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Myasthenia gravis (MG) is an acquired disorder of neuromuscular transmission caused by the binding of pathogenic autoantibodies to muscle's postsynaptic nicotinic acetylcholine receptor (AChR). Synaptic transmission fails when these pathogenic autoantibodies cause a critical loss of the AChR cation channel protein, which is required to activate the muscle action potential.
It is estimated that approximately 20% of adult patients have a paraneoplastic basis for MG. Thymoma is the most common neoplasm, often occult at the onset of MG, its diagnosis may precede MG onset. Thymoma is thought to be an endogenous source of muscle and neuronal antigens that drive production of characteristic autoantibodies. Other autoimmune neurological disorders sometimes accompany thymoma, with and without MG, including neuromuscular hyperexcitability, autonomic neuropathy, especially gastrointestinal dysmotilities encephalopathy, subacute hearing loss, or polymyositis.
MG can affect children as well as adults, but a paraneoplastic context is rare in children (neuroblastoma or thymoma are sometimes found).
Some of the antibodies in this profile are not pathogenic (eg, antibodies directed at cytoplasmic epitopes accessible in solubilized ion channels, or sarcomeric proteins that constitute the striational antigens).
Autoimmune serology is indispensable for initial evaluation and monitoring the course of patients with acquired MG. The neurological diagnosis depends on the clinical context, electromyographic findings, and response to anticholinesterase administration. MG is confirmed more readily by the individual patient's serological profile than by any single test.
See Myasthenia Gravis: Thymoma Diagnostic Algorithm in Special Instructions.
Investigating patients with suspected or proven thymoma, whether or not symptoms or signs of myasthenia gravis (MG) are present
Serially monitoring patients for recurrence or metastasis after removal of thymoma
Providing a quantitative autoantibody baseline for future comparisons in monitoring a patient's clinical course and the response to thymectomy and immunomodulatory treatment
Assessing the likelihood of occult thymoma in a patient with an acquired disorder of neuromuscular or autonomic transmission
Evaluating bone marrow transplant recipients with suspected graft-versus-host disease, particularly if there is evidence of weakness
Confirming that a recently acquired neurological disorder has an autoimmune basis (eg, MG or dysautonomia)
A patient's autoantibody profile is more informative than the result of any single test for predicting the likelihood of thymoma, and for supporting a diagnosis of myasthenia gravis (MG) or other paraneoplastic neurological complication.
Muscle acetylcholine receptor (AChR) and striational autoantibodies are characteristic but not diagnostic of MG in the context of thymoma. One or more antibodies in the MG/thymoma evaluation are positive in more than 60% of nonimmunosuppressed patients who have thymoma without evidence of any neurological disorder.
Titers of muscle AChR and striational antibodies are generally higher in MG patients who have thymoma, but severity of weakness cannot be predicted by antibody titer. A rising antibody titer (or appearance of a new antibody specificity) following thymoma ablation suggests thymoma recurrence or metastasis, or development of an unrelated neoplasm.
Antibodies specific for the alternative muscle autoantigen of MG, muscle-specific receptor tyrosine kinase, are not associated with thymoma.
Because the autoantibody profile may change with tumor recurrence, single autoantibody testing is not recommended for follow-up after thymoma treatment.
A positive result in the myasthenia gravis (MG)/thymoma evaluation is not per se diagnostic of MG. Positive values for muscle acetylcholine receptor (AChR) and striational antibodies occur in 59% of patients with neurologically uncomplicated thymoma, 13% of Lambert-Eaton syndrome (LES) patients (Note: P/Q-type calcium channel antibodies are not found in MG, except for rare non-thymomatous paraneoplastic cases), 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.
In this laboratory, false-positive results for AChR binding antibodies are excluded by reflexively retesting all positive sera with (125)I-alpha-bungarotoxin in the absence of muscle AChR. False-positive results occur most frequently in the bioassay for AChR modulating antibody; serum redraw will be requested when only this assay yields a positive result.
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.
ACh RECEPTOR (MUSCLE) BINDING ANTIBODY
< or =0.02 nmol/L
ACh RECEPTOR (MUSCLE) MODULATING ANTIBODIES
0-20% (reported as __% loss of AChR)
STRIATIONAL (STRIATED MUSCLE) ANTIBODIES
CRMP-5-IgG WESTERN BLOT
AChR GANGLIONIC NEURONAL ANTIBODY
< or =0.02 nmol/L
NEURONAL (V-G) K+ CHANNEL AUTOANTIBODY
< or =0.02 nmol/L
GAD65 ANTIBODY ASSAY
< or =0.02 nmol/L
1. Cikes N, Momoi MY, Williams CL, et al: Striational autoantibodies: quantitative detection by enzyme immunoassay in myasthenia gravis, thymoma and recipients of D-penicillamine and allogenic bone marrow. Mayo Clin Proc 1988 May;63(5):474-481
2. Lennon VA: Serological profile of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology 1997;48(Suppl 5):S23-S27
3. Vernino S, Lennon VA: Autoantibody profiles and neurological correlations of thymoma. Clin Can Res 2004;10:7270-7275
4. 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
5. Chan K-H, Lachance DH, Harper CM, Lennon VA: Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 2007;36:651-658