Lauren B. Krupp, MD
Professor of Neurology
Director of the
National Pediatric MS Center
sclerosis (MS) is an immune mediated inflammatory demyelinating
the central nervous system (CNS).
Children and adolescents can develop MS although less commonly
An estimated 2-3 % of patients with
MS are under age 18.
To facilitate clinical
research and establish uniform criteria for the diagnosis, an
operational and consensus based definition for pediatric MS was
The criteria for the diagnosis require:
1) Multiple episodes of CNS demyelination
disseminated in time and space with no lower age limit
2) MRI findings can be applied to meet
dissemination in space criteria if they show three of the
following four features – 1) nine or more white matter lesions
or one gadolinium enhancing lesion, 2) three or more
periventricular lesions 3) one juxtacortical lesion, 4) an
infratentorial or spinal cord lesion
3) The combination of an abnormal cerebral
spinal fluid (CSF) and two lesions on the MRI, of which one must
be in the brain, can also be used to meet dissemination in space
criteria; the CSF must show either oligoclonal bands (OCB) or an
elevated IgG index
4) MRI can be used to satisfy criteria for
dissemination in time following the initial clinical event, even
in the absence of a new clinical demyelinating event. A new
gadolinium enhancing lesion or new T2 lesion 3 months after the
clinical event can be a surrogate for another clinical event.
This definition is distinguished from
self-limited demyelinating disorders such as acute disseminated
encephalomyelitis (ADEM) which in contrast to pediatric MS is
associated with encephalopathy and typically shows large ( 1 – 2
cm or more) lesions of the white matter as well as the deep grey
matter within the brain.
DEMOGRAPHIC FEATURES OF PEDIATRIC MS
The disease usually
begins with a mean age of onset between 8- 14 years of age,
depending on whether the cohort has a cut off below 16 or 18.
The distribution of
boys and girls varies according to age. For children equal to or
above age 10, girls outnumber boys by approximately 2.5:1.
2, 5, 6]
For children below age 10 the ratio
of girls and boys is approximately 0.5:1. [7,
These demographic features suggest sex hormones play a role in
MS pathogenesis which is also suggested from data in adult MS.
Presenting symptoms of
MS often depend on the location of the white matter lesions.
Initial symptoms can include optic neuritis (unilateral or
bilateral), motor weakness, balance problems, sensory
disturbance, loss of coordination, bladder dysfunction, or
problems related to brainstem involvement (facial numbness,
A polysymptomatic onset occurs in 8-67% of the patients.
2, 5, 10]
children tend to have more brainstem and cerebellar symptoms,
encephalopathy, or optic neuritis than do adults. [11,
12] Among those under six,
seizures, marked alteration in consciousness, a polysymptomatic
onset, and atypical MRIs
involve the white matter. In contrast, cortical or central gray
involvement is uncommon. 
In figure 1, an MRI from a typical patient with MS is shown. The
lesions tend to be discrete, often associated with gadolinium
enhancement, and are usually periventricular in location.
However, some children lack typical MRI findings of MS and have
either large tumefactive lesions associated with edema or deep
grey matter involvement. 
Figure 1: 15 year old with MS and typical
white matter lesions
In over 93% - 98% of
the disease course at onset is characterized by relapses and
remissions. A progressive course without relapses in pediatric
MS usually suggests an alternative diagnosis.
transition to secondary progressive MS, 7-10 years after
diagnosis, In contrast children transition more slowly,
approximately 20 years following the diagnosis. [6,
Features at the time
of a child’s first demyelinating event, increase the likelihood
of a subsequent event include the presentation of
neuritis or if the child is older than 10 years. 
A decreased risk for a second event
is noted in children presenting with spinal cord symptoms or
alteration in mental status. 
factors regarding disease course have been identified for both
children and adults. These include a progressive course at onset
12, 15], poor clinical
recovery from an event, numerous attacks in the first 2 – 5
years after diagnosis ,
short interval between the first and second attack, symptoms of
sphincter dysfunction, and absence of encephalopathy. [11,
12, 15, 17]
Pediatric MS, like
other chronic illnesses, poses psychosocial
to families. Behavioral problems include denial, difficulty with
family and peers, and non-compliance with therapy. 
A further concern is that perceived stress can increase the
probability of increased disease activity. 
Young people with MS
may be at a particular high risk for additional psychological
problems due to the effects of the disease on the CNS..
For example, among
with MS, depression is associated with an increased lesion
burden in the inferior – medial frontal-temporal areas. 
In our experience at
our Center approximately 46% of children have some form of
affective disorder. More information is available on the
psychiatric complications of adults with MS. 
Over 25% of adults with MS from community samples 
have depression. In clinical populations the life time
prevalence of major depression is 40-50%. [24,
25] and the frequency of
anxiety disorders ranges from 25 – 34%. 
and academic functioning.
Over one third of
children with MS have cognitive deficits attributed to the
disease. The must vulnerable areas are memory, perceptual and
visual motor skills, executive functioning, cognitive processing
speed, and global IQ. [18,
26-29] A similar range of
deficits are also observed in adults. The rate of progression of
cognitive loss is not known.
declines in academic functioning can be mitigated by educating
school personnel, providing special accommodations, such as
reduced work load due to fatigue and teaching compensatory
strategies to assist memory loss. [18,
Both genetic and environmental factors contribute to
MS. Examples of
environmental influences include the increased
of MS at greater distances from the equator ,
season of birth 
and exposure to sunlight during childhood. 
The association between low sunlight exposure and increased MS
risk may be mediated via Vitamin D levels. which have been shown
to be low in Caucasian
Migration studies suggest that place of residence during
childhood may also be associated with MS risk.[35,
there is clearly a role for environmental effects on MS
pathogenesis, genetics also contributes. 
A monozygotic twin
sibling of an MS patient has a 20-30% risk for the disease in
contrast to the reduced risk of a dyzygotic twin of an
individual with MS. The gene most closely associated with MS
risk is HLA DR1B. This genetic marker shows an increased
frequency in adults as well as children with the disease.
Recently, an association of the genes coding for the
receptors of the cytokines IL-7 and IL-2 have been identified in
adult MS. [38,
These cytokines play a role in T and B cell development. Both T
and B cells contribute to the pathogenesis of MS. However, the
exact role of the cytokines is still under investigation.
The differential diagnosis of MS is large and includes other
inflammatory disorders of the white matter, infections,
neoplasms, vasculitis, hereditary disorders of the white
matter, metabolic disorders, mitochondrial disorders, and
Examples of several entities within each category are listed
is another inflammatory and demyelinating disorder of the CNS
which unlike MS is self limited. While the two disorders can
overlap in presentation certain features as shown in Table 1 are
more typical of ADEM than MS. 
Typical clinical features of ADEM not usually found in MS are
fever and encephalopathy (manifested by stupor, severe lethargy,
seizures, confusion, and rarely coma). Focal and multifocal
signs of cerebral white matter dysfunction which mimic MS
include optic neuritis (bilateral or unilateral), pyramidal
signs (hemiparesis, paraparesis, or monoparesis), sensory loss,
or brainstem and cerebellar signs. The MRI in ADEM in contrast
to MS, typically shows large poorly defined lesions which
involve the white matter but can also affect deep grey
structures such as the basal ganglia. Positive OCB are present
in 25% or less of ADEM cases. [5,
30, 41, 42]
which is a lower
of positive OCB in MS which ranges from 55 - 95%.
The clearest distinction between MS and ADEM is the ultimate
disease course. While rarely ADEM may relapse over time, these
relapses do eventually stop and the MRI resolves partially or
Table 1 Clinical differences between ADEM and
Typical age group
< 10 years
> 10 years
Required in definition
Grey matter involvement on MRI
CSF pleocytosis greater than 50
must always need to be excluded and include entities such as
meningitis, encephalitis, brain abscess, 
Lyme disease, and HIV.
enter the differential diagnosis among patients with single
tumefactive lesions which can resemble
primary CNS neoplasm or lymphoma. Most often grey matter
involvement will lead to an alternative diagnosis than MS but
occasionally biopsy is needed.
can include neurological complications which can be mistaken for
MS. Among the disorders to exclude are systemic lupus
erythematosus, Bechet’s disease, sarcoidosis, CNS vasculitis, or
involve the cerebral white matter and occasionally can have an
MRI appearance that resembles MS. However these conditions can
be distinguished from MS by their progressive course, the
presence of developmental
delay, and the onset during infancy. This group of disorders
includes but is not limited to:
metachromatic leukodystrophy (MLD); Pelizaeus-Merzbacher
disease; leukoencephalopathy with vanishing
ataxia with cerebral hypomyelination of the brain stem and
and juvenile onset Alexander’s disease; and cerebral autosomal
dominant arteriography (CADASIL).
are also included in the differential. For the patient with
optic neuritis, Leber’s Hereditary Optic Neuritis must be
considered. Other conditions which rarely may be confused for MS
include Leigh’s disease, Kearns-Sayne syndrome, and
Mitochondrial Encephalopathy with Lactic Acidosis and Stroke
like episodes as well as other mitochondrial disorders.
that can have symptoms which overlap with those of MS include
B12, folate, and vitamin
Treatment of relapses
Management of acute
relapses includes neurological evaluation and initiation of
steroid therapy for relapses which affect daily functioning. The
goal is to decrease the duration of the relapse and enhance the
rate of recovery. [44,
45] Since no clinical trials
for relapse management have been done in pediatric MS the
treatment follows the approach used for adults. High doses of
parenteral methyprednisolone (typically one gram) appear more
effective than lower oral doses. 
Treatment regimens vary from 3 to 5 days. In our experience
children respond to doses ranging from 20 to 30 mg per kilogram.
adults, high doses of oral methyprednisolone have been
substituted for parenteral therapy. 
Complications can develop with
steroid therapy and include gastrointestinal upset,
irritability, insomnia, and at their most extreme – psychosis.
It is not easy to predict which individuals will be at greatest
risk for behavior related side effects
On occasion, children
with MS treated with high doses of steroids and followed by an
oral taper, develop steroid dependence (inability to wean off
therapy due to reoccurrence of symptoms.) Patients may also fail
to respond to steroid therapy.
the event of steroid dependence or steroid failure pulse
intravenous immunoglobulin therapy (.4mg/kg per day x 5 days)
can be tried.
patients failing to improve with steroids may respond to
Disease modifying therapies
therapies (DMT) constitute the principal approach to altering
the disease course. These treatments have only been shown to be
useful in relapsing remitting MS or in adults with a single
relapse who are at high risk for a subsequent event. The
medications are most effective in decreasing the frequency and
severity of relapses. To a lesser degree they lessen the
accumulation of neurological impairments or disability. As shown
in table 2, the most commonly used agents (in order of their
timing of FDA approval) are interferons beta 1b
SQ (Betaseron) at a dose of 250 ug
every other day; interferon beta 1a intramuscular (Avonex) at a
dose of 30 ug once a week; glatiramer acetate (Copaxone) SQ at a
dose of 20mg daily; and interferon beta 1a SQ)(Rebif) at a dose
of 44 ug three time a week. The interferons and glatiramer
acetate affect the immune system by slightly different
mechanisms. However, each of these therapies has their own
advantages and disadvantages, largely based on adverse event
profile, convenience, and relative effect on MRI. Psychiatric
complications have been anecdotally associated with the
interferon therapies. However, in the pivotal clinical trials,
in including the most recent, the frequency of mood disorder was
not significantly different than placebo. 
Natilizumab (Tysabri), mitoxantrone (Novantrone),
and cyclophosphamide (Cytoxan) are second line therapies which
are given intravenously. They are usually prescribed when first
line agents fail but their use as induction therapies is being
Current Disease Modifying Therapies
used in MS
First Line Treatments
Dose and frequency
Interferon beta 1b (Betaseron)
30 mg once a week
Interferon beta 1a
44 micrograms three times a week
Glatiramer acetate (Copaxone)
250 micrograms every other day
Interferon beta 1a subcutaneous
20 mg daily
Second Line Treatments
300mg in normal saline, monthly
12 mg/kg IV every three months
to a maximum of 144mg/kg
600- 800 mg/kg monthly x 3-6
months followed by biannual pulses
A major principle of
therapy is symptomatic management. [44,
50] Problems to treat include
mood disturbance, spasticity, fatigue, bladder and bowel
dysfunction, and pain. If mood related problems are not treated
they tend to worsen.
studies of depression in MS support the use of antidepressant
therapy and cognitive behavioral therapy. 
Spasticity and painful
spasms can be managed very well with exercise and physical
therapy either with or without medications. Medications which
treat spasticity unresponsive to exercise or stretching include
baclofen, a GABA agonist, tizanidine, a central alpha-adrenergic
agonist, and benzodiazepams such as clonazepam. These agents can
monotherapy or in combination.
Pain, such as
trigeminal neuralgia, responds best to carbamazepam or other
anti-convulsants. Non-neuropathic pain syndromes can be managed
with exercise, physical therapy as well as analgesics such as
non-steroidal anti-inflammatory agents. Another very frequent
problem is fatigue. Fatigue is both intrinsic to MS as well as a
consequence of the depression, sleep disturbance, and pain
associated with the disease. Management includes steps to
conserve energy, exercise and medication. Medications considered
effective and well tolerated in children include amantadine, an
NMDA receptor antagonist and modafinil. 
HCL has also been used, albeit infrequently.
Other MS related problems include bladder
dysfunction where both a hyperactive bladder and hypotonic
bladder can be the problem. Oxybutrin and tolterodine are among
several medications available to control urgency. Both are
available in a slow release formulation.
Ideally the management of children with MS is
multidisciplinary. A recreational program for teens with MS is
also available through the Teen Adventure Program. This activity
helps teens meet others their age in a pleasant non-medical
As progress in the
management of MS grows
individuals can expect better and
more convenient treatment options.
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