What are the differential diagnoses and treatment options for a young to middle-aged adult presenting with optic neuritis, considering their medical history and potential underlying conditions such as multiple sclerosis?

Differential Diagnoses of Optic Neuritis

The differential diagnosis of optic neuritis must immediately distinguish between typical MS-associated disease and atypical forms—particularly neuromyelitis optica spectrum disorder (NMOSD) and MOG-antibody disease (MOGAD)—because these require fundamentally different treatment approaches and have dramatically different prognoses. 1, 2

Primary Demyelinating Disorders

Multiple Sclerosis (MS)

• MS is the most common cause of demyelinating optic neuritis, though bilateral presentation is less common than unilateral involvement 1
• Even a single clinically silent T2 hyperintense brain lesion on MRI dramatically increases MS risk, with hazard ratios of 5.1 for 1-3 lesions and 11.3 for ≥10 lesions 2, 3
• CSF oligoclonal bands combined with brain MRI lesions dramatically reduce the likelihood of monophasic illness 2, 3
• Nearly 50% of MS patients will develop optic neuritis, and in 15-20% of cases, ON is the initial manifestation 4

Neuromyelitis Optica Spectrum Disorder (NMOSD)

• NMOSD frequently presents with bilateral optic neuritis and is characterized by AQP4 antibodies 1
• Expect more severe vision loss and poorer recovery than MS-related optic neuritis—only 30% maintain visual acuity >20/25 1, 3
• Red flags include posterior optic nerve involvement extending to the chiasm, simultaneous bilateral involvement, and long optic nerve lesions 1, 3
• Requires aggressive immunosuppression to prevent devastating relapses 1

MOG-Antibody Disease (MOGAD)

• Long optic nerve lesions and bilateral simultaneous involvement particularly suggest anti-MOG-IgG disease 1, 3
• Soft tissue enhancement extrinsic to the nerve, affecting the orbit, orbital apex, or cavernous sinus signifies MOGAD rather than MS 1
• 50-60% relapse rate during corticosteroid taper, necessitating maintenance immunosuppressive therapy 1, 3

Acute Disseminated Encephalomyelitis (ADEM)

• ADEM diagnosis should not be made unless new symptoms or imaging abnormalities appear more than three months after clinical onset 2
• Longitudinally extensive transverse myelitis (LETM) is characteristic of ADEM, NMOSD, or MOGAD 1

Autoimmune and Inflammatory Conditions

Systemic Lupus Erythematosus (SLE)

• SLE can cause inflammatory optic neuritis with poor visual outcomes—only 30% maintain visual acuity >20/25 2, 3
• May present bilaterally 1, 3
• Treatment delay beyond 2 weeks is an unfavorable prognostic factor in SLE-related cases 2, 3

Rare Autoimmune Optic Neuropathies

• Glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein 5 (CRMP5) autoimmunity should be considered in bilateral painless optic neuropathy with optic disc edema 5

Infectious Etiologies

Viral Causes

• Measles (rubeola) can cause bilateral optic neuritis, particularly in unvaccinated individuals 1
• Epstein-Barr virus has been associated with optic neuritis 1
• Zika virus has been reported to cause bilateral non-purulent conjunctivitis and optic neuritis 1

Bacterial and Spirochetal Infections

• Lyme disease can present striking similarities to MS and must be excluded 2
• Meningovascular syphilis should be considered based on exposure history 2

Other Infectious Causes

• HTLV1 can mimic MS and must be excluded 2

Vascular Causes

• Multifocal cerebral ischemia or infarction in young adults can mimic MS, particularly from phospholipid antibody syndrome, acute disseminated lupus erythematosus, CADASIL, Takayasu's disease, or carotid dissection 2
• Anterior ischemic optic neuropathy (AION) can be initially misdiagnosed as optic neuritis 6

Granulomatous Diseases

• Perioptic nerve sheath enhancement is recognized in typical optic neuritis, but soft tissue enhancement extrinsic to the nerve indicates non-MS etiology such as granulomatous disease, tumor, or infection 1

Hereditary Optic Neuropathies

• Leber's hereditary optic neuropathy does not show acute T2-hyperintense lesions on MRI, distinguishing it from inflammatory optic neuritis 1

Critical Red Flags Mandating Immediate Antibody Testing

Immediate serum testing for AQP4-IgG and MOG-IgG is mandatory when any of the following atypical features are present: 1, 2, 3

• Bilateral simultaneous involvement 1, 3
• Severe vision loss with poor recovery after steroids or steroid dependence 1, 5
• Prominent optic disc edema 1, 5
• Posterior optic nerve involvement extending to chiasm 1, 3
• Long optic nerve lesions on MRI 1, 3
• Soft tissue enhancement extrinsic to the nerve 1
• Bilateral demyelination on VEP 1
• Negative brain MRI in acute optic neuritis 1
• Childhood or late adult onset 5

Diagnostic Algorithm

Primary Imaging

• MRI of orbits and brain with and without IV contrast is the primary diagnostic study and must be obtained urgently 1, 2, 3
• T1-weighted post-contrast images with fat suppression identify abnormal optic nerve enhancement in 95% of cases 1, 3
• Coronal fat-suppressed T2-weighted sequences are optimal for visualizing optic nerve lesions 1, 3

Antibody Testing

• Cell-based assays using full-length human MOG are the gold standard for MOG-IgG testing 1
• Testing should employ Fc-specific or IgG1-specific secondary antibodies to avoid cross-reactivity 1

Spinal Imaging

• MRI complete spine with and without IV contrast to assess for LETM, which is characteristic of NMOSD, MOGAD, or ADEM 1
• Contrast enhancement detects active demyelinating lesions in the first 4-6 weeks of formation 1

CSF Analysis

• Lumbar puncture with CSF analysis when MS risk stratification is needed 2
• Absence of CSF-restricted oligoclonal bands favors MOGAD over MS 1
• Neutrophilic CSF pleocytosis or white cell count >50/μL suggests MOGAD rather than MS 1

Additional Workup Based on Clinical Context

• Infectious workup including Lyme serology, HTLV1, syphilis testing based on exposure history 2
• Autoimmune panel including ANA, anti-dsDNA for SLE consideration 2
• Visual evoked potentials (VEPs) confirm optic nerve dysfunction with slowed conduction 3
• Optical coherence tomography (OCT) documents both acute changes and chronic sequelae 3

Treatment Approach

Typical Optic Neuritis (MS-Associated)

• Intravenous methylprednisolone is the first-line treatment, accelerating recovery and reducing the risk of MS conversion 7, 6, 4, 8
• Oral prednisolone alone is contraindicated due to increased risk of a second episode 6
• Treatment delay beyond 2 weeks is an unfavorable prognostic factor 1, 2, 3

Atypical Optic Neuritis

• NMOSD requires plasma exchange for acute attacks and long-term immunosuppression (commonly rituximab) to prevent devastating relapses 1, 5
• MOGAD requires maintenance therapy due to 50-60% relapse rate during steroid taper 1, 3

Disease-Modifying Therapy

• Interferon β-1a,b reduces risk of MS conversion and should be considered at initial presentation in patients with brain MRI demyelinating lesions 6, 4

Common Pitfalls

• Never assume typical MS-associated optic neuritis without checking for red flags—missing NMOSD or MOGAD leads to inappropriate treatment and devastating outcomes 1, 5
• Do not use oral prednisolone alone, as it increases recurrence risk 6
• Do not delay antibody testing in atypical presentations—therapeutic consequences are significant 1, 2
• CT has limited role in optic neuritis evaluation; MRI is essential 3