Pediatric Myasthenia Gravis

Jason H. Peragallo, MD*,†

Myasthenia gravis is a disorder of neuromuscular transmission that leads to fatigue of skeletal

muscles and fluctuating weakness. Myasthenia that affects children can be classified into the
following 3 forms: transient neonatal myasthenia, congenital myasthenic syndromes, and
juvenile myasthenia gravis (JMG). JMG is an autoimmune disorder that has a tendency to
affect the extraocular muscles, but can also affect all skeletal muscles leading to generalized
weakness and fatigability. Respiratory muscles may be involved leading to respiratory failure
requiring ventilator support. Diagnosis should be suspected clinically, and confirmatory
diagnostic testing be performed, including serum acetylcholine receptor antibodies, repetitive
nerve stimulation, and electromyography. Treatment for JMG includes acetylcholinesterase
inhibitors, immunosuppressive medications, plasma exchange, intravenous immunoglobulins,
and thymectomy. Children with myasthenia gravis require monitoring by a pediatric
ophthalmologist for the development of amblyopia from ptosis or strabismus.
Semin Pediatr Neurol 24:116-121 C 2017 Elsevier Inc. All rights reserved.

Introduction
The myasthenic syndromes are due to defects of transmission
at the neuromuscular junction. Myasthenic syndromes in
children have 3 distinct forms with pathophysiologically
different mechanisms. The congenital myasthenic syndromes
(CMS) are a group of genetic disorders that lead to muscle
weakness through structural or functional abnormalities of
the proteins involved in neuromuscular transmission itself.
Transplacental transfer of maternal antibodies of a myasthenic
mother causes transient neonatal myasthenia (TNM) in infants.
Juvenile myasthenia gravis (JMG) is an autoimmune disorder
that leads to dysfunction of acetylcholine receptors (AChR).
All forms of myasthenia lead to muscle fatigue and weakness
of varying degrees. Fluctuations in weakness are a hallmark of
this disease. If weakness involves the musculature involved in
respiration, these diseases can be life threatening.1,2 This review
will focus primarily on the JMG form.
From the *Department of Ophthalmology, Emory University School of
Medicine, Atlanta, GA.
†
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
Supported in part by an unrestricted departmental Grant (Department of
Ophthalmology) from Research to Prevent Blindness, Inc, New York, and
by NIH/NEI core Grant P30-EY06360 (Department of Ophthalmology).
Address reprint requests to Jason H. Peragallo, MD, Department of Ophthal-
mology, Emory University School of Medicine, 1365B Clifton Rd NE,
Atlanta, GA 30322. E-mail: jperaga@emory.edu
Pathophysiology
In normal synaptic transmission in the neuromuscular junc-
tion, the axon is depolarized and this depolarization travels to
the axon terminal. Voltage-gated calcium channels open,
leading to acetylcholine containing vesicles to fuse to the cell
membrane. Acetylcholine is then released from synaptic
vesicles into the synaptic cleft from the axon terminal. The
acetylcholine travels across the synaptic cleft to the AChR sites
where binding causes sodium channels to open, depolarizing
the motor end plate of the muscle fiber. Acetylcholinesterase
degrades the acetylcholine, and the sodium channels close,
allowing repolarization of the muscle fiber.
Congenital Myasthenic Syndromes
The CMS are not autoimmune diseases, but are a group of
disorders caused by alterations in the structure or function of
proteins in the neuromuscular junction. These disorders must
be suspected to distinguish them from myopathies or other
neurogenic conditions.3 The disease can be the result of, for
example, inability to form normal acetylcholine, inability to
transport and release acetylcholine, abnormal nicotinic AChR,
primary AChR decifiency, end plate development and main-
tenance protein abnormalities, defects in protein glycosylation,
and many others.4 The most common cause of CMS is
alterations in the structure, presence, or kinetics of the AChR
itself.4 Performing a genetic analysis for the specific mutation
causing CMS is necessary to direct treatment for that specific

116 http://dx.doi.org/10.1016/j.spen.2017.04.003
1071-9091/11/& 2017 Elsevier Inc. All rights reserved.
Pediatric myasthenia gravis
syndrome. A treatment modality for CMS caused by one
mutation may actually be harmful to the patient if a different
mutation is present, and treatment must be tailored to the
specific mutation causing CMS. Children with CMS often will
have a relative who is similarly affected. They will present with
fatigable weakness, usually at a very early age, and can present
in infancy. The affected muscles may be ocular alone, which
can lead to isolated fatigable ptosis, or all skeletal muscles may
be affected leading to more widespread weakness. Investiga-
tions for autoantibodies found in JMG and TNM will be
negative. Making the distinction between CMS and JMG may
be difficult if a known genetic mutation causative for CMS
cannot be identified and autoantibodies leading to JMG are not
detected.
Transient Neonatal Myasthenia
TNM is an antibody-mediated disorder that differs from JMG
and CMS. This disease presents shortly after birth in infants of
mothers who have autoimmune myasthenia gravis. The
circulating maternal autoantibodies cross the placenta to the
fetus, leading to an affected child after birth. Children of
mothers who have myasthenia gravis will develop TNM
approximately 5%-30% of the time.5,6 Infants can present
with generalized hypotonia, feeble cry, respiratory distress,
poor suck, and extraocular muscle weakness.6 Symptoms are
usually self-limited but respiratory support may be necessary.
Patients respond well to neostigmine treatment and plasma
exchange. TNM can be distinguished from CMS by the
detection of autoantibodies, and when the disease is demon-
strated to be transient once autoantibodies are cleared from the
infant and symptoms resolve. No long-term treatment is
required once the autoantibodies are no longer present.
Juvenile Myasthenia Gravis
Juvenile myasthenia gravis is an autoimmune disorder pre-
senting with fatigability before the age of 19 years, which in
contrast to the CMS is not due to a structural abnormality in
the neuromuscular junction.7 JMG is also not a transient
disease, such as TNM. Autoantibodies against targets such as
the AChR and muscle-specific kinase (MuSK) lead to
decreased AChR activity though complement-mediated lysis
of the postsynaptic membrane, increased rate of degradation of
the receptor, and direct inhibition of activity.8-10 Lipoprotein
receptor–related membrane protein 4 (LRP-4) is another target
of autoantibodies implicated in the development of myasthenia
gravis in patients in whom the antibodies to the AChR or
MuSK were not detected.11 LRP-4 is a protein necessary for
MuSK activation.12 Up to 18.4% of patients who do not have
antibodies to the AChR or MuSK were found to have
antibodies to LRP-4 in one analysis.12 Other autoimmune
diseases, such as Hashimoto disease and autoimmune
polymyositis, may be present in the same individual who has
JMG.13 A recent study analyzed data from patients who had
both myasthenia gravis and aquaporin 4 antibody–positive
neuromyelitis optica.14 In this study, 20% of patients had
JMG before developing neuromyelitis optica.14 As JMG is a
117
B-cell–mediated disease, recent studies have proposed B-cell–
activating factor as playing a role in its pathogenesis and as a
marker of disease activity in JMG.15,16
Demographics
There have been varying estimates of the incidence of
myasthenia gravis occurring in the general population in the
literature ranging from 1.7-30.0 cases per million person years,
with a prevalence of 77.7 cases per million persons.17,18 Many
studies estimating the incidence and prevalence of JMG have
also been published. A meta-analysis of the literature on this
subject concluded that the incidence of JMG is approximately
between 1.0 and 5.0 cases per million person years.17 Pediatric
patients were found to make up approximately 10%-15% of all
patients with autoimmune myasthenia gravis in a prevalence
study in Virginia.19 Among Asian populations, there appears to
be a higher prevalence of JMG compared to white populations,
with JMG representing up to 50% of all autoimmune
myasthenia gravis cases.20,21
Clinical Presentation
Fatigable skeletal muscle weakness that fluctuates is the
characteristic sign of myasthenia gravis. Myasthenia gravis is
known to preferentially target the extraocular muscles. Cases in
which only the extraocular muscles are affected are termed
ocular myasthenia gravis (OMG). If any other skeletal muscles
are involved, the patient is diagnosed with generalized
myasthenia gravis. The vast majority of patients who have
myasthenia gravis will have involvement of the extraocular
muscles at some point during the course of their disease.
Ocular Myasthenia Gravis
Approximately 10%-35% of all cases of JMG are of the OMG
subtype.1,22 OMG is a more common form of JMG in Asian
populations than in other populations.20,21 The muscles
involved include the vertical and horizontal rectus muscles,
inferior and superior oblique muscles, orbicularis oculi, and
the levator palperae superioris. The initial presentation in these
children may be ptosis, strabismus, or diplopia. In one
community-based case-control study, JMG was the underlying
cause of ptosis in 0.81% of pediatric patients.23 JMG was
present in children with ptosis at 26.7-fold the rate of children
who did not have ptosis.23 Patients may actually have eyelid
retraction, most prominent upon awakening, of the eyelid
that is found to be ptotic in the clinic. Directed questions
about ptosis should address not only if it is worse in the
evenings, but also if it appears resolved upon awakening in the
morning.
Patients with JMG with or without the purely ocular form of
disease can present with pseudo-cranial nerve palsies, and may
have variable strabismus measurements when presenting to a
pediatric ophthalmologist for evaluation for strabismus sur-
gery. It is important to note that the pupils are not involved to a
clinically detectable degree in myasthenia gravis, distinguishing
118
this disease from other neurologic causes of strabismus.
Pupillary abnormalities should prompt evaluation for other
neurological causes. Rates of progression from OMG to
generalized myasthenia gravis has been reported from
8%-49%, with rates of conversion for JMG specifically ranging
from 8%-33%.2,24-29 Preadolescent patients with OMG may
be less likely to progress to the generalized form than
adolescents.25
Generalized Myasthenia Gravis
The generalized form of JMG can be life threatening, as any
skeletal muscle can be involved, including the muscles
involved in respiration. If this occurs, patients may develop
respiratory failure requiring intubation.1,8 Presenting signs can
include the ocular motility abnormalities and ptosis described
earlier, but must include other limb or facial weakness,
difficulty breathing or swallowing, and chocking. Speech can
be affected leading to a change in voice characteristics. Severity
of myasthenia gravis can be classified according to the
Myasthenia Gravis Foundation of America’s classification
system, which allows for uniform criteria to be used cross-
institution for research purposes and for monitoring disease
severity.30
Diagnosis
Making the diagnosis of myasthenia gravis begins when a
patient demonstrates some form of fatigable weakness.
A thorough targeted clinical examination should include some
evaluation of fatigability to address suspicion of myasthenia
gravis. Ancillary testing for its diagnosis includes serologic,
pharmacologic, and electrophysiologic testing.
Clinical Examination Techniques
Fatigability on sustained upgaze is one of the simplest tests to
perform on patients in whom JMG is suspected. First,
palpebral fissure height is taken and an extraocular
motility examination is performed. The patient is then directed
to look at a target above their heads, and instructed to look at
the target without moving their head out of primary
position. The target is held there for a certain period while
the eyelid and ocular alignment is closely observed. Patients
with JMG may demonstrate a change in palpebral height and
ocular alignment while being observed, which suggests
fatigability. The target can then be removed, and the ocular
motility examination and measurement of palpebral fissure
height can be repeated. Changes in these measurements
suggest the presence of myasthenia gravis.
The Cogan lid twitch is another feature that can be seen in
patients who have levator palpebrae superioris involvement
leading to ptosis. This sign can be elicited by having a patient
look in downgaze for a certain period, followed by asking them
to quickly look up. The eyelid overelevates briefly (this is the
“twitch”), followed by fatigue and return to a ptotic position.
J.H. Peragallo
Having the patient look in downgaze causes relative rest of the
levator palpebrae, which is “overstimulated” upon upgaze.
Another simple in office test that can suggest myasthenia
gravis if positive is the ice pack test. After measuring the initial
palperbral fissure height, an ice-filled glove or ice pack is
placed over the patient’s eye or eyes. The ice is left there for 1-2
minutes while the patient rests. Once the ice is removed, the
palpebral fissure is measured again. An improvement of ptosis
of 2 mm of more is a positive result. This test has been found to
be approximately 80% sensitive for the detection of myasthe-
nia gravis.31,32 An alternative to the ice pack test is the rest test,
in which a patient is asked to rest for 30 minutes after being
examined. Following a period of rest, the examination is
repeated, and measurements compared.33 The ice pack test
may be more sensitive than the rest test for the detection of
myasthenia gravis.34
Serologic Testing
Acetylcholine receptor antibody testing is readily available
commercially. The 3 main AChR antibodies tested are binding,
blocking, and modulating antibodies. Their presence is
important as it can definitively make the diagnosis of myas-
thenia gravis in uncertain cases.8,35 One study of patients
with JMG found an AChR antibody positivity rate of 72% of
those presenting with generalized symptoms, and 41% in
those presenting with ocular symptoms alone.36 Patients who
were initially AChR antibody negative became positive 41% of
the time within 2 years.36 However, most of those patients
who converted to positive AChR antibody status did not
have worsening of symptoms. Remission was associated
with conversion from AChR antibody positive to AChR
antibody–negative status.36 Another more recent study found
an AChR antibody positivity rate of 86% in patients with
JMG.22 The finding that patients with the ocular form have
autoantibodies to the AchR less frequently than the generalized
form is similar to what is found in adults.37 Patients who are
negative for AChR antibodies can also be tested for anti-MuSK
antibodies, which have been found to be positive in up to 40%
of all patients with autoimmune myasthenia gravis who are
AChR antibody negative.38 Similar rates have been found in
AChR antibody–negative JMG series.39 Children who have
anti-MuSK antibodies tend to have more severe, acute,
generalized symptoms, with respiratory distress, similar to
what is found in adults with anti-MuSK antibodies.39,40
Response to treatment for JMG due to anti-MuSK antibodies
can be variable.39 Patients who are negative for both AChR
antibodies and MuSK antibodies but clinically have myasthe-
nia gravis are called “double seronegative”. Another antibody
that has been found to be positive in double-seronegative
patients is the lipoprotein receptor-related membrane protein 4
(LRP-4).41 Pediatric patients may be affected in anti-LRP-
4–mediated myasthenia gravis as well.12 The incidence of
anti-LRP-4 positivity varies widely from study to study, likely
due to different assays used by research teams.42 Anti-LRP-4–
associated myasthenia gravis tends to manifest mild
symptoms.12,41,42
Pediatric myasthenia gravis
Pharmacologic Testing
The classic pharmacologic test for myasthenia gravis uses a
short-acting antiacetylcholinesterase, edrophonium, in the
edrophonium (Tensilon) test. By inhibiting acetylcholinester-
ase, the amount of acetylcholine is effectively increased in the
neuromuscular junction, and acetylcholine is able to bind to
the AChR for a longer period, leading to improved neuro-
muscular transmission. This test is performed with cardiac
monitoring and cardiopulmonary resuscitation equipment
(including atropine) readily available owing to the risk of
bradycardia and asystole. During the test, attention should be
directed to a sign of myasthenia the patient exhibits (muscle
weakness, ptosis, etc) that can be readily monitored. Compar-
ison to photographs can be useful. A small dose is given
initially to test for supersensitivity to edrophonium, followed
by escalating doses. Parasympathetic side effects including
excessive salivation, hypotension, diarrhea, flushing, nausea,
and sweating can occur. False negatives and false positives can
occur with edrophonium testing as other diseases can respond
to this test, or the patient may fail to respond to it.1 Neo-
stigmine is an alternative drug to edrophonium that can be
used in young children. Another alternative is to simply treat
the patient with a trial of pyridostigmine and observe for
improvements in symptoms over time.
Electrophysiological Testing
Two methods of electrophysiological testing are primarily used
for diagnosing myasthenia gravis. In one test, repetitive nerve
stimulation, trains of stimuli are delivered to a target muscle,
and quantitative analysis of the motor responses is performed.
A decremental response of 10% from the first to the fourth
response is considered a positive result.43 This test is more
sensitive in patients who have generalized JMG in comparison
to those who have ocular JMG.44 Currently the “gold-standard”
for testing for neuromuscular junction disorders is single-fiber
electromyography (sfEMG) performed on the orbicularis
oculi.43 The sfEMG is particularly useful in cases of suspected
myasthenia gravis with negative serologies as it has very high
sensitivity for MG.45 Unfortunately, traditional single-fiber
EMG studies are difficult to perform on children due to
discomfort and the length of the test. As an alternative, a less
invasive test termed stimulated single-fiber EMG has been
developed that can be used in children.43,46
Treatment
Acetylcholinesterase Inhibitors
Pyridostigmine is the main pharmacologic agent used in the
treatment of myasthenia gravis, whether in children or adults.
Edrophonium has too short a half-life to be of use in long-term
treatment of myasthenia gravis. Even with the appropriate
usage and dosing of pyridostigmine, symptoms and signs of
myasthenia gravis may continue.1 Pyridostigmine may be
combined with other agents such as immunosuppressives.
Side effects of pyridostigmine are similar to those of edropho-
nium described earlier.
119
Immunosuppressive Agents
The most common immunosuppressive agent prescribed
for myasthenia gravis is prednisone. This medication is easily
administered orally to children with JMG, but long-term
use can be harmful due to systemic side effects.1 Children
treated with prednisone demonstrated a good overall response
in a retrospective study.47 Additionally, treatment with pre-
dnisone has been found to have a protective effect on the
conversion from ocular to generalized myasthenia.48,49
Treatment with prednisone appeared to provide control
of OMG in a randomized clinical trial compared with
placebo.50
Azathioprine can be considered for use in myasthenia gravis.
Children who do not have an adequate response to steroids
and anticholinesterase treatment can be placed on azathio-
prine, and it can be used as a steroid-sparing agent.2,51-53
It should be kept in mind that azathioprine has a delayed
treatment effect from time of initiation of therapy, is potentially
teratogenic, and is considered carcinogenic.52,54
Other immunomodulatory medications can be considered
for use in myasthenia gravis. Rituximab has been found to be
effective in its treatment, improve symptoms, and reduce the
amount of steroids required for treatment.55-57 Rituximab has
also been found to be effective for long-term treatment of
refractory myasthenia gravis.58 Mycophenolate mofetil has also
been found to be effective in the treatment of myasthenia
gravis, but randomized control trials have not demonstrated
the ability to taper steroids while on this agent.59-61 However,
discontinuation of mycophenolate mofetil in patients taking
this medication does lead to more frequent myasthenia gravis
exacerbations.62 Tacrolimus has been used for the treatment of
myasthenia gravis as well, including JMG.63,64
Other Medical Treatment Modalities
Intravenous immunoglobulin (IVIG) can be administered
for myasthenia gravis in an effort to reduce the circulating
autoantibodies by decreasing B-cell antibody production
and T-cell function. In a randomized controlled trial against
placebo, IVIG was found to be effective in improving
myasthenia gravis symptoms.65 Therapy with IVIG has
been used for patients with JMG, but appeared to have
better efficacy for short-term treatments and exacerbations
than for long-term treatment.66,67 Plasmapheresis can also
be used in patients with myasthenia gravis to directly filter
autoantibodies and cytokines from the affected patient’s
serum. A comparison in patients with JMG between IVIG
and plasmapheresis for maintenance therapy demonstrated
high response rates for both modalities, but a more
consistent response with plasmapheresis.68 However, pre-
vious studies performed in adults have shown no signifi-
cant difference between the 2 treatments.69 Consensus
statements state that IVIG and plasmapheresis are appro-
priate for acute exacerbations or crises only, and are not
appropriate for maintenance therapy unless patients are
unable to tolerate immunosuppressive agents or have
refractory myasthenia gravis.70
120
Thymectomy
Approximately 10%-15% of all adults with myasthenia gravis
are found to have a thymoma, and 30% of patients who have a
thymoma develop myasthenia gravis.71,72 Children who have
myasthenia gravis have rarely been found to harbor thymo-
mas.22,73 However, thymectomy for patients with seropositive
JMG has been evaluated and has been found to be associated
with improved remission rates.22,74 Therefore, thymectomy
may have a role for children who are unresponsive to medical
therapy or who cannot undergo standard immunsuppression,
although the long-term effects of thymectomy in children are
unclear.70 Thymectomy may protect patients with the ocular
form of JMG from undergoing generalization, and may
improve ocular symptoms as well.9,24 A randomized trial of
thymectomy for adult patients on prednisone for myasthenia
gravis demonstrated a reduction in prednisone dose require-
ment and improvement in symptoms for those who under-
went thymectomy.75
Ophthalmic Outcomes
Patients with JMG should be monitored for the development of
amblyopia and strabismus.76 Amblyopia should be treated to
prevent permanent vision loss. Up to 96% of patients with the
ocular form of JMG will have ptosis, and up to 88% will
present with strabismus.28 Amblyopia has been found in 21%-
50% of children with ocular JMG, but following properly
diagnosis and treatment, that proportion of patients with
amblyopia has been found to decrease as low as 3%.24,25,28
Strabismus is more difficult to treat in patients with ocular
JMG, with its presence at final follow-up ranging from 15%-
57%.24,25 Ptosis may remain in patients who have stable
disease in 46%-66% of patients.24,25 Upon stabilization of the
underlying disease, surgical correction of the strabismus and
ptosis can be considered, with a 56% long-term success rate
found in one retrospective study.77 Counseling should
be given about realistic expectations of strabismus surgery
and about the possibility of requiring multiple surgical
interventions.
Conclusions
Pediatric myasthenia gravis can present as neonatal myasthenia
gravis (CMS, TNM) or during adolescence (JMG). The latter is
an autoimmune disease that can have a variable presentation,
ranging from mild ophthalmic symptoms, such as isolated
fatigable ptosis, to myasthenic crises involving the respiratory
muscles, requiring ventilator support. Making a formal diag-
nosis of the disease can be difficult, but when suspicion is
raised for a fatigable deficit, appropriate diagnostic testing can
be pursued. Treatments should be tailored to the subtype of
disease and the severity of illness. Variable responses to
medications and surgical interventions can be seen between
patients. Children with involvement of the extraocular mus-
culature should be followed by a pediatric ophthalmologist to
monitor for ophthalmic complications associated with JMG.
J.H. Peragallo
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