In a patient with progressive painless bilateral visual acuity loss over several months, acute retrobulbar optic neuritis, a monoallelic TUBB3 mutation, and negative testing for the three common Leber hereditary optic neuropathy mitochondrial DNA variants, who experienced a brief visual improvement after an ocrelizumab infusion, what is the recommended diagnostic work‑up and management strategy?

Recommended Diagnostic Work-Up and Management Strategy

This patient requires immediate MRI orbits and brain without and with IV contrast to evaluate for antibody-mediated optic neuropathies (MOGAD, NMO), followed by comprehensive serum antibody testing (AQP4-IgG, MOG-IgG) and complete mitochondrial genome sequencing to definitively exclude all LHON variants. 1

Imaging Protocol

The 2025 ACR Appropriateness Criteria explicitly recommend MRI orbits without and with IV contrast as the initial imaging study for suspected optic nerve abnormalities 1. Given the bilateral retrobulbar involvement and progressive nature, this should be complemented with MRI brain and spine without and with IV contrast to detect demyelinating lesions and distinguish between MS, MOGAD, and NMO 1.

Key Imaging Features to Assess:

• Bilateral simultaneous optic nerve enhancement with longer segment involvement suggests MOGAD or NMO rather than MS 1
• Optic nerve sheath and perioptic enhancement is distinctive of MOGAD 1
• Posterior optic nerve, chiasm, or tract involvement trends toward NMO 1
• MS characteristically shows shorter segment unilateral involvement 1

Critical Diagnostic Testing

1. Antibody Panel (Priority)

The transient response to ocrelizumab strongly suggests an antibody-mediated inflammatory optic neuropathy rather than a hereditary condition:

• MOG-IgG antibodies (cell-based assay)
• AQP4-IgG antibodies (for NMO spectrum disorder)
• Consider additional autoimmune markers if initial testing negative

Rationale: Ocrelizumab is a B-cell depleting anti-CD20 monoclonal antibody approved for MS 2. The brief visual improvement following infusion has biological plausibility only if this represents an antibody-mediated inflammatory process where B-cell depletion temporarily reduced pathogenic antibody production.

2. Complete Mitochondrial Genome Sequencing

Testing only the three common LHON mutations (m.11778G>A, m.14484T>C, m.3460G>A) is insufficient. Over 40 pathogenic variants exist 3, 4, 5, 6. Recent cases demonstrate:

• Rare variants like m.3890G>A and m.13042G>A can cause LHON with atypical presentations 3, 5
• Heteroplasmic mutations with low mutant loads (even 23.8%) can cause disease, particularly in MT-ND5 gene variants 5
• LHON can present with MRI findings mimicking optic neuritis or perineuritis 4

3. TUBB3 Mutation Significance

The monoallelic TUBB3 mutation is a confounding factor. TUBB3 mutations typically cause congenital fibrosis syndromes and developmental eye movement disorders, not progressive adult-onset optic neuropathy. This finding is likely incidental and unrelated to the current presentation.

Management Algorithm

If Antibody Testing Positive (MOGAD/NMO):

1. Continue or restart ocrelizumab at standard dosing (600 mg IV every 6 months) 2
2. Consider acute treatment with IV methylprednisolone if active inflammation present
3. Long-term immunosuppression is indicated for antibody-mediated disorders

If Complete mtDNA Sequencing Confirms LHON:

1. Idebenone 900 mg daily (300 mg three times daily) - the only treatment with evidence for visual recovery 3, 6, 7
2. Counsel regarding prognosis: Some rare variants show favorable outcomes with treatment 3, 5, 6
3. Avoid mitochondrial toxins (tobacco, excessive alcohol)
4. Genetic counseling for maternal relatives

If All Testing Negative:

Consider:

• Chronic relapsing inflammatory optic neuropathy (steroid-dependent)
• Idiopathic bilateral optic neuropathy
• Trial of immunosuppression may be warranted given ocrelizumab response

Critical Pitfalls to Avoid

Do not dismiss LHON based solely on negative testing of the three common mutations - complete genome sequencing is essential 3, 4, 5. Recent literature demonstrates LHON can present with:

• MRI enhancement mimicking inflammatory optic neuritis 4
• Atypical age of onset (even 76 years old) 8
• Initial unilateral presentation 9
• Low heteroplasmy levels in blood 5

Do not assume the ocrelizumab response excludes hereditary causes - however, a genuine therapeutic response strongly favors an inflammatory/antibody-mediated etiology over mitochondrial disease, as LHON has no immunological treatment mechanism.

The progressive painless bilateral pattern over months is atypical for MS (which usually shows acute unilateral involvement) but consistent with both LHON and antibody-mediated optic neuropathies 1, 9, 4.

The temporal response to ocrelizumab is the most diagnostically significant feature and should drive investigation toward antibody-mediated inflammatory causes as the primary differential, with complete mitochondrial sequencing as a parallel essential investigation.