Pediatric Demyelination.16

Review Article
Pediatric Demyelination
Sona Narula, MD; Brenda Banwell, MD
ABSTRACT
Purpose of Review: This review summarizes a general approach to pediatric
demyelination as well as specific features of each of the acquired demyelinating
syndromes to help clinicians in their evaluation of children with these disorders.
Case studies are included to illustrate the expanding phenotype of many of
these syndromes.
Recent Findings: With the creation of consensus definitions for the pediatric
acquired demyelinating syndromes, recognition of demyelination in children has
increased, as has understanding of the clinical and radiologic features, prognosis,
and response to treatment. Collaborative studies and multicenter clinical trials are
ongoing and needed to appropriately evaluate emerging therapies for some of the
chronic demyelinating disorders, such as multiple sclerosis and neuromyelitis optica
(NMO) spectrum disorder.
Summary: This review will aid the clinician in identifying key features of the
pediatric acquired demyelinating syndromes and highlights a general approach for
the diagnosis and treatment of these disorders.
Address correspondence to
Dr Sona Narula, Colket
Translational Research
Building, 3501 Civic Center
Blvd, Philadelphia, PA 19104,
narulas@email.chop.edu.
Relationship Disclosure:
Dr Narula has received
fellowship support from the
National Multiple Sclerosis
Society. Dr Banwell serves as
editor-in-chief of Multiple
Sclerosis and Related
Disorders and as a consultant
for Novartis AG. Dr Banwell
receives research support
from the Multiple Sclerosis
Society of Canada.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Drs Narula and Banwell discuss
the unlabeled/investigational use
of glatiramer acetate, interferon
beta, and natalizumab
for the treatment of
pediatric multiple sclerosis.
* 2016 American Academy
of Neurology.
Continuum (Minneap Minn) 2016;22(3):897915.
INTRODUCTION
Acquired demyelinating syndromes are
immune-mediated central nervous system (CNS) disorders that can be either
monophasic or relapsing. These disorders include acute disseminated encephalomyelitis (ADEM), isolated or
relapsing optic neuritis, idiopathic
transverse myelitis, multiple sclerosis
(MS), and neuromyelitis optica (NMO)
spectrum disorders. While these disorders may be characterized by overlapping clinical symptoms, the prognosis,
treatment, and characteristic radiographic features of each entity differ.
The International Pediatric Multiple Sclerosis Study Group, which consists of
more than 150 expert clinicians and
researchers from over 40 countries
worldwide, initially proposed definitions for these acute demyelinating
syndromes in 20071 and provided updated criteria in 2013,2 which are summarized in Table 11-1.3Y5
Continuum (Minneap Minn) 2016;22(3):897915
Acquired demyelinating syndromes

can be categorized by the extent of
CNS inflammation during an episode. For
instance, events can be termed monofocal, meaning that the neurologic
examination localizes findings to only
a single area of the CNS, or multifocal,
which reflects that multiple sites of
acute CNS inflammation exist. Acquired demyelinating syndromes can
also be categorized based on whether
they are monophasic or relapsing,
although predicting whether a child is
likely to have a monophasic course or
is in fact experiencing the first attack of
a chronic demyelinating disease remains
challenging. As a result, all children with
acute demyelinating syndromes should
be investigated with a standardized
workup and should receive ongoing
clinical and imaging follow-up so that
any accrual of disease activity can be
appropriately addressed. Structured
follow-up is especially important in the
www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
897
Syndromes
TABLE 11-1 Summary of the Proposed Definitions for Acquired Demyelinating
and Their Associated Key Clinical and Radiologic Featuresa
Diagnosis
Definition
Key Clinical Features
Key MRI Features
Monophasic acute
disseminated
encephalomyelitis
(ADEM)2
An initial clinical attack

with a presumed
inflammatory demyelinating
cause, with acute or
subacute onset that affects
multifocal areas of the
central nervous system (CNS)
Multifocal neurologic
symptoms
Bilateral asymmetric large T2

hyperintense lesions in white
matter and deep gray nuclei
Multiphasic ADEM2
Clinically isolated
syndrome2
Pediatric MS2
Encephalopathyb
After 3 months from
symptom onset, no new
clinical symptoms or MRI
abnormalities develop
ADEM followed by a new

clinical attack also meeting
criteria for ADEM
characterized either by
new symptoms/areas of
CNS involvement or by
reemergence of initial clinical
symptoms; attack occurs at
least 3 months after initial
ADEM episode
Multifocal neurologic
symptoms
An initial CNS inflammatory

demyelinating event that
does not meet criteria for
ADEM, multiple sclerosis
(MS), or a neuromyelitis
optica (NMO) spectrum
disorder as applied using
baseline features and first
MRI; transverse myelitis and
optic neuritis are subtypes
Monofocal or multifocal
presentations
Clinical or radiographic
evidence of lesion
dissemination in both time
and space4; one event that
fulfills criteria initially for
ADEM followed by a
second non-ADEM event at
least 3 months later
associated with new MRI
lesions demonstrating 2010
McDonald criteria for
dissemination in space4
Relapsing disease course
Encephalopathyb
T1 hypointense lesions
are rare
MRI does not demonstrate

accrual of silent lesions
between attacks
At the time of each ADEM
event, MRI may demonstrate
new areas of involvement
distinct from the initial
ADEM attack
Original lesions may have
enlarged or resolved
Can involve any area of
the CNS
Encephalopathy is
not present
Monofocal or multifocal
features
New T2 and T1 lesions on

repeat imaging
Periventricular, juxtacortical,
brainstem, and spinal cord
lesions are highly typical and
contribute to diagnosis
T1 hypointense lesions
commonly present at onset
and can accrue over time
Continued on page 899
898
June 2016
Syndromes
TABLE 11-1 Summary of the Proposed Definitions for Acquired Demyelinating
and Their Associated Key Clinical and Radiologic Featuresa Continued from page 898
Diagnosis
Definition
Key Clinical Features
Key MRI Features
NMO spectrum
disorder5
Diagnostic criteria for an NMO

spectrum disorder with
antiYaquaporin-4
immunoglobulin seropositivity:
Monophasic (ie, single

optic neuritis and
transverse myelitis
episodes)
Longitudinally extensive
spinal cord lesions
1. At least one core clinical

characteristic
Relapsing NMO
(recurrent optic neuritis
and transverse myelitis
episodes)
2. Detection of the
antiYaquaporin-4
immunoglobulin using best
available method
3. Exclusion of alternative
diagnoses
Diagnostic criteria for an NMO
spectrum disorder without
antiYaquaporin-4
immunoglobulin seropositivity,
or if antiYaquaporin-4
immunoglobulin status
is unknown:
Core clinical features

include:
Increased T2 signal, swelling,

or gadolinium enhancement
of optic nerves
Brain lesions tend to be in
hypothalamic region,
brainstem, or in a pattern
not otherwise consistent
with MS
& Optic neuritis

& Acute myelitis
& Area postrema
syndrome: episode of
otherwise unexplained
hiccups or nausea
and vomiting
& Acute brainstem

syndrome
1. At least two core clinical

characteristics occurring as a
result of one or more clinical
attacks and meeting all of
the following requirements:
& At least one core clinical
characteristic must be optic

neuritis, acute myelitis with
longitudinally extensive
transverse myelitis, or an
area postrema syndrome
& Dissemination in space

& Fulfillment of additional
& Symptomatic
narcolepsy or acute
diencephalic clinical
syndrome with NMO
spectrum disorderY
typical diencephalic
MRI lesions
& Symptomatic cerebral

syndrome with NMO
spectrum disorderY
typical brain lesions
MRI requirements, as
applicable
2. Negative test for

antiYaquaporin-4
immunoglobulin using best
available detection method,
or testing is unavailable
3. Exclusion of alternative
diagnoses
MRI = magnetic resonance imaging.
a
Modified with permission from Narula S, Banwell B, Wiley-Blackwell.3 B 2016 Wiley-Blackwell.
b
Encephalopathy is defined by behavioral change or alteration in consciousness (eg, confusion, excessive irritability, lethargy, coma) not
explained by fever.
899
KEY POINTS
h Acquired demyelinating
syndromes may
represent a monophasic
illness or may be the first
attack of a chronic
disease such as multiple
sclerosis or a
neuromyelitis optica
spectrum disorder.
h All children with

acquired demyelinating
syndromes are at risk for
future relapse, even if
their baseline MRI does
not demonstrate
features consistent with
multiple sclerosis or a
spectrum disorder, and
thus careful prospective
observation is required.
Such observation must
be alert to subtle
neurologic findings
(such as mild uniocular
visual loss or mild
sensory impairment)
that may be
underreported by very
young children.
h Red flags that suggest

an etiology other than
acute demyelination in
children include
demonstration of a
progressive course from
onset; evidence of
peripheral nervous
system involvement;
prominent psychiatric
symptoms; or ongoing
systemic symptoms
such as fever,
end-organ dysfunction,
or headache.
900
pediatric population as subtle neurologic symptoms, such as mild sensory

or visual disturbances, can be difficult to
describe and are likely underreported
by young children.
Before confirming a diagnosis of a
demyelinating syndrome, it is important to ensure that all mimics have
been excluded (Table 11-2). Red flags
that suggest an etiology other than
acute demyelination in children include
demonstration of a progressive course
from onset; evidence of peripheral
nervous system involvement; prominent
psychiatric symptoms; or ongoing systemic symptoms such as fever, endorgan dysfunction, or headache.
This review presents a general approach for evaluation of children with
acquired demyelination and highlights
specific clinical and radiologic features
of each of these disorders through discussion of clinical cases. Unique prognostic features and a therapeutic
approach for each of the disorders are
also presented.
DIAGNOSTIC EVALUATION
A detailed history is of utmost importance when evaluating a patient with a
possible acquired demyelinating syndrome. Aspects that require particular
focus include the characterization of
current symptoms, the time course of
symptom onset and progression, and
prior neurologic events. Common demyelinating symptoms that should be
specifically evaluated for include visual
loss due to optic neuritis (either unilateral or bilateral), limb weakness, sensory symptoms (paresthesia), bowel
and bladder dysfunction due to spinal
cord disease, and ataxia or cranial
nerve abnormalities due to brainstem
involvement. Demyelinating symptoms secondary to an acute attack
typically persist for at least 24 hours.
A complete neurologic examination
is important to localize acute neurologic deficits, which then permits as-
sessment of whether changes on the

MRI are clinically silent or not. Neurologic examination may also reveal features of a remote episode, such as optic
disc pallor, which insinuates that demyelination (either clinical or subclinical)
affecting the optic nerves has occurred
at some point.
Although a thorough neurologic examination is critical, identifying areas
of subclinical (asymptomatic) inflammation is also important in the evaluation
of an acquired demyelinating syndrome. MRI of the brain, orbits (in
patients with possible optic nerve involvement), and spinal cord should be
done when possible to determine the
extent of CNS inflammation and to
determine if any imaging patterns suggestive of either MS or an NMO spectrum disorder exist.
CSF analysis should be considered
in all children with suspected demyelination and always obtained if CNS infection is suspected. Cell counts, protein,
glucose, and a Gram stain and culture
should be obtained. An oligoclonal
band profile should also be obtained,
which requires simultaneous procurement of CSF and serum. CSF oligoclonal band testing is considered
positive if intrathecal synthesis of immunoglobulins leads to more than two
unique bands in CSF that are not
present in serum. In addition, CSF viral
studies and tests for paraneoplastic
antibodies and antiYaquaporin-4 antibody (serum and CSF) should be considered on an individual basis in
suspected cases of demyelination.
ACUTE DISSEMINATED
ENCEPHALOMYELITIS
ADEM is an acute CNS inflammatory
syndrome that is defined by encephalopathy (behavioral change, irritability,
or altered consciousness not attributable to concurrent fever or illness) and
June 2016
a
TABLE 11-2 Differential Diagnosis of Acute Demyelination in Children
Diagnostic Category
Characteristic Clinical Features

That May Be Present
Additional Investigations to
Consider (To Be Determined on
a Case-By-Case Basis)
Infectious (bacterial, viral, fungal,

or parasitic infections)
Herpesviruses; Epstein-Barr virus;
Mycoplasma; enterovirus;
neuroborreliosis; human
immunodeficiency virus;
neurosyphilis; tuberculosis;
human T-cell lymphotropic
virus type 1 (HTLV-1);
hepatitis A, B,
and C; Cryptococcus
Fever, meningismus, rash (such as

petechiae in bacterial meningitis or
vesicles in herpesviruses), systemic
evidence of infection,
alteration in mental status
Blood and CSF cell counts and

cultures, PCR testing for infection
in CSF, tuberculosis testing,
Lyme serologies
Persistent and prominent headache,

systemic evidence of vasculitis
Sedimentation rate, antinuclear

antibody profile, angiotensinconverting enzyme level, magnetic
resonance angiography (MRA) of
head, cerebral angiography, brain
biopsy, skin examination for
detection of papules or lesions
that may be amenable to biopsy in
cases of vasculopathy/vasculitis,
ophthalmologic examination to
evaluate for evidence of vasculitis
History of prior malignancy or

chemotherapy, systemic symptoms
(eg, weight loss, night sweats, fever)
CSF cytology, brain biopsy,

ophthalmologic examination
Encephalopathy, vital sign instability,

movement abnormalities,
psychiatric symptoms
Paraneoplastic antibody studies

from CSF and blood (including
antiYN-methyl-D-aspartate [NMDA]
receptor antibodies); consider
evaluation for underlying tumor
with scans of chest, abdomen, pelvis;
special attention should be given to
ovaries in suspected cases of
anti-NMDA receptor encephalitis
History of similarly affected

sibling; systemic signs of liver, skin,
renal, or bone marrow involvement;
persistent fever
Serum ferritin; triglycerides;

fibrinogen; soluble interleukin
2 receptor level; blood, CSF, and
bone marrow evaluation for
evidence of hemophagocytosis
Rheumatologic
Primary central nervous system
(CNS) angiitis, sarcoidosis, Sjogren
syndrome, systemic lupus
erythematosus, Behet syndrome,
Degos disease
Malignancy
CNS lymphoma, metastasis, glioma
Autoimmune encephalopathies
Limbic encephalitis
Macrophage activation syndromes

Hemophagocytic
lymphohistiocytosis
901
a
TABLE 11-2 Differential Diagnosis of Acute Demyelination in Children Continued from page 901
Characteristic Clinical Features

That May Be Present
Diagnostic Category
Additional Investigations to
Consider (To Be Determined on
a Case-By-Case Basis)
Metabolic or mitochondrial disease

Mitochondrial encephalomyopathy,
lactic acidosis, and strokelike
episodes (MELAS)
Symptomatic worsening with fever,

preexisting progressive neurologic
deterioration, developmental
delay, or cognitive dysfunction
Serum and CSF lactate/pyruvate,

magnetic resonance spectroscopy
(MRS); consider plasma amino
acids, urine organic acids,
ammonia, acylcarnitine profile,
mitochondrial genome analysis
Leber hereditary optic neuropathy
Recurrent vision loss
Genetic testing
Stroke
Neurologic symptoms can develop

over minutes to hours in acute
vascular events
MRI with diffusion-weighted

sequence, MRA
Sickle cell disease
History of pain crises, transient

neurologic symptoms, dactylitis,
acute chest syndrome, splenic
dysfunction
Hemoglobin electrophoresis
Moyamoya disease
Episodic decline with dehydration,

illness, blood pressure fluctuations
MRA, cerebral angiography
Cerebral autosomal dominant

arteriopathy with subcortical
infarcts and leukoencephalopathy
(CADASIL)
Progressive neurologic decline

occurs in CADASIL, cognitive and
psychiatric symptoms are common,
family history of migraines,
early-onset dementia, and strokes
NOTCH3 mutation
Complicated migraine
Headache associated with

neurologic symptoms
Consider MRI
Vitamin B12 deficiency
Consider in patients with recent

gastrointestinal surgeries (gastric
bypass), malabsorption disorders,
or eating disorders
Vitamin B12, methylmalonic acid,

homocysteine level, peripheral
blood smear
Folate deficiency
Consider in patients with poor

nutrition or alcoholism
Folate level
Vascular
Nutritional
CSF = cerebrospinal fluid; PCR = polymerase chain reaction.

a
Modified with permission from Narula S, Banwell B, Wiley-Blackwell.3 B 2016 Wiley-Blackwell.
multifocal neurologic signs.2 The clinical symptoms of ADEM often occur in

the context of a preceding viral illness,
although it is rare that a microbial
trigger is identified. Although ADEM is
most commonly a monophasic illness,
902
a multiphasic form (defined by two or

more events, each meeting criteria for
ADEM, and without MRI evidence of
subclinical new lesions between episodes)2 can rarely occur. If a patient
experiences subsequent relapses that
June 2016
do not meet criteria for ADEM, however, chronic demyelinating disorders

such as MS or an NMO spectrum disorder must be considered.
Although ADEM occurs in both
children and adults, it has been most
commonly reported in children aged
5 to 8 years.6Y8 Studies have reported
the incidence of ADEM to range from
0.07 per 100,000 to 0.64 per 100,000,
although the consensus definition of
ADEM was only applied in later studies.9Y12 As clinicians become more aware
of the consensus definition of ADEM,
incidence rates will be better estimated.
With regard to diagnostic workup,
brain MRI and CSF studies can provide
supporting diagnostic evidence. Cerebral white matter lesions in ADEM are
typically large and multifocal and have
poorly demarcated borders. Additional
lesions involving the deep gray matter structures are also often identified.2 Spinal cord lesions are reported
in approximately one-fourth of children
with ADEM6,13 and are typically longitudinally extensive (spanning more than
three spinal segments). Although ADEM
is an acute inflammatory process, many
patients do not have any areas of lesion
enhancement, and in a given patient
with enhancing lesions, only a small
number of areas of abnormality will
enhance.14 Unlike MS (where a preclinical disease phase with accrual of
focal lesions is likely), T1 hypointense
lesions are rare in ADEM, consistent
with the likelihood that ADEM is a
more acute response to a recent triggering exposure.
Since patients with ADEM are encephalopathic and generally appear ill,
CNS infection is almost always on the
differential, and procurement of CSF
is a priority. In typical cases of ADEM,
patients demonstrate a mild to moderate CSF lymphocytic pleocytosis and
a normal or mildly elevated CSF protein. Although detection of immunoContinuum (Minneap Minn) 2016;22(3):897915
globulins in CSF is somewhat dependent

on the technique used and the experience of the laboratory, oligoclonal bands
are typically negative in ADEM.15
Treatment
To date, no clinical trials have evaluated
therapeutic options for ADEM, and
treatment protocols have been based
on expert consensus opinion and observational studies. Typically, initial
treatment of ADEM consists of IV methylprednisolone at a dose of 20 mg/kg/d
to 30 mg/kg/d (up to 1 g/d) for 3 to
5 days. If clinical symptoms improve
but do not fully resolve, children are
often given an oral prednisone taper
(starting at 1 mg/kg/d and tapering
over 10 to 14 days). If symptoms are
severe despite treatment with corticosteroids, additional therapy with either
IV immunoglobulin (IVIg) or plasma
exchange should be initiated.
Although clinical symptoms of
ADEM can be severe acutely, children
often start to improve soon after treatment is initiated, and the majority of
patients recover fully within a period of
6 months. Despite the overall favorable
prognosis, some patients have been
reported to have minor residual cognitive and behavioral deficits.16
The overlap between demyelination
and autoimmune encephalitis has recently become an area of active study as
patients with antiYN-methyl-D-aspartate
(NMDA) receptor encephalitis have
been reported to have either preceding, subsequent, or simultaneous demyelinating syndromes (Case 11-1),17Y19
although the frequency with which
children with ADEM develop antiNMDA receptor encephalitis, and vice
versa, is unknown. It is important for
clinicians to recognize that these entities can occur in the same patient and
that each event should be treated and
evaluated appropriately.
KEY POINTS
h CSF examination
remains an important
diagnostic test and
should be considered in
all cases of suspected
demyelination,
especially if central
nervous system infection
is being considered.
h Acute disseminated
encephalomyelitis is an
acute central nervous
system inflammatory
syndrome that is
defined by
encephalopathy (not
attributable to
concurrent fever or
illness) and multifocal
neurologic signs.
h Acute disseminated
encephalomyelitis can
occur at any age, but
most commonly occurs
in school-aged children
(5 to 8 years of age),
and is a monophasic
illness in the majority
of patients.
h Despite the overall

favorable prognosis of
acute disseminated
encephalomyelitis, some
patients have been
reported to have minor
residual cognitive and
behavioral deficits.
h Patients with acquired

demyelinating syndromes
are also at risk for
concurrent or subsequent
antibody-associated
encephalopathies.
903
Case 11-1
A 3-year-old developmentally normal boy presented to the hospital with progressive sleepiness and
ataxia over 4 days. His parents reported that he had upper respiratory symptoms, low-grade fever,
and a diffuse erythematous rash about 1 week prior to presentation, all of which resolved. He had not
received recent vaccinations.
Upon initial examination, the patient was found to be afebrile. He was noted to be very lethargic and
was unable to appropriately answer questions because of sleepiness. He had a mild left hemiparesis and
was unable to walk independently because of ataxia. His reflexes were brisk throughout. MRI of the brain
revealed bilateral nonenhancing multifocal lesions involving the deep gray structures and white matter
(Figure 11-1). Lumbar puncture revealed a mild CSF pleocytosis (10 white blood cells/mm3, 84%
lymphocytes) and normal glucose and protein levels. CSF oligoclonal bands were negative. Viral studies,
including tests for herpesviruses and enterovirus, were also negative.
Imaging of the patient in Case 11-1. A, B, Axial fluid-attenuated inversion

recovery (FLAIR) MRI of a child with acute disseminated encephalomyelitis
(ADEM). Multifocal poorly defined white matter lesions are present in addition
to lesions involving the deep gray nuclei (arrows).
FIGURE 11-1
Panel A reprinted with permission from Narula S, Banwell B, Wiley-Blackwell. B 2016 Wiley-Blackwell.
After reviewing the clinical presentation, MRI, and CSF studies, the patient was given a diagnosis
of acute disseminated encephalomyelitis (ADEM) and subsequently began treatment with IV
methylprednisolone (30 mg/kg/d). His symptoms began to improve by the third day of treatment. He
completed 5 days of IV methylprednisolone and then was started on an oral prednisone taper (at a
starting dose of 1 mg/kg/d, tapered over 10 days).
The patient had completely returned to baseline by his follow-up visit 1 month after discharge.
A repeat brain MRI obtained 6 months after his hospitalization showed complete resolution of the
previously seen areas of T2 signal hyperintensity. The patient was followed closely over the next few
years and remained well until about 2 years later, when he presented with sudden behavioral change
and seizures. He was readmitted to the hospital where he became more encephalopathic and had
progressive speech disturbance, orofacial dyskinesia, and autonomic dysregulation with
904
June 2016
Continued from page 904

hypoventilation and tachycardia. A brain MRI was repeated and found to be normal. CSF studies
3
revealed a moderate pleocytosis (25 white blood cells/mm , 90% lymphocytes) and a mildly elevated
protein. Paraneoplastic antibodies were sent, and the antiYN-methyl-D-aspartate (NMDA) receptor
antibody was found to be positive in both CSF and serum. Surveillance imaging did not reveal evidence
of an underlying tumor. He was treated with IV methylprednisolone and IV immunoglobulin (IVIg)
with significant improvement of symptoms. He was subsequently transferred for rehabilitation, where
he continued to make steady progress and, ultimately, completely returned to baseline over the course
of 8 weeks.
Comment. This child presented with typical corticosteroid-responsive ADEM, followed by
anti-NMDA receptor encephalitis, highlighting an emerging awareness of patients with acquired
demyelination and either preceding, concurrent, or subsequent autoimmune encephalitis.
TRANSVERSE MYELITIS
Transverse myelitis is a spinal cord demyelinating syndrome characterized by
acute to subacute sensory, motor, or
autonomic symptomatology. In 2002,
the Transverse Myelitis Consortium
Working Group developed diagnostic
criteria for idiopathic acute transverse
myelitis that includes: (1) bilateral impairment of sensory, motor, or autonomic function; (2) demonstration of a
clearly defined sensory level; (3) exclusion of a compressive or infectious
etiology; (4) evidence of inflammation
with a CSF pleocytosis, elevated IgG
index, or MRI lesion enhancement;
and (5) progression to peak symptoms
within 4 hours to 21 days of symptom
onset.20 A complete cord syndrome
causes bilateral sensory, motor, and
autonomic impairment, while a partial
cord syndrome is diagnosed when less
complete involvement exists below
the level of the lesion. If a hyperacute
presentation occurs (maximal deficits
reached within 4 hours of onset), other
etiologies (especially vascular) must also
be considered.
Transverse myelitis can occur at any
age, with about 20% of all cases occurring in children.21 Within the pediatric population, a bimodal peak of
incidence occurs at 0 to 2 years of age
and 5 to 17 years of age.22 Aside from
paresthesia, numbness, and weakness,
other symptoms that suggest spinal cord

inflammation include bowel or bladder
dysfunction, acute respiratory failure, or
a Lhermitte symptom, which is an abnormal electrical or vibratory sensation that
radiates down the spine when a patient flexes his or her neck forward.
Radiologically, isolated transverse
myelitis in children is commonly characterized by a T2 hyperintense signal
abnormality involving the central cord
and surrounding white matter.23 If a
lesion is at least three vertebral segments
in length, it is considered to be longitudinally extensive. Although longitudinally extensive lesions are historically
considered to be a key feature of NMO
spectrum disorders, the majority of
children with isolated transverse myelitis also have longitudinally extensive
cord lesions.23 Enhancement of lesions
with gadolinium has been reported in
20% to 74% of patients,22,23 with this
variability possibly resulting from the
timing of the study relative to onset of
symptoms. Although it is exceedingly
rare, spinal cord imaging has also
occasionally been reported as normal
in some children with clinical symptoms consistent with transverse myelitis.22 Imaging such patients again a
few days later may be revealing.
KEY POINT
h Within the pediatric

population, a bimodal
peak of incidence for
transverse myelitis occurs
at 0 to 2 years of age and
5 to 17 years of age.
Treatment
Initial treatment of transverse myelitis consists of high-dose IV methylprednisolone
905
KEY POINT
h Transverse myelitis is a
serious illness, with risk
of incomplete recovery.
Failure to improve
promptly with IV
corticosteroids should
prompt use of
plasma exchange.
(20 mg/kg/d to 30 mg/kg/d, up to 1 g/d)

for 3 to 5 days. Class II evidence exists
that plasma exchange may be effective
in cases of transverse myelitis with fulminant demyelination in which symptoms worsen or do not improve with
3 to 5 days of high-dose IV methylprednisolone (Case 11-2).24 IVIg, cyclophosphamide, and rituximab have also
been used anecdotally in severe cases
with success.
Although many children with transverse myelitis improve rapidly with treat-
ment, the overall extent of recovery is

variable, and some children may require
long-term assistance for self-care activities and ambulation.22 Impaired bladder control and chronic pain are other
neurologic issues that can persist in
patients who have experienced isolated transverse myelitis.25 In a study that
identified prognostic factors for relapse
and disability, female sex and the presence of concurrent brain lesions were
associated with risk of relapse after the
episode of transverse myelitis.26 Factors
Case 11-2
A 7-year-old girl presented for evaluation of neck pain, left arm paresthesia, and new-onset right-sided
weakness. The neck pain and paresthesia had started about 2 weeks prior to presentation and had
progressively worsened. She was unable to walk independently because of the weakness in her right leg.
She had no preceding illness or trauma.
Upon arrival to the hospital, the patient had
a brain and spine MRI. Her brain MRI was
unremarkable. Her spine MRI revealed a T2
hyperintense nonenhancing lesion extending
from C1 to T3 (Figure 11-2). CSF studies were
notable for elevated protein (110 mg/dL) and
a pleocytosis (90 white blood cells/mm3). Viral
studies from the CSF were all negative. Serum
antiYaquaporin-4 immunoglobulin was
negative. Her ophthalmologic examination
was normal with no evidence of optic disc
swelling or pallor.
She began treatment with IV
methylprednisolone and noted only minimal
improvement after 3 days of treatment. As her
deficits remained severe, she began treatment
with plasma exchange. She received a total of
five exchanges, and her symptoms began to
improve. Her deficits improved slowly, and she
was able to walk independently about 2 weeks
after her admission to the hospital. She was
discharged to inpatient rehabilitation. She was
seen back in the neurology clinic 1 month after
her discharge from rehabilitation and was
completely back to baseline at that time.
Comment. This is a case of idiopathic
transverse myelitis that required plasma
FIGURE 11-2 Sagittal T2-weighted image of a patient
with idiopathic transverse myelitis with a
exchange in the setting of an inadequate
longitudinally extensive lesion (arrow).
response to initial treatment with high-dose
Notable cord swelling and edema is evident.
corticosteroids.
906
June 2016
that were associated with poor outcome

include female sex, presence of gadolinium enhancement, the absence of a
pleocytosis, the absence of a cervical or
cervical-thoracic lesion, and a severe
American Spinal Injury Association
(ASIA) scale (a clinical tool often used
to measure dysfunction in spinal cord
disease) at onset.26 Other studies have
shown that children with complete cord
syndromes or young age at onset and
those who reach maximal severity of
symptoms within 24 hours are less
likely to recovery fully.27
While the clinical characteristics,
imaging findings, and prognosis described above are typical of cases of
isolated inflammatory transverse myelitis, a particular subtype of myelitis,
acute flaccid myelitis, deserves special
mention. Acute flaccid myelitis describes
patients who present with acute limb
weakness with primarily gray matter involvement on spinal cord imaging. Over
the past few years, clusters of patients
with acute flaccid myelitis have been
reported throughout the United States
and other countries,28,29 with the most
recent cluster occurring in the fall of
2014 and affecting children. While many
of these cases have been associated
with concomitant enteroviral infections
(of the D68 or 71 subtype), researchers
have not yet been able to prove these
viruses to be directly pathogenic.
With the most recent pediatric cluster of acute flaccid myelitis, the Centers
for Disease Control and Prevention
(CDC) performed surveillance throughout the United States to better describe
the features and prognosis of the
cohort involved. A case was defined as
acute onset of focal limb weakness occurring on or after August 1, 2014, with
an MRI showing a spinal cord lesion
largely restricted to gray matter in a
patient 21 years of age or younger.30 As
of April 2015, the CDC had collected
data on 118 cases from 34 states nationwide. The median age of children
was 7 years, and most patients were reported to have fever or respiratory
symptoms prior to the onset of neurologic symptoms. In this particular cohort, the limb weakness was often
asymmetric, and many cases of monoplegia were reported.30 Cranial nerve
abnormalities were reported in some
cases. CSF studies typically revealed a
moderate pleocytosis, and some patients had an elevated CSF protein.30
Although enterovirus was found in a
number of respiratory specimens, it was
not found in the CSF of any patient.30
Radiologically, cord lesions in acute
flaccid myelitis primarily involve the
gray matter and anterior horn regions
(Figure 11-3). Lesions were noted at
various levels throughout the cord, and
some were longitudinally extensive.31
When compared to patients with typical inflammatory transverse myelitis,
lesions in acute flaccid myelitis have
prominent anterior horn cell involvement and significantly less cord edema
and white matter involvement. The
prognosis for acute flaccid myelitis is
guarded with variable recovery. With
the most recent cluster, although twothirds of patients were reported to have
some improvement within the first
month,30 few have been reported to
fully recover to date. Slow and incomplete recovery has been reported in
prior clusters of acute flaccid myelitis.28,32 Studies are now ongoing to
better determine the etiology of acute
flaccid myelitis and to identify possible
genetic differences among patients
who develop acute flaccid myelitis.
KEY POINTS
h Acute flaccid myelitis is

an emerging entity with
acute flaccid limb
weakness associated
with primarily gray
matter involvement. A
possible association
with enteroviral
infection requires
further elucidation.
h About 2% to 10% of all

multiple sclerosis patients
will have their first clinical
symptom before the age
of 18 years.
MULTIPLE SCLEROSIS
Although MS is more common in
adults, about 2% to 10% of all patients
with MS will have their first clinical
symptom before the age of 18 years.33Y36
907
FIGURE 11-3
Spinal cord imaging from two children with acute flaccid myelitis. A, Axial
T2-weighted MRI shows prominent anterior horn cell involvement (arrows). B,
Sagittal T2-weighted MRI reveals T2 signal abnormality (arrow) primarily
involving the gray matter of the spinal cord. No significant cord edema is evident.
Typical presenting features of MS include optic neuritis, focal partial transverse myelitis, brainstem symptoms,
hemimotor or hemisensory symptoms,
ataxia, or multifocal features involving
more than one deficit (Case 11-3). Of
children who initially present with clinical features consistent with ADEM, 6%
to 18% experience future relapses that
confirm a diagnosis of MS.37,38 As outlined in the International Pediatric
Multiple Sclerosis Study Group consensus criteria,2 subsequent relapses in a
patient with ADEM must be nonencephalopathic (not ADEM-like), occur at
least 3 months after the initial attack,
and be associated with new MRI lesions
that meet the 2010 McDonald criteria
for dissemination in time4 for a diagnosis of MS to be considered. Of note,
the 2010 McDonald criteria cannot be
applied at the time a child presents
with ADEM.
While many features of pediatric MS
overlap with adult-onset disease, some
distinguishing characteristics exist. For
example, while pediatric-onset MS is
more common in females after the age
of about 12 years, the ratio of boys to
girls is equal in prepubertal children.
908
Pediatric MS is nearly always relapsingremitting at onset, and genetic, metabolic, or structural etiologies should be
strongly considered if a patient presents
with a seemingly progressive phenotype from onset. As compared with
adult-onset disease, relapse rate in the
first few years in pediatric MS is higher;
over 75% of children will experience
a second event within 1 year of their
initial demyelinating attack.35,39,40
Although pediatric patients may experience more attacks early in their
disease, their recovery from attacks is
generally quite good, and patients are
rarely left with residual postattack physical disability. Accrual of progressive
physical disability unrelated to attacks
(secondary progressive MS) does occur in patients with pediatric-onset
disease, with about 50% of patients
reaching this stage 20 years after their
initial attack.35 As more children are
initiating disease-modifying therapy
early in their disease course, additional
long-term prospective studies are needed
to determine the impact of treatment
on disability in pediatric patients.
Despite the lack of physical disability,
more than half of children with MS are
June 2016
Case 11-3
A previously healthy 12-year-old girl presented for evaluation in the setting of new binocular diplopia.
Her neurologic examination was notable for a left internuclear ophthalmoplegia, bilateral optic nerve
pallor, and hyperreflexia. Her visual acuity was normal. A brain MRI revealed a lesion in the pons in
addition to multiple periventricular and juxtacortical white matter lesions, with some of these
clinically silent lesions enhancing with gadolinium (Figure 11-4). Her spinal cord imaging was normal.
CSF studies were notable for normal cell counts, protein, and glucose. Oligoclonal bands were positive,
Imaging of the patient in Case 11-3. A, B, Axial fluid-attenuated inversion recovery

(FLAIR) MRI reveals lesions typical of multiple sclerosis in a patient presenting with
diplopia and found to have an internuclear ophthalmoplegia. C, Sagittal FLAIR MRI
reveals pericallosal lesions typical of multiple sclerosis in the above mentioned patient. D, Axial
postcontrast T1-weighted MRI reveals an enhancing (clinically silent) lesion in the subcortical
white matter.
FIGURE 11-4

909
Continued from page 909

revealing more than five unique bands in the CSF. AntiYaquaporin-4 immunoglobulin was negative,
and a total 25-OH vitamin D level was found to be 10 ng/mL. Using the revised 2010 McDonald
criteria, this patient met diagnostic criteria for multiple sclerosis (MS) as she had a clinical
demyelinating attack typical of MS and met dissemination in space (one or more T2 lesions in at least
two of the following four locations: periventricular, juxtacortical, infratentorial, spinal cord), and
dissemination in time (simultaneous presence of clinically silent gadolinium-enhancing and
nonenhancing lesions) criteria on her baseline MRI.4 She was subsequently started on glatiramer
acetate and vitamin D supplementation.
Comment. This is a case of pediatric-onset MS diagnosed after a first clinical demyelinating event
using the revised 2010 McDonald criteria.
KEY POINTS
h Pediatric multiple
sclerosis is almost always
relapsing-remitting at
onset, and treatment
with first-line therapies is
recommended early. The
role of new agents is the
subject of clinical trials.
h Pediatric patients with

multiple sclerosis tend
to have more brainstem
and cerebellar disease
and a higher lesion
volume early on in their
disease course as
compared with adults.
h Although the 2010

revised McDonald
criteria have allowed for
earlier diagnosis of
multiple sclerosis in
adolescents and adults,
these criteria must be
applied with caution in
prepubertal patients.
910
found to have debilitating fatigue or

cognitive impairment within a few
years of diagnosis. Awareness and
management of these comorbidities is
important as they may have significant
impact on quality of life.
Risk factors for MS in children are
similar to those seen in adults and include having the HLA-DRB1*15 allele,
prior exposure to the Epstein-Barr
virus, vitamin D deficiency, and obesity.38,41 Children exposed to parental smoking have been found to have
a higher risk for MS.42 Earlier age at
menarche has also recently been associated with higher MS risk.43 In a study
following children from the time of
their incident acquired demyelinating
syndrome, 57% of cases with HLADRB1*15, vitamin D deficiency, and
Epstein-Barr virus seropositivity were
subsequently confirmed to have MS.
Cases without any of the three risk
factors typically remained monophasic,
with only one such patient diagnosed
with MS to date.38
Radiologically, the appearance of
pediatric MS can differ from adultonset disease. For example, as opposed
to the focal ovoid lesions typically seen
in adult MS, prepubertal patients may
have large ill-defined lesions that may
resolve over time.44 Pediatric patients
with MS tend to have more brainstem
and cerebellar disease and a higher
lesion volume early in the disease as
compared with adults.45 Despite these
differences, the presence of one or

more periventricular or one or more
T1 hypointense lesions is suggestive
of MS in children in the appropriate
clinical context.14
CSF studies should be obtained in all
cases where acute CNS infection is considered and if the diagnosis of MS is
unclear based on the clinical and radiologic features available. While oligoclonal bands are often positive in
postpubertal pediatric patients with MS,
they are less commonly detected in prepubertal patients.46 A mild pleocytosis
is commonly seen in children with MS,
although a white blood cell count
greater than 50 cells/mm3 or the presence of neutrophils in CSF is highly
atypical and should prompt consideration of other diagnoses in the postpubertal age group. Prepubertal children
are more likely to have higher white
blood cell counts and a higher percentage of neutrophils as compared with
adolescent and adult patients with MS.47
Although the 2010 revised McDonald
criteria have allowed for earlier diagnosis
in adolescents and adults with MS, these
criteria must be applied with caution in
prepubertal patients. Sadaka and colleagues48 applied the 2010 criteria to
the baseline MRI of a cohort of children with acute demyelination prospectively for 2 years, with clinical and
MRI evaluations looking for evidence
of new attacks or accrual of MRI lesions
(confirming the diagnosis of relapsing
June 2016
MS), and found that the application of

the 2010 criteria at the time of the
incident attack had a positive predictive value of 76% and negative predictive value of 100% in children 12 years
and older. In younger children (with a
non-ADEM presentation), the positive
predictive value was only 55%.48
Treatment
Treatment of pediatric MS has traditionally been based on data from randomized controlled trials in the adult
population, expert consensus, and observational studies. First-line therapy
includes injectable formulations of interferon beta and glatiramer acetate,
with the selection of a particular agent
based on side effects, patient comorbidities, and potential for adherence.
Natalizumab is used in the pediatric
population and typically considered
when patients have active disease despite adherence to an injectable agent.
Although its use can be limited by the
risk of progressive multifocal leukoencephalopathy, natalizumab has been
reported to be very effective in the pediatric population, with the majority
of patients remaining free of new disease activity.49 Oral agents are now
approved for use in adults with MS
and are currently under study in the
pediatric population.
NEUROMYELITIS OPTICA
SPECTRUM DISORDER
NMO spectrum disorder is a CNS
inflammatory disorder that has been
traditionally characterized by repeated
attacks involving the spinal cord and/or
optic nerves in the setting of antiY
aquaporin-4 antibody seropositivity.
The antiYaquaporin-4 antibody is
thought to be a pathogenic in NMO
spectrum disorder as it attacks
aquaporin-4, a water channel found
in foot processes of astrocytes that form
the blood-brain barrier. Over the past
few years, the phenotype of NMO spectrum disorder has expanded, and patients have now been recognized to
have inflammatory lesions in brain regions where aquaporin-4 is highly expressed, such as the area postrema/
dorsal medulla and hypothalamus. Additionally, patients with clinical manifestations consistent with an NMO
spectrum disorder without antiY
aquaporin-4 seropositivity can now
be given a diagnosis of an NMO
spectrum disorder.
As is seen in some cases of MS, an
episode of ADEM can sometimes be
the first manifestation of an NMO spectrum disorder.50 Should a patient with
ADEM have antiYaquaporin-4 antibody
seropositivity, a diagnosis of an NMO
spectrum disorder should be strongly
considered. Further studies are needed
to determine whether these patients
are at high risk for relapse and if they
would benefit from preventive therapy.
Although many of the clinical and
radiographic feature of pediatric NMO
spectrum disorder are similar to adult
disease, differences include that a
higher proportion of children may have
monophasic disease51 and that the
finding of longitudinally extensive myelitis is less specific for an NMO spectrum disorder in children. With regard
to CSF findings, a pleocytosis is seen in
most children (either neutrophilic or
lymphocytic predominant) and can be
higher than 50 cells/mm3 in some
cases.52 CSF protein is also typically
elevated, and oligoclonal bands are
usually negative.51,52
The diagnostic criteria for NMO
spectrum disorder have been recently
updated and require further validation
in the pediatric population.5 The criteria are based on the presence of at
least one or two core clinical features
(depending on whether associated
antiYaquaporin-4 seropositivity exists),
which include optic neuritis, acute
KEY POINT
h Longitudinally extensive
spinal cord lesions can
be seen in all of the
pediatric acquired
demyelinating syndromes
and are not specific
for pediatric
spectrum disorders.
911
KEY POINT
h Relapses in neuromyelitis
optica spectrum
disorder tend to be
severe and render patients
at risk for relapse-related
disability. Rituximab,
azathioprine, and
mycophenolate mofetil
have all been used
successfully in children to
reduce relapse rates.
myelitis, an area postrema syndrome,

an acute brainstem syndrome, symptomatic narcolepsy or an acute diencephalic syndrome with NMO spectrum
disorderYtypical brain lesions, or a
symptomatic cerebral syndrome with
NMO spectrum disorder-typical brain
lesions. Cell-based serum assays are the
most sensitive and specific tests for the
antiYaquaporin-4 antibody and should
be used whenever possible.5,53
Treatment
As with adults, chronic immunosuppressive therapies should be initiated
as soon as a diagnosis of an NMO spectrum disorder is confirmed as attacks
can be severe and can result in permanent visual or motor dysfunction. Reduction of relapses has been reported
in children treated with therapies such
as rituximab, azathioprine, or mycophenolate mofetil,52 and some evidence
also exists that disability may also be
reduced with early initiation of these
medications.54 Further studies are required to determine adequate length
of therapy and effects of these medications on long-term disability and disease progression in pediatric patients.
MYELIN OLIGODENDROCYTE
GLYCOPROTEIN ANTIBODIES IN
THE CONTEXT OF PEDIATRIC
DEMYELINATION
The role of myelin oligodendrocyte glycoprotein (MOG) antibodies in the
pathogenesis of acquired demyelinating syndromes is an area of recent interest and requires further study. These
antibodies have been identified in about
35% of patients with pediatric acquired
demyelinating syndromes.55 Based on
recent observational studies and case
reports, patients with demyelinating syndromes and MOG antibodies may differ
phenotypically from those without the
antibodies. For instance, patients with
clinical characteristics typical of an NMO
912
spectrum disorder and positive antiMOG antibodies may be more likely to

have monophasic disease and a younger age of onset.56,57 Additionally, in a
prospective study of 33 patients with
ADEM, those with MOG antibodies were
more likely to have large widespread
lesions, an increased frequency of longitudinally extensive cord lesions, and a
better prognosis as compared to those
without MOG antibodies.58 Recent data
also suggest that identification of MOG
antibodies at the time of an acute demyelinating attack is associated with a
non-MS course at 1 year.55 Further investigation into the relevance of MOG
antibodies and other potential biomarkers is currently ongoing with the
goal of better defining the clinical
course and prognosis of each of the
acquired demyelinating syndromes.
CONCLUSION
Although diagnostic criteria for the acquired demyelinating syndromes are
now well established, the expansion of
clinical phenotypes and better understanding of pathogenic mechanisms is
still ongoing. As the overall incidence
of these syndromes is low, collaboration among national and international
centers is needed to collect accurate
data regarding clinical features and
prognosis, which may be evolving with
early initiation of preventive therapies.
Collaboration is also needed for clinical
trials that have been initiated in pediatric MS and NMO spectrum disorders,
which, it is hoped, will lead to better
treatment options for children with
pediatric demyelination.
REFERENCES
1. Krupp LB, Banwell B, Tenembaum S;
International Pediatric MS Study Group.
Consensus definitions proposed for pediatric
multiple sclerosis and related disorders.
Neurology 2007;68(16 suppl 2):S7YS12.
doi:10.1212/01.wnl.0000259422.44235.a8.
June 2016
2. Krupp LB, Tardieu M, Amato MP, et al;

International Pediatric Multiple Sclerosis
Study Group. International Pediatric Multiple
Sclerosis Study Group criteria for pediatric
multiple sclerosis and immune-mediated
central nervous system demyelinating
disorders: revisions to the 2007 definitions.
Mult Scler 2013;19(10):1261Y1267.
doi:10.1177/1352458513484547.
3. Narula S, Banwell B. Acute disseminated
encephalomyelitis. In: R Lisak, D Truong, W
Carroll, R Bhidayasiri, eds. International
neurology. 2nd edition. Oxford, UK:
Wiley-Blackwell, 2016.
4. Polman CH, Reingold SC, Banwell B, et al.
Diagnostic criteria for multiple sclerosis:
2010 revisions to the McDonald criteria.
Ann Neurol 2011;69(2):292Y302. doi:10.1002/
ana.22366.
5. Wingerchuk DM, Banwell B, Bennett JL, et al.
International consensus diagnostic criteria for
neuromyelitis optica spectrum disorders.
Neurology 2015;85(2):177Y189. doi:10.1212/
WNL.0000000000001729.
6. Tenembaum S, Chamoles N, Fejerman N.
Acute disseminated encephalomyelitis: a
long-term follow-up study of 84 pediatric
patients. Neurology 2002;59(8):1224Y1231.
doi:10.1212/WNL.59.8.1224.
7. Hynson JL, Kornberg AJ, Coleman LT, et al.
Clinical and neuroradiologic features of
acute disseminated encephalomyelitis in
children. Neurology 2001;56(10):1308Y1312.
doi:10.1212/WNL.56.10.1308.
8. Anlar B, Basaran C, Kose G, et al. Acute
disseminated encephalomyelitis in children:
outcome and prognosis. Neuropediatrics 2003;
34(4):194Y199. doi:10.1055/s-2003-42208.
9. Leake JA, Albani S, Kao AS, et al. Acute
disseminated encephalomyelitis in childhood:
epidemiologic, clinical and laboratory features.
Pediatr Infect Dis J 2004;23(8):756Y764.
10. 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. doi:10.1007/
s00431-006-0249-2.
11. Banwell B, Kennedy J, Sadovnick D, et al.
Incidence of acquired demyelination of the
CNS in Canadian children. Neurology 2009;
72(3):232Y239. doi:10.1212/01.wnl.
0000339482.84392.bd.
12. Torisu H, Kira R, Ishizaki Y, et al. Clinical
study of childhood acute disseminated
encephalomyelitis, multiple sclerosis, and
acute transverse myelitis in Fukuoka
Prefecture, Japan. Brain Dev 2010;32(6):
454Y462. doi:10.1016/j.braindev.2009.10.006.
13. Murthy SN, Faden HS, Cohen ME, Bakshi R.

Acute disseminated encephalomyelitis in
children. Pediatrics 2002;110(2 pt 1):e21.
14. Verhey LH, Branson HM, Shroff MM, et al;
Canadian Pediatric Demyelinating Disease
Network. MRI parameters for prediction of
multiple sclerosis diagnosis in children with
acute CNS demyelination: a prospective
national cohort study. Lancet Neurol 2011;
10(12):1065Y1073. doi:10.1016/S1474-4422
(11)70250-2.
15. Tenembaum S, Chitnis T, Ness J, Hahn JS;
International Pediatric MS Study Group.
Acute disseminated encephalomyelitis.
Neurology 2007;68(16 suppl 2):S23YS36.
doi:10.1212/01.wnl.0000259404.51352.7f.
16. Kuni BJ, Banwell BL, Till C. Cognitive
and behavioral outcomes in individuals
with a history of acute disseminated
encephalomyelitis (ADEM). Dev
Neuropsychol 2012;37(8):682Y696.
doi:10.1080/87565641.2012.690799.
17. Titulaer MJ, Hoftberger R, Iizuka T, et al.
Overlapping demyelinating syndromes
and antiYN-methyl-D-aspartate receptor
encephalitis. Ann Neurol 2014;
75(3):411Y428.
18. Lekoubou A, Viaccoz A, Didelot A, et al.
Anti-N-methyl-D-aspartate receptor
encephalitis with acute disseminated-like
MRI features. Eur J Neurol 2012;19(2):e16Ye17.
doi:10.1111/j.1468-1331.2011.03617.x.
19. Kruer MC, Koch TK, Bourdette DN, et al.
NMDA receptor encephalitis mimicking
seronegative neuromyelitis optica.
Neurology 2010;74(18):1473Y1475.
doi:10.1212/WNL.0b013e3181dc1a7f.
20. Transverse Myelitis Consortium Working
Group. Proposed diagnostic criteria and
nosology of acute transverse myelitis.
Neurology 2002;59(4):499Y505. doi:10.1212/
WNL.59.4.499.
21. Kerr DA, Krishnan C, Pidcock F. Acute
transverse myelitis. In: HS Singer, EH Kossoff,
AL Hartman, TO Crawford, eds. Treatment
of pediatric neurologic disorders.
Boca Raton, FL: Taylor and Francis;
2005:445Y451.
22. Pidcock FS, Krishnan C, Crawford TO, et al.
Acute transverse myelitis in childhood:
center-based analysis of 47 cases. Neurology
2007;68(18):1474Y1480. doi:10.1177/
1352458510381393.
23. Alper G, Petropoulou KA, Fitz CR, Kim Y.
Idiopathic acute transverse myelitis in
children: an analysis and discussion of MRI
findings. Mult Scler 2011;17(1):74Y80.
doi:10.1177/1352458510381393.
913
24. Cortese I, Chaudhry V, So YT, et al.

Evidence-based guideline update:
plasmapheresis in neurologic disorders:
report of the Therapeutics and Technology
Assessment Subcommittee of the American
Academy of Neurology. Neurology 2011;
76(3):294Y300. doi:10.1212/WNL.
0b013e318207b1f6.
25. 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. doi:10.1177/
0883073811420495.
34. Banwell B, Ghezzi A, Bar-Or A, et al. Multiple

sclerosis in children: clinical diagnosis,
therapeutic strategies, and future directions.
Lancet Neurol 2007;6(10):887Y902.
doi:10.1016/S1474-4422(07)70242-9.
35. Renoux C, Vukusic S, Mikaeloff Y, et al.
Natural history of multiple sclerosis with
childhood onset. N Engl J Med 2007;356(25):
2603Y2613. doi:10.1056/NEJMoa067597.
26. Deiva K, Absoud M, Hemingway C, et al.

Acute idiopathic transverse myelitis in children:
early predictors of relapse and disability.
Neurology 2015;84(4):341Y349. doi:10.1212/
WNL.0000000000001179.
36. 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. doi:10.1177/
1352458508101933.
27. 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. doi:10.1177/
08830738030180060601.
37. Mikaeloff Y, Caridade G, Husson B, et al.

Acute disseminated encephalomyelitis
cohort study: prognostic factors for relapse.
Eur J Paediatr Neurol 2007;11(2):90Y95.
doi:10.1016/j.ejpn.2006.11.007.
28. Ayscue P, Van Haren K, Sheriff H, et al.

Acute flaccid paralysis with anterior
myelitisVCalifornia, June 2012YJune 2014.
MMWR Morb Mortal Wkly Rep 2014;
63(40):903Y906.
38. 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.
doi:10.1016/S1474-4422(11)70045-X.
29. Messacar K, Schreiner TL, Maloney JA, et al.

A cluster of acute flaccid paralysis and cranial
nerve dysfunction temporally associated
with an outbreak of enterovirus D68 in
children in Colorado, USA. Lancet 2015;
385(9978):1662Y1671. doi:10.1016/
S0140-6736(14)62457-0.
30. Division of Viral Diseases, National Centers
for Immunization and Respiratory Diseases,
CDC; Division of Vector-Borne Diseases,
Division of High-Consequence Pathogens
and Pathology, National Center for Emerging
and Zoonotic Infectious Diseases, CDC;
Childrens Hospital Colorado; Council of
State and Territorial Epidemiologists. Notes
from the field: acute flaccid myelitis among
persons aged e21 yearsVUnited States,
August 1YNovember 13, 2014. MMWR
Morb Mortal Wkly Rep 2015;
63(53):1243Y1244.
31. Maloney JA, Mirsky DM, Messacar K, et al.
MRI findings in children with acute flaccid
paralysis and cranial nerve dysfunction
occurring during the 2014 enterovirus D68
outbreak. AJNR Am J Neuroradiol 2015;
36(2):245Y250. doi:10.3174/ajnr.A4188.
32. Lee HF, Chi CS. Enterovirus 71
infection-associated acute flaccid paralysis: a
case series of long-term neurologic follow-up.
J Child Neurol 2014;29(10):1283Y1290.
doi:10.1177/0883073813516193.
914
33. Simone IL, Carrara D, Tortorella C, et al. Early

onset multiple sclerosis. Neurol Sci 2000;
21(4 suppl 2):S861YS863.
39. 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. doi:10.1001/archneurol.2008.505.
40. 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. doi:10.1016/
j.jpeds.2003.10.056.
41. Langer-Gould A, Brara SM, Beaber BE,
Koebnick C. Childhood obesity and risk of
pediatric multiple sclerosis and clinically
isolated syndrome. Neurology 2013;
80(6):548Y552. doi:10.1212/WNL.
0b013e31828154f3.
42. Mikaeloff Y, Cardidade G, Tardieu M, Suissa S;
KIDSEP study group. Parental smoking at
home and risk of childhood-onset multiple
sclerosis in children. Brain 2007;130(pt 10):
2589Y2595. doi:10.1093/brain/awm198.
43. Ahn JJ, OMahony J, Moshkova M, et al.
Puberty in females enhances the risk of an
outcome of multiple sclerosis in children and
the development of central nervous system
autoimmunity in mice. Mult Scler 2015;
21(6):735Y748. doi:10.1177/
1352458514551453.
June 2016
44. 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.
doi:10.1212/01.wnl.0000326896.66714.ae.
45. Ghassemi R, Narayanan S, Banwell B, et al;
Network. Quantitative determination of
regional lesion volume and distribution in
children and adults with relapsing-remitting
multiple sclerosis. PLoS One 2014;9(2):
e85741. doi:10.1371/journal.pone.0085741.
46. Huppke B, Ellenberger D, Rosewich H, et al.
Clinical presentation of pediatric multiple
sclerosis before puberty. Eur J Neurol 2014;
21(3):441Y446. doi:10.1111/ene.12327.
47. Chabas D, Ness J, Belman A, et al; US Network
of Pediatric MS Centers of Excellence.
Younger children with MS have a distinct CSF
inflammatory profile at disease onset.
Neurology 2010;74(5):399Y405. doi:10.1212/
WNL.0b013e3181ce5db0.
48. Sadaka Y, Verhey LH, Shroff MM, et al;
Network. 2010 McDonald criteria for diagnosing
pediatric multiple sclerosis. Ann Neurol
2012;72(2):211Y223. doi:10.1002/ana.23575.
49. Ghezzi A, Pozzilli C, Grimaldi LM, et al; Italian
MS Study Group. Natalizumab in pediatric
multiple sclerosis: results of a cohort of
55 cases. Mult Scler 2013;19(8):1106Y1112.
doi:10.1177/1352458512471878.
50. Lotze TE, Northrop JL, Hutton GJ, et al.
Spectrum of pediatric neuromyelitis optica.
Pediatrics 2008;122(5):e1039Ye1047.
doi:10.1542/peds.2007-2758.
51. Banwell B, Tenembaum S, Lennon VA, et al.
Neuromyelitis optica-IgG in childhood
inflammatory demyelinating CNS disorders.
Neurology 2008;70(5):344Y352. doi:10.1212/
01.wnl.0000284600.80782.d5.
52. McKeon A, Lennon VA, Lotze T, et al. CNS

aquaporin-4 autoimmunity in children.
Neurology 2008;71(2):93Y100. doi:10.1212/
01.wnl.0000314832.24682.c6.
53. Waters PJ, McKeon A, Leite MI, et al. Serologic
diagnosis of NMO: a multicenter comparison
of aquaporin-4-IgG assays. Neurology 2012;
78(9):665Y671; discussion 669. doi:10.1212/
WNL.0b013e318248dec1.
54. Longoni G, Banwell B, Filippi M, Yeh EA.
Rituximab as a first-line preventive treatment
in pediatric NMOSDs: preliminary results in
5 children. Neurol Neuroimmunol
Neuroinflamm 2014;1(4):e46. doi:10.1212/
NXI.0000000000000046.
55. Hacohen Y, Absoud M, Deiva K, et al.
Myelin oligodendrocyte glycoprotein
antibodies are associated with a non-MS
course in children. Neurol Neuroimmunol
Neuroinflamm 2015;2(2):e81. doi:10.1212/
NXI.0000000000000081.
56. Kitley J, Waters P, Woodhall M, et al.
Neuromyelitis optica spectrum disorders with
aquaporin-4 and myelin-oligodendrocyte
glycoprotein antibodies: a comparative study.
JAMA Neurol 2014;71(3):276Y283.
doi:10.1001/jamaneurol.2013.5857.
57. Sato DK, Callegaro D, Lana-Peixoto MA, et al.
Distinction between MOG antibody-positive
and AQP4 antibody-positive NMO spectrum
disorders. Neurology 2014;82(6):474Y481.
doi:10.1212/WNL.0000000000000101.
58. Baumann M, Sahin K, Lechner C, et al.
Clinical and neuroradiological differences of
paediatric acute disseminating
encephalomyelitis with and without
antibodies to the myelin oligodendrocyte
glycoprotein. J Neurol Neurosurg
Psychiatry 2015;86(3):265Y272. doi:10.1136/
jnnp-2014-308346.
915

Pediatric Demyelination.16

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Pediatric Demyelination.16

Transféré par

Droits d'auteur :

Formats disponibles

Review Article

Continuum (Minneap Minn) 2016;22(3):897915.

Acquired demyelinating syndromes

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

Key Clinical Features

Key MRI Features

An initial clinical attack

Bilateral asymmetric large T2

ADEM followed by a new

An initial CNS inflammatory

Relapsing disease course

MRI does not demonstrate

New T2 and T1 lesions on

Continued on page 899

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

Key Clinical Features

Key MRI Features

Diagnostic criteria for an NMO

Monophasic (ie, single

1. At least one core clinical

Core clinical features

Increased T2 signal, swelling,

& Optic neuritis

& Acute brainstem

1. At least two core clinical

& At least one core clinical

characteristic must be optic

& Dissemination in space

& Symptomatic cerebral

2. Negative test for

Continuum (Minneap Minn) 2016;22(3):897915

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

h All children with

h Red flags that suggest

pediatric population as subtle neurologic symptoms, such as mild sensory

sessment of whether changes on the

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

Characteristic Clinical Features

Infectious (bacterial, viral, fungal,

Fever, meningismus, rash (such as

Blood and CSF cell counts and

Persistent and prominent headache,

Sedimentation rate, antinuclear

History of prior malignancy or

CSF cytology, brain biopsy,

Encephalopathy, vital sign instability,

Paraneoplastic antibody studies

History of similarly affected

Serum ferritin; triglycerides;

Macrophage activation syndromes

Continued on page 902

Continuum (Minneap Minn) 2016;22(3):897915

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

Characteristic Clinical Features

Metabolic or mitochondrial disease

Symptomatic worsening with fever,

Serum and CSF lactate/pyruvate,

Leber hereditary optic neuropathy

Recurrent vision loss

Neurologic symptoms can develop

MRI with diffusion-weighted

Sickle cell disease

History of pain crises, transient

Episodic decline with dehydration,