Neuromyelitis Optica¶
Chapter 456 | Part 13: Neurologic Disorders
KEY CLINICAL POINTS¶
- NMO is an autoimmune disorder characterized by AQP4 antibody-mediated inflammation and astrocytopathy, distinct from MS.
- Diagnostic criteria for NMOSD include AQP4-IgG positivity, MRI findings, and clinical features like optic neuritis, myelitis, and brainstem syndromes.
- Treatment for acute attacks includes high-dose corticosteroids and plasma exchange, while prophylaxis uses monoclonal antibodies (eculizumab, satralizumab, inebilizumab).
- NMO has a high relapse risk without treatment, with 5-year survival rates improving to 91–98% with modern therapies.
- AQP4-seronegative NMOSD may present with similar features but requires alternative diagnostic criteria and treatment approaches.
1. DEFINITION & OVERVIEW¶
Neuromyelitis optica (NMO) is an aggressive, antibody-mediated inflammatory disorder characterized by recurrent attacks of optic neuritis (ON) and myelitis. The more inclusive term 'NMO spectrum disorder (NMOSD)' encompasses individuals with partial forms or involvement of additional CNS structures. NMO is distinct from multiple sclerosis (MS) due to its pathophysiology involving AQP4 antibodies and astrocyte damage.
Table 456-1: Diagnostic Criteria for NMOSD¶
| Criteria | Details |
|---|---|
| AQP4-IgG Positive | At least one core clinical characteristic (ON, LETM, area postrema syndrome) + positive AQP4-IgG test (cell-based assay) |
| AQP4-IgG Negative | At least two core clinical characteristics + dissemination in space + MRI requirements (e.g., LETM, optic neuritis) |
| MRI Requirements | Acute optic neuritis: T2-hyperintense optic nerve lesion >1/2 length; acute myelitis: ‡3 contiguous spinal segments |
| Exclusion | Rule out MS and other autoimmune disorders |
1.1 Pathophysiology¶
NMO is an autoimmune disease with pathogenic anti-AQP4 antibodies targeting astrocytic water channels. This leads to inflammation, astrocyte loss, complement-mediated injury, and demyelination. AQP4 antibodies trigger complement fixation and antibody-dependent cell-mediated cytotoxicity (ADCC), contributing to tissue damage.
1.2 Clinical Features¶
Key features include bilateral optic neuritis with severe vision loss, longitudinally extensive transverse myelitis (LETM), brainstem syndromes (e.g., area postrema syndrome), and diencephalic lesions. MRI shows T2-hyperintense spinal cord lesions spanning ≥ 3 segments and optic nerve enhancement.
2. EPIDEMIOLOGY¶
NMO is more common in women (9:1 male ratio) with a mean age of onset at 40 years. Prevalence varies globally (0.1–4.0 per 100,000), with higher rates in Asian and African populations (e.g., Martinique). MS is more common than NMO in white populations.
2.1 Risk Factors¶
Genetic predisposition, viral infections (e.g., HSV, EBV), and paraneoplastic associations (breast, lung cancers) may contribute. AQP4-seronegative NMOSD has lower relapse risk ( ≈ 50% single attack).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
NMO is driven by pathogenic anti-AQP4 antibodies targeting astrocytic water channels. These antibodies trigger complement-mediated astrocyte injury, leading to inflammation, demyelination, and tissue destruction. T17 cells and B-cell dysregulation also contribute to pathogenesis.
3.1 Molecular Mechanisms¶
Anti-AQP4 antibodies bind to astrocytic foot processes and paranodal regions. Complement activation (C5b-9) and ADCC mediate astrocyte death. Proinflammatory cytokines (IL-6) and glial fibrillary acidic protein (GFAP) are elevated during attacks.
4. CLINICAL FEATURES¶
NMO presents with optic neuritis (bilateral, severe vision loss), LETM, brainstem syndromes (hiccups, vomiting, sleep disorders), and diencephalic lesions. MRI shows T2-hyperintense spinal cord lesions >3 segments and optic nerve enhancement. CSF findings include pleocytosis, neutrophils, and elevated GFAP.
4.1 Complications¶
Respiratory failure from cervical myelitis, permanent paralysis, and blindness. AQP4-seronegative cases may have milder, monophasic courses.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate from MS (more demyelinating, less astrocytic involvement), MOGAD (papillitis, unilateral ON), and other autoimmune disorders. AQP4-seronegative NMOSD may mimic MS but lacks AQP4 antibodies.
5.1 Key Differentiators¶
Bilateral ON, LETM, and brainstem lesions in NMO vs. MS (unilateral ON, shorter spinal lesions). MOGAD presents with papillitis and rapid response to steroids.
6. INVESTIGATIONS & DIAGNOSIS¶
MRI shows T2-hyperintense spinal cord lesions >3 segments, optic nerve enhancement, and brainstem lesions. CSF findings include pleocytosis, neutrophils, and elevated GFAP. AQP4-IgG testing (cell-based assay) is diagnostic in 90% of cases.
Table 456-1: Diagnostic Criteria for NMOSD¶
| Criteria | Details |
|---|---|
| AQP4-IgG Positive | At least one core clinical characteristic (ON, LETM, area postrema syndrome) + positive AQP4-I, IgG test (cell-based assay) |
| AQP4-IgG Negative | At least two core clinical characteristics + dissemination in space + MRI requirements (e.g., LETM, optic neuritis) |
| MRI Requirements | Acute optic neuritis: T2-hyperintense optic nerve lesion >1/2 length; acute myelitis: ‡3 contiguous spinal segments |
| Exclusion | Rule out MS and other autoimmune disorders |
6.1 Diagnostic Algorithms¶
- Confirm AQP4-IgG positivity (cell-based assay). 2. MRI for LETM, optic neuritis, or brainstem lesions. 3. Exclude MS and other autoimmune disorders. 4. Use MRI criteria for AQP4-seronegative cases (e.g., optic neuritis with LETM).
7. MANAGEMENT & TREATMENT¶
Acute attacks are treated with high-dose corticosteroids (methylprednisolone 1 g/d for 5–10 days) and plasma exchange for nonresponders. Prophylaxis uses monoclonal antibodies: eculizumab (complement inhibitor), satralizumab (IL-6 receptor blocker), and inebilizumab (B-cell depleter).
Table 456-2: Attack Risk Reductions of Approved NMOSD Treatments¶
| Treatment | Risk Reduction (%) | p-value |
|---|---|---|
| Eculizumab (add-on to immune suppression) | 94% | <0.001 |
| Ravulizumab (add-on to immune suppression) | 100% | <0.001 |
| Inebilizumab (monotherapy) | 78% | 0.01 |
| Satralizumab (monotherapy) | 77% | <0.001 |
| Satralizumab (add-on to immune suppression) | 74% | 0.001 |
7.1 Acute Attack Management¶
High-dose corticosteroids (methylprednisolone 1 g IV daily for 5–10 days) followed by prednisone taper. Plasma exchange (5–7 sessions) for nonresponders.
7.2 Prophylaxis¶
Eculizumab (900 mg weekly for 4 weeks, then 1200 mg every 2 weeks), satralizumab (120 mg subcutaneously every 4 weeks), and inebilizumab (300 mg IV every 6 months).
8. PROGNOSIS & COMPLICATIONS¶
Untreated NMO is severely disabling, with 60% of patients blind and 50% with paralysis after 8 years. 5-year survival improved to 91–98% with therapies. Complications include respiratory failure, permanent disability, and meningococcal infections with eculizumab.
8.1 Long-Term Outcomes¶
Early treatment reduces disability and relapse rates. AQP4-seronegative cases have better outcomes but may require rituximab or mycophenolate mofetil.
9. SPECIAL CONSIDERATIONS¶
NMO is associated with systemic autoimmune disorders (e.g., lupus, Sjögren’s). AQP4-seronegative cases may have milder courses. Vaccination against meningococcus is required for eculizumab/ravulizumab due to infection risks.
9.1 Pregnancy & Pediatrics¶
Avoid live vaccines during treatment. Monitor for relapses in pregnant patients. AQP4-seronegative NMOSD may present in children with MOGAD-like features.
10. KEY POINTS & CLINICAL PEARLS¶
- AQP4-IgG testing is diagnostic in 90% of NMO cases. 2. MRI shows LETM and optic nerve enhancement. 3. Eculizumab/satralizumab reduce relapse risk by 74–94%. 4. Meningococcal vaccination is mandatory for complement inhibitors. 5. Differentiate from MS using AQP4-IgG and MRI patterns.