10

Review Article
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.
Continuum (Minneap Minn) 2013;19(4):10231045.
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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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1023
Pediatric Demyelinating Diseases

KEY POINT
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
Paradigm for presenting symptoms of demyelinating disease in children.
(2) alteration in consciousness (eg,

lethargy, coma not due to fever or
medications), and is indicative of a
diagnosis of acute disseminated encephalomyelitis (ADEM) in a child with
a polyfocal presentation.1 Chronic or
polyphasic pediatric demyelinating diseases include multiple sclerosis (MS)
and neuromyelitis optica (NMO), as
well as recurrent forms of optic neuritis
and transverse myelitis. The acute
presentation has implications for acute
management as well as for long-term
prognosis; however, there are always
exceptions to general rules, as will be
discussed.
Demyelinating disease in children
usually presents subacutely, with symptoms appearing over 24 to 48 hours.
Occasionally, patients may awaken with
or notice the sudden appearance of a
symptom such as blurred vision or loss
of vision. In others, the recognition of
symptoms can be delayed for days or
even weeks and may be dependent on
the level of recognition by both the
1024
patient and the parent. Sometimes

patients delay in reporting symptoms
to caregivers. We have found a wide
spectrum in the time from reporting of
first symptoms to the seeking of medical care since symptoms may occasionally be attributed to other reasons or
families may opt to wait it out to see if
symptoms resolve spontaneously.
Symptoms may occur during or shortly
after an infectious illness and may be
difficult to distinguish from that infectious disease process. Children are
often referred first to their pediatrician or ophthalmologist and occasionally to the emergency department,
depending on the severity and type of
symptoms. An MRI generally raises the
first indication of a demyelinating disease, and further workup may include
blood tests for the differential diagnosis as well as a CSF examination for cell
count, oligoclonal bands, and an IgG
index.
Once a diagnosis is reached, management may include acute treatment
August 2013
of the demyelinating symptoms, symptomatic treatment, and, in the cases of

chronic or polyphasic disease, initiation of disease-modifying treatment.
A management team including a neurologist, nurse, counselor, neuropsychologist, and educational liaison is
important to provide both medical and
supportive services.
CLINICALLY ISOLATED
SYNDROMES
Children may present with CIS, which
often are monophasic in course. However, a proportion of these children
may eventually develop a chronic
demyelinating disease such as MS or
NMO (discussed in sections below). A
general approach to CIS or ADEM is to
evaluate the location of symptoms,
presence of mental status changes
or encephalopathy at onset, and the
presence of additional lesions along
the neuraxis (optic nerves, brain, and
spinal cord) (Figure 7-1). Transverse
myelitis and optic neuritis are common presentations of CIS in children
and are discussed in detail here. Other
presentations, including brainstem
syndromes and polyfocal presentations, may also occur.
Optic Neuritis
Optic neuritis can occur in children
and adolescents of any age. A summary of four case series (n = 170)
suggests a mean age of onset from 9
to 12 years of age and an approximate
1.5:1 female to male ratio.2 In these
studies, approximately one-third of
patients report a preceding viral infection. Optic nerve involvement can
present with reports of blurred vision
or loss of vision, a black spot in
central vision, loss of color vision, and
occasionally pain on eye movement.
In children, the vision loss is usually
severe, with visual acuity of 20/200 or
worse in approximately 75% of paContinuum (Minneap Minn) 2013;19(4):10231045
tients.2 Bilateral involvement has been

reported in up to 50% of patients. In
children, pain on eye movement is a
specific but not a sensitive test, with
only 40% of pediatric patients reporting this symptom.3 A normal funduscopic examination is seen in 30% of
patients and does not rule out the diagnosis, since many cases are due to
retrobulbar inflammation. Examination may also reveal an afferent pupillary defect and color vision difficulties
in patients with optic neuritis.
Patients with optic neuritis should
be evaluated by an ophthalmologist.
Testing should include formal visual
field testing, low contrast sensitivity,
and color vision assessment. Additional
testing should be guided by clues in
the history, examination, or neuroimaging. Other neuro-ophthalmologic
techniques, such as visual evoked potentials to evaluate nerve conduction
and optical coherence tomography to
evaluate the extent of damage to the
nerve fiber layer, may be considered.
An orbital MRI including coronal sequences with thin cuts through the
orbits should be obtained in all patients with optic neuritis. Brain and
spinal cord MRI is recommended in all
patients to define the extent of demyelination, which has implications for
prognosis. Lumbar puncture should be
performed if direct CNS infection cannot be ruled out clinically. After appropriate neuroimaging to rule out mass
lesions, lumbar puncture with measurement of opening pressure is also
required if idiopathic intracranial hypertension is suspected.
The differential diagnosis of optic
neuritis includes vitamin B12 deficiency, adrenoleukodystrophy, Leber
hereditary optic neuropathy, and optic
nerve glioma. Sarcoidosis may present
with optic neuritis or cranial nerve
defects. Isolated optic neuritis can be
confused with Leber hereditary optic
KEY POINTS
h Typical clinically isolated

syndromes in children
include optic neuritis
and transverse myelitis.
h Optic neuritis in children

typically presents with
central vision loss and
pain on eye movement.
1025

KEY POINTS
h The presence of brain

lesions at the time
of optic neuritis
presentation is a
strong predictor for
the development of
multiple sclerosis.
h The mean age of acute

transverse myelitis in
children is 8 years old,
and boys and girls are
equally affected.
1026
neuropathy, especially when pain on

eye movement is absent. Family history, brain MRI, and mitochondrial
DNA mutation analysis can be used
to distinguish these conditions. In the
case of tumor, papilledema from increased intracranial pressure can appear the same as swelling of the optic
discs from bilateral optic neuritis. The
former typically presents more slowly,
is not usually associated with severe
vision loss (especially early in the
course), and is not associated with an
afferent pupillary defect.
Similar to other acute CNS demyelinating syndromes, patients with optic neuritis are often treated with highdose IV methylprednisolone. In the
Optic Neuritis Treatment Trial in
adults, a 3-day course of IV methylprednisolone increased the rate of
recovery in patients with visual acuity
less than 20/40 but did not affect the
long-term visual acuity outcomes.4
However, at 2 years, color vision and
contrast sensitivity were better in
treated patients. No controlled data
exist on the effect of IV steroids on
optic neuritis outcomes in children.
The authors practice is generally to
administer high-dose IV steroids to
optic neuritis cases. The author has
occasionally used IV immunoglobulin
(IVIg) or plasmapheresis in refractory
cases of optic neuritis in children that
do not show sufficient improvement
within 5 to 10 days after completing a
course of IV steroids; however, few
published data support this practice.
Most children recover well from
optic neuritis, and approximately 50%
to 75% have a visual acuity of 20/40 or
better at follow-up.2,5 However, patients with optic neuritis frequently report subjective changes in vision, even
when visual acuity returns to 20/20.
Abnormalities may only be detected
with specialized techniques such as optical
coherence tomography or visual evoked
potentials.6,7 In some cases, adaptive

equipment and visual rehabilitation
may be required.
Despite the favorable prognosis for
immediate functional recovery, some
patients may later develop MS or NMO.
A distinguishing factor for the later
development of MS after optic neuritis
is the presence of one or more brain
MRI lesions typical for MS.2,8 Bilateral
optic neuritis was more likely to be
associated with the development of
MS.2 In the Kids With MS (KIDMUS)
study, 86% of patients with initial optic
neuritis developed MS; however, the
presence of brain MRI lesions in this
cohort was not defined.9
Acute Transverse Myelitis
Approximately 300 cases of acute
transverse myelitis in pediatric patients in the United States are estimated to occur annually.10 The mean
age of presentation is 8 years of age,
with a bimodal distribution in toddlers
and children 10 to 12 years of age. Boys
and girls are equally affected. Approximately 50% of patients report a preceding infection, typically a nonspecific
upper respiratory tract infection in the
preceding month.10 Occasional cases
of acute transverse myelitis are associated with recent vaccination.
The majority of patients experience
motor, sensory, and bowel and bladder symptoms.10,11 Patients with acute
transverse myelitis universally report
acute to subacute bilateral leg weakness. Arm involvement is present in
approximately 40% of patients. Approximately 90% of patients report
bowel and bladder dysfunction. The
majority of patients also experience
sensory symptoms, including paresthesia and numbness and back pain. A
spinal cord sensory level is usually located in the thoracic region (80%)
and less commonly in the cervical
(10%) or lumbar (10%) levels. In one
August 2013
cohort of 38 patients, 58% had longitudinally extensive transverse myelitis

extending over three or more segments, 24% had focal lesions, and 13%
had both.11
Several disorders can mimic idiopathic acute transverse myelitis. Acute
compressive lesions, such as tumors,
spinal epidural abscesses, and spinal
epidural hematomas, are neurosurgical emergencies that must be diagnosed rapidly for effective treatment.
Intramedullary lesions that can mimic
acute transverse myelitis include primary spinal cord tumors (commonly
astrocytomas and ependymomas), radiation injury, spinal cord infarction,
and vascular malformations. Infections
of the spinal cord, typically viral in
etiology, can also occur, and cytomegalovirus, human T-cell lymphotropic
virus I or Mycoplasma infections
should be considered in those at risk.
Acute transverse myelitis can also be
secondary to a variety of systemic
autoimmune disorders, including systemic lupus erythematosus. The initial
clinical presentation of acute transverse myelitis can be very similar to
that of Guillain-Barr2 syndrome. Both
can present with back pain, paraparesis,
and sensory abnormalities. However,
the presence of a spinal cord sensory
level and bowel and bladder involvement is highly suggestive of acute
transverse myelitis. The presence of
reflexes or exaggerated reflexes is suggestive of acute transverse myelitis,
although areflexia may be present in
some cases.
An emergent gadolinium-enhanced
MRI of the brain and entire spine
should be performed in patients with
suspected acute transverse myelitis in
order to confirm the diagnosis and
rule out alternative diagnoses, particularly compressive lesions, and to
evaluate the extent of disease. Spinal
MRI in acute transverse myelitis typiContinuum (Minneap Minn) 2013;19(4):10231045
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.
1027
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-
1028
ing event.9,15 As opposed to complete

acute transverse myelitis, focal acute
transverse myelitis seems to carry a
higher risk of MS.8 Evaluation for
NMO should be considered in patients
with the presence of a longitudinally
extensive lesion in the spinal cord
extending over three or more segments; however, it is recognized that
this finding may be seen in pediatric
patients with idiopathic isolated transverse myelitis, ADEM, and MS who do
not fulfill criteria for NMO.11
Polyfocal Clinically
Isolated Syndromes
Presentations involving more than one
area of CNS are referred to as polyfocal. Those without encephalopathy
may be termed polyfocal CIS, while
those with encephalopathy are termed
ADEM. An example of polyfocal CIS is
simultaneous presentation of brain,
brainstem, and spine involvement, as
illustrated in Case 7-1. Presentations
of polyfocal CIS are at high risk for
conversion to MS, in contrast to presentations of ADEM. 8 Therefore,
the distinction of polyfocal CIS from
ADEM is important.
Acute Disseminated
Encephalomyelitis
ADEM is defined as a polysymptomatic demyelinating illness with the
presence of encephalopathy.1 ADEM
is seen more frequently in children
than in adults. Most children present
during 5 to 8 years of age. In the United
States, a study from southern California
estimated the mean incidence of
ADEM as 0.4/100,000/year among
those under the age of 20.16 A German
study found a similar incidence of pediatric ADEM patients as 0.07/100,000/
year for those under 16 years of age.17
Some cases of ADEM have been linked
to specific vaccines, such as the Semple
rabies vaccine, the smallpox vaccine,
August 2013
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.
1029

KEY POINTS
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.
1030
and older forms of the measles vaccine.

Boys and girls are generally equally
affected.
A viral infection or vaccination may
have occurred 2 days to 4 weeks
before the onset of neurologic symptoms of ADEM. ADEM is characterized
by a rapid onset of encephalopathy in
association with a combination of
multifocal neurologic deficits. Prodromal symptoms can include fever, malaise, headache, nausea, and vomiting
and may also be observed shortly
before the development of meningeal
signs and drowsiness. The clinical
course is typically rapidly progressive,
with the development of maximum
deficits within 2 to 5 days18 ADEM can
also present with more subtle disease,
with nonspecific irritability, headache,
or somnolence lasting more than 1
day. Respiratory failure or severe impaired consciousness, usually due to
brainstem involvement, can occur.
Neurologic symptoms of ADEM can
include unilateral or bilateral pyramidal signs (60% to 95%), ataxia (18% to
65%), acute hemiplegia (76%), visual
loss due to optic neuritis (7% to 23%),
cranial nerve involvement (22% to 45%),
seizures (13% to 35%), spinal cord involvement (24%), impairment of speech
(slow, slurred, or aphasic) (5% to 21%),
and hemiparesthesia (2% to 3%). Encephalopathy can range from lethargy to
coma. Seizures are largely seen in children aged 5 years or younger and are
usually described as focal motor seizures.18 Peripheral nervous system involvement in ADEM has been reported
in both children19,20 and adults.21
Cases of pediatric recurrent or multiphasic ADEM have been reported.18
However, the distinction with pediatric
MS is unclear, and these cases should
be monitored closely.
Typical diagnostic evaluation for
ADEM should include a neurologic examination, MRI of the brain and spine,
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,
August 2013
TABLE 7-1 Typical Evaluation for Common Pediatric Demyelinating Diseases

Diagnosis
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

Brain MRI
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, and IgG
index; NMO-IgG; CSF viral PCR for HSV, enterovirus, CMV, EBV, VZV, and West
Nile virus; Mycoplasma, Mycoplasma titers, and fungal and bacterial cultures
Blood studies: ANA, anti-Ro, anti-La, EBV titer, vitamin D level, NMO-IgG
Other: urodynamic testing, somatosensory evoked potentials, funduscopic evaluation
Additional tests to consider: human T-cell lymphotropic virus type 1 antibodies
in serum and CSF, VEP, BAEP, and MRI orbits if clinically indicated
Multiple sclerosis
Brain 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.
and bacterial cultures; and CSF viral

PCR assay for herpes simplex virus,
enterovirus, cytomegalovirus, EpsteinBarr virus, varicella-zoster virus, and
West Nile virus should be performed.
Mycoplasma serology may reveal an
underlying infection. A large number

of inflammatory and noninflammatory
disorders may have a similar clinical
and radiologic presentation to ADEM
and related demyelinating disorders
and should be considered in the
1031
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.
diagnostic evaluation on a case-bycase basis (Table 7-2).

IV corticosteroids are typically used
to treat acute episodes of ADEM. The
1032
typical dose of methylprednisolone is

1 g/d for 5 days in both adults and
children over 40 kg (88 lbs), and 20
mg/kg/d to 30 mg/kg/d for 5 days in
August 2013
TABLE 7-2 Differential Diagnosis of Pediatric Demyelinating Diseases

Differential
Tumor
CNS lymphoma
Workup
MRI; magnetic resonance spectroscopy (MRS); PET;
CSF cytology; cell count
Astrocytoma/glioma
MRI; MRS; PET imaging
Metastasis
MRI; MRS; PET imaging; tumor survey
Immunologic
Systemic lupus erythematosus
Antinuclear antibody (ANA) (extractable nuclear antibodies

if ANA is positive); complement; double-stranded DNA;
rheumatologic evaluation
Antiphospholipid syndrome
Antiphospholipid antibodies (anti-cardiolipin, -2 glycoprotein

1); lupus anticoagulant; rheumatologic evaluation
Rheumatoid arthritis
Rheumatoid factor; erythrocyte sedimentation rate;

rheumatologic evaluation
Poststreptococcal syndrome
Antistreptococcal antibody
Behet syndrome
Examination for orogenital ulcers; pathergy test
Sarcoidosis
Angiotensin-converting enzyme level serum and CSF; chest

x-ray; rheumatologic evaluation
Sjogren syndrome
ANA; anti-Ro (SSA) antibody; anti-La (SSB) antibody
Wegener granulomatosis
Antineutrophil cytoplasmic antibody; rheumatologic evaluation

Consider uveal biopsy
Lymphomatoid granulomatosis
CSF cytology with B-cell subsets; immunohistochemistry

PCR-single-stranded conformational polymorphism analysis for
heavy-chain immunoglobulin and T-cell receptor gamma
Hemophagocytic
lymphohistiocytosis
Histiocytes on peripheral blood smear or bone marrow, or

biopsy of lymph node or CNS lesion
Hashimoto encephalopathy
Antithyroid peroxidase; antithyroglobulin antibodies in serum;

thyroid function tests
Limbic encephalitis
Anti-N-methyl-D-aspartate (NMDA) receptor and anti-voltage-gated

potassium channel-complex antibodies in serum and CSF
Infection
Lyme disease
Lyme antibody in serum and CSF PCR in endemic areas
HIV
HIV testing; screening for opportunistic infections
Herpes simplex virus
Herpes simplex virus PCR in CSF
Human T-cell lymphotropic

virus type 1
Human T-cell lymphotropic virus type 1 antibody in CSF
Progressive multifocal
leukoencephalopathy
JC virus PCR in CSF
Neurosyphilis
Serum and CSF Venereal Disease Research Laboratory (VDRL) test
Catscratch disease
Serology for Bartonella henselae
Whipple disease
Histopathologic study or PCR; lymph node biopsy with Gram stain

Continued on next page
1033
TABLE 7-2 Differential Diagnosis of Pediatric Demyelinating Diseases (continued )

Differential
Vascular disorders
Stroke
Arteriovenous malformation
Workup
MRI with diffusion-weighted imaging sequences; stroke in
young workup
Magnetic resonance angiogram (MRA)
Consider conventional angiogram
Sickle cell disease
Hemoglobin electrophoresis; peripheral blood smear
Moyamoya disease
MRA
Consider conventional angiogram
Cerebral autosomal dominant

arteriopathy with subcortical
infarcts and leukoencephalopathy
(CADASIL)
Notch 3 mutation; skin biopsy
Complicated migraine
Point mutations in the CACNA1A, ATP1A2, and SCN1A genes if history is

suggestive of familial hemiplegic migraine
Primary angiitis of the CNS
Serum erythrocyte sedimentation rate, C-reactive protein, von

Willebrand factor antigen, MR angiogram
Consider conventional angiogram and brain biopsy
Susac syndrome
Nutritional
Vitamin B12 deficiency
Folate deficiency
Retinal fluorescein angiogram; audiometric testing

Vitamin B12 in serum; methylmalonic acid; homocysteine level;
peripheral blood smear for macrocytes; mean corpuscular volume
Folic acid level in serum and CSF
Consider methylenetetrahydrofolate reductase levels
Metabolic
Fabry disease
Low or absent "-galactosidase A; enzyme level in plasma, serum,

leucocytes, or cultured fibroblasts; DNA analysis; skin, kidney, or
conjunctival biopsy
Biotinidase deficiency
Serum biotinidase; ammonium and lactic acid levels
3-Methylglutaric acid deficiency
Urine organic acids (3-methylglutaric acid)
Neuronal ceroid lipofuscinosis
Skin biopsy; enzyme assay for CLN1 and CLN2; molecular genetic testing
for CLN1, CLN2, CLN3, CLN6; electroretinogram
Adult polyglucosan disease
Glycogen branch enzyme; molecular genetic testing
Leukodystrophy
Adrenoleukodystrophy or
adrenomyeloneuropathy
Plasma very long chain fatty acids; ABCD1 genetic mutation
Metachromatic leukodystrophy
Arylsulfatase A in leukocytes and culture fibroblasts; sulfatides in

urine; evoked potentials including visual evoked potentials,
somatosensory evoked potentials, and brainstem auditory evoked
potentials; nerve conduction study; molecular genetic testing for SUMF1
Alexander disease
Molecular genetic testing for GFAP mutation
Krabbe disease
Galactocerebroside- galactosidase in leukocytes or cultured fibroblasts

and CSF; EMG/nerve conduction velocity; GALC genetic testing
Pelizaeus-Merzbacher disease
PLP gene mutation
Vanishing white matter disease
EIF2B1-5 genetic mutation

Continued on next page
1034
August 2013
TABLE 7-2 Differential Diagnosis of Pediatric Demyelinating Diseases (continued )

Differential
Workup
Mitochondrial Disease
Mitochondrial encephalomyopathy,
lactic acidosis, and strokelike
episodes
Lactate and pyruvate levels in CSF and serum; mitochondrial genetic

testing; muscle biopsy and histopathology
Leber hereditary optic neuropathy

Degenerative
Hereditary spastic paraparesis
Lactate and pyruvate levels in CSF and serum; mitochondrial genetic

testing; muscle biopsy and histopathology study
Hereditary spastic paraparesis genetic testing
Friedrich ataxia
Levels of vitamin E, albuminemia, cholesterol and triglyceride; ECG; nerve

conduction studies; ophthalmologic testing; molecular genetic testing
Spinocerebellar atrophy
SCA/ADCA genetic testing
JC virus = John Cunningham virus.
children up to 40 kg (88 lbs). Treatment with corticosteroids requires

monitoring of blood pressure, urine
glucose, and serum potassium, and
administration of gastric protection.
Prophylactic antiviral treatment with
acyclovir (30 mg/kg/d) is recommended acutely, particularly when
viral encephalitis such as herpes simplex encephalitis is considered and
has not been ruled out through PCR
testing. Antibiotic prophylaxis for suspected bacterial meningitis may also
be initiated in cases where this is a
consideration.
IVIg as a second-line treatment for
acute ADEM treatment has been reported in several case studies. The
usual total dose of IVIg is 2 g/kg and is
administered over 2 to 5 days. IVIg
may be useful in cases refractory to IV
steroid treatment, and the authors
practice is to typically start treatment 2
to 3 days after a 5-day steroid course.
In the authors experience, IVIg may
also be useful in cases of steroiddependent demyelination, when new
or fluctuating signs and symptoms
occur as corticosteroids are being
tapered. Side effects of IVIg can include headache, aseptic meningitis,
thrombotic events, and increased risk

of infection. The use of plasmapheresis in ADEM has been reported in a
small number of severe cases that
were generally unresponsive to corticosteroid or IVIg treatment.22 Three to
five exchanges are typically employed,
and this is considered sufficient to reduce antibody and inflammatory factors.
Side effects associated with plasmapheresis include moderate to severe
anemia, symptomatic hypotension, hypocalcemia, and heparin-associated
thrombocytopenia. In cases of ADEM
with progressive deterioration due to
increased uncontrolled intracranial
pressure, aggressive strategies such as
surgical decompression should be considered to prevent secondary injury to
the brain and brainstem.
Acute hemorrhagic leukoencephalopathy is associated with high rates
of morbidity and mortality and is often
considered the most acute and severe
form of ADEM. Case reports have used
high-dose IV corticosteroid therapy, IVIg,
plasmapheresis, and decompressive craniotomies in severe cases of acute hemorrhagic leukoencephalopathy.16,24,25
Limited data exist documenting the
natural history of ADEM. The natural
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.
1035

KEY POINTS
h Rarely, acute
disseminated
encephalomyelitis cases
may go on to develop
pediatric multiple
sclerosis or
h Over 95% of pediatric

multiple sclerosis
cases present with a
relapsing-remitting
course, and children
experience more
frequent relapses than
adults in the first few
years of disease.
history of untreated ADEM in most

children is one of gradual improvement over several weeks, with 50% to
70% of patients experiencing full recovery.26 Recovery may depend in
part on antecedent infections,27 with
preceding rubella and varicella infections (29% to 33%) being associated
with a worse outcome than cases without a defined infection (70%). Other
studies have similar findings,16Y18,23
with 8% to 30% experiencing residual
focal neurologic deficits and 4% to
30% having residual behavioral or
cognitive problems. Behavioral problems are most prominent in children
less than 5 years old with ADEM. Residual cognitive deficits include poor
visuospatial/visuomotor function, even
in those with fully resolved lesions
on MRI.28,29
Children with ADEM are at higher
risk of developing chronic or recurrent demyelination than the general
population; however, they appear to
be at lower risk than those with CIS.
Between 6% and 29% of ADEM cases
were found to develop MS in longitudinal follow-up.8,9 Lower conversion
rates were found when stricter definitions for ADEM, requiring the presence
of encephalopathy, were applied.1
MULTIPLE SCLEROSIS
MS affects over 400,000 people in the
United States and usually starts in
early adulthood. However, over the
past decade it has been increasingly
recognized that MS can present in
childhood or adolescence. In the medical literature, the youngest age of
onset of MS is 2 years; however, the
majority of children are diagnosed in
their early teens. Studies have estimated the incidence of pediatric MS
as between 0.18 and 0.51/100,000/
year.17,30Y32 Of adult patients with
MS, 3% reported a first attack in
childhood.33
1036
Children with MS overwhelmingly experience a relapsing-remitting course at

onset. Primary progressive MS is extremely rare. Children with MS have
recently been shown to experience annualized relapse rates 2 to 3 times that
of adults with MS during the first 3 years
of disease.34 Moreover, recovery from
relapses appears to be more rapid in
children than in adult MS patients
(mean time of relapse-related symptoms 4.3 weeks in pediatric MS versus
6 to 8 weeks in adult MS.35
Common presenting symptoms of
pediatric MS include optic neuritis,
sensory deficits, and cranial nerve or
brainstem symptoms, as well as gait
disorders. Children typically experience a polysymptomatic presentation,
although monosymptomatic presentations also occur. In contrast to adults,
children can also present with encephalopathy and seizures, likely representing the overlap of ADEM and MS.
In addition to physical disability, 30%
to 40% of children with MS can
demonstrate cognitive dysfunction early
in the disease course.36,37
The International Pediatric MS
Study group definition of MS1 stipulated that the McDonald 2005 criteria
for MS be applied to patients under
the age of 10 years, including MRI
criteria for dissemination in space and
in time.38,39 Neurologic events should
be separated by at least 3 months and
occur while off steroids for at least 1
month to prevent confusion with
steroid-withdrawal relapses. Although
this original definition stipulated that
an event of ADEM cannot contribute
to an MS diagnosis, several studies have
since suggested that ADEM may be the
presenting feature of MS in younger
children, necessitating that revised criteria be developed. More recently, the
McDonald 2010 MRI criteria were evaluated in children with an initial demyelinating event and were found to be
August 2013
highly sensitive and specific in children

older than 11 years and in those without an ADEM presentation at onset.40
These new developments have been incorporated into revised diagnostic
criteria for pediatric MS (Table 7-3).41
Evaluation of a child with suspected
MS includes neurologic examination,
MRI of the brain and spine, and potentially MRI of the orbits. Funduscopic
examination and visual evoked potential testing should be performed to
evaluate subclinical visual changes.6,7
CSF examination may be performed,
especially in younger children or in
those with progressive or atypical presentations. Serology to rule out other
mimics of MS typically includes antinuclear antibody, erythrocyte sedimentation rate, C-reactive protein,
angiotensin-converting enzyme level
and chest x-ray, folate, vitamin B12 levels,
and thyroid-stimulating hormone. Testing for other disorders should be
considered on a case-by-case basis, as
TABLE 7-3
discussed in the differential diagnosis

section below.
All patients with suspected MS
should undergo gadolinium-enhanced
MRI of the brain and spine. Similar to
adults with MS, MRI in children with
MS shows discrete ovoid T2 and fluidattenuated inversion recovery (FLAIR)
hyperintensities involving the white
matter, with a predilection for the
periventricular regions (Case 7-3). A
characteristic pattern involves such
lesions oriented perpendicularly to
the corpus callosum called Dawson
fingers, which are shown especially well
on sagittal FLAIR sequences. When applied to children, adult MRI MS diagnostic criteria appear to be less sensitive,
reflecting an overall lower disease burden in a pediatric population.42 Younger
children with MS (aged under 11 years)
may present with atypical MRI features,
rendering diagnosis challenging and
possibly delaying the initiation of preventive therapies.42 Brain lesions in
International Pediatric MS Study Group (IPMSSG) 2012 Updated

Criteria for Pediatric Multiple Sclerosisa
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.
1037
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.
these children may be large, with poorly

defined borders, and are frequently confluent at disease onset. Such T2-bright
foci in younger children may vanish on
repeat scans, unlike those seen in
teenagers or adults. This suggests that
the disease processes in the developing
brain may be different from those in
older patients43 or that the reparative
and compensatory mechanisms may be
different.
CSF examination typically shows
white blood cell counts that range
from 0 to 50 cells/2L with a lymphocytic predominance. The CSF profile
in childhood-onset MS may vary
by age. Children under 11 years of
age can have more neutrophils in the
1038
CSF than older children.44 Protein

levels may be slightly elevated; however, glucose levels are normal. Interestingly, the absence of neutrophils in
the CSF at onset is predictive of an
earlier second neurologic episode. Although one study reports oligoclonal
bands to be present in the CSF of up
to 92% of children with MS,45 this may
be dependent upon laboratory, disease
duration, and age.
The differential diagnosis of pediatric MS includes tumor, other autoimmune disorders, infection, vascular
disorders, nutritional disorders, metabolic disorders, leukodystrophies, and
mitochondrial disorders (Table 7-2).
Patients presenting with white matter
August 2013
lesions should be classified into those

with static versus progressive disorders. Perinatal hypoxic ischemic injury
is a consideration for children with
long-standing static white matter disorders. Children with progressive neurologic deficits should be fully evaluated
for structural, vascular, as well as
metabolic defects. This evaluation
should include a dermatologic examination for stigmata of neurofibromatosis, tuberous sclerosis, Lyme disease,
systemic lupus erythematosus, Fabry
disease, and Behcet disease. NMO
(Devic disease) should be considered,
particularly in cases with optic neuritis.
Complicated migraine, antiphospholipid syndrome, cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL), CNS vasculitis, and
arteriovenous malformation should be
considered in cases where headache is
prominent. Basal ganglia lesions may
suggest Leigh disease, Wilson disease,
post-streptococcal syndromes,
histiocytosis, and moyamoya disease.
Friedrich ataxia and the inherited
spinocerebellar ataxias should be considered in cases with predominant
cerebellar deficits. The presence of
white matter lesions with a peripheral
neuropathy bring up the considerations
of adrenomyeloneuropathy, Krabbe disease, metachromatic leukodystrophy,
and mitochondrial disorders.
As with adult MS patients, acute
attack-related care in children with MS
typically involves administration of IV
corticosteroids.46 The typical steroid
and dose administered is methylprednisolone 20 mg/kg/d to 30 mg/kg/d in
children under 40 kg, or a maximum of
1g daily for 3 to 7 days. We typically do
not use a prednisone taper for children
with an established diagnosis of MS.
IVIg at a dose of 0.4 g/kg/day for 5 days
or plasma exchange (5 to 7 exchanges)
are employed in refractory cases.
Interferon-" subcategories and

glatiramer acetate have been used as
prophylactic therapy in children and
are considered standard first-line therapies for pediatric MS.47 Available studies have shown that both treatments
are relatively safe, and the side effect
profile is similar to that in adults. Although most studies are retrospective
observational studies, some efficacy in
terms of relapse rate reduction has
been observed. Typical side effects of
the interferon-" subcategories include
postinjection flulike symptoms and
myalgia, headaches, depression, increased liver function test results, and,
rarely, suppression of white blood cell
counts. Side effects of glatiramer acetate include injection site reactions,
lymphadenopathy, and, rarely, immediate postinjection anxiety syndromes.
The definition of treatment failure is
not uniform across clinicians and centers. However, evidence of ongoing
relapses, MRI activity, and disability
accrual indicates the need to change
treatment. However, few studies describe the use of second-line treatments
in children with MS. Refractory disease
has been treated with cyclophosphamide as either pulse or induction
therapy,48 and with natalizumab.49 Although natalizumab was effective in
controlling relapse rates in very active
cases, the risks of progressive multifocal leukoencephalopathy and other
serious side effects in children require
further assessment. Evaluation of new
therapies in the pediatric population is
now mandated, introducing the opportunity for robust clinical trials in
pediatric MS.47 However, this small
population requires close international
cooperation to ensure completion of
promising studies.
Pediatric MS is a lifelong chronic
disease, and along with relapses and
disease progression, patients may experience a variety of chronic symptoms,
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.
1039

KEY POINTS
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.
1040
including fatigue, depression, bladder

urgency or retention, bowel constipation or dyssynergy, and neuropathic
pain. Many of these symptoms may be
ameliorated with symptomatic treatments. In addition, evaluation by other
specialists, including urologists, pain
clinicians, neuro-ophthalmologists,
psychiatrists, and rehabilitation specialists may play an important role in
the pediatric patients management
(see Case 7-1).
Several studies have demonstrated
that initial disease progression is
slower in patients with pediatric-onset
MS compared with patients with adultonset MS matched by geographic region.50 This likely represents a difference in accrual of locomotor disability,
although these studies also demonstrated that at any given age a patient
with pediatric-onset MS may have a
higher disability score than a patient
with adult-onset MS.
Cognitive dysfunction can present
early in the course of pediatric MS.
Studies have found that between 50%
and 60% of children are impaired in
one cognitive domain, and about onethird have impairment in two domains.
The areas that were most commonly
affected were complex attention, naming, delayed recall, and visual memory.
In contrast, verbal fluency and immediate recall were relatively intact.
Therefore, neuropsychological testing
should be considered for all children
with MS and related demyelinating
diseases, since symptoms may occasionally be subtle. Moreover, children
with identified cognitive issues may
benefit from the implementation of
an Individualized Educational Plan.
In some cases cognitive rehabilitation
may be warranted.51 Depression or
anxiety disorders are present in approximately half of children with
MS.36,37 These findings underline the
need for routine neuropsychological
testing and psychiatric evaluation as a

part of the management of childhood
MS. A tailored educational program
(504 Plan or Individualized Education
Plan) should be considered for children with significant cognitive or
physical deficits.
NEUROMYELITIS OPTICA
NMO, or Devic disease, is a subtype of
demyelinating disease characterized
by clinical episodes of optic neuritis
and transverse myelitis and the demonstration of contiguous lesions in the
spinal cord. 52 NMO-IgG targeting
aquaporin-4,53 is found in between
60% and 75% of adult subjects with
NMO and is included in the diagnostic
criteria for adults and children.1,52
The antibody appears to be specific
for the NMO phenotype in children
and is not found in those with
relapsing-remitting MS.54
NMO occurs rarely in children;
however, early recognition is important for the initiation of appropriate
treatment. NMO-IgG is less often
found in children meeting diagnostic
criteria for NMO,54 although longitudinal studies evaluating the conversion rates are lacking.
In one series of 88 children who
tested positive for NMO-IgG, 64 (73%)
were nonwhites, with 20 (23%) of
African ethnicity.55 Median age at symptom onset was 12 years (range 4 to 18
years), and 88% of the children were
girls. Additional autoantibodies were
detected in 57 of 75 patients (76%),
and 16 of 38 (42%) had a coexisting
autoimmune disorder (eg, systemic
lupus erythematosus, Sjo
gren syndrome, juvenile rheumatoid arthritis,
Graves disease).55
Children with NMO can present
with either optic neuritis or transverse
myelitis. In addition, 45% of children
had episodic cerebral symptoms (eg,
encephalopathy, ophthalmoparesis,
August 2013
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.
ataxia, seizures, intractable vomiting,

hiccups).55 Encephalopathic presentations of NMO can resemble ADEM,
and NMO should be kept in mind in
patients presenting with ADEM. The
FIGURE 7-4
clinical symptoms of optic neuritis

include blurred vision, pain on eye
movement, and loss of color vision.
Typically, children may report eye
pain and have frequent eye rubbing.
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.
1041

KEY POINTS
h Neuromyelitis
opticaYIgG may be
negative in some
pediatric patients
with a clinical
presentation of
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.
1042
Transverse myelitis may present with

upper or lower extremity weakness or
numbness. Gait may be also affected,
and bowel or bladder retention or
incontinence is common. Painful sensations in the lower extremities and a
bandlike sensation around the torso
can occur. The current diagnostic
definitions for pediatric NMO include
the presence of simultaneous or sequential optic neuritis and transverse
myelitis and two of the following: (1)
brain lesions characteristic of NMO,
(2) longitudinally extensive transverse
myelitis, and (3) NMO-IgG.1,41
Diagnostic evaluation of suspected
NMO includes serum NMO-IgG, as
well as testing employed in MS (Table
7-1). Additionally, evaluation for other
autoimmune disorders including systemic lupus erythematosus (eg, rheumatologic examination, antinuclear
antibody, erythrocyte sedimentation
rate), Sjo
gren syndrome, rheumatoid
arthritis, and autoimmune thyroid disease should be considered, since
these disorders can occur concomitantly with NMO.55 Rarely, NMO-IgG
may be positive in the CSF in the
absence of serum antibody,56 and CSF
testing should be considered in cases
with high clinical suspicion. CSF testing typically shows elevations in white
blood cells (5 to 600) with approximately
equal lymphocyte and neutrophil proportions, as well as elevated protein
levels.55 CSF oligoclonal band testing is
typically negative. MRI of the brain can
demonstrate lesions in aquaporin-4Yrich
areas, including the periaqueductal gray,
subcortical white matter, and the
hypothalamus (Figure 7-4),57 which
are distinct from the typical MS brain
lesion distribution (Case 7-4). More
recently, cloudlike enhancement has
been described in subjects with NMO58
and anecdotally reported in pediatric
NMO cases. Spinal cord MRI typically
demonstrates longitudinally extensive
lesions extending over three or more

segments; however, children with
monophasic disease of transverse myelitis can also have this feature.11 Optic
neuritis may be diagnosed clinically,
and supporting studies include funduscopic examination, visual evoked
potential testing, and orbital MRI.
The differential diagnosis of NMO
largely includes MS and ADEM. Leber
hereditary optic neuropathy and vitamin B12 deficiency may be considered
in cases of chronic optic neuropathy.
Systemic lupus erythematosus, adrenoleukodystrophy, human T-cell lymphocytic virus I infection, and ischemia
should be considered for transverse
myelitis presentations.
No US Food and Drug AdministrationY
approved treatments for NMO exist.
The key to NMO treatment is aggressive treatment of attacks in order to
prevent deficits. IV steroids are typically used for acute attacks, and typical
dosing is 20 mg/kg/d to 30 mg/kg/d (up
to 1 g/d) for 3 to 5 days. Plasmapheresis
may be used as a first-line or secondline treatment for acute attacks, and
particularly for attacks refractory to
steroid treatment. Five exchanges are
generally administered every other
day. NMO titers can be reduced after
plasmapheresis. IVIg (up to 2 g/kg total
dose divided into two to five daily
doses) has been used as third-line
therapy by some.59 Prophylactic NMO
therapies used in adults include
rituximab (anti-CD20 antibody), azathioprine, and mycophenolate mofetil.60
The same treatments have been used
in children with NMO, and one group
has described their approach with
initial immunosuppression with azathioprine or mycophenolate mofetil,
while refractory cases are treated with
rituximab.59
In one study investigating longerterm outcomes after attacks in children
with NMO, visual impairment persisted
August 2013
in 26 patients (54%), and 21 patients

(44%) had residual weakness.55 One series found that subjects with pediatriconset NMO had a longer time to
Expanded Disability Status Scale 4.0
and 6.0 milestones than those with
adult NMO, largely related to the increased incidence of transverse myelitis
in the adult NMO subjects.61 Cognitive
dysfunction and long-term outcomes
in children with NMO have not been
systematically studied.
SUMMARY
Over the past 10 years considerable
advances have occurred in the field of
pediatric demyelinating diseases that
have contributed to improved recognition, earlier diagnosis, and more
effective management of these young
patients. It should be recognized that
much work still needs to be done,
particularly in refining diagnostic
criteria, gaining objective data on safe
and effective treatments, and increasing research into the etiologies of
early-onset disease. These efforts may
contribute to the understanding of MS
pathogenesis in general. Given the
small number of subjects and the
importance of validating findings in
larger cohorts, further national and
international collaborative studies are
required in order to realize these goals.
REFERENCES
1. Krupp LB, Banwell B, Tenembaum S.
Consensus definitions proposed for pediatric
multiple sclerosis and related disorders.
Neurology 2007;68(16 suppl 2):S7YS12.
2. Wilejto M, Shroff M, Buncic JR, et al. The
clinical features, MRI findings, and outcome
of optic neuritis in children. Neurology
2006;67(2):258Y262.
optic neuritis. The Optic Neuritis Study

Group. N Engl J Med 1992;326(9):581Y588.
5. Absoud M, Cummins C, Desai N, et al.
Childhood optic neuritis clinical features
and outcome. Arch Dis Child 2011;96(9):
860Y862.
6. Pohl D, Rostasy K, Treiber-Held S, et al.
Pediatric multiple sclerosis: detection of
clinically silent lesions by multimodal
evoked potentials. J Pediatr 2006;149(1):
125Y127.
7. Yeh EA, Weinstock-Guttman B, Lincoff N,
et al. Retinal nerve fiber thickness in
inflammatory demyelinating diseases of
childhood onset. Mult Scler 2009;15(7):
802Y810.
8. Banwell B, Bar-Or A, Arnold DL, et al.
Clinical, environmental, and genetic
determinants of multiple sclerosis in children
with acute demyelination: a prospective
national cohort study. Lancet Neurol
2011;10(5):436Y445.
9. Mikaeloff Y, Suissa S, Vallee L, et al.
First episode of acute CNS inflammatory
demyelination in childhood: prognostic
factors for multiple sclerosis and disability.
J Pediatr 2004;144(2):246Y252.
10. Pidcock FS, Krishnan C, Crawford TO, et al.
Acute transverse myelitis in childhood:
center-based analysis of 47 cases. Neurology
2007;68(18):1474Y1480.
11. Thomas T, Branson HM, Verhey LH, et al.
The demographic, clinical, and magnetic
resonance imaging (MRI) features of
transverse myelitis in children. J Child
Neurol 2012;27(1):11Y21.
12. Defresne P, Meyer L, Tardieu M, et al.
Efficacy of high dose steroid therapy in
children with severe acute transverse
myelitis. J Neurol Neurosurg Psychiatry
2001;71(2):272Y274.
13. Lahat E, Pillar G, Ravid S, et al. Rapid
recovery from transverse myelopathy in
children treated with methylprednisolone.
Pediatr Neurol 1998;19(4):279Y282.
14. Defresne P, Hollenberg H, Husson B, et al.
Acute transverse myelitis in children:
clinical course and prognostic factors.
J Child Neurol 2003;18(6):401Y406.
3. Morales DS, Siakowski RM, Howard CW,

Warman R. Optic neuritis in children. J
Ophthalmic Nurs Technol
2000;19(6):270Y274; quiz 275Y276.
15. Weinshenker BG, Wingerchuk DM,

Vukusic S, et al. Neuromyelitis optica
IgG predicts relapse after longitudinally
extensive transverse myelitis. Ann Neurol
2006;59(3):566Y569.
4. Beck RW, Cleary PA, Anderson MM Jr,

et al. A randomized, controlled trial of
corticosteroids in the treatment of acute
16. Leake JA, Albani S, Kao AS, et al.

Acute disseminated encephalomyelitis
in childhood: epidemiologic, clinical and
1043
laboratory features. Pediatr Infect Dis J

2004;23(8):756Y764.
17. Pohl D, Hennemuth I, von Kries R,
Hanefeld F. Paediatric multiple sclerosis and
acute disseminated encephalomyelitis in
Germany: results of a nationwide survey.
Eur J Pediatr 2007;166(5):405Y412.
30. Banwell B, Kennedy J, Sadovnick D, et al.

Incidence of acquired demyelination of the
CNS in Canadian children. Neurology
2009;72(3):232Y239.
18. Tenembaum S, Chamoles N, Fejerman N.

Acute disseminated encephalomyelitis:
a long-term follow-up study of 84
pediatric patients. Neurology 2002;59(8):
1224Y1231.
31. Langer-Gould A, Zhang JL, Chung J, et al.

Incidence of acquired CNS demyelinating
syndromes in a multiethnic cohort
of children. Neurology 2011;77(12):
1143Y1148.
19. Amit R, Glick B, Itzchak Y, et al. Acute severe

combined demyelination. Childs Nerv Syst
1992;8(6):354Y356.
32. Absoud M, Lim MJ, Chong WK, et al.

Paediatric acquired demyelinating
syndromes: incidence, clinical and magnetic
resonance imaging features. Mult Scler
2012;19(1):76Y86.
20. Erazo-Torricelli R. Acute disseminated

encephalomyelitis in children [in Spanish].
Rev Neurol 2006;42(suppl 3):S75YS82.
21. Marchioni E, Marinou-Aktipi K, Uggetti C,
et al. Effectiveness of intravenous
immunoglobulin treatment in adult
patients with steroid-resistant monophasic
or recurrent acute disseminated
encephalomyelitis. J Neurol 2002;249(1):
100Y104.
33. Chitnis T, Glanz B, Jaffin S, Healy B.

Demographics of pediatric-onset multiple
sclerosis in an MS center population from
the Northeastern United States. Mult Scler
2009;15(5):627Y631.
34. Gorman MP, Healy BC, Polgar-Turcsanyi M,
Chitnis T. Increased relapse rate in
pediatric-onset compared with adult-onset
multiple sclerosis. Arch Neurol 2009;66(1):
54Y59.
22. Khurana DS, Melvin JJ, Kothare SV, et al.

Acute disseminated encephalomyelitis in
children: discordant neurologic and
neuroimaging abnormalities and response
to plasmapheresis. Pediatrics 2005;116(2):
431Y436.
35. Ruggieri M, Iannetti P, Polizzi A, et al.

Multiple sclerosis in children under 10 years
of age. Neurol Sci 2004;25(suppl 4):
S326YS335.
23. Dale RC, de Sousa C, Chong WK, et al.

Acute disseminated encephalomyelitis,
multiphasic disseminated encephalomyelitis
and multiple sclerosis in children. Brain
2000;123(pt 12):2407Y2422.
36. Julian L, Serafin D, Charvet L, et al.

Cognitive impairment occurs in children
and adolescents with multiple sclerosis:
results from a United States network. J Child
Neurol 2013;28(1):102Y107.
24. Mader I, Wolff M, Niemann G, Kuker W.

Acute haemorrhagic encephalomyelitis
(AHEM): MRI findings. Neuropediatrics
2004;35(2):143Y146.
37. Amato MP, Goretti B, Ghezzi A, et al.

Cognitive and psychosocial features of
childhood and juvenile MS. Neurology
2008;70(20):1891Y1897.
25. Payne ET, Rutka JT, Ho TK, et al. Treatment

leading to dramatic recovery in acute
hemorrhagic leukoencephalitis. J Child
Neurol 2007;22(1):109Y113.
38. McDonald WI, Compston A, Edan G, et al.

Recommended diagnostic criteria for
multiple sclerosis: guidelines from the
International Panel on the diagnosis of
multiple sclerosis. Ann Neurol 2001;50(1):
121Y127.
26. Tenembaum S, Chitnis T, Ness J, et al. Acute

disseminated encephalomyelitis. Neurology
2007;68(16 suppl 2):S23YS36.
27. Idrissova Zh R, Boldyreva MN, Dekonenko EP,
et al. Acute disseminated encephalomyelitis
in children: clinical features and HLA-DR
linkage. Eur J Neurol 2003;10(5):537Y546.
28. Hahn CD, Miles BS, MacGregor DL, et al.
Neurocognitive outcome after acute
disseminated encephalomyelitis. Pediatr
Neurol 2003;29(2):117Y123.
29. Hynson JL, Kornberg AJ, Coleman LT, et al.
Clinical and neuroradiologic features of
1044
acute disseminated encephalomyelitis

in children. Neurology 2001;56(10):
1308Y1312.
39. Polman CH, Reingold SC, Edan G, et al.

Diagnostic criteria for multiple sclerosis:
2005 revisions to the McDonald Criteria.
Ann Neurol 2005;58(6):840Y846.
40. Sadaka Y, Verhey LH, Shroff MM, et al. 2010
McDonald criteria for diagnosing pediatric
multiple sclerosis. Ann Neurol 2012;72(2):
211Y223.
41. Krupp LB, Tardieu M, Amato MP, et al;
the International Pediatric Multiple Sclerosis
Study Group. International Pediatric
August 2013
Multiple Sclerosis Study Group criteria

for pediatric multiple sclerosis and
immune-mediated central nervous system
demyelinating disorders: revisions to
the 2007 definitions [published online
ahead of print April 9. 2013]. Mult Scler.
doi: 10.1177/1352458513484547.
42. Hahn CD, Shroff MM, Blaser SI, et al. MRI
criteria for multiple sclerosis: evaluation in a
pediatric cohort. Neurology 2004;62(5):
806Y808.
43. Chabas D, Castillo-Trivino T, Mowry EM,
et al. Vanishing MS T2-bright lesions
before puberty: a distinct MRI phenotype?
Neurology 2008;71(14):1090Y1093.
44. Chabas D, Ness J, Belman A, et al. Younger
children with MS have a distinct CSF
inflammatory profile at disease onset.
Neurology 2010;74(5):399Y405.
45. Pohl D, Rostasy K, Reiber H, Hanefeld F.
CSF characteristics in early-onset multiple
sclerosis. Neurology 2004;63(10):1966Y1967.
46. Banwell B. Treatment of children and
adolescents with multiple sclerosis. Expert
Rev Neurother 2005;5(3):391Y401.
47. Chitnis T, Tenembaum S, Banwell B, et al.
Consensus statement: evaluation of new
and existing therapeutics for pediatric
multiple sclerosis. Mult Scler 2012;18(1):
116Y127.
51. Portaccio E, Goretti B, Zipoli V, et al.

Cognitive rehabilitation in children and
adolescents with multiple sclerosis. Neurol
Sci 2010;31(suppl 2):S275YS278.
52. Wingerchuk DM, Lennon VA, Pittock SJ,
et al. Revised diagnostic criteria for
neuromyelitis optica. Neurology 2006;
66(10):1485Y1489.
53. Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG
marker of optic-spinal multiple sclerosis
binds to the aquaporin-4 water channel.
J Exp Med 2005;202(4):473Y477.
54. Banwell B, Tenembaum S, Lennon VA,
et al. Neuromyelitis optica-IgG in
childhood inflammatory demyelinating
CNS disorders. Neurology 2008;70(5):
344Y352.
55. McKeon A, Lennon VA, Lotze T, et al. CNS
aquaporin-4 autoimmunity in children.
Neurology 2008;71(2):93Y100.
56. Klawiter EC, Alvarez E 3rd, Xu J, et al.
NMO-IgG detected in CSF in seronegative
neuromyelitis optica. Neurology 2009;
72(12):1101Y1103.
57. Pittock SJ, Lennon VA, Krecke K, et al. Brain
abnormalities in neuromyelitis optica. Arch
Neurol 2006;63(3):390Y396.
58. Ito S, Mori M, Makino T, et al. Cloud-like
enhancement is a magnetic resonance
imaging abnormality specific to neuromyelitis
optica. Ann Neurol 2009;66(3):425Y428.
48. Makhani N, Gorman MP, Branson HM, et al.

Cyclophosphamide therapy in pediatric
multiple sclerosis. Neurology 2009;72(24):
2076Y2082.
59. Lotze TE, Northrop JL, Hutton GJ, et al.

Spectrum of pediatric neuromyelitis optica.
Pediatrics 2008;122(5):e1039Ye1047.
49. Ghezzi A, Pozzilli C, Grimaldi LM, et al.

Safety and efficacy of natalizumab in
children with multiple sclerosis. Neurology
2010;75(10):912Y917.
60. Kimbrough DJ, Fujihara K, Jacob A, et al.

Treatment of neuromyelitis optica: review
and recommendations. Mult Scler Relat
Disord 2012;1(4):180Y187.
50. Renoux C, Vukusic S, Mikaeloff Y, et al.

Natural history of multiple sclerosis with
childhood onset. N Engl J Med 2007;356(25):
2603Y2613.
61. Collongues N, Marignier R, Zephir H, et al.

Long-term follow-up of neuromyelitis optica
with a pediatric onset. Neurology
2010;75(12):1084Y1088.
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Review Article

Continuum (Minneap Minn) 2013;19(4):10231045.

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Pediatric Demyelinating Diseases

Paradigm for presenting symptoms of demyelinating disease in children.

(2) alteration in consciousness (eg,

patient and the parent. Sometimes

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of the demyelinating symptoms, symptomatic treatment, and, in the cases of

tients.2 Bilateral involvement has been

h Typical clinically isolated

h Optic neuritis in children

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Pediatric Demyelinating Diseases

h The presence of brain

h The mean age of acute

neuropathy, especially when pain on

potentials.6,7 In some cases, adaptive

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cohort of 38 patients, 58% had longitudinally extensive transverse myelitis

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Pediatric Demyelinating Diseases

ing event.9,15 As opposed to complete

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Continuum (Minneap Minn) 2013;19(4):10231045

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Pediatric Demyelinating Diseases

and older forms of the measles vaccine.

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TABLE 7-1 Typical Evaluation for Common Pediatric Demyelinating Diseases

Cervical and thoracic spine MRI

and bacterial cultures; and CSF viral

underlying infection. A large number

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Pediatric Demyelinating Diseases

diagnostic evaluation on a case-bycase basis (Table 7-2).

typical dose of methylprednisolone is

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TABLE 7-2 Differential Diagnosis of Pediatric Demyelinating Diseases

MRI; MRS; PET imaging

MRI; MRS; PET imaging; tumor survey

Antinuclear antibody (ANA) (extractable nuclear antibodies

Antiphospholipid antibodies (anti-cardiolipin, -2 glycoprotein

Rheumatoid factor; erythrocyte sedimentation rate;

Examination for orogenital ulcers; pathergy test

Angiotensin-converting enzyme level serum and CSF; chest

ANA; anti-Ro (SSA) antibody; anti-La (SSB) antibody

Antineutrophil cytoplasmic antibody; rheumatologic evaluation

CSF cytology with B-cell subsets; immunohistochemistry

Histiocytes on peripheral blood smear or bone marrow, or

Antithyroid peroxidase; antithyroglobulin antibodies in serum;

Anti-N-methyl-D-aspartate (NMDA) receptor and anti-voltage-gated

Lyme antibody in serum and CSF PCR in endemic areas

HIV testing; screening for opportunistic infections

Herpes simplex virus

Herpes simplex virus PCR in CSF

Human T-cell lymphotropic

Human T-cell lymphotropic virus type 1 antibody in CSF

JC virus PCR in CSF

Serum and CSF Venereal Disease Research Laboratory (VDRL) test

Serology for Bartonella henselae

Histopathologic study or PCR; lymph node biopsy with Gram stain

Continuum (Minneap Minn) 2013;19(4):10231045

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.