MYASTHENIA GRAVIS: DIAGNOSTIC TESTS

General Principles

• As thymectomy or long term immunotherapy may be necessary to treat MG, it is essential to establish a firm diagnosis. This avoids inappropriate treatments, and their side effects, in patients who do not have the disease. The mainstays of diagnostic testing have traditionally been: 1) pharmacological, 2) serological and 3) electrodiagnostic. As a general rule, a firm diagnosis is based upon a characteristic history and physical examination, and two positive diagnostic tests.
• Diagnostic investigations of MG should usually include both testing for serum anti-AChR antibodies and RNS studies.
• Tensilon tests may be readily performed at the bedside, but are not as sensitive, or specific, as the serological and electrophysiological studies.
• Single fiber EMG is reserved for selected patients in whom other tests have been negative or equivocal.
  
  
• There are other diagnostic tests, such as motor point muscle biopsies (to count AChRs at neuromuscular junctions, or to evaluate neuromuscular transmission by in vitro electrophysiologic methods), immunocytochemical staining of muscle endplates for immunoglobulin and complement, tests of ocular movement and genetic evaluation for defects in AChR subunits. However, these are generally not required or indicated in the great majority of MG cases.

Edrophonium (Tensilon) is a rapid-onset, short-acting medication that inhibits acetylcholinesterase, thereby prolonging the presence of the neurotransmitter, acetylcholine, in the NMJ. This action results in enhanced muscle strength for a few minutes in patients with NMJ dysfunction.

• The edrophonium test is only useful in patients with objective, preferably measurable, findings on physical examination. Tensilon testing is only rarely helpful in the diagnostic evaluation of equivocal cases of MG. It should be performed with the patient free of all cholinesterase-inhibitor medications.
• A positive test requires objective improvement in muscle strength. Subjective or minor responses, such as reduction of a sense of fatigue, should not be over interpreted.
• Initially, 2 mg of edrophonium is administered intravenously as a test dose while monitoring the heart rate, as bradycardia or ventricular fibrillation may develop. After observing for about 2 minutes, if no clear response develops, up to 8 additional mg of edrophonium is injected. A double-blind protocol with a saline injection as placebo has been advocated.
• Most myasthenic muscles respond in 30 to 45 seconds after injection with an improvement in strength that may persist for up to 5 minutes.
• Cholinergic side effects of edrophonium may occur including increased salivation and lacrimation, mild sweating, flushing, urgency and perioral fasciculations. Atropine should be readily available to reverse the effects of edrophonium in case of hemodynamic instability. The extra precautions are especially important in elderly patients.
• The sensitivity of the Tensilon test is relatively low (60%) compared to other diagnostic tests.
• False positive results can occur in patients with LES, ALS or even localized, intracranial mass lesions. Also, positive Tensilon testing does not necessarily predict that a patient will respond to a longer-acting AChE such as pyridostigmine.
• Tensilon testing should not be used to determine adjustments in the dose of pyridostigmine.

Serum antibodies that bind to acetylcholine receptors are measured using immunoprecipitation assays in which human AChRs are labeled with ¹²⁵I-a-Bungarotoxin.

• Measurement of serum IgG & IgM antibodies that bind to AChRs
• Antigenic target
• AChRs from human skeletal muscle: Mixed innervated & denervated, or
• Myogenic cell line expressing both adult & fetal AChRs
• Relatively specific and sensitive test for MG
• Anti-AChR antibodies occur in
• Adults with generalized MG: 85 to 90%
• Childhood MG: 50%
• Ocular MG: 50% to 70%

• MG and thymoma: Nearly 100%
• Some patients taking penicillamine with or without MG
• "False" positives

• Antibodies with other effects on AChRs
• Modulation: Accelerate endocytosis & degradation of AChRs
• May occur in a rare patient when anti-AChR antibody binding is negative.
• MG: Usual loss = 20% to 90% of AChRs (Normal < 20%)
• MG with thymoma: > 90% loss
• False positives: Hemolysis; Muscle relaxant drugs; Serum heating
• Blocking binding site for ACh on AChR (positive = 26% to 100% blocking).
• Prevalence: 52% of generalized MG; 30% of ocular
• 1% of patients with no binding or blocking antibodies
• Clinical correlations of MG & anti-AChR antibodies
• Absolute titer of antibodies
• No relation with severity of MG
• Antibody blocking & modulation of AChRs
• Some correlation with disease severity
• Change in titer of antibodies in individual patient
• Improvement often seen with reduction of > 50%
• Neonatal MG: Transient
• High anti-fetal/anti-adult muscle anti-AChR antibody ratio
• Patients with MG but no anti-AChR antibodies
• Rule out hereditary MG
• Low frequency of thymic pathology & thymoma
• May have antibodies to other neuromuscular junction antigens

Repetitive nerve stimulation (RNS) is the most frequently used electrodiagnostic test for MG. The nerve to be studied is electrically stimulated six to ten times at 2 or 3 Hertz. The compound muscle action potential (CMAP) is recorded with surface electrodes over the muscle.

• In MG, there is a progressive decline in CMAP amplitudes with the first 4 to 5 stimuli. The test is positive if there is a decrement of more than 10% in CMAP amplitude from the first to the fourth or fifth potential. Exercising the muscle briefly before testing may exacerbate the decremental response, an effect known as post-exercise exhaustion. In normal muscles, no change in CMAP amplitude is seen.

• RNS is positive in about 75% of patients with generalized MG, if proximal and clinically involved muscles are tested.
• The sensitivity of RNS may be further enhanced by ensuring that the muscle is warm and by testing more than one muscle. The sensitivity of RNS is greatly reduced when distal muscles are tested.
• RNS is positive in only 50% of patients with ocular MG.
• A decremental response to RNS is not specific for MG and may also be seen in presynaptic disorders such as LES and in motor neuron diseases, including ALS.

Single fiber electromyography (SFEMG) is a sensitive test for disorders of neuromuscular transmission. A physiological effect of NMJ blockade in MG is increased variability of the latencies at which the muscle fibers innervated by an individual axon are activated. SFEMG, by simultaneously recording the potentials of two muscle fibers innervated by an individual axon, is able to measure this variability or "jitter". At times, the muscle fiber potential may even be blocked when transmission at its NMJ fails completely.

• This test is the most sensitive - above 95% in both generalized and ocular MG when the test site includes facial muscles.
• Abnormal jitter is not specific. It may occur in other neuromuscular disorders, including ALS, polymyositis or LES.

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6/14/97