Neonatal Myasthenia Gravis

Etiology

This is an autoimmune disorder and affects neonates born to mothers with autoimmune MG. Neonatal MG occurs due to the transplacental passage of antibodies directed against various neuromuscular junction antigens. The most common antigen is the nicotinic acetylcholine receptor (AChR). Another important antigen is the muscle-specific receptor tyrosine kinase (MuSKR).

Epidemiology

The incidence of MG in the general population ranges from 1.7 TO 30.0 cases per million person-years, with a prevalence of 77.7 cases per million persons.[2][3] A meta-analysis concluded that the incidence of juvenile MG is approximately between 1.0 and 5.0 cases per million person-years.[2] Pediatric patients were found to make up approximately 10% TO 15% of all patients with autoimmune MG in a prevalence study in Virginia.[4] Among Asian populations, there appears to be a higher prevalence of JMG compared to white populations, with JMG representing 50% of all autoimmune MG. Epidemiological data specific to neonatal MG is scarce.[5][6][7] Due to poor detection rate and difficulty with clinical identification of neonatal MG in mildly affected infants, underreporting this MG is likely. In general, neonatal MG is noted to be rare and may present in 10% to 15% of newborns born to mothers with MG. However, the risk of neonatal MG in a sibling is significantly higher in subsequent pregnancies. There is no reported race or gender preference. There is no definite association between the mother's disease severity and the newborn's clinical presentation. 

Pathophysiology

Neonatal MG is an antibody-mediated disorder caused by the transplacental transmission of maternal antibodies. Approximately three-quarters of the mothers with MG possess anti-acetylcholine receptor (anti-AChR) antibodies. These circulating maternal autoantibodies cross the placenta to the fetus. They are responsible for nicotinic acetylcholine receptor loss by speeding up their degradation, blocking acetylcholine binding, and prompting the lysis of the postsynaptic membrane through activation of the complement system. This leads to an affected child after birth(rarely before birth with decreased fetal movements and the formation of arthrogryposis multiplex congenita and decreased fetal swallowing and polyhydramnios). The antibodies can be directed against the fetus (present until 33 weeks gestation) or the adult acetylcholine receptor. Children of mothers who have MG develop neonatal MG approximately 5% to 30% of the time.[8][9]

History and Physical

The neonates become symptomatic 3 to 72 hours after birth. Most symptomatic babies have poor sucking, respiratory distress, and generalized hypotonia in association with a weak cry and facial diplegia. Gavage feeding for swallowing difficulties and ventilator support due to breathing difficulties can be necessary in severe cases. In contrast to older children, ptosis (may be unilateral, bilateral, and symmetric) and ophthalmoplegia are relatively uncommon in neonatal MG.[6][10][11] Atypical and severe presentation of neonatal MG can be of arthrogryposis multiplex congenita with the development of multiple joint contractures. However, most neonates completely recover before 4 months, and more than 90% even before 2 months. This improvement correlates with the disappearance of maternal antibodies. Pure ocular MG is not seen in neonatal MG, which is more common in children than adults and tends to occur more often in prepubertal children. In contrast, generalized MG is more common in postpubertal adolescents.[12][9][13] The physical examination in neonates with MG can be significant for the frog-leg position suggestive of diffuse hypotonia. An open mouth and apparent ptosis can help diagnose this condition. Flabby muscles and prominent head lags are common. Deep tendon reflexes are generally intact, but primitive reflexes can be difficult to elicit or absent.

Evaluation

Neonatal MG, like adult MG, is ultimately a clinical diagnosis. A strongly suggestive history (mother with known autoimmune MG) and physical examination may be sufficient to make the diagnosis; however, in rare cases, the clinical presentation is not classic, and the mother is asymptomatic for MG, and it is usually helpful to have positive results on 1 or more standard diagnostic tests.

Antibody Testing for Anti-acetylcholine Receptor

Antibody testing is usually highly specific for MG. In the appropriate clinical setting, positive antibody titers confirm the diagnosis and further testing may only be indicated if the clinical presentation is atypical. Antibody testing only involves serum testing and is relatively inexpensive and straightforward, especially in the case of acetylcholine receptor antibodies. 

Intramuscular Neostigmine Test

Intramuscular neostigmine can be administered to evaluate the response of ptosis, dysphagia, and head lag. In the case of negative or equivocal results, a second dose can be administered after 4 hours. It is best if this testing is performed in a monitored setting (ie, with cardiac telemetry) where advanced cardiorespiratory support is available in case of bradycardia or asystole, which in rare instances occurs during this testing, especially when higher doses are used. Other adverse effects are abdominal cramps, sudden diarrhea, cardiac arrhythmia, and excessive tracheobronchial secretions. Intravenous neostigmine is contraindicated before 2 years of age due to the risk of cardiac arrhythmia. 

Electromyogram/Nerve Conduction Study (EMG/NCS)

This test measures the electrical activity of a muscle or a group of muscles. In some cases, a single-fiber EMG test may be done, which is a more sensitive test. Traditional single-fiber electromyography is not practical for most children, especially as it cannot be performed under sedation or general anesthesia. A variant of single-fiber electromyography, stimulated single-fiber electromyography, is much more helpful in children and adolescents than traditional single-fiber electromyography.[14] A 10% decremental response in the amplitude of the compound muscle action potential with repetitive nerve stimulation can be helpful in the diagnosis but is usually not performed in neonates in most centers.

Treatment / Management

Medical therapies for neonatal MG differ from those for juvenile MG, including chronic pharmacotherapy to increase the availability of acetylcholine neurotransmitters and immunomodulatory and immunosuppressive drugs.[14] Immunomodulation and immunosuppression are more powerful approaches to medical therapy. However, immunomodulation and immunosuppression are typically more invasive or carry greater side effect burdens.[15][16] As in adults, pediatric patients and their families should be counseled regarding medications that may exacerbate MG.[17] In the neonatal age group, the use of aminoglycoside should be given particular importance, as it may potentiate symptoms of MG. However, for neonatal MG, the treatment lasts, if necessary, only for a few days to a few months. If mildly symptomatic, small and frequent feeding is necessary with proper surveillance for aspiration and dysphagia. In more severe cases, oral or IM neostigmine may be necessary, as well as gavage feeding. Administration of neostigmine 30 minutes before feeding can help with dysphagia. Pyridostigmine (a slightly longer-acting agent) can be used alternatively. Fortunately, plasmapheresis, intravenous immunoglobulins, and corticosteroids are all efficacious in treating MG in older children and adults but rarely are needed and only necessary for managing severely affected neonates for rapid removal of circulating antibodies.[18][19] Infants born to mothers who have taken corticosteroids during pregnancy should be monitored for adrenal inefficiencies during the newborn period. This topic focuses on neonatal MG, and thymectomy is not necessary for these patients. Please refer to numerous retrospective pediatric studies that indicate that thymectomy is potentially beneficial for juvenile MG.[20][21][22][10][23](A1)

Differential Diagnosis

The following conditions mimic neonatal MG:

• Spinal muscular atrophy
• Congenital MG
• Morphologically distinct congenital myopathies like central core disease, nemaline myopathy, and myotubular myopathy.
• Congenital muscular dystrophies
• Limb-girdle or facioscapulohumeral muscular dystrophy
• Infantile myotonic dystrophy
• Mitochondrial myopathy
• Brainstem anomaly
• Mobius syndrome
• Congenital fibrosis of extraocular muscles
• Infantile botulism
• Seropositive and seronegative forms of autoimmune MG

Prognosis

The outcome in the classical form of neonatal MG is excellent, assuming appropriate respiratory and nutritional support. Severe and rare variants of this disease cause long-term complications in neonates born with MG. Most patients experience spontaneous remission after weeks to months.

Complications

Traditionally, neonatal MG has been regarded as a relatively benign disease with few to no long-term consequences when properly treated. However, more severe variants associated with long-term medical consequences have been described, including the fetal acetylcholine receptor inactivation syndrome. Thus, these variants should be considered in the differential diagnosis of children with unexplained muscle weakness in the setting of distinct clinical features associated with these forms of neonatal MG.