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  1. 1. Clinical manifestations and diagnosis of myasthenia gravis INTRODUCTION — The diagnosis of myasthenia gravis (MG) can be established by clinical and serologic testing [1]. It is useful, however, to first review the clinical manifestations of this disorder to appreciate the settings in which it should be suspected. The pathogenesis and treatment of this disorder are discussed separately. (See "Pathogenesis of myasthenia gravis" and see "Treatment of myasthenia gravis"). Myasthenia in a neonate may result from transplacental passage of maternal antibodies that interfere with function of the neuromuscular junction, or it may be the result of a mutation that affect junctional function. Neonatal and congenital myasthenia are discussed separately. (See "Neuromuscular junction disorders in newborns"). CLINICAL MANIFESTATIONS — Myasthenia presents in two main groups of patients: women in their 20s and 30s and men over the age of 60. The cardinal feature of the illness is its association with fatigue as the degree of muscle weakness increases with exercise of the affected muscles and improves with rest [2]. Weakness often begins in the eyes, but may begin in the bulbar muscles or the muscles of the limbs and trunk. Eye muscles — Weakness of the eye muscles can lead to ptosis, the degree of which can be variable, switching from one eye to the other on separate examinations and occasionally increasing with sudden exposure to bright light. The extraocular eye muscles are also often involved. The clinical manifestations of these changes vary from subtle blurring of vision to severe diplopia. (See "Neuromuscular diplopia"). Physical examination may reveal unusual eye movements that do not conform to the anatomy of one nerve or muscle. The pupils are always spared in myasthenia gravis, helping in the differentiation from other disorders such as botulism. Bulbar muscles — A "myasthenic snarl" may be seen when the bulbar muscles are affected. This problem of facial muscle weakness occurs when smiling and can cause embarrassment. Other bulbar manifestations include nasal speech devoid of consonant sounds due to weakness of the palate and tongue, difficulty chewing, and less often difficulty swallowing and choking on liquids. The problem with chewing may be so severe that the patient must support his or her chin with a hand to finish chewing something tough. Supporting the chin may also be necessary if there is neck extensor weakness which can cause the head to fall forward out of the patient's control. Limb and trunk muscles — Involvement of the limbs and trunk in myasthenia produces symptoms similar to other muscle diseases. The proximal limbs are most commonly affected. However, predominately distal presentations of otherwise typical myasthenia occurred in 6 of 84 patients in one prospective series [3]. One important feature suggesting myasthenia is the marked association with fatiguability. The respiratory muscles can be affected in advanced disease, producing
  2. 2. a potentially life-threatening situation called "myasthenic crisis". (See "Treatment of myasthenia gravis"). DIAGNOSIS OF MYASTHENIA — The diagnostic approach to myasthenia begins with the physical examination and then proceeds to more specific testing. The major aim on physical examination is to test for fatiguability of the different muscle groups: Ptosis induced by fatigue can be demonstrated by having the patient sustain upward gaze by looking at your finger. Slowly the lids begin to drift down. This sign, if present, is very useful in the Tensilon test discussed below. Fatigue of the upper extremities can be tested for by having the patient sit with arms stretched in front, looking for a slow downward drift. Grip fatigue can be measured with a dynamometer that the patient grasps repetitively. Lower extremity fatigue can be demonstrated by having the patient step up and down from a footstool as if climbing stairs. This gets progressively more difficult and the patient begins to push off their knee with their arm in order to help the weakening quadriceps. Tensilon test — Once a group of muscles is shown to weaken with exercise and improve with rest, the diagnosis of myasthenia gravis can be confirmed most easily by an intravenous injection of the acetylcholinesterase inhibitor Tensilon (edrophonium chloride; 10 mg/mL). Tensilon begins to act in 30 to 60 seconds and its effect lasts five to 10 minutes. The ensuing potentiation of the muscarinic effects of acetylcholine is not without risk, especially in the elderly; as a result, atropine (0.5 to 2.0 mg) should be available if a severe cholinergic reaction occurs. Signs of cholinergic crisis include sweating, increased weakness and respiratory secretions, laryngospasm, bradycardia, hypotension, nausea, and vomiting. To minimize the risk of an adverse reaction, a test dose of 1 mg (0.1 mL) of Tensilon should be given. After one minute, a further 4 mg (0.4 mL) is given and, if no change in the examination is noted in one minute, the remainder of the vial (5 mg, 0.5 mL) is given and the response quantified. However, quantifying the response can be a problem. Although sustained upward gaze that produces ptosis can quickly reverse with Tensilon, this response is often absent and, even if present, can be open to interpretation. A grip strength test with a dynamometer is more useful if the grip muscles are affected, since this can be quantified and the response repeated. The Tensilon test is associated with both false negative and false positive results. As an example, it is negative in up to 50 percent of patients presenting with eye signs alone and may be difficult to interpret in patients with involvement of other muscle groups. On the other hand, a positive ocular test is not specific for myasthenia gravis, also occurring in other conditions, such as amyotrophic lateral sclerosis (ALS) and cavernous sinus lesions, which can present in a similar fashion (see below) [4]. As a result, it is often necessary to perform other confirmatory tests: immunologic testing for acetylcholine receptor antibodies; and electromyography. Acetylcholine receptor antibodies — Myasthenia gravis is a condition that fulfills all the major criteria for a disorder mediated by autoantibodies against the acetylcholine receptor (AChR-Ab) [1]. (See "Pathogenesis of myasthenia gravis").
  3. 3. The antibody is present in at least 80 to 90 percent of affected patients. The condition can be passively transferred to an animal model. Injection of the human antigen in other species produces a model disease. Reduction in antibody levels is associated with clinical improvement. As a first step, therefore, the presence of circulating AChR-Ab should be evaluated in the patient suspected of having myasthenia gravis. The demonstration of such antibodies in a competent laboratory is usually diagnostic of myasthenia. These antibodies are found in 93, 88, and 71 percent of individuals with moderate to severe generalized myasthenia gravis, mild generalized myasthenia, and ocular myasthenia, respectively [5]. There are few reports of false-positive results and these occur in disorders that are not usually confused with myasthenia (eg, primary biliary cirrhosis, tardive dyskinesia, autoimmune thyroiditis, systemic lupus erythematosus, thymoma without myasthenia, and amyotrophic lateral sclerosis) [6-12]. As with the Tensilon test, however, some patients with ocular and even significant generalized myasthenia have a false negative test for AChR-Ab; thus, a negative test does not exclude the disease (see "Conditions that mimic ocular myasthenia" below). Antibody-negative myasthenia — Antibody-negative or seronegative myasthenia gravis (SNMG) refers to patients with clinical myasthenia who have a negative standard assay for AChR-Ab, which occurs in approximately 10 to 20 percent of affected patients [5,13]. In one review, the use of multiple AChR-Ab tests, such as binding, blocking, and modulating antibodies, did not appreciably alter the number of individuals found to be antibody negative [13]. In other studies, AChR blocking and modulating antibodies are positive in approximately 5 percent of patients with negative binding antibodies. These additional AChR antibody tests may fulfill an important role when screening for a thymoma. The presence of a thymoma is suggested if AChR modulating antibodies are present and produce more than 90 percent loss of AChR sites in cultured human muscle cells [5]. Muscle-specific receptor tyrosine kinase antibodies — Some patients with seronegative myasthenia gravis have autoantibodies directed against another target on the surface of the muscle membrane, the muscle-specific receptor tyrosine kinase (MuSK). MuSK antibody positive myasthenia gravis may have a different cause and pathologic mechanism than AChR-Ab positive disease [14]. (See "Pathogenesis of myasthenia gravis", section on Muscle-specific receptor tyrosine kinase antibodies). The diagnostic utility of MuSK testing in clinical practice is probably limited, as myasthenia gravis is a relatively rare disorder, and antibody negative myasthenia gravis is even less common. In addition, the pathophysiological link between MuSK antibodies and myasthenia gravis remains unclear.
  4. 4. In the appropriate clinical setting (lack of AChR-Ab and typical clinical features listed below), MuSK testing can clarify the diagnosis and perhaps direct treatment [15]. The notion that SNMG patients with MuSK antibodies do not have thymic pathology [16,17] is one rationale for testing for MuSK in SNMG. (See "Pathogenesis of myasthenia gravis", section on Muscle-specific receptor tyrosine kinase antibodies). However, initial management of clinically apparent myasthenia should be the same for patients with or without AChR antibodies; this would change only if future studies find additional therapeutic differences related to MuSK status. MuSK antibody testing is commercially available in the United States. In the UK testing can be arranged through Dr. Angela Vincent's laboratory; more information is available at the following internet address: ( Clinical features — The following observations have been made regarding the clinical features of "seronegative" myasthenia, including MuSK positive myasthenia [15,17-22]: Onset at any age Female preponderance Marked bulbar and neck or respiratory weakness Bulbar and especially tongue atrophy No thymic pathology and lack of responsiveness to thymectomy Poor responsiveness to anticholinergic medications Good responsiveness to plasma exchange and immunosuppression Electromyography and repetitive nerve stimulation — Electromyography (EMG) takes advantage of the main physiologic defect in myasthenia - the partial blockade of neuromuscular transmission. Repetitive stimulation normally leads to a decremental response in compound action potentials on EMG as acetylcholine release drops with succeeding stimuli. This produces excitatory postsynaptic potentials which fail to reach the threshold needed for generating a muscle action potential in myasthenia because of the combination of less acetylcholine and decreased number of available receptors. The test is performed by placing the recording electrode over the belly of a muscle and stimulating the motor nerve to that muscle. The height of the recorded compound action potential is proportional to the number of muscle fibers firing when a supramaximal stimulus is used. At a stimulation rate of 1 to 5/second (usually 3/second), the muscle will show a loss of amplitude of greater than 10 percent by the fourth compound action potential (show figure). One of the problems with EMG is optimal muscle selection. Proximal muscles are more likely to be positive but are also harder to stimulate. Thus, sampling several muscles is recommended to increase the sensitivity of the test. As with the AChR-Ab test, repetitive stimulation is less likely to be positive in ocular myasthenia. Single
  5. 5. fiber EMG and the Lancaster red-green test of ocular motility, although not readily available, may help confirm myasthenia in this setting [23]. CONDITIONS THAT ARE ASSOCIATED WITH MYASTHENIA — Autoimmune disorders and thymic tumors can cause myasthenia and, like thyroid disease, they can also exacerbate underlying myasthenia. Hyperthyroidism, for example, is associated with myasthenia in three to eight percent of cases (see below) [1]. Thymic tumors and other malignancies — The thymus is intimately involved in the pathogenesis of myasthenia gravis. (See "Pathogenesis of myasthenia gravis"). It is postulated that all patients with myasthenia have B cells that produce AChR-Ab in the thymus. In addition, 75 percent of patients with myasthenia have thymic disease; thymic hyperplasia is most common (85 percent) but various tumors may also be seen [24]. The thymic tumors are usually noninvasive cortical thymomas, but invasive thymic carcinoma can occur. (See "Pathology of mediastinal tumors" and see "Clinical presentation and management of thymoma and thymic carcinoma"). Thus, CT scan or MR imaging of the mediastinum is an important component of the evaluation of myasthenia gravis. It has been suggested that the concurrent presence of antibodies directed against titin (a striated muscle antigen) are predictive of a thymic epithelial tumor (sensitivity 69 percent and specificity 100 percent in one series) [25,26]. Myasthenia gravis has also been associated with extrathymic tumors, such as small cell lung cancer and Hodgkin's disease [27-29]. Cure of the underlying disease may lead to resolution of myasthenic symptoms [28]. Autoimmune disorders — Systemic lupus erythematosus and rheumatoid arthritis may be associated with myasthenia. In rare cases, myasthenia precedes the other manifestations of these diseases. Thus, screening for antinuclear antibodies and rheumatoid factor should also be part of the initial evaluation. CONDITIONS THAT MIMIC OCULAR MYASTHENIA — Most of the conditions that are likely to be confused with myasthenia gravis involve weakness of the extraocular muscles. The diagnosis of ocular myasthenia is often difficult to confirm, since the ancillary tests described above are often negative. It is estimated that the Tensilon test is positive in 50 to 85 percent of such patients, AChR-Ab in 50 to 70 percent, and repetitive stimulation in 30 to 40 percent [4]. In this setting, the absence of positive confirmatory tests for thyroid disease, a mitochondrial disorder, and brainstem pathology may permit a tentative diagnosis of ocular myasthenia by exclusion. Thyroid disease — Grave's disease produces unusual eye movements due to a constrictive hypertrophic ophthalmopathy. The correct diagnosis is often obvious when exophthalmos is present. However, thyroid disease can coexist with myasthenia gravis. As a result, screening thyroid studies are usually a good idea before treatment is instituted, even when the diagnosis of myasthenia gravis is clear. Kearns-Sayre syndrome — The Kearns-Sayre syndrome is a mitochondrial disorder that produces progressive ophthalmoplegia and ptosis. As it progresses, generalized muscle weakness can occur. Associated problems with cerebellar disease and retinal degeneration eventually make this disorder distinct from myasthenia.
  6. 6. Muscle biopsy shows "ragged red" fibers and plasma lactate and pyruvate levels are elevated. (See "Myopathies affecting the extraocular muscles in children", section on Kearns-Sayre syndrome). Brainstem pathology — Structural disease of the brainstem can cause isolated ocular disease. Parasellar tumors and aneurysms, for example, can impair function of the third, fourth, and sixth cranial nerves, leading to symptoms similar to ocular myasthenia. Searching for fifth nerve dysfunction in such patients (especially an absent corneal reflex) may confirm a structural lesion. CT or MRI scanning to exclude these disorders is advocated by some neurologists when evaluating patients with ocular myasthenia [30]. CONDITIONS THAT MIMIC GENERALIZED MYASTHENIA — There are a number of conditions that can mimic myasthenia clinically. However, careful history, physical examination, and testing usually allow the correct diagnosis to be established. Depression — Because of the distinctive problem of muscle fatigue in myasthenia, the disease is often unrecognized or, worse, is mistaken for a conversion reaction. This is especially true when the patient's demeanor suggests depression. It is therefore important to differentiate generalized fatigue from muscle fatigue produced by repetitive muscle contraction. As an example, the depressed patient complains of fatigue that is often maximal in the morning; in comparison, patients with myasthenia often relate their fatigue to a specific activity, such as climbing stairs, brushing their hair, or a full day at work, many of which are maximal in the evening. Amyotrophic lateral sclerosis — ALS is a relentlessly progressive disease that, like myasthenia, can involve the bulbar muscles and can produce a false positive Tensilon test and even a false positive test for AChR-Ab [10]. However, its progressive nature and the presence of hyperreflexia with Babinski signs can usually distinguish ALS from myasthenia. (See "Amyotrophic lateral sclerosis") Lambert-Eaton myasthenic syndrome — The Lambert-Eaton myasthenic syndrome shares the same pathologic site with myasthenia gravis (the neuromuscular junction) and has a similar pathophysiology (an autoimmune disease usually associated with malignancy). However, the clinical presentation is markedly different in the Lambert-Eaton syndrome [30]. Hip girdle weakness is typically an early symptom, making it difficult for the patient to rise from a chair or to climb stairs. Less dramatic shoulder girdle weakness eventually occurs. Involvement of the bulbar muscles or diplopia is rare, but ptosis is frequently seen. In addition to the differences in muscle distribution, there are several other differences between the Lambert-Eaton syndrome and myasthenia gravis [30]: Symptoms in the Lambert-Eaton syndrome are more likely to be present in the morning and to improve during the day and with exercise. Autonomic dysfunction, consisting of erectile impotence in men or dry mouth, is a frequent finding in the Lambert-Eaton syndrome. Repetitive nerve stimulation at high rates (20 to 50 cycles per second) produces an increase in response, in contrast to the progressive weakness in myasthenia.
  7. 7. Approximately 70 percent of patients have cancer, usually small cell lung cancer. The Lambert-Eaton syndrome is associated with unique autoantibodies. Over 95 percent of patients have antibodies against P/Q-type calcium channels; in comparison, less than 5 percent of patients with myasthenia have such antibodies [31]. (See "Paraneoplastic syndromes of the nervous system", section on Lambert- Eaton myasthenic syndrome). Occasional patients with LEMS have AChR-Ab [32]. Distinction from myasthenia gravis in this setting is made by the usual presence of small cell lung cancer and antibodies directed against the P/Q type calcium channels [32]. Botulism — Botulism can be confused with myasthenia because it affects the bulbar and eye muscles; the most frequently occurring botulinum toxin, for example, produces pupillary paralysis. (See "Botulism"). It is distinguished by its rapid progression and the usual association with ingestion of food contaminated by Clostridium botulinum. Thus, botulism is likely to affect a group, not just an individual. It also shows an increase in response during repetitive nerve stimulation, similar to that seen in the Lambert-Eaton syndrome. Penicillamine-induced myasthenia — Approximately 1 percent of patients treated with penicillamine develop myasthenia gravis [33]. Penicillamine-induced disease shares many of the characteristics of primary myasthenia gravis. It often begins with ocular manifestations and then progresses to generalized weakness; it is also associated with elevated AChR-Ab titer, a positive Tensilon test, and a decremental response on repetitive nerve stimulation. However, the diagnosis may be missed if a symptom such as weakness or dyspnea is ascribed to some underlying disease, such as rheumatoid arthritis or chronic lung disease [34]. Myasthenia induced by penicillamine resolves when the drug is withdrawn in the majority of cases [33]. However, resolution of myasthenia may be quite slow and, if incomplete, treatment for myasthenia may be required [35]. This phenomenon should not be confused with exacerbation of myasthenia that can be produced by a variety of drugs. (See "Treatment of myasthenia gravis"). Congenital myasthenic syndromes — There are several rare, congenital myasthenic syndromes. They should be considered when there is a positive family history, a lack of response to anticholinesterase drugs (with a negative Tensilon test), and the absence of AChR-Ab [36]. Although these conditions are not immune-mediated, they are confused with myasthenia gravis because they also involve dysfunction of the acetylcholine mediated neuromuscular synaptic transmission. Presynaptic, synaptic and post synaptic dysfunction can all lead to weakness in the neonate or infant. In some of these disorders, mutations in the acetylcholine receptor subunits result in gated channels that show either increased or reduced sensitivity to acetylcholine stimulation [36,37]. Autosomal recessive inheritance of mutations in the enzyme choline acetyltransferase are one cause of presynaptic dysfunction [38]. As noted in the introduction, transplacental passage of antibodies to the neuromuscular junction may cause neonatal myasthenia. The presence of
  8. 8. autoantibodies in both mother and neonate help differentiate this disorder from those due to mutations that lead to myasthenia in the neonate. Both disorders are discussed in more detail separately. (See "Neuromuscular junction disorders in newborns"). RECOMMENDATIONS — The optimal approach to the diagnosis of myasthenia gravis varies with the clinical setting. As an example, the Tensilon test permits quick confirmation of the diagnosis in patients with the classical distribution of weakness that can be shown to be fatigable in the office. Because of its specificity, AChR-Ab testing should also be performed while EMG with repetitive stimulation may not be necessary. However, all three tests should be done when the diagnosis is uncertain. Important negative tests to exclude other diseases in the differential diagnosis of myasthenia gravis are also indicated in this setting and should include thyroid function tests, antinuclear antibody and rheumatoid factor titers. Once the diagnosis of myasthenia gravis is established, a chest CT scan should be performed to exclude an associated thymoma especially in the patient over 40.