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Published: May 2012Print Record of Viewing
An algorithmic testing approach using established autoantibody profiles can assist the clinician in the diagnosis of myasthenia gravis and Lambert-Eaton myasthenic syndrome. Dr. McKeon will review the serological diagnostic algorithms for myasthenia gravis (MG), thymoma, and Lambert-Eaton myasthenic syndrome (LES). He will define the clinical aspects of each disorder and describe diagnostic laboratory testing recommendations.
Presenter: Andrew McKeon, MB, BCh, MD
Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.
Our presenter for this program is Dr. Andrew McKeon, consultant in the Neuroimmunology Laboratory in the Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. Dr. McKeon will review the serological diagnostic algorithms for myasthenia gravis, thymoma, and Lambert-Eaton myasthenic syndrome. He will define the clinical aspects of each disorder and describe diagnostic laboratory testing recommendations. Thank you, Dr. McKeon.
Thank you, Sharon, for that introduction.
There are four antibody test-based diagnostic algorithms for the diagnosis of myasthenia gravis and thymoma, and Lambert-Eaton syndrome, depending on four clinical scenarios that may be encountered. This includes an adult myasthenia gravis evaluation, pediatric myasthenia gravis evaluation, myasthenia gravis and thymoma evaluation, and then a myasthenia gravis or Lambert-Eaton myasthenic syndrome evaluation.
In this presentation, I will discuss the individual antibody tests and their interpretation. I will also discuss a recent change that now excludes testing for the acetylcholine receptor blocking antibody alone. I will finally describe the revised diagnostic algorithms.
Before I do all that, let’s briefly review what are myasthenia gravis and Lambert-Eaton syndrome and how are these disorders diagnosed. These are autoimmune disorders of neuromuscular transmission caused by antibodies binding to extracellular segments of ion channels in nerve and muscle membranes. Loss of channel protein function leads to weakness. Cancer in some cases drives the autoimmune response.
So what are myasthenia gravis and Lambert-Eaton syndrome? Myasthenia gravis, antibodies bind to the acetylcholine receptors in the muscle membrane. Sodium and potassium ions passing through the acetylcholine receptor-gated channels depolarize the muscle end-plate. In Lambert-Eaton syndrome, antibodies bind to voltage-gated calcium channels in nerve terminals that regulate acetylcholine release.
What about clinical diagnosis of myasthenia gravis? Well characteristic findings are weakness and fatiguability that are improved by rest or anticholinesterase medication. EMG demonstrates decrement in compound muscle action potentials during repetitive motor nerve stimulation. Chest CT or MRI may reveal thymic enlargement or a mass and the mass may represent thymoma or thymic carcinoma.
Other neoplastic accompaniments other than thymoma include gynecological cancers, prostate cancer, breast cancer, bladder cancer, and lung cancer.
For Lambert-Eaton syndrome, the characteristic clinical findings include proximal weakness, sometimes including cranial facial muscle involvement. This can be improved by brief exercise. Limited dysautonomia is frequently encountered and this can include dry mouth and eyes, impaired sweating, and erectile dysfunction.
The EMG findings demonstrate baseline compound muscle action potential reduction The CMAP decrement occurs with slow repetitive nerve stimulation. And facilitation of the CMAP can occur usually greater than 200% after brief exercise or high frequency nerve stimulation.
Neoplastic accompaniments include small-cell lung carcinoma in about 90% of paraneoplastic cases.
Autoantibodies aiding the diagnosis of myasthenia gravis include the acetylcholine receptor binding antibody, modulating antibody, and striational antibody. The binding antibody distinguishes acquired from congenital myasthenia gravis, raises the question of subclinical myasthenia gravis in thymoma patients. There is a low but significant frequency in other autoimmune neurological disorders including Lambert-Eaton syndrome, peripheral neuropathies, encephalopathies, radiculopathies, and myelopathies.
The modulating antibody selectively binds to the surface of live muscle cells. This is expressed as percent acetylcholine receptor loss by comparison with 0% loss induced by normal serum.
A single assay detects the acetylcholine receptor modulating and blocking antibody. Both lower the number of surface binding sites for radiolabeled alpha-bungarotoxin. Acetylcholine receptor modulating antibody accelerates endocytosis and degradation of the acetylcholine receptor. Acetylcholine receptor blocking antibody inhibits alpha-bungarotoxin binding to acetylcholine receptors.
Results from the modulating assay should be interpreted as follows: for non-myasthenia gravis patients this would be 0% to 20% loss, myasthenia gravis patients >30% loss, that is generally proportional to clinical severity, patients with myasthenia gravis and thymoma have >90% loss, patients with Lambert-Eaton syndrome can have >30% loss in 5% to 10% of patients.
Previously a test that measured acetylcholine receptor blocking antibodies was offered, but this was to be found of minimal clinical utility because it measures acetylcholine receptor blocking antibody only. The test is positive in 66% of patients with myasthenia gravis with moderate or severe generalized weakness. The test is never positive when acetylcholine receptor binding and modulating antibody tests are negative. The actual test for modulating antibody detects blocking antibody in addition. The blocking antibody test was not additionally informative for thymoma risk. Taking all of the factors into account, it is felt at this point that it is not cost effective.
Another test that when positive is supportive of a diagnosis of myasthenia gravis is the striational antibody test. This is detected by enzyme immunoassay using a mixture of muscle sarcomeric proteins as antigen. Detection of this antibody supports a clinical diagnosis of acquired myasthenia gravis in immunosuppressed patients. Striational antibody seropositivity supports a diagnosis of thymoma or other neoplasm only when acetylcholine receptor modulating antibody is of >90% loss. Positivity is also detected in other autoimmune diseases such as thyroiditis and pernicious anemia.
These and other antibody tests are positive in patients with thymoma, as well as myasthenia gravis. Acetylcholine receptor binding antibody in 100%, acetylcholine receptor modulating antibody in 99%, striational antibodies in 76%, neuronal antibodies in 43% including antibodies targeting voltage-gated potassium channels, CRMP-5, ganglionic alpha-3 acetylcholine receptor and GAD65.
Testing for antibodies with neuronal calcium channel specificity 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, P/Q and N-type. P/Q-type calcium channel antibodies are positive in 95% of non-immunosuppressed patients and 99% of patients with cancer. This distinguishes Lambert-Eaton from myasthenia gravis in the appropriate clinical and electrophysiological context.
N-type calcium channel antibodies are positive in 36% of patients without cancer and positive in 73% of patients with lung cancer.
The diagnostic algorithms 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 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 antibody markers which would support a diagnosis of thymoma. So, the testing that is always performed includes the muscle acetylcholine receptor binding antibody, modulating antibodies, and striational antibody. If the acetylcholine receptor modulating antibody loss is >90% and striational antibody is positive, then the testing is reflexed to ganglionic acetylcholine receptor antibody, GAD65 antibody, the voltage-gated potassium channel antibody, and CRMP-5-IgG testing.
In relation to the pediatric myasthenia gravis evaluation, there is no additional testing offered since neoplasia is very rare in children with myasthenia gravis.
For the thymoma evaluation, testing that is always performed includes the acetylcholine receptor binding antibody, modulating antibody, the striational antibody, ganglionic alpha-3 acetylcholine receptor, GAD65, potassium channel antibody, and CRMP-5 IgG.
For the myasthenia gravis and Lambert-Eaton syndrome evaluation, testing that is always performed includes the P/Q and N-type calcium channel antibodies, acetylcholine receptor muscle binding and modulating antibodies, and striational antibody. If the acetylcholine receptor modulating antibody loss is >90% and the striational antibody is positive, then this is reflexed to the ganglionic alpha-3 acetylcholine receptor antibody and also CRMP-5 IgG testing.
In summary, autoantibody profiles aid the diagnosis of myasthenia gravis and Lambert-Eaton syndrome. However, characteristic clinical and electrophysiological features are also required for the diagnosis. Seronegativity does not exclude the diagnosis. An algorithmic approach helps identify those patients most at risk for thymoma or carcinoma.