MYASTHENIA GRAVIS - A SUMMARY
James F. Howard, Jr., M.D.
Department of Neurology
The University of North Carolina at Chapel Hill
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. The usual cause is an acquired immunological abnormality, but some cases result from genetic abnormalities at the neuromuscular junction. Much has been learned about the pathophysiology and immunopathology of myasthenia gravis during the past 20 years. What was once a relatively obscure condition of interest primarily to neurologists is now the best characterized and understood autoimmune disease. A wide range of potentially effective treatments are available, many of which have implications for the treatment of other autoimmune disorders.
The 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.
The 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 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.
Weakness 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.
Repetitive 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.
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.
Intravenous 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.
A controlled clinical trial has never been reported for any medical or surgical modality used to treat myasthenia gravis. All recommended regimens are empirical and experts disagree on treatments of choice. Treatment decisions should be based on knowledge of the natural history of disease in each patient and the predicted response to a specific form of therapy. Treatment goals must be individualized according to the severity of disease, the patient's age and sex, and the degree of functional impairment. The response to any form of treatment is difficult to assess because the severity of symptoms fluctuates. Spontaneous improvement, even remissions, occur without specific therapy, especially during the early stages of the disease.
Copyright © 2015 by Myasthenia Gravis Foundation of America and James F. Howard, Jr., M.D. All rights reserved.
Reviewed by the MGFA's Medical Advisory Board, June 2015
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