Myasthenia gravis is an autoimmune disease with fluctuating muscle weakness that is caused by autoantibodies that target the neuromuscular junction. The most common antigenic target is the postsynaptic acetylcholine receptor (AChR). Other pathogenic antibodies recognize muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein (LRP4). These antibodies lead to loss of receptors and damage to the structure of the junctions. The disease has an incidence of approximately 2 in 100,000 persons. Anti-AChR mediated cases have bimodal age distribution with somewhat distinctive clinical features. Early onset before age 50 years is more common in females and is frequently associated with enlargement of the thymus due to the presence of B cell follicles and germinal centers (follicular thymic hyperplasia). Late-onset cases show a more equal gender distribution and are associated with thymoma (Chapter 12), a neoplasm derived from thymic epithelium. Both of these thymic lesions are believed to perturb tolerance to self-antigens, setting the stage for the generation of autoreactive T and B cells.
Clinically, myasthenia gravis frequently manifests with ptosis (drooping eyelids) or diplopia (double vision) because of weakness in the extraocular muscles. This pattern of weakness is distinctly different from that of most primary myopathic diseases, in which there is relative sparing of facial and extraocular muscles. The severity of the weakness often fluctuates rapidly, sometimes over periods of a few minutes. Characteristically, repetitive firing of muscles makes the weakness more severe, whereas cholinesterase inhibitors improve strength markedly, features that are are diagnostically useful. Effective treatments include cholinesterase inhibitors, immunosuppression, plasmapheresis, and (in patients with thymic lesions) thymectomy. These interventions have improved the 5-year survival rate to greater than 95%.
Lambert-Eaton syndrome is caused by autoantibodies that inhibit the function of presynaptic calcium channels, thereby reducing the release of acetylcholine into the synaptic cleft. Patients with Lambert-Eaton syndrome experience improvement in weakness with repetitive stimulation, in contrast to those suffering from myasthenia gravis. Repetitive stimulation serves to build up sufficient intracellular calcium to facilitate acetylcholine release.
Lambert-Eaton syndrome often arises as a paraneoplastic disorder, particularly in patients with small cell lung carcinoma. Cholinesterase inhibitors are not effective, and therapy is therefore directed toward reducing the titer of causative antibodies, through either plasmapheresis or immunosuppression. The prognosis is worse than that of myasthenia gravis because of the frequent coexistence of an underlying malignancy.
Several other neuromuscular junction disorders merit brief mention.
Congenital myasthenic syndromes comprise a heterogeneous group of diseases that result from mutations that disrupt the function of various neuromuscular junction proteins. Depending on the affected protein, the defects may occur at the level of acetylcholine release (presynaptic), the transport of acetylcholine across the synaptic cleft (synaptic), or the responsiveness of skeletal muscle (postsynaptic). Hence they may present with symptoms mimicking Lambert-Eaton syndrome or myasthenia gravis. Some forms respond to treatment with acetylcholinesterase inhibitors.