Myasthenia Gravis (MG)/Lambert-Eaton Syndrome (LES) Evaluation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Myasthenia gravis (MG) and Lambert-Eaton syndrome (LES) are acquired disorders of neuromuscular transmission. MG is caused by pathogenic autoantibodies binding to muscle's nicotinic acetylcholine receptor (AChR) or, in a small minority of patients, muscle-specific receptor tyrosine kinase (MuSK); LES is caused by autoantibodies binding to motor nerve terminal's voltage-gated P/Q-type calcium channel. Synaptic transmission fails when autoantibodies cause a critical loss of junctional cation channel proteins that activate the muscle action potential.
Both MG and LES can affect children (see MGEP/83371 Myasthenia Gravis [MG] Evaluation, Pediatric) as well as adults, although LES is very rare in children. In adults MG is 10 times more frequent than LES, but it is sometimes difficult to distinguish the 2 disorders, clinically and electromyographically. In adults with MG, there is at least a 20% occurrence of thymoma or other neoplasm.
Neoplasms associated with LES or MG are an endogenous source of the antigens driving production of the autoantibodies that characterize each disorder. LES is frequently associated with small-cell lung carcinoma (SCLC). Thus far, MuSK antibody has not been associated with any neoplasm.
Autoimmune serology is indispensable for both the initial evaluation and monitoring of patients with acquired disorders of neuromuscular transmission. The neurological diagnosis depends on the clinical context and electromyographic findings, and is confirmed more readily by a serological profile than by any single test.
Not all of the antibodies in this profile impair neuromuscular transmission (eg, N-type calcium channel antibodies, antibodies directed at cytoplasmic epitopes accessible in detergent solubilized P/Q-type calcium channels and muscle AChRs, or antibodies against sarcomeric proteins that constitute the striational antigens).
See Myasthenia Gravis/Lambert Eaton Syndrome Diagnostic Algorithm in Special Instructions.
Confirming the autoimmune basis of a defect in neuromuscular transmission (eg, myasthenia gravis [MG], Lambert-Eaton syndrome [LES])
Distinguishing LES from 2 recognized autoimmune forms of MG
Raising the index of suspicion for cancer, particularly primary lung carcinoma (N-type calcium channel antibody)
Providing a quantitative autoantibody baseline for future comparisons in monitoring a patient's clinical course and response to immunomodulatory treatment
Note: Single antibody tests may be requested in the follow-up of patients with positive results previously documented in this laboratory.
A patient's autoantibody profile is more informative than the result of any single test for supporting a diagnosis of Myasthenia Gravis (MG) or Lambert-Eaton syndrome (LES), and for predicting the likelihood of lung carcinoma. Muscle acetylcholine receptor (AChR) and striational antibodies are characteristic but not diagnostic of MG. One or both are found in 13% of patients with LES, but calcium channel antibodies are not found in MG (with exception of rare non-thymomatous paraneoplastic cases).
Muscle AChR binding antibody is found in 90% of nonimmunosuppressed MG patients who have thymoma, and 80% have a striational antibody. Calcium channel antibodies have not been encountered with thymoma. The likelihood of thymoma is greatest when striational antibody is accompanied by a high muscle AChR modulating antibody value (> or =90% AChR loss). Detection of CRMP-5-IgG also is consistent with thymoma in patients not at risk for lung carcinoma.
N-type calcium channel antibodies are more highly associated with primary lung cancer than P/Q-type. One or all of the autoantibodies in the MG/LES evaluation can occur with neoplasia without evidence of neurological impairment. Calcium channel antibodies may disappear soon after commencing immunosuppressant therapy. Other serological markers of lung cancer also may disappear.
One or both calcium channel antibodies (P/Q and N) can occur with paraneoplastic and idiopathic cerebellar ataxia, encephalomyeloneuropathies, and autonomic neuropathy.
Titers are generally higher in patients with severe weakness, but severity cannot be predicted by antibody titer.
AChR and striational antibodies may be undetectable for 6 to 12 months after MG symptom onset and similarly P/Q-type calcium channel antibody may be undetectable for 6 to 12 months after LES onset. Only about 5% of nonimmunosuppressed adult patients with generalized MG remain seronegative for muscle AChR and striational autoantibodies beyond 12 months.
The alternative muscle autoantigen, MuSK, accounts for approximately 1/3 of seronegative MG cases with predominantly oculobulbar symptoms.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Antibodies may disappear with immunosuppressant therapy; the neurological diagnosis is further confounded if steroid myopathy develops.
Unexplainable positive muscle acetylcholine receptor (AChR) or striational antibody values occur in 40% of patients with autoimmune liver disorders, approximately 10% of patients with lung cancer, and in patients with graft-versus-host disease and recipients of D-penicillamine.
Low false-positive values for calcium channel antibodies may occur with hypergammaglobulinemia.
In this laboratory, false-positive results for AChR binding antibodies are excluded by routinely retesting positive sera with (125)I-alpha-bungarotoxin in the absence of muscle AChR. False-positive results are most frequent in the bioassay for AChR modulating antibodies; serum redraw will be requested when only this assay yields a positive result. Curare-like drugs used during general anesthesia can yield transient false-positive AChR modulating antibody results.
Seropositive rates differ in different laboratories.
This test should not be requested in patients who have recently received radioisotopes, therapeutically or diagnostically, because of potential assay interference. The specific waiting period before specimen collection will depend on the isotope administered, the dose given and the clearance rate in the individual patient. Specimens will be screened for radioactivity prior to analysis. Radioactive specimens received in the laboratory will be held one week and assayed if sufficiently decayed, or canceled if radioactivity remains.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
ACh RECEPTOR (MUSCLE) BINDING ANTIBODY
< or =0.02 nmol/L
ACh RECEPTOR (MUSCLE) MODULATING ANTIBODIES
0-20% (reported as __% loss of AChR)
N-TYPE CALCIUM CHANNEL ANTIBODY
< or =0.03 nmol/L
P/Q-TYPE CALCIUM CHANNEL ANTIBODY
< or =0.02 nmol/L
STRIATIONAL (STRIATED MUSCLE) ANTIBODIES
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Lennon VA: Serological profile of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology 1997;48(Suppl 5):S23-S27
2. Harper CM, Lennon VA: Lambert-Eaton syndrome. In Current Clinical Neurology: Myasthenia Gravis and Related Disorders. Edited by HJ Kaminski. Totowa, NJ, Humana Press, 2007, (in press)
3. Hoch W, McConville J, Helms S, et al: Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001 Mar;7(3):365-368