SAGE-Hindawi Access to Research [626941]

SAGE-Hindawi Access to Research
Autoimmune Diseases
V olume 2011, Article ID 404101, 7pages
doi:10.4061/2011/404101
Review Article
Juvenile Myasthenia Gravis: A Paediatric Perspective
Maria F . Finnis and Sandeep Jayawant
Department of Paediatric Neurology, Children’s Hospital, John Radcli ffeH o s p i t a l ,O x f o r dO X 39 D U ,U K
Correspondence should be addressed to Sandeep Jayawant, [anonimizat]
Received 1 June 2011; Accepted 10 August 2011
Academic Editor: Johan A. Aarli
Copyright © 2011 M. F. Finnis and S. Jayawant. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and repro duction in any medium, provided the original work is properly
cited.
Myasthenia gravis (MG) is an autoimmune disease in which antibodies are directed against the postsynaptic membrane of the
neuromuscular junction, resulting in muscle weakness and fatigability. Juvenile myasthenia gravis (JMG) is a rare conditionof childhood and has many clinical features that are distinct from adult MG. Prepubertal children in particular have a higher
prevalence of isolated ocular symptoms, lower frequency of acetylcholine receptor antibodies, and a higher probability of achieving
remission. Diagnosis in young children can be complicated by the need to di fferentiate from congenital myasthenic syndromes,
which do not have an autoimmune basis. T reatment commonly includes anticholinesterases, corticosteroids with or withoutsteroid-sparing agents, and newer immune modulating agents. Plasma exchange and intravenous immunoglobulin (IVIG) are
effective in preparation for surgery and in treatment of myasthenic crisis. Thymectomy increases remission rates. Diagnosis and
management of children with JMG should take account of their developmental needs, natural history of the condition, and side-effect profiles of treatment options.
1. Introduction
Myasthenia gravis (MG) is an autoimmune disease in which
antibodies are directed at the postsynaptic membrane ofthe neuromuscular junction, leading to varying degrees ofmuscle weakness and fatigability. Where MG presents before19 years of age, it is termed juvenile myasthenia gravis (JMG).Although JMG shares many features with the more commonadult MG, there are many important di fferences.
In this paper we discuss the pathogenesis, epidemiology,
presentation, treatment, and outcome of JMG and highlightsome of the clinical features and challenges particular topaediatric patients.
2. Pathogenesis
In the majority of cases MG is caused by antibodies tothe nicotinic acetylcholine receptor (AChR). Antibodies tothe AChR are found in over 80% adults with generaliseddisease but only in 55% of adults with weakness confinedto the oculomotor muscles. Patients with AChR antibodiesare often referred to as seropositive. AChR antibodies areprobably less frequent in prepubertal patients than inadolescent and adult patients [ 1,2] (see Ta b l e 1 ). Antibodies
to muscle-specific kinase (MuSK) and to Leucine rich protein4 (LRP4) have been reported in some seronegative patients.
Childhood myasthenias encompass JMG, which is the
subject of this paper; congenital myasthenic syndromes, a
heterogeneous group of genetically inherited disorders of the
neuromuscular junction [ 3]; transient neonatal myasthenia,
which results from placental transfer of maternal AChR (orvery occasionally MuSK antibodies) to infants of motherswith autoimmune MG [ 4].
3. Epidemiology and Clinical Features
JMG is a rare disorder of childhood, but its incidence and
prevalence vary geographically. Precise data on incidence and
prevalence are not known. Paediatric presentation of MG is
more common in Oriental than in Caucasian populations
[5].Up to 50% of all cases of MG in Chinese populations
present in childhood, mostly with ocular features, witha peak age at presentation of 5–10 years [ 6].Caucasian
patients, in contrast, are more likely to present in adulthood
[7,8], with prepubertal onset in less than 10% cases [ 2,9].

2 Autoimmune Diseases
Ta ble 1: Comparisons of prepubertal and postpubertal features of
JMG.
Prepubertal PubertalPostpubertal/
adult
Male : female ratio M =FF >M4 . 5:1 F >M4 . 5:1
Patients with AChR
antibodies detected in
generalised disease50–71%
[1,2]68–92%
[1,2]80–90%
Ocular presentation
Caucasian 40% [ 7]9–16% [ 12] 28% [ 6]
Chinese 75% [ 6]
Progression of OMG
to generalised MG8–15%
[17,18]23–43%
[16,19]79% [ 8]
Remission
(spontaneous or withtreatment)42–60%
[1,2,20]26% [ 2] 38% [ 9]
The most frequent clinical presentation of JMG is with
ptosis, which is often associated with other ocular symp-toms namely unilateral or asymmetric ophthalmoplegia,strabismus, and lid twitch, which may only be elicited aftersustained upgaze [ 10]. These symptoms cause particular
problems in children as, if severe, they may cause persistentamblyopia [ 11].Most children also develop generalised
muscle weakness, which presents as painless fatigability ofthe bulbar and limb musculature, with resultant dyspho-nia, dysphagia, and proximal limb weakness. Weakness isoften fluctuating and usually becomes more pronouncedthrough the day and improves with rest. Children are atrisk of choking or aspiration and are at increased risk ofchest infection. Occasionally, impairment of the respiratorymuscles necessitates ventilatory support. This is known as“myasthenic crisis” .
Prepubertal children presenting with JMG have some
interesting and distinct clinical features compared with thosewho present around or after puberty [ 1,2]. Prepubertal
JMG is more likely to manifest as ocular myasthenia [ 12].
There is an equal male: female ratio [ 13],in contrast to
the female predominance that is seen in peri-/postpubertalchildren, and a better prognosis, with a higher rate ofspontaneous remission in prepubertal presenters [ 1,12].
Peri- or postpubertal patients presenting with JMG sharemore similarities with adult-onset MG (see Ta b l e 1 ).
Ocular myasthenia gravis (OMG) is, by definition, MG
restricted to the oculomotor muscles for 2 years withoutbecoming generalised [ 14].In adult populations up to
80% patients with OMG at presentation will progress togeneralised disease [ 8,9,15].Case series in children (using
a variety of treatment protocols and follow-up intervals)have reported lower rates of generalisation than adults[16].Progression may be even less frequent in prepubertal
children [ 17,18].
3.1. Transient Neonatal Myasthenia. This results from trans-
fer of maternal AChR antibodies across the placenta leadingto defects of neuromuscular transmission in the neonate[4]. Not all mothers have detectable AChR antibodies and a
few are asymptomatic at the time. Usually the a ffected baby
is normal at birth, subsequently developing signs such ashypotonia, weak cry, poor suck, reduced movements, ptosis
and facial weakness, and occasional respiratory insu fficiency
requiring mechanical ventilation. Short-term treatment with
anticholinesterases is usually su fficient.
4. Diagnosis of JMG
JMG is primarily a clinical diagnosis with classical patterns
of fluctuating weakness and fatigability as described above.A number of diagnostic tools are available to aid with diag-
nosis. In very young children it is particularly important to
distinguish between autoimmune myasthenia and congenital
myasthenic syndromes (CMS) as the treatment options,
prognosis, and genetic implications are very di fferent (see
Ta b l e 2 ).
CMS usually present in the first years of childhood with
variable disability. There is often a positive family history,and diagnosis is aided primarily by electrophysiology andDNA analysis and occasionally by muscle biopsy [ 21].With
the exception of the autosomal dominantly inherited slow-channel syndrome, the CMS are inherited by autosomalrecessive mutations, which result in loss of function at theneuromuscular junction [ 10].
4.1. Serology. Detection of antibodies to the AChR supports
the diagnosis of JMG. In young children where AChR anti-bodies are negative this can lead to di fficulty in di fferentiating
from CMS. Some of these children who are negative forAChR antibodies will have “low a ffinity” antibodies to the
AChR which were not detectable using the standard assays[22].Some children will, in fact, turn out to have CMS.
A variable percentage (0–49%) of MG patients without
AChR antibodies are found to have antibodies againstanother neuromuscular junction protein, the muscle-specifickinase (MuSK) [ 23].MuSK positive MG is rare in children,
and these children represent a distinct subgroup of JMG ,
with a marked female predominance. MuSK antibodiesappear to be associated with more severe disease with promi-nent facial and bulbar weakness and frequent respiratorycrises [ 24].
Patients without antibodies to AChR or MuSK are
described as having seronegative myasthenia gravis (SNMG).SNMG patients are phenotypically more similar to AChR
seropositive patients than MuSK positive patients, both in
clinical presentation and in response to treatment. “Lowaffinity” antibodies to clustered AChRs can be found in 60%
of previously defined SNMG patients. These antibodies arefound in all age groups [ 22].
Seroconversion has been described in a small number of
cases of children who have developed MuSK antibodies afterthymectomy for AChR seropositive MG [ 25]. This has not
been described in adults.
Other potential antigens at the neuromuscular junction
have been identified in adults with later-onset MG, but

Autoimmune Diseases 3
Ta ble 2: Di fferential diagnosis of JMG.
Congenital myasthenic syndromesUsually presents in infancy
but can present later
Mitochondrial cytopathiesChildren frequently have
additional neurological
impairments or epilepsy
MyopathiesIncluding congenital
myopathies and muscular
dystrophies
NeurotoxinsFor example, botulism,
venoms
Guillain-Barr ´e syndrome
Acute disseminated encephalomyelitis
Multiple sclerosisBrainstem tumourHypothyroidism
the relevance to the childhood population has not been
established [ 26].
4.2. Pharmacological Investigation. The T ensilon test involves
intravenous infusion of edrophonium, a fast-acting, short-duration cholinesterase inhibitor. This prevents the break-down of acetylcholine, thereby increasing the concentrationof the neurotransmitter at the neuromuscular junction. Thepatient is observed, and ideally a video recorded, looking fora transient improvement in previously documented weak-ness, for example, ptosis, dysphonia. This test is not without
risk and should only be performed by sta ffexperienced in
paediatric resuscitation, due to the cholinergic e ffects of
edrophonium, which can result in bradycardia, nausea, andexcess salivation.
4.3. Electrophysiology. Electrophysiological testing can be
invaluable in investigation of suspected JMG. Repetitivenerve stimulation in JMG will show a decrement in thecompound motor action potential of >10% by the 4th or 5th
stimulation.
Single fibre EMG (SFEMG) is especially useful in
diagnosis of seronegative MG and congenital myasthenicsyndromes. It can be technically more di fficult in children
due to discomfort of the procedure and the level of cooper-ation required. It can be done under local or even generalanaesthetic. Sensitivity for a neurotransmission disorder is97% [ 27].A normal result therefore makes a diagnosis of
myasthenia very unlikely [ 28].
4.4. Imaging. Although thymoma in children is rare, the
thymus must be imaged (usually by CT) once JMG has beendiagnosed. AChR seropositive MG is frequently associatedwith changes in the thymus, with histological changes andin vitro e ffects suggesting that the thymus plays a pathogenic
role [ 47].Thymus hyperplasia is the commonest abnormality
of the thymus in JMG [ 20]. Thymoma is particularly rare in
prepubertal children [ 12].Thymus changes are not a common feature of MuSK
positive disease, and thymoma has not been reported inMuSK-positive children.
Thymus abnormalities in SNMG patients have been
found to be histologically very similar to the thymus hyper-plasia seen in AChR seropositive MG [ 47].
5. Management
Management of children with JMG should be delivered
by a multidisciplinary team comprising a paediatrician
with support from a paediatric neurologist, physiotherapist,occupational therapist, psychologist, speech therapist anddietician. Other members of the team may also need tobe involved, depending on associated comorbidities such asbulbar weakness leading to di fficulty with oral feeding, or
respiratory insu fficiency requiring noninvasive ventilatory
support, which should be managed by a respiratory paedi-atrician.
T reatment of JMG has largely been extrapolated from
adult studies and experience with adult patients. There arefew studies looking specifically at interventions in children,particularly prepubertal children (see Ta b l e 3 ). Some case
series include paediatric patients but they are often notsubdivided into prepubertal and postpubertal age groupsfor analysis. Given the evidence that prepubertal JMG maybehave quite di fferently in terms of disease severity and
progression, this may impact on necessity for treatment andtreatment response. Side-e ffect profiles and considerations
are not always directly comparable between adult andpaediatric populations.
5.1. Acetylcholinesterase Inhibitors. Acetylcholinesterase in-
hibitors are first-line treatment in JMG and provide symp-tomatic relief. In mild cases and in some cases of ocularMG, acetylcholinesterase therapy may be su fficient. Pyri-
dostigmine is a long-acting cholinesterase inhibitor that iscommonly used. Dosing is usually 4–6 times per day and istailored to e ffects. Cautious use in MuSK-positive children is
advised due to risk of acetylcholine hypersensitivity [ 48].
5.2. Thymectomy. Because of the presumed role of the thy-
mus in the pathogenesis of MG, thymectomy is a recognisedaspect of management. Thymectomy may remove thymicgerminal centres and disrupt antibody diversification [ 47].
A systematic review of the literature concluded that thymec-
tomy increases the probability of remission or improve-ment of symptoms in AChR seropositive, nonthymomatous,autoimmune MG [ 49]. This paper included only one pae-
diatric study [ 31]. More recent reviews of children including
prepubertal patients, also suggested increased remission ratesafter thymectomy [ 30,32]. Caution needs to be taken in
early childhood due to subsequent immunosuppression andthe high rates of spontaneous remission in prepubertalpresenters.
Current evidence suggests that thymectomy should not
be recommended in MuSK-positive disease as it is unclearwhether it confers any benefit [ 29,50,51].

4 Autoimmune Diseases
Ta ble 3: T reatment options in JMG.
Treatment Evidence of e fficacy in generalised JMG Reference
Acetylcholinesterase
inhibitorsFirst line therapy.May be su fficient in ocular JMG
or mild generalised JMGSkeie et al., 2010 [ 29]
ThymectomyRecommended to increase remission rates in
postpubertal, seropositive children. Not
recommended in prepubertal childrenHennessey et al., 2011 [ 30]
Rodriguez et al., 1983 [ 31]
T racy et al., 2009 [ 32]
Lindner et al., 1997 [ 20]
SteroidsOften used in combination with steroid sparing
agents. Significant side-e ffect profile if used
long-term at high doseSchneider-Gold et al., 2005 Cochrane review: one
JMG study, others adult or unspecified age ranges
[33]
Zhang et al., 1998 [ 6]
Steroid sparing agents
AzathioprineUsually used in combination with corticosteroids.
Occasionally used alone.Mertens et al., 1981 [ 34] includes some children
but no subgroup analysisGold et al., 2008 [ 35]
Palace et al., 1998 [ 36] adult study
Cyclosporin AAs monotherapy or in conjunction with
corticosteroidsTindall et al., 1987 [ 37] adult study
Hart et al., 2009 (Cochrane) [ 38] series include
some children
CyclophosphamideDe Feo et al., 2002 [ 39] adult population
Hart et al., 2009 [ 38] (Cochrane) series include
some children
T acrolimusFurukawa et al., 2008 [ 40]
Ponseti et al., 2008 [ 41]
both include post pubertal children
Ishigaki et al., 2009 [ 42] prepubertal female
MMFHehir et al., 2010 [ 43] includes some
peri-/postpubertal children
Rituximab Wylam et al., 2003 [ 44] pediatric case
IVIG/Plasma exchangeSelcen et al., 2000 [ 45]
Gajados et al., 2008, Cochrane database [ 46]
Thymectomy in pure OMG remains controversial .
Whereas OMG is not life threatening, patients may bedependent on long-term immunosuppressant medications,including corticosteroids, with the resultant side e ffects
which can be substantial in children. Persistent amblyopiacan result in children as the visual system is maturing. Asdiscussed above, we know that a proportion of children willprogress to generalised disease. Thymectomy is not proven toreduce risk of progression of OMG to generalised JMG [ 52]
and is not routinely indicated in pure OMG in children buthas been performed in refractory cases.
A variety of surgical methods for thymectomy have
been described: full or partial sternotomy, thorascopic, ortranscervical approaches. Evidence suggests that symptomresolution is equivalent regardless of surgical approach [ 53,
54].After thymectomy there is increased risk of antimus-
carinic side e ffects of cholinesterase inhibitors, and they
should therefore be used under close supervision in thepostoperative period.
5.3. Immunosuppressive Therapies. Frequently some form
of immunosuppression or immunomodulation is requiredto improve symptoms of JMG. Corticosteroids are ofteneffective and are the mainstay of therapy but can worsensymptoms in the first few weeks of use, particularly if started
at high doses [ 33].Because of the numerous adverse e ffects
associated with long-term high-dose steroids, steroids areoften used in combination with a steroid-sparing immuno-suppressant, for example, azathioprine .Children are at par-
ticular risk of steroid side e ffects, including growth failure,
susceptibility to severe infection, and delay in receiving livevaccinations.
Azathioprine is a purine analogue that suppresses B and
T cell proliferation. It has been found to be e ffective when
used alone [ 34],but is most commonly used in combination
with prednisolone as a steroid-sparing agent. Beneficialeffects may take months to be seen [ 35] but eventually result
in weaning of steroid doses [ 36].
Some studies have suggested that azathioprine or corti-
costeroids may reduce the likelihood of progression of OMGto the generalised form of disease [ 55,56]. Although these
studies included some children in their case series, these werenot specifically paediatric studies, and given the lower ratesof progression in prepubertal children anyway, these findingsare of uncertain relevance in paediatric practice.
Patients unresponsive or intolerant to azathioprine
should be considered for other immunosuppressive agents,which could include cyclosporin A (which has a faster

Autoimmune Diseases 5
time to symptomatic benefit than azathioprine [ 37]) or
cyclophosphamide [ 39]. A Cochrane review suggests that
cyclosporin either as monotherapy or with corticosteroids,or cyclophosphamide in conjunction with corticosteroids,improves symptoms of MG within 1 year [ 38].
Mycophenolate mofetil (MMF) blocks purine synthesis
by selectively inhibiting proliferation of activated T and Blymphocytes [ 57].A recent retrospective study of AChR
seropositive patients, which included children (age range11–87 y), concluded some benefit of MMF when usedeither as monotherapy or in conjunction with prednisolone .
Maximum e ffects may not be seen until after one year of
treatment [ 43].
T acrolimus inhibits interleukin 2 .Efficacy studies have
been carried out in adults and postpubertal children andhave shown early and sustained improvement of symptomswith tacrolimus, allowing dose reduction of prednisoloneand in many cases its complete withdrawal .These steroid
sparing e ffects were seen within 6 months [ 40,41]. A case
has also been reported of tacrolimus being successfully usedas adjunctive therapy in refractory pure ocular myasthenia ina3 – y e a r – o l dg i r l[ 42].
Rituximab is a chimeric IgG monoclonal antibody that
depletes B cells and has been used in refractory JMG [ 44].
5.4. Plasma Exchange/Intravenous Immunoglobulin (IVIG).
Improvement in symptoms after plasma exchange or admin-
istration of IVIG is usually temporary, 4–10 weeks. Their use
is therefore largely reserved to optimise condition for surgery
before thymectomy and in management of myasthenic crisis[45,46,58]. A single randomised controlled trial showed no
evidence for superior benefit of plasma exchange over IVIG
in treatment of myasthenic crisis [ 59].
Efficacy studies are not available for prepubertal children.
Allogeneic hematopoietic cell transplantation has been
reported as successful in treating a 17-year-old male with
refractory JMG that had been diagnosed aged 11 months[60].
6. Outcome
Outcomes in JMG have improved significantly over the last
decade, with better recognition, diagnosis, and more e ffective
therapies, and long-term prognosis is good [ 61]. Children
with JMG exhibit higher rates of remission than adults. This
includes spontaneous remission and remission following a
period of drug therapy. Prepubertal children have the highest
rates of spontaneous remission. Remission rates also appear
to be influenced by ethnic origin [ 1].
7. Summary
JMG is a rare, autoimmune condition of childhood that
shares many characteristics of clinical presentation and
management strategies with the adult form of the disease.
However, as described in this paper, there are many impor-
tant aspects that are specific to the paediatric population,in particular the distinct clinical features of the prepubertal
presentations, di fferences in rates of AChR seropositivity,
diagnostic challenges including di fferentiation from CMS,
and response to therapy. Further studies looking at e fficacy
of therapies in pre- and postpubertal children are neededto better understand and support this distinct group of
patients.
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