What exams should be done for differential diagnosis in a patient with optic neuritis, bilateral demyelination on visual evoked potential, and a negative brain Magnetic Resonance Imaging (MRI)?

Diagnostic Workup for Optic Neuritis with Bilateral Demyelination and Negative Brain MRI

You should immediately order serum antibody testing for AQP4-IgG (aquaporin-4) and MOG-IgG (myelin oligodendrocyte glycoprotein), along with MRI of the complete spine with contrast, to differentiate between neuromyelitis optica spectrum disorder (NMOSD), MOG-antibody disease (MOGAD), and multiple sclerosis (MS). 1, 2

Priority Serological Testing

Antibody testing is critical in this clinical scenario:

• AQP4-IgG (aquaporin-4 antibodies) should be ordered immediately, as NMOSD frequently presents with bilateral optic neuritis and carries a particularly poor visual prognosis with only 30% maintaining visual acuity greater than 20/25 2, 3
• MOG-IgG antibodies are essential to test, as MOG-antibody disease is particularly suggested by bilateral simultaneous involvement and long optic nerve lesions 2, 4
• These antibody tests have potentially significant therapeutic consequences, as NMOSD and MOGAD require different treatment approaches than MS 1

Essential Imaging Studies

Spinal Cord MRI

MRI of the complete spine with and without IV contrast is your next critical imaging study 1:

• Helps differentiate between NMOSD, MOGAD, and MS by assessing disease burden in demyelinating disorders 1
• Longitudinally extensive transverse myelitis (LETM) - defined as lesions extending ≥3 vertebral segments - is characteristic of NMOSD, acute demyelinating encephalomyelitis, or MOG-antibody disease 1
• Contrast administration detects active demyelinating lesions, as enhancing lesions represent inflammatory infiltrates causing blood-brain barrier breakdown 1
• Enhancement is typically observable in the first 4-6 weeks of lesion formation 1

Orbital MRI Optimization

If not already performed, ensure dedicated orbital MRI with specific sequences 1, 4:

• Coronal fat-suppressed T2-weighted sequences are optimal for visualizing optic nerve lesions 2, 4
• T1-weighted post-contrast images with fat suppression identify abnormal optic nerve enhancement in 95% of optic neuritis cases 1
• Look specifically for long optic nerve lesions (>1/2 length of pre-chiasmal optic nerve) which suggest NMOSD or MOGAD 1, 4
• Perioptic gadolinium enhancement during acute optic neuritis is a red flag for MOG-antibody disease 1
• Posterior optic nerve involvement extending to the chiasm suggests AQP4-IgG-positive NMOSD 1, 4

Cerebrospinal Fluid Analysis

Lumbar puncture with CSF analysis helps differentiate between demyelinating disorders 2, 4:

• Absence of CSF-restricted oligoclonal bands (detected by isoelectric focusing) favors MOGAD over MS, particularly in European patients 1
• Presence of oligoclonal bands combined with brain MRI lesions dramatically reduces likelihood of monophasic illness and increases MS risk 4
• Neutrophilic CSF pleocytosis or white cell count >50/μL suggests MOGAD rather than MS 1
• CSF analysis may help differentiate between MS and NMOSD 2

Additional Serological Testing

Consider autoimmune and infectious workup based on clinical context:

• Systemic lupus erythematosus (SLE) screening including ANA, anti-dsDNA, as SLE can cause bilateral inflammatory optic neuritis with poor visual outcomes 2
• Infectious serologies if clinically indicated:
  • Measles (rubeola) serology in unvaccinated individuals 2
  • Epstein-Barr virus serology 2
  • Zika virus testing if epidemiologically relevant 2

Critical Red Flags in This Case

Your patient has several concerning features that elevate suspicion for NMOSD or MOGAD rather than typical MS 1, 2, 4:

• Bilateral demyelination on VEP - bilateral simultaneous involvement is a red flag for atypical optic neuritis 1, 4
• Negative brain MRI - normal supratentorial MRI in patients with acute optic neuritis suggests non-MS etiology 1
• Young male with no prior neurological symptoms presenting with unilateral vision loss but bilateral electrophysiological abnormalities

Prognostic Implications

The results of these tests have major therapeutic and prognostic implications:

• If AQP4-IgG positive (NMOSD): Expect more severe vision loss, poorer recovery, and need for aggressive immunosuppression to prevent devastating relapses 2, 3
• If MOG-IgG positive (MOGAD): Different treatment approach than MS, with 50-60% relapse rate during corticosteroid taper requiring maintenance therapy 1, 3
• If both antibodies negative with no brain lesions: 22% risk of MS at 10 years, suggesting possible monophasic illness 5
• If brain lesions develop on repeat MRI: Even one T2 hyperintense brain lesion is highly associated with eventual MS diagnosis 4, 5

Common Pitfalls to Avoid

• Do not assume MS based solely on optic neuritis - bilateral involvement and negative brain MRI should trigger broader differential 1, 2
• Do not delay antibody testing - therapeutic decisions depend on accurate diagnosis, and NMOSD/MOGAD require different management than MS 1
• Do not skip spinal MRI - it may reveal the only demyelinating lesions and is critical for diagnosis 1
• Ensure proper antibody assay selection - cell-based assays are preferred for MOG-IgG and AQP4-IgG testing over older ELISA methods 1