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Ocular Aspects of Myasthenia Gravis

Jason J. S. Barton, M.D., Ph.D., F.R.C.P.C., and Mohammad Fouladvand, M.D., 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.

[Sem Neurology 20(1):7-20, 2000. © 2000 Thieme Medical Publishers, Inc.]

Abstract

Ocular myasthenia gravis is a not uncommon autoimmune disorder causing diplopia, ptosis, and weakness of lid closure. The predilection of myasthenia for the ocular muscles may be related to differences between limb and extraocular muscles in either physiological function or antigenicity. Clinically, ocular myasthenia can mimic any form of pupil-sparing ocular motility disorder. Dynamic abnormalities of myasthenic eye movements may reflect the primary hallmarks of the disease, which are fatigability and variability in strength, or secondary adaptive effects by the central nervous system. Tests to confirm the diagnosis include edrophonium challenge, repetitive nerve stimulation, single-fiber electromyography (EMG) of the frontalis, and assays for antibody directed against the acetylcholine receptor: all are less sensitive for ocular myasthenia than for generalized myasthenia. There is a higher incidence of other autoimmune conditions in myasthenia, notably thymoma and thyroid dysfunction. The differential diagnosis includes other diseases of the neuromuscular junction, such as Lambert-Eaton syndrome and botulism. Treatment consists of symptomatic use of acetylcholinesterase inhibitors and immunosuppression with steroids or azathioprine. Between 50 and 70% of patients with ocular myasthenia will eventually develop generalized disease: there is some retrospective data that steroids or azathioprine may reduce this by about 75%. The role of thymectomy in ocular myasthenia remains unclear.

Introduction

Myasthenia gravis is a disorder of transmission at the neuromuscular junction. The two defining clinical characteristics of myasthenic weakness are variability and "fatigability," which is weakness that worsens with exertion and improves with rest. While rare congenital forms exist, caused by genetic anomalies or deficiencies in various components of the neuromuscular junction,[1] acquired myasthenia is an autoimmune condition, marked by antibodies directed against the nicotinic acetylcholine receptor in the motor end-plate of striated muscles.

It has no racial or geographic predilection2 and may occur at any age. Neonatal forms are rarely encountered, and the clinical course in children and infants differs from that in adults.[3] Before age 40 the disease is more common in women.[2] Purely ocular myasthenia, which tends to start at a slightly later age than generalized myasthenia, is more common in men.[2,4]

Myasthenic weakness may affect virtually any striated muscle, including the diaphragm, limb and bulbar musculature, but the extra-ocular muscles are particularly susceptible. Ptosis and diplopia are the initial complaint in 75% and eventually develop in 90% of all myasthenic patients.[4,5] Also, in a substantial minority, the manifestations of the disease continue to be limited to the eyes over many years.[2,5,6] Thus, awareness of the ocular manifestations of this disease is critical to clinical practice.

Pathogenesis: Why The Eyes?

Circulating antibodies against the nicotinic acetylcholine receptor are the immunopathogenic hallmark in acquired myasthenia gravis.[7,8] Such antibodies may affect the acetylcholine receptor in a variety of ways, including accelerated degradation of receptors and blockade of the ligand-binding site of the receptor.[9-12]

Normal function at the neuromuscular junction involves neuronal action potentials triggering the release of acetylcholine stored in presynaptic vesicles. Acetylcholine in the synaptic cleft must interact with a receptor before it is quickly degraded by acetylcholinesterase in the cleft. Interaction of acetylcholine with the postsynaptic receptor creates an excitatory end-plate potential; if a sufficient number of transmitter-receptor interactions occur, the graded end-plate potential will reach a threshold that triggers an action potential in the muscle, causing contraction. The amount of acetylcholine released declines with repetitive action potentials, but normally the amount of acetylcholine and available receptor comfortably exceeds the probability requirements for generating an end-plate potential capable of triggering a muscle action potential. This excess is the "safety factor" that ensures faithful transmission of nerve-to-muscle impulses.[13]

The physiological result of the immune attack is reduced availability of acetylcholine receptors on the postsynaptic membranes of neuromuscular junctions in striated muscle. Reduced receptor availability means that the probability of interaction between acetylcholine and its postsynaptic receptor is decreased, creating a reduced "safety factor." Reduced probability of interaction means that the graded end-plate potential cannot be guaranteed to trigger a muscle action potential, and will fail or succeed at different times -- hence, the variability in myasthenia. Furthermore, the normal decline in transmitter release with repeated impulses causes the probability of transmitter-receptor interaction to fall further with repeated use, with greater likelihood of failure of neuromuscular transmission -- hence, the fatigability of myasthenia.

Why are ocular muscles so frequently involved by myasthenia? Several different explanations have been hypothesized,14 although the answer is still not certain (Table 1).

Functional hypotheses holds that ocular weakness may be simply more evident to patients. A subtle degree of weakness in a limb may not be apparent, but even slight weakness of extra-ocular muscles may cause diplopia that cannot be ignored.[14] Also, because the control mechanisms for extra-ocular muscles use visual rather than proprioceptive feedback, it has been speculated that this may somehow make them less able to adapt to variable weakness.[14,15]

Immunological hypotheses propose differences in the antibody-antigen interaction. Because ocular myasthenics tend to have lower titres of antibodies,[7,16,17] it may be that ocular myasthenia simply reflects less severe disease, which is most noticeable in the eyes for the reasons above. In support, patients with ocular myasthenia also have evidence of subclinical myasthenia in their limb muscles.[18-20] Another possibility is that there are differences between extra-ocular and limb acetylcholine receptors.[14,21,22] The acetylcholine receptor is a pentameric protein with different adult and fetal isoforms. The fetal isoform is composed of two alpha subunits, a beta, a delta, and a gamma. Adult receptors contain an epsilon subunit instead of a gamma. Because mature extra-ocular muscles persistently express the fetal acetylcholine receptor,23,24 it may be that extra-ocular muscles are selectively compromised when the fetal form is the antigenic target. However, the fetal antigen theory does not explain the frequent finding of ptosis in ocular myasthenia gravis because the levator palpebrae superioris does not express the fetal isoform.[25] Also, one study found that sera from ocular myasthenics were more positive with assays that used mixtures of fetal and adult receptor isoforms than with traditional assays using denervated muscle, which have mainly fetal isoforms.[26]

Nevertheless, there is some evidence that a different spectrum of antibodies is seen in generalized versus ocular myasthenia.[21] The sera of a few patients with ocular myasthenia gravis failed to block bungarotoxin binding to the receptor, despite high titers of acetylcholine receptor antibodies by immunoprecipitation assays, whereas bungarotoxin binding was inhibited by sera of 40% of patients with generalized myasthenia gravis. The implication is that the antibody binds to a different part of the receptor in the two different processes. A related finding in some studies,[17,27,28] but not all29 is that patients with ocular myasthenia, including some with negative antibody titres in traditional assays using limb muscle,28 have sera that react more strongly in assays using antigen derived from ocular muscles, whereas the opposite is true for patients with generalized myasthenia.[17]

Physiological hypotheses cite differences in the structure and function of extra-ocular muscles.[14] Extra-ocular muscle fibers are small, more variable in size, and more richly innervated than extremity muscle fibers. They are among the fastest contracting in the body,[30] and paradoxically, may be more resistant to fatigue.[31] Two broad classes of extra-ocular muscle have been described.[32] Fast (twitch) fibers have a single end-plate per fiber and can generate an action potential in response to a single neuronal impulse[33]: they constitute about 80% of extra-ocular muscle. Slow (tonic) fibers have multiple end-plates per fiber and do not generate action potentials; rather, they show slow, graded contractions, which are proportional to the end-plate potentials induced by acetylcholine[14]; hence, the concept of safety factor of transmission does not apply to them. These comprise about 5% of extra-ocular muscle,[30] and are located mainly in the muscle layer adjacent to the globe.[34] "Intermediate" fibers, with multiple terminals, and capable of generating both action potentials and sustained graded contractions, also exist, mainly in the muscle layer adjacent to the orbital wall.[35] Arguments for myasthenic vulnerability have been constructed for both twitch and tonic fibers.

Compared with twitch fibers in limb muscles, those in extra-ocular muscle develop tension in 50% less time[14] and their peak firing frequency during saccades may exceed 400 Hz, over twice that in limb muscle.[30] This extreme level of activity may increase susceptibility to fatigue.[14] Also, extra-ocular muscle twitch fibers have less prominent secondary synaptic folds, leading to speculation that there may be fewer postsynaptic acetylcholine receptors[36]: there is also some evidence that mean acetylcholine concentration in these fibers is less than half that in limb muscle.[14] All these features could reduce the safety factor for neurotransmission in extraocular muscle twitch fibers.

On the other hand, others argue that tonic fibers are more vulnerable in myasthenia.[36,37] Animal studies comparing tonic and twitch fibers show that tonic fibers have fewer postsynaptic junctional folds and lower densities of acetylcholine receptors, by a factor of 1.3 to 1.5,[36] again pointing to a reduced safety factor. A combined immunological/physiological hypothesis notes that tonic fibers are more likely to have some fetal receptor isoforms than twitch fibers.[38] Clinicians have also used their observations to indirectly support involvement of tonic fibers. Some suggest that the high frequency of ptosis in myasthenia points to selective weakness of muscles with a predominantly tonic pattern of activity.[14] Some[39] deduce from the normal velocities of small amplitude saccades in myasthenia that there is relative sparing of twitch fibers. With an analog computer model of saccades,[40] many of the eye movements seen in myasthenia gravis could be simulated by a defect in the component of muscle force that sustains eccentric gaze (which may be the primary responsibility of the slow tonic fibers).

Clinical Ocular Signs

Myasthenia gravis causes weakness, predominantly in bulbar, facial, and extra-ocular muscles, often fluctuating over minutes to weeks, in the absence of wasting, sensory loss, or reflex changes. The picture of fluctuating, asymmetric external ophthalmoplegia with ptosis and weak eye closure is virtually diagnostic of myasthenia.

Nevertheless, it is common for patients with ocular myasthenia to receive several misdiagnoses initially. It is often taught that myasthenia should be considered with any ocular motility disturbance that spares the pupil and is atypical for a single nerve palsy. However, myasthenia can mimic nerve palsies too,[41,42] and will be missed in such patients if the physician fails to consider myasthenia. Awareness, attention to historical details suggesting variability and fatigue, and proficiency in detecting subtle myasthenic eye signs are important in improving the rate of early diagnosis.

Clearly, myasthenia is strongly suggested by a history of paretic symptoms worsened by activity, improved by rest, and varying from day to day, hour to hour, and week to week. A diurnal pattern with worse symptoms in the evening is not uncommon. Another typical presentation of variability is a patient whose ocular motor pattern has received different diagnoses by different physicians.

Equally clearly, combined patterns of weakness of the extra-ocular muscles, levator palpebrae superioris, and orbicularis oculi are highly indicative of myasthenia. In one survey of patients with ocular myasthenia, 10% had ptosis only, 90% had a combination of diplopia and ptosis, and 25% had added weakness of the orbicularis oculi.[6] Combined weakness of lid and eye muscles can occur with other diseases, though, particularly the ocular myopathies.

When reviewing the sometimes complex findings in myasthenia, it should be remembered that the ocular features represent a combination of paresis and secondary central compensatory mechanisms (Table 2). Some aspects of the former are highly suggestive of myasthenia, particularly when they reveal excessive fatigue or variability, but the latter are nonspecific responses to any type of peripheral ocular weakness.

Lid Weakness

Ptosis may occur alone or with other ocular weakness. It may be unilateral or bilateral, and is usually asymmetric initially. It is typically variable, with prominent fatiguability, sometimes not apparent on awakening, only to develop and worsen over the course of the day.

Fatigue and Variability. On exam, lid signs of fatigue include ptosis that worsens with repeated eye opening or prolonged upgaze. Cogan's lid twitch sign[43] may be seen when the patient first looks down for a short period and then makes a saccade back to primary position. The upper eyelid elevates excessively during this upward saccade, sometimes causing a transient lid retraction, and then twitches in nystagmoid fashion or slowly droops back to a ptotic position. This is interpreted as transient improvement in lid strength after rest of the levator in downgaze, followed by droop in the primary position as the levator fatigues. As with many myasthenic signs, Cogan's lid twitch has sometimes been reported with brain stem or ocular motor disorders.[44]

Another sign is lid hopping, fluttering of a ptotic eyelid, particularly during lateral eye movements or sustained upgaze.[45]

Paradoxical reversal of ptosis[46] has been described, in which ptosis switches eyes during the course of a day, as a function of rest, or administration of edrophonium. While this may simply reflect the moment-to-moment variability of the disease, the explanation of reversal with edrophonium is still not clear.

Secondary Adaptive Features. As with other cause of ptosis, a lid droop may appear mild because of partial compensation: the true extent of ptosis can be revealed by covering the ptotic eye and observing the gradual increase in ptosis behind the cover over several minutes. Enhanced ptosis is a related sign[47] in which manual lifting of a ptotic eyelid -- thus eliminating the need for compensation -- causes the other apparently normal eye to develop ptosis, showing that the lid dysfunction is actually bilateral. This second-eye ptosis had been masked because the central compensatory increase in innervation directed at overcoming the more severe ptosis in the first eye is distributed to both eyes by Hering's law.[48] Manual elevation of one eyelid reduces the effort required to raise that eyelid and thus according to Hering's law less effort is also exerted by the contralateral levator muscle, and that eyelid becomes more ptotic. Enhancement of ptosis is not pathognomonic for myasthenia gravis, as it can be seen in patients with other causes of congenital and acquired ptosis, but in patients with appropriate history, it is highly suggestive of myasthenia gravis.

Occasionally, the diagnostic impression with a myasthenic patient is led astray because of apparent lid retraction rather than ptosis. Sometimes this reflects co-existent thyroid ophthalmopathy.[49,50] Lid retraction may be a manifestation of compensatory mechanisms. In response to unilateral or asymmetric ptosis, the system increases innervation to both lids (Hering's law): the resulting lid retraction on the less affected side may appear more prominent than the ptosis on the weaker side.[48,51,52] As with enhancement of ptosis, manual lifting of the ptotic lid will allow the opposite retracted lid to return to a more normal position, revealing the compensatory origin of the retraction. The lid elevation in Cogan's lid twitch can be transiently excessive[43]; the rest afforded the levator in downgaze allows a transient unmasking of the increased innervation of the lid from central adaptation, causing the lid to overshoot on upgaze. Last, prolonged upgaze may cause a post-tetanic facilitation of the levator in a few rare patients, causing lid retraction.[53] This sign should raise the possibility of Lambert-Eaton syndrome as well.[54]

Orbicularis Oculi

The combination of ptosis and orbicularis oculi weakness is highly suggestive of myopathic disorders in general. Orbicularis weakness is demonstrated by the examiner attempting to open the lids against forceful lid closure by the patient.

Fatigable weakness of the orbicularis can cause afternoon ectropion of the lower lid. The peek sign is another manifestation of orbicularis fatigue.[55] On lid closure to command, the orbicularis muscle initially may achieve lid apposition; however, as the patient continues to try to keep the eyes forcefully closed over a minute, the orbicularis oculi fatigues, and sometimes the lids separate to show a rim of sclera, with the patient appearing to "peek" at the examiner. With profound orbicularis fatigue, the cornea may become visible. In severe cases of orbicularis weakness, exposure keratitis may result. The peek sign is occasionally seen with VII nerve palsies, but not in other neuropathic or myopathic disease.[55]

Extra-Ocular Muscles

Diplopia is the second most common manifestation of ocular myasthenia. Most patients with ocular myasthenia affecting the extra-ocular muscles also have ptosis,[6] but exceptions are not infrequent. Any pattern of incomitant strabismus may develop, from single muscle paresis to total external ophthalmoplegia. It can mimic peripheral nerve palsies, such as IV nerve palsy,[41] VI nerve palsy, and partial III nerve palsy,[42] and also central disorders of gaze, including unilateral or bilateral internuclear ophthalmoplegia,[56-58] one-and-a-half syndromes59 and double elevator palsy. Although any muscle may be affected, the medial rectus, inferior rectus, and superior oblique may be more commonly affected.[45]

When severe and diffuse, ocular myasthenia gravis may be hard to distinguish from chronic progressive external ophthalmoplegia (CPEO), as both can have symmetric total external ophthalmoplegia, ptosis, and orbicularis oculi weakness.[60] Furthermore, increased jitter on single-fiber-electromyography (EMG) can occur with myasthenia and CPEO.[61] Historical data may help, with a slow, progressive symmetric course without fluctuation favoring CPEO. Saccades tend to be much slower in CPEO than myasthenia.[39,62] Ultimately, muscle biopsy may be required to confirm ragged red fibers.

Bell's phenomenon, elevation of the eyes on forced eyelid closure, may be also diminished or absent in myasthenia gravis. This usually is related to the degree to which upgaze is affected by myasthenia. However, an intact Bell's phenomenon was reported in a patient with ocular myasthenia gravis who was unable to elevate either eye above the midline voluntarily on oculocephalic testing (doll's head maneuver).[63] This indicates that a vertical gaze paresis with an intact Bell's phenomenon is not pathognomonic for a "supranuclear palsy."

Dynamic Eye Movement Abnormalities

Close observations of ocular motility in myasthenia reveal a complex mixture of peripheral paretic and central adaptive effects.[15] These are often discerned best from eye movement recordings, but some are easily evident clinically. Quantitative measures have yielded variable data, with some reports suggesting mild relative slowing of saccades[64] and quick phases of optokinetic nystagmus,[65] and others finding that myasthenic saccadic velocities are slightly faster than those of patients with other ocular palsies.[39,62,66] In general, the quantitative characteristics of eye movements do not adequately distinguish myasthenia from other types of weakness,[67] with the exception that the eye movements of CPEO are much slower than those in myasthenia.[39,62]

Fatigue and Variability. Signs of fatigue are prominent. While the initial velocity of saccades may be nearly normal, fatigue from repetitive eye movements eventually reduces saccadic amplitude and velocity.[68] Intrasaccadic fatigue of twitch fibers also causes abrupt decelerations of the eye during a saccade (Figs. 1 and 3), with the eye carried slowly to its final position,[15,69] sometimes with a series of stuttering bursts of speed.[70] The durations of such saccades are prolonged, but increased saccadic duration also occurs in nonmyasthenic palsies.[71] If the tonic fibers are also paretic, the eye may even stop short of its goal. The peak velocity of such a saccade is excessive for its truncated amplitude, giving the appearance of an abnormally rapid small saccade. Eye movement recordings can show moment-to-moment saccadic variability in either velocity profiles[69] or the relation of peak velocity to saccadic amplitude: this "saccadic jitter" can be quantitated and is diagnostic of myasthenia in about 40% of patients[72] (Fig. 2).

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Figure 1. Sleep test in a myasthenic patient. The subject is making saccades to follow a target (dotted line) making 20-degree steps repetitively. Black lines show his eye position (y-axis) over time (x-axis). Initially, in top trace, saccades are slow and hypometric, with occasional intrasaccadic fatigue (arrow). Speed and amplitude increase after 15 min of rest with eyes closed (bottom trace).
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Figure 2. Saccadic jitter. Peak velocity is plotted against amplitude for two patients. Circles indicate average peak velocities for bins grouping saccades of similar amplitude, dots indicate data for individual saccades. Curves represent fitted exponential functions. Note the greater degree of scatter of individual saccades around the curve in the myasthenic patient (left), compared to the patient with VI nerve palsy (right). This variability is reflected statistically in the root mean square error (RMSE). (From Barton and Sharpe, 1995,[72] with permission. Copyright of the Association for Research in Vision and Ophthalmology.)
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Figure 3. Edrophonium effect on saccades in a myasthenic patient. The subject is making saccades to follow a target (dotted line) making 20-degree steps repetitively. Black lines show his eye position (y-axis) over time (x-axis). Prior to edrophonium (top trace), saccades are hypometric and slow, and show intrasaccadic fatigue at times (small arrow). One minute after edrophonium (bottom trace), saccades are larger and faster, with gross hypermetria (large arrows), and no more intrasaccadic fatigue.
Effective recording protocols for measuring ocular motor fatigue have not yet been devised,[66,67] although there are qualitative results suggesting increase in the variability of saccadic trajectories.[69] Sustained gaze may induce a decrease in saccadic amplitude in myasthenia, but can do so in other conditions.[73] Fatigue and complex saccadic trajectories have also been reported in Guillain-Barré syndrome.[70]

Fatigue of the tonic fibers also causes "quiver" eye movements, in which saccades are immediately followed by glissadic drifts in the opposite direction because the tonic fibers cannot sustain the eccentric position.[74] A slow drift back to center or a gaze-paretic nystagmus can follow prolonged gaze for the same reason.[75-77]

Fatigue can also be revealed by the "sleep test," in which eye movements are examined before and after a 30-min rest with eyes closed.[78] This may be a useful alternative in elderly subjects with relative contraindications to the use of the edrophonium test (Fig. 1).

Secondary Adaptive Features. While large saccades are often hypometric in myasthenia, secondary adaptive shifts of the pulse of innervation to this weakness are thought to result in excessive force for small saccades, which may generate hypermetric small saccades[39] because small movements may be less paretic than large ones. Dissociated gaze-evoked nystagmus in the eye contralateral to a markedly paretic one can represent adaptive efforts to increase the pulse of innervation,[77] much as occurs in internuclear ophthalmoplegia from central lesions of the medial longitudinal fasciculus and other ocular motor palsies. Adaptive dissociated nystagmus may emerge only after administration of cholinergic agents.[76]

Pupil and Accommodation

As a rule, clinically significant internal ophthalmoplegia is rare in myasthenia. Nevertheless, abnormalities have been reported occasionally. Anisocoria has been noted,[79,80] with supposed resolution after treatment with cholinesterase inhibitors, but given the natural variability in anisocoria, this cannot be considered firm evidence of a causal relationship to myasthenia. Both reports also claimed sluggish pupillary light reactions with improvement on cholinesterase inhibitors. Pupillographic studies have confirmed reduced velocities of pupillary constriction.[81] Pupilloconstriction fatigue to prolonged light stimulation has been reported.[82,83] Also reported are abnormalities in pupil cycle times. There are also reports of fatigue of accommodation with improvement after edrophonium.[84,85]

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).[88-90]

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.[98-101] "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).

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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).
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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]

Differential Diagnosis

Most commonly the clinician is faced with a problem of differentiating ocular myasthenia from other common peripheral or central neuropathic conditions, such as the ocular motor palsies. Less commonly, there is confusion with myopathic disorders, chiefly oculopharyngeal dystrophy, myotonic dystrophy, and CPEO. The slowly progressive nature of these conditions, family history in some, and additional systemic features in others, help make the diagnosis. Isolated CPEO without other features of Kearns-Sayre syndrome can occasionally be confused with ocular myasthenia because it too is associated with increased jitter on single-fiber EMG.[61] Deletions on mitochondrial DNA analysis and ragged red fibers on biopsy confirm the diagnosis.

It must also be remembered that there are other disorders that affect the neuromuscular junction.

Lambert-Eaton myasthenic syndrome (LEMS) is less common than myasthenia gravis. It affects adults primarily and males at least twice as frequently as women. Like myasthenia, LEMS is autoimmune in nature, but its antigenic target is presynaptic, not postsynaptic. Morphological studies show reduced density and abnormal distribution of active zone particles on the presynaptic membrane, and the serum has antibodies against voltage-gated calcium channels. Fifty percent of LEMS are paraneoplastic, most often associated with small cell lung carcinoma[109]; in others it is associated with other autoimmune disorders, such as pernicious anemia, autoimmune thyroid disease, and Sjogren's syndrome.

Compared with myasthenia gravis, weakness in LEMS is often less severe and may improve with exertion. Large muscles are affected, with abnormal gait a frequent initial symptom. Ocular signs are rare, but occasional patients note intermittent ptosis and diplopia. Eye movement recordings can show subclinical abnormalities such as hypometric saccades. Ocular signs of postexertional facilitation include lid retraction after prolonged upgaze.[54] Hyporeflexia and autonomic cholinergic disturbances such as dry mouth and impotence are important clues to the diagnosis.

Rapid (20-50 Hz), repetitive stimulation or forceful voluntary contraction causes an increase in the amplitude of the compound muscle action potential. There is increased jitter on single-fiber EMG, but repetitive stimulation decreases jitter in LEMS and increases it in myasthenia gravis.[110] Assays for antibodies against P-type voltage-gated calcium channels are reported to have sensitivity of 85%, and specificity of 100%.[111]

Several rare congenital myasthenic syndromes exist, with inherited defects of pre- or postsynaptic components of the neuromuscular junction.[1] Some such as familial infantile myasthenia and familial limb girdle myasthenia are autosomal recessive, others such as slow channel syndrome are autosomal dominant or sporadic. Most are apparent from birth, although the slow channel syndrome may present in adulthood. Extra-ocular muscle dysfunction is frequent but unlikely to be the sole manifestation. Sophisticated evaluation is often required for diagnosis.

Toxins can impair neuromuscular transmission and cause generalized and ocular symptoms similar to myasthenia. Many of the drugs that exacerbate known cases of myasthenia can produce weakness in individuals with other neuropathic or muscular disorders, including amyotrophic lateral sclerosis, polymyositis, and polio, among others.[112] Vincristine and vinblastine may cause signs of ocular weakness in cancer patients.

Intoxication with organophosphate insecticides causes a cholinergic crisis, presenting as a combination of autonomic and neuromuscular signs. Treatment is with atropine or pralidoxime.

Botulism causes ptosis, diplopia, dysphagia, and generalized weakness. Unlike myasthenia, it also causes blurred vision, nausea, and vomiting. Saccades may show quiver movements.[113] Clues include similar weakness in friends and family members (if they have a common exposure) and signs of cholinergic autonomic hypofunction, including dilated unreactive pupils, urinary retention, and decreased bowel sounds. Increased jitter is seen on single fiber EMG. Treatment is supportive care with antitoxin administration.

The toxins of certain snakes (cobras, kraits, coral snakes, and sea snakes) block acetylcholine receptors and cause bilateral ptosis, extraocular weakness, and dysphagia, followed by increasing bulbar dysfunction and respiratory failure. Patients require supportive care, antitoxin, and possibly acetylcholinesterase inhibitors.

Associated Disorders

There is an increased frequency of other autoimmune conditions with myasthenia. Examination and investigations in such patients are not complete without consideration of these potentially important issues.

Between 7-26% of patients with myasthenia gravis have thymoma,[114,115] in such patients mortality rates are higher and morbidity tends to be more severe. Thymic hyperplasia, characterized by infiltration of the thymus with lymphocytes and plasma cells, is found in as many as 65-70% of myasthenic patients.[116] All patients with myasthenia should have a computed tomography (CT) scan of the thorax looking for thymoma. The presence of antibodies directed against striated muscle are said to correlate with thymoma, but the sensitivity of such assays is only about 84% and the specificity 56-77%.[17,114,115] Assuming that 12% of patients with myasthenia have thymoma, this means that only about a third of those with a positive test have thymoma, though 97% of those with a negative test will not have it. These antibodies may be generated by an immunological cross reaction with antigens in the thymic tumour, specifically to neurofilaments containing titin epitopes. Anti-titin antibodies may be a better test, in that they supposedly have 100% specificity[115]: hence, all patients with a positive test will have thymoma, and the negative predictive value will range from 82 to 95%, depending upon the prevalence of thymoma.

Autoimmune thyroid disease is commonly associated with myasthenia. Either hyper- or hypothyroidism may precede or follow the development of myasthenia.[49,50] Twenty-five percent of those with normal levels of thyroid hormone will have antithyroid antibodies.[50] Conversely, 8% of patients with Graves' disease have antibodies against the acetylcholine receptor.[108]

Other autoimmune processes are occasionally found, including polymyositis.[117] In particular, patients with myasthenia and thymoma may be at increased risk for other autoimmune processes,[118] including rheumatoid arthritis, thyroiditis, polymyositis, pernicious anemia, and thrombocytopenia. Thymoma may also carry an increased risk of nonthymic cancers.[118] Rarer associations include Lambert-Eaton syndrome[119] and opsoclonus.[120]

Treatment

Management of myasthenia also includes awareness and avoidance of medications that can worsen neuromuscular transmission (Table 5).[112,121,122] Most frequently reported112 are aminoglycoside antibiotics, beta-blockers,[123,124] and chloroquine. Other clinically important associations include other antibiotics, anti-arrhythmics, calcium channel blockers,[125] some anticonvulsants, and intravenous iodinated contrast.[126] On occasion these drugs may cause weakness in a previously normal subject: in some, this may be the unmasking of underlying myasthenia.[121] Penicillamine does not impair neuromuscular transmission, but may induce auto-antibodies, causing an iatrogenic myasthenic syndrome.[112,121]

Symptomatic treatment can be offered. The mainstays are acetylcholinesterase inhibitors such as pyridostigmine and neostigmine.[45] Ninety percent of patients have some benefit from such drugs, although this may be relatively mild in half.[127] In particular, these may be less effective for diplopia than ptosis.[6] Their main side effects are dose-related and due to muscarinic excess, such as hypotension, bradycardia, excess salivation, abdominal cramps, and diarrhea. Relative contraindications include asthma, arrhythmias, and prostatic hypertrophy. Laxatives may reduce absorption of these drugs.[122]

The major risk of acetylcholinesterase inhibitors in myasthenic patients is cholinergic crisis, in which excessive acetylcholine causes weakness due to depolarization block. Patients unaware that weakness may be caused by an excess as well as a deficiency of medication run this risk if they increase their dose routinely as a response to weakness. Cholinergic crisis may be suspected if weakness is accompanied by salivation, abdominal cramping, and muscle fasciculations; however, it is not always possible to differentiate cholinergic crisis from myasthenic crisis (subacute severe weakness due to cholinergic deficiency), even with an edrophonium test. The safest course is usually to admit the patient to an intensive care unit, consider ventilatory support, stop all medications temporarily, and treat with plasma exchange or possibly intravenous immunoglobulin.

Physical adaptive therapies can be used also as symptomatic treatment, with varying success. While an eye patch is always effective against diplopia, prisms are difficult to use in situations where ocular alignment fluctuates from one minute to the next. Lid crutches are generally more hindrance than help for ptosis. Only in long-standing cases of "burned out" myasthenia, where careful documentation has revealed no further change in severely limited eye muscles, can strabismus surgery be considered, although it is rarely done.

Immunosuppression with drugs is an important goal in the treatment of generalized myasthenia.[122] Low-dose, alternate-day prednisone is helpful in almost 90% of patients with ocular myasthenia also,[127] and improves diplopia in about 75%,[128] with minimal side effects. Initiation of steroid therapy traditionally involves higher dose daily regimens, which can be associated with transient worsening of myasthenic weakness in the first few weeks.[129] Azathioprine is widely used as a steroid-sparing (or steroid-reducing) immunosuppressant in the long-term treatment of myasthenia.[122] There is little data on its use in ocular myasthenia; however, its combination with low-dose prednisone was helpful in 91% of a small sample of 23 patients.[127] It requires monitoring for neutropenia, bone marrow depression, and hepatitis, and is teratogenic.[45] Other immunosuppressant drugs such as cyclosporine[130] are more toxic and there is even less data on their use for ocular myasthenia.

Thymectomy is indicated in those patients with demonstrated thymoma, of course, and is helpful in inducing remission in 10-30% and improvement in up to 80% of patients with generalized myasthenia.[122,131] Whether it should be routinely used in other patients with pure ocular myasthenia, with or without suspected thymic hyperplasia, is more controversial. Most neurologists limit its use in ocular myasthenia to those with severe signs.[132] However, the evidence is mixed. Some claim that it offers no benefit,[127] while others claim significant improvement in 80% of patients who fail to respond or relapse with drug therapy.[133]

Short-term immunomodulation can be achieved with plasmapharesis and intravenous immunoglobulin. These are usually reserved for severe systemic weakness and crisis, and are seldom required for ocular myasthenia.

Prognosis

In a patient with signs limited to the ocular muscles, a key issue is the likelihood of developing generalized myasthenia. A study of nearly 1500 patients showed that about 50% presented with strictly ocular involvement. Of this group with ocular myasthenia, about 30% did not generalize over a mean of 17 years of follow-up; among the 70% who progressed, 94% did so within the first 3 years.[2] Similar findings were reported in another study,[4] with 50% of patients with ocular myasthenia developing generalized disease, and 80% of these doing so within 2 years of diagnosis. Ten percent actually achieved complete remission, although remission at a later date remained possible.[134] Of note, EMG findings of subclinical disease in limb muscles in this study[4] did not predict generalization. Development of generalized myasthenia after 3 years can occur, but it does so at a slower rate.[127]

Anticholinesterase medications do not improve the outlook for ocular myasthenia.[2] Whether predisone, thymectomy, or other immunosuppression alters the likelihood of generalization is not yet entirely clear. Two retrospective reviews have suggested that steroids and azathioprine may reduce the rate of generalization by as much as 75%.[127,128] Available data are too scant to show whether thymectomy adds any prognostic advantage.[127,133]

Table 1. Vulnerability of Extra-ocular Muscles to Myasthenia Gravis[14]

Physiological reasons
  twitch fibers
       higher discharge frequencies, up to 400 Hz[30]
     less acetylcholine per quantum released presynaptically
     fewer acetylcholine receptors at endplate[36]
  tonic/intermediate fibers
       no safety factor
     few acetylcholine receptors at endplate[36]
     more fetal isoforms than twitch fibers[38]
Functional reasons
  slight extra-ocular weakness is more apparent than slight limb weakness
  use of visual rather than proprioceptive feedback is less adaptive to weakness[15]
Immunological reasons
  low antibody titres,[7,16,17] mean less severe disease -- just ocular symptoms
  fetal receptor isoforms in extraocular muscle only[14,24]
  other antigenic differences in extraocular muscle?[17,27,28]

Table 2. Clinical Signs in Ocular Myasthenia

Signs of fatigue
  levator palpebrae
       lid twitch[43]
     ptosis after sustained up-gaze
     lid nystagmus after sustained up-gaze
  orbicularis oculi
       afternoon ectropion
     peek sign[55]
  extra-ocular muscles
       saccadic slowing or truncation with repeated saccades
     intra-saccadic fatigue[15,69,71]
     rapid small saccade
     gaze-evoked nystagmus after sustained gaze[75-77]
     quiver eye movements[74]
  improvement with the sleep test[78]
Signs of variability
  levator palpebrae
       lid hopping
  extra-ocular muscles
       saccadic jitter[72]
Signs of adaptation
  levator palpebrae
       enhanced ptosis[47]
     lid retraction contralateral to ptotic eye[51,52]
  extra-ocular muscles
       hypermetric small saccades[39]
     dissociated gaze-evoked jerk nystagmus[77]
Signs of combined weakness and adaptation
  levator palpebrae
       lid retraction with Cogan's lid twitch
  extra-ocular muscles
       saccadic hypermetria after edrophonium[97]

Table 3. False-positive Edrophonium Tests[88]

Lambert-Eaton syndrome (37% positive)
Botulism (27% positive)
Congenital end-plate acetylcholine receptor deficiency
Guillain-Barré
Amyotrophic lateral sclerosis
Brain stem glioma[89,90]

Table 4. Other Disorders of the Neuromuscular Junction

Lambert-Eaton (myasthenic) syndrome
Congenital (genetic) myasthenic syndromes
Drugs impairing neuromuscular transmission (Table 5)
Organophosphates
Botulism
Snake toxins

Table 5. Drugs that Exacerbate Myasthenia

Antibiotics aminoglycosides
  polymixin
  clindamycin
  lincomycin
  tetracycline
  chloroquine
  pyrantel
Anti-arrhythmics quinidine
  procainamide
  lidocaine
  propafenone
Beta-blockers
Calcium channel blockers
Anticonvulsants		 phenytoin
  trimethadione
Psychiatric drugs lithium
  chlorpromazine
  phenelzine
  cocaine
Other steroids
  magnesium
  iodinated contrast

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