What is the recommended workup and treatment for a patient with recurrent optic neuritis, possibly associated with multiple sclerosis or other demyelinating diseases?

Workup for Recurrent Optic Neuritis

In patients with recurrent optic neuritis, immediately test for MOG-IgG and AQP4-IgG antibodies using cell-based assays, as distinguishing between MS-associated ON, MOG-antibody disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) is critical because these conditions have fundamentally different treatments and prognoses. 1

Essential Serologic Testing

• Test MOG-IgG antibodies in all patients with recurrent optic neuritis, particularly when there is unusually high ON frequency or disease mainly characterized by recurrent ON 1
• Test AQP4-IgG antibodies to identify NMOSD, especially in patients with severe visual deficits, bilateral involvement, or poor steroid response 1, 2, 3
• Use cell-based assays with full-length human MOG protein as the gold standard methodology, not ELISA-based tests which have poor specificity 1, 4
• If costs are a concern and disease is stable, test AQP4-IgG first since it is more frequent in NMOSD than MOG-EM 1

Critical MRI Imaging Protocol

• Obtain MRI of brain and orbits with gadolinium contrast to assess for specific patterns that distinguish between etiologies 5, 6
• Look for longitudinally extensive optic nerve lesions (>1/2 length of pre-chiasmal optic nerve on T2 or T1/Gd), which suggests MOG-EM or NMOSD 1
• Assess for perioptic gadolinium enhancement during acute ON, which is characteristic of MOG-EM 1
• Evaluate brain MRI for MS-typical lesions (periventricular ovoid lesions, Dawson's fingers, juxtacortical U-fiber lesions) versus normal or atypical patterns suggesting MOG-EM 1
• Repeat MRI at 3-6 months to assess for new demyelinating lesions indicating MS 5

Cerebrospinal Fluid Analysis

• Perform lumbar puncture to assess for CSF-restricted oligoclonal bands (OCB) detected by isoelectric focusing 1
• Absence of CSF OCB strongly suggests MOG-EM or NMOSD rather than MS (applies particularly to continental European patients) 1
• Check for neutrophilic CSF pleocytosis or WCC >50/μl, which suggests MOG-EM 1
• Document cell count, protein, and glucose to exclude infectious or inflammatory mimics 3, 7

Ophthalmologic Assessment

• Document fundoscopy findings looking for prominent papilledema/papillitis/optic disc swelling, which is characteristic of MOG-EM 1
• Assess for bilateral simultaneous acute ON, which suggests MOG-EM or NMOSD 1
• Evaluate severity: particularly severe visual deficit or blindness in one or both eyes suggests MOG-EM or NMOSD 1
• Perform visual evoked potentials (VEP) to objectively assess optic nerve function and detect subclinical bilateral involvement 5
• Monitor visual acuity, visual fields, funduscopy, and contrast sensitivity every 4-6 weeks 5

Additional Autoimmune Screening

• Test for anti-SSA and anti-SSB antibodies to identify Sjögren syndrome, which commonly coexists with NMOSD 2
• Consider testing for GFAP and CRMP5 antibodies in patients with bilateral painless optic neuropathy with optic disc edema and other neurologic symptoms 3
• Screen for systemic autoimmune diseases if clinical features suggest (ANA, complement levels, inflammatory markers) 3, 7

Clinical Features Requiring Specific Antibody Testing

MOG-IgG testing is specifically indicated when: 1

• Recurrent ON with unusually high frequency
• Steroid-dependent symptoms or frequent flare-ups after IV methylprednisolone (including CRION pattern)
• Clear increase in relapse rate following treatment with interferon-beta or natalizumab
• Bilateral simultaneous acute ON
• Particularly severe visual deficit or blindness

AQP4-IgG testing is specifically indicated when: 1, 2, 3

• Longitudinally extensive transverse myelitis (≥3 vertebral segments)
• Area postrema syndrome (intractable nausea/vomiting or hiccups)
• Severe ON with poor recovery despite steroids
• Female predominance with rapid succession of severe ON events 8

Prognostic Stratification

• Conversion risk to MS: 14.4% at 5 years in recurrent ON patients; higher with 2+ brain lesions on MRI (40% conversion rate) 8
• Conversion risk to NMOSD: 12.5% at 5 years; occurs earlier than MS conversion (2.3 vs 5.3 years); higher in women (7:1 ratio) and those with higher annual ON frequency 8
• Visual prognosis: Worst in NMOSD and CRION patients; MOG-EM patients have intermediate outcomes; MS-associated ON typically recovers well 9, 8, 3
• Patients with >2 ON events in first 2 years are at higher risk for NMOSD conversion 8

Critical Pitfalls to Avoid

• Never use interferon-beta or natalizumab in MOG-positive disease, as these MS therapies worsen MOG-EM and increase relapse rates 1, 4, 10
• Do not use oral prednisone alone as initial treatment, as this increases risk of recurrence per the Optic Neuritis Treatment Trial 7
• Do not rely on ELISA-based MOG antibody tests, which have poor specificity and lead to false positives 1
• Avoid rapid steroid cessation in MOG-EM patients, as 50-60% relapse during dose reduction; use prolonged tapers over weeks to months 4
• Retest MOG-IgG at 6-12 months after initial attack, as antibody disappearance may indicate monophasic disease and allow discontinuation of maintenance therapy 4

Treatment Implications Based on Etiology

For MS-associated recurrent ON: 5, 6

• Acute treatment: IV methylprednisolone 1000 mg/day for 3 days, followed by oral prednisone 1 mg/kg/day for 11 days with 4-day taper
• Consider disease-modifying therapy (interferon-beta, glatiramer acetate, or newer agents) to prevent future relapses

For MOG-EM: 4

• Acute treatment: IV methylprednisolone 1000 mg/day for 3-5 days
• Prolonged oral steroid taper over weeks to months (not rapid cessation)
• Maintenance therapy with rituximab, IVIG, or oral immunosuppressants for relapsing disease
• Avoid interferon-beta and natalizumab

For NMOSD: 5, 4, 2

• Acute treatment: IV methylprednisolone 1000 mg/day for 3-5 days
• Lower threshold for plasma exchange (5-7 exchanges) if no improvement after 3-5 days
• Long-term immunosuppression with rituximab, azathioprine, or mycophenolate required to prevent relapses