A 38-year-old woman presents with progressive ptosis and diplopia over 3 weeks. On examination, she has bilateral ptosis that worsens with sustained upward gaze and improves after rest. Antibody testing for anti-acetylcholine receptor (AChR) is negative. Which is the most appropriate next investigation to confirm the diagnosis of seronegative myasthenia gravis?

Explanation

## Investigation Strategy in Seronegative Myasthenia Gravis **Key Point:** Single-fiber electromyography (SFEMG) is the gold standard confirmatory test for seronegative myasthenia gravis (MG), with sensitivity >95% even when antibodies are absent. ### Why SFEMG is the Answer SFEMG detects neuromuscular junction dysfunction through increased "jitter" (variability in time interval between action potentials of muscle fiber pairs) and blocking, which are pathognomonic features of MG regardless of antibody status. This test does not depend on the presence of anti-AChR or anti-MuSK antibodies. **High-Yield:** SFEMG is: - Most sensitive test for MG (>95% sensitivity in generalized MG, ~90% in ocular MG) - Abnormal in both seropositive and seronegative cases - Not specific to MG (also abnormal in Lambert-Eaton myasthenic syndrome, myopathies, neuropathies) - Technically demanding and requires expert interpretation ### Comparison of Diagnostic Tests in MG | Investigation | Sensitivity (Seropositive) | Sensitivity (Seronegative) | Specificity | Role | |---|---|---|---|---| | **Anti-AChR antibodies** | 80–90% | — | Very high | Initial screening | | **Anti-MuSK antibodies** | — | 40–50% | High | Seronegative subset | | **RNS (decremental response)** | 60–70% | 50–60% | Moderate | Confirmatory; less sensitive in ocular MG | | **SFEMG (jitter/blocking)** | >95% | >90% | Low | Gold standard; abnormal in almost all MG | | **Edrophonium test** | >95% | >95% | High | Rarely used; side effects; diagnostic value superseded by SFEMG | | **Ice pack test** | 80–90% (ocular) | 80–90% (ocular) | Moderate | Bedside screening; limited to ocular MG | **Clinical Pearl:** In this patient: - Negative anti-AChR antibodies rule out 10–20% of generalized MG cases (seronegative MG) - Anti-MuSK testing should be done next, but if also negative, SFEMG is the confirmatory test - RNS would be less sensitive in ocular-predominant disease ### Algorithm for Diagnosis of Seronegative MG ```mermaid flowchart TD A[Clinical suspicion of MG]:::outcome --> B[Anti-AChR antibodies]:::action B -->|Positive| C[Diagnosis confirmed]:::outcome B -->|Negative| D[Anti-MuSK antibodies]:::action D -->|Positive| E[Diagnosis confirmed]:::outcome D -->|Negative| F[Seronegative MG suspected]:::outcome F --> G[RNS electromyography]:::action G -->|Abnormal| H[Likely MG]:::outcome G -->|Normal| I[SFEMG]:::action I -->|Abnormal jitter/blocking| J[Diagnosis confirmed]:::outcome I -->|Normal| K[Consider alternative diagnosis]:::outcome ``` **Mnemonic:** **SFEMG = Single-Fiber is the Gold standard** — when serology fails, physiology confirms. [cite:Harrison 21e Ch 378]