A 28-year-old woman from Mumbai presents with a 6-week history of progressive bilateral ptosis, diplopia, and difficulty swallowing. Symptoms fluctuate throughout the day, worsening in the afternoon and improving after sleep. On examination, sustained upward gaze for 30 seconds results in increased ptosis. Repetitive nerve stimulation (RNS) shows a decremental response. Anti-AChR antibodies are negative, and anti-MuSK antibodies are also negative. CT chest is normal with no thymoma. What is the most appropriate next diagnostic step?

Explanation

## Diagnosis of Seronegative Myasthenia Gravis **Key Point:** Approximately 10–15% of MG patients are seronegative (negative for both anti-AChR and anti-MuSK antibodies). Single-fiber electromyography (SFEMG) is the gold standard confirmatory test in seronegative MG. ### Clinical Scenario Analysis This patient has: - **Classic MG symptoms:** Ptosis, diplopia, dysphagia with diurnal fluctuation - **Positive fatigability:** Worsening with sustained upward gaze - **Abnormal RNS:** Decremental response (diagnostic for NMJ disorder) - **Seronegative status:** Both anti-AChR and anti-MuSK antibodies negative - **No thymoma:** CT chest normal ### Diagnostic Hierarchy in Seronegative MG | Test | Sensitivity in Seronegative MG | Specificity | Role | |------|--------------------------------|-------------|------| | **Anti-AChR antibodies** | ~50% in generalized MG | ~99% | Initial screening | | **Anti-MuSK antibodies** | ~40% in seronegative MG | ~99% | Screen for MuSK-MG subset | | **Repetitive nerve stimulation** | ~60–70% in seronegative | ~95% | Confirms NMJ disorder | | **Single-fiber EMG (SFEMG)** | **>95% in seronegative MG** | ~90% | **Gold standard for seronegative confirmation** | | **Ice pack test** | ~80% sensitivity | ~95% specificity | Bedside screening tool | **High-Yield:** SFEMG detects neuromuscular junction dysfunction even when antibodies and RNS are inconclusive. It measures "jitter" (variability in neuromuscular transmission) and blocking — both abnormal in MG regardless of serology. ### Why SFEMG Is the Answer 1. **Highest sensitivity in seronegative MG:** >95% (vs. 60–70% for RNS) 2. **Confirms NMJ pathology:** Demonstrates increased jitter and blocking characteristic of MG 3. **Guides treatment:** Positive SFEMG in a seronegative patient justifies immunosuppression 4. **Prognostic value:** Degree of abnormality correlates with disease severity **Clinical Pearl:** SFEMG is technically demanding and requires specialized equipment and expertise. It is not a screening test but rather a confirmatory test for suspected MG when antibodies are negative. ### Why Ice Pack Test Is Not the Best Next Step While the ice pack test is a simple, bedside diagnostic tool with good sensitivity (~80%) and specificity (~95%), it is: - A **screening/confirmatory tool**, not a definitive diagnostic test - Useful when SFEMG is unavailable, but inferior to SFEMG - Already clinically confirmed in this case (RNS abnormal, classic symptoms) - Does not provide objective electrophysiologic confirmation ### Management After SFEMG Confirmation Once SFEMG confirms seronegative MG: 1. **Symptomatic treatment:** Pyridostigmine (anticholinesterase) 2. **Immunosuppression:** Corticosteroids (first-line) or azathioprine/mycophenolate (steroid-sparing) 3. **Thymectomy:** Consider even without thymoma (improves remission rates in seronegative MG) 4. **Intravenous immunoglobulin (IVIg) or plasmapheresis:** For acute exacerbations **Mnemonic:** **SFEMG = Seronegative Final Electrophysiologic Marker of Gravis** — when antibodies fail, SFEMG succeeds.