Myasthenia Gravis - MG

Indications for Testing

Testing for MG should be considered in patients presenting with new-onset fatigable 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 (e.g., 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

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 has limited diagnostic value, 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, the majority of patients have AChR antibodies, whereas these antibodies are present in roughly half 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.

Current evidence indicates there may be a positive correlation between AChR autoantibody levels and disease severity, as well as treatment response, although additional studies are needed. ^, 

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.  Although radioimmunoassay (RIA) has traditionally been recognized as the definitive test for detection of MuSK antibodies, other laboratory testing methods have been shown to have comparable accuracy, including enzyme-linked immunosorbent assay (ELISA) and fixed cell-based immunofluorescence assay (f-CBA-IFA).  Individuals with MG who are seropositive for MuSK antibodies are more likely than those without these antibodies to have atypical clinical features (e.g., selective muscle weakness that often spares the ocular and limb muscles), onset at a younger age, and no thymic pathology; this presentation is more likely to occur in females and is more typically severe. ^,  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. LRP4 antibody may be pathogenic in a small percentage of patients. ^,  In contrast to detection of AChR or MuSK antibodies, detection of anti-LRP4 antibodies should be carefully interpreted within the clinical context, as the presence of these antibodies does not directly correlate with a diagnosis. ^, 

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 may correlate with disease severity; however, more research is required before these antibodies are recommended for use as disease biomarkers. ^,