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 condition of 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 differentiate from congenital myasthenic syndromes, which do not have an autoimmune basis. Treatment commonly includes anticholinesterases, corticosteroids with or without steroid-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.
Myasthenia gravis (MG) is an autoimmune disease in which antibodies are directed at the postsynaptic membrane of the neuromuscular junction, leading to varying degrees of muscle weakness and fatigability. Where MG presents before 19 years of age, it is termed juvenile myasthenia gravis (JMG). Although JMG shares many features with the more common adult MG, there are many important differences.
In this paper we discuss the pathogenesis, epidemiology, presentation, treatment, and outcome of JMG and highlight some of the clinical features and challenges particular to paediatric patients.
In the majority of cases MG is caused by antibodies to the nicotinic acetylcholine receptor (AChR). Antibodies to the AChR are found in over 80% adults with generalised disease but only in 55% of adults with weakness confined to the oculomotor muscles. Patients with AChR antibodies are often referred to as seropositive. AChR antibodies are probably less frequent in prepubertal patients than in adolescent and adult patients [
Comparisons of prepubertal and postpubertal features of JMG.
Prepubertal | Pubertal | Postpubertal/ | |
---|---|---|---|
Male : female ratio | M = F | F > M 4.5 : 1 | F > M 4.5 : 1 |
Patients with AChR antibodies detected in generalised disease | 50–71% | 68–92% | 80–90% |
Ocular presentation | |||
Caucasian | 40% [ | | |
Chinese | 75% [ | ||
Progression of OMG to generalised MG | 8–15% | 23–43% | 79% [ |
Remission (spontaneous or with treatment) | 42–60% | 26% [ | 38% [ |
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 [
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 [
The most frequent clinical presentation of JMG is with ptosis, which is often associated with other ocular symptoms namely unilateral or asymmetric ophthalmoplegia, strabismus, and lid twitch, which may only be elicited after sustained upgaze [
Prepubertal children presenting with JMG have some interesting and distinct clinical features compared with those who present around or after puberty [
Ocular myasthenia gravis (OMG) is, by definition, MG restricted to the oculomotor muscles for 2 years without becoming generalised [
This results from transfer of maternal AChR antibodies across the placenta leading to defects of neuromuscular transmission in the neonate [
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 diagnosis. 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 different (see Table
Differential diagnosis of JMG.
Congenital myasthenic syndromes | Usually presents in infancy but can present later |
Mitochondrial cytopathies | Children frequently have additional neurological impairments or epilepsy |
Myopathies | Including congenital myopathies and muscular dystrophies |
Neurotoxins | For example, botulism, venoms |
Guillain-Barré syndrome | |
Acute disseminated encephalomyelitis | |
Multiple sclerosis | |
Brainstem tumour | |
Hypothyroidism |
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 and DNA analysis and occasionally by muscle biopsy [
Detection of antibodies to the AChR supports the diagnosis of JMG. In young children where AChR antibodies are negative this can lead to difficulty in differentiating from CMS. Some of these children who are negative for AChR antibodies will have “low affinity” antibodies to the AChR which were not detectable using the standard assays [
A variable percentage (0–49%) of MG patients without AChR antibodies are found to have antibodies against another neuromuscular junction protein, the muscle-specific kinase (MuSK) [
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. “Low affinity” antibodies to clustered AChRs can be found in 60% of previously defined SNMG patients. These antibodies are found in all age groups [
Seroconversion has been described in a small number of cases of children who have developed MuSK antibodies after thymectomy for AChR seropositive MG [
Other potential antigens at the neuromuscular junction have been identified in adults with later-onset MG, but the relevance to the childhood population has not been established [
The Tensilon test involves intravenous infusion of edrophonium, a fast-acting, short-duration cholinesterase inhibitor. This prevents the breakdown of acetylcholine, thereby increasing the concentration of the neurotransmitter at the neuromuscular junction. The patient is observed, and ideally a video recorded, looking for a transient improvement in previously documented weakness, for example, ptosis, dysphonia. This test is not without risk and should only be performed by staff experienced in paediatric resuscitation, due to the cholinergic effects of edrophonium, which can result in bradycardia, nausea, and excess salivation.
Electrophysiological testing can be invaluable in investigation of suspected JMG. Repetitive nerve stimulation in JMG will show a decrement in the compound 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 myasthenic syndromes. It can be technically more difficult in children due to discomfort of the procedure and the level of cooperation required. It can be done under local or even general anaesthetic. Sensitivity for a neurotransmission disorder is 97% [
Although thymoma in children is rare, the thymus must be imaged (usually by CT) once JMG has been diagnosed. AChR seropositive MG is frequently associated with changes in the thymus, with histological changes and in vitro effects suggesting that the thymus plays a pathogenic role [
Thymus changes are not a common feature of MuSK positive disease, and thymoma has not been reported in MuSK-positive children.
Thymus abnormalities in SNMG patients have been found to be histologically very similar to the thymus hyperplasia seen in AChR seropositive MG [
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 and dietician. Other members of the team may also need to be involved, depending on associated comorbidities such as bulbar weakness leading to difficulty with oral feeding, or respiratory insufficiency requiring noninvasive ventilatory support, which should be managed by a respiratory paediatrician.
Treatment of JMG has largely been extrapolated from adult studies and experience with adult patients. There are few studies looking specifically at interventions in children, particularly prepubertal children (see Table
Treatment options in JMG.
Treatment | Evidence of efficacy in generalised JMG | Reference |
---|---|---|
Acetylcholinesterase inhibitors | First line therapy.May be sufficient in ocular JMG or mild generalised JMG | Skeie et al., 2010 [ |
Thymectomy | Recommended to increase remission rates in postpubertal, seropositive children. Not recommended in prepubertal children | Hennessey et al., 2011 [ |
Steroids | Often used in combination with steroid sparing agents. Significant side-effect profile if used long-term at high dose | Schneider-Gold et al., 2005 Cochrane review: one JMG study, others adult or unspecified age ranges [ |
Steroid sparing agents | ||
Azathioprine | Usually used in combination with corticosteroids. Occasionally used alone. | Mertens et al., 1981 [ |
Cyclosporin A | As monotherapy or in conjunction with corticosteroids | Tindall et al., 1987 [ |
Cyclophosphamide | De Feo et al., 2002 [ | |
Tacrolimus | Furukawa et al., 2008 [ | |
MMF | Hehir et al., 2010 [ | |
Rituximab | Wylam et al., 2003 [ | |
IVIG/Plasma exchange | Selcen et al., 2000 [ |
Acetylcholinesterase inhibitors are first-line treatment in JMG and provide symptomatic relief. In mild cases and in some cases of ocular MG, acetylcholinesterase therapy may be sufficient. Pyridostigmine is a long-acting cholinesterase inhibitor that is commonly used. Dosing is usually 4–6 times per day and is tailored to effects. Cautious use in MuSK-positive children is advised due to risk of acetylcholine hypersensitivity [
Because of the presumed role of the thymus in the pathogenesis of MG, thymectomy is a recognised aspect of management. Thymectomy may remove thymic germinal centres and disrupt antibody diversification [
Current evidence suggests that thymectomy should not be recommended in MuSK-positive disease as it is unclear whether it confers any benefit [
Thymectomy in pure OMG remains controversial
A variety of surgical methods for thymectomy have been described: full or partial sternotomy, thorascopic, or transcervical approaches. Evidence suggests that symptom resolution is equivalent regardless of surgical approach [
Frequently some form of immunosuppression or immunomodulation is required to improve symptoms of JMG. Corticosteroids are often effective and are the mainstay of therapy but can worsen symptoms in the first few weeks of use, particularly if started at high doses [
Azathioprine is a purine analogue that suppresses B and T cell proliferation. It has been found to be effective when used alone [
Some studies have suggested that azathioprine or corticosteroids may reduce the likelihood of progression of OMG to the generalised form of disease [
Patients unresponsive or intolerant to azathioprine should be considered for other immunosuppressive agents, which could include cyclosporin A (which has a faster time to symptomatic benefit than azathioprine [
Mycophenolate mofetil (MMF) blocks purine synthesis by selectively inhibiting proliferation of activated T and B lymphocytes [
Tacrolimus inhibits interleukin 2
Rituximab is a chimeric IgG monoclonal antibody that depletes B cells and has been used in refractory JMG [
Improvement in symptoms after plasma exchange or administration 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 [
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 [
Outcomes in JMG have improved significantly over the last decade, with better recognition, diagnosis, and more effective therapies, and long-term prognosis is good [
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 important aspects that are specific to the paediatric population, in particular the distinct clinical features of the prepubertal presentations, differences in rates of AChR seropositivity, diagnostic challenges including differentiation from CMS, and response to therapy. Further studies looking at efficacy of therapies in pre- and postpubertal children are needed to better understand and support this distinct group of patients.