What is the next step in managing a 30-year-old female patient with left-sided ptosis that worsens with fatigue, minimal improvement on pyridostigmine (Mestinon) and steroids, and a negative single-fiber electromyography (EMG) result, with no other neurologic deficits?

Next Step: Serologic Testing for Myasthenia Gravis

Your next step is to obtain anti-acetylcholine receptor (AChR) antibodies and anti-muscle-specific kinase (MuSK) antibodies, as a negative single-fiber EMG does not exclude myasthenia gravis, and approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone, requiring antibody-guided escalation of immunosuppressive therapy. 1, 2

Why Serologic Testing is Critical Now

• Single-fiber EMG has >90% sensitivity but is not 100%, and your patient's clinical presentation (fatigable ptosis in a young woman) remains highly suspicious for myasthenia gravis despite the negative test 1, 2
• AChR antibodies are present in approximately 80% of generalized MG but only 50% of purely ocular myasthenia, making this test essential even with negative electrodiagnostics 2, 3
• Anti-MuSK antibodies must be tested when AChR antibodies are negative, as approximately one-third of seronegative patients will be MuSK-positive, and MuSK-positive patients often respond poorly to pyridostigmine and steroids, requiring different treatment strategies 2, 3
• Anti-striated muscle antibodies should also be included in the initial workup 1, 2

Additional Diagnostic Maneuvers to Perform Immediately

• Ice pack test: Apply ice pack over the closed left eye for 2 minutes and observe for reduction in ptosis—this is highly specific for myasthenia gravis, particularly for ocular symptoms 1, 2, 4
• Edrophonium (Tensilon) test has 95% sensitivity for generalized MG and 86% for ocular MG, but requires experienced practitioners with atropine available due to muscarinic side effects 2
• Repetitive nerve stimulation is less sensitive (positive in only one-third of ocular cases) but more widely available if not already performed 2

Essential Supplementary Workup After Diagnosis Confirmation

• CT chest with contrast to evaluate for thymoma, which occurs in 10-20% of AChR-positive patients 2
• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory muscle involvement, as 50-80% of patients with initial ocular symptoms develop generalized myasthenia within a few years 1, 2
• CPK, aldolase, ESR, and CRP to evaluate for concurrent myositis, which can coexist with myasthenia gravis and explain the poor response to standard therapy 1, 5, 6
• Troponin and ECG to rule out concomitant myocarditis 1, 2

Treatment Escalation Based on Antibody Results

If AChR-Positive:

• Increase prednisone to 1-1.5 mg/kg orally daily (you appear to be underdosing steroids currently), as 66-85% of patients respond positively to corticosteroids at this dose 1, 2
• Consider thymectomy evaluation, as it may substantially reduce symptoms in appropriate AChR-positive patients 2
• If refractory to conventional therapy, efgartigimod alfa-fcab is FDA-approved specifically for AChR-positive patients 2

If MuSK-Positive:

• MuSK-positive patients often respond poorly to pyridostigmine and steroids and may require earlier escalation to IVIG (2 g/kg IV over 5 days) or plasmapheresis 1, 2, 3
• Rituximab (B-cell depletion) shows particular efficacy in MuSK-positive disease 3

If Seronegative (Both AChR and MuSK Negative):

• Consider testing for anti-LRP4 antibodies, though <1% of patients have these 3
• Approximately 10% of patients are seronegative for all known antibodies, but clinical diagnosis with positive ice pack test or edrophonium test still warrants treatment 3

Critical Medication Review

Immediately review and stop any medications that worsen myasthenia, including β-blockers, IV magnesium, fluoroquinolones, aminoglycosides, and macrolide antibiotics 1, 2

Important Pitfalls to Avoid

• Do not assume treatment failure means wrong diagnosis—approximately 50% of ocular myasthenia patients show minimal response to pyridostigmine alone and require immunosuppressive escalation 1, 2
• Beware of cholinergic crisis from pyridostigmine overdosage, which paradoxically causes increasing muscle weakness and can be difficult to distinguish from myasthenic crisis 7
• Consider concurrent myositis if CK is elevated and muscle weakness persists despite treatment, as this requires muscle biopsy and different management 5, 6
• Thyroid eye disease can mimic myasthenia but shows proptosis, eyelid retraction, and mechanical restriction on forced duction testing rather than fatigable weakness 1