Autoantibody Profiles of Myasthenia Gravis, Thymoma and Lambert-Eaton Myasthenic Syndrome
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Published: July 2009Print Record of Viewing
A review of the serological diagnostic algorithms for Myasthenia Gravis (MG), Thymoma, and Lambert-Eaton Myasthenic Syndrome (LES). Dr. McKeon defines the clinical aspects of each disorder and describe diagnostic laboratory testing recommendations.
Presenter: Andrew McKeon, MB, BCh, MD
- Consultant in the Neuroimmunology Laboratory in theDivision of Clinical Biochemistry and Immunology at Mayo Clinic
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In this presentation I will discuss the individual antibody tests and their interpretation. I will discuss a recent change that now excludes testing for the AChR blocking antibody alone. And I will, finally, describe the revised diagnostic algorithms.
What are MG and LES?
So, first of all, what are myasthenia gravis and Lambert-Eaton syndrome? Let’s briefly review the clinical and electrophysiological features and how these disorders are diagnosed. Both myasthenia gravis and Lambert-Eaton syndrome are autoimmune disorders of neuromuscular transmission. They are caused by antibodies binding to extracellular segments of ion channels in nerve and muscle membranes. The loss of channel protein function in these disorders leads to weakness. Neoplasia or cancer in some cases drives the autoimmune response.
Myasthenia Gravis. In this disorder, antibodies bind to the acetylcholine receptors in the muscle membrane. If this occurs, this impairs the passage of sodium and potassium ions passing through the ACh-gated channels that depolarize the muscle end-plate. In Lambert-Eaton syndrome, the antibodies bind to voltage-gated calcium channels in nerve terminals that regulate acetylcholine release.
The clinical diagnosis of myasthenia gravis is based on characteristic clinical findings and EMG (electromyogram) findings. Clinically, the patients have weakness and fatiguability, and this may be limited to the extraocular muscles and/or bulbar muscles and sometimes it is a generalized disorder that affects all muscle types including limb muscles. The weakness is usually improved by rest or anticholinesterase medication. The characteristic EMG findings consist of a decrement in the compound muscle action potential amplitude during repetitive motor nerve stimulation. Frequently in this disorder, chest CT or MRI may reveal thymic enlargement or a mass, which is usually a thymoma.
MG: Neoplastic Accompaniments
Fifteen percent of adult patients with myasthenia gravis will have thymoma. Carcinomas in this setting are rarer, but have been reported, and include gynecological cancers, prostate cancer, breast cancer, bladder cancer, and lung cancer.
LES: Clinical Diagnosis
For Lambert-Eaton syndrome, the clinical diagnosis is based on characteristic clinical findings of proximal weakness, which is sometimes oculobulbar. But, unlike in myasthenia gravis, weakness is actually improved by brief exercise. Other characteristic features include limited dysautonomia. Usually patients complain of dry mouth and dry eyes, and sometimes impaired sweating and erectile dysfunction.
LES: Electromyography (EMG) Findings
The EMG findings in Lambert-Eaton syndrome are also characteristic. This consists of a baseline compound muscle action potential (CMAP) that is reduced. The CMAP decrement is also seen with slow repetitive nerve stimulation. And then facilitation, usually greater than 200%, occurs after brief exercise or high frequency nerve stimulation.
LES: Neoplastic Accompaniments
Neoplastic accompaniments include lung cancer. Overall, the patients with Lambert-Eaton syndrome, 45% have cancer diagnosed and in 90% of paraneoplastic cases, the cancer detected will be small cell lung carcinoma.
Autoantibodies Aiding MG Diagnosis
So what autoantibody tests aid the diagnosis of myasthenia gravis? Well, first of all, the acetylcholine receptor binding antibody. This can distinguish myasthenia gravis of an acquired type from congenital myasthenia gravis. The presence of this antibody will also raise the question of subclinical myasthenia gravis in thymoma patients where no weakness has been detected. The antibody is also detected in a few patients who have other autoimmune neurological disorders, including Lambert-Eaton syndrome in 10% and, rarely but significantly, in patients with peripheral neuropathies, encephalopathies, and radiculomyelopathies.
The AChR modulating antibody is also a useful test for diagnosing myasthenia gravis. This antibody selectively binds to the surface of live muscle cells and is expressed as percent AChR loss compared with 0% loss, which is induced by normal serum.
Single Assay Detects AChR Modulating and AChR Blocking Antibodies
Now a single assay detects both modulating and blocking antibodies. Both lower the number of surface binding sites for radiolabeled alpha-bungarotoxin, but do it by 2 different ways. The acetylcholine receptor modulating antibody accelerates endocytosis and degradation of the acetylcholine receptor; whereas, the acetylcholine receptor blocking antibody inhibits alpha-bungarotoxin binding to AChR.
Serum AChR Modulating Antibody Values and Interpretation
Results from the modulating assay should be interpreted as follows: for patients who do not have myasthenia gravis, one can detect 0% to 20% loss of the acetylcholine receptor. Patients with myasthenia gravis, you see >30% loss, and the amount of loss is generally proportional to clinical severity. In patients who have myasthenia gravis with thymoma, the loss of acetylcholine receptor is usually >90%. In patients with Lambert-Eaton syndrome, >30% loss can be encountered in 5% to 10% of patients. All of these antibody values will be lower in immunosuppressed patients.
Reasons to Discontinue Testing for AChR Blocking Antibody
So previously a test that measured acetylcholine receptor blocking antibodies alone was offered, but this was to be found of minimal clinical utility because the antibody only measures the acetylcholine receptor blocking antibody; whereas, the acetylcholine receptor modulating antibody test detects both modulating and blocking antibodies. The sole clinical utility of the blocking antibody is that it is generally detected in patients who have very severe myasthenia gravis with severe generalized weakness. However, the blocking antibody alone is never positive when the acetylcholine receptor binding and modulating antibody tests are negative. There is no additional information gained from this test for assessing thymoma risk in patients with myasthenia gravis. Therefore, the test is not cost effective.
Another test, when positive, that is supportive of a diagnosis of myasthenia gravis is the striational antibody test. This antibody is detected by an enzyme immunoassay using a mixture of muscle sarcoma proteins as antigen. Seropositivity supports a clinical diagnosis of acquire myasthenia gravis in immunosuppressed patients. Seropositivity supports the diagnosis of thymoma or other neoplasm only when acetylcholine receptor modulating antibody is present and >90% loss is detected. The striational antibody may also be positive in other autoimmune diseases including autoimmune thyroiditis and pernicious anemia.
Autoantibodies Detected in MG Patients with Thymoma
These and other antibody tests are positive in patients with thymoma, as well as myasthenia gravis. The acetylcholine receptor binding antibody is present in 100% of patients with thymoma. The acetylcholine receptor modulating antibody is present in almost all patients - 99% of patients with thymoma. Striational antibodies are present in 76% of patients with thymoma. And then a variety of other neural-specific antibodies are present in 43% of patients with thymoma. This includes the voltage-gated potassium channel antibody, CRMP-5 IgG, the ganglionic acetylcholine receptor antibody, and GAD65 antibody, which is the commonest neural antibody detected in patients with thymoma.
Autoantibodies Aiding the Diagnosis of LES
Testing for antibodies with neuronal calcium channel specificity also aids the diagnosis of Lambert-Eaton syndrome. There are 2 types of calcium channel antibodies tested for in the myasthenia gravis/Lambert-Eaton syndrome evaluation. These are of P/Q-type and N-type. P/Q-type calcium channel antibodies are positive in 95% of patients who are non-immunosuppressed and 99% of patients with cancer that have Lambert-Eaton syndrome. This antibody distinguishes Lambert-Eaton syndrome from myasthenia gravis in the appropriate clinical and electrophysiological context that I outlined earlier. Sometimes the P/Q-type calcium channel antibodies are undetectable at symptom onset and should be reevaluated at 12 months, if the disorder is clinically suspected. And, seronegativity for this antibody does not exclude a diagnosis of Lambert-Eaton syndrome.
The N-type calcium channel antibody is positive in 36% of Lambert-Eaton syndrome patients without cancer, but is positive in 73% of patients with Lambert-Eaton syndrome who do have lung cancer.
Serological Diagnostic Algorithms
There are 4 antibody test-based diagnostic algorithms for the diagnosis of myasthenia gravis and thymoma, and Lambert-Eaton syndrome, and these depend on 4 clinical scenarios that may be encountered. There is a myasthenia gravis adult panel, there is a myasthenia gravis pediatric algorithm, a myasthenia gravis and thymoma algorithm, and finally a myasthenia gravis or Lambert-Eaton myasthenic syndrome evaluation.
Myasthenia Gravis: Adult Diagnostic Algorithm
The diagnostic algorithms that I am now going to describe consist of tests that are always done and then additional testing that is done depending on the initial results. As you will see from these algorithms in this and the following slides, this additional reflex testing is only undertaken where the initial results are suspicious for a diagnosis of thymoma. The additional testing in that setting is to look for other antibodies which would support a diagnosis of thymoma. So, with regard to the myasthenia gravis adult diagnostic algorithm, the testing that is always performed consists of the muscle acetylcholine receptor binding antibody, modulating antibodies, and striated muscle antibodies. If the acetylcholine receptor modulating antibody loss is >90% and striational antibodies are present, then there is reflex testing performed in addition that consists of the ganglionic acetylcholine receptor antibody, GAD65 antibody, the voltage-gated potassium channel autoantibody, and CRMP-5-IgG western blot.
Myasthenia Gravis: Pediatric Diagnostic Algorithm
For the pediatric diagnostic algorithm, there are just 2 tests. Testing consists of the acetylcholine receptor binding antibody and modulating antibodies alone. There is no additional testing offered in the pediatric myasthenia gravis evaluation since neoplasia is very rare in children with myasthenia gravis.
Myasthenia Gravis: Thymoma Diagnostic Algorithm
The myasthenia gravis thymoma diagnostic algorithm. The following tests are always performed in this algorithm. The acetylcholine receptor binding antibody, modulating antibodies, the striational antibody, ganglionic acetylcholine receptor antibody, GAD65, voltage-gated potassium channel antibody, and CRMP-5-IgG.
Myasthenia Gravis/Lambert Eaton Syndrome Diagnostic Algorithm
For the myasthenia gravis and Lambert-Eaton syndrome diagnostic algorithm, this is generally undertaken where there is some clinical uncertainly as to the diagnosis. Testing always consists of antibodies tests for Lambert-Eaton syndrome consisting of the P/Q-type calcium channel antibody, N-type calcium channel antibody, and then antibody tests pertaining to myasthenia gravis consisting of acetylcholine receptor binding antibody, modulating antibodies, and striational antibody. Again, if the acetylcholine receptor modulating antibodies loss is >90% and the striational antibody is present, testing is automatically reflexed to the ganglionic acetylcholine receptor antibody and CRMP-5-IgG testing.
So, in summary, the autoantibody profiles that I have described aid the diagnosis of myasthenia gravis and Lambert-Eaton syndrome. However, characteristic clinical and electrophysiological features also need to be present to make a diagnosis of either of these disorders. Seronegativity for these antibodies does not exclude diagnosis. An algorithmic approach as I have outlined helps identify those patients most at risk for thymoma or carcinoma.