Description

Primary disorder of neuromuscular transmission characterized by fluctuating muscle weakness:

• Ocular myasthenia gravis (MG) (15%): weakness limited to eyelids and extraocular muscles
• Generalized MG (85%): commonly affects ocular as well as a variable combination of bulbar, proximal limb, and respiratory muscles
• 50% of patients who present with ocular symptoms develop generalized MG within 2 years.
• Onset may be sudden and severe, but it is typically mild and intermittent over many years, maximum severity reached within 3 years for 85%.
• System(s) affected: neurologic, hematologic, lymphatic, immunologic, musculoskeletal

Epidemiology

Occurs at any age but a bimodal distribution to the age of onset:

• Female predominance: 20 to 40 years
• Male predominance: 60 to 80 years

Incidence
Estimated annual incidence 7 to 23/1 million

Prevalence
In the United States, 70 to 320/1 million; increasing over the past 5 decades

Pediatric Considerations
A transient form of neonatal MG seen in 10–20% of infants born to mothers with MG. It occurs as a result of the transplacental passage of maternal antibodies that interfere with function of the neuromuscular junction; resolves in weeks to months. Autoimmune juvenile MG makes up 10–15% of cases of MG in North America.

Etiology and Pathophysiology

• Reduction in the function of acetylcholine receptors (AChRs) at muscle end plates, resulting in insufficient neuromuscular transmission
• Antibody-mediated autoimmune disorder
• Antibodies are present in most cases of MG.
  • Seropositive/antiacetylcholine receptor (anti-AChR): a humoral, antibody-mediated, T-cell–dependent attack of the AChRs or receptor-associated proteins at the postsynaptic membrane of the neuromuscular junction. Found in 85% of generalized MG and 50% of ocular MG; thymic abnormalities common (1)
  • Muscle-specific kinase (MuSKs): 5% of generalized MG patients. Typically females. Is a severe form, respiratory and bulbar muscles involved. Thymic abnormalities are rare (1).
  • In remainder of seronegative, 12–50% with anti-LRP4, a molecule that forms a complex with MuSK, mild generalized weakness most common (1)
  • Seronegative MG (SNMG): 5%; may have anti-AChR detectable by cell-based assay. Clinically similar to anti-AChR; thymic hyperplasia may be present (1).
• Also documented immediately after viral infections (measles, Epstein-Barr virus [EBV], HIV, and human T-lymphotropic virus [HTLV])

Genetics

• Congenital MG syndrome describes a collection of rare hereditary disorders. This condition is not immune-mediated but instead results from the mutation of a component of the neuromuscular junction (autosomal recessive).
• Familial predisposition is seen in 5% of cases.

Risk Factors

• Familial MG
• D-penicillamine (drug-induced MG)
• Other autoimmune diseases

Commonly Associated Conditions

• Thymic hyperplasia (60–70%)
• Thymoma (10–15%)
• Autoimmune thyroid disease (3–8%)