## Pathophysiology of Myasthenia Gravis (MG) **Key Point:** Myasthenia gravis is an autoimmune disorder characterized by IgG antibodies against nicotinic acetylcholine receptors (AChR) at the neuromuscular junction. ### Mechanism of AChR Dysfunction The anti-AChR antibodies cause neuromuscular junction dysfunction through three mechanisms: 1. **Direct blockade** — Antibodies physically block acetylcholine binding to its receptors 2. **Complement-mediated destruction** — IgG binding activates the classical complement cascade, leading to membrane attack complex (MAC) formation and destruction of the postsynaptic membrane 3. **Cross-linking and internalization** — Antibodies cross-link adjacent AChR molecules, accelerating receptor internalization and degradation **Result:** Reduced number of functional AChR molecules → decreased neuromuscular transmission → muscle weakness that worsens with activity (due to depletion of acetylcholine stores). ### Clinical Correlation **High-Yield:** The **decremental response** on repetitive nerve stimulation (RNS) is pathognomonic — successive muscle action potentials decrease in amplitude because fewer AChRs are available with each stimulus. **Clinical Pearl:** Symptoms improve with anticholinesterase drugs (e.g., pyridostigmine) because prolonged acetylcholine dwell time in the synaptic cleft increases the probability of binding to remaining AChRs. ### Diagnostic Confirmation | Feature | Finding | |---------|----------| | Serology | Anti-AChR antibodies (positive in ~85% of generalized MG) | | Electrophysiology | Decremental response on RNS | | Pharmacological test | Edrophonium (anticholinesterase) improves weakness | | Imaging | CT chest to exclude thymoma | **Warning:** Not all MG patients are seropositive; ~15% have seronegative MG (often anti-MuSK antibodies or double-seronegative). [cite:Guyton & Hall Ch 9]
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