Myasthenia Gravis - MG

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 of the disease that is limited to the eyelid and extraocular muscles) or generalized MG (MG 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 testing is 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

How is myasthenia gravis diagnosed?

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.  

What is the difference between ocular myasthenia gravis and generalized myasthenia gravis, and how does the distinction affect laboratory testing?

Myasthenia gravis (MG) can be categorized as ocular or generalized. In ocular MG, weakness is limited to eyelids and extraocular muscles. Generalized MG is characterized by weakness that often involves ocular muscles and weakness that often involves 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.

Can antibody testing be used to monitor myasthenia gravis?

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. 

What is seronegative myasthenia gravis?

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 for 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 before beginning therapy to avoid false-negative results. 

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, the most clinically useful and frequently utilized test, 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. Tests of modulating AChR antibodies are 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 been administered 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 AChR negative.  MuSK antibody-seropositive individuals with MG 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 AChR antibodies, the absence of MuSK antibodies does not rule out the diagnosis of MG.

Decreasing antibody levels may be associated with therapeutic response, suggesting that MuSK antibody levels might serve as a valuable biomarker to follow. 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. Recent studies have found anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG. 

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 AChR, are associated with late-onset MG; as a marker for thymoma, striational antibodies are most useful in AChR antibody-seropositive patients in early-stage MG.  Titin is one of the major antigenic targets of striational antibodies, and 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 antibodies appear to correlate with disease severity and have been postulated for use as a marker to assess disease prognosis. However, more research is required in this area before these antibodies are recommended for use as disease biomarkers. 

ARUP Lab Tests

Antibody Testing
Panel Tests

Preferred reflexive panel for diagnosing or confirming a clinical diagnosis of MG

Components include binding, blocking, and modulating antibodies

Acceptable reflexive panel for diagnosing or confirming a clinical diagnosis of MG

Components include binding, blocking, and modulating antibodies; titin antibody; and striated muscle antibodies with reflex to titer

Extended panel for diagnosing MG

Components include AChR binding and blocking antibodies with reflex to AChR modulating antibodies or MuSK antibodies

Acceptable reflexive panel for the differential diagnosis of acquired neuromuscular junction disorders

Components include binding, blocking, and modulating antibodies; voltage-gated calcium and potassium channel antibodies; titin antibody; striated muscle antibodies; and LGI1 and CASPR2 antibodies, IgG

Reflex and Single Tests

Initial diagnostic testing for MG

Diagnose MG or confirm a clinical diagnosis of MG

Components include acetylcholine receptor (AChR) binding antibodies with reflex to muscle-specific kinase (MuSK) antibodies

Secondary diagnostic test for patients with generalized or ocular MG and no detectable antibodies to AChR

Secondary diagnostic test for MG when first-line diagnostic tests are negative

Recommended for differential evaluation of neuromuscular junction diseases, including MG

Secondary diagnostic test for MG when first-line diagnostic tests are negative

Screen for presence of thymoma in patients with MG

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References

Resources from the ARUP Institute for Clinical and Experimental Pathology®