What is Neuromyelitis Optica Spectrum Disorder (NMOSD)?

What is Neuromyelitis Optica Spectrum Disorder (NMOSD)?

NMOSD is a rare autoimmune inflammatory disease of the central nervous system that primarily attacks the optic nerves, spinal cord, and brainstem, characterized by severe demyelination and axonal damage that leads to blindness, paralysis, and potentially death if untreated. 1, 2, 3

Core Pathophysiology

• NMOSD is caused by autoantibodies targeting aquaporin-4 (AQP4), the most prevalent water channel protein in the CNS, which is expressed on astrocytes 3, 4
• Approximately 75% of patients have detectable AQP4-IgG antibodies, making this the most specific diagnostic marker 1, 5
• The remaining 25% are seronegative, though some may have anti-MOG antibodies representing a distinct disease entity 2, 6

Classic Clinical Presentations

The hallmark clinical syndromes that should immediately trigger NMOSD evaluation include: 1, 2

• Severe optic neuritis - often bilateral and simultaneous, with posterior optic nerve involvement extending to the chiasm, causing significant visual deficit or blindness 1, 2
• Longitudinally extensive transverse myelitis (LETM) - spinal cord inflammation spanning ≥3 contiguous vertebral segments, causing limb weakness and bladder dysfunction 1, 2, 4
• Area postrema syndrome - intractable nausea, vomiting, or hiccups due to brainstem involvement 1
• Brainstem encephalitis with radiological signs of demyelination 1
• Acute respiratory insufficiency with demyelinating lesions 1

Diagnostic Criteria

For AQP4-IgG positive patients, diagnosis requires only one core clinical characteristic (optic neuritis, myelitis, area postrema syndrome, brainstem syndrome, diencephalic syndrome, or cerebral syndrome). 2

For AQP4-IgG negative patients, definite NMOSD requires optic neuritis AND acute myelitis AND at least 2 of 3 supportive criteria: 2

• Contiguous spinal cord MRI lesion extending ≥3 vertebral segments
• Brain MRI at onset nondiagnostic for MS
• NMO-IgG (aquaporin-4 antibody) seropositivity

Key Imaging Features

Spinal cord lesions: 2

• Longitudinally extensive (≥3 segments), distinguishing from MS which typically shows short lesions (<2 segments)
• Central cord involvement with associated swelling
• Contrast enhancement during acute attacks

Optic nerve lesions: 2

• T2 hyperintensity with gadolinium enhancement extending over >50% of optic nerve length or involving the optic chiasm
• Perioptic enhancement (optic nerve sheath involvement) occurs in NMOSD but not typically in MS 1

Brain MRI: 1, 2

• Often normal or shows only nonspecific white matter lesions initially
• When present, lesions tend to be periependymal (especially around brainstem and area postrema) rather than periventricular
• Up to 70% of NMOSD patients have brain MRI lesions at onset, which can lead to misdiagnosis as MS 1

Prognosis Without Treatment

Untreated NMOSD has a devastating natural history: 5

• Approximately 50% of patients will be wheelchair users and blind within 5 years
• One-third will have died within 5 years of their first attack
• Disability accrues through relapses, not progressive disease (unlike MS) 5

Critical Diagnostic Pitfalls to Avoid

• Do not delay diagnosis waiting for dissemination in space - many NMOSD patients present with isolated syndromes that warrant immediate antibody testing 2
• Do not assume all NMOSD is AQP4-positive - approximately 25% are seronegative, and some may have anti-MOG antibodies requiring different management 2
• Do not misdiagnose as MS - up to 70% of NMOSD patients have brain lesions at onset that can be confused with MS 1
• When both AQP4-IgG and MOG-IgG are positive, retest using alternative methodologies - true double-positive results are extremely rare 1

Treatment Implications

Acute relapse treatment requires immediate high-dose intravenous methylprednisolone (1 gram daily for 3-5 consecutive days), often followed by plasma exchange for severe or refractory cases. 6, 4

Long-term immunosuppression is mandatory for all NMOSD patients to prevent relapses: 1, 3, 4

• B-cell depleting therapies (rituximab, ocrelizumab, ofatumumab) are highly effective for AQP4-positive patients 1
• Anti-IL-6 receptor monoclonal antibodies represent breakthrough therapy with impressive efficacy 3, 7
• Complement-inhibiting monoclonal antibodies are also highly effective 1
• Traditional immunosuppressants (azathioprine, mycophenolate, methotrexate) are alternatives 4

MS-approved drugs may be ineffective or cause harm in AQP4-positive NMOSD and should be avoided. 1