112: Myasthenia Gravis (Transient Neonatal)

Myasthenia gravis is a neuromuscular disorder affecting synaptic transmission at the motor end plate. It is characterized by abnormal muscle fatigability and can be either genetic or acquired. Infants born with the genetic form of the disease (very rare) are born to healthy mothers and suffer permanent disability. Transient neonatal myasthenia gravis (TNMG) is an acquired form of the disease that occurs only in infants born to mothers with myasthenia gravis and is the predominant type and is discussed here.

The incidence of myasthenia gravis varies from 9 to 21 cases per million. TNMG is a rare disorder affecting 10–15% of infants born to mothers with myasthenia gravis. There is no race or sex preference. There is no correlation between disease severity in the mother and the clinical outcome of the infant. The risk of disease in a sibling is significantly higher than that of a first born.

1. Anti-acetylcholine receptor antibodies. A total of 75–80% of mothers with myasthenia gravis have anti-acetylcholine receptor (anti-AChR) antibodies. These antibodies cause nicotinic acetylcholine receptor loss by accelerating their degradation, blocking acetylcholine binding, and inducing the lysis of the postsynaptic membrane through induction of the complement system. TNMG is caused by the passive transfer of these maternal antibodies to the fetus. The antibodies can be directed against the fetal acetylcholine receptor (present until 33 weeks' gestation) or the adult receptor. Higher maternal antibody titers directed against the fetal versus the adult acetylcholine receptor has been shown to increase the risk and severity of TNMG.

2. Anti–muscle-specific kinase antibodies. Although anti-AChR antibody–mediated TNMG is the most common cause of the disease, there have been case reports of infants developing TNMG as a result of anti–muscle-specific kinase (anti-MuSK) antibodies. There is some suggestion that this form of TNMG may be more difficult to treat with anticholinesterase agents.

See Sections II and III.

1. Antenatal. Although rare, neonatal weakness can present in utero, and mothers may comment on reduced fetal movements. Polyhydramnios can be present as a result of poor fetal swallowing. Arthrogryposis multiplex congenita can also rarely occur as a result of decreased fetal movement.

2. Postnatal. In 67% of patients symptoms are present within a few hours after birth, and 78% of patients will have symptoms within 24 hours of life. Infants whose mothers have been taking anticholinesterase agents tend to present later than infants whose mothers have not been treated. There have been no known cases with symptoms presenting after day 3 of life.

   The majority of patients present with hypotonia and inadequate suck. Many will have a weak cry, facial diparesis, lack of facial expression, feeding difficulties, and mild respiratory distress. Ptosis and ophthalmoparesis can be present although this is less common. Deep tendon reflexes should still be present.

The key to making the diagnosis is a history of myasthenia gravis in the mother with a symptomatic infant. The diagnosis is confirmed with the use of pharmacologic challenge tests.

1. Anticholinesterase agents. To confirm the diagnosis of TNMG, the infant should show a symptomatic improvement after the administration of an anticholinesterase agent. When evaluating the patient, improvement should be defined as the reversal of definite neurologic impairments (usually sucking or swallowing difficulties) or a decrease in ventilatory requirements. Observing for changes in hypotonia or spontaneous motor activity is not as accurate, particularly in premature infants, infants with hypoxic ischemic encephalopathy, or those with intraventricular hemorrhage. When administering these drugs, atropine may be required to help manage the muscarinic side effects (ie, diarrhea and tracheal secretions).

   1. Neostigmine methylsulfate. Most commonly used diagnostic agent. Consists of a single, 0.15 mg/kg dose administered intramuscularly (IM) or subcutaneously (SC). In a positive test, neurologic improvement is seen 10–15 minutes after administration and persists for 1–3 hours. Muscarinic side effects, in particular, tracheal secretions, can be problematic. False-negative results have been reported.

   2. Edrophonium chloride (Enlon). Administer 0.15 mg/kg IM or SC or 0.1 mg/kg intravenously (IV). Positive effects are seen within 3 minutes (IV) or 3–5 minutes (IM or SC) and last for 10–15 minutes. Muscarinic side effects are not as severe. Can rarely cause respiratory arrest (especially in larger doses). False-negative results are known, particularly in premature infants.

2. Repetitive nerve stimulation. Used rarely for diagnosis when pharmacologic testing has yielded equivocal results. May be useful in patients with prematurity or intrapartum asphyxia where the response to an anticholinesterase inhibitor is questionable and also as a quantitative assessment of neuromuscular function. In the test, the amplitude of the fifth evoked muscle action potential is compared with the first both before and after an anticholinesterase agent is administered. The test is considered positive when the fifth action potential is noted to be decreased by at least 10% and restored to normal after anticholinesterase treatment.

1. Supportive care. The management of TNMG focuses mainly on supportive care. In 20% of patients, symptoms are mild, requiring only small, frequent oral feeding and close observation. These patients are usually discharged from hospital after 1 week. The majority of patients, however, will present with moderate/severe symptoms, many of whom will require gavage feeds and ventilatory support.

2. Anticholinesterase treatment. In addition to supportive care, affected infants can benefit from anticholinesterase treatment. Neostigmine methylsulfate 0.05 mg/kg IM or SC administered 20 minutes before feeding or 0.5 mg/kg NG administered 30 minutes before feeding is the treatment of choice. Doses may be titrated gradually until sucking and swallowing are reestablished. As the dose is increased, careful monitoring for side effects (eg, diarrhea, increased secretions, muscle fasciculations) must occur. As symptoms improve, the dose can be decreased. When symptoms are no longer present and/or when repetitive nerve stimulation is normal, the medication can slowly be discontinued. For the patients presenting with moderate/severe symptoms, 50% will require anticholinesterase treatment for 1–2 weeks, 30% will require treatment for 3–4 weeks, and 20% will need more than 5 weeks of therapy.

3. Intravenous immunoglobulin (IVIG). IVIG has been used with some benefit in those few infants who have anti-MuSK–mediated TNMG and are resistant to anticholinesterase therapy.

4. Plasmapheresis. In mothers with a history of previous children with TNMG, plasmapheresis during pregnancy may help to reduce symptoms in subsequent infants.

Although TNMG can be life-threatening if not identified and treated promptly, for the majority of infants it is a transient illness with no lasting effects. Symptoms last for an average of 18 days (5 days to 4 weeks), and full recovery is seen in 90% of patients by 2 months of age. The remaining 10% of patients recover by 4 months. There have been reports of more prolonged illness; however, these are usually associated in the more atypical cases and in infants with arthrogryposis. Permanent facial diparesis has also rarely been reported.