In a patient with strongly positive striational‑muscle antibodies and negative acetylcholine‑receptor antibodies, what is the appropriate diagnostic work‑up and management for suspected seronegative myasthenia gravis?

Diagnostic Work-Up and Management for Seronegative Myasthenia Gravis with Positive Striational Antibodies

In a patient with strongly positive striational-muscle antibodies but negative AChR antibodies, immediately order anti-MuSK and anti-LRP4 antibodies, perform single-fiber EMG (the gold standard with >90% sensitivity), obtain chest CT with contrast to evaluate for thymoma (which can occur even in seronegative cases), and initiate pyridostigmine 30 mg orally three times daily while escalating rapidly to immunosuppressive therapy if symptoms are moderate to severe. 1, 2

Critical Diagnostic Testing Sequence

Serological Work-Up

• Order anti-MuSK antibodies immediately, as approximately one-third of AChR-negative patients will be MuSK-positive, and this distinction fundamentally alters prognosis and treatment response 1, 2, 3
• Test anti-LRP4 antibodies if both AChR and MuSK are negative, as these are associated with both generalized and ocular myasthenia gravis 1, 3
• Recognize that approximately 50% of purely ocular myasthenia cases are AChR-seronegative, so negative AChR does not exclude the diagnosis 1, 2

Electrodiagnostic Studies

• Perform single-fiber EMG (SFEMG) as the definitive test, with sensitivity exceeding 90% for ocular myasthenia and even higher for generalized disease 1, 2, 3
• Include repetitive nerve stimulation testing, though sensitivity is lower (positive in only one-third of ocular cases) 2
• Test cranial muscles in addition to limb muscles during electrodiagnostic studies, as this increases diagnostic yield in seronegative cases 4

Imaging and Concurrent Condition Assessment

• Obtain chest CT with contrast immediately to evaluate for thymoma, even though the patient is seronegative—case reports document malignant thymoma in seronegative MG, challenging conventional wisdom 5
• The positive predictive value of striational antibodies plus AChR antibodies for thymoma is 50% in patients under age 40, but striational antibodies alone (without AChR) have lower predictive value 6
• Check CPK, aldolase, ESR, and CRP to evaluate for concurrent myositis 7, 3
• If respiratory symptoms, dysphagia, or elevated CPK are present, obtain troponin T, ECG, and echocardiogram to rule out myocarditis 7, 3
• Perform pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory muscle involvement 7, 3

Bedside Clinical Tests

• Perform the ice pack test: apply ice over closed eyes for 2 minutes (for ptosis) or 5 minutes (for strabismus); improvement of ptosis by ≥2 mm or reduction in ocular deviation by ≥50% is highly specific for myasthenia gravis 1, 2, 3
• Consider the edrophonium (Tensilon) test if performed by experienced clinicians with atropine 0.4–0.5 mg IV available; sensitivity is 86% for ocular MG 1, 2

Treatment Algorithm Based on Disease Severity

Initial Symptomatic Management

• Start pyridostigmine 30 mg orally three times daily, gradually increasing to maximum 120 mg four times daily based on symptoms 7, 1, 2, 3
• Recognize that approximately 50% of patients—particularly those with ocular or MuSK-positive disease—show minimal response to pyridostigmine alone and require escalation 1, 2
• MuSK-positive patients are more likely to display poor tolerance or lack of improvement with anticholinesterase agents, so have a lower threshold for advancing to immunosuppressive therapy 4

Escalation for Moderate Disease (MGFA Class II-III)

• Add prednisone 0.5–1.5 mg/kg orally daily if symptoms persist despite pyridostigmine or if symptoms interfere with activities of daily living 7, 2, 3
• Corticosteroids demonstrate 66–85% positive response rates compared to pyridostigmine's 50% response rate 1, 2
• Taper prednisone gradually based on symptom improvement 7

Aggressive Therapy for Severe Disease (MGFA Class III-V)

• Initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/day) OR plasmapheresis for 3–5 days in addition to high-dose corticosteroids (prednisone 1–1.5 mg/kg/day) 7, 2, 3
• Admit to hospital with ICU-level monitoring capability for patients with dysphagia, respiratory symptoms, or rapidly progressive weakness 7, 3
• Obtain urgent neurology consultation 7, 3
• Perform daily neurologic evaluation and frequent pulmonary function assessment 7, 3

Third-Line Immunosuppression

• Consider azathioprine as steroid-sparing therapy for moderate to severe disease requiring long-term immunosuppression 1, 2

Thymectomy Considerations

• Evaluate for thymectomy even in seronegative patients if thymoma is present on chest CT, as thymoma is an absolute indication for surgical resection 2, 6, 5
• The need for thymectomy in seronegative MG is lower than in seropositive MG, and evidence for favorable response to thymectomy in seronegative (non-thymomatous) MG is limited 8, 4
• Do not delay thymectomy if thymoma is identified, as approximately 20% of thymoma-related mortality is due to myasthenia gravis 1

Critical Medication Avoidance

• Immediately review and discontinue medications that worsen myasthenia: β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics 1, 2, 3

Monitoring and Prognostic Counseling

• Counsel that 50–80% of patients with initial ocular symptoms progress to generalized myasthenia within a few years, most commonly within the first two years 1, 2, 3
• Maintain regular pulmonary function assessment, as dysphagia and bulbar weakness are present in more than 50% of cases that precede myasthenic crisis 1
• Seronegative MG patients generally have favorable outcomes with proper immunotherapy, though MuSK-positive patients tend to have a higher rate of crises and refractory disease 8, 4
• MuSK-positive patients have prominent cranial and bulbar involvement and tend to present earlier (third or fourth decade) 4

Key Pitfalls to Avoid

• Do not assume absence of thymoma based solely on negative AChR antibodies—case reports document malignant thymoma in seronegative MG 5
• Do not rely solely on limb muscle testing for electrodiagnostic studies in seronegative cases; include cranial muscles to increase yield 4
• Do not delay immunosuppressive therapy in MuSK-positive patients who fail pyridostigmine, as they are less likely to respond to anticholinesterase agents 4
• Do not overlook respiratory assessment—inability to count to 15 on a single breath or diminished cough strength mandates urgent ICU evaluation 1