Which statement by the client supports the diagnosis of myasthenia gravis?
James F. Howard, Jr., M.D. Show
Epidemiology Clinical Presentation Pathophysiology of MG The Thymus in MG Diagnostic Procedures Treatment The Future
EpidemiologyThe prevalence of myasthenia gravis in the United States is estimated at 14 to 20 per 100,000 population, approximately 36,000 to 60,000 cases in the United States. However, myasthenia gravis remains underdiagnosed and the prevalence is probably higher. Previous studies have shown that women are more often affected than men. The most common age at onset is the second and third decades in women and the seventh and eighth decades in men. As the population ages, the average age at onset has increased correspondingly, and now males are more often affected than females, and the onset of symptoms is usually after age 50. A 2015 study in acetylcholine receptor antibody (AChR-Abs) positive Caucasian has demonstrated that there is no specific causal gene for myasthenia gravis there are specific regulatory genes that influence immune regulation. In addition, about 3% of the study population had a primary relative with myasthenia gravis suggesting a small but distinct but not direct genetic influence. Clinical PresentationPatients with myasthenia gravis come to the physician complaining of specific muscle weakness and not of generalized fatigue. Ocular motor disturbances, ptosis or diplopia, are the initial symptom of myasthenia gravis in two-thirds of patients; almost all had both symptoms within 2 years. Oropharyngeal muscle weakness, difficulty chewing tough, chewy or fibrous foods, swallowing, or talking, is the initial symptom in one-sixth of patients, and limb weakness in only 10%. Initial weakness is rarely limited to single muscle groups such as neck or finger extensors or hip flexors. The severity of weakness fluctuates during the day, usually being least severe in the morning and worse as the day progresses, especially after prolonged use of affected muscles. The course of disease is variable but usually progressive. Weakness is restricted to the ocular muscles in about 10% to 40% of cases. The rest have progressive weakness during the first 2 years that involves oropharyngeal and limb muscles. Maximum weakness occurs during the first year in two-thirds of patients. In the era before corticosteroids were used for treatment, approximately one-third of patients improved spontaneously, one-third became worse, and one-third died of the disease. Spontaneous improvement frequently occurred early in the course. Symptoms fluctuated over a relatively short period of time and then became progressively severe for several years (active stage). The active stage is followed by an inactive state in which fluctuations in strength still occurred but are attributable to fatigue, intercurrent illness, or other identifiable factors. After 15 to 20 years, weakness often becomes fixed and the most severely involved muscles are frequently atrophic (burnt-out stage). Factors that worsen myasthenic symptoms are emotional upset, systemic illness (especially viral respiratory infections), hypothyroidism or hyperthyroidism, pregnancy, the menstrual cycle, drugs affecting neuromuscular transmission, and increases in body temperature. Pathophysiology of Myasthenia GravisThe normal neuromuscular junction releases acetylcholine (ACh) from the motor nerve terminal in discrete packages (quanta). The ACh quanta diffuse across the synaptic cleft and bind to receptors on the folded muscle end-plate membrane. Stimulation of the motor nerve releases many ACh quanta that depolarize the muscle end-plate region and then the muscle membrane causing muscle contraction. In acquired myasthenia gravis, the post-synaptic muscle membrane is distorted and simplified, having lost its normal folded shape. The concentration of ACh receptors on the muscle end-plate membrane is reduced, and antibodies are attached to the membrane. ACh is released normally, but its effect on the post-synaptic membrane is reduced. The post-junctional membrane is less sensitive to applied ACh, and the probability that any nerve impulse will cause a muscle action potential is reduced. The Thymus in Myasthenia GravisThymic abnormalities are clearly associated with myasthenia gravis but the nature of the association is uncertain. Ten percent of patients with myasthenia gravis have a thymic tumor and 70% have hyperplastic changes (germinal centers) that indicate an active immune response. These are areas within lymphoid tissue where B-cells interact with helper T-cells to produce antibodies. Because the thymus is the central organ for immunological self-tolerance, it is reasonable to suspect that thymic abnormalities cause the breakdown in tolerance that causes an immune-mediated attack on AChR in myasthenia gravis. The thymus contains all the necessary elements for the pathogenesis of myasthenia gravis: myoid cells that express the AChR antigen, antigen presenting cells, and immunocompetent T-cells. Thymus tissue from patients with myasthenia gravis produces AChR antibodies when implanted into immunodeficient mice. However, it is still uncertain whether the role of the thymus in the pathogenesis of myasthenia gravis is primary or secondary. Most thymic tumors in patients with myasthenia gravis are benign, well-differentiated and encapsulated, and can be removed completely at surgery. It is unlikely that thymomas result from chronic thymic hyperactivity because myasthenia gravis can develop years after thymoma removal and the HLA haplotypes that predominate in patients with thymic hyperplasia are different from those with thymomas. Patients with thymoma usually have more severe disease, higher levels of AChR antibodies, and more severe EMG abnormalities than patients without thymoma. Almost 20% of patients with myasthenia gravis whose symptoms began between the ages of 30 and 60 years have thymoma; the frequency is much lower when symptom onset is after age 60. Diagnostic ProceduresThe diagnosis of MG is often delayed months or even years (in the mildest cases). The unusual distribution and fluctuating symptoms often suggests psychiatric disease. Patients with drooping eyelids, double vision and difficulty with speech or swallowing symptoms suggest intracranial pathology and often lead to an evaluation for stroke, brain tumor or multiple sclerosis. Patients with anti-MuSK-antibody positive MG may have focal or regional weakness and muscle atrophy that are more suggestive of motor neuron or muscle membrane (myopathy) disease. The Edrophonium Chloride (Tensilon®) TestWeakness caused by abnormal neuromuscular transmission characteristically improves after intravenous administration of edrophonium chloride, commonly referred to as the Tensilon® Test. Some patients who do not respond to intravenous edrophonium chloride may respond to intramuscular neostigmine, because of its longer duration of action. Intramuscular neostigmine is particularly useful in infants and children whose response to intravenous edrophonium chloride may be too brief for adequate observation. In some patients, a therapeutic trial of daily oral pyridostigmine may produce improvement that can't be appreciated after a single dose of edrophonium chloride or neostigmine. Serum Antibodies in Myasthenia GravisSeveral types of antibodies are found in the majority of patients with MG and include forms directed against the acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). Ten percent of patients with acquired, presumably immune-mediated MG do not have detectable serum antibodies to AChR or MuSK. In these seronegative patients, the diagnosis is based on the clinical presentation, the response to cholinesterase inhibitors and electrodiagnostic findings. Anti-striational muscle antibodies (Str-Abs), which react with contractile elements of skeletal muscle, are not pathogenic. They are found in more than 90% of MG patients with thymoma, and in one-third of patients with thymoma who do not have MG. One-third of MG patients without thymoma also have these antibodies; they are more frequent in older patients and in those with more severe disease. Str-Abs are also elevated in other disorders including autoimmune liver disease and infrequently in Lambert-Eaton syndrome and in primary lung cancer. Str-Abs are rarely, if ever, elevated in MG in the absence of acetylcholine receptor antibodies and are therefore of limited use in confirming the diagnosis. The main clinical value of Str-Abs is in predicting thymoma: 60% of patients with MG with disease onset before age 50 who have elevated Str-Abs acetylcholine receptor antibodies (AChR-Abs) have thymoma. At least 85% of patients with acquired generalized myasthenia and 54% with ocular myasthenia have serum antibodies that bind human acetylcholine receptor (AChR) although there is wide variation in reported studies. The serum concentration of AChR antibody varies widely among patients with similar degrees of weakness and its level cannot predict the severity of disease in individual patients. Approximately 10% of patients who do not have binding antibodies, have other antibodies that modulate the turnover of AChR in tissue culture. The concentration of binding antibodies may be low or absent at symptom onset and become elevated later. AChR binding antibodies concentrations are sometimes increased in patients with systemic lupus erythematosus, inflammatory neuropathy, amyotrophic lateral sclerosis, rheumatoid arthritis taking D-penicillamine, thymoma without myasthenia gravis, and in normal relatives of patients with myasthenia gravis. False positive tests are reported when blood is drawn within 48 hours of a surgical procedure involving the use of general anesthesia and muscle relaxants. In general, an elevated concentration of AChR binding antibodies in a patient with compatible clinical features confirms the diagnosis of myasthenia gravis, but normal antibody concentrations do not exclude the diagnosis. Antibodies to muscle-specific receptor tyrosine kinase (MuSK), a surface membrane component essential in the development of the neuromuscular junction, have recently been identified and are found in up to 40% of MG patients who are seronegative for AChR antibodies. Another small percentage of these seronegative patients have antibody to the agrin receptor low-density lipoprotein receptor–related protein 4 (LRP4). These patients typically will have prominent weakness of the neck, oro-bulbar and sometimes respiratory musculature, are often poorly responsive to cholinesterase inhibitors. ElectromyographyRepetitive Nerve Stimulation (RNS) The amplitude of the compound muscle action potential (CMAP) elicited by repetitive nerve stimulation is normal or only slightly reduced in patients without MG. The amplitude of the fourth or fifth response to a train of low frequency nerve stimuli falls at least 10% from the initial value in myasthenic patients. This decrementing response to RNS is seen more often in proximal muscles, such as the facial muscles, biceps, deltoid, and trapezius than in hand muscles. A significant decrement to RNS in either a hand or shoulder muscle is found in about 60% of patients with myasthenia gravis. Single Fiber EMG (SFEMG)Voluntary SFEMG is done with the patient making minor contraction of the muscle with the physician using either a standard single fiber electrode or a concentric needle EMG electrode with the smallest recording surface. The third technique, axonal micro-stimulation, requires the terminal nerve branch to be activate with a small amount of electrical current while recording with the electrode. All of the techniques are technically demanding. Each have specific normative values to which the patient’s study can be compared if the same methodology is used. The latter technique is very useful in sedated infants and children. Comparison of Diagnostic TechniquesIntravenous edrophonium chloride is often diagnostic in patients with ptosis or ophthalmoparesis, but is less useful when other muscles are weak. Elevated serum concentrations of AChR binding and probably MuSK antibodies virtually assures the diagnosis of myasthenia gravis, but normal concentrations do not exclude the diagnosis. Repetitive nerve stimulation confirms impaired neuromuscular transmission but is not specific to myasthenia gravis and is frequently normal in patients with mild or purely ocular disease. The measurement of jitter by SFEMG is the most sensitive clinical test of neuromuscular transmission and is abnormal in almost all patients with myasthenia gravis. A normal test in a weak muscle excludes the diagnosis of myasthenia gravis, but an abnormal test can occur when other motor unit disorders cause defects in neuromuscular transmission.
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