Diagnosis and Treatment of NMOSD
Diagnostic Approach
For patients with suspected NMOSD, immediately test for AQP4-IgG antibodies using cell-based assays in anyone presenting with longitudinally extensive transverse myelitis (≥3 vertebral segments), severe or bilateral optic neuritis, area postrema syndrome, brainstem encephalitis, or acute respiratory insufficiency with demyelinating features. 1, 2
When to Test for AQP4-IgG and MOG-IgG
- Test both antibodies in parallel if cost is not a limiting factor or if the disease is active, as this prevents diagnostic delay 1, 3
- Test AQP4-IgG first only when cost is a concern and disease is stable, since AQP4-IgG is more frequent in NMOSD than MOG-IgG 1
- Use only cell-based assays for both AQP4-IgG and MOG-IgG testing, as ELISA has poor specificity for MOG 3
- Do not wait for dissemination in space before testing, as many patients present with isolated syndromes that warrant immediate antibody testing 2
Key Clinical Presentations Requiring Testing
- Optic neuritis: Severe visual deficit/blindness, bilateral simultaneous presentation, posterior involvement extending to chiasm, lesions >50% optic nerve length, or prominent papilledema 4, 1, 2
- Myelitis: Longitudinally extensive lesions (≥3 vertebral segments), conus medullaris involvement, central cord involvement with swelling, or severe sphincter/erectile dysfunction 4, 1, 2
- Brainstem syndromes: Area postrema syndrome with intractable nausea/vomiting/hiccups, acute respiratory insufficiency, or disturbance of consciousness 4, 1
- ADEM-like presentations: Patients diagnosed with "ADEM," "recurrent ADEM," "multiphasic ADEM," or "ADEM-ON" 4
MRI Features Supporting NMOSD Diagnosis
Spinal cord findings:
- Longitudinally extensive lesions ≥3 contiguous vertebral segments (LETM) 1, 2, 3
- Longitudinally extensive spinal cord atrophy in patients with prior myelitis history 4
- Central cord involvement with associated swelling 2
- Conus medullaris lesions, especially at onset 4
Optic nerve findings:
- T2 hyperintensity with gadolinium enhancement extending >50% of optic nerve length or involving optic chiasm 4, 2
- Perioptic enhancement (optic nerve sheath involvement) 4, 1
Brain findings:
- Normal brain MRI in patients with acute optic neuritis, myelitis, or brainstem encephalitis supports NMOSD over MS 4
- Periependymal lesions, especially around brainstem and area postrema, are characteristic of NMOSD 1
- Absence of MS-typical features: No ovoid periventricular lesions adjacent to lateral ventricles, no Dawson's fingers, no juxtacortical U-fiber lesions 4, 1
CSF Analysis
- Neutrophilic pleocytosis or WCC >50/μl strongly suggests NMOSD or MOG-EM rather than MS 4, 3
- Absence of oligoclonal bands (OCB) is seen in 87-88% of MOG-EM patients and supports NMOSD over MS in continental European patients 4, 3
- However, positive OCB does NOT exclude MOG-EM or NMOSD 4
Diagnostic Criteria
For AQP4-IgG positive patients:
- Diagnosis requires at least one core clinical characteristic: optic neuritis, myelitis, area postrema syndrome, brainstem syndrome, diencephalic syndrome, or cerebral syndrome 2
For AQP4-IgG negative patients:
- Requires optic neuritis AND acute myelitis AND at least 2 of 3 supportive criteria: contiguous spinal cord lesion ≥3 vertebral segments, brain MRI nondiagnostic for MS, or consider MOG-IgG testing 2
Critical Diagnostic Pitfalls
- Up to 70% of NMOSD patients have brain MRI lesions at onset, which frequently leads to misdiagnosis as MS 1
- AQP4-IgG/MOG-IgG "double-positive" results are extremely rare and should prompt retesting using alternative methodologies 1
- Do not restrict testing to patients meeting AQP4-IgG-negative NMOSD criteria, as this delays diagnosis in patients with isolated LETM, isolated bilateral optic neuritis, or isolated brainstem encephalitis 4
- Approximately 25% of NMOSD patients are seronegative for AQP4-IgG, and some may have MOG antibodies requiring different management 2
Treatment of NMOSD
Acute Attack Management
Treat relapses aggressively with high-dose intravenous corticosteroids as first-line therapy to prevent residual disability, followed by plasma exchange for steroid-refractory cases 3, 5, 6
Long-Term Relapse Prevention
For AQP4-IgG positive NMOSD, initiate immunosuppression early with one of three FDA-approved monoclonal antibodies or off-label rituximab:
FDA-approved first-line options:
- Eculizumab (complement C5 inhibitor) - demonstrated significant relapse reduction in AQP4-IgG positive patients 7, 8
- Inebilizumab (anti-CD19+ B cell antibody) - effective in both AQP4-IgG positive and negative NMOSD 7, 8
- Satralizumab (IL-6 receptor inhibitor) - shown efficacy in AQP4-IgG seropositive and seronegative patients 7, 8
Off-label established therapy:
- Rituximab (B cell-depleting therapy) - increasingly regarded as established therapy with long-term efficacy and acceptable safety profile, recommended as first-line by expert consensus 1, 5, 7
Second-line immunosuppressive options:
- Azathioprine (suggested as first-line in some guidelines) 5
- Methotrexate, mycophenolate mofetil, or mitoxantrone for refractory cases 5
Treatment Rationale
- Relapse prevention is crucial because untreated, approximately 50% of NMOSD patients become wheelchair users and blind, with one-third dying within 5 years of first attack 6
- Disability accrues from relapses, not progressive disease, making aggressive relapse prevention the primary management objective 7, 6
- Some MS disease-modifying drugs may exacerbate NMOSD, making accurate diagnosis essential before initiating therapy 5, 9
MOG-IgG Positive Disease Considerations
- For MOG-IgG positive patients with severe or refractory disease, consider rituximab after prolonged oral prednisone taper over weeks to months 3
- Monitor for symptom recurrence after steroid tapering, as this is characteristic of MOG-EM 4, 3