Myasthenia Gravis

Posted by Alex

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 commonest 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. Additionally, cellular immune activity against the receptor is found. Clinically, this leads to weakness; initially powerful movements fatigue readily. 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.

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, especially the ocular muscles, or may become generalized. 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 increases the weakness, which improves after a brief rest. Sensation is normal, and there are usually no reflex changes.
The diagnosis can generally be confirmed by the response to a short-acting anticholinesterase.
Edrophonium can be given intravenously in a dose of 10 mg (1 mL), 2 mg being given initially and the remaining 8 mg about 30 seconds later if the test dose is well tolerated; in myasthenic patients, there is an obvious improvement in strength of weak muscles lasting for about 5 minutes.
Alternatively, 1.5 mg of neostigmine can be given intramuscularly, and the response then lasts for about 2 hours; atropine sulfate (0.6 mg) should be available to reverse muscarinic side effects.

B. Imaging: Lateral and anteroposterior x-rays of the chest and CT scans should be obtained to demonstrate a coexisting thymoma, but normal studies do not exclude this possibility.

C. Laboratory and Other Studies: Electrophysiologic demonstration of a decrementing muscle response to repetitive 2- or 3-Hz stimulation of motor nerves indicates a disturbance of neuromuscular transmission. Such an abnormality may even be detected in clinically strong muscles with certain provocative procedures. Needle electromyography of affected muscles
shows a marked variation in configuration and size of individual motor unit potentials, and single-fiber electromyography reveals an increased jitter, or variability, in the time interval between two muscle fiber action potentials from the same motor unit.
Assay of serum for elevated levels of circulating acetylcholine receptor antibodies is another approach—increasingly used—to the laboratory diagnosis of myasthenia gravis and has a sensitivity of 80–90%.

Treatment
Medication such as aminoglycosides that may exacerbate myasthenia gravis should be avoided.
Anticholinesterase drugs provide symptomatic benefit without influencing the course of the disease. Neostigmine, pyridostigmine, or both can be used, the dose being determined on an individual basis. The usual dose of neostigmine is 7.5–30 mg (average, 15 mg) taken four times daily; of pyridostigmine, 30–180 mg (average, 60 mg) four times daily. Overmedication may temporarily increase weakness, which is then unaffected or enhanced by intravenous
edrophonium.
Thymectomy usually leads to symptomatic benefit or remission and should be considered in all patients younger than age 60, unless weakness is restricted to the extraocular muscles. If the disease is of recent onset and only slowly progressive, operation is sometimes delayed for a year or so, in the hope that spontaneous remission will occur.
Treatment with corticosteroids is indicated for patients who have responded poorly to anticholinesterase drugs and have already undergone thymectomy. It is introduced with the patient in the hospital, since weakness may initially be aggravated. Once weakness has stabilized after 2–3 weeks or any improvement is sustained, further management can be on an outpatient basis.
Alternate-day treatment is usually well tolerated, but if weakness is enhanced on the nontreatment day it may be necessary for medication to be taken daily. The dose of corticosteroids is determined on an individual basis, but an initial high daily dose (eg, prednisone, 60–100 mg) can gradually be tapered to a relatively low maintenance level as improvement occurs; total withdrawal is difficult, however. Treatment with azathioprine may also be effective. The usual dose is 2–3 mg/kg orally daily after a lower initial dose.
In patients with major disability in whom conventional treatment is either unhelpful or contraindicated, plasmapheresis or intravenous immunoglobulin therapy may be beneficial. It may also be useful for stabilizing patients before thymectomy and for managing acute crisis.