A 52-year-old woman with small-cell lung cancer (SCLC) presents with diplopia, ptosis, and muscle weakness that improves with rest. Serum calcium and glucose are normal. Which investigation is most specific for confirming the underlying paraneoplastic mechanism?

## Paraneoplastic Myasthenia Gravis (MG) in SCLC ### Clinical Presentation Analysis The patient exhibits: - **Ocular symptoms** (diplopia, ptosis) — classic MG onset - **Fatigability** (weakness improves with rest) — pathognomonic for MG - **SCLC** — associated with paraneoplastic MG in 3–5% of cases - **Normal metabolic workup** — excludes Lambert-Eaton myasthenic syndrome (LEMS) ### Why Anti-AChR Antibody Is Most Specific **Key Point:** Anti-AChR antibodies are the gold standard for diagnosing myasthenia gravis, whether autoimmune or paraneoplastic. They are positive in ~80–90% of generalized MG and ~50% of purely ocular MG. **High-Yield:** Anti-AChR antibodies directly cause: 1. Complement-mediated destruction of the neuromuscular junction 2. Blockade of acetylcholine binding 3. Cross-linking and internalization of AChR ### Differential Diagnosis: Paraneoplastic Antibodies in SCLC | Syndrome | Antibody | Clinical Features | Investigation of Choice | |----------|----------|------------------|-------------------------| | **Myasthenia Gravis** | Anti-AChR | Fatigable weakness, ocular symptoms, improves with rest | **Anti-AChR serology** | | Lambert-Eaton | Anti-VGCC | Proximal weakness, autonomic symptoms, improves with activity | Anti-VGCC serology | | Encephalomyelitis | Anti-Hu, Anti-CRMP5 | Cognitive decline, ataxia, seizures | Anti-Hu/CRMP5 serology | | Stiff-person | Anti-GAD | Rigidity, spasms, hyperekplexia | Anti-GAD serology | **Clinical Pearl:** The **fatigability pattern** (worse with activity, improves with rest) is the clinical hallmark that immediately points to MG rather than LEMS (which improves with activity). ### Diagnostic Hierarchy ```mermaid flowchart TD A[Ocular weakness + fatigability + SCLC] --> B{Suspect paraneoplastic MG} B --> C[Anti-AChR serology] C -->|Positive| D[Paraneoplastic MG confirmed] C -->|Negative| E[Proceed to RNS/SF-EMG] E --> F[Consider seronegative MG] ``` **Tip:** In paraneoplastic MG, anti-AChR positivity is slightly lower (~60–70%) than in autoimmune MG, but it remains the most specific initial test. [cite:Harrison 21e Ch 390]