Edrophonium hydrochloride (Enlon; formerly “Tensilon”) is a fast, short-acting parenteral cholinesterase inhibitor. It reaches peak effect within 1 minute after intravenous injection and persists to some extent for at least 10 minutes. Myasthenic weakness typically improves transiently after administration of 4 to 10 mg (0.4 to 1.0 mL). The edrophonium test may be blinded, with drug or normal saline being injected. Whether drug or placebo, a 0.2-mL test dose is given to screen for excessive cholinergic side effects, such as cardiac arrhythmia, gastrointestinal hyperactivity, or diaphoresis. A crash cart should always be available, and patients with known cardiac disease and elderly patients warrant electrocardiographic monitoring. The remaining 0.8 mL is given after 1 minute. Interpretation of the test depends on identifying and observing an unequivocal baseline muscular deficit that can be improved following the injection of edrophonium. Ptosis and ophthalmoparesis, if present, are semiquantifiable and well suited; if respiratory compromise is present, monitoring maximum inspiratory pressure (MIP) or vital capacity is useful. As a general rule, positive responses are dramatic; if there is any doubt about the positivity of the test, it should be considered negative. False-positive edrophonium tests are quite rare; false negatives are common. In children, the appropriate test dose is 0.03 mg per kg, one-fifth of which may be given as a test dose.

Neostigmine is a longer-acting parenteral cholinesterase inhibitor that sometimes affects a more obvious clinical response. It is also typically associated with more obvious autonomic side effects. The 1.5-mg test dose (0.04 mg per kg in children) should therefore be preceded by 0.5 mg of atropine; both may be given subcutaneously.

Recognition of the immune nature of myasthenia gravis has provided a relatively sensitive and highly specific diagnostic study. Approximately 85% of myasthenics have detectable serum antibodies, which bind to acetylcholine receptors (AChR) [5]. The sensitivity drops to 70% in those with purely ocular myasthenia [6]. The antibodies themselves constitute a heterogeneous group, reacting against various receptor subunits. Although the actual antibody titer is of little significance, correlating poorly with the severity of disease or clinical response to therapy, the presence of antibodies is a strong indication of the disease. A normal test does not exclude the diagnosis, especially in the patient presenting with predominantly ocular symptoms and signs. Of note, these antibodies have also been found in a small percentage of patients with Lambert–Eaton myasthenic syndrome, autoimmune liver disorder, and patients with lung cancer without neurologic disease [6].

Among seronegative myasthenic patients, from 30% to 70% may be found to have antibodies directed against muscle-specific tyrosine kinase [MuSK], an enzyme that catalyzes acetylcholine receptor aggregation in the formation of neuromuscular junctions [7]. Animal models have also recently shown that MuSK antibodies may reduce acetylcholine receptor clustering and thus impair neuromuscular transmission [8]. Patients who have antibodies to MuSK are often young women (onset of symptoms before 40 years of age) with prominent bulbar involvement [9] and neck or respiratory muscle weakness [7]. They tend to have more severe disease requiring aggressive immunosuppressive treatment [9] and have a higher frequency of respiratory crisis compared to seronegative or AChR-positive myasthenics [10]. Unlike patients with antibodies to AChR, there appears to be a correlation between MuSK antibody levels and disease severity, with antibody levels often decreasing after various immunosuppressive treatments except thymectomy [11].

Striated muscle antibodies that react with muscle proteins titin and ryanodine receptor have also been found, mainly in patients with thymoma and in those with late onset myasthenia (onset of symptoms > 50 years of age) [12]. Thus, they may be helpful in the detection or recurrence of thymoma. In addition, they tend to be associated with more severe disease, and therefore may aid in prognosis [12].

Myasthenics also have an increased incidence of other autoantibodies, including antithyroid antibodies, antiparietal cell antibodies, and antinuclear antibodies, although routine screening for these is not part of the diagnostic evaluation for suspected myasthenia gravis.

The electromyographic hallmark of myasthenia gravis is a decrement in the amplitude of the muscle potential seen after exercise or slow repetitive nerve stimulation. The decrement should be at least 10% and preferably 15% or more. Routine motor and sensory conduction studies are normal, as is the conventional needle examination. The more severely
affected patient is more likely to show a decremental response; responses are most consistently elicited from facial and proximal muscles. If a significant decrement is observed, exercising the muscle briefly for 10 seconds transiently reverses the decrement [13]. Single-fiber electromyography is relatively sensitive, documenting increased jitter [14]—variability in the temporal coupling of single fibers within the same motor unit. Increased jitter, however, is far from specific; most peripheral neurogenic diseases also lead to increased jitter.

Crisis refers to threatened or actual respiratory compromise in a myasthenic patient. It may reflect respiratory muscle insufficiency or inability to handle secretions and oral intake, but it is typically a combination of both. With currently available treatments, myasthenic crisis is not common. An occasional patient presents with fulminating disease; crisis management then coincides with initial evaluation and institution of therapy. Otherwise, crisis may be precipitated by other illnesses, such as influenza or other infections, or by surgery.

The respiratory function of any acutely deteriorating or severely weak myasthenic should be monitored compulsively. When the weakening myasthenic reaches a point at which increased respiratory effort is required, fatigue often prevents the effective use of secondary muscles, and respiratory failure rapidly ensues. Arterial blood gas values and even oxygen saturation are poor indicators of incipient failure in the face of respiratory muscle compromise. Forced vital capacity (FVC) and MIP are better indices and should be serially charted. The FVC should be assessed with the patient both sitting and supine, because diaphragmatic paresis may be accentuated in the supine position. MIP measurement requires special care if the patient also has significant facial weakness. An FVC less than 20 mL per kg or an MIP greater than (i.e., not as negative as) -40 cm H₂O suggests impending failure and usually warrants intubation. If a downward trend is noted (greater than 30% decrease) [15], elective intubation should be considered even sooner, unless there is a realistic expectation of rapid reversal.

Acute deterioration in a myasthenic always warrants consideration of contributing circumstances or concurrent illness that may accentuate the underlying defect in neuromuscular transmission. The major considerations are listed in Table 176.1 and discussed later.

The possibility of cholinergic crisis in patients receiving anticholinesterase drugs (e.g., pyridostigmine), although no longer common, should not be overlooked. The presence of fasciculations, diaphoresis, or diarrhea should alert the clinician to this possibility. In the past, the importance of differentiating between myasthenic crisis and cholinergic crisis was stressed. Edrophonium testing was used to differentiate between the two; abrupt deterioration after a conventional 10-mg test dose indicated overdosage with cholinesterase inhibitors. One had to be adequately prepared for deterioration and increased respiratory secretions. Because oftentimes it is very difficult to determine the response and because of the potential side effects with overdosage of anticholinesterase drugs of increased pulmonary secretions, many authors now recommend discontinuation of cholinesterase inhibitors at the time of crisis [2,16,17] and reinstituting them when patients are stronger. This assumes that adequate respiratory monitoring and support are in effect. A brief holiday from cholinesterase inhibition also often results in an enhanced response to therapy when reinstituted.

Intercurrent infection is often associated with increased weakness in the myasthenic patient. There should be a comprehensive search for systemic infection in the deteriorating patient, particularly the patient receiving immunosuppressive therapy. Any infections should be treated aggressively. Both hypothyroid and hyperthyroid states are often associated with increased weakness. Again, there is an increased association between thyrotoxicosis and myasthenia gravis. The manifestations of electrolyte imbalance may be enhanced in myasthenics. Otherwise, insignificant electrolyte effects on transmitter release or muscle membrane excitability may be amplified at the myasthenic neuromuscular junction. Potassium, calcium, phosphate, and magnesium alterations should be corrected. Myasthenia gravis may also impart enhanced sensitivity to a number of medications that have only minimal effects on neuromuscular function in normal individuals. Aminoglycoside antibiotics, beta-blockers, and many cardiac antiarrhythmics may have adverse effects. Anticholinergics, respiratory depressants, and sedatives of any kind should be avoided or used only with great caution. Neuromuscular-blocking agents should never be administered to myasthenics in the intensive care unit (ICU) setting, because they often have profound and prolonged effects. This increased sensitivity occasionally results in postoperative failure to wean in an undiagnosed mild myasthenic who has undergone surgery for an unrelated problem. Table 176.2 provides a comprehensive listing of medications that may further impair neuromuscular transmission in myasthenic patients.