A 28-year-old woman from Mumbai presents with a 6-week history of progressive weakness affecting the eyelids, face, and neck. She reports that her symptoms are worse in the afternoon and improve after a night's sleep. On examination, she has bilateral ptosis, facial weakness, and mild neck flexor weakness. Vital capacity is 85% of predicted. Serum AChR antibodies are negative. Repetitive nerve stimulation (RNS) shows a decremental response. Anti-muscle-specific kinase (MuSK) antibodies are negative. What is the most likely diagnosis?

Explanation

## Clinical Presentation Analysis **Key Point:** This patient presents with classic features of myasthenia gravis: - Ocular symptoms (ptosis, diplopia implied by eyelid weakness) - Bulbar and neck weakness - Fatigability (worse in afternoon, improves with rest) - Preserved vital capacity (85% — no significant respiratory compromise yet) ## Serological and Electrophysiological Findings **High-Yield:** The critical clue is the **negative AChR antibodies** combined with **positive RNS decremental response**. | Feature | Seropositive MG | Seronegative MG | LEMS | CMS | |---------|-----------------|-----------------|------|-----| | AChR Ab | Positive (80%) | Negative | Negative | Negative | | MuSK Ab | Negative | Positive (40%) | Negative | Negative | | RNS | Decremental | Decremental | **Incremental** | Decremental | | Ocular involvement | Common | Common | Rare | Rare | | Autonomic symptoms | Absent | Absent | **Present** (dry mouth, impotence) | Absent | | Associated malignancy | Thymoma (10–15%) | Rare | SCLC (50–60%) | None | **Clinical Pearl:** Seronegative MG accounts for ~10–15% of MG cases. It is defined by: 1. Clinical features of MG (ocular, bulbar, limb weakness with fatigability) 2. Positive RNS (decremental response) 3. **Negative AChR AND MuSK antibodies** MuSK antibodies are found in ~40% of seronegative MG patients; this patient is **double-seronegative**, which is still consistent with MG if RNS is positive. ## Why Other Options Are Wrong ### LEMS (Option 2) **Warning:** LEMS mimics MG but has key distinguishing features: - RNS shows **incremental response** (not decremental) — this patient has decremental response - Autonomic symptoms (dry mouth, impotence, constipation) — absent here - Leg weakness typically precedes ocular involvement — opposite of this case - Associated with SCLC in 50–60% of cases ### Congenital Myasthenic Syndrome (Option 3) - Presents in infancy or early childhood, not at age 28 - RNS pattern depends on the subtype but often does not show classic decremental response - No family history mentioned ### Polymyositis (Option 4) - Does not cause ptosis or ocular weakness - Presents with proximal muscle weakness, elevated CK, and myositis on EMG - Fatigability is not a feature ## Diagnostic Confirmation **Mnemonic:** **SEROPOSITIVE vs SERONEGATIVE MG** — **"SERONEG = Seronegative (no AChR/MuSK), but RNS Positive (decremental), so still MG"** This patient meets diagnostic criteria for seronegative MG: 1. ✓ Clinical features (ocular, bulbar, neck weakness) 2. ✓ Fatigability pattern 3. ✓ Positive RNS (decremental) 4. ✓ Negative AChR and MuSK antibodies ## Next Steps - Edrophonium (Tensilon) test or ice pack test may help confirm (though less commonly used now) - CT chest to exclude thymoma (10–15% of seronegative MG) - Start pyridostigmine and consider immunosuppression if symptoms progress [cite:Harrison 21e Ch 385]