Ocular Aspects of Myasthenia Gravis

Jason J. S. Barton, MD, PhD, FRCPC, and Mohammad Fouladvand, MD, Human Vision and Eye movement Laboratory, Departments of Neurology and Ophthalmology, Beth Israel Deaconess Medical Center, Harvard Medical School; and the Department of Biomedical Engineering, Boston University, Boston, Massachusetts.

Semin Neurol. 2000;20(1) 

In This Article

Diagnostic Testing

There are three main confirmatory procedures for myasthenia: response to acetylcholinesterase inhibitors, electrophysiological testing, and antibody assays. In general, all three share the same problem of lower sensitivity in ocular myasthenia than in general myasthenia.

Acetylcholinesterase Inhibitors

Short-acting drugs like edrophonium or neostigmine are given to determine if paresis is due to deficient activation of postsynaptic receptors by acetylcholine.[86,87] By inhibiting acetylcholinesterase in the synaptic cleft, the life span of acetylcholine transmitter released from the presynaptic terminal is prolonged, increasing the probability of interaction with the postsynaptic receptor. In normal subjects, the time span of synaptic acetylcholine is more than adequate to ensure sufficient interactions to generate a muscle action potential, so that any further increase does not increase muscle strength. In fact, there is some evidence that the standard dose of edrophonium of 10 mg actually weakens normal muscles, probably through a mild depolarization blockade.[66] The sensitivity of the edrophonium test is about 95% in generalized myasthenia,87 and reportedly similar in ocular myasthenia with ptosis.[6] However, diplopia fails to respond in about a third of patients,[6] and long-standing myasthenia may not respond at all. Also, false-positive results have been described in other neuromuscular, neuropathic, and central conditions, including brain stem gliomas and other tumours ( Table 3 ).[88,89,90]

Intravenous edrophonium is given with an initial dose of 2 mg,[87] followed after a minute by another 3-4 mg. The effect begins within 30-40 sec and fades after about 8-10 min. Pediatric doses are 1 mg for those under 34 kg and 2 mg for those above.[87] Side effects of excess muscarinic activity are common, including tearing, salivation, sweating, abdominal cramps and nausea, and provide useful confirmation that the patient has received an active systemic dose of the drug. Bradycardia, hypotension, and syncope may occur, and atropine in a ready syringe should be at hand for rapid reversal should such problems occur. Asthma and cardiac disease are relative contraindications: the sleep test[78] may be a useful substitute in patients with these. Placebo control can be used if the endpoint is difficult to measure: with ocular signs, however, a vague endpoint usually means that the test will be inconclusive,[91] regardless of placebo control. Intramuscular neostigmine can be used in patients with minimal or highly variable signs because it will allow observation of effects over a period of 30-60 min, including orthoptic measurements of ocular alignment.[92]

The measure of edrophonium effect in ocular myasthenia is contentious. Improvement in ptosis is the most reliable sign.[93] For the extra-ocular muscles, assessment of ocular alignment has been used frequently,[92] sometimes supplemented with the Lancaster red-green test[94] or Hess screens.[95] However, the ocular alignment in up to 25% of patients with myasthenia will paradoxically worsen with edrophonium,[94] and increased deviations can also be found in patients with other ocular motor palsies.[96] The major problem is that changes in alignment may not only reflect increased strength but also increased weakness after edrophonium,[91] which can occur in normal muscles and nonmyasthenic weakness.[66] Therefore, the measure of edrophonium effect is best served by observation of increased strength of a single muscle rather than changes in the relative strength of two muscles (i.e., ocular alignment).

Certain qualitative changes with edrophonium may suggest myasthenia. Saccadic hypermetria may occur as strength recovers, unmasking underlying central adaptation, which had increased the neural pulse to the muscle in response to peripheral weakness.[97] If pronounced, this may even generate a transient oscillation of hypermetric saccades around the target because even the corrective saccades are hypermetric.

Laboratory methods for quantitating the effect of edrophonium on ocular aspects of myasthenia have been devised.[67] Edrophonium increases intraocular pressure in myasthenic patients, reflecting improved tone in weak muscles.[98,99,100,101] "Tensilon tonography" is only a moderately effective test, with sensitivity and specificity of 82%.[67] Eye recording studies have concentrated on rapid eye movements, such as saccades and the quick phases of optokinetic nystagmus. The amplitude, peak velocity and frequency of optokinetic quick phases all increase after edrophonium,[65] as do the amplitude and peak velocity of saccades[66,67] (Fig. 3). Saccadic duration decreases in myasthenia also, due to a reduction in deceleration time as intrasaccadic fatigue resolves.[72] In contrast, in patients with nonmyasthenic palsies, edrophonium increases saccadic duration[71] and decreases peak velocities[66] (Fig. 4). With criteria adjusted to yield specificities equal to sensitivities, these ocular motor tests have diagnostic accuracy rates of between 80 and 97% correct[67] (Fig. 5).

Figure 4.

Edrophonium effect on saccades in a patient with III and VI palsy. The subject is making saccades to follow a target (dotted line) making 20-degree steps repetitively. Black lines show her eye position (y-axis) over time (x-axis). There are slowed hypometric saccades in both directions initially (top trace), and this worsens after edrophonium (bottom trace).

Figure 5.

Edrophonium effect quantified by eye movement data. Asymptotic peak velocities (Vmax) are calculated from curves fit to peak-velocity/amplitude plots using, first, saccades after 4 min of repetitive saccades (fatigue period), and then saccades from 1 min after edrophonium (edrophonium period). Vmax from the two different periods are then plotted against each other. Diagonal line indicates no change. Points above the line indicate improvement with edrophonium, points below indicate worsening. Note the clear separation between myasthenic patients (black diamonds) and nonmyasthenic patients (clear diamonds). (From Barton et al, 1994,[66] with permission.)

Almost all of these edrophonium studies used patients whose diagnoses were known at the time of testing. When the diagnosis is obvious, tests are more likely to be positive, but on the other hand, their results add little clinically. Unfortunately, there is little prospective data on use of these tests in patients with more ambiguous clinical signs and uncertain diagnoses. One study[65] did find that optokinetic nystagmus results were equally accurate in a group of patients whose diagnoses became apparent later. Good differentiating accurary was also claimed in a smaller study of saccades, using a criterion of a 10% increase in amplitude.[73]

Electrophysiology

This is used to demonstrate and quantitate fatigability and variability. With repetitive stimulation of a motor nerve at 2-5 Hz, a decrement in the amplitude of the compound muscle action potential of at least 10% is considered abnormal fatigue. Repetitive stimulation is positive in most patients with generalized myasthenia, but may be normal in well over 50% of patients with ocular myasthenia.[6,88]

Single-fiber EMG makes repeated measures of the temporal relationship between the action potentials of two different fibers in a single muscle during contraction.[102,103] Normally this is stereotyped; in myasthenia, the instability of neuromuscular transmission is reflected in variability ("jitter") of this interval, and even occasional failure of one of the action potentials to be generated. When applied to a symptomatic muscle -- in the case of ocular myasthenia, the frontalis is used[104] -- the sensitivity is over 90% in generalized myasthenia[103] and about 85% in ocular myasthenia[61]; hence, it is better than repetitive nerve stimulation for those with ocular findings alone. Jitter on single fiber EMG of limb muscles is positive in only 63% of patients with ocular myasthenia.[105]

Abnormal fatigue or variability on these electrophysiological tests may also be seen with polymyositis, muscular dystrophy, chronic progressive external ophthalmoplegia, neuropathy, radiculopathy, motor neuron disease, and even brain stem disorders.[61] Nevertheless, the specificity of single-fiber EMG of the frontalis in ocular myasthenia has been reported as 90%.[61,104]

Assays for Antibodies Against the Acetylcholine Receptor

These confirm the immunopathology of the disease and are present in 80-90% of patients with generalized[7,8,17] and in about 50-75% of patients with ocular myasthenia gravis.[6,8,16,17,106,107] Some patients with ocular myasthenia and normal antibody titres will develop low positive titres after several months.[8] Actual antibody titer correlates poorly with severity of the disease, although in the individual patient changes in disease severity correlate with changes in antibody titre.[107] Several studies have found that positive titres are lower in patients with ocular myasthenia,[7,16,17] although one study suggested no difference.[107] Antibodies in ocular myasthenia may also differ qualitatively from those in generalized myasthenia: sera from such patients are more likely to be positive when tested against acetylcholine receptor from ocular muscle than against those from limb muscle.[17,27,28]

False-positive antibody results are unusual,[7] but may occur in apparently unaffected family members of myasthenic patients[8] and in other autoimmune conditions such as systemic lupus erythematosis[107] and Graves' ophthalmopathy.[108]

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