The 1980s and 1990s witnessed spectacular progress in the understanding of the microstructure, physiology, and molecular composition of the nicotinic AChR. This, in turn, has been
applied to the clinical problem of MG. The AChR is a gated channel and intrinsic membrane glycoprotein of molecular weight 290,000, composed of five subunits. Distinct but related genes encode the individual subunits, and complementary DNA for each has been cloned, showing remarkable homology.

The mechanisms of the end plate current (EPC) and end plate potential (EPP) have been elucidated by noise analysis and patch or voltage clamping. In response to an incoming nerve action potential, highly localized regions of the nerve terminal (Fig. 180-1) release approximately 200 quantal packets, each containing 6 to 10,000 molecules of ACh. Binding of ACh to specific sites on the AChR results in the transient openings of the AChR channel, allowing a net influx of Na⁺ ions and thus producing the depolarizing potential. The circular arrangement of the five subunits delineates a 2.5-nm channel whose narrowest point is 0.65 nm in diameter. Each subunit contains four membrane-spanning alpha helices termed M1 to M4, with the M2 segment effectively lining the channel. More quantal packets of ACh are released into the synaptic cleft, and more receptor channels are present than are needed to depolarize the muscle fiber to threshold. This creates a “safety factor.” Even when the number of receptors is reduced experimentally, the EPP does not fall below the threshold needed to generate a muscle action potential. The autoimmune attack on AChRs, which leads to the reduction in the number of functioning receptors at myasthenic end plates, also leads to many EPPs falling below threshold. This translates into muscle weakness and fatigue, particularly with repetitive or sustained contraction.

The hypothesis that MG originated in the thymus gland, as first suggested by Weigert³⁵ in 1901, was difficult to prove and still remains speculative. The presumed initial event in the pathogenesis of myasthenia is loss of self-tolerance, a process attributed to the thymus gland for several intuitive reasons. The thymus contains all of the elements theoretically necessary for the activation of AChR-specific T cells. They include local antigen-presenting cells (APCs) or, in this case, myoid cells, which take up AChR derived from myoid cells, process it, and then express AChR-derived peptide fragments on their surface in the context of the trimolecular complex. The latter includes the APC, AChR-specific antigen linked to the major histocompatibility complex class II molecules, and AChR-specific reactive T cells. Although myoid cells are equally abundant in normal and myasthenic thymuses, hyperplastic glands contain many more myoid cells than atrophic glands. AChR-specific T cells are enriched in myasthenic thymus glands with and without epithelial cell tumors (thymomas). Whether the AChR-specific T cells in the myasthenic thymus always resided there or return after a sojourn in the peripheral immune system is not known. The peripheral blood of patients with MG contains an enhanced portion of these autoreactive T cells, which are capable of recruiting AChR-responsive B cells for the production of pathogenic anti-AChR antibodies. In actively induced or passively transferred EAMG, where the myasthenic process is initiated outside the gland, germinal centers are not observed. Finally, transplantation of myasthenic thymus fragments into mice with severe combined immunodeficiency results in the production of pathogenic mouse antibodies.

The term myasthenia has been used interchangeably for the acquired autoimmune form of the disease, and the term myasthenic has generally been used for other syndromes of the neuromuscular junction. Similarly, the classification of MG has been difficult. Early attempts emphasized duration of symptoms because it was believed that the disorder might be progressive. Younger and colleagues^37,38 emphasized indices of maximal severity, functional status, and response to therapy, prompting more exact nosology, classification, and comparative methods of analysis of patient outcome.

The clinical diagnosis of autoimmune acquired MG is made by recognizing a pattern of weakness that has the features of fluctuation and variability over the course of a day, months, or years, leading to perceptible exacerbations and remissions. The distribution of weakness is characteristic, affecting ocular, facial, oropharyngeal, and limb muscles. The useful Osserman and Genkins classification is listed in Table 180-1. The diagnosis is confirmed by unequivocal and reproducible improvement after intravenous administration of edrophonium chloride, a rapidly acting anticholinesterase drug. Formal diagnosis is bolstered by eliciting a decremental response to repetitive motor nerve stimulation as well as the detection of AChR antibodies in the serum. Selective involvement of limb and respiratory muscles, sparing ocular or oropharyngeal muscles, is rarely if ever encountered.