Myasthenia Gravis Overview

MG is a chronic autoimmune disease of the neuromuscular junction characterized by fluctuating weakness and fatigability of skeletal and extraocular muscles. The natural history is characterized by exacerbations and remissions. Symptoms increase during the day, and may be masked by rest. Patients may have respiratory (and swallowing) difficulties during myasthenic crisis, requiring artificial ventilation and airway protection; respiratory compromise is the most common cause of death in MG patients. In 1997, the death rate was reported to be less than 10%.

In adults, there are two forms - ocular and generalized. In children, there are three forms: autoimmune or juvenile MG, genetic or congenital MG and transient neonatal. In addition, the adult forms can be subtyped by autoantibody profile, the presence or absence of thymic abnormalities, age of onset, and severity18'19 (see Table 1). Approximately half of MG patients present with the ocular form and symptoms of ptosis and diplopia; most of these progress to generalized MG, with involvement of the bulborpharyngeal and skeletal muscles. Eventually, almost all MG patients have some eye muscle involvement.

MG is rare during childhood, and almost never occurs before 1 year of age; in North America, onset before the age of 20 years accounts for about 10-15% of all patients with MG. The demographic data are complex, varying by subtype.18 Generally, however, the disease shows two peaks for age of onset: one, between 20 and 40 years, is dominated by women; the other, between 60 and 80 years, is shared equally by men and women. Pathogenesis

While the etiology of MG is not known, it is perhaps the best understood of the autoimmune diseases.18 Unlike some types of GBS, microbial infections have not been shown to cause any of the chronic autoimmune diseases. However, onset and exacerbation of symptoms of MG may follow febrile illness and insect bites, and some data suggest a possible role for molecular mimicry. A genetic basis is suggested by the finding that 30% of patients have one maternal relative with MG or another autoimmune disorder.

Thymic pathology occurs in 80-90% of MG patients: about 15% of MG patients have a thymoma and 50-70% have thymic hyperplasia with proliferation of germinal centers. There is evidence to suggest that thymoma-associated MG is a paraneoplastic disease. In normal thymus, muscle epitopes can be found at low levels and confined to the medulla. In thymoma MG, however, muscle epitopes (AChR-like and others) and co-stimulatory molecules are overexpressed on neoplastic antigen-presenting epithelial cells found throughout the thymoma; these, in turn, are surrounded by large numbers of T cells.18

Although both T helper and B cells are involved in the autoimmune response, the attack on the neuromuscular junction is carried out exclusively by antibodies - most commonly against a portion of the extracellular domain of the AChRa subunit, the main immunogenic region. AChR antibodies impair neuromuscular transmission by three basic mechanisms, all involving the actual or functional loss of AChRs. The first and primary mechanism is complement-mediated destruction of the postsynaptic membrane. The second mechanism is blockade of ACh binding (the ACh-binding site and the main immunogenic region are both located on the a subunit), although such blocking antibodies are present in small amounts and probably play a minor role in most cases. The third mechanism is cross-linking of AChRs by bivalent antibody molecules, leading to accelerated AChR internalization; this mechanism appears to play a relatively minor role as well. Interestingly, the titer of AChR antibody does not appear to correlate with disease severity.

Some of the autoantibodies found in MG patients are against proteins localized to the cytoplasm, where they should be protected from immune attack. For example, 15% of MG patients with AChR antibodies also have antibodies against the muscle cytoplasmic protein rapsyn. Some of these antibodies to intracellular antigens appear to play a pathogenic role. They may be formed as a result of intermolecular epitope spreading.

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