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Myasthenia gravis involves episodic muscle weakness and easy fatigability caused by autoantibody- and cell-mediated destruction of acetylcholine receptors. It is more common among young women but may occur in men or women at any age. Symptoms worsen with muscle activity and lessen with rest. Diagnosis is by measurement of serum acetylcholine receptor (AChR) antibody levels, electromyography, and sometimes IV edrophonium challenge, which briefly lessens the weakness. Treatment includes anticholinesterase drugs, immunosuppressants, corticosteroids, plasma exchange, IV immune globulin, and possibly thymectomy.
(See also Overview of Peripheral Nervous System Disorders.)
Myasthenia gravis develops most commonly in women aged 20 to 40.
Myasthenia gravis results from an autoimmune attack on postsynaptic acetylcholine receptors, which disrupts neuromuscular transmission. The trigger for autoantibody production is unknown, but the disorder is associated with abnormalities of the thymus, autoimmune hyperthyroidism, and other autoimmune disorders (eg, RA, SLE, pernicious anemia).
The role of the thymus in myasthenia is unclear, but 65% of patients have thymic hyperplasia, and 10% have a thymoma. About half of the thymomas are malignant.
Precipitating factors for myasthenia gravis include
Only about 10 to 20% of patients with generalized myasthenia have no antibodies to acetylcholine receptors (AChR) in serum; up to 50% of these AChR antibody‒negative patients have antibodies to muscle-specific receptor tyrosine kinase (MuSK), a surface membrane enzyme that helps AChR molecules aggregate during development of the neuromuscular junction. However, anti-MuSK antibodies do not occur in most patients with AChR antibodies or with isolated ocular myasthenia.
The clinical significance of anti-MuSK antibodies is still under study, but patients with these antibodies are much less likely to have thymic hyperplasia or a thymoma, may be less responsive to anticholinesterase drugs, and may require more aggressive early immunotherapy than patients who have AChR antibodies.
Ocular myasthenia gravis involves only extraocular muscles. It represents about 15% of cases.
Congenital myasthenia is a rare autosomal recessive disorder that begins in childhood. It is not immune-mediated and results from presynaptic or postsynaptic abnormalities, including the following:
Ophthalmoplegia is common.
Neonatal myasthenia affects 12% of infants born to women with myasthenia gravis. It is due to IgG antibodies that passively cross the placenta. It causes generalized muscle weakness, which resolves in days to weeks as antibody titers decline. Thus, treatment is usually supportive.
The most common symptoms are ptosis, diplopia, and muscle weakness after use of the affected muscle. Weakness resolves when the affected muscles are rested but recurs when they are used again.
Ocular muscles are affected initially in 40% of patients and eventually in 85% and are the only muscles affected in 15%. If generalized myasthenia is going to develop after ocular symptoms, it usually does so within the first 3 yr.
Hand grip may alternate between weak and normal (milkmaid’s grip). Neck muscles may become weak. Proximal limb weakness is common. Some patients present with bulbar symptoms (eg, altered voice, nasal regurgitation, choking, dysphagia). Sensation and deep tendon reflexes are normal. Manifestations fluctuate in intensity over minutes to hours to days.
Myasthenic crisis, a severe generalized quadriparesis or life-threatening respiratory muscle weakness, occurs in about 15 to 20% of patients at least once in their life. It is often due to a supervening infection that reactivates the immune system. Once respiratory insufficiency begins, respiratory failure may occur rapidly.
Cholinergic crisis is muscular weakness that can result when the dose of anticholinesterase drugs (eg, neostigmine, pyridostigmine) is too high. A mild crisis may be difficult to differentiate from worsening myasthenia. Severe cholinergic crisis can usually be differentiated because it, unlike myasthenia gravis, results in increased lacrimation and salivation, tachycardia, and diarrhea.
The diagnosis of myasthenia gravis is suggested by symptoms and signs and confirmed by tests.
The traditional anticholinesterase test, done at bedside and using the short-acting (< 5 min) drug edrophonium, is positive in most patients who have myasthenia with overt weakness. However, this test should only be done in patients with obvious ptosis or ophthalmoparesis; these deficits must be present to be able to clearly see improvement to normal strength and thus provide unequivocal objective evidence of a positive test result. For the test, patients are asked to exercise the affected muscle until fatigue occurs (eg, to hold the eyes open until ptosis occurs); then, edrophonium 2 mg IV is given. If no adverse reaction (eg, bradycardia, atrioventricular block) occurs within 30 sec, another 8 mg is given. Rapid (< 2 min) recovery of muscle function is a positive result. However, this test is not ideal for the following reasons:
A positive result is not definitive for myasthenia gravis because such improvement may occur in other neuromuscular disorders.
Results may be equivocal, particularly if the test is done in patients without obvious ptosis or ophthalmoparesis.
During the test, weakness due to cholinergic crisis may worsen; thus, resuscitation equipment and atropine (as an antidote) must be available during the test.
Because weakness due to myasthenia lessens in cooler temperature, patients with ptosis can be tested using the ice pack test. For this test, an icepack is applied to a patient's closed eyes for 2 min, then removed. A positive result is full or partial resolution of ptosis. The ice pack test usually does not work if patients have ophthalmoparesis.
Patients with opthalmoparesis can be tested using the rest test. For this test, patients are asked to lie quietly in a dark room for 5 min with their eyes closed. If ophthalmoparesis resolves after this rest, the result is positive.
Even if a bedside test is unequivocally positive, one or both of the following are required to confirm the diagnosis:
AChR antibodies are present in 80 to 90% of patients with generalized myasthenia but in only 50% with the ocular form. Antibody levels do not correlate with disease severity. Up to 50% of patients without AChR antibodies test positive for anti-MuSK antibodies.
EMG using repetitive stimuli (2 to 3/sec) shows a > 10% decrease in amplitude of the compound muscle action potential response in 60% of patients. Single-fiber EMG can detect abnormal neuromuscular transmission in > 95%.
Once myasthenia is diagnosed, CT or MRI of the thorax should be done to check for thymic hyperplasia and a thymoma.
Other tests should be done to screen for autoimmune disorders frequently associated with myasthenia gravis (eg, pernicious anemia, autoimmune hyperthyroidism, RA, SLE).
Patients in myasthenic crisis should be evaluated for an infectious trigger. Bedside pulmonary function tests (eg, forced vital capacity) help detect impending respiratory failure.
In patients with congenital myasthenia, anticholinesterase drugs and immunomodulating treatments are not beneficial and should be avoided. Patients with respiratory failure require intubationand mechanical ventilation.
Anticholinesterase drugs are the mainstay of symptomatic treatment but do not alter the underlying disease process. Moreover, they rarely relieve all symptoms, and myasthenia may become refractory to these drugs.
Pyridostigmine is begun at 60 mg po q 3 to 4 h and titrated up to a maximum of 120 mg/dose based on symptoms. When parenteral therapy is necessary (eg, because of dysphagia), neostigmine (1 mg = 60 mg of pyridostigmine) may be substituted. Anticholinesterase drugs can cause abdominal cramps and diarrhea, which are treated with oral atropine 0.4 to 0.6 mg (given with pyridostigmine or neostigmine) or propantheline 15 mg tid to qid.
Patients who have been responding well to treatment and then deteriorate require respiratory support because they may have cholinergic crisis, and anticholinesterase drugs must be stopped for several days.
Immunosuppressants interrupt the autoimmune reaction and slow the disease course, but they do not relieve symptoms rapidly. After being given IVIG 400 mg/kg once/day for 5 days, 70% of patients improve in 1 to 2 wk. Effects may last 1 to 2 mo. Plasma exchange (eg, 5 exchanges of 3 to 5 L plasma over 7 to 14 days) can have similar effects.
Corticosteroids are necessary as maintenance therapy for many patients but have little immediate effect in myasthenic crisis. Over half of patients worsen acutely after starting high-dose corticosteroids. Initially, prednisone 10 mg po once/day is given; dose is increased by 10 mg weekly up to 60 mg, which is given for about 2 mo, then tapered slowly. Improvement may take several months; then, the dose should be reduced to the minimum necessary to control symptoms.
Azathioprine 2.5 to 3.5 mg/kg po once/day may be as effective as corticosteroids, although significant benefit may not occur for many months. Cyclosporine 2 to 2.5 mg/kg po bid may allow the corticosteroid dose to be reduced. These drugs require the usual precautions.
Other drugs that may be beneficial include methotrexate, cyclophosphamide, and mycophenolate mofetil. For patients with refractory disease, monoclonal antibodies (eg, rituximab, eculizumab) may be beneficial but are costly.
Thymectomy may be indicated for patients with generalized myasthenia if they are < 80 yr; it should be done in all patients with a thymoma. Subsequently, in 80%, remission occurs or the maintenance drug dose can be lowered.
Plasma exchange or IVIG is useful for myasthenic crisis and, for patients unresponsive to drugs, before thymectomy.
Consider myasthenia gravis in patients with ptosis, diplopia, and muscle weakness after use of the affected muscle.
To confirm the diagnosis, measure serum levels of AChR antibody (usually present in myasthenia gravis), do electromyography (EMG), or both.
After the diagnosis is confirmed, test for thymic hyperplasia, thymomas, hyperthyroidism, and autoimmune disorders, which commonly accompany myasthenia gravis.
For most patients, use anticholinesterase drugs to relieve symptoms and immunomodulating treatment to slow disease progression and help relieve symptoms; do not use these treatments in patients with congenital myasthenia.
If patients suddenly deteriorate after responding well to treatment, provide respiratory support and stop anticholinesterase drugs for several days.
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procainamideNo US brand name
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