10 years or more after disease
In a detailed database analysis of clinical outcome in
394 patients with paediatric-onset MS, the median times
from onset to EDSS scores of 4, 6, and 7 were 20 years,
29 years, and 37 years, respectively.129 When compared
with 1775 patients with adult-onset MS enrolled in the
same database cohort, patients with paediatric-onset MS
took 10 years longer to accrue disability but were about
10 years younger than patients with adult-onset MS with
Four studies describe in detail the long-term risk of
secondary-progressive MS in 441 patients with paediatric-
progressive disease was seen in 60 of 113,94 21 of 49,102 12
of 83,96 and 9 of 19768 patients after mean disease durations
of 17·7 years, 12·9 years, 10·0 years, and 4·8 years,
respectively, which suggests that a key determinant of
entry into secondary-progressive MS is disease duration.
Furthermore, although the mean disease duration
associated with a 50% risk of secondary-progressive MS
is 23 years in patients with paediatric-onset, relapsing-
remitting MS, compared with 10 years in patients with
adult-onset, relapsing-remitting MS,94 the actual age at
which disability progression occurs is much younger in
patients with paediatric-onset disease.94 The risk of
secondary-progressive MS was also associated with a
high frequency of relapse and shorter intervals between
attacks in the fi rst few years of disease.94,96
Predictors of clinical disease severity
Prognostic factors for early disease severity were assessed
in a prospective study of 197 children from onset of the
fi rst MS attack.68 Severe disease outcome was defi ned by
the occurrence of a third attack or by an EDSS score
greater than 4 (persisting for more than 12 months). At a
mean observation of 5·5 years, severe disease outcome
Patients <6 years of age
Mean (median) age at fi rst attack
Features of fi rst attack
Mean (median) age at second attack
Initial multiple sclerosis course
6·1 (6·3) years
7·2 (7·1) years
87 relapsing-remitting multiple
43 SPMS, 1 PPMS
Multiple sclerosis outcome
*Data from all articles in which specifi c clinical information was provided on
children presenting with their fi rst attack of MS under the age of 10 years,
including 21 patients from the paediatric MS programme in
Toronto.74,86,98-100,104,106,108,109,111,114,115,117,118,126–128 †Polysymptomatic and
monosymptomatic are used, rather than polyfocal or monofocal, because the case
descriptions were not suffi ciently detailed to determine whether a single lesion or
multiple lesions would best describe the clinical presentation. ‡Cognitive
impairment was specifi cally mentioned in the case histories of 20 of the 30
children, for whom cognition was specifi cally discussed. In the histories of the
remaining 57 patients, cognitive ability was not mentioned. PPMS=primary-
progressive MS SPMS=secondary-progressive MS.
Table 2: Clinical features and outcome of MS with onset under the age of
http://neurology.thelancet.com Vol 6 October 2007 895
was recorded in 144 children (73%), of whom 139 had a
third attack and 30 had sustained EDSS scores greater
than 4. Predictors of severity included being a girl, the
absence of encephalopathy at onset, well-defi ned lesions
or lesions perpendicular to the corpus callosum seen on
MRI, less than 1 year between the fi rst and second attacks,
and secondary-progressive disease (noted in nine
children). The accrual of disability within 1 year of disease
onset or a high frequency of relapse in the fi rst 2 years of
the disease have also been associated with higher EDSS
scores at 8 years.73
The published work has focused on disability-related
outcomes; little is known about the long-term cognitive
outcomes, vocational success, or measures of societal
independence. Whether outcomes can be predicted by
detailed MRI measures or whether demographic
characteristics infl uence disease severity is unknown.
These issues are of paramount importance if the true
morbidity of MS onset in childhood is to be fully
The care of children with MS needs a multidisciplinary
team comprising paediatric and adult neurologists,
nurses, physiotherapists, occupational therapists, social
workers, psychologists, and psychiatrists.130 The diagnosis
of chronic illness has substantial emotional eff ects on
children with MS and their families. Compliance with
medication, particularly in adolescents, rests on a strong
relationship between medical teams, patients, and
Acute demyelination in children is managed with
corticosteroid therapy. Although there are no specifi c
studies of the dose or eff ectiveness of corticosteroids,
most regimens for severe
10–30 mg/kg/dose (to a maximum of 1000 mg/dose) of
methylprednisolone by intravenous infusion for 3–5 days.
The decision to off er oral prednisone, the starting dose
(typically 1–2 mg/kg/day), and the tapering schedule are
empirical. If substantial resolution of symptoms is
achieved within 3–5 days of intravenous therapy, oral
prednisone might be therapeutically unnecessary, and
the risk of adrenal suppression is short lived.131 Mild
attacks that do not limit activities or school attendance do
not require corticosteroid therapy.
Children with acute relapses who do not respond to
the fi rst course of corticosteroids might respond to a
further 3–5 days of intravenous therapy (doses as above).
For children in whom corticosteroid therapy is
contraindicated or ineff ective, treatment with intravenous
immunoglobulin (IVIg) might be of value (class IV
evidence).132,133 Published case series advocate doses of
2 g/kg over 2–5 days.
Life-threatening acute demyelination
Acute demyelination in children can be life threatening
because of profound encephalopathy, respiratory
depression (commonly associated with extensive white-
matter oedema of the brainstem and upper cervical
spine), and tetraplegia. There is class I evidence for the
benefi t of plasma exchange for life-threatening
demyelination in adults who do not respond to
corticosteroids;134 fi ve to eight exchanges are typically
needed. Optimisation of therapeutic strategies for
children with this devastating disorder is urgently
Class I level evidence for a reduction in the relapse
frequency in adults with MS135–139 has led to the use of
interferon beta (30 μg interferon beta-1a by intramuscular
injection once a week, 22–44 μg interferon beta-1a by
subcutaneous injection three times a week, or
8 mIU interferon beta-1b by subcutaneous injection every
second day) and glatiramer acetate (20 mg by
subcutaneous injection daily) in children. None of the
immunomodulatory therapies has been formally assessed
in large clinical trials of children. A single-centre study of
16 children randomly assigned to low-dose interferon
beta-1a (15 μg/week) or placebo reported a favourable
eff ect of therapy on relapse rate (p=0·04), disability
EndpointPositive correlation No correlation
Shift to SPMS
Relapse rate >0·6*
Brainstem involvement at onset
High number of relapses in the fi rst year
and in the fi rst 5 years
EDSS after the fi rst year†
Number of relapses in the fi rst 2 years
Short interval between fi rst and second
Interattack interval <1 year
No mental change
Short interval between fi rst and second
Involvement of sphincter at onset
Interattack interval <1 year
First relapse in the fi rst 2 years
Age at onset
Age at onset
Age at onset
Age at onset
Age at onset
Cognitive impairment at onset
Shift to SPMS
Age at onset
Symptoms at onset
Cognitive impairment at onset
*Annualised relapse rate calculated for all patients in the study, over the entire study period. †EDSS 0=healthy
neurological examination; EDSS 10=death due to MS; EDSS <4=abnormal neurological signs in one or more functional
systems, with no restriction on physical independence; EDSS between 4 and 6 indicates some limitations in daily
motor function; and EDSS >6 indicates marked limitations in gait that require assistance. ‡MRI criteria: lesions
perpendicular to the corpus callosum or only well-defi ned lesions. EDSS=Kurtzke’s expanded disability status score.
Table 3: Studies of predictors of clinical outcome in paediatric MS
http://neurology.thelancet.com Vol 6 October 2007
progression (p=0·01), and accrual of T2-visualised lesions
Favourable safety and
immunomodulatory therapies in children have been
shown in the results of several recent open studies
(table 4);140–148 a few patients developed depression,147
generalised oedema,146 and high titres of liver enzymes.142
The rationale for starting immunomodulatory therapy
in children with MS is based on data that show these
therapies are eff ective in the early stages of the
disease,139,149,150 that the risk of future disability might be
reduced, and that early treatment might limit the rate of
cerebral atrophy in adults.150–152
Although safety and tolerability studies cannot formally
address treatment effi cacy, a reduction in relapse rate is
seen in all studies of interferon therapy in children. The
annual relapse rate decreased from 2·4 to 0·4 in children
and adolescents treated with interferon beta-1a once a
week, and from 3·2 to 0·85 in children and adolescents
treated with interferon beta-1a three times a week or
interferon beta-1b on alternate days.146 Similar results
were obtained in a larger group after an additional follow-
up of 1 year.153 Relapse rate decreased from 1·9 to 0·8
in 51 children and adolescents
interferon beta-1a three times a week.147 Glatiramer
acetate might also have a favourable eff ect on relapse
rate,145 although the small number of reported patients
limits interpretation of these data. Interpretation of the
effi cacy of disease-modifying therapies must be viewed
in light of the fact that relapse rate declines over time in
untreated patients. EDSS scores in treated groups did
not seem to change substantially but the eff ect of
treatment on disability accrual needs longer observation.
tolerability profi les of
Immunomodulatory therapies in young children
Several studies have investigated immunomodulatory
therapy in patients of age less than 12 years.141,147 Young
children treated with interferon beta-1a have a prominent
reduction in relapse rate;148 however, elevation of liver
enzyme concentrations seems more probable in these
White-blood-cell count and liver function should be
monitored monthly for the fi rst 6 months, and every
3 months thereafter. Thyroid function should be
monitored annually. All sexually active adolescents with
MS should receive contraceptive counselling because
the potential teratogenicity of immunomodulatory
therapies has yet to be studied fully. Paracetamol or
ibuprofen help to reduce the severity of fl u-like
symptoms. 20% of children treated with glatiramer
acetate have a transient fl ushing-like reaction associated
with tachycardia.144 Children and their parents must be
made aware of this potential side-eff ect because this is a
self-limited reaction that has not been associated with
Escalation of therapy in severe MS
There are no published studies of safety, effi cacy, or the
selection of drugs for children with relapsing-remitting
MS refractory to interferon or glatiramer acetate; however,
anecdotal reports describe
mitoxantrone, cyclophosphamide, or methotrexate. Few
children have been off ered treatment with natalizumab,
which is not licensed for patients under the age of
18 years, and rigorous safety-monitoring protocols are
required for its use in adults. The safety and effi cacy of
these powerful immunosuppressive drugs in children
with MS requires collaborative study.
Evidence from adults with MS suggests that frequent
relapses, shorter intervals between attacks, and failure
to recover from early relapses predict a greater
probability of fi xed disability—as measured with the
EDSS—and a greater propensity to enter the secondary-
progressive phase of MS, in which disability is
irrevocable. The currently available immunomodulatory
therapies are most eff ective in patients with active
disease. The paediatric MS programmes in France, Italy,
and Toronto, Canada, use a clinical-care model that
off ers immunomodulatory therapies to all children with
confi rmed relapsing-remitting MS. More than 90% of
children in Toronto begin immunomodulatory therapy
after their second demyelinating attack (ie, at the time
of diagnosis), irrespective of the age of the patient.
Interferon is started at 25% of the recommended adult
dose and, if monthly laboratory tests of liver function
tests are normal, the dose is increased monthly to the
full dose. Immunomodulatory therapies are off ered in
France to children with a clinical score predictive of
early severe disease.68 Children with mild relapses or
clinical or MRI fi ndings that suggest mild disease are
off ered therapy if their disease activity increases. In
Italy, treatment protocols vary with clinical centre but
are typically started in patients with frequent relapses in
the fi rst few years of disease.146 In all centres, selection
of the type of interferon or glatiramer acetate was
determined by discussion with the patient and family.
Compliance is closely aligned with patient autonomy, in
the authors’ experience, and even young patients are
capable of determining whether they are more likely to
accept weekly intramuscular injections or more frequent
HLA-DR2 was more common in 47 children154 and
adults155 with MS from Russia than in the general
population. Unlike in adults from the same region with
MS, a high prevalence of the TNFα 7 allele was also
found, and this was proposed as a potential biomarker
for paediatric MS.156 By contrast, a study of 24 children
with MS in Turkey did not detect MS-specifi c TNFα
http://neurology.thelancet.com Vol 6 October 2007 897
mutations.157 Genetic studies of MOG, the gene
encoding myelin oligodendrocyte glycoprotein, located
in close proximity to the HLA region on chromosome 6,
did not show any disease-specifi c associations in a study
of 75 German children with MS.158
Epidemiological evidence suggests that the risk of MS is
strongly infl uenced by place of residence during
childhood,159 and that childhood viral exposures might
have a role in the MS disease process.159–161 Serological
evidence of remote infection with Epstein Barr virus has
been documented in over 85% of children with MS,
which diff ers signifi cantly from the seroprevalence of
40–60% in age-matched, healthy children.162–164 Adults
with MS are also more likely to be seropositive for Epstein
Barr virus, to have high Epstein Barr virus nuclear
antigen titres relative to healthy adults, and to have high
Epstein Barr virus titres before the onset of their MS.165
Infection with Epstein Barr virus is biologically plausible
in the pathogenesis of MS because of its innate ability to
transform and chronically activate B cells166 and the
potential for molecular mimicry between Epstein Barr
virus proteins and specifi c epitopes of myelin basic
protein,167 which is one of the putative target myelin
antigens in MS. The same myelin basic protein epitopes
have been used to induce experimental allergic
encephalomyelitis, a commonly used animal model of
demyelination.168 In contrast to Epstein Barr virus,
exposure to several common childhood infectious agents,
age at fi rst
Side-eff ectsClinical results
IFNB-1b43 10·925·429·2 No serious or unexpected events
Flu-like symptoms (15)
Injection-site reaction (9)
Abnormal liver enzymes (9)
Flu-like symptoms (19)
Myagia or arthralgia (6)
Injection-site reaction (4)
Haematological abnormalities (< 10%)
Chest pain (1)
No haematological abnormalities (NA)
Reduction of relapse rate of 50%
Decreased relapse rate (2·4 to 0·4)
Final EDSS unchanged
Decreased relapse rate (3·2 to 0·85)
Final EDSS unchanged
Decreased relapse rate (2·8 to 0·25)
Final EDSS slightly improved
No change in mean EDSS
Treatment failure (25%)
GA7 13·735 24 No laboratory abnormalities
Transient systemic reaction (1)
Flu-like symptoms (11)
Injection-site reactions (3)
Transient abnormal liver enzymes (1)
No signifi cant side-eff ects
No discontinuation of treatment
16 48Signifi cantly fewer relapses, less
disability progression, and fewer
new lesions in treated group
Decreased relapse rate (1·9 to 0·8)
EDSS score stable (48)
IFNB-1a‡51 13·424 21·6Injection-site reaction (36)
Flu-like symptoms (33)
Gastrointestinal symptoms (5)
Abnormal liver enzymes (18)
Abnormal blood counts (20)
Two serious adverse events (chronic
arthritis and attempted suicide)
Flu-like symptoms (14)
Myagia or arthralgia (4)
Injection-site reaction (18)
Abnormal liver enzymes (8)
Flu-like symptoms (4)
Injection-site reaction (1)
IFNB-1a‡24 9·340·3 44·4
Signifi cant reduction of relapse
Decreased EDSS (in patients
≤ 10 years)
IFNB-1a†9 113617 No eff ect on relapse rate
*Injection pain (1), perceived lack of effi cacy (5), lack of adherence (4), funding (4), lost to follow-up (5), other diagnosis (3), unknown (3). †Once a week. ‡Three times a
week. §Alternate days. ¶ Once a day. ||Randomised design: 8 patients treated with 15 μg IFNB-1a by weekly intramuscular injection; 8 patients untreated. GA= glatiramer
acetate. IFNB-1a=interferon beta 1a. IFNB-1b=interferon beta 1b. EDSS=Kurtzke’s expanded disability status scale. NA=not available.
Table 4: Treatment studies in paediatric MS
http://neurology.thelancet.com Vol 6 October 2007
such as varicella, parvovirus B19, and cytomegalovirus,
does not diff er between children with MS and age-
matched controls,162,163 nor do children with MS diff er
from controls in serological responses to vaccine-related
agents (measles, mumps, rubella, or pertussis).169
However, not all children with MS are Epstein Barr virus
positive; thus, if infection triggers MS pathogenesis, then
other infections must be implicated. Although seven of
25 children with MS had intrathecal antibodies against
Chlamydia pneumoniae, this was thought to be part of a
polyspecifi c immune response, rather than a disease-
Although vaccinations have been frequently deemed as
potential triggers of the MS disease process, recent
studies did not show an association between hepatitis B
vaccine and recurrent demyelination in children or adults
with the disease.171,172
An early study of three children with relapsing
demyelination (two diagnosed with MS, one with
neuromyelitis optica) showed, through T-cell subset
analyses, acute and chronic reduction of circulating T
cells and relapse-specifi c depletion of the T-suppressor
and T-cytotoxic subsets.173 Myelin basic protein, myelin
basic protein exon 2, and myelin oligodendroglial-specifi c
T-cell lines were obtained from 18 patients who had MS
onset in childhood.174 T-cell proliferative responses against
specifi c immunodominant myelin basic protein and
myelin oligodendroglial epitopes, and the amount of
interferon γ produced by these T-cell lines were similar to
those from adults with MS, and there was no obvious
diff erence in these T-cell responses between children and
adults with MS. Future studies are needed to determine
whether, and how, T-cell responses in children with MS
diff er from those in matched control groups.
The results of a tetramer radioimmunoassay show that
myelin-oligodendroglial-specifi c auto antibodies seem to
be a more important target antigen in ADEM than in
MS.175 Further studies are needed to investigate the
humoural responses to other CNS targets, including
antigens such as myelin basic protein, that can be
extracted directly from CNS tissue, which undergoes
important biochemical changes during early childhood.
Studies of cellular injury and cellular stress responses
Axonal injury and glial cell activation are important
features of neurodegeneration in MS. The results of a
study of CSF from 25 children with MS and 67 controls
showed nine children sampled at the time of MS relapse
had high concentrations of tau protein, suggestive of
axonal injury.176 Cellular responses to injury or stress are,
in part, mediated by mitochondria. So far, sequencing of
mitochondrial DNA, and specifi cally the loci implicated
in Leber’s hereditary optic neuropathy, from children
with MS has not identifi ed mutations specifi c for MS.177–
179 Although these preliminary analyses do not identify a
mitochondrial contribution to MS, there are no
functional assays of oxidative
mitochondrial calcium homoeostasis, or the protein-
folding responses in neurons or glial cells from children
with MS. The potential contribution of intracellular
stress responses to autoimmune disease is highlighted
by recent evidence of impaired folding mechanisms for
endoplasmic reticulum proteins in infl ammatory bowel
There are many key questions in the pathobiology of MS:
whether individuals have an inherent CNS or
immunological predisposition to the disease; whether
myelin is structurally or biochemically aberrant or
abnormally immunogenic; whether immunological
regulatory processes are fundamentally defi cient in their
capacity to distinguish self from non-self proteins and to
limit suffi ciently target-directed injury to a monophasic
event; and whether certain environmental exposures lead
to improperly regulated or misdirected immunological
responses. Studies of children with MS provide
opportunities to explore these questions in patients only
recently exposed to the disease trigger. As such, research
into paediatric MS might provide new directions for
therapeutic strategies to stop the immunological
components early in the disease process.
Search strategy and selection criteria
Publications in English were identifi ed by MEDLINE searches
(1975 to March, 2007), and the respective bibliographies.
Search terms included “multiple sclerosis”, “acute disseminated
encephalomyelitis”, “encephalomyelitis”, “transverse myelitis”,
“optic neuritis”, “neuromyelitis optica”, “Devic’s disease”, and
the more general term “demyelination”, combined with either
“child(ren)(hood)”, “pediatric(s)”, “adolescen(t)ce”, “early
onset”, or “very early onset”. Single case reports or case series
of fewer than fi ve children were included only if the manuscript
covered specifi c clinical issues (such as MS onset under the age
of 10 years) or issues of historical relevance. Published review
articles were not selected but their references were reviewed.
Data published only in abstract form were not included.
Adolescent patients included in series that focused on adult
MS might have been missed. For discussion of therapies, the
standardised rating of therapeutic trials was applied: class I are
prospective, randomised, controlled clinical trials, with clear
outcome measures, defi ned populations of patients, adequate
accounting for people who dropped out of studies, and relative
consistency between treated patients and controls; class II are
prospective matched group cohort trials with masked
outcome evaluations, with at least three of four features
defi ned for class I; class III are controlled trials in appropriate
populations of patients, with outcome assessments that are
independent of treatment; and class IV are uncontrolled
studies, case series, case reports, or expert opinion.
http://neurology.thelancet.com Vol 6 October 2007 899
The diagnosis and care of children with MS will be
helped by the recognition of the presenting features of
the disease, the use of MRI, and the laboratory exclusion
of the other disorders considered in the diff erential.
Consensus criteria for the diagnosis of paediatric MS
now exist, and the development of evidence-based
radiographic criteria will promote even greater diagnostic
certainty. Immuno modulatory therapies are well tolerated
and effi cacious, although prospective studies are required
to appreciate fully the long-term eff ect of these therapies
on MS outcome in children. The potential for physical
and cognitive disability, even early in the disease,
highlights the urgent need for therapeutic strategies for
neurorehabilitation, neuroregeneration, and neurorepair.
The opportunity to gain insights into such strategies
might actually rest with the population of patients with
MS most likely to benefi t; identifi cation of the early
features of what turns on the MS disease process might,
in turn, identify the mechanisms required to turn off the
BB designed the content of the manuscript, reviewed all referenced
articles, contributed patient-related data, and was the primary author.
MT, YM, and AG assisted in the design of the manuscript, contributed
to, and edited the fi nal manuscript. AB-O contributed to the text of the
manuscript and edited the fi nal manuscript.
Confl icts of interest
We have no confl icts of interest related to the present work. BB has
received speakers’ honoraria from Biogen-Idec, Serono, Teva
Neurosciences, and Schering. AG has received honoraria for consultancy
from Biogen-Idec, and travel grants or grants as a speaker from Teva
Neuroscience, Aventis, Dompe, and Serono. AB-O has received
honoraria for speaking at meetings supported by, or consulting for,
Aventis, Bayhill Therapeutics, Berlex, Biogen-Idec, Genentech, Serono,
Teva Neuroscience, BioMS, and the Immune Tolerance Network/NIH.
YM and TD have nothing to declare.
The authors thank Julia Kennedy for her invaluable assistance, the
Canadian Multiple Sclerosis Society and the Canadian Multiple
Sclerosis Scientifi c Research Foundation, the Italian centres involved
in the prospective study of early-onset muliple sclerosis, the ITEMS
study group, and the Société Française de Neurologie Pédiatrique. BB,
AB-O, and JK are supported by the Multiple Sclerosis Scientifi c
Research Foundation of Canada. AB-O holds a Don Paty Career
Development Award from the Multiple Sclerosis Society of Canada.
YM and MT are supported by Institut National de la Recherche
Médicale (INSERM U802), Université Paris Sud 11, Assistance
Publique—Hôpitaux de Paris.
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