Ocular Muscles and Myasthenia Gravis

ABSTRACT & COMMENTARY
Sources: MacLennan BA, et al. Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis. Ann Neurology 1997;41:423-431; Kaminski HJ, Ruff RL. Editorial. Ann Neurology 1997;41:419-420.

Fifty percent of myasthenia gravis (mg) pa-tients present with extraocular muscle (EOM) symptomatology, with ptosis and diplopia each in 25% (Grob D, et al. Ann NY Acad Sci 1981;377:652-669). Within one month of onset, 80% of all patients have EOM weakness, 40% limited to the eyes and 40% with generalized muscle involvement including EOMs (ibid). Sixteen percent remain purely ocular throughout their course, yet only 50% of these have positive anti-acetylcholine receptor (AchR) antibodies (ibid, and Drachman DB. N Engl J Med 1994;330:1797-1810). Why are the ocular muscles so susceptible, and why are their AchR antibody titers negative as often as positive?

Adult bovine EOMs express fetal-type AchR (a2bgd) not present in skeletal muscle, where the adult-type prevails (a2bed), and one attractive hypothesis suggests that this may explain the preferential EOM involvement in myasthenia (Horton RM, et al. Neurology 1993;43:983-986). Using RNase protection assays and human tissue, however, MacLennan et al demonstrate that expression of fetal-type AchR g subunit mRNA is comparable in EOM and skeletal (intercostal and gastrocnemius) muscles alike, whereas expression of adult type e subunit mRNA is substantially greater (10-fold higher) in EOM. In fact, sera from ocular MG patients specifically bound to adult-type AchR. The authors suggest that a diagnostic assay rich in adult AchR antigen would increase the positivity of AchR antibody detection in ocular myasthenia, but, alas, an explanation for EOM susceptibility in myasthenia must be sought elsewhere.

COMMENTARY

Although 80% of EOM fibers have only a single neuromuscular junction, 20% are multi-innervated, receiving several synapses per muscle fiber (Kaminski HJ, et al. Neurology 1990;40:1663-1669). These multi-terminal muscle fibers share properties in common with both tonic and twitch muscle fibers, including the ability to generate sustained contraction to prolonged depolarization and twitch responses to nerve stimulation (Ruff R, et al. Bull Soc Belge Ophthalmol 1989;237:321-352). Further, the neuromuscular junctions of these multi-innervated fibers are unique morphologically, consisting of one en plaque (platelike) and several en grappe (grapelike) synapses arising from one or more nerves (Kaminski HJ, et al. ibid). These differences suggest that ocular muscle susceptibility in myasthenia may be due to several factors. Unique epitopes, other than the AchR g subunit, may be associated with the multi-terminal EOM muscle fibers and be specifically targeted by the autoimmune response. Secondly, force generation in tonic fibers is directly proportional to membrane depolarization. Consequently, tonic fibers have no safety factor for neuromuscular transmission, and AchR loss will result in a drop in endplate potential with a resultant decrease in force and clinical weakness (Kaminski HJ, et al. ibid). Most appealing, however, is the fact that even the slightest asymmetric ocular muscle weakness will express itself as the sudden onset of symptomatic diplopia. This simple scenario would explain why ocular symptoms occur early on, not only in myasthenia but in botulism as well. —mr