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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 at any age. Symptoms worsen
with muscle activity and lessen with rest. Diagnosis is by antibody
testing to acetylcholine receptor (AChR), electromyography, and
IV edrophonium challenge, which briefly lessens the weakness. Treatment
includes anticholinesterase drugs, immunosuppressants, corticosteroids, plasmapheresis,
and possibly thymectomy.
Myasthenia gravis develops most commonly in women aged 20 to 40. It 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, thyrotoxicosis, and other autoimmune disorders. 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 include infection, surgery, and certain drugs (eg, aminoglycosides, quinine , Mg sulfate, procainamide , Ca channel blockers).
Some patients with generalized myasthenia have no antibodies to acetylcholine receptors (AChR) in serum. About half of these 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. Anti-MuSK antibodies do not occur in patients with AChR antibodies or with isolated ocular myasthenia. The clinical significance of anti-MuSK antibodies is still under study, but patients with them may be less responsive to anticholinesterase drugs and require more aggressive early immunotherapy than patients who have AChR antibodies.
Uncommon forms:
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 results from structural abnormalities in the postsynaptic receptor rather than an autoimmune disorder. 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.
Symptoms and Signs
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%. Only ocular muscles are affected in 15%. Hand grip may alternate between weak and normal (milkmaid's grip). Neck muscles may become weak. If generalized myasthenia is going to develop after ocular symptoms, it usually does so within the first 3 yr. 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 hours to days.
Myasthenic
crisis, a severe generalized quadriparesis or life-threatening respiratory muscle weakness, occurs in about 10% of patients. It is often due to a supervening infection that reactivates the immune system. Once respiratory insufficiency begins, respiratory failure may occur rapidly.
Diagnosis
Diagnosis is suggested by symptoms and signs and confirmed by tests. An 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. A muscle with obvious weakness is tested. Patients are asked to exercise the affected muscle until fatigue occurs (eg, to hold the eyes open until ptosis occurs or to count aloud until slurred speech develops); 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, a positive result is not definitive for myasthenia gravis because such improvement may occur in other neuromuscular disorders. Also, results may be equivocal. During the test, weakness due to cholinergic crisis may worsen. Resuscitation equipment and atropine (as an antidote) must be available during the test.
Even if the anticholinesterase test is unequivocally positive, serum AChR antibody levels, electromyography (EMG), or both 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. About half of patients without AChR antibodies test positive for anti-MuSK antibodies.
EMG using repetitive stimuli (2 to 3/sec) shows a significant decrease in amplitude of the compound muscle action potential response in 60% of patients. Single-fiber EMG can detect such a decrease in > 95%.
Once myasthenia is diagnosed, CT or MRI of the thorax should be done to check for a thymoma. Other tests should be done to screen for autoimmune disorders frequently associated with myasthenia gravis (eg, vitamin B12 deficiency, 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.
Treatment
In patients with congenital myasthenia, anticholinesterase drugs and immunomodulating treatments are not beneficial and should be avoided. Patients with respiratory failure require intubation and mechanical ventilation.
Symptomatic
treatment:
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 30 to 60 mg po q 3 to 4 h and titrated up to a maximum of 180 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 propantheline 15 mg tid to qid.
Cholinergic
crisis is muscular weakness caused by a dose of neostigmine or pyridostigmine that 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 approach to deterioration in patients who have been responding well to treatment is controversial. Some experts believe an edrophonium test is useful because strength improves only during myasthenic crisis. Others recommend initiating respiratory support and stopping anticholinesterase drugs for several days.
Immunomodulating
treatment:
Immunosuppressants interrupt the autoimmune reaction and slow the disease course, but they do not relieve symptoms rapidly. After being given IV immune globulin 400 mg/kg once/day for 5 days, 70% of patients improve in 1 to 2 wk. Effects may last 1 to 2 mo.
Corticosteroids are necessary as maintenance therapy for many patients but have little immediate effect in myasthenic crisis. Over 1⁄2 of patients worsen acutely after starting high-dose corticosteroids. Initially, prednisone 20 mg po once/day is given; dose is increased by 5 mg q 2 to 3 days up to 60 or 70 mg, which is then given every other day. 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 .
Thymectomy is an option for most patients with generalized myasthenia if they are < 60 yr and should be done in all patients with a thymoma. Subsequently, for 80%, remission occurs or the maintenance drug dose can be lowered.
Plasmapheresis may be useful during myasthenia crisis and, for patients unresponsive to drugs, before thymectomy.
Last full review/revision February 2008 by Michael Rubin, MD
Content last modified February 2008
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