Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease of the central nervous system (CNS) that mainly affects the optic nerves and spinal cord; the brainstem and other brain regions may also be involved.^[1] Most patients have aquaporin-4 immunoglobulin G antibodies (AQP4-IgG), which target a water-channel protein on astrocytes, supporting cells of the CNS.^[2] It often begins in adulthood and predominantly affects women.^[1] Coexisting autoimmune disorders may indicate a shared autoimmune predisposition.^[3] The principal presentations are optic neuritis, acute myelitis, and area postrema syndrome, characterized by otherwise unexplained persistent nausea, vomiting, or hiccups.^[4] Relapsing attacks can leave permanent visual impairment, limb weakness, sensory loss, and bowel or bladder dysfunction.^[3] Diagnosis combines clinical findings, magnetic resonance imaging (MRI), and serum antibody testing.^[5] Diagnostic requirements differ according to AQP4-IgG status, with stricter criteria for antibody-negative disease.^[4] NMOSD is distinct from multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).^[6] Management focuses on prompt attack treatment and long-term immunotherapy to prevent relapses and limit disability.^[5]

Discovery of a disease-specific serum autoantibody in 2004, subsequently shown to target aquaporin-4, helped distinguish NMOSD from MS. The 2015 international consensus criteria recognized a broader spectrum than combined optic nerve and spinal cord disease.^[4]

In AQP4-IgG-positive NMOSD, antibody binding promotes complement-mediated inflammation and astrocyte injury. This can cause secondary demyelination, meaning loss of the protective myelin surrounding nerve fibers, and damage to neurons.^[2]

AQP4-IgG is pathogenic in most patients. The underlying mechanisms in patients meeting NMOSD criteria who lack both AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G antibodies (MOG-IgG) remain uncertain.^[2]

Published diagnostic criteria distinguish NMOSD with AQP4-IgG from NMOSD without AQP4-IgG or with unknown antibody status. Diagnosis in the latter groups requires more stringent clinical and imaging findings.^[4]

MS and MOGAD are important differential diagnoses. MOGAD can also present with optic neuritis or myelitis but has distinct diagnostic criteria and should be identified separately.^[6]

NMOSD is uncommon and often begins in adulthood. AQP4-IgG-positive disease predominantly affects women.^[3] Children and older adults can also be affected.^[3]

Coexisting autoimmune disorders, including systemic lupus erythematosus and Sjögren’s syndrome, suggest a shared autoimmune predisposition. Their presence does not exclude NMOSD.^[3]

Antibody testing should be guided by compatible clinical presentations. Broad, unselected AQP4-IgG testing in otherwise typical MS is discouraged.^[3]

Recurrent attacks can leave substantial residual disability. Early recognition, prompt attack treatment, and effective relapse prevention improve outcomes.^[1] AQP4-IgG-positive NMOSD usually follows a relapsing course, with disability accumulating mainly through incomplete recovery from attacks.^[2] Gradual neurological progression independent of attacks is uncommon.^[4]

Diagnosis integrates a compatible clinical syndrome, serum AQP4-IgG testing with a validated cell-based assay, MRI findings, and exclusion of alternative diagnoses.^[5]

Optic neuritis causes visual loss; myelitis causes limb weakness, sensory changes, and bowel or bladder dysfunction. Area postrema syndrome and other brainstem, diencephalic, or cerebral presentations may also occur.^[4]

Assessment should include both eyes, visual acuity, pupillary responses, motor and sensory function, and bowel or bladder involvement. Findings depend on the location and severity of the attack.^[3]

Serum AQP4-IgG is the key diagnostic antibody. A negative result requires careful evaluation for alternative diagnoses.^[5] Serum MOG-IgG testing helps identify MOGAD when the clinical presentation is compatible.^[6]

MRI of the brain, optic nerves, and spinal cord supports diagnosis and helps distinguish competing disorders.^[1] Spinal cord lesions extending over three or more vertebral segments are characteristic, although shorter lesions can occur.^[4]

Lumbar puncture with cerebrospinal fluid (CSF) analysis helps assess inflammation and alternative diagnoses. CSF findings alone cannot establish or exclude NMOSD.^[3]

Acute attacks require prompt high-dose intravenous methylprednisolone. Plasma exchange should be used early for severe attacks or inadequate response to corticosteroids. Long-term treatment is individualized by antibody status, patient characteristics, and availability. Options for AQP4-IgG-positive disease include rituximab, inebilizumab, eculizumab, ravulizumab, and satralizumab.^[5]

Long-term immunotherapy should be offered after the first attack in AQP4-IgG-positive NMOSD to reduce further attacks and disability.^[2]

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