Myasthenia Gravis

An autoimmune disease characterized by episodic muscle weakness caused by loss or dysfunction of acetylcholine receptors at the skeletal muscle motor end plate.

Myasthenia gravis can occur at any age, but the incidence peaks among women in the 3rd and 4th decades and among men in the 6th and 7th decades. Among the elderly, myasthenia gravis is more common in men.

This receptor deficiency is caused by circulating anti-acetylcholine receptor antibodies that block the -bungarotoxin binding sites to the acetylcholine receptor and accelerate the turnover rate (ie, internalization and destruction) for the receptor. The role of the thymus gland is unknown, but about 65% of patients have thymic hyperplasia, and 10 to 15% have thymoma.

Symptoms and Signs

Muscle weakness and fatigability are characteristic. Symptoms typically fluctuate; they are most pronounced at night and are relieved by rest. Initial symptoms include ptosis, diplopia, or blurred vision in > 50% of patients; generalized weakness and fatigue in about 10%; and dysphagia, facial weakness, or slurred nasal speech in about 5%. In the elderly, symptoms are usually most severe in the extraocular and bulbar muscles. Symptoms remain limited to the extraocular muscles in about 15% of patients and become generalized in 85%, usually within the first year. Symptoms reach maximum severity in the first year in 50% of patients and within 5 years in almost all patients.

Myasthenic crisis is characterized by the acute onset of respiratory insufficiency, often with difficulty swallowing and speaking, and by increased weakness in the arms and legs. Infection, trauma, or use of aminoglycosides, cardiac drugs, antihistamines, or anxiolytics may precipitate myasthenic crisis.

Diagnosis

The diagnosis is usually based on the history and physical examination. The most sensitive and accurate diagnostic test is a quantitative measurement of anti-acetylcholine receptor antibodies. These antibodies are increased in 85 to 90% of patients with generalized myasthenia gravis and in 50 to 70% of patients with ocular myasthenia. The number of antibodies is also increased in > 90% of patients with thymoma.

Measurement of acetylcholine receptor modulating antibodies is useful in patients with negative results on anti-acetylcholine receptor antibody testing. Patients with thymoma also often have increased numbers of anti-striated muscle antibodies, as do about 55% of patients > 60 with myasthenia gravis alone. Thymoma is diagnosed by CT or MRI; MRI provides more information about the soft tissue and vascular supply.

An anticholinesterase test can temporarily reverse the muscle weakness in those with myasthenia. Edrophonium (a short-acting anticholinesterase) is given IV as a single initial dose of 2 mg and compared with placebo in a double-blind fashion while the patient is monitored by ECG; IV atropine and resuscitative equipment must be available because of the risk of cardiac rhythm disturbance, particularly in elderly persons.

The repetitive stimulation test can identify a pathologic decline in the electrical response to repeated nerve impulses to a specific muscle. A decremental response often occurs 1 to 2 minutes after exercise. As many as 50 to 60% of patients with known myasthenia have positive results when two or three muscles are tested.

Treatment

First-line therapy is often an anticholinesterase drug, such as pyridostigmine bromide at an initial dose of 30 to 60 mg po tid or qid. Some patients require dosing every 2 to 3 hours. Dosage must be carefully adjusted to individual requirements, and mild exacerbations may require an increase in dosage. Concomitant use of ephedrine 25 mg bid or tid with pyridostigmine may have a synergistic effect (the exact mechanism by which ephedrine affects skeletal muscle contraction is unknown).

The elderly usually require additional therapy to these first-line drugs, because their extraocular and bulbar symptoms are especially resistant to anticholinesterase treatment. Immunosuppressants (eg, azathioprine) and corticosteroids (eg, prednisone) are the mainstays of long-term management. Plasmapheresis and IV immune globulin are useful for myasthenic crisis or episodes of severe exacerbation.

Thymectomy is not typically recommended to relieve myasthenia in patients whose myasthenia begins after age 60 because this approach has not been proven to be more effective than immunosuppressants. However, thymoma should be sought and removed because of its potential for malignancy. Surgery has a higher initial risk and often takes 2 to 3 years to achieve maximum benefit for myasthenia. In elderly patients, immunosuppressants offer less long-term risk (eg, for lymphoma, leukemias) because life expectancy is often shorter than the time required to develop malignancy.

Rarely, treatment causes cholinergic crisis, characterized by increasing muscle weakness and increasing cholinergic effects. If cholinergic crisis occurs, treatment consists of withholding drugs, intubating the patient, and providing ventilatory support.