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CHAPTER 76
ACQUIRED DEMYELINATION OF
THE CENTRAL NERVOUS SYSTEM
BRENDA L. BANWELL, MD
Acquired inflammatory demyelination of the central nervous system (CNS) may occur as a monophasic illness or as a component of a chronic disease such as multiple sclerosis (MS). This chapter focuses on treatment of acute demyelinating attacks
and management of specific symptoms and on long-term immunomodulatory therapies.
Acute demyelination of the central nervous system (CNS)
is associated with immune-cell targeting of white matter,
leading to dysfunction of the neurologic processes subserved by the affected white matter pathways. Individual
patients may experience clinical symptoms referable to
dysfunction of a single white matter pathway or multiple
deficits due to simultaneous demyelination of multiple
sites in the brain, optic nerves, or spinal cord.
Many children with acute CNS demyelination experience a single episode (monophasic disease). However, some
children will experience recurrent episodes of demyelination over time, leading to a diagnosis of multiple sclerosis
(MS). This chapter discusses manifestations of acute
demyelination, treatment of acute attacks and specific
symptoms, and chronic immunomodulatory therapies.
Clinical Phenotypes
Optic Neuritis
Optic neuritis (ON) caused by demyelination of the optic
nerves presents with acute visual loss of one or both eyes
(simultaneously or sequentially), in the presence of at least
two of the following symptoms: impairment of color
vision, pain with ocular movement, afferent pupillary
defect, disc pallor, abnormal visual evoked potentials, and
central or centrocecal field defect. In children, ON is often
associated with a febrile illness and is more likely to be
bilateral than when it occurs in adults. The prognosis for
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visual recovery is generally excellent, with approximately
80% of children recovering to better than 20/100 vision in
the affected eye.
Transverse Myelitis
A recent international panel defined transverse myelitis
(TM) as bilateral sensory or motor dysfunction localized
to the spinal cord, a defined sensory level, and magnetic resonance imaging (MRI) or myelography exclusion of spinal
compression, plus one of the following: (1) cerebrospinal
fluid (CSF) pleocytosis or increased immunoglobulin (Ig)
G index or (2) gadolinium-enhancement of cord, progressing to maximal deficit between 4 hours and 21 days
after symptom onset. Bladder and bowel dysfunction may
also occur and must be managed acutely.
Neuromyelitis Optica (Devic Disease)
Devic disease is characterized by acute, severe transverse
myelitis and bilateral optic neuritis occurring simultaneously or sequentially (within 2 years, but often within
weeks). Symptoms may occur as a monophasic syndrome
(ie, no further attacks after the initial ON and TM) or may
be associated with multiple relapses of ON and TM. A key
distinguishing feature from typical MS is that clinical and
MRI evidence of white matter involvement in the brain is
absent. The spinal cord involvement in Devic syndrome is
also distinct, in that it involves multiple, contiguous spinal
cord segments. Symptoms are often severe, leading to permanent disability or even death. Pathological studies
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Acquired Demyelination of the Central Nervous System / 487
demonstrate a severe necrotizing myelopathy, distinct from
the typical pathological features of transverse myelitis in
MS patients. Devic syndrome has been reported in children and seems to have a more favorable prognosis. In the
pediatric series, however, ON and TM occurred within 8
weeks of each other, a factor that was also associated with
a better clinical outcome in a series of adult Devic syndrome patients.
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is the most
controversial of the demyelinating phenotypes. Clearly
defined clinical criteria for ADEM have not been established. The classic description of ADEM includes polysymptomatic demyelination with at least two of the following: fever, encephalopathy, meningismus, and
headache. ADEM may be associated with a history of viral
illness or vaccination within 2 weeks of symptom onset.
ADEM after measles infection was particularly severe.
Effective measles vaccination programs have led to fewer
cases of severe ADEM. MRI typically demonstrates bilateral, asymmetric white and gray matter lesions. However,
MRI cannot be used to confirm a specific diagnosis of
ADEM and cannot distinguish an attack of ADEM from
the first attack of MS. Application of the term ADEM varies
among clinicians. In some centers, the presence of multiple white matter lesions alone is used to confer the diagnosis of ADEM, irrespective of the clinical symptoms. This
has resulted in considerable clinical heterogeneity in published ADEM series and may contribute to the variable
outcomes reported.
ADEM is classically considered to be a monophasic disease. However, some children with ADEM experience
recurrent neurologic symptoms. Recurrence of the same
symptoms as the initial event, typically during taper of
corticosteroids, is considered an incomplete response to
therapy rather than a new event. However, some children
develop new symptoms (clinically and associated with
radiologic evidence of new areas of demyelination). If
these relapses occur in close proximity to the original
symptoms the term multiphasic ADEM has been applied.
Children who experience a single relapse, with subsequent
resolution of white matter lesions on MRI, have been diagnosed with biphasic ADEM. Recurrent demyelinating
attacks, well separated in time from the initial ADEM
episode and associated with evidence of involvement of
previously uninvolved white matter pathways, leads to a
diagnosis of MS. However, there remains considerable controversy regarding the diagnosis of MS in children for
whom the first demyelinating attack was considered to be
ADEM. Longitudinal studies of carefully characterized
ADEM patients are required to truly determine MS risk in
this population.
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Polysymptomatic Demyelination
The presence of neurologic deficits referable to multiple
sites within the CNS, but without symptoms of
encephalopathy, fever, or meningismus, is termed polysymptomatic demyelination.
Monosymptomatic Demyelination
Clinical symptoms referable to discreet neurologic pathways other than the optic nerve or spinal cord may also be
the presenting feature of CNS demyelination. Children
may present with hemisensory or hemimotor deficits, cerebellar symptoms, or with symptoms referable to a discrete
brainstem lesion (ie, intranuclear ophthalmoplegia).
Monosymptomatic demyelination (including ON) is now
referred to as a clinically isolated syndrome in the adult
demyelinating disease literature.
Multiple Sclerosis
MS is a chronic autoimmune inflammatory and neurodegenerative disorder of the CNS. MS is defined by recurrent
attacks of inflammatory demyelination, separated in time
by more than 30 days and involving separate CNS white
matter pathways. Recently proposed diagnostic criteria for
MS now incorporate MRI as a means of confirming dissemination of demyelinating lesions within the CNS and
for recognition of emergence of new (clinically silent)
lesions over time. Clinical symptoms must persist for more
than 24 hours to constitute a clinical “attack.” All attacks
must be clearly distinct from acute infection. Separate from
acute attack symptoms, MS patients may also suffer profound physical and cognitive fatigue, emotional lability,
depression, and cognitive decline. Over time, patients may
develop permanent physical disability, spasticity, tremor, or
bladder dysfunction.
Although MS is typically considered a disease that
affects young adults, at least 5% of all MS patients present
prior to their 16th birthday. The number of children diagnosed with MS has increased in recent years, likely owing
to improved diagnostic awareness among pediatric health
care practitioners and to MRI confirmation of active white
matter disease. However, numerous barriers remain to the
diagnosis of MS in children. Many pediatricians are unfamiliar with MS or do not believe MS occurs in childhood,
many children who recover from an inciting demyelinating event are not followed in a systematic manner and thus
the significance of their second attack is not fully appreciated, and MRI criteria for the diagnosis of MS in children
have yet to be established.
The clinical course of MS is variable. More than 80% of
adult MS patients and more than 95% of all pediatric MS
patients have a course of MS initially characterized by
relapses (MS attacks) and remissions (partial or complete
resolution of relapse symptoms). Over time, the vast
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majority of adult patients with relapsing-remitting MS
(RRMS) begin to accrue disability between attacks, a phase
of the disease known as secondary progressive MS (SPMS).
Retrospective, longitudinal studies of pediatric-onset MS
patients indicate that 50% of patients will progress to
SPMS after 23 years of disease. Primary progressive MS, in
which patients experience progressive disability from
onset, without discrete clinical relapses, is exceptionally
rare in children.
To date, there are no serologic or immunologic factors
known to predict MS risk at the time of an inciting attack nor
are there biologic markers that definitively distinguish MS
from other diseases. The presence of multiple white matter
lesions, in a distribution typical for MS, is associated with
clearly increased likelihood of MS in adults. MRI features
predictive of MS risk have yet to be validated in children.
Comprehensive, longitudinal clinical and neuroradiologic assessments of all children experiencing an initial
demyelinating attack, irrespective of the demyelinating
phenotype, are required if the true risk of MS is to be
understood in these children.
Differential Diagnoses of
CNS Demyelination
One of the key tenets of MS diagnosis or the diagnosis of
an initial demyelinating attack is that other etiologies be
excluded. The clinical signs and symptoms of CNS
demyelination typically peak for a few days or, occasionally, even for a few weeks. This is a helpful distinction from
acute vascular syndromes, hemorrhage (posttraumatic,
vascular malformations, tumor-related), or acute intoxication, in which deficits peak within 24 hours. Gradual
neurologic deterioration, over weeks to months, is more
typical of leukodystrophies (adrenoleukodystrophy,
metachromatic leukodystrophy, late-onset Krabbe’s disease), juvenile Alexander disease (which can have MRI features very similar to MS), CNS malignancy, mitochondrial disease (although intermittent deficits can also occur,
and thus mitochondrial disease must always be considered), and nutritional deficiency (ie, vitamin B12). As mentioned previously, the primary progressive form of MS, in
which deficits progress over months, is exceptionally rare
in children. The advent of MRI has greatly improved the
diagnostic evaluation of CNS demyelination. MRI appearance of mitochondrial disorders, leukodystrophies, malignancies, and vascular disorders are well described.
The main disorders included in the differential of acute
CNS demyelination include viral infection, CNS vasculitis,
neurosarcoid (rare), and vitamin B12 deficiency (in
patients with dorsal column or spinal cord symptoms or
with macrocytic anemia). Mitochondrial disease must
always be considered, particularly if there is a history of
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BC Decker Inc
short stature, diabetes, deafness, or myopathy in the patient
or family. CNS vasculitis, particularly systemic lupus erythematosus (SLE), can mimic CNS demyelination. Signs of
systemic illness, cognitive change, and headache would
prompt specific consideration of vasculitis. Serum autoimmune markers (double-stranded deoxyribonucleic acid
[DNA], antinuclear antigen, and erythrocyte sedimentation rate) and magnetic resonance (MR) angiography are
performed for all children in whom this diagnosis is entertained. All children with acute demyelination seen in our
institution are investigated with a comprehensive viral
serology, Lyme serology, West Nile virus serology (seasonal), angiotensin-converting enzyme level, serum and
CSF lactate, MR spectroscopy for brain lactate, chest radiography, and serum B12 levels (when indicated). Spinal
fluid analysis for infection should be performed on all children with fever or encephalopathy but is more controversial for evaluation of otherwise well-appearing children
with monosymptomatic demyelination. CSF oligoclonal
bands, present in over 90% of adult MS patients, can be
transiently present in children with ADEM and can be
absent in children with confirmed MS. Further studies are
needed to clarify the diagnostic utility of CSF oligoclonal
bands in pediatric demyelination.
Management of Acute Demyelination
Figure 76-1 outlines a proposed treatment algorithm for
acute symptomatic demyelination. Initiation of the algorithm should only be instituted for children in whom
demyelinating symptoms are so severe they interfere with
daily function. Mild symptoms do not require acute medical therapy.
Corticosteroids
The putative mechanism of action and rationale for corticosteroid therapy in acute demyelination have been
reviewed. In brief, corticosteroids act at the cellular level
through the glucocorticoid steroid receptor, leading to
upregulation and repression of messenger ribonucleic acid
(mRNA) transcription of antiinflammatory and proinflammatory genes, respectively. Corticosteroids also act
at the endothelial cell membrane to reduce permeability of
the blood-brain barrier (BBB) to immune cells, mediated
by steroid-induced reduction in leukocyte receptors. This
effect is seen clinically by a reduction in gadolinium
enhancement of demyelinating lesions in steroid-treated
patients. Steroids also reduce the total circulating lymphocyte population, as well as the circulating levels of the
harmful cytokines and chemokines secreted by activated
lymphocytes. Thus, corticosteroid therapy affects numerous aspects of the immunologic cascade involved in the
pathogenesis of an acute demyelinating episode.
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Clinical Assessment
• MRI brain ± spine
• Laboratory studies
Confirmation of Dx:
Acute delmyelination
Mild signs and
symptoms
Significant signs and
symptoms
IV methylprednisolone
20–30 mg/kg/dose
Observe
Improvement
Dramatic
improvement
Minimal or
no improvement
Prednisone
start at 1 mg/kg/d,
taken as a single
morning dose
IV methylprednisolone
20–30 mg/kg/dose
2 additional days
No further
treatment
Taper by 5 mg
every 2–3 days
Improvement
Relapse of S+S
during taper
No improvement
IVIg
2 mg/kg total dose
Improved/
stabilized
Pt < 50 kg
1 g/kg/d
2d
Pt > 50 kg
0.4 g/kg/d
5d
Initiate immunomodulatory
treatment if patient meets
criteria for MS diagnosis
FIGURE 76-1. Once the diagnosis of acute central nervous system (CNS) demyelination is confirmed, treatment is initiated for children whose symptoms are severe enough to interfere with function. Treatment is initiated with high-dose intravenous methylprednisolone (IVMP) for 3 days. If symptoms resolve completely, no further therapy (and no prednisone taper) is required. Children with incomplete resolution of symptoms should receive
2 further days of IVMP. Oral prednisone, starting at 1 mg/kg given as a single morning dose, is then initiated. The dose of prednisone is then reduced
after 3 days by 5 mg q3 days until discontinued (ie, taper over 14 to 21 days). Children must be closely monitored and the speed of prednisone modified if necessary. Children who fail to respond to IVMP or those who experience clinical recurrence of symptoms during prednisone taper should
either receive a second course of IVMP or should be offered intravenous immunoglobulin (IVIg). IVIg is given at high dose, 2 g/kg divided over 2 days
(small children) or over 5 days (children over 40 to 50 kg). In our experience, low-dose IVIg is ineffective.
The efficacy of corticosteroids in the treatment of
demyelination is well recognized clinically. However, there
are few placebo-controlled corticosteroid trials. The Optic
Neuritis Treatment Trial (ONTT) randomly assigned adult
patients to placebo, low-dose oral prednisone, or intraCurrent Management in Child Neurology, Third Edition
© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
venous methylprednisolone (IVMP). Patients treated with
IVMP improved more quickly than did those who took oral
prednisone or placebo, although visual function at 1 year
was similar for all three groups. The benefit in terms of quality of life of the patients was not specifically addressed in this
Acquired Demyelination of the Central Nervous System
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490 / The Office Visit: Other Neurologic Complaints and Conditions
study. Clinical experience dictates that rapid recovery of
vision has enormous benefit to the patient’s ability to pursue normal daily activities. IVMP has also been shown to
hasten clinical recovery from other demyelinating phenotypes. Several studies have confirmed the short-term benefit of IVMP and high-dose oral prednisone.
There are no published trials on the use of corticosteroids in pediatric demyelination. IVMP is widely used to
treat children with acute demyelinating syndromes, as
reflected in several published series in which treatment is
mentioned. The treatment algorithm presented in Figure
76-1 is based on our experience in treating more than 130
children with acute demyelination in the past 4 years.
Management of Multiple Sclerosis
Figure 76-2 outlines a proposed treatment overview for
pediatric MS. This is meant as a general guideline only. As
the vast majority of children with MS have relapsingremitting disease, treatments discussed will focus on this
type of MS only. Primary progressive MS therapy in children is extremely rare, and treatments for these children
are individualized.
The Pediatric MS Clinic at the Hospital for Sick
Children uses a comprehensive, multidisciplinary model of
care. The clinic is staffed by a pediatric neurologist, two
MS-certified nurses, a social worker, a pediatric neuro-
Immunoglobulin
A proportion of children with acute demyelination will
either fail to respond to IVMP or will demonstrate reemergence of their demyelinating symptoms upon reduction of
corticosteroid therapy. The risks of prolonged corticosteroid therapy (reduced somatic growth, osteopenia,
hyperglycemia, hypertension, acne, etc) are of significant
concern. Several case reports and small case series have
suggested a role for intravenous immunoglobulin (IVIg)
for these children. Our experience with IVIg has been similarly favorable. IVIg is given at a dose of 2 gm/kg, in
divided doses, as indicated in Figure 76-1.
The mechanisms of action of IVIg are not fully understood. In general, IVIg is thought to bind circulating antibodies, thus preventing them from entering the CNS. IVIg
binds complement components, inhibiting tissue damage, inhibits B cell production of antibodies, interacts with
the mechanisms of action of macrophages, and may
inhibit the production of pro-inflammatory cytokines. A
recent meta-analysis in which four trials of IVIg were analyzed demonstrated that IVIg significantly reduced the
annual number of MS relapses and raised the proportion
of relapse-free patients, compared with placebo. A largescale IVIg trial in adult MS is currently under way. We
have used IVIg in select pediatric MS patients. In our
clinic, IVIg is used to stabilize children with very frequent
relapses, usually as an adjunct to their MS-targeted
immunomodulatory therapy.
Physical and Occupational Therapy
Rehabilitation is a key component of any acute neurologic
injury. Active range-of-movement exercises are important
for children with severe hemi- or paraparesis to reduce the
risk of secondary complications such as contractures, disuse atrophy, or skin breakdown. Children with incomplete
recovery or those with a prolonged recovery phase will
benefit from exercises dedicated to reduce spasticity,
improve strength and coordination, and increase early
mobilization.
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Clinically definite MS
Patient and parent review of available therapies
Demonstration and teaching
Patient selection of therapy
Baseline LFTs and CBC
Contraceptive counseling
First injection
(done by nurse in MS clinic)
Start as
target dose
4 wk
LFTs
CBC
Review tolerability
Increase dose*
3 months
6 months
Bi-annually
LFTs
CBC
Review tolerability
Review contraception
methods
FIGURE 76-2. The model used at the Pediatric Multiple Sclerosis
(MS) Clinic at The Hospital for Sick Children for the initiation of
immunomodulatory therapy. Liver function test (LFT) abnormalities do
occur in children receiving interferons and must be closely monitored.
*Escalation of dose should only occur if liver indices are normal, and
once the patient is tolerating their current interferon dose. Glatiramer
acetate is given at full dose (20 mg/d subcutaneous) from initiation of
therapy. LFT abnormalities are not a reported side effect of glatiramer
acetate. CBC = complete blood count.
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Acquired Demyelination of the Central Nervous System / 491
physiotherapist, a clinic coordinator, two child psychiatrists, and a pediatric neuro-ophthalmologist. The clinic is
linked with the local chapter of the MS Society of Canada,
and patients and families are provided printed material
and online literature relating to pediatric MS.
Disease-Modifying Therapies
Interferons and Glatiramer Acetate
The development of disease-modifying therapies for MS
has led to a significant change in MS care. Table 76-1 outlines dosage and mode of administration for each of the
four approved medications.
The presumed mechanisms of action of interferons and
glatiramer acetate (GA) differ, but both act to reduce CNS
inflammation. Interferons decrease syntheses within the
immune system of requisite costimulatory molecules, proinflammatory cytokines, and other pro-inflammatory mechanisms leading to inhibition of reactive T cells. Interferons
also inhibit trafficking of T cells across the blood-brain barrier. GA, a random polymer, acts as a molecular “decoy.” GA
is engulfed by antigen-presenting cells, leading to presentation of GA-specific antigens and subsequent GA-specific T
cells. These GA-specific T cells favor the more antiinflammatory Th2 T cell subtype, rather than the pro-inflammatory
Th1 phenotype. Furthermore, the GA-specific T cells may
further suppress autoimmunity by acting through a mechanism known as “bystander suppression.”
Detailed reviews of the disease-modifying therapies have
recently been published. All reduce the frequency of annual
clinical relapses by 29 to 34%. Interferon β-1a (Avonex®
and Rebif®) has been shown to reduce the progression of
disability. All four medications have shown a reduction in
inflammatory activity as assessed by gadolinium enhancement on MRI, and interferon β-1a (Avonex®) has been
shown to reduce the rate of brain atrophy.
Side effects of interferons include flu-like symptoms,
elevation in serum of hepatic transaminases, menstrual
irregularities, reduction in white blood cell count, and
injection-site reactions. The flu-like side effects are usually
mild and respond well to administration of acetaminophen or ibuprofen. For some patients, however, the
flu-like side effects limit tolerability. GA does not lead to
the flu-like side effects of the interferons but is associated
with injection site reactions and with a self-limited systemic reaction characterized by an unpleasant flushingsensation, dyspnea, palpitations, and anxiety.
Initiation of therapy with interferon β-1a at the time of
a first demyelinating event delayed conversion to MS in
adult patients at high risk for MS (on the basis of MRI
findings). Recent studies also suggest that initiation of disease-modifying therapies as early as possible after confirmation of MS diagnosis leads to improved long-term outcome (as measured by reduced physical disability)
compared with untreated natural history cohorts.
Interferon β-1a (Avonex®) has also been shown to have a
beneficial effect on cognitive outcome in adult MS patients.
The available literature on the use of interferons and GA
in pediatric MS patients is restricted to tolerability data in
isolated small case series or single case reports. Use of these
agents in children requires a carefully structured patientcare model. The fact that the disease-modifying agents are
administered via injection poses a challenge for all MS
patients but is a particular challenge for young children. In
our clinic, we spend a great deal of time educating children
and their parents about the treatment options and involve
the child or adolescent in the choice of therapy. Injections
are demonstrated by the use of a puppet, which also allows
the parent (or adolescent if self-injection is planned) to
practice injection techniques.
We use an arbitrary method to determine the dose of
interferons on the basis of the child’s weight relative to a normal adult female body weight (ie, a 30 kg child is 50% of a
normal 60 kg woman and would have a target dose that is
50% of the normal adult dose). We then initiate therapy with
one-half the target dose, and in 2-week increments increase
to three-quarters the dose and then the full target dose.
Escalation of dose depends on tolerability and on results of
liver function tests (LFTs) and complete blood count studies. These laboratory studies are performed at baseline, and
then monthly for 6 months. If liver function results are normal at 6 months, then subsequent studies can be performed
every 6 months thereafter. GA is initiated at the full adult
dose. Before initiating therapy, contraceptive counseling is
provided to all sexually active adolescents, as the safety of
these medications during pregnancy is unknown.
To date, we have documented elevation in serum liver
transaminases in four of our patients, necessitating
TABLE 76-1. Immunomodulatory Therapies in Multiple Sclerosis
Medication
Trade Name
Dose
Route
Frequency
Interferon β-1a
Interferon β-1a
Interferon β-1b
Glatiramer acetate
Avonex®
Rebif®
Betaseron®
Copaxone®
30 µg
22 or 44 µg
8 mIU
20 mg
IM
SQ
SQ
SQ
Once weekly
3 times weekly
Every other day
Daily
IM =intramuscular; SQ= subcutaneous.
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BC Decker Inc
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492 / The Office Visit: Other Neurologic Complaints and Conditions
reduction in dose in three and discontinuation of interferon in one child. Flu-like side effects have been noted
in 20% of children on interferons, but these symptoms
have been easily managed with ibuprofen. Brief episodes
of chest tightness and tachycardia were described by two
children receiving GA. Overall, we have found diseasemodifying therapies to be well tolerated in children.
Efficacy of disease-modifying agents cannot be accurately assessed without a formal efficacy trial. Such a trial
would require collaboration among multiple sites and poses
numerous logistical considerations. It is unlikely that a
placebo-controlled trial would be considered, given the
proven efficacy of disease-modifying therapies in adult MS.
Mitoxantrone
Mitoxantrone is a cytotoxic anthracenedione antineoplastic agent that has potent immunomodulatory effects
on both humoral and T cell–mediated immunity.
Mitoxantrone is administered as a monthly intravenous
dose of 8 mg/m2 or as 12 mg/m2 every 3 months. In the
pivotal trial, mitoxantrone was shown to reduce the rate
of disability progression. However, mitoxantrone is associated with a cumulative dose-related cardiotoxicity and
a significant risk of leukopenia. Thus, the use of this
agent is largely restricted to adults with aggressive MS.
The use of mitoxantrone in pediatric MS has yet to be
described.
Cyclophosphamide
Cyclophosphamide is an alkylating agent with potent
immunosuppressive properties. The use of cyclophosphamide in MS is controversial. One trial found no benefit of cyclophosphamide, whereas another demonstrated a significant reduction in disease progression.
Cyclophosphamide is used in pediatric patients with
neoplastic or autoimmune disorders (ie, SLE). Familiarity
with the use of cyclophosphamide in pediatrics, combined with data from the studies of cyclophosphamide
in adults that suggest a role for this medication in
patients with aggressive MS associated with frequent
relapses, has led to the use of cyclophosphamide in a
small number of pediatric MS patients worldwide.
Cyclophosphamide is associated with long-term risks of
infertility and bladder carcinoma or other malignancies
and short-term risks of alopecia, immune suppression,
hemorrhagic cystitis, and nausea. Thus, toxicity will
restrict the use of cyclophosphamide to children with
highly active disease who have failed all other forms of
conventional MS therapy. Our experience, and that of
other centers (personal communications), is that
cyclophosphamide reduces acute relapse disability,
reduces relapse frequency, and improves fatigue significantly in some highly selected patients.
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Novel Agents
Several immunomodulatory agents are currently under
investigation for use in MS. Humanized anti-α4 integrin
(Antegren®), altered peptide ligand, and various statins
are currently at phase I to III trials. Bone marrow transplantation with stem cell rescue is currently being investigated for patients with aggressive MS. Combination therapies may also be a logical extension of the increasing body
of knowledge on MS pathogenesis.
Symptomatic Therapies
The most important aspect of symptomatic therapy is to
fully evaluate the symptoms in the context of the child’s
daily life. Increasing fatigue may be a sign of MS or a feature of poor sleep hygiene, depression, stress, or school
pressures. Bladder dysfunction may be due to spinal cord
involvement or to urinary tract infection. Depression can
yield numerous symptoms and may not be readily identified by a young child or their parents. Management of
pediatric MS patients requires an in-depth understanding
of the child and a well-established relationship of trust. It
is important for patients, particularly adolescents, to have
an opportunity to discuss their concerns privately with
their health care team. Sexual dysfunction, alcohol and
drug use, pregnancy and contraception, and mental health
issues may never be mentioned unless the patient has the
opportunity to confide in his or her physician.
There are several specific symptoms that will be discussed:
Fatigue is defined in our pediatric MS population as a
subjective lack of physical or mental energy of sufficient
severity as to interfere with the child’s ability to complete
requisite school work, engage in extracurricular activities,
or interact socially with peers. Modafinil (Provigil®) and
amantadine have been shown to be efficacious in reducing
fatigue in MS and have proved beneficial for those children
for whom therapy was indicated.
Management of spasticity requires physiotherapy as
well as medication. Oral botulinum toxin, tizanidine, and
benzodiazepines may be effective. Neuropathic pain is
managed with use of gabapentin.
Bladder dysfunction may occur acutely during transverse myelitis or as a chronic condition. Treatment of acute
bladder failure centers on avoidance of infection by the use
of intermittent catheterization or indwelling catheters (if
necessary). Chronic bladder dysfunction is a common
symptom in adult MS but appears to be less frequent in
children. Symptoms of urgency, hesitancy, or incontinence
require careful evaluation. Infection must be excluded.
Bladder spasticity, leading to difficulty with initiation of
voiding, frequency, and urgency, is managed with the use
of oral Ditropan®. Bladder retention, leading to overflow
incontinence and risk of urinary tract infection, may
require intermittent catheterization or other techniques
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Acquired Demyelination of the Central Nervous System / 493
to ensure bladder emptying. A full urodynamic evaluation
is strongly advised to ensure proper bladder care.
Cognitive deficits occur in 50 to 65% of adult MS
patients and may occur early in the disease. The onset of
MS during early childhood occurs during the period of
primary myelin maturation and during the formative academic years. Cognitive deficits have also been demonstrated in children with MS. These deficits are notable in
children with no demonstrable physical disability, suggesting that cognitive deficits may be the most functionally
important consequence of early-onset MS.
Cognitive rehabilitation is an area of research in adult
MS and is most certainly an area that merits urgent exploration in pediatric-onset MS as well.
The onset of MS in a child or adolescent invariably leads
to shock and dismay for parents and caregivers facing the
diagnosis of an “adult disease” in their child. The psychological impact of MS on the child or adolescent may also be
profound, although in our experience most children cope
well with their diagnosis. This perception of coping may
reflect the common “invincible” attitude adopted by children and adolescents. Depression is diagnosed in 30 to 50%
of adult MS patients at some point during their disease. The
Pediatric MS Clinic is staffed by two pediatric psychiatrists
who offer assessments for all children and adolescents in
our clinic. This has proved to be invaluable.
Summary
The onset of demyelination in childhood or adolescence
poses a wealth of challenges to the patient, family, and medical team. Acute symptoms must be fully investigated and
managed. Many children will experience a monophasic illness. However, the risk of the subsequent diagnosis of MS
must be recognized and appropriate long-term care provided. Advances in MS therapeutics highlight the importance of prompt diagnosis and early initiation of MS-targeted
therapies. The long-term impact of pediatric-onset MS on
physical and mental functioning, as well as on ultimate vocational and social independence, is likely to be profound. It is
hoped that comprehensive care of MS-affected children will
serve to mitigate the long-term impact of this disease.
Current Management in Child Neurology, Third Edition
© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
Suggested Readings
Andersson PB, Goodkin DE. Glucocorticosteroid therapy for
multiple sclerosis: a critical review. J Neurol Sci 1998;
160:16–25.
McDonald W, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the
International Panel on the diagnosis of multiple sclerosis.
Ann Neurol 2001;50:121–7
Mikaeloff Y, Moreau T, Debouverie M, et al. Interferon-beta treatment in patients with childhood-onset multiple sclerosis.
J Pediatr 2001;139:443–6.
O’Connor P. Key issues in the diagnosis and treatment of multiple
sclerosis. An overview. Neurology 2002;59(6 Suppl 3):S1–33.
Ozakbas S, Idiman E, Baklan B, Yulug B. Childhood and juvenile
onset multiple sclerosis: clinical and paraclinical features.
Brain Dev 2003;25:233–6.
Pinhas-Hamiel O, Sarova-Pinhas I, Achiron A. Multiple sclerosis
in childhood and adolescence: clinical features and management. Paediatr Drugs 2001;3:329–36.
Sahlas DJ, Miller SP, Guerin M, et al. Treatment of acute disseminated encephalomyelitis with intravenous immunoglobulin.
Neurology 2000;54:1370–2.
Tenembaum S, Chamoles N, Fejerman N . Acute disseminated
encephalomyelitis: a long-term follow-up of 84 pediatric
patients. Neurology 2002;59:1224–31.
Waubant E, Hietpas J, Stewart T, et al. Interferon beta-1a in children with multiple sclerosis is well tolerated. Neuropediatrics
2001;32:211–3.
Practitioner and Patient Resources
National Multiple Sclerosis Society
http://www.nmss.org/
The Society and its network of chapters nationwide promote
research, educate, advocate on critical issues, and organize a wide
range of programs—including support for the newly diagnosed
and those living with MS over time.
Canadian Multiple Sclerosis Society
http:// www.mssociety.ca
[email protected]
Acquired Demyelination of the Central Nervous System
Pages 486–493