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Key Clinical Updates in Disorders of Neuromuscular Transmission

Eculizumab is FDA-approved for acetylcholine receptor antibody positive myasthenia in patients who have disease refractory to at least two alternate immunosuppressive therapies.

1. MYASTHENIA GRAVIS

ESSENTIALS OF DIAGNOSIS

  • Fluctuating weakness of commonly used voluntary muscles, producing symptoms such as diplopia, ptosis, and difficulty in swallowing.

  • Activity increases weakness of affected muscles.

  • Short-acting anticholinesterases transiently improve the weakness.

General Considerations

Myasthenia gravis occurs at all ages, sometimes in association with a thymic tumor or thyrotoxicosis, as well as in rheumatoid arthritis and lupus erythematosus. It is most common in young women with HLA-DR3; if thymoma is associated, older men are more commonly affected. Onset is usually insidious, but the disorder is sometimes unmasked by a coincidental infection that leads to exacerbation of symptoms. Exacerbations may also occur before the menstrual period and during or shortly after pregnancy. Symptoms are due to a variable degree of block of neuromuscular transmission caused by autoantibodies binding to acetylcholine receptors; these are found in most patients with the disease and have a primary role in reducing the number of functioning acetylcholine receptors (eFigure 24–18). Additionally, cellular immune activity against the receptor is found.

eFigure 24–18.

Pathogenesis of myasthenia gravis. Acetylcholine released at the nerve ending by the nerve impulse normally binds with acetylcholine receptors. This evokes the action potential in the muscle. In myasthenia gravis, antiacetylcholine receptor antibody binds to the acetylcholine receptor and inhibits the action of acetylcholine. Bound antibody evokes immune-mediated destruction of the end plate. (Reproduced, with permission, from Chandrasoma P, Taylor SE. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)

Clinical Findings

A. Symptoms and Signs

Patients present with ptosis, diplopia, difficulty in chewing or swallowing, respiratory difficulties, limb weakness, or some combination of these problems. Weakness may remain localized to a few muscle groups or may become generalized. The external ocular muscles and certain other cranial muscles, including the masticatory, facial, and pharyngeal muscles, are especially likely to be affected, and the respiratory and limb muscles may also be involved. Symptoms often fluctuate in intensity during the day, and this diurnal variation is superimposed on a tendency to longer-term spontaneous relapses and remissions that may last for weeks. Nevertheless, the disorder follows a slowly progressive course and may have a fatal outcome owing to respiratory complications such as aspiration pneumonia.

Clinical examination confirms the weakness and fatigability of affected muscles. In most cases, the extraocular muscles are involved, and this leads to ocular palsies and ptosis, which are commonly asymmetric. Pupillary responses are normal. The bulbar and limb muscles are often weak, but the pattern of involvement is variable. Sustained activity of affected muscles ...

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