Although not directly relevant to myasthenia, it is of interest that a number of curious neurologic disorders occur in association with thymoma. Among our own patients were 2 with “limbic encephalitis” with memory loss and confusion that could not be differentiated from the paraneoplastic variety of encephalitis (see Chap. 30), 1 case of midbrain encephalitis, 1 of Morvan’s fibrillary chorea (see further on), and 1 of aplastic anemia. Some of these neurologic processes are associated with antibodies directed against voltage-gated potassium channels (VGKC). Such cases appear in the literature, and all are considered to have a humoral immune basis.
Of biologic and even greater clinical importance is the coexistence of myasthenia gravis and other autoimmune diseases. Thyrotoxicosis with periodic paralysis (5 percent of myasthenic patients), lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, mixed connective tissue disease, anticardiolipin antibody, and (curiously) polymyositis have all been associated with myasthenia more often than can be explained by chance. A proportion of young women with myasthenia have moderately elevated titers of antinuclear antibody without the clinical manifestations of systemic lupus.
The present view, well founded, is that myasthenic weakness and fatigue are a result of the failure of effective neuromuscular transmission on the postsynaptic side. The greatly reduced number of receptors and the competitive activity of anti-AChR antibodies (see later) produce postsynaptic potentials of insufficient amplitude to discharge some muscle fibers. Blocked transmission at many endplates results in a reduction in the contractile power of the muscle. This deficiency is reflected first in the ocular and cranial muscles that are both the most continuously active and have the fewest AChRs per motor unit. Fatigue is understandable as the result of the normal decline in the amount of ACh released with each successive impulse.
Antibodies to AChR protein are present in more than 85 percent of patients with generalized myasthenia and in 60 percent of those with ocular myasthenia (Newsom-Davis). The presence of receptor antibodies has proved to be a reasonably sensitive and reliable test of the disease, as discussed later. The manner in which the antibodies that are directed against proteins in the intracellular compartment (such as anti-MuSK discussed later) causes weakness is not known.
Neuromuscular transmission is therefore impaired in several ways: (1) the antibodies block the binding of ACh to the AChR; (2) serum IgG from myasthenic patients has been shown to induce an increase in the degradation rate of AChR. This may be the result of the capacity of antibodies to cross-link the receptors; (3) antibodies cause a complement-mediated destruction of the postsynaptic folds (Engel and Arahata).