Myasthenia Gravis: Etiologic and Pathophysiologic Concepts

Early in the disease course, a presumptive diagnosis of myasthenia gravis is supported by a test dose of edrophonium chloride (Tensilon), an acetylcholinesterase inhibitor characterized by very rapid onset (30-45 seconds) and short duration (5-10 minutes). This increases the availability of acetylcholine by briefly blocking the inherent neuromuscular junction postsynaptic acetylcholinesterase that normally leads to ACh breakdown. Thus ACh has a longer postsynaptic half-life, resulting in improvement in the strength of weak muscles. A test dose of 2 mg of Tensilon is given intravenously (to assess for any adverse affects), followed by 2to 10 mg to assess for improvement. It is prudent to have atropine at the bedside, to ameliorate a bradycardia associated with hypotension. One should be very cautious and possibly not utilize this test in senior citizens with a proclivity for heart block. A faster and easier, but very non-specific bedside test, involves placing a bag filled with ice over a ptotic eyelid for 1 to 2 minutes (cold pack test), which is sometimes useful to evaluate for immediate improvement in ptosis (a positive test result).

Traditionally, electromyography (EMG) has been utilized to provide confirmation of an MG diagnosis. Today EMG is most useful in the acutely ill MG patient when AChRAb results are not immediately available. Repetitive motor nerve stimulation (RMNS) and single fiber EMG (SFEMG) are designed to provide evidence for a postsynaptic defect in neuromuscular transmission and are sensitive (75% and 95%, respectively) in generalized MG. RMNS is performed by stimulating a motor nerve 6 to 10 times at low rates (2-3 Hz) and recording the amplitude of the response from the muscle that the nerve supplies. In the normal neuromuscular junction, RMNS elicits responses with identical amplitudes from stimulus to stimulus. In myasthenia gravis, however, a decrement (>10%) in the amplitude may be seen from the first to the subsequent stimuli, especially if the muscle is weak. Single fiber EMG is technically challenging, but highly sensitive, and uses a needle electrode to measure the variability in time of one action potential to reach threshold relative to another action potential from different muscle fibers innervated by the same axon. This variability, or “jitter,” is increased when the transmission at the neuromuscular junction is compromised.

Patients with MG have an increased incidence of thymoma; although usually benign, a small percentage of these tumors are malignant. Therefore evaluation for the presence of thymoma should be done in all myasthenic patients by imaging the mediastinum with computed tomography (CT) or magnetic resonance imaging (MRI).

Treatment of myasthenia gravis consists of symptomatic control, immunosuppressive and/or immunomodulating therapy, and, in selected patients, thymectomy. For patients with mild symptoms, for example, isolated ptosis, anticholinesterase inhibitors (pyridostigmine) are used with good response. For patients with bulbar or limb involvement, corticosteroids and other immunosuppressive agents (azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, rituximab, etc.) are necessary.

For the most severely affected patients—those with bulbar and respiratory muscle weakness and who are in or close to developing myasthenic crisis—immediate transfer to the intensive care unit (ICU) and treatment with immunomodulating agents, such as intravenous immune globulin (IVIg) or plasmapheresis, is necessary. Thymectomy is an absolute indication for myasthenic patients with thymoma; however, in those patients without thymoma, who are younger than 60 years, thymectomy is considered an “option to increase the probability of remission.” Prospective, randomized controlled trials are underway for more definitive evidence of benefit.

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