What is the initial workup and management for a patient presenting with total ophthalmoplegia and severe ptosis?

Total Ophthalmoplegia with Severe Ptosis: Initial Workup

Urgent neuroimaging with MRI brain with and without gadolinium plus MRA or CTA is mandatory to rule out life-threatening compressive lesions, particularly posterior communicating artery aneurysm, followed by targeted evaluation for myasthenia gravis if imaging is negative. 1

Immediate Diagnostic Priorities

Neuroimaging (First-Line)

MRI brain with and without contrast including high-resolution T2-weighted sequences of cranial nerves III-VI is the preferred initial imaging modality. 1

• Add MRA or CTA to evaluate for aneurysm, particularly involving the posterior communicating artery, which is the most urgent consideration in complete ophthalmoplegia 1
• If high suspicion for aneurysm persists despite normal MRA/CTA, proceed to catheter angiography 1
• Include dedicated imaging of the cavernous sinus and orbital apex, as multiple ipsilateral cranial nerve palsies (III, IV, VI) suggest lesions at these locations 1

Critical Anatomic Localizations to Assess

The imaging must evaluate for bilateral paramedian midbrain-thalamic lesions, which can cause complete ophthalmoplegia through combined third nerve, pseudoabducens, and vertical gaze palsies. 2

• Midbrain hemorrhage affecting the oculomotor complex, medial longitudinal fasciculus, and rostral parapontine reticular formation can produce this presentation 3
• Basilar subarachnoid space pathology from infectious meningitis (TB, fungal, Lyme) or noninfectious causes (sarcoid, neoplasm, leptomeningeal spread) 1
• Cavernous sinus or orbital apex lesions including meningioma, schwannoma, or metastatic disease 1, 4

If Neuroimaging is Normal: Myasthenia Gravis Evaluation

Bedside Clinical Tests

Perform the ice pack test: apply ice over closed eyes for 5 minutes for strabismus assessment, which is highly specific for myasthenia gravis and may demonstrate reduction of ophthalmoplegia. 1, 5, 6

• Variable strabismus and ptosis that worsen with fatigue and improve with rest are pathognomonic for myasthenia 1, 5
• Look for Cogan lid-twitch sign and slow saccades 1
• Rest test without ice pack can also aid diagnosis 1

Serologic Testing

Acetylcholine receptor antibody testing is the gold standard with 80-88% sensitivity for generalized myasthenia and 98-100% specificity. 5

• If acetylcholine receptor antibodies are negative, test for anti-MuSK antibodies (found in one-third of seronegative patients) 5
• Single-fiber EMG has >90% sensitivity even in seronegative cases, though technically demanding 5
• Repetitive nerve stimulation is less sensitive (positive in only one-third of ocular myasthenia cases) 5

Associated Workup for Myasthenia

Obtain chest CT to screen for thymoma, as 10-15% of myasthenia patients have thymoma, and assess for respiratory involvement to detect myasthenic crisis. 5

• Thyroid function and associated immune studies should be ordered, as there is increased risk with autoimmune thyroid disease 1

If Both Imaging and Myasthenia Testing are Negative

Infectious and Inflammatory Workup

Proceed with serologic testing for syphilis and Lyme disease, with strong consideration for lumbar puncture including glucose, protein, cell count, cytology, and culture. 1

• Consider viral etiologies including COVID-19, Epstein-Barr virus, and other viral illnesses 1, 7
• Evaluate for demyelinating disease (multiple sclerosis in younger patients) 1

Additional Considerations

Assess for chronic progressive external ophthalmoplegia (CPEO), a rare mitochondrial disorder, particularly if ptosis preceded ophthalmoplegia. 8

• This requires muscle biopsy and genetic analysis of mitochondrial DNA for definitive diagnosis 8
• CPEO presents with progressive symptoms rather than acute onset, helping distinguish it from vascular or compressive etiologies 8

Critical Clinical Pitfalls

Do not assume pupil-sparing indicates benign microvascular disease when ophthalmoplegia is complete or bilateral—compressive lesions can present this way and require urgent imaging. 1

• Complete ophthalmoplegia is rarely vasculopathic and demands comprehensive evaluation 2
• Improvement with steroids does not exclude structural lesions like meningioma—MRI remains essential even with apparent steroid response 4
• In myasthenia, the examination may appear entirely normal at certain times due to variable control, requiring repeated assessments 6
• Assess respiratory function immediately in suspected myasthenia, as myasthenic crisis is life-threatening 5