What is the next step in evaluating a patient with ocular‑only ptosis suspected of myasthenia gravis who has a negative single‑fiber electromyography and negative anti‑acetylcholine‑receptor antibodies?

Next Diagnostic Step: Anti-MuSK Antibody Testing

With negative single-fiber EMG and negative anti-acetylcholine receptor antibodies in a patient with suspected ocular myasthenia gravis, you should immediately order anti-muscle-specific kinase (anti-MuSK) antibodies, as approximately one-third of seronegative patients will be MuSK-positive. 1, 2

Rationale for Anti-MuSK Testing

• Anti-MuSK antibodies must be tested when AChR antibodies are negative, as this represents the next most important diagnostic step in the serological workup 3
• The pooled analysis shows 5% positivity for anti-MuSK in ocular myasthenia gravis patients, making this a clinically meaningful subset to identify 4
• A stepwise approach is recommended where anti-MuSK is ordered only if the initial anti-AChR returns negative, given the relatively low prevalence and higher cost of anti-MuSK testing 4

Additional Serological Testing to Consider

• Anti-lipoprotein-related protein 4 (LRP4) antibodies should also be considered, as LRP4 has been associated with both generalized and ocular myasthenia gravis 1
• Anti-striated muscle antibodies should be included in the workup if not already performed 2, 3

Critical Diagnostic Considerations

• The negative single-fiber EMG is unusual and concerning, as SFEMG has >90% sensitivity for ocular myasthenia and is considered the gold standard 1, 2, 3
• This raises the possibility of either:
  • Technical issues with the SFEMG (operator-dependent test requiring specialized equipment and expertise) 2
  • Alternative diagnosis requiring reconsideration
  • True seronegative myasthenia gravis

Clinical Testing to Perform Now

• Ice pack test should be performed if not already done—apply ice pack over closed eyes for 2 minutes for ptosis or 5 minutes for strabismus, looking for reduction of ptosis by approximately 2mm or reduction of misalignment 1, 2, 3
• This test is highly specific for myasthenia gravis and can provide immediate diagnostic support 1, 2
• Rest test without ice pack can also aid in diagnosis 1

Edrophonium (Tensilon) Test Consideration

• Edrophonium testing may be considered but requires experienced practitioners with proper intravenous administration capability 1
• The test has 86% sensitivity for ocular myasthenia 1
• Must be performed in a monitored setting with atropine available (0.4-0.5 mg IV) for potential muscarinic side effects including excess tearing, salivation, sweating, abdominal cramping, bradycardia, bronchospasm, hypotension, and syncope 1, 5
• Dosing: Prepare 1 mL (10 mg) in tuberculin syringe, inject 0.2 mL (2 mg) IV over 15-30 seconds, wait 45 seconds, then inject remaining 0.8 mL (8 mg) if no reaction occurs 5

Imaging and Supplementary Workup

• CT chest with contrast must be ordered after diagnosis confirmation to evaluate for thymoma, which occurs in 10-20% of AChR-positive patients 3
• Even with negative AChR antibodies, chest imaging is warranted given the clinical suspicion 3
• Brain imaging may help exclude brainstem lesions that can mimic myasthenia gravis 2

Empiric Treatment Consideration

• If clinical suspicion remains high despite negative testing, empiric trial of pyridostigmine starting at 30 mg orally three times daily can be both diagnostic and therapeutic 2, 3
• Response to treatment can confirm the diagnosis in seronegative patients who are clinically likely to have ocular myasthenia gravis 6
• Approximately 50% of patients with ocular myasthenia show minimal response to pyridostigmine alone, which does not rule out the diagnosis 1, 2

Important Caveats

• Approximately 50% of patients with purely ocular myasthenia are seronegative for AChR antibodies, so negative antibodies do not exclude the diagnosis 1, 7
• The combination of negative SFEMG and negative AChR antibodies is atypical and warrants careful reconsideration of the differential diagnosis 1, 2
• Consider alternative diagnoses including third nerve palsy (check for pupillary involvement), thyroid eye disease (check for proptosis, lid retraction, forced duction testing), chronic progressive external ophthalmoplegia, and orbital pathology 2

Monitoring Strategy

• Regular assessment is crucial as 50-80% of patients with initial ocular symptoms develop generalized myasthenia within a few years, typically within the first 2 years 2, 3, 8
• Pulmonary function testing with negative inspiratory force (NIF) and vital capacity (VC) should be performed to assess for subclinical respiratory muscle involvement 3