The most immediate and readily accessible confirmatory study is the edrophonium (Tensilon) test. To perform the test, choose 1 or 2 weak muscles to judge. Ptosis, dysconjugate gaze, and other cranial deficits provide the most reliable endpoints. Use a setting where hypotension, syncope, or respiratory failure can be managed as patients occasionally decompensate during the test. If the patient has severe dyspnea, defer the test until the airway is secure. Start an intravenous (IV). Have IV atropine 0.4 mg readily available in the event of bradycardia or extreme gastrointestinal (GI) side effects. Edrophonium 10 mg (1 ml) is drawn up in a syringe, and 1 mg (0.1 ml) should be given as a test dose while checking the patient’s heart rate (to assure the patient is not supersensitive to the drug). If no untoward side effects occur after 1 minute, another 3 mg is given. Many MG patients will show improved power within 30 to 60 seconds of giving the initial 4 mg at which point the test can be stopped. If after 1 minute there is no improvement, give additional 3 mg, and if there is still no response, 1 minute later give the final 3 mg. If the patient develops muscarinic symptoms or signs at any time
during the test (sweating, salivation, and GI symptoms), or should fasciculations be detected then one can assume that enough edrophonium has been given to see improvement in strength and the test can be stopped. When a placebo effect or examiner bias is of concern, the test is performed in a double-blind placebo control fashion. The 1 ml control syringe contains either saline, 0.4 mg atropine, or nicotinic acid 10 mg. Improved strength from edrophonium lasts for just a few minutes. When improvement is clear-cut, the test is positive. If the improvement is borderline, it is best to consider the test negative. The test can be repeated several times. Sensitivity of the edrophonium test is about 90%. The specificity is difficult to determine because improvement following IV edrophonium has been reported in other neuromuscular diseases including Lambert-Eaton’s syndrome (LES), botulism, Guillain-Barré syndrome, motor neuron disease, and with lesions of the brainstem, pituitary, and cavernous sinus. Neostimine has a longer duration of effect and in selected patients may be an alternative cholinesterase inhibitor (CEI) for diagnostic testing, especially in children. For performance of a “neostigmine test,” 0.04 mg per kg is given intramuscularly or 0.02 mg per kg intravenously (one time only).

The primary serologic test is the immunoprecipitation assay for ACh receptor binding antibodies. In addition, assays for receptor modulating and blocking antibodies are available. Binding antibodies are present in about 80% of all myasthenia patients (40% to 50% of patients with pure ocular MG, 80% of those with mild generalized MG, and 90% of patients with moderate to severe generalized MG, and 70% of those in clinical remission). By also testing for modulating and blocking antibodies, the sensitivity improves to 90% overall. Specificity is superb with false positives exceedingly rare in reliable labs.

Approximately 25% of patients seronegative for ACh receptor antibodies have antibodies to muscle specific kinase (MuSK). The clinical features of MuSK positive patients may differ from non-MuSK MG patients. Such patients tend to be younger women (under age 40) with disproportionate bulbar, neck extensor, shoulder, and respiratory symptoms with increased likelihood of “fixed weakness” and have a lower likelihood of abnormal repetitive stimulation and edrophonium test results. MuSK patients have no associate thymus abnormalities and are more likely to be refractory to medical management.

Repetitive stimulation testing is widely available and has variable sensitivity depending on the number and selection of muscles studied and various provocative maneuvers. However, in most labs this technique has a sensitivity of about 50% in all patients with MG (lower in patients with mild or pure ocular disease). In general, the yield from repetitive stimulation is higher when testing muscle groups having clinically significant weakness. Single fiber EMG (SFEMG) is a highly specialized technique, usually available in major academic centers, with a sensitivity of about 90%. Abnormal single fiber results are common in other neuromuscular diseases; therefore, the test must be used in the correct clinical context. The specificity of SFEMG is an important issue in that mild abnormalities can clearly be present with a variety of other diseases of the motor unit including motor neuron disease, peripheral neuropathy, and myopathy. Disorders of neuromuscular transmission other than MG can have abnormalities on SFEMG. In contrast, ACh receptor antibodies (and MuSK antibodies) are not found in non-MG patients. In summary, the two highly sensitive laboratory studies are SFEMG and ACh receptor antibodies; nonetheless, neither test is 100% sensitive.

CEIs are safe, effective, and first-line therapy in all patients. Inhibition of acetylcholinesterase (AChE) reduces the hydrolysis of ACh, increasing the accumulation of ACh at the nicotinic postsynaptic membrane. The CEIs used in MG bind reversibly (as opposed to organophosphate CEIs, which bind irreversibly) to AChE. These drugs cross the blood-brain barrier poorly and tend not to cause CNS side effects. Absorption from the GI tract tends to be inefficient and variable, with oral bioavailability of about 10%. Muscarinic autonomic side effects of GI cramping, diarrhea, salivation, lacrimation, diaphoresis are common and dose-related, and occasional patients may have bradycardia. A feared potential complication of excessive CEI use is skeletal muscle weakness (cholinergic weakness). Patients receiving parenteral CEI are at the greatest risk to have cholinergic weakness. It is uncommon for patients receiving oral CEI to develop significant cholinergic weakness even while experiencing muscarinic cholinergic side effects. Generally available CEIs are summarized in Table 48.1.

Association of the thymus gland with MG was first noted around 1900 and thymectomy has become standard therapy for over 50 years. As the benefit from thymectomy is anecdotal and controversial, a large randomized international multicenter controlled trial is currently in progress. Until the completion of that study, the general consensus is that thymectomy should be considered for patients with moderate to severe MG, especially those inadequately controlled on CEI, and those under age 55 years. All patients with suspected thymoma undergo surgery. About 75% of MG patients appear to benefit from thymectomy. Patients may improve or simply stabilize. For unclear reasons, the onset of improvement tends to be delayed by a year or two in most patients (some patients may improve 5 to 10 years after surgery). The majority of centers use the transsternal approach for thymectomy with the goal of complete removal of the gland. The limited transcervical approach has been largely abandoned due to the likelihood of incomplete gland removal. Many centers perform a “maximal thymectomy” in order to ensure complete removal. The procedure involves a combined transternal-transcervical exposure with en bloc removal of the thymus. Thorascopic and video-assisted thymectomy offer less invasive options. If thymectomy is to be performed, choose an experienced surgeon, anesthesiologist, and center with a good track record and insist that the entire gland is removed.