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Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by weakness of voluntary muscles, including the ocular, facial, oropharyngeal, limb, and respiratory muscles. MG can be broadly characterized as either ocular MG (a form that is limited to the eyelid and extraocular muscles) or generalized MG (a form that commonly involves ocular weakness as well as a variable combination of weakness in the bulbar, limb, and respiratory muscles). Clinical and serologic testing can be used to diagnose MG, but diagnostic sensitivity varies depending on whether the patient has ocular or generalized MG. Demonstration of acetylcholine receptor (AChR) binding antibodies, which are present in the majority of patients with generalized disease, provides laboratory confirmation of MG. If AChR antibody test results are negative, muscle-specific tyrosine kinase (MuSK) antibody testing should be performed. Because thymic abnormalities are not uncommon in individuals with MG, imaging and neurophysiologic studies may also be part of the initial evaluation.
Quick Answers for Clinicians
A diagnosis of myasthenia gravis (MG) is often based on clinical presentation and laboratory confirmation. Antibodies against acetylcholine receptors (AChRs) and muscle-specific tyrosine kinase (MuSK) are specific and sensitive for the detection of MG. Because of the high specificity and sensitivity of these antibodies in the appropriate clinical scenario, these laboratory tests have largely supplanted traditional bedside testing, including edrophonium testing (which is no longer available in the United States) and the ice pack test. In the case of negative antibody test results, neurophysiologic and imaging studies can confirm the diagnosis.
In ocular MG, weakness is limited to eyelids and extraocular muscles. Generalized MG is characterized by weakness that often involves ocular muscles as well as bulbar, limb, and respiratory muscles. Acetylcholine receptor (AChR) blocking and modulating antibodies are usually found in association with binding antibodies and have a higher prevalence in generalized MG than in ocular MG. Muscle-specific tyrosine kinase (MuSK) antibodies have been reported in up to 50% of patients with generalized MG who lack AChR antibodies ; these antibodies are generally not found in those with established ocular MG.
There is no clear correlation between acetylcholine receptor (AChR) antibody serum titers and myasthenia gravis (MG) disease severity, and the usefulness of following AChR antibody levels to monitor treatment response is unclear. Decreasing muscle-specific tyrosine kinase (MuSK) antibody levels may be associated with therapeutic response; however, more studies are needed in this area.
Seronegative myasthenia gravis (MG) refers to the lack of detectable acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) antibodies; this form of the disease occurs in roughly 7-8% of individuals with MG. These individuals may prove to be seropositive for AChR or MuSK antibodies if tested by a more sensitive method (eg, cell-based immunofluorescence assays), but these tests are not in widespread commercial use.
Indications for Testing
Testing for MG should be considered in patients presenting with new-onset muscle weakness, particularly when this weakness is accompanied by ptosis or diplopia.
Laboratory Testing
Diagnosis
MG is a condition that fulfills all major criteria for a disorder mediated by autoantibodies against AChR. After establishing a clinical diagnosis of MG based on characteristic presentation (eg, ocular and bulbar muscle weakness), AChR serum antibody status should be determined. If AChR testing is negative, MuSK testing is advised. Serologic testing should be performed to confirm the diagnosis before beginning therapy.
Antibody Testing
Acetylcholine Receptor Antibodies
Circulating AChR antibodies are present in ~85% of patients with MG. AChR antibodies are classified into three types: binding, blocking, and modulating. The AChR binding assay is the most clinically useful and frequently utilized test and is highly specific for MG. In general, a positive AChR binding test in a patient with a compatible clinical presentation is diagnostic for MG. AChR blocking antibodies are usually found in association with binding antibodies and have a higher prevalence in generalized MG than in ocular MG. Testing for modulating AChR antibodies is less clinically useful but may be considered in the event of a negative binding test and high suspicion of MG.
AChR testing sensitivity varies depending on the type of MG; in generalized MG, about 85% of patients have AChR antibodies, whereas these antibodies are present in roughly 40% of patients with ocular MG. A large number of individuals with AChR antibody-positive MG have thymic abnormalities, including thymic hyperplasia (most common) and thymic tumors. The absence of AChR antibodies does not rule out the diagnosis of MG. False-negative results may occur in the setting of immunosuppression or in patients who have received antivenom therapy.
There is no clear correlation between AChR antibody serum titers and MG disease severity, and the usefulness of following AChR antibody levels to monitor treatment response is unclear.
Muscle-Specific Tyrosine Kinase Antibodies
In cases of generalized MG, approximately half of individuals without AChR antibodies have MuSK antibodies. Therefore, MuSK antibody measurement is recommended if a patient is negative for AChR antibodies. Individuals with MG who are seropositive for MuSK antibodies are more likely than those without these antibodies to have atypical clinical features (eg, selective muscle weakness that often spares the ocular muscles), onset at a younger age, and no thymic pathology; this presentation is more likely to occur in females. As with the absence of AChR antibodies, the absence of MuSK antibodies does not rule out the diagnosis of MG.
Decreasing antibody levels may be associated with therapeutic response, which suggests that MuSK antibody levels might serve as a valuable biomarker when monitoring MG. However, more studies are needed in this area.
Other Myasthenia Gravis-Associated Antibodies
Other antibodies have been detected in patients with MG, including lipoprotein-related protein 4 (LRP4) and striated muscle antibodies. The LRP4 protein activates MuSK activity and promotes the clustering of AChRs and their stabilization at the neuromuscular junction. Two recent studies found anti-LRP4 antibodies in 2% and 50% of patients, respectively, with double-seronegative MG (ie, patients had no detectable AChR or MuSK antibodies).
Striational antibodies are not specific for MG and may be seen in individuals with other autoimmune diseases and in cases of thymoma without MG. Striated muscle antibodies, when detected in the presence of AChRs, are associated with late-onset MG; as a marker for thymoma, striational antibody measurement is most useful in patients who are seropositive for AChR antibodies in early-stage MG. Titin is one of the major antigenic targets of striational antibodies, and testing for antititin antibodies may be useful when first-line diagnostic tests are negative or when screening for the presence of thymoma in patients with MG. Titin antibody levels appear to correlate with disease severity and have been postulated as useful to assess disease prognosis. However, more research is required before these antibodies are recommended for use as disease biomarkers.
ARUP Laboratory Tests
Quantitative Radioimmunoassay/Semi-Quantitative Flow Cytometry
Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Flow Cytometry
Components include binding, blocking, and modulating antibodies; titin antibody; and striated muscle antibodies with reflex to titer
Quantitative Radioimmunoassay (RIA)/Semi-Quantitative Flow Cytometry
Components include AChR binding and blocking antibodies with reflex to AChR modulating antibodies or MuSK antibodies
Quantitative Radioimmunoassay/Qualitative Radiobinding Assay/Semi-Quantitative Flow Cytometry/Semi-Quantitative Indirect Fluorescent Antibody
Components include acetylcholine receptor binding, blocking, and modulating antibodies; P/Q-type voltage-gated calcium channel antibodies; N-type voltage gated calcium channel antibodies; voltage-gated potassium channel antibodies; titin antibody; striated muscle antibodies; LGI1 antibodies, IgG; CASPR2 antibodies, IgG; and ganglionic acetylcholine receptor antibodies
Quantitative Radioimmunoassay
Semi-Quantitative Flow Cytometry
Semi-Quantitative Flow Cytometry
Quantitative Radioimmunoassay (RIA)
Components include AChR binding antibodies with reflex to muscle-specific kinase (MuSK) antibodies
Semi-Quantitative Cell-Based Indirect Fluorescent Antibody
Semi-Quantitative Indirect Fluorescent Antibody
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
References
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Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69(4):445-451.
Components include binding, blocking, and modulating antibodies