Pediatric Demyelinating
Diseases
Tanuja Chitnis, MD
ABSTRACT
Purpose of Review: In the past decade, the number of studies related to demyelinating diseases in children has exponentially increased. Demyelinating disease
in children may be monophasic or chronic. Typical monophasic disorders in children
are acute disseminated encephalomyelitis and clinically isolated syndromes, including optic neuritis and transverse myelitis. However, some cases of acute
disseminated encephalomyelitis or clinically isolated syndrome progress to become
chronic disorders, including multiple sclerosis and neuromyelitis optica. This review
summarizes the current knowledge on monophasic and chronic demyelinating
disorders in children, focusing on an approach to diagnosis and management.
Recent Findings: Improved diagnostic definitions for pediatric demyelinating diseases have led to enhanced recognition of these disorders. Additionally, increased
awareness and focused national and international efforts continue to inform about
the clinical course, response to treatment, and disease pathogenesis.
Summary: Significant advances have been made in the recognition, diagnosis, and
management of pediatric demyelinating disorders over the past 10 years. This review summarizes these advances and provides an updated approach to the diagnosis and management of pediatric demyelinating disorders.
Address correspondence to
Dr Tanuja Chitnis,
Massachusetts General
Hospital, Department of Child
Neurology, 75 Fruit St, ACC
708, Boston, MA 02114,
tchitnis@partners.org.
Relationship Disclosure:
Dr Chitnis serves as a
consultant for Biogen
Idec, Novartis, and Teva
Neuroscience, and receives
research support from Merck
Serono and grants from the
National Multiple Sclerosis
Society.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Chitnis discusses
the unlabeled use of
disease-modifying therapies
for children with multiple
sclerosis.
* 2013, American Academy
of Neurology.
APPROACH TO PEDIATRIC
DEMYELINATING DISEASES
When faced with a potential case of
demyelination of the CNS in a child or
adolescent, an increasing amount of
literature is available to turn to for guidance. For an adult neurologist familiar
with demyelinating diseases, the general principles of assessment and diagnosis are similar. However, nuances
exist in terms of the types of presentations, prognosis, and general management of the pediatric patient. The child
neurologist may be more familiar with
the differential diagnosis of pediatric demyelinating disorders but may have
more limited experience with treatments
used in chronic demyelinating diseases.
Although teenagers are often considered young adults, their management
within a pediatric practice is beneficial
Continuum (Minneap Minn) 2013;19(4):10231045
in order to provide age-appropriate supportive services, including an educational liaison, neuropsychologist, and
counselors, as appropriate.
Pediatric demyelinating diseases
can involve the optic nerve(s), spinal
cord, cerebrum, or brainstem and
cerebellar regions. Symptoms depend
on the location of involvement. One
general approach often useful in the
initial assessment is to classify patients
according to the presence of monofocal or polyfocal involvement of the
CNS (Figure 7-1). Monophasic disease, often termed clinically isolated
syndrome (CIS) may be characterized
as either monofocal or polyfocal symptom onset, with or without encephalopathy. The presence of encephalopathy
is defined by (1) a behavioral change
(eg, confusion, excessive irritability) or
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h Pediatric demyelinating
diseases may present
with monofocal or
polyfocal CNS
involvement, and the
course of disease can be
classified as monophasic
or polyphasic (chronic).
Monophasic diseases
are clinically isolated
syndromes and
acute disseminated
encephalomyelitis, while
polyphasic diseases are
multiple sclerosis and
neuromyelitis optica.
FIGURE 7-1
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KEY POINTS
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cally reveals T1-isointense and T2hyperintense signal over several contiguous spinal cord segments and may
involve the entire spine. Spinal cord
swelling with effacement of the surrounding CSF spaces may be present
in severe cases. Contrast enhancement
is present in up to 74% of patients.10
In some patients with very suggestive
clinical features, the initial spine MRI
may be normal and should be repeated several days later.
Patients with acute transverse myelitis should undergo lumbar puncture.
Approximately 50% of pediatric patients with acute transverse myelitis
have CSF pleocytosis ranging from
mean white blood cell count of 136 T
67 cells/2L (range from 6 to 950 cells),
typically with a lymphocytic predominance.10 Elevated CSF protein levels,
either in isolation or in conjunction
with pleocytosis, are also detected in
about 50% of patients.10 Glucose is
typically normal. A normal CSF profile
does not rule out acute transverse myelitis, as this pattern is seen in approximately 25% of patients.
The initial treatment of acute transverse myelitis is high-dose IV corticosteroids, generally administered for 5
to 7 days. There have been no randomized controlled trials in acute
transverse myelitis to support this approach; however, case reports have
found a beneficial effect of high-dose
corticosteroids. For patients who do
not adequately improve with IV steroids, IVIg or plasmapheresis may be
considered. Additional treatment includes pain management, urinary bladder catheterization, bowel regimens,
peptic ulcer and deep venous thrombosis prophylaxis, physical therapy,
and psychosocial support. Mechanical
ventilation is required in approximately
5% of patients.
Although limited by variable definitions in the literature, the prognosis
KEY POINT
h Symptoms of transverse
myelitis include motor
and sensory deficits,
pain, and bowel and
bladder symptoms.
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for pediatric patients with acute transverse myelitis is generally good. Using
the four-point grading scale devised
by Paine and Byers, approximately
80% of pediatric patients who receive
high-dose IV steroids achieve full or
good recovery, and 20% have a fair or
poor outcome.12,13 Among patients
not treated with high-dose IV steroids, 60% have a full or good recovery, while 40% have a fair or poor
outcome. Higher rostral levels and
number of overall spinal segments on
spine MRI predict worse outcome.10 A
retrospective study of children with
acute transverse myelitis treated at a
quaternary referral center studied the
long-term outcome in 47 cases.10 Factors associated with a better functional
outcome included older age at time
of diagnosis, shorter time to diagnosis,
lower sensory and anatomic levels of
spinal injury, absence of T1 hypointensity on spinal MRI obtained during the
acute period, lack of white blood cells
in the CSF, and fewer affected spinal
cord segments.
During recovery, motor function
returns first, with an average time to
independent ambulation of 56 days in
one study14 and 25 days in a group of
patients treated with high-dose IV
steroids.12 Bowel and bladder control
recovers more slowly, with an average
time to recovery of normal urinary
function of 7 months in those patients
with complete recovery.14
The overwhelming majority of pediatric patients with idiopathic, complete acute transverse myelitis have
a monophasic course. In a series of
24 pediatric patients with complete
acute transverse myelitis with a mean
follow-up of 7 years, none had recurrences.14 In another study of children with a variety of initial acute
demyelinating events, only 2 of 29
(7%) patients with transverse myelitis
experienced a subsequent demyelinat-
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Case 7-1
An 11-year-old girl presented to the emergency department after a severe
fall and with a history of worsening leg weakness over the past 2 weeks.
On further questioning, she had experienced several falls over the past
4 months, with episodic leg weakness and incoordination. She had been
seen at several emergency departments, but no diagnosis had been made.
Examination revealed an awake, alert young girl. Cranial nerves were
intact with the exception of mild difficulty with left eye abduction. Motor
examination revealed 4/5 strength in her deltoids, biceps, triceps, and
intrinsic muscles bilaterally, as well as 4/5 strength in her left iliopsoas,
hamstrings, and anterior tibialis. Vibration sense was mildly decreased in
all four extremities, and cerebellar examination revealed dysmetria on
heel-to-shin testing bilaterally. Reflexes were increased throughout, and a
left Babinski sign was present. She walked with a wide-based unsteady
gait. An MRI of the brain and spinal cord was performed at this visit,
showing multiple T2 lesions in the brain and pons. Lesions were present in
the spinal cord at C3 and T2, both of which enhanced with gadolinium.
A lumbar puncture was performed and showed a normal glucose and
protein count, IgG index of 0.95, cell count of 15 cells/2L (differential: 90%
lymphocytes), three oligoclonal bands, and negative neuromyelitis optica
(NMO)YIgG. Serum NMO-IgG was also negative. She was admitted to the
child neurology department and treated with a 5-day course of IV steroids,
followed by a 4-week taper on prednisone. Physical therapy was started
as an inpatient and continued for 4 months on an outpatient basis. Given
her clinical presentation and the history of neurologic deficits occurring
4 months ago, she was diagnosed with relapsing-remitting multiple
sclerosis (MS). After a thorough discussion of treatment options, she and
her mother agreed to start IM interferon-"-1a 30 2g every week. This
was initiated at half dose (15 2g IM every week for 2 weeks), then
escalated to the full dose. She was monitored closely with neurologic
visits every 3 months. She experienced a relapse 6 months after initiation
of interferon-", characterized by an abdominal bandlike sensation,
urinary retention, severe leg weakness, and ataxia, with new
gadolinium-enhancing lesions in the spine at T5Y6 and T9Y10. She was
treated with a 5-day course of methylprednisolone with minimal recovery
1 month later. Because of the frequency and severity of her attacks, a
decision was made to change her therapy to IV natalizumab every 4 weeks
(6 mg/kg/dose). Serum testing for John Cunningham virus (JC virus)
antibody was negative. She tolerated natalizumab treatment well and had
no further attacks over the ensuing 1 year, and her motor coordination
improved significantly. Seven months after her diagnosis she underwent
neuropsychological testing, which revealed significant deficits in attention
and concentration and an IQ of 89. An Individualized Education Plan
was recommended for school. She was also found to be depressed and
began weekly counseling sessions.
Comment. This case illustrates the challenge in recognizing pediatric
MS and applies the current diagnostic criteria and management
recommendations as discussed in the text.
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h Acute disseminated
encephalomyelitis is
more common in
children than adults and
occurs mostly in children
under the age of 10.
h Acute disseminated
encephalomyelitis
presents with acute
encephalopathy as well
as other neurologic
symptoms.
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and serologic studies for suspected infections, as well as a standard CSF evaluation including cell count, bacterial
and fungal cultures, oligoclonal bands
and IgG index testing, and CSF testing for infections in suspicious cases
(Table 7-1). Examination of the optic
fundus, visual evoked potentials, and
orbital MRI should be considered in
cases in which optic neuritis is suspected. MRI studies typically show
multifocal white matter lesions involving the cerebrum, brainstem, cerebellum, and spinal cord, which may or may
not enhance with gadolinium. Brain
lesions may be present in the subcortical and cortical white matter, as well as
the cortical and deep gray matter nuclei
(Case 7-2). Four typical MRI patterns
have been described in ADEM: (1) small
focal punctate lesions, (2) bithalamic
lesions, (3) diffuse large white matter
lesions, and (4) hemorrhagic, demyelinating lesions consistent with acute
hemorrhagic leukoencephalopathy.18
MRI lesions generally resolve over time;
however, clinical improvement may
precede MRI improvement.22 In some
cases there may be residual MRI lesions.
The CSF examination is characterized by normal pressure, moderately
elevated cell count (5/2L to 100/2L),
moderately elevated protein (40 mg/
dL to 100 mg/dL), and normal glucose.
Large numbers of red blood cells in
the CSF may indicate a diagnosis of
acute hemorrhagic leukoencephalopathy. Oligoclonal bands may be present and have been described in up to
29% of ADEM patients23; they are generally transient.
Because of the acute therapeutic
implications, it is important to first
exclude acute CNS infections in every
child with a febrile illness and neurologic signs, with lumbar puncture and
additional microbiological laboratory
tests (Table 7-1). Serology for suspected organisms; CSF viral, fungal,
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Workup
Acute disseminated
encephalomyelitis
Brain MRI
Cervical and thoracic spine MRI
Lumbar puncture: cell count, protein, glucose, bacterial culture, oligoclonal
bands, IgG index, neuromyelitis optica (NMO)YIgG, CSF viral PCR assay for
herpes simplex virus (HSV), enterovirus
If clinically indicated, consider cytomegalovirus (CMV), Epstein-Barr virus
(EBV), varicella-zoster virus (VZV), and West Nile virus; and Mycoplasma PCR,
Mycoplasma titers, and fungal cultures.
Blood studies: antinuclear antibody (ANA), erythrocyte sedimentation rate
(ESR), C-reactive protein (CRP), NMO-IgG (more sensitive than CSF), EBV titers,
and Vitamin D level. If clinically indicated, consider Mycoplasma titers.
Funduscopic evaluation
Additional tests to consider: serum and CSF angiotensin-converting enzyme
(ACE) level and chest x-ray if sarcoidosis is suspected.
Consider visual evoked potentials (VEP), brainstem auditory evoked potentials
(BAEP), urodynamic testing, and MRI orbits if clinically indicated.
Transverse myelitis
Multiple sclerosis
Brain MRI
Cervical and thoracic spine MRI
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, IgG index,
NMO-IgG, viral PCR for HSV. Consider PCR for enterovirus, CMV, EBV, VZV,
and West Nile virus if clinically indicated.
Blood studies: ANA, ESR, CRP, NMO-IgG, EBV titers, vitamin D level, and
thyroid-stimulating hormone
Funduscopic examination
Visual evoked potentials
Additional tests to consider: folate and vitamin B12 levels, ACE level in serum
and CSF, and chest x-ray if sarcoidosis is suspected. Perform BAEP and MRI
orbits if clinically indicated.
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Case 7-2
A 13-year-old boy presented with leg weakness and stupor, which developed
into quadriparesis with respiratory suppression within 24 hours. Two weeks ago,
he had a fever and upper respiratory tract illness, which resolved 1 week ago.
Axial brain MRI fluid-attenuated inversion recovery (FLAIR) image showed
fluffy T2-hyperintense lesions in the subcortical white matter and in the pons
extending bilaterally into the cerebellum (Figure 7-2). CSF testing showed 2 red
blood cells/2L and 30 white blood cells/2L, with 60% lymphocytes. Protein and
glucose levels in the CSF were within normal limits. No oligoclonal bands were
present in the CSF, and IgG Index was 0.50. CSF PCR testing for herpes simplex
virus, enterovirus, and Mycoplasma were negative. He was diagnosed with acute
disseminated encephalomyelitis (ADEM) and treated with a 5-day course of
methylprednisolone (20 mg/kg/d). On day 5 of treatment, his condition had
not improved, and a course of IV immunoglobulin (IVIg) was initiated (0.5 g/kg
daily for 4 days). By the second IVIg treatment, he began to move his legs to
noxious stimuli, and his respiratory status improved. By the fifth IVIg dose, his
mental status improved, and he no longer required the ventilator. Two weeks
later, he was discharged to a pediatric rehabilitation facility, where he spent
8 weeks. One year after the event, his neurologic examination was grossly
normal, and he was attending school.
Comment. This case illustrates the presentation of ADEM in an adolescent and
use of first-line and then second-line treatment.
FIGURE 7-2
Axial brain MRI of the patient in Case 7-2. A, Axial brain MRI fluid-attenuated
inversion recovery (FLAIR) image shows fluffy T2-hyperintense lesions in
the subcortical white matter. B, Axial brainstem MRI FLAIR image shows
T2-hyperintense lesions in the pons extending bilaterally into the cerebellum.
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Workup
MRI; magnetic resonance spectroscopy (MRS); PET;
CSF cytology; cell count
Astrocytoma/glioma
Metastasis
Immunologic
Systemic lupus erythematosus
Antiphospholipid syndrome
Rheumatoid arthritis
Poststreptococcal syndrome
Antistreptococcal antibody
Behet syndrome
Sarcoidosis
Sjogren syndrome
Wegener granulomatosis
Lymphomatoid granulomatosis
Hemophagocytic
lymphohistiocytosis
Hashimoto encephalopathy
Limbic encephalitis
Infection
Lyme disease
HIV
Progressive multifocal
leukoencephalopathy
Neurosyphilis
Catscratch disease
Whipple disease
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Workup
MRI with diffusion-weighted imaging sequences; stroke in
young workup
Magnetic resonance angiogram (MRA)
Consider conventional angiogram
Moyamoya disease
MRA
Consider conventional angiogram
Complicated migraine
Susac syndrome
Nutritional
Vitamin B12 deficiency
Folate deficiency
Metabolic
Fabry disease
Biotinidase deficiency
Skin biopsy; enzyme assay for CLN1 and CLN2; molecular genetic testing
for CLN1, CLN2, CLN3, CLN6; electroretinogram
Leukodystrophy
Adrenoleukodystrophy or
adrenomyeloneuropathy
Metachromatic leukodystrophy
Alexander disease
Krabbe disease
Pelizaeus-Merzbacher disease
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Workup
Mitochondrial Disease
Mitochondrial encephalomyopathy,
lactic acidosis, and strokelike
episodes
Friedrich ataxia
Spinocerebellar atrophy
KEY POINT
h IV high-dose
methylprednisolone
for 3 to 7 days is the
standard treatment
regimen for acute
disseminated
encephalomyelitis.
Use of IV
immunoglobulin
and plasmapheresis
in refractory cases is
anecdotal.
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h Rarely, acute
disseminated
encephalomyelitis cases
may go on to develop
pediatric multiple
sclerosis or
neuromyelitis optica.
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TABLE 7-3
A diagnosis of pediatric multiple sclerosis (MS) can be satisfied by any of the following:
b Two or more nonencephalopathic (eg, nonYacute disseminated encephalomyelitis
[ADEM]) clinical CNS events with presumed inflammatory cause separated by more than
30 days involving more than one area of the CNS
b One nonencephalopathic episode typical of MS that is associated with MRI findings
consistent with 2010 Revised McDonald criteria for dissemination in space (DIS) (at least
one T2 lesion in two of the following areas: periventricular, juxtacortical, infratentorial,
and spinal cord) and in which a follow-up MRI shows at least one new enhancing or
nonenhancing lesion consistent with dissemination in time (DIT) MS criteria (irrespective
of its timing with reference to a baseline scan)
b One ADEM attack followed by a nonencephalopathic clinical event, 3 or more months
after symptom onset, that is associated with new MRI lesions that fulfill 2010 Revised
McDonald DIS criteria (at least one T2 lesion in two of the following areas:
periventricular, juxtacortical, infratentorial, and spinal cord)
b A first, single acute event that does not meet ADEM criteria and whose MRI findings are
consistent with the 2010 Revised McDonald criteria for DIS and DIT (simultaneous
presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any
time)Vthis criteria applies only to children Q12 years old
a
Reprinted from Krupp et al; International Pediatric Multiple Sclerosis Study Group, Mult Scler.41 B 2013, by
permission of SAGE Publications. msj.sagepub.com/content/early/2013/04/08/1352458513484547.abstract.
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Case 7-3
A 13-year-old boy presented with left leg weakness. He was fully conscious. Two months later,
he developed right arm weakness. The diagnosis was relapsing-remitting multiple sclerosis (MS).
Axial brain MRI fluid-attenuated inversion recovery (FLAIR) image showed well-circumscribed
T2-hyperintense lesions in the periventricular and subcortical white matter; sagittal brain MRI T2
image showed lesions perpendicular to the long axis of the corpus callosum; and axial brainstem MRI
FLAIR image showed T2 lesions limited to the middle cerebellar peduncles (Figure 7-3). The patient
was started on a disease-modifying MS therapy (glatiramer acetate 20 mg/d subcutaneously).
Comment. This case of pediatric MS demonstrates typical MRI findings. Contrast the MRI findings in
this case to the acute disseminated encephalomyelitis in Case 7-2.
FIGURE 7-3
MRI of the patient in Case 7-3. A, Axial brain MRI fluid-attenuated inversion recovery (FLAIR) image shows
well-circumscribed T2-hyperintense lesions in the periventricular and subcortical white matter. B, Sagittal
brain MRI T2 image shows lesions perpendicular to the long axis of the corpus callosum. C, Axial brainstem
MRI FLAIR image shows T2 lesions (arrows) limited to the middle cerebellar peduncles.
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KEY POINT
h Interferon-"
subcategories or
glatiramer acetate
are used as first-line
treatments in children
with multiple sclerosis;
however, some children
have refractory disease
and require second-line
treatments.
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h Cognitive dysfunction
may be present at
onset and may
worsen over time;
therefore,
neuropsychological
testing and evaluation
by an educational
consultant is
recommended in
all cases of pediatric
multiple sclerosis.
h Neuromyelitis optica
rarely occurs in children,
and adult diagnostic
criteria for neuromyelitis
optica may be applied
to pediatric cases.
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Case 7-4
A 14-year-old girl with a history of acute transverse myelitis 1 year ago
presented with no light perception bilaterally. Orbital MRI showed T2
lesions in the optic chiasm, axial brain MRI fluid-attenuated inversion
recovery (FLAIR) image showed T2 lesions adjacent to the third ventricle,
and sagittal spine MRI showed a longitudinally extensive T2 lesion
extending from the medulla to the thoracic spinal cord. Neuromyelitis
optica (NMO)YIgG was positive in serum. The patient was diagnosed with
NMO and started a 5-day course of IV methylprednisolone (20 mg/kg/d).
Her vision showed no improvement on day 5 of treatment, so a course of
plasmapheresis was initiated. Her vision began to improve after the second
plasma exchange, and by the fifth exchange her visual acuity was 20/40
bilaterally. Examination 2 weeks later showed 20/20 vision bilaterally. She
was started on rituximab 375 mg/m2 weekly for 4 weeks, and 2 months
later, her CD19 count was measured as 0%. She had no further relapses
over the next 6 months. Nine months after initiation of rituximab, her
CD19 count was 1%, and her neurological examination was essentially
normal. The treating clinician decided to switch her from rituximab
maintenance therapy to mycophenolate mofetil 500 mg twice a day, which
she tolerated well. She had no further attacks over the ensuing 2-year
follow-up period.
Comment. This is a case of an adolescent with NMO. Note the pattern
and affected areas of involvement, which differ from those of patients
with multiple sclerosis.
FIGURE 7-4
MRI of the patient in Case 7-4. A, Orbital MRI shows T2 lesions (arrow) in the optic chiasm. B, Axial brain
MRI fluid-attenuated inversion recovery (FLAIR) image shows T2 lesions (arrow) adjacent to the third ventricle.
C, Sagittal spine MRI shows a longitudinally extensive T2 lesion extending from the medulla to the thoracic
spinal cord.
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h Neuromyelitis
opticaYIgG may be
negative in some
pediatric patients
with a clinical
presentation of
neuromyelitis optica.
h Use of IV steroids or
plasmapheresis has
been reported for
acute attacks in
pediatric cases of
neuromyelitis optica;
long-term prophylactic
treatment can
include rituximab,
mycophenolate mofetil,
and azathioprine.
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