Key Facts

NMOSD is a severe autoimmune inflammatory CNS disorder that must be distinguished from MS because treatment strategies differ fundamentally. AQP4-IgG seropositivity is the hallmark. Early immunosuppression reduces relapse rate and disability.

Epidemiology

Prevalence ~1-5 per 100,000. More common in non-Caucasian populations (African, Asian, Hispanic). F:M 9:1 (for AQP4+ disease). Mean age of onset 30-40 years (older than MS). Relapsing course in >90% of AQP4+ patients.

Aetiology

• AQP4-IgG seropositive NMOSD (~80%): pathogenic IgG1 antibodies against aquaporin-4 (most abundant water channel in CNS — expressed on astrocyte foot processes, particularly at optic nerves, spinal cord, and area postrema)
• AQP4-IgG seronegative NMOSD (~20%): some have MOG-IgG antibodies (MOGAD — now considered separate disease); others remain seronegative
• Associated autoimmune conditions: SLE, Sjögren syndrome, myasthenia gravis, autoimmune thyroiditis

Pathophysiology

AQP4-IgG binds aquaporin-4 on astrocyte foot processes → complement activation → astrocyte destruction (astrocytopathy) → secondary demyelination and neuronal loss. This differs from MS (primary oligodendrocyte/myelin attack). The predilection for optic nerves, spinal cord (central grey matter — long segments), and area postrema reflects the high density of AQP4 in these regions. Attacks tend to be more severe than MS relapses with poorer recovery.

Core Clinical Features

• Optic neuritis: often bilateral or rapidly sequential; severe visual loss; poor recovery compared to MS-related ON
• Longitudinally extensive transverse myelitis (LETM): ≥3 vertebral segments of T2 lesion on MRI; severe paraparesis/tetraparesis, sensory level, bladder dysfunction; often central cord
• Area postrema syndrome: intractable nausea, vomiting, hiccups (may be presenting feature — days to weeks)
• Brainstem syndrome: diplopia, facial palsy, vertigo
• Diencephalic syndrome: narcolepsy, SIADH
• Cerebral syndrome: encephalopathy (rare)

Key Differences from MS

• More severe relapses with poorer recovery
• Bilateral/severe optic neuritis (MS usually unilateral, milder)
• LETM ≥3 segments (MS usually <2 segments)
• Brain MRI often normal or atypical for MS (periependymal/hypothalamic lesions)
• Relapsing course without progressive phase

Red Flags

• Bilateral severe optic neuritis (NMOSD until proven otherwise)
• LETM on MRI (≥3 segments)
• Intractable hiccups/vomiting (area postrema)
• Worsening on interferon-β or other MS DMTs

Serology

• AQP4-IgG (NMO-IgG): cell-based assay (best sensitivity ~80% and specificity >99%); MUST be tested in all suspected NMOSD
• MOG-IgG: if AQP4 negative; cell-based assay
• ANA, dsDNA, ENA, complement: associated autoimmune conditions

MRI

• MRI brain: often normal or shows atypical lesions for MS (periependymal, hypothalamic, area postrema); does NOT typically show periventricular Dawson fingers
• MRI spine: LETM (≥3 vertebral segments of T2 hyperintensity); central cord predominance; bright spotty lesions
• MRI orbits (fat-suppressed): optic nerve enhancement (often posterior, long segment, bilateral)

CSF

• OCBs: often absent (present in only ~20% of NMOSD vs >95% in MS — key distinguishing feature)
• Pleocytosis: neutrophilic (unusual in MS where lymphocytic)
• Elevated protein: more common than in MS
• GFAP levels: raised (astrocyte damage marker)

Other

• VEPs: delayed/absent (severe optic nerve damage)
• OCT: significant RNFL thinning (often more severe than MS)

Acute Relapse

• IV methylprednisolone 1 g daily × 5 days: first-line
• Plasma exchange (PLEX): 5-7 exchanges; use early if poor response to steroids or severe attack (especially LETM or severe ON)
• More aggressive treatment than MS relapses — NMOSD attacks cause more permanent damage

Relapse Prevention (Maintenance Immunosuppression)

• First-line: rituximab 1 g IV × 2 doses (2 weeks apart), then 500 mg-1 g every 6 months; anti-CD20 B cell depletion; widely used; monitor CD19 count
• Eculizumab 900-1200 mg IV every 2 weeks (anti-C5 complement; PREVENT trial; NICE TA853); highly effective for AQP4+ NMOSD; risk of meningococcal infection — must vaccinate
• Satralizumab 120 mg SC monthly × 3 then every 4 weeks (anti-IL-6R; SAkuraStar/SAkuraSky trials)
• Inebilizumab 300 mg IV every 6 months (anti-CD19; N-MOmentum trial)
• Older agents: azathioprine 2.5 mg/kg/day, mycophenolate mofetil 1-3 g/day (used where biologics unavailable)
• DO NOT USE MS DMTs: interferon-β, natalizumab, fingolimod — can worsen NMOSD

Symptom Management

• Spasticity, pain, bladder — as per MS
• Rehabilitation: physiotherapy, occupational therapy
• Low-vision aids for severe visual loss

Referral Criteria

• All suspected NMOSD: urgent neurology (specialist NMO centre)
• AQP4 testing in all atypical demyelinating presentations
• MDT management at specialist centre

AQP4+ NMOSD: relapsing course in >90%; each relapse can cause significant irreversible disability; 5-year mortality ~20-30% without treatment (mainly respiratory failure from cervical myelitis). With modern immunosuppression (rituximab, eculizumab), outcomes have greatly improved — annualised relapse rate reduced by >90%. MOGAD: generally better prognosis; more likely to be monophasic; better relapse recovery. Seronegative NMOSD: variable prognosis.

NMOSD vs MS

Key NMOSD Trials