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  • Updated 02.15.2021
  • Released 12.07.1994
  • Expires For CME 02.15.2024

Myasthenia gravis



Myasthenia gravis is a potentially fatal neuromuscular disorder, but myasthenic patients typically lead normal lives when properly diagnosed and managed. In this article, the author reviews the immunopathogenesis, clinical features, diagnostic evaluation, and treatment of myasthenia gravis. The full range of diagnostic methods, including electrophysiologic and immunologic tests, is detailed along with surgical and pharmacologic treatments. Developments include the growing use of monoclonal antibody and other novel immunotherapies, including eculizumab, which has been approved by the FDA for use in acetylcholine receptor–positive myasthenia gravis patients.

Key points

• Myasthenia gravis is fatal in up to one third of patients if untreated.

• The most dangerous manifestation of myasthenia is bulbar and respiratory crisis due to rapidly progressive muscle weakness.

• Hospitalization and observation with respiratory monitoring and support are essential in myasthenia gravis crisis.

• Acute therapy is best achieved with IVIG or plasma exchange.

• Chronic immunomodulatory therapy can effectively control symptoms in the vast majority of patients.

• Ten percent of patients with myasthenia gravis will have a thymoma.

Historical note and terminology

As early as 1904, Elliot proposed that neurotransmitter release at the neuromuscular junction could mediate muscle contraction (01). In 1934, specific release of acetylcholine at the neuromuscular junction was demonstrated (Nachmansohn 1939). During this same period, a number of reports of pathologic thymic abnormalities in myasthenic patients and of symptomatic improvement following thymectomy appeared, prompting Blalock to further investigate and ultimately recommend removal of the thymus as a primary therapy (10; 13). In 1960, Simpson proposed an autoimmune pathogenesis for myasthenia gravis based on the high prevalence of immunologic disorders in myasthenic patients, the transient neonatal form of the disease, and the well-described thymic abnormalities.

Later studies demonstrated antibodies in the sera of affected patients that reacted with the cross striations of skeletal muscle, as well as muscle membrane damage following the application of myasthenic sera to nerve-muscle preparations. In 1962, alpha-bungarotoxin (a snake alpha-toxin) was found to specifically bind and irreversibly inactivate the acetylcholine receptor (AChR) in skeletal muscle. The density of AChRs is particularly high in the electric organs of the Torpedo marmorata electric fish (127), providing a rich source of AChRs for basic scientific investigation. In 1973, a group of rabbits was immunized with solubilized membranes from torpedo electric organs in an attempt to create anti-AChR antibodies for labeling studies. These animals developed a syndrome that closely paralleled human myasthenia gravis (120). The detection of antibodies in these animals that cross-reacted with rabbit AChRs confirmed the first animal model of experimental allergic myasthenia gravis. In 1974, Alman, Andrew, and Appel identified anti-AChR antibodies in human sera (04), further opening a promising new immunologic frontier in the pathogenesis of human disease. Subsequent animal models have been created in rats, mice, goats, monkeys, frogs, and hens (81). Passive transfer has also been accomplished by injection of human myasthenia gravis IgG into mice and of experimental allergenic myasthenia gravis sera and purified monoclonal anti-AChR antibodies into normal mice or rats (155). The data from these early experiments confirmed an autoimmune pathogenesis for myasthenia gravis, satisfying the criteria proposed by Milgrom and Witebsky for an autoimmune etiology (94).

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