++
Demyelinating disorders comprise the largest subgroup within
CNS immune-mediated disorders. Myelin is composed of a lipid bilayer
of cholesterol, phospholipids, and glycolipids along with membrane-associated
proteins, such as proteolipid protein and myelin basic protein.1,2 In
the CNS, oligodendrocytes produce myelin, which surrounds axons
with periodic interruptions at nodes of Ranvier. The main functions
of myelin are to speed the conduction of action potentials along
axons and to support the development and maintenance of axons.
++
Myelin can be injured by many different mechanisms, such as hypoxia,
metabolic derangements, and toxic insults. The disorders discussed
in this chapter are considered to have an autoimmune etiology, with
loss of tolerance resulting in an aberrant, self-reactive inflammatory
process directed against CNS myelin.
++
Demyelination leads to slowing or blockade of action potential
propagation, with resulting symptoms referable to the affected CNS
areas. Although remyelination can occur in the CNS, the thickness
of the original myelin sheath is never reachieved.3 Demyelination
can also lead to secondary axonal loss, which leads to permanent
disability.4
+++
First Attack
of Demyelination
+++
Definitions,
Terminology, and Classification
++
In the past, variable terminology and lack of consistent definitions
in the literature hampered our understanding of pediatric CNS demyelinating
disorders. In April 2007, diagnostic definitions were proposed by
the International Pediatric Multiple Sclerosis (MS) Study Group.5 Although
they have not yet been prospectively validated, these definitions
provide a very useful framework both for clinical and research purposes.
++
With a first presentation of a CNS demyelinating disorder, determining
whether mental status changes are present or absent serves as the
initial step in classification (Fig. 556-1). When
present and accompanied by multifocal symptoms, the appropriate
diagnosis is acute disseminated encephalomyelitis (ADEM), which
can be confirmed with magnetic resonance imaging (MRI). When the
patient’s mental status is normal, first-time acute demyelinating
events are collectively referred to as clinically isolated syndromes
(CIS). Clinically isolated syndromes can be subdivided based on
whether the symptoms and signs are focal or multifocal. Common locations
for focal CIS include the optic nerve (optic neuritis), spinal cord
(transverse myelitis), brain stem, and cerebellum. If multiple CNS
locations are involved simultaneously but the mental status is normal,
the appropriate diagnosis is a polysymptomatic CIS.
++
++
A patient with a CIS may have evidence of demyelination on MRI
in numerous CNS sites without accompanying clinical symptoms and
signs. Although such an MRI finding is important for the patient’s
prognosis for the development of MS, it does not alter the diagnosis, which
is based on clinical findings. For example, a patient with optic
neuritis, normal mental status, and multiple, asymptomatic brain
and spine MRI lesions should be classified as having optic neuritis,
not ADEM, and is at high risk to develop MS.
++
Demyelination of the spinal cord (myelitis) can be partial with
mild, asymmetric motor and sensory symptoms, or complete with severe, symmetric
motor, sensory, and autonomic symptoms. Partial myelitis is a type
of CIS and carries a high risk for the development of MS, and the complete
form poses little risk of recurrence in the pediatric population.
The term acute transverse myelitis (ATM) should
be reserved for the complete form. Definitions of ATM have varied
significantly in the literature. In 2002, the Transverse Myelitis
Consortium Working Group published useful diagnostic criteria.6
+++
General Aspects
of the Differential Diagnosis
++
Although the differential diagnosis varies somewhat based on the
site of CNS demyelination, general principles can be applied to
all of the disorders. There are many conditions that can mimic and
be mimicked by pediatric CNS demyelinating disorders. In addition,
as there are no absolutely definitive diagnostic tests for CNS demyelinating
disorders, a broad differential diagnosis must be considered. A
complete discussion of the entire differential diagnosis is beyond
the scope of this chapter but it has recently been reviewed.7 In
common practice, one will obtain laboratory tests including erythrocyte
sedimentation rate, C reactive protein, serum Lyme titers, antinuclear
antibody, and vitamin B12 level in all patients with CNS demyelinating
disorders, with additional testing if necessary as guided by the
history and examination. In general, the differential diagnosis
and subsequent workup should be expanded in patients with younger
onset, progressive decline in function, poor response to immunomodulation,
and extra-CNS organ system involvement. The main disease categories
that should be considered are infectious diseases, rheumatological disorders,
metabolic disorders, and neoplastic conditions.
++
Regarding infectious diseases, microorganisms can directly infect
the CNS (Fig. 556-2A) or can infect peripheral
organs and secondarily trigger an autoimmune response. If there
is any clinical concern for CNS infection in a patient with suspected CNS
demyelination, cerebrospinal fluid (CSF) should be examined for common
infections, such as enterovirus, and serious, treatable infections,
such as herpes simplex virus, with polymerase chain reaction testing. Additional
infectious disease testing can be tailored based on the season of
the year and the patient’s geographic region, exposures,
and immunocompetence, with strong consideration given to testing
for Borrelia burgdoferi, Mycoplasma pneumoniae,
and Epstein-Barr virus.
++
++
Many rheumatological disorders such as systemic lupus erythematosus
(SLE) have been associated with CNS complications, which may be
partially mediated by inflammatory demyelination (Fig.
556-2B). If there are organ systems other than the CNS affected,
particularly the skin, joints, and kidneys, these disorders should
be assessed with appropriate diagnostic testing. Primary and secondary
CNS vasculitis can also mimic demyelination and should be considered, particularly
when headaches are a prominent symptom, symptoms recur during steroid
withdrawal, or MRI reveals significant cortical involvement (Fig. 556-2C).
++
Leukodystrophies are genetic and metabolic disorders that preferentially
affect the white matter and therefore mimic CNS demyelination. In
patients with a subacute to chronic course, progressive degeneration,
and symmetric white matter involvement on MRI, metabolic testing
should be considered, with specific tests based on the patient’s
age, presentation, and MRI findings (Fig. 556-2D).
These disorders are discussed in Chapter 576.
++
Neoplasms can be confused with demyelination, particularly when there
is a large, focal inflammatory lesion (ie, tumefactive demyelination)
(Fig. 556-2E). MRI of the entire neuroaxis
to look for multifocal involvement and cytological examination of
the CSF should be obtained in such circumstances. Rarely, biopsy of
the lesion is needed to make a definitive diagnosis.
+++
General Aspects
of Acute Treatment
++
The treatment of pediatric CNS demyelinating disorders can be generally
divided into acute and prophylactic phases. Acutely, attacks of
demyelination are treated similarly, regardless of etiology (Fig. 556-3). High-dose intravenous (IV) corticosteroids
are the first-line treatment. They likely act via multiple mechanisms
in CNS demyelinating disorders, including apoptosis of autoreactive
T cells, reduction in the production of proinflammatory cytokines,
and decreased transmigration of immune cells across the blood-brain barrier.8
++
++
Within the adult MS population, high-dose intravenous corticosteroids
have been shown to speed the rate of recovery in acute attacks of
MS and optic neuritis, but do not significantly alter long-term
disability or risk of recurrence.9,10 Although not
formally tested in pediatric patients, high-dose IV corticosteroids
are used for the initial treatment of acute attacks of demyelination.
The most commonly used protocol consists of methylprednisolone 20
to 30 mg/kg/dose (maximum 1 gram) intravenously once
a day for 3 to 5 days. During use of this steroid, pulse, vital signs,
especially blood pressure, and glucose control should be monitored.
Ulcer prophylaxis should be used. Common adverse side effects include
insomnia and mood changes. Rare acute side effects include aseptic
necrosis of the hip. Short courses of IV steroids are not associated
with long-term adverse effects on adrenal function or bone mineralization. Although
there are many potential side effects, this protocol is usually
well-tolerated in the pediatric population.
++
The use of oral steroid tapers following intravenous treatment
is controversial. Patients who have complete or nearly complete symptom
resolution may not need tapers, but those with incomplete recovery
may benefit from a 2- to 3-week taper. Due to the adverse effects
of chronic corticosteroid use and the availability of other immunomodulatory
agents, prolonged courses of oral steroids for the treatment of
CNS demyelinating disorders is not recommended.
++
If significant functional disability remains after several days
of observation following high-dose steroid treatment, additional
options include intravenous immunoglobulin (IVIg) and plasma exchange. Based
on case reports, IVIg 0.4 grams/kg for 5 days or 1 gram/kg for
2 days can be used as second-line treatment.11,12 The
mechanism of action of IVIg is uncertain, but likely involves decreased
production of autoantibodies.13 Based on case reports,
IVIg 0.4 grams/kg for 5 days or 1 gram/kg for
2 days can be used as second-line treatment.11,12 The
mechanism of action of IVIg is uncertain, but likely involves decreased
production of autoantibodies.13 The most common
side effect of IVIg is a nonspecific headache, which can be managed
with slower infusion rates and nonsteroidal anti-inflammatory medications.
Rare side effects include aseptic meningitis and thrombosis.
++
If IVIg is ineffective, plasma exchange administered every other day
for a total of 5 exchanges can be considered. This regimen has been
used successfully in 1 case series of 6 pediatric patients with
ADEM who did not respond adequately to steroids and IVIg.14 The
use of plasma exchange is also supported by a randomized trial in
adult patients with steroid-refractory CNS demyelination and appears
to be more effective when administered within the first 3 weeks
of symptom onset.15,16 Plasma exchange may work
via the removal of pathogenic autoantibodies from the circulation.17 Potential
adverse effects of plasma exchange include the complications associated
with a central venous line (if one is needed), such as pneumothorax
and infection, as well as side effects of the treatment, such as
hypotension and hypocalcemia.
++
It is unclear from the existing literature whether the improvements
observed in some patients following IVIg and plasma exchange reflect
delayed effects of the previously administered treatments or a combined
effect of therapies. The potential benefits of IVIg and plasma exchange
should be weighed against the potential adverse effects described
above. The proposed algorithm (Fig. 556-3)
has been useful in practice but requires further study.
+++
Acute Disseminated Encephalomyelitis (ADEM)
++
Acute disseminated encephalomyelitis (ADEM) is defined as an acute
or subacute inflammatory demyelinating event affecting multifocal
areas of the CNS with multiple accompanying symptoms, which must
include encephalopathy.5 The incidence of ADEM
is approximately 4 cases per 1 million persons under the age 20
per year.18 It is more common in children than
adolescents and adults, with a mean age of onset between 5 and 8 years
of age.
++
Although the pathophysiology of ADEM is likely autoimmune mediated,
the precise mechanisms remain uncertain. Indirect evidence implicating
the immune system includes the frequent association with a preceding
viral infection or, less commonly, a vaccination, as well as the apparent
effectiveness of immunomodulation. The former point suggests that
molecular mimicry, whereby epitopes on microorganisms mimic those
found in CNS myelin and thus provoke an autoimmune response, may
play a role in the pathophysiology of ADEM. As most of the infections
reported to act as triggers for ADEM are very common, additional
host susceptibility factors must be present in patients with ADEM
but are largely undefined.
++
Both B and T lymphocytes appear to play a role in ADEM. Regarding
B cells, autoantibodies to myelin oligodendrocyte glycoprotein were found
in 20% of patients with ADEM.20 Antimyelin
autoreactive T cells have also been found in the serum of a small
group of patients with ADEM.21 Additional work is
needed to clarify the immune and genetic mechanisms of ADEM.
++
Although biopsies are rarely needed to establish the diagnosis
of ADEM, those that are performed provide more direct evidence of
the role of the immune system. Biopsy specimens typically show perivenous
infiltrates of lymphocytes and macrophages with accompanying demyelination and
relative axonal sparing (Fig. 556-4).
++
++
Both
B and T lymphocytes appear to play a role in ADEM. Regarding B cells,
autoantibodies to myelin oligodendrocyte glycoprotein were found in
20% of patients with ADEM.20 Antimyelin
autoreactive T cells have also been found in the serum of a small
group of patients with ADEM.21 Additional work is
needed to clarify the immune and genetic mechanisms of ADEM.
+++
Clinical Presentation
++
Children with ADEM present with a combination of nonspecific
symptoms and signs suggestive of meningoencephalitis, as well as
focal neurologic deficits. Approximately 70% of cases follow
a viral illness or vaccination, usually occurring 7 to 14 days prior
to the onset of neurological symptoms. The most common associated
infection is a nonspecific upper respiratory tract infection. Pooled
data from nine case series totaling 411 patients yield the following
estimates for presenting symptoms and signs: motor (60%),
fever (50%), headache (40%), vomiting (40%),
ataxia (40%), cranial nerve deficits (40%), seizures
(25%), and vision loss (15%).18,22-29 Thus,
a typical clinical scenario is that of a previously healthy child
who develops a nonspecific infection, fully recovers, and then develops
acute encephalopathy and multifocal neurological symptoms and signs.
+++
Differential Diagnosis
++
As suggested by these symptoms, the presentation of ADEM can
be indistinguishable from meningoencephalitis. Thus, direct CNS
infection should be ruled out with lumbar puncture and appropriate
studies in all patients with suspected ADEM. Cerebrospinal fluid
(CSF) analysis is abnormal in approximately 60% of patients
with ADEM, with the most common findings being lymphocytic pleocytosis
or elevated protein concentration, or both.18,22-29 Thus,
basic CSF studies may not distinguish ADEM from encephalitis, and
testing for specific causes of viral encephalitis should be performed.
Additional testing should be guided by clues in the history, examination,
or neuroimaging as described above.
+++
Diagnostic Evaluation
++
All patients with acute disseminated encephalomyelitis (ADEM)
should undergo contrast-enhanced MRI of the brain and spine. Although
patients with ADEM may initially require computerized tomography
(CT) of the head to rule out other emergent conditions, CT has a
poor sensitivity of approximately 40% when compared to
MRI in patients with ADEM.18,22-29 MRI typically
shows bilateral, asymmetric, multifocal hyperintense lesions on
T2 and fluid-attenuated inversion recovery (FLAIR) sequences. The
lesions predominantly affect the cerebral white matter, more so
in subcortical rather than periventricular regions. However, cortical,
deep grey nuclei, brain stem, cerebellar, and spinal cord lesions
are also seen (Fig. 556-5). Lesions tend
to be large with ill-defined borders and lack contrast enhancement.
++
++
The initial treatment of ADEM is similar to that used for all
acute attacks of CNS demyelination (see above). In addition to immunomodulation, supportive
care during the acute attack may include airway management in patients
with depressed mental status, anticonvulsants in patients with seizures,
and pain management. As ADEM is a terrifying event for patients
and their families, psychosocial support should also be given. By
definition, ADEM is a monophasic disorder and does not require chronic
immunomodulation. However, patients with ADEM are at risk for long-term
sequelae (see below) and therefore should be followed by a pediatric
neurologist with treatment of cognitive deficits, physical handicaps,
and epilepsy, as appropriate.
++
Approximately 80% of patients with ADEM make a full
recovery.18,22-29 Most show significant improvement
prior to hospital discharge, with the remainder of the recovery
occurring gradually over several months. However, some patients
are left with motor (10–15%), cognitive or behavioral (10%),
epileptic (5–10%), or visual (5%) sequelae.18,22-29 Cognitive
sequelae may be more common than previously appreciated, as suggested
by 2 recent studies that demonstrated a high percentage of cognitive
deficits with formal neuropsychological testing, particularly in
patients with the onset of ADEM at less than 6 years of age.30,31 Thus,
children with ADEM should be followed closely for declines in cognition
or school performance following the acute illness.
++
Approximately 80% of patients with ADEM experience a single
event without recurrences.18,22-29 Based on the
expert opinion of the International Pediatric MS Study Group, symptoms occurring
within 3 months of the initial onset of ADEM can be considered part
of the initial event.5 Patients who have later
relapses of neurological symptoms following ADEM comprise a controversial group.
++
The reemergence of the initial symptoms after 3 months has been
designated recurrent ADEM. If the symptoms are different than the
initial presentation, the term multiphasic ADEM can be
used5 (Fig. 556-6). Both
recurrent and multiphasic ADEM require that the relapses be accompanied
by mental status changes. In 1 series of 84 patients with ADEM,
10% developed a second attack identical to the first attack
and would be classified as having recurrent ADEM.26 None
of these patients developed further attacks or met criteria for MS
with follow-up ranging from 3 to 16 years. Multiphasic ADEM is less
common than recurrent ADEM, occurring in less than 5% of
patients overall.18,22-29 Given the relative rarity
of recurrent and multiphasic ADEM, a broad differential diagnosis
should be reconsidered before making these diagnoses. Patients with
recurrent or multiphasic ADEM do not generally require chronic immunomodulation,
but it could be considered for unusual patients with frequent or
severe attacks. If mental status changes are not present during
the second event following ADEM, it will most likely represent a
CIS-type event (ie, optic neuritis). Whether
or not such patients should be classified as having MS is very controversial.
The International Pediatric MS Study Group took a conservative approach
and required that 2 CIS-type events occur following ADEM prior to
making a diagnosis of MS.5
++
++
The percentage of patients with an initial diagnosis of ADEM
who later develop MS is uncertain. Estimates of this risk have ranged
from 0%26 to as high as 18%32 in
the existing literature, with a pooled average of approximately
10%.18,22-29 Although there are no highly
predictive risk factors, optic nerve involvement with ADEM, family
history of CNS demyelination, and MRI features suggestive of MS
may increase the risk of developing MS following ADEM.32
+++
Acute Transverse
Myelitis
++
Idiopathic, complete acute transverse myelitis (ATM) affects
approximately 1.34 persons per million per year.33 In
the pediatric age group, patients present at a mean age of 8 years
with an equal gender ratio.34-40 Approximately
280 cases of ATM occur in pediatric patients in the United States
per year.41,42
++
Although the pathophysiology of ATM is uncertain, the frequent
association with preceding infections and accumulating immunological
data support an inflammatory cause for the disorder.33,34,43,44 Approximately
50% of patients report a preceding infection, typically
a nonspecific upper respiratory tract infection, with an intervening
symptom-free interval of 5 to 11 days.33,34,39,41 Some
cases of ATM are associated with recent vaccination.
++
Increased responses to myelin basic protein by peripheral blood
lymphocytes have been demonstrated in the research setting in patients
with ATM.45 In addition, the production of interleukin-6
by astrocytes appears to lead to nitric oxide–induced injury to
spinal cord oligodendrocytes and axons in patients with idiopathic
ATM.43
+++
Clinical Presentation
++
Pooled data from 7 published case series (n = 205) of
pediatric ATM patients reveal common symptoms.34-39,41 Patients
with ATM universally report acute to subacute, bilateral leg weakness.
Arm involvement occurs in about 40% of patients. Approximately
90% complain of bowel and bladder dysfunction and sensory
symptoms, including parasthesias and numbness. A spinal cord sensory level
is usually located in the thoracic region (80%) and less
commonly in the cervical (10%) or lumbar (10%)
area.33 Back pain and fever afflict nearly 50% of
patients. These symptoms develop rapidly, peaking at an average
of 2 to 5 days.34,41
+++
Differential Diagnosis
++
Numerous disorders can affect the spinal cord and produce identical symptoms
and signs that mimic idiopathic ATM. Such conditions must be ruled
out through a combination of history, physical examination, neuroimaging,
and laboratory evaluation.
++
In patients with acute, isolated spinal cord dysfunction, extramedullary
compressive lesions, including spinal epidural abscesses,46 spinal
epidural hematomas,47 and tumors,48 are
neurosurgical emergencies that must be diagnosed rapidly for effective treatment.
Intramedullary lesions that can mimic ATM include primary spinal
cord tumors (most commonly astrocytomas and ependymomas),49-51 radiation injury,52 spinal
cord infarction, and vascular malformations.53 Direct
infections of the spinal cord, typically viral in etiology, can
also occur. Acute transverse myelitis can also be secondary to a variety
of systemic autoimmune disorders.
++
The initial clinical presentation of ATM can be similar to that
of Guillain Barre 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 ATM.
++
Some patients may present with spinal cord dysfunction, as well
as symptoms or signs referable to other parts of the CNS. The presence
of mental status changes and cerebral white matter magnetic resonance
imaging (MRI) abnormalities suggest ADEM as the correct diagnosis. Mild,
asymmetric spinal cord symptoms, previous episodes of transient
neurological symptoms attributable to locations other than the spinal cord,
and subclinical brain MRI lesions point toward MS.54 Concurrent
or preceding optic neuritis suggests neuromyelitis optica (NMO)
as a possible diagnosis.55
+++
Diagnostic Evaluation
++
Every patient with suspected ATM should undergo emergent gadolinium-enhanced
MRI of the entire spine in order to confirm the diagnosis and rule
out alternative diagnoses, particularly compressive lesions. All
patients with ATM should also undergo gadolinium-enhanced MRI of
the brain to assess for additional demyelinating lesions suggestive
of ADEM or MS. Spinal MRI in ATM typically reveals T1 isointense
and T2 hyperintense signal over several contiguous spinal cord segments34 and
may involve the entire spine56 (Fig.
556-7). Spinal cord swelling with effacement of the surrounding
cerebrospinal fluid spaces may be present in severe cases. Contrast
enhancement is present in as many as 74% of patients.41 In
some patients with very suggestive clinical features, the initial
spine MRI may be normal, and it should be repeated several days
later.34,35,37
++
++
Unless a specific contraindication exists, all patients with ATM
should undergo lumbar puncture. Approximately 50% of pediatric
patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance.41 Elevated
CSF protein levels, either in isolation or in conjunction with pleocytosis,
are also detected in about 50% of patients.41 Glucose
concentration is typically normal. A normal CSF profile does not
rule out ATM, as it occurs in approximately 25% of patients.
In addition to MRI and lumbar puncture (LP), further testing should
be guided by clues in the history, examination, or neuroimaging
as described above.
++
The initial treatment of ATM is similar to that used for all
acute attacks of CNS demyelination (see above). There have been
no randomized, controlled trials in ATM to support this approach. However,
case reports and series have suggested a beneficial effect of high-dose
corticosteroids.36,57,58 In 1 series of 12 children
with severe ATM compared to a historical control group of 17 patients,
the use of high-dose intravenous methylprednisolone significantly
increased the proportion of children walking independently at 1
month (66% compared to 18%) and with full recovery
at 1 year (55% compared to 12%).36 For
patients who do not improve adequately with intravenous steroids, intravenous
immunoglobulins12 or plasmapharesis can 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 for pediatric patients with ATM is generally favorable.59 Paine
and Byers’ recovery categories have been the most widely reported
outcome scale.39 Based on this scale, approximately
80% of pediatric patients who receive high-dose IV steroids
achieve full or good recovery, and 20% have a fair or poor
outcome.36,57 Among patients not treated with high-dose
IV steroids, 60% have a full or good recovery, and 40% have
a fair or poor outcome.39 Higher rostral levels
and number of overall spinal segments on spine MRI predicts worse
outcome.41
++
One large, quaternary-referral, center-based study of 47 children
with ATM, of whom 70% were treated with IV steroids, has cast
doubt on the favorable prognosis of the disorder in childhood.41 In
this study, approximately 40% of patients were nonambulatory
and 50% required bladder catheterization at a median follow-up
of 3.2 years. However, these results may have been influenced by referral
bias, as well as a higher percentage of patients less than age 3
years and patients with cervical involvement compared to other studies.
++
During recovery, motor function returns first, with an average
time to independent ambulation of 56 days in one study34 and
25 days in a group of patients treated with high-dose IV steroids.36 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.34
++
The overwhelming majority of pediatric patients with idiopathic,
complete ATM have a monophasic course. In a series of 24 pediatric
patients with complete ATM with a mean follow-up of 7 years, there
were no recurrences.34 In another study of children
with a variety of initial acute demyelinating events, only 2 of
29 (7%) patients with transverse myelitis had a later demyelinating event.22,60 As
opposed to complete ATM, partial ATM carries a much higher risk
of MS (Fig. 556-8). Adult patients with partial ATM
and additional asymptomatic brain MRI lesions have a greater than
80% of developing MS within the first few years, and those with
normal brain MRI have a 10% to 20% chance.40
++
++
Patients who have complete ATM followed by subsequent attacks
of optic neuritis or complete ATM may have neuromyelitis optica
(NMO). NMO is a distinct CNS demyelinating disorder that can be
diagnosed in patients with optic neuritis, transverse myelitis,
and at least 2 of 3 supportive criteria: spinal cord MRI lesion
extending Å 3 vertebral segments, brain MRI not consistent with
MS, and detection of serum NMO-IgG.55 NMO-IgG is
an autoantibody that targets the predominant CNS water channel protein
aquaporin-4 which is concentrated in astrocytic foot processes in
the blood-brain barrier. It has been detected in 78% of
pediatric patients with relapsing NMO.61 The ideal
management of NMO is uncertain. For acute attacks, initial treatment consists
of high-dose IV corticosteroids. However, given the likely pathogenic
role of the NMO-IgG, patients who do not respond to corticosteroids
should be promptly treated with plasma exchange. Chronic treatment
with the goal of preventing relapses may include chronic low-dose
oral prednisone, azathioprine,62 IVIg, or rituximab.63
+++
Epidemiology
and Pathophysiology
++
The incidence of optic neuritis in children is unclear. Data
from 4 case series (n = 170) suggest a mean age of onset
from 9 to 12 years of age and an approximate 1.5:1 female to male
ratio.64-67
++
Similar to the other CNS demyelinating disorders, indirect evidence
suggests that autoimmune mechanisms are involved in the pathogenesis
of optic neuritis. Approximately 35% of patients report
a viral infection.64-67 Due to the high risk of
complications and the availability of noninvasive diagnostic techniques,
biopsy of the optic nerve in patients with suspected optic neuritis
is rarely performed. Direct pathological data are therefore limited.
However, the frequent association of optic neuritis with more diffuse disorders
such as acute disseminated encephalomyelitis (ADEM) or multiple
sclerosis (MS) suggests common autoimmune mechanisms.
++
The major presenting symptom of optic neuritis is vision loss,
which typically affects the central visual field more than the periphery.
In children, the vision loss is usually severe, with visual acuity
of 20/200 or worse in approximately 75% of patients64-67;
bilateral involvement occurs in 50%.64-67 Although highly
suggestive of optic neuritis when present, pain with eye movements
is not required for the diagnosis, as only 40% of pediatric patients
report this symptom.64-67 In addition, a normal
fundoscopic exam is seen in 30% of patients and does not
rule out the diagnosis.64-67 Examination may also
reveal an afferent pupillary defect and poor color vision.
+++
Differential Diagnosis
and Evaluation
++
The differential diagnosis of optic neuritis is extensive and
reviewed elsewhere.68 Optic neuritis can be isolated or
associated with more widespread involvement of the CNS, as in ADEM,
MS, or NMO. It can also be associated with a variety of systemic
autoimmune disorders. Isolated optic neuritis can be confused with
Leber’s hereditary optic neuropathy, especially when pain
with eye movements is absent. Family history, brain MRI, and mitochondrial
DNA mutation analysis can be used to distinguish these conditions.
Optic neuritis can also be confused with an optic nerve glioma,
although the latter usually presents more slowly and is frequently
associated with neurofibromatosis type I. Although 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.
++
Brain magnetic resonance imaging (MRI) with thin cuts through
the orbits should be obtained in all patients with optic neuritis.
Spine MRI should also be considered to define the extent of demyelination.
Lumbar puncture should be performed if direct CNS infection cannot
be ruled out clinically. Following appropriate neuroimaging to rule
out mass lesions, lumbar puncture with measurement of opening pressure
is also required if idiopathic intracranial hypertension is suspected.
All patients with optic neuritis should be evaluated by an ophthalmologist
with formal visual field testing. Additional testing should be guided
by clues in the history, examination, or neuroimaging.
+++
Treatment and Prognosis
++
Similar to other acute CNS demyelinating syndromes, patients
with optic neuritis are often treated with high-dose intravenous
methylprednisolone. In the Optic Neuritis Treatment Trial in adults,
a 3-day course of intravenous methylprednisolone sped the rate of
recovery in patients with visual acuity less than 20/40
but did not affect the long-term visual outcome.10 Limited trials in adults
suggest that IVIg is not useful as monotherapy in the acute treatment
of optic neuritis,69 but its role in steroid-refractory
optic neuritis is unclear. One case series of 10 adult patients
with steroid or IVIg refractory optic neuritis suggested a 70% rate
of improvement with plasma exchange.70
++
Despite the initially severe symptoms, most pediatric patients
recover well from optic neuritis, with approximately 75% having
visual acuity of 20/40 or better at follow-up.64-67 However,
patients with optic neuritis frequently report subjective changes
in vision, even when visual acuity returns to 20/20; this
may only be detected with specialized techniques.
++
Despite the favorable prognosis for functional recovery, a significant
minority of patients later develop MS. In a study of 79 patients
with a median follow-up of 19.4 years, 26% of patients
were estimated to develop MS by 40 years.64 The
risk of MS was even higher in a study of 36 children with optic
neuritis, with 36% of patients developing MS within 2 years.67 The
presence of neurological abnormalities outside of the optic nerve
on physical examination and asymptomatic brain MRI lesions significantly
increases the risk of later development of MS.67 Contrary
to conventional teaching, bilateral optic neuritis is also associated
with a higher risk of MS compared to unilateral optic neuritis in
children.64,67
+++
Other Clinically
Isolated Syndromes
++
In addition to the optic nerve and spinal cord, demyelination
can affect the supratentorium, brain stem, or cerebellum. Symptoms
and signs of supratentorial demyelination depend on the specific
site affected and can include language, motor, and sensory deficits.
Brain stem demyelination commonly affects extraocular movements,
resulting in diplopia. Less common symptoms include facial weakness
and vertigo. Common symptoms and signs of cerebellar involvement
include ataxia and dysmetria. The diagnostic workup, differential
diagnosis, and treatment of these clinically isolated syndromes
are similar to that described above for optic neuritis and transverse
myelitis. Each of these syndromes can be monophasic or portend the
later development of MS; exact recurrence rates following such CIS
are unclear.
++
A clinically isolated brain stem demyelinating syndrome should
be distinguished from Miller-Fisher syndrome and Bickerstaff’s
brain stem encephalitis. Miller-Fisher syndrome and Bickerstaff’s
brain stem encephalitis are related conditions that share the core
features of ataxia and ophthalmoplegia, with the latter also having
mental status changes and long-tract signs.71 More
than 90% of patients with Miller-Fisher syndrome and 66% of
patients with Bickerstaff’s brain stem encephalitis have
a serum IgG antibody directed against GQ1b.71,72 GQ1b
is a ganglioside in myelin and is particularly enriched in cranial
nerves, which may explain the associated symptoms. These disorders
are typically monophasic and have complete remission of symptoms.
Brain MRI reveals abnormal T2 hyperintensity in the brain stem in
patients with a CIS but is typically normal in patients with Miller-Fisher
syndrome and Bickerstaff’s brain stem encephalitis. There
may also be asymptomatic demyelinating lesions outside of the brain
stem in patients with CIS. In uncertain cases, serum GQ1b should
be checked to distinguish CIS from these other conditions.
++
A CIS involving the cerebellum should be distinguished from cerebellitis
and acute cerebellar ataxia. Patients with cerebellitis typically
have headache and altered mental status, and patients with a cerebellar CIS
have isolated cerebellar symptoms.73 Brain MRI
in cerebellar CIS typically reveals small, discrete lesions with
sharp borders, but in cerebellitis there are often large, bilateral
lesions with associated edema which can cause obstructive hydrocephalus73 (eFig. 556.1). Acute cerebellar ataxia appears
to be a distinct syndrome affecting young children and will be discussed
below.
++
++
In children with recurrent CNS demyelination, the most likely
diagnosis is pediatric-onset multiple sclerosis (MS). The International
Pediatric MS Study Group defined pediatric-onset as occurring prior
to the 18th birthday.5 Pediatric-specific criteria
for the diagnosis of MS are based on the adult MS diagnostic criteria,74 with
minor revisions,5 and incorporate both clinical
and MRI findings. Following an initial CIS, patients can satisfy
diagnostic criteria for MS with either a second attack or new MRI
lesions affecting a different part of the CNS (“dissemination
in space”). The second attack or new MRI lesions must occur
at least 30 days beyond the initial event (“dissemination
in time”).
++
The exact incidence of pediatric MS is uncertain. Overall, between
2.7% and 10.5% of patients with MS develop their
first symptoms prior to 18 years of age.75,76 With
approximately 400,000 patients with MS in the United States, these
figures would yield about 20,000 pediatric patients with MS. The
vast majority of pediatric patients develop their first symptoms
after age 10, with a steady increase in incidence during the teenage
years and into adulthood.75,77-79 Overall, the mean
age of onset within the pediatric MS population is between 11 and
14 years of age. Prior to age 10 to 12 years, the ratio of girls
to boys affected is approximately 1:1; after this age, the ratio
assumes the adult figure of approximately 2:1.75,79 This
change in gender ratios around the onset of puberty likely reflects
the influence of sex hormones on MS susceptibility.
++
Another unique aspect of pediatric MS is a significantly higher
percentage of non-Caucasian patients being affected compared to
the adult MS population.80 Whether this difference
reflects genetic or environmental factors or their interaction is
unclear. Further study of this phenomenon may yield important clues
into MS pathogenesis.
++
The pathological hallmark of acute MS is the inflammatory plaque,
with demyelination and variable degrees of axonal loss.3 Although
many different types of immune cells participate in this process,
perivascular lymphocytes and macrophages are the main cells in biopsy
specimens.3 Helper CD4+ T cells with a
Th1 phenotype, which produce proinflammatory cytokines such as interleukin
2 and tumor necrosis factor, play a central role. However, cytotoxic
CD8+ T cells and antigen-presenting and auto-antibody-producing
B cells also contribute to the pathogenesis of MS.
++
Autoreactive T cells directed against CNS myelin antigens such as
proteolipid protein and myelin basic protein can be detected in
the peripheral blood of both patients with MS, including pediatric
patients,81 as well as healthy and other neurological
disease controls.82,83 Two factors may explain
the discrepant clinical expression of such cells in patients with
MS (“pathologic autoimmunity”) compared to healthy
controls (“physiologic autoimmunity”). First,
the autoreactive T cells exist in a more activated state in patients
with MS.82,83 Second, they are more abundant in
patients with MS in some studies, especially in the cerebrospinal
fluid.82,83 Thus, blood-brain barrier disruption
via the upregulation of proinflammatory adhesion molecules on lymphocytes
and vascular endothelial cells is likely to be a key component of
MS.
++
In general, with increasing disease duration, MS lesions change
from an active to a chronic state, with inflammation becoming less
apparent and axonal loss becoming more prominent.3 Although
more common in chronic lesions, axonal loss is also seen in early,
acute lesions, as well as in the “normal appearing white
matter” of patients with MS.3,4 Abnormalities
in the normal-appearing brain tissue of adult patients with MS have
been demonstrated.3 However, in a small series
of 13 patients with pediatric-onset MS, there were minimal differences
in the normal-appearing brain and spinal cord tissue when comparing patients
with healthy controls using advanced diffusion tensor and magnetization
transfer MRI techniques.84 This discrepancy in
the normal-appearing white matter between pediatric-onset and adult-onset
MS patients may partly explain differences in the disease course
of these 2 groups (see below).
++
Both genetic and environmental factors contribute to the autoimmune
response in MS. The higher incidence of MS in relatives of patients
with MS (3–5%) compared to adopted relatives and the
general population (0.2%) supports the role of genetics
in the development of MS.85,8 6Monozygotic twins
also have a higher concordance for MS compared to dizygotic twins.86 Linkage
studies in patients with MS suggest the involvement of many genes,
with a complex inheritance pattern.87 The major
histocompatibility complex on chromosome 6, particularly the HLA DB1*1501
allele, carries the strongest genetic association with the development
of MS, but many other genes are involved.86 Single-nucleotide
polymorphisms in the interleukin-2 receptor alpha gene and the interleukin-7
receptor alpha gene also contribute to the genetic risk of MS.88
++
Environmental factors also clearly play a role in MS pathogenesis.
There is a positive correlation between the incidence of MS and
distance from the equator, with viral infections and sunlight exposure
partly explaining this phenomenon. Among the many viruses that have
been studied, Epstein-Barr virus (EBV) appears to be the most important. A
significantly higher percentage of children and adolescents with MS
have been previously infected with EBV, but not other common viruses,
compared to age-matched controls.89,90 Incorporating
the “hygiene hypothesis,” the timing of infection,
with a protective effect afforded by infection during infancy and
a deleterious effect after infancy, may be particularly important.91
++
In addition to viral infections, sunlight exposure may also partially
explain the latitude effect in MS; the effect could be related to
vitamin D levels. In adults, higher circulating levels of vitamin
D have been associated with a lower risk of the development of MS.92
++
Pediatric patients with MS typically present with an acute to
subacute attack of neurological symptoms, with the specific symptoms
dependent on the affected CNS location. Data can be pooled from
8 series of pediatric-onset MS patients (n = 592) to yield
common clinical features.75-77,93-97 The presenting symptoms
are similar to adult patients with MS with minor differences and
include the following: sensory (25%), optic neuritis (20–25%),
brain stem (20–25%), motor (20%), cerebellar
(10–15%), and bowel/bladder (0–5%).
Patients with pediatric-onset MS may initially present with acute
disseminated encephalomyelitis (ADEM), although the percentage is
uncertain. ADEM may be a more common presentation in patients with
disease onset younger than 10 years. Seizures also appear to be
more common in this subgroup.98,99 Subsequent attacks
involve similar symptoms as above, but recovery from attacks may
be slower or less complete as disease duration progresses.
++
More than 95% of pediatric-onset MS patients follow
a relapsing-remitting course,100 with discrete
attacks followed by complete or nearly complete recovery with intervening
attack-free periods. Many patients will later enter the secondary
progressive phase, during which acute attacks decline and eventually
stop, but disability gradually accumulates. The percentage of patients who
ultimately enter this phase is unclear, but increases with longer follow-up.100 Primary
progressive MS, in which a steady decline in function occurs from
disease onset without discrete attacks, is rare in children. This
diagnosis should be made with caution and only after extensive evaluation
for genetic and metabolic leukodystrophies.
+++
Differential
Diagnosis and Evaluation
++
As described above and reviewed in detail elsewhere,7 there
is an extensive differential diagnosis to consider when making the
diagnosis of pediatric-onset MS. Despite the broad differential,
the diagnosis of MS can be made with confidence and with focused
testing in the overwhelming majority of patients, with adherence
to the recommended criteria.5
++
All patients with suspected MS should undergo gadolinium-enhanced
MRI of the brain and spine. MRI shows discrete, ovoid T2 and FLAIR
hyperintensities involving the white matter, with a predilection
for the periventricular regions (Fig. 556-9).
A characteristic pattern involves such lesions oriented perpendicularly
to the corpus callosum called “Dawson’s fingers,” which
is shown especially well on sagittal FLAIR sequences (Fig.
556-10). When applied to children, adult MRI diagnostic criteria
for MS appear to be less sensitive, reflecting an overall lower
disease burden in the younger patients.101
++
++
++
Most patients with suspected pediatric-onset MS should undergo
lumbar puncture for routine studies, as well as testing for cerebrospinal
fluid (CSF) oligoclonal bands and IgG index. Oligoclonal band testing
involves a comparison of immunoglobulin patterns in the CSF to the serum.
The presence of bands in the CSF but not the serum indicates abnormal
synthesis of immunoglobulin in the CSF. The presence of 2 or more
of such bands is considered a positive result and supports the diagnosis
of MS. Isoelectric focusing followed by immunoblot testing is preferred
over agarose gel electrophoresis for detecting oligoclonal bands
as it has higher sensitivity. When isoelectric focusing followed
by immunoblot testing is used, more than 90% of patients
with pediatric-onset MS have CSF oligoclonal bands.18,22-29,102 as
compared with less than 10% of patients with ADE.18,22-29 In
addition to oligoclonal bands, 66% of pediatric-onset MS
patients have an elevated CSF white blood cell count, typically
less than 50 cells/mm3with a lymphocytic
predominance.102 A mildly elevated total protein
level may also be present. In addition to MRI and LP, additional
testing should be performed to rule out diagnoses that can mimic
MS (see above and reviewed in detail elsewhere).7
+++
Treatment and Prognosis
++
The treatment of MS includes pharmacologic and nonpharmacologic
approaches. The treatment of acute attacks is similar to that for other
acute CNS demyelination (see above). The majority of attacks are
likely to be treated with high-dose IV steroids, with the goal of
speeding symptom resolution. However, as steroids do not significantly
alter the long-term prognosis, mild attacks that do not impair function
can be treated supportively.
++
Once the diagnosis of MS in children is made, prophylactic treatment
should be offered. In adult patients with MS, large-scale randomized
controlled trials of the beta interferons and glatiramer acetate
have shown that these medications effectively reduce relapse rates
by approximately 35%, which led to US Food and Drug Administration
(FDA) approval for this indication.103-106 The
beta interferons have multiple mechanisms of action in MS, including
shifting production of cytokines from a Th1 to Th2 profile, reducing
lymphocyte proliferation and activation, and decreasing migration
of lymphocytes across the blood-brain barrier.107 The
mechanism of action of glatiramer acetate may involve the production
of regulatory immune cells and shifting cytokine production from
a Th1 to Th2 profile. Although the effect of these medications on
long-term disability is less clear, emerging studies suggest that
they prolong the time to secondary progression and permanent disability.108
++
The interferons used in MS are once-weekly intramuscular interferon
beta-1a (Avonex), every other day subcutaneous interferon beta-1b
(Betaseron), and thrice weekly subcutaneous interferon beta-1a (Rebif). The
most common side effects are flu-like symptoms, including fever,
chills, and myalgias, which typically occur within 24 hours of administration. Preinjection
ibuprofen or acetaminophen can be used to decrease these side effects
and can be taken as needed following the injections. The flu-like side
effects tend to be most prominent when first starting therapy and
gradually diminish over time. Asymptomatic leukopenia and liver
function test abnormalities are also common and may require dose
adjustments.109 Baseline complete blood counts
and liver function tests should be obtained monthly for 3 months
and then approximately every 3 to 6 months. Rarely, interferons
can also cause depression and should be used with caution in patients
with preexisting mood disorders.
++
Glatiramer acetate (Copaxone) is administered subcutaneously
once a day. The most common side effects are injection site reactions,
with redness and swelling, which can be managed with application
of ice or antihistamine creams. Rarely, patients experience a panic-attack-like
reaction immediately after the injection. Although frightening,
it is not dangerous and typically lasts less than 30 minutes. Routine laboratory
monitoring is not needed with glatiramer acetate.
++
None of these medications have been tested in randomized controlled
trials in pediatric patients. However, open-label studies of beta
interferons and glatiramer acetate in children have shown comparable
levels of efficacy and tolerability compared to the adult data.97,109-111 Although
2 studies in adult patients suggested an advantage of subcutaneous
interferon beta-1a and subcutaneous interferon beta-1b over intramuscular
interferon beta-1a,112,113 there are limited data
to strongly suggest 1 medication over another among the interferons
and glatiramer acetate. Therefore, it is the author’s practice
to describe each of the available medications and make a collaborative
decision with the patient and family, taking into account their
preferences regarding the route and frequency of injection and side
effects.
++
There are no clear guidelines in determining whether or not these medications
have been successful in an individual patient. However, increases
in relapse rates or the appearance of new MRI lesions, especially
gadolinium-enhancing lesions, should prompt consideration of a change
in therapy. If a patient is failing treatment on an interferon,
although very controversial, it may be reasonable to check neutralizing
antibodies to interferon, which may decrease their effectiveness.114 Patients
failing on low-dose interferon (Avonex) who are antibody negative
can be switched to high-dose interferon (Betaseron or Rebif) or
glatiramer acetate, with the latter a probable better choice in
antibody-positive patients. Glatiramer acetate can also be considered
for patients failing on high-dose interferon.
++
Some patients may require treatment beyond the interferons and
glatiramer acetate. There is minimal published data on second- or
third-line treatments in pediatric MS. One option is to add scheduled
monthly intravenous steroids to the patient’s existing
treatment. More intensive treatment options include chemotherapy
with cyclophosphamide or mitoxantrone. Cyclophosphamide has been
extensively used in adult MS115 and pediatric lupus
patients, but has rarely been reported in pediatric MS.116 It
is the author’s experience that this medication is useful
in stopping relapses in treatment-refractory pediatric MS patients,
but all patients require additional ongoing treatment following
completion of the cyclophosphamide course. There are numerous potential
acute and chronic side effects that must be considered before using
cyclophosphamide. There is very little experience with mitoxantrone
in pediatric MS and concerns regarding cardiotoxicity limit its
use.
++
The modern era of MS treatment has ushered in the use of monoclonal
antibodies that more specifically target components of the immune
system. Natalizumab (Tysabri) binds to alpha 4 integrin and thus
inhibits the migration of lymphocytes across the blood-brain barrier.
It was highly effective in reducing relapse rates (by 60% to
70%) and MRI disease activity (by 80% to 90%)
as monotherapy or add-on treatment in adult MS patients in randomized controlled
trials.117,118 However, 3 cases of progressive
multifocal leukoencephalopathy in combination treated patients (2 with
MS, 1 with Crohn disease) have led to its use as monotherapy with
strict monitoring. Its use in pediatric MS patients is not generally
recommended. Rituximab (Rituxan) that targets CD20 on circulating
B lymphocytes and daclizumab (Zenapax) that targets CD25 on activated
T lymphocytes are other monoclonal antibodies that appear to be
effective based on limited data in adults119,120 and
may be considered in selected pediatric MS patients.
++
In addition to disease-modifying therapies, symptomatic treatment
may be needed. Fatigue is present in up to 50% of pediatric
MS patients121 and may require treatment with amantadine,
modafanil, or stimulant medications. Mood disorders are also common121 and may
require both pharmacologic as well as psychologic approaches. Bladder
dysfunction is present in some patients and can be addressed with
behavioral techniques, as well as anticholinergic agents. Spasticity
is an uncommon symptom in pediatric MS patients, especially early
in the disease course, but can be treated with baclofen if needed.
Physical and occupational therapy may also be useful for some patients.
++
In addition to pharmacologic therapy, pediatric MS patients and
their families benefit from a comprehensive treatment approach.
Cognitive dysfunction, particularly affecting executive function
and attention, has been detected in approximately 35% of
patients.121 This cognitive dysfunction, in addition
to school disruption caused by acute relapses and medical appointments,
can cause significant educational problems. Therefore, neuropsychological testing
should be obtained in most, if not all, patients. Individualized education
plans to address the student’s identified deficits may
be needed. Patients and families should also be offered psychological
counseling to help address the psychosocial stresses encountered in
the course of a chronic disease like MS.
++
Compared to adult patients, children with MS appear to have more
frequent acute relapses.122 Despite higher relapse
rates, they have slower rates of disability accumulation compared
to adults.76,77,123 Pediatric MS patients enter
the secondary progressive phase in about 20 years as compared with about
10 years in adults.76,77,123 Additional disability
benchmarks include the time it takes patients to reach an Extended
Disability Status Scale of 4 (limited walking ability but can walk
more than 500 meters without rest or aid) or 6 (ability to walk
with unilateral support no more than 100 meters without rest). In
pediatric MS patients, the average times to reach these landmarks
are 20 and 30 years, respectively, which is approximately 10 years
longer than adult patients.76,77,123 However, because
pediatric patients are starting their disease course at an earlier
age, they reach these landmarks when they are younger than adult-onset
patients. On average, pediatric MS patients reach EDSS of 4 and
6 at ages 30 to 35 and 40 to 45, respectively, which is about 10
years younger than adult patients.77,123 Nearly
all of these data come from the pre-disease modifying treatment
era, and it remains uncertain whether these treatments will improve
the prognosis for pediatric-onset MS patients.