Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies directed against the postsynaptic neuromuscular junction of skeletal muscle. MG is characterized by fluctuating weakness that worsens with activity and improves with rest. In ocular MG, weakness is limited to periocular muscles, resulting in fluctuating ptosis and double vision. In generalized MG, weakness may also involve limb muscles, respiratory muscles, or pharyngeal muscles.
Anti–acetylcholine receptor (AChR) antibodies are present in about 85% of patients with generalized MG and in 40%–50% of patients with ocular MG. Anti–muscle-specific kinase (MuSK) antibodies are found in 40%–50% of patients with generalized MG who lack anti-AChR antibodies. Anti-LRP4 antibodies are present in a small subset of patients, but the clinical utility of testing for these antibodies is unclear. Patients who lack detectable antibodies but have evidence of MG on ancillary tests are termed “seronegative.”
Slow repetitive nerve stimulation (RNS) at a rate of 2–3 Hz may produce a decrement in motor response amplitudes in both pre- and postsynaptic neuromuscular junction disorders. A decrement is considered significant when the drop in amplitude is > 10%. In patients with generalized MG, a decrement with slow RNS is seen in ~ 80%. The sensitivity of slow RNS is much lower in patients with ocular MG. Decrement may also be seen in patients with congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome (LEMS), or botulism, and occasionally in patients with motor neuron disease.
Single fiber electromyography (SFEMG) is the most sensitive test for myasthenia gravis (90% sensitive in generalized MG, 80%–95% sensitive in ocular MG). However, SFEMG is not specific for MG and may be abnormal in other disorders of the neuromuscular junction, myopathies, neuropathies, or motor neuron diseases.
LEMS is a presynaptic disorder of neuromuscular transmission characterized by antibodies directed against voltage-gated calcium channels (VGCC). LEMS can be a paraneoplastic disorder, most frequently associated with small cell lung cancer or a primary autoimmune disorder. Patients present most frequently with proximal muscle weakness and reduced reflexes. Strength and reflexes often improve after brief exercise (postexercise facilitation), but weakness often worsens with protracted exercise. Ptosis, diplopia, and oropharyngeal symptoms may be present, but are less common and less prominent than in MG. Autonomic dysfunction is common in patients with LEMS. In LEMS, motor response amplitudes are reduced at baseline. High-frequency (10–50 Hz) RNS or repeat testing of motor response amplitude after brief, maximal exercise that produces an increment in amplitude > 100% of baseline is considered diagnostic of a presynaptic neuromuscular junction disorder. In patients with clinical features and electrodiagnostic findings suggestive of LEMS, serum anti-P/Q-type VGCC antibodies should be sent to confirm the diagnosis. All patients with LEMS should undergo a thorough evaluation for malignancy.
Functional neurologic disorders are a diagnosis of exclusion, but may be considered if a thorough and appropriate examination and workup fails to disclose an organic cause of symptoms.
Congenital myasthenic syndromes (CMSs) are caused by genetic defects in proteins that facilitate neuromuscular junction transmission. Unlike LEMS or MG, these are not disorders of autoimmunity. Most individuals with CMS are affected at birth or soon after, but milder forms may present in childhood or adolescence with fatigable limb or oculobulbar weakness. CMS can be difficult to diagnose and often requires genetic testing.
Thymic tumors, primarily thymoma, are present in up to 15% of patients with anti-AChR antibody-positive MG, and these patients should have mediastinal imaging with chest computed tomography (CT). If thymoma is identified, resection is indicated, which may improve MG symptoms. Though less likely to be revealing, CT chest to assess for thymoma should also be performed in patients with seronegative MG. Patients with anti-MuSK antibody–positive MG are not at increased risk of thymoma.