A patient with myasthenia gravis has anti-AChR antibodies. On repetitive nerve stimulation (RNS) at 3 Hz, there is a >10% decrement in compound muscle action potential (CMAP) amplitude. Which physiological mechanism explains this decrement?
- A Pre-synaptic depletion of ACh vesicles at 3 Hz stimulation, reducing quantal content
- B Reduced ACh production due to cholinesterase inhibitor deficiency prevents adequate summation at 3 Hz
- C Post-synaptic AChR blockade by antibodies reduces the safety factor; quantal content is normal but fewer functional AChRs remain, so at rest many EPPs are suprathreshold but repetitive depletion of the available ACh quanta causes EPPs to fall below AP threshold ✓
- D Anti-AChR antibodies inhibit vesicular ACh loading (VAChT), reducing quantal size with each stimulus
Explanation
In myasthenia gravis, anti-AChR antibodies reduce functional postsynaptic AChR numbers (via complement-mediated destruction and endocytosis). The safety factor — the ratio of EPP amplitude to AP threshold — is reduced from normal (~3–5x) to near threshold. At rest, EPPs may barely exceed threshold. During repetitive 3 Hz stimulation, normal presynaptic ACh release diminishes slightly (normal quantal rundown) from the readily releasable pool, which in a normal NMJ doesn't matter (high safety factor). But in MG, this small ACh reduction causes EPPs to fall below AP threshold in progressively more fibers, causing CMAP decrement. This is a postsynaptic, not presynaptic, defect. Lambert-Eaton (VGCC antibodies, presynaptic) shows increment at high-frequency stimulation.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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