ESSENTIALS OF DIAGNOSIS
Fluctuating weakness of commonly used voluntary muscles, producing symptoms such as diplopia, ptosis, and difficulty in swallowing.
Activity increases weakness of affected muscles.
Short-acting anticholinesterases transiently improve the weakness.
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 most common 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 (eFigure 24–18). Additionally, cellular immune activity against the receptor is found.
Pathogenesis of myasthenia gravis. Acetylcholine released at the nerve ending by the nerve impulse normally binds with acetylcholine receptors. This evokes the action potential in the muscle. In myasthenia gravis, antiacetylcholine receptor antibody binds to the acetylcholine receptor and inhibits the action of acetylcholine. Bound antibody evokes immune-mediated destruction of the end plate. (Reproduced, with permission, from Chandrasoma P, Taylor SE. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
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 or may become generalized. 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. 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.
Life-threatening exacerbations of myasthenia (so-called myasthenic crisis) may lead to respiratory weakness requiring immediate admission to the intensive care unit, where respiratory function can be monitored and ventilator support is readily available.
B. Laboratory and Other Studies
Assay of serum for elevated levels of circulating acetylcholine receptor antibodies is useful because it has a sensitivity of 80–90% for the diagnosis of myasthenia gravis. Certain patients without antibodies to acetylcholine receptors have serum antibodies to muscle-specific tyrosine kinase (MuSK), which should therefore be determined; these patients are more likely to have facial, respiratory, and proximal muscle weakness than those with antibodies to acetylcholine receptors. Other antibodies associated with myasthenia gravis include low-density lipoprotein receptor-related protein 4 (LRP4) and agrin, but tests for these antibodies are not widely commercially available.
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.
A CT scan of the chest with and without contrast should be obtained to demonstrate a coexisting thymoma.
Anticholinesterase medications 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) orally taken four times daily; of pyridostigmine, 30–180 mg (average, 60 mg) orally four times daily. Overmedication may temporarily increase weakness. A wide range of medications (eg, aminoglycosides) may exacerbate myasthenia gravis and should be avoided.
Thymectomy should be performed when a thymoma is present. A multicenter randomized trial demonstrated the benefit of thymectomy even in the absence of a radiologically identifiable thymoma, with improved strength, lower immunosuppression requirements, and fewer hospitalizations in the surgically treated group. Thus, thymectomy should be considered in all patients younger than age 65 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 medications. Some patients experience transient exacerbation of weakness and even develop respiratory failure within the first 1–2 weeks if corticosteroids are initiated at high doses (eg, prednisone 1 mg/kg/day). Therefore, in stable patients, corticosteroids are introduced gradually in the outpatient setting. Prednisone can be started at 20 mg orally daily and increased by 10 mg increments weekly to a target of 1 mg/kg/day (maximum daily dose 100 mg). For patients hospitalized with severe myasthenia and treated with IVIG or plasmapheresis, the higher dose can be given initially because the more rapid onset of action of the former two therapies mitigates the initial dip in strength due to corticosteroids. Corticosteroids can be prescribed as alternate-day or daily treatment, with alternate-day therapy potentially mitigating side effects. Once the patient has stabilized at the initial high dose, corticosteroids can gradually be tapered to a relatively low maintenance level (eg, 10 mg prednisone orally daily) as improvement occurs; total withdrawal is difficult, however. Treatment with azathioprine may be effective in allowing a lower dose of corticosteroids. The usual dose is 2–3 mg/kg orally daily after a lower initial dose. Other immunosuppressive agents that are used in myasthenia gravis to reduce the corticosteroid dose include mycophenolate mofetil, rituximab, cyclosporine, methotrexate, and tacrolimus. Eculizumab, a complement inhibitor, is approved by the FDA for acetylcholine receptor antibody positive myasthenia in patients who have disease refractory to at least two alternate immunosuppressive therapies. It is administered intravenously (900 mg weekly for four doses, followed by 1200 mg at week 5, then 1200 mg every 2 weeks). Patients must be vaccinated against meningococcus prior to receiving eculizumab.
In patients with major disability, plasmapheresis or IVIG therapy may be beneficial and have similar efficacy. It is also useful for stabilizing patients before thymectomy and for managing acute crisis.
All patients should be referred.
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