Myasthenia gravis is caused by a defect of neuromuscular transmission due to an antibody-mediated attack upon nicotinic acetylcholine receptors (AChR). It is characterized by fluctuating weakness that is improved by inhibitors of cholines terase.
The pathogenesis of myasthenia is related to the destructive effects of autoantibodies to AChR, as indicated by several lines of evidence: (1) Experimental immunization of several different species of animals with purified AChR from a torpedo, an electric fish, induces high titers of antibody to the receptor. Concomitantly, the animals show evidence of weakness that is accompanied by the essential electrophysiologic and pathologic features of human myasthenia. This was first found in rabbits by Patrick, Lindstrom, and their associates. (2) Human serum antibodies that react with human AChR were then found in patients with myasthenia gravis. (3) Toyka, Drachman, and colleagues found that the electrophysiologic features of myasthenia were reproduced by passive transfer of human immunoglobulin G (IgG) to mice. By analogy, human transient neonatal myasthenia could then be explained by transplacental transfer of maternal antibody. (4) Pinching found that plasmapheresis reduced plasma levels of anti-AChR and ameliorated myasthenic symptoms and signs.
The polyclonal IgG antibodies to AChR are produced by plasma cells in peripheral lymphoid organs, bone marrow, and thymus. These cells are derived from B cells that have been activated by antigen-specific T-helper (CD4+) cells as well as antigen-presenting cells that bear AChR antigenic units (epitopes) of the cell surface.
The antibodies react with multiple determinants on AChR, and enough antibody circulates to saturate up to 80% of AChR sites on muscle. A small percentage of the anti-AChR molecules interfere directly with the binding of acetylcholine (ACh), but the major damage to end-plates seems to result from actual loss of receptors due to complement-mediated lysis of the membrane and to acceleration of normal degradative processes (internalization, endocytosis, lysosomal hydrolysis) with inadequate replacement by new synthesis. As a consequence of the loss of AChR and the erosion and simplification of the end-plates, the amplitude of miniature end-plate potentials is about 20% of normal, and patients are abnormally sensitive to the competitive antagonist, curare. The characteristic decremental response to repetitive stimulation of the motor nerve reflects failure of end-plate potentials to reach threshold so that progressively fewer fibers respond to arrival of a nerve impulse.
Excessive and inappropriately prolonged synthesis of thymic hormones that normally promote differentiation of T-helper cells may contribute to the autoimmune response. Still another possible initiating factor is immunogenic alteration of the antigen, AChR, at end-plates, because D-penicillamine therapy of patients with rheumatoid arthritis may initiate a syndrome that is indistinguishable from myasthenia gravis except that it subsides when administration of the drug is stopped.
There are few familial cases of the disease, but disproportionate frequency of HLA haplotypes (B8, DR3) in myasthenic patients suggests that genetic predisposition may be important. Other autoimmune diseases also seem to occur with disproportionate frequency in patients with myasthenia, especially hyperthyroidism and other thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis, and pemphigus.
Although most antibodies seem directed against antigenic determinants on the AChR molecule other than the acetylcholine binding site the summated effects of the polyclonal anti-AChR antibodies with differing modes of action result in destruction of the receptors. Physiologic studies indicate impaired responsiveness to the acetylcholine, thereby accounting for the physiologic abnormalities, clinical symptoms, and beneficial effects of drugs that inhibit acetylcholinesterase.
Typical myasthenia gravis may begin at any age, but it is most common in the second to fourth decades. It is less common before age 10 or after age 65. Circulating AChR antibodies are demonstrated using all available assays in 85 to 90% of these patients. Patients without antibodies do not differ clinically. These are the typical forms of myasthenia; other forms are rare.
About 12% of infants born to myasthenic mothers have a syndrome characterized by impaired sucking, weak cry, limp limbs, and sometimes respiratory insufficiency. Symptoms begin in the first 48 hours and may last several days or weeks, after which the children are normal. The mothers are usually symptomatic, but may be in complete remission; in either case, AChR antibodies are demonstrable in both mother and child. Symptoms disappear as the antibody titer in the infant declines. Severe respiratory insufficiency may be treated by exchange transfusion, but the natural history of the disorder is progressive improvement and total disappearance of all symptoms within days or weeks. Respiratory support and nutrition are the key elements of treatment.
Children with congenital myasthenia, although rarely encountered, show several characteristics. The mothers are asymptomatic and do not have circulating anti-AChR in the blood. Usually no problem occurs in the neonatal period; instead, ophthalmoplegia is the dominant sign in infancy. The condition is often familial. Antibodies to AChR are not found, but there are decremental responses to repetitive stimulation. Ultrastructural and biochemical examination of motor end-plates and microelectrode analysis have shown that the disorder is heterogeneous, including either presynaptic or postsynaptic anomalies. Several distinct conditions have been identified: disorders of the ion channel that is formed by the AChR molecule (slow channel syndrome; AChR deficiency with increased channel open time); absence of end-plate ACh; or a defective AChR epsilon subunit. Anticholinesterase drugs may help some of these disorders, but parents should be warned that sudden apneic spells may be induced by mild infections.
The best example of this condition occurs in patients who receive D-penicillamine for rheumatoid arthritis, scleroderma, or hepatolenticular degeneration. The clinical manifestations and AChR antibody titers are similar to those of typical adult myasthenia but both disappear when drug administration is discontinued. Cases attributed to trimethadione or phenytoin have been less thoroughly studied.
The overt pathology of myasthenia is found primarily in the thymus gland. About 70% of thymus glands from adult patients with myasthenia gravis are not involuted and weigh more than normal. The glands show lymphoid hyperplasia: In normal individuals, germinal centers are numerous in lymph nodes and spleen but are sparse in the thymus. Immunocytochemical methods indicate that these thymic germinal centers contain B cells, plasma cells, HLA Class II DR positive T cells, and interdigitating cells. Both normal and myasthenic glands contain beta-thymosin, a thymic hormone that is important for T-cell maturation.
Another 10% of myasthenic thymus glands contain thymomas of the lymphoepithelial type. The lymphoid cells in these tumors are T-cells; the neoplastic elements are epithelial cells. Benign thymomas may nearly replace the gland, with only residual glandular material at the edges, or they may rest within large hyperplastic glands. The tumors tend to occur in older patients, but in Castleman s series, 15% occurred in patients between the ages of 20 and 29. The tumor may invade contiguous pleura, pericardium, or blood vessels or it may seed onto more distant thoracic structures, including the diaphragm, but it almost never spreads to other organs. In older patients without thymoma, thymus glands that appear involuted often show hyperplastic foci within fatty tissue on careful microscopic examination of multiple samples.
In about 50% of cases, there are lymphorrhages in muscle, which are focal clusters of lymphocytes near small necrotic foci without perivascular predilection. In a few cases, especially in patients with thymoma, there is diffuse muscle fiber necrosis with infiltration of inflammatory cells; similar lesions are rarely encountered in the myocardium. Lymphorrhages are not seen near damaged neuromuscular junctions (although inflammatory cells may be seen in necrotic end-plates in rat experimental autoimmune myasthenia gravis), but morphometric studies have shown loss of synaptic folds and widened clefts. Some nerve terminals are smaller than normal, and multiple small terminals are applied to the elongated simplified postsynaptic membrane; others are absent. Other end-plates appear normal. On residual synaptic folds, immunocytochemical methods show Y-shaped antibody-like structures, IgG, complement components 2 and 9, and complement membrane attack complex.
Myasthenia gravis is a common disease. An apparent increase in the incidence of the disease in recent years is probably due to improved diagnosis. According to Kurtzke, the prevalence rate is 3/100,000 (or about 6,000 cases) in the United States. Before age 40, the disease is 3 times more common in women, but at older ages both sexes are affected equally.
Familial cases are rare; single members of pairs of fraternal twins and several sets of identical twins have been affected. Young women with myasthenia tend to have HLA B-8, DR3 haplotypes (young Japanese women HLA-A12), implying a linked immune response gene that codes for a protein involved in the autoimmune response. First-degree relatives show an unusual incidence of other autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, thyroid disease) and HLA-B-8 haplotype.
The symptoms of myasthenia have three general characteristics that, together, provide a diagnostic combination. Formal diagnosis depends on demonstration of the response to cholinergic drugs, electrophysiologic evidence of abnormal neuromuscular transmission, and demonstration of circulating antibodies to AChR.
The fluctuating nature of myasthenic weakness is unlike any other disease. The weakness varies in the course of a single day, sometimes within minutes, and it varies from day to day, or over longer periods. Major prolonged variations are termed remissions or exacerbations; when an exacerbation involves respiratory muscles to the point of inadequate ventilation, it is called a crisis. Variations sometimes seem related to exercise; this and the nature of the physiologic abnormality have long been termed ""excessive fatigability,"" but there are practical reasons to de-emphasize fatigability as a central characteristic of myasthenia. Patients with the disease almost never complain of fatigue or symptoms that might be construed as fatigue except when there is incipient respiratory muscle weakness. Myasthenic symptoms are always due to weakness not to rapid tiring. In contrast, patients who complain of fatigue, if they are not anemic or
The second characteristic of myasthenia is the distribution of weakness. Ocular muscles are affected first in about 40% of the cases and are ultimately involved in about 85%. Ptosis and diplopia are the symptoms that result. Other common symptoms affect facial or oropharyngeal muscles, resulting in dysarthria, dysphagia, and limitation of facial movements. Together, oropharyngeal and ocular weakness cause symptoms in virtually all patients with myasthenia. Limb and neck weakness is also common, but in conjunction with cranial weakness. Almost never are limbs affected alone.
Crisis seems most likely to occur in patients with oropharyngeal or respiratory muscle weakness. It seems to be provoked by respiratory infection in many cases, or by surgical procedures, including thymectomy, although it may occur with no apparent provocation. Both emotional stress and systemic illness may aggravate myasthenic weakness for reasons that are not clear; in patients with oropharyngeal weakness, aspiration of secretions may occlude lung passages to cause rather abrupt onset of respiratory difficulty. Major surgery may be followed by respiratory weakness without aspiration, however, so this cannot be the entire explanation. ""Spontaneous"" crisis seems to be less common now than it once was.
The third characteristic of myasthenic weakness is the clinical response to cholinergic drugs. This occurs so uniformly that it has become part of the definition, but it may be difficult to demonstrate in some patients, especially those with purely ocular myasthenia.
Aside from the fluctuating nature of the weakness, myasthenia is not a steadily progressive disease. The general nature of the disease, however, is usually established within weeks or months after the first symptoms. If myasthenia is restricted to ocular muscles for 2 years, certainly if it is restricted after 3 years, it is likely to remain restricted, and only in rare cases does it then become generalized. (Solely ocular myasthenia differs serologically from generalized myasthenia because AChR antibodies are found in lower frequency--50%--and in low titer.) Spontaneous remissions are also more likely to occur in the first 2 years.
Before the advent of respiratory care units and the introduction of positive pressure respirators in the 1960s, crisis was a life-threatening event and the mortality of the disease was about 25%. With improved respiratory care, however, patients rarely die of myasthenia, except when cardiac, renal, or other disease complicates the picture.
The vital signs and general physical examination are usually within normal limits, unless the patient is in crisis. The findings on neurologic examination depend on the distribution of weakness. Weakness of the facial and levator palpabrae muscles produces a characteristic expressionless facies with drooping eyelids. Weakness of the ocular muscles may cause paralysis or weakness of isolated muscles, paralysis of conjugate gaze, complete ophthalmoplegia in one or both eyes, or a pattern resembling internuclear ophthalmoplegia. Weakness of oropharyngeal or limb muscles, when present, can be shown by appropriate tests. Respiratory muscle weakness can be detected by pulmonary function tests, which should not be limited to measurement of vital capacity but also should include inspiratory and expiratory pressures, the measurements of which may be abnormal even before overt symptoms exist. Muscular wasting of variable degree is found in about 10% of cases, but is not focal and is usually encountered only in patients with malnutrition due to severe dysphagia. Fasciculations do not occur, unless the patient has received excessive amounts of cholinergic drugs. Sensation is normal and the reflexes are preserved, even in muscles that are weak.
Routine examinations of blood, urine, and cerebrospinal fluid (CSF) are normal. The characteristic electrodiagnostic abnormality is progressive decrement in the amplitude of muscle action potentials evoked by repetitive nerve stimulation at 3 or 5 Hz. In generalized myasthenia, the decremental response can be demonstrated in about 90% of patients, if at least 3 nerve-muscle systems are used (median-thenar; ulnar-hypothenar; accessory-trapezius). In microelectrode study of intercostal muscle, the amplitude of miniature end-plate potentials is reduced to about 20% of normal. This is caused by a decrease in the number of AChR available to agonists applied by microiontophoresis. In single-fiber electromyography (SFEMG), a small electrode measures the interval between evoked potentials of the muscle fibers in the same motor unit. This interval normally varies, a phenomenon called
jitter, and the normal temporal limits of jitter have been defined. In myasthenia, the jitter is increased and an impulse may not appear at the expected time; this is called blocking and the number of blockings is increased in myasthenic muscle. All these electrophysiologic abnormalities are characteristic of myasthenia,
Figure 115-1 (Figure Not Available) Myasthenia gravis. A, Severe ptosis of the lids. B, Same patient 1 minute after intravenous injection of 10 mg of edrophonium. (From Rowland LP, Hoefer PFA, Aranow H Jr. Res Publ Assoc Res Nerv Ment Dis 1961; 38:548-600.)
Antibodies to AChR are found in 85 to 90% of patients of all ages if human muscle is used as the test antigen. There have been no false-positive results except for rare patients with Lambert-Eaton syndrome or thymoma without clinical or provocable myasthenia, or remission, but antibodies may not be detected in patients with strictly ocular disease, in some patients in remission (or after thymectomy), or even in some patients with severe symptoms. The titer does not match the severity of symptoms; patients in complete clinical remission may have high titers. Antibodies to myofibrillar proteins (myosin, actin, actomyosin), titin are found in 85% of patients with thymoma and may be the first evidence of thymoma in some cases.
The different forms of congenital myasthenia can be identified only in a few special centers that are prepared to perform microelectrode and ultrastructural analyses of intercostal muscle biopsies for miniature end-plate potentials, AChR numbers, and determination of bound antibodies.
Other serologic abnormalities are encountered with varying frequency, but in several studies, antinuclear factor, rheumatoid factor, and thyroid antibodies were encountered more often than in control populations. Laboratory (and clinical) evidence of hyperthyroidism occurs at some time in about 5% of patients with myasthenia. Radiographs of the chest (including 10° oblique films) provide evidence of thymoma in about 15% of patients, especially in those older than 40. CT of the mediastinum demonstrates all but microscopic thymomas. MRI does not appear to be any more useful than CT.
The diagnosis of myasthenia gravis can be made without difficulty in most patients from the characteristic history and physical examination. The dramatic improvement that follows the injection of neostigmine or edrophonium makes the administration of these drugs essential. Return of strength in weak muscles (Fig. 115-1) (Figure Not Available) occurs uniformly after the injection of edrophonium or neostigmine, as described later; if no such response occurs, the diagnosis of myasthenia can be doubted. Demonstration of the pharmacologic response is sometimes difficult, however; if the clinical features are suggestive, the test should be repeated, perhaps with a different dosage or rate of administration. Withholding anticholinesterase medication overnight may be helpful. False-positive responses to edrophonium are exceptional but have been recorded with structural lesions, such as a brain stem tumor. (Myasthenia can also co-exist with other diseases, such as Graves ophthalmopathy or the Lambert-Eaton syndrome.)
The diagnosis of myasthenia is buttressed by the finding of high titers of antibodies to AChR (also rarely a false-positive finding), but a normal titer does not exclude the diagnosis. Somnier found that the test had a specificity of more than 99.9%; sensitivity was 88% because of the negative tests.
The response to repetitive stimulation and single-fiber EMG also help. If a thymoma is present, the diagnosis of myasthenia (as compared to some other neuromuscular disease) is likely. In the past, clinicians used the increased sensitivity to curare as a test to prove that a syndrome simulating myasthenia was actually psychasthenia or something else; however, the test was inconvenient and, if done without proper precautions, was even hazardous. Since the advent of the antibody test, the curare test has virtually disappeared.
For all practical purposes, a positive response is diagnostic of myasthenia gravis.
The differential diagnosis includes all diseases that are accompanied by weakness of oropharyngeal or limb muscles, such as the muscular dystrophies, amyotrophic lateral sclerosis, progressive bulbar palsy, ophthalmoplegias of other causes, and the asthenia of psychoneurosis or hyperthyroidism. There is usually no difficulty in differentiating these conditions from myasthenia gravis by the findings on physical and neurologic examination and by the failure of symptoms in these conditions to improve after parenteral injection of neostigmine or edrophonium.
The only other conditions in which clinical improvement has been documented after use of edrophonium are other disorders of neuromuscular transmission--botulinum intoxication, snake bite, organophosphate intoxication, or unusual cases that include features of both myasthenia and the Lambert-Eaton syndrome. Denervating disorders, such as motor neuron disease or peripheral neuropathy, do not show a reproducible or unequivocal clinical response to edrophonium or neostigmine. The response should be unequivocal and reproducible. If a structural lesion of the third cranial nerve seems to respond, the result should be photographed (and even published).
Clinicians must choose the sequence and combination of five different kinds of therapy: anticholinesterase drug therapy and plasmapheresis are symptomatic treatments, whereas thymectomy, steroids, and other immunosuppressive drugs may alter the course of the disease.
It is generally agreed that anticholinesterase drug therapy should be given as soon as the diagnosis is made. Of the three available drugs (neostigmine, pyridostigmine, and ambenonium), pyridostigmine is most popular, but has not been formally assessed in controlled comparison with the other drugs. The muscarinic side-effects of abdominal cramps and diarrhea are the same for all three drugs, but are least severe for pyridostigmine treatment; none has more side effects than another. The usual starting dose of pyridostigmine is 60 mg, given orally, every 4 hours while the patient is awake. Depending on clinical response, the dosage can be increased, but incremental benefit is not to be expected in amounts greater than 120 mg every 2 hours. If patients have difficulty eating, doses can be taken about 30 minutes before a meal. If patients have special difficulty on waking in the morning, a prolonged-release 180-mg tablet of pyridostigmine (Timespan) can be taken at bedtime. Muscarinic symptoms can be ameliorated by preparations containing atropine, with each dose of pyridostigmine. Other drugs may be taken if diarrhea is prominent. There is no evidence that any one of the three drugs is more effective than the others in individual patients and there is no evidence that combinations of two drugs are better than any one alone.
Although cholinergic drug therapy sometimes gives impressive results, there are serious limitations. In ocular myasthenia, ptosis may be helped, but some diplopia almost always persists. In generalized myasthenia, patients may improve remarkably, but some symptoms usually remain. Cholinergic drugs do not return function to normal and the risk of crisis persists because the disease is not cured. Therefore, one of the other treatments is usually used promptly to treat generalized myasthenia.
Thymectomy was originally reserved for patients with serious disability because the operation had a high mortality. With advances in surgery and anesthesia, however, the operative mortality is now negligible in major centers. About 80% of patients without thymoma become asymptomatic or go into complete remission after thymectomy; although there has been no controlled trial of thymectomy, these results seem to diverge from the natural history of the untreated disease. Thus, thymectomy is now recommended for most patients with generalized myasthenia. Decisions made for children or patients older than 65 must be individualized. Although it is safe, thymectomy is a major operation and is not usually recommended
Prednisone therapy is used by some authorities to prepare patients for thymectomy, but that function is also served by plasmapheresis. Exchanges of about 5% of calculated blood volume may be given several times before the day of surgery to be certain that the patient is functioning as well as possible, and to ameliorate or avoid a postoperative respiratory crisis. Plasmapheresis is also used for other exacerbations; the resulting improvement, seen in most patients, may be slight or dramatic and may last only a few days or several months. Plasmapheresis is safe but expensive and is not convenient for many patients.
If a patient is still seriously disabled after thymectomy, most clinicians use prednisone in a dose of 60 to 100 mg every other day to achieve a response within a few days or weeks. An equally satisfactory response can be seen with a lower dosage, but it takes a longer time; for instance, if the dose is 25 to 40 mg, benefit may be seen in 2 to 3 months. Once improvement is achieved, the dosage should be reduced gradually to 20 to 39 mg every other day. This has become a popular form of treatment for disabled patients, but there has been no controlled trial. If the patient does not improve in about 6 months, treatment with azathioprine or cyclophosphamide would be considered, in doses up to 2.5 mg/kg daily for an adult. The dosage should be increased gradually and may have to be taken with food to avert nausea. Whether steroids and immunosuppressive drugs have additive effects is uncertain and the relative risks are difficult to assess. The numerous side effects of prednisone must be weighed against the possibilities of marrow suppression, susceptibility to infection, or delayed malignancy in patients who are taking immunosuppressive drugs.
Prednisone, in doses of 20 to 35 mg on alternate days, is also recommended by some clinicians for ocular myasthenia, weighing risks against potential benefit. For some patients in sensitive occupations, the risks of prednisone therapy may be necessary (e.g., actors, police officers, roofers or others who work on heights, or those who require stereoscopic vision). Ocular myasthenia is not a threat to life, however; pyridostigmine may alleviate ptosis. An eye-patch can end diplopia, and prisms help some patients with stable horizontal diplopia. Thymectomy has become so safe that it might be considered for ocular myasthenia that is truly disabling.
Patients with thymoma are likely to have more severe myasthenia and are less likely to improve after thymectomy; nevertheless, many of these patients also improve if the surrounding thymus gland is excised in addition to the tumor.
Myasthenic crisis is defined as the need for assisted ventilation, a condition that arises in about 10% of myasthenic patients. It is more likely to occur in patients with dysarthria, dysphagia, and documented respiratory muscle weakness, presumably because they are liable to aspirate oral secretions, but crisis may also occur in other patients after respiratory infection or major surgery (including thymectomy). The principles of treatment are those of respiratory failure in general. Cholinergic drug therapy is usually discontinued once an endotracheal tube has been placed and positive pressure respiration started; this practice avoids questions about proper dosage or cholinergic stimulation of pulmonary secretions. Crisis is viewed as a temporary exacerbation that subsides in a few days or weeks. The therapeutic goal is to maintain vital functions and to avoid or treat infection until the patient spontaneously recovers from the crisis. Cholinergic drug therapy need not be restarted unless fever and other signs of infection have subsided, there are no pulmonary complications, and the patient is breathing without assistance.
The determination of whether plasma exchange or intravenous immunoglobulin actually shortens the duration of crisis would require a controlled trial, but the efficacy of pulmonary intensive care is now so good that crisis is almost never fatal and many patients remit. Because of advances in therapy, myasthenia is still serious, but not so grave.