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INTRODUCTION

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Myasthenia gravis (MG) is a neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at NMJs due to an antibody-mediated autoimmune attack. Treatment now available for MG is highly effective, although a specific cure has remained elusive.

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PATHOPHYSIOLOGY

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At the NMJ (Fig. 440-1, Video 440-1), 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, 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.

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VIDEO 440-1: Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

Anthony A. Amato

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FIGURE 440-1

Illustrations of (A) a normal presynaptic neuromuscular junction, (B) a normal postsynapatic terminal, and (C) a myasthenic neuromuscular junction. AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a reduced number of acetylcholine receptors (AChRs); flattened, simplified postsynaptic folds; and a widened synaptic space. See Video 440-1 also. (From AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016, Figures 25-3 [p 588], 25-4 [p 589], and 25-5 [p 590]; with permission.)

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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 results in weakness of muscle contraction.

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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 ...

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