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

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,[56,57,58] 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).

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).

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.)

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.[75,76,77]

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-evokednystagmus 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]

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