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

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.[9,10,11,12]

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.[18,19,20] 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).

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