MYASTHENIA GRAVIS (MG)
This is a an autoimmune disorder that results in the destruction of post synaptic acetylcholine receptors or muscle-specific Kinase (MuSK) with resultant muscular weakness that is exacerbated by physical exertion. Women are affected at an earlier age (females are affected in their twenties or thirties) than are male patients (men are affected in their fifties or sixties). The Lambert-Eaton syndrome is often a paraneoplastic disorder often associated with small cell lung cancers with a presentation similar to MG that is associated with the presence of anti-voltage-gated calcium channel (anti-VGCC) antibodies.
Normally, neural impulses are transmitted across neuromuscular junctions when an action potential initiates the release of acetylcholine from presynaptic vesicles. Once released into the synaptic cleft, acetylcholine combines with postsynaptic receptors causing depolarization. The postsynaptic signal for depolarization is terminated when acetylcholine releases from its receptor. Acetylcholine is then hydrolyzed by acetylcholinesterase.
In myasthenia gravis, there is an autoimmune mediated destruction of postsynaptic acetylcholine receptors along with flattening of the postsynaptic folds. Clinically, this results in fluctuating weakness and fatigability that is exacerbated by muscular exertion and improves with rest. Ocular symptoms to include diplopia, blurry vision, and ptosis are common manifestations. Difficulty in chewing, an abnormal smile, dysphagia (secondary to weakness of the tongue and palatal muscles), or nasal speech are manifestations of facial muscle involvement. A major clinical concern is when respiratory musculature is so affected as to impair a patients ability to breath. When impairment is severe, mechanical ventilation is required. When the limb musculature is affected it manifests as an asymmetric proximal weakness. On physical exam, deep tendon reflexes are normal. The presence of normal deep tendon reflexes helps distinguish myasthenia gravis from Lambert-Eaton syndrome in which deep tendon reflexes are depressed or absent.
Once the diagnosis is suspected, several tests are available to help establish the diagnosis. The easiest test is the ice pack test. This test is especially reliable when ocular symptoms predominate. The ice pack test is performed by applying an ice pack to the eyes for 60 to 90 seconds. This test is based on the fact that neuromuscular transmission improves at lower temperatures. The test is considered positive if ptosis or other ocular neuromuscular symptoms improve after the application of ice packs. Another test for patients with predominantly ocular symptoms is the edrophonium (Tensilon) test. Edrophonium is an anticholinesterase drug that inhibits acetylcholinesterase and thus prevents the breakdown of acetylcholine. The diagnosis of MG may be suggested when symptoms improve after the administration of intravenous edrophonium. In patients with more generalized symptoms, the diagnosis is inferred when symptoms improve after oral pyridostigmine (Mestinon). Other tests used to help establish the diagnosis include repetitive nerve stimulation testing and single-fiber electromyography (SFEMG). SFEMG is very sensitive and is considered to be the gold standard for diagnosing MG. With repetitive nerve stimulation testing the ulnar or median nerves are usually tested. If there is a reduction of greater than 10% in amplitude, then this is diagnostic of MG.
Serologic testing for acetylcholine receptor antibodies (anti-AChR) and muscle-specific kinase (anti-MuSK) should be performed. Anti-AChR antibodies are present in approximately 90% of patients with generalized myasthenia symptoms but in only 50% with ocular myasthenia. The detection of serum acetylcholine receptor antibodies has a sensitivity of 89% in patients with generalized symptoms and a sensitivity of 64% in patients with ocular myasthenia. Anti-MuSK antibodies may be found in approximately 6% of those patients with generalized myasthenia who are anti-AChR negative. The level of anti-AChR does not correlate with the severity of disease. If the Lambert-Eaton syndrome is suspected, testing for anti-voltage-gated calcium channels antibodies (anti-VGCC) should be performed on a blood sample.
The differential diagnosis for patients with a history and symptoms compatible with MG includes Lambert-Eaton syndrome, neurasthenia, botulism, intracranial mass lesions (patients should undergo imaging of the head as part of the workup), and progressive external ophthalmoplegia. Patients taking the drug penicillamine (Cuprimine, Depen) may develop MG as a side effect of the medication. Medications that may exacerbate underlying MG include aminoglycoside antibiotics, tetracyclines, antiarrhythmic agents (lidocaine, quinidine, procainamide, and phenytoin), anesthetic agents, thyroid preparations, magnesium citrate, and magnesium sulfate. Other factors that may exacerbate underlying MG include superimposed infections, hypokalemia, pregnancy or emotional stress. Diseases associated with an increased incidence of MG include hypothyroidism, hyperthyroidism, rheumatoid arthritis, and systemic lupus erythematosus.
Once the diagnosis of MG is established, patients should undergo evaluation for the presence of a thymoma (approximately 10 to 28% of MG patients have a thymoma). Routine chest radiographs will miss 25 to 30% of thymomas so computed tomography of the anterior mediastinum is recommended.
Therapy for MG should be tailored to each individual case. Thymectomy is recommended in all MG patients who have reached puberty but are less than 60 years old. In younger patients, the decision to perform thymectomy should be made on a case-to-case basis. Medical therapy for MG entails the use of the anticholinesterase drugs pyridostigmine, neostigmine, and ambenonium. Patients suffering with mild MG often do well with pyridostigmine alone; however, for moderate or severe disease corticosteroids, azathioprine, cyclophosphamide, cyclosporine, or plasmapheresis may be required in addition to anticholinesterase therapy. For acute episodes of weakness, plasmapheresis and intravenous immunoglobulin are effective; however, because the benefit is transient, this form of therapy should be administered along with other immunosuppressive therapy. It is imperative to counsel patients to avoid medications that may exacerbate their disease, specifically aminoglycoside antibiotics, propranolol, procainamide, phenytoin, quinine, and lidocaine.
When patients require elevated doses of anticholinesterase therapy, there is the possibility of precipitating a cholinergic crisis. Cholinergic crisis is characterized by myasthenic symptoms along with loose stools, cramping, nausea, profuse salivation, miosis, lacrimation, sweating, and bradycardia. It is often difficult to differentiate a cholinergic crisis from a myasthenic crisis. When confusion exists and the patient is stable (stable referring to a lack of respiratory compromise), the edrophonium test may be administered to determine the cause of the patients symptoms. The patient is given 1 mg of edrophonium intravenously, and if the patient remains stable, another 1 mg dose is administered. If respiration worsens or does not improve, then the patient is in cholinergic crisis and all anticholinesterase therapy should be temporarily withheld until symptoms improve. If the patients symptoms improve after receiving the edrophonium boluses, then the patient is in myasthenic crisis.
If myasthenic crisis is established, an attempt should be made to identify the inciting etiology. Infection, emotional stress, hypokalemia, thyroid disease, and certain medications (aminoglycosides, quinine, procainamide, quinidine, propranolol, lidocaine, polymyxin, or colistin) may all serve to initiate a crisis. Therefore, the workup should include blood and urine cultures (culture other body fluids if indicated), chest radiograph, TSH measurement, electrolyte screening, and a thorough drug history. Anticholinergics (some advocate holding all anticholinergics even if cholinergic crisis is not suspected as this drug-free interval often serves to increase the patients responsiveness to this class of medication), steroids (initially steroids may worsen the symptoms of a myasthenic crisis---if this method of therapy is employed, prednisone 100 mg/day or its equivalent should be employed for several weeks followed by gradual tapering), plasmapheresis, and/or intravenous immunoglobulin 400 mg/kg/day for 5 days are all potential therapies. If an inciting etiology is identified, treatment should be instituted.