Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuromuscular junctions due to an antibody-mediated autoimmune attack. Treatment now available for MG is highly effective, although a specific cure has remained elusive.
At the neuromuscular junction (Fig. 461-1, Video 461-1), acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in vesicles (quanta). When an action potential travels down a motor nerve and reaches the nerve terminal, ACh from 150 to 200 vesicles is released and combines with AChRs that are densely packed at the peaks of postsynaptic folds. The AChR consists of five subunits (2α, 1β, 1δ, and 1γ or ε) arranged around a central pore. When ACh combines with the binding sites on the α subunits of the AChR, the channel in the AChR opens, permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase (AChE), which is present within the synaptic folds, and by diffusion of ACh away from the receptor.
Video 461–1 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction
Diagrams of (A) normal and (B) myasthenic neuromuscular junctions. AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a normal nerve terminal; a reduced number of acetylcholine receptors (AChRs) (stippling); flattened, simplified postsynaptic folds; and a widened synaptic space. See Video 461-1 also. (Modified from DB Drachman: N Engl J Med 330:1797, 1994; with permission.)
In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or “simplified.” These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.
The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.
The neuromuscular abnormalities in MG are caused by ...