Myasthenia Gravis - MG

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. ¹

  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. 2

Sussman J, Farrugia ME, Maddison P, et al. Myasthenia gravis: Association of British Neurologists' management guidelines. Pract Neurol. 2015;15(3):199-206.

Antibody Testing

Acetylcholine Receptor Antibodies

Circulating AChR antibodies are present in ~85% of patients with MG. ³

 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. 2

Sussman J, Farrugia ME, Maddison P, et al. Myasthenia gravis: Association of British Neurologists' management guidelines. Pract Neurol. 2015;15(3):199-206.

 3

Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-438.

 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. 3

Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-438.

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. ⁵

 A large number of individuals with AChR antibody-positive MG have thymic abnormalities, including thymic hyperplasia (most common) and thymic tumors. 5

Drachman DB. Myasthenia gravis. Semin Neurol. 2016;36(5):419-424.

 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. ³

 4

Sanders DB, Burns TM, Cutter GR, et al. Does change in acetylcholine receptor antibody level correlate with clinical change in myasthenia gravis? Muscle Nerve. 2014;49(4):483-486.

Muscle-Specific Tyrosine Kinase Antibodies

In cases of generalized MG, approximately half of individuals without AChR antibodies have MuSK antibodies. ³

 Therefore, MuSK antibody measurement is recommended if a patient is negative for AChR antibodies. 2

Sussman J, Farrugia ME, Maddison P, et al. Myasthenia gravis: Association of British Neurologists' management guidelines. Pract Neurol. 2015;15(3):199-206.

 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. 1

Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-2581.

 3

Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-438.

 6

Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol. 2016;263(4):826-834.

 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. ³

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). ⁷

Striational antibodies are not specific for MG and may be seen in individuals with other autoimmune diseases and in cases of thymoma without MG. ³

 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. 3

Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-438.

 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. 3

Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427-438.