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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Neuromyelitis optica spectrum disorder (NMOSD) has its historical roots in the optic nerve and spinal cord syndrome characterized by Eugène Devic and Fernand Gault in 1894, although similar cases had been reported earlier.^[1] Discovery of a specific serum autoantibody in 2004^[2] and identification of aquaporin-4 as its target in 2005 transformed understanding of the disease.^[3] International diagnostic criteria published in 2015 recognized a broader clinical spectrum.^[4] Larger trials published from 2019 onward established the relapse-prevention benefits of new targeted therapies.^[5]

Neuromyelitis optica spectrum disorder may be represented in nineteenth-century reports associating visual loss with spinal cord disease. Giovanni Battista Pescetto described a possible early case in 1844, and Thomas Clifford Allbutt’s 1870 report helped attract sustained clinical interest.^[1]

In 1894, Devic presented the association of acute myelitis and optic neuritis in Lyon, France. That year, his student Gault published a doctoral thesis reviewing previous reports and analyzing Devic’s case. Their work introduced the term neuromyelitis optica (NMO). The eponym Devic’s disease was proposed by Peppo Acchioté in 1907.^[1]

Neuromyelitis optica spectrum disorder evolved from a clinically described opticospinal syndrome into a disease classified using antibody findings and characteristic clinical and imaging presentations.^[4]

Neuromyelitis optica spectrum disorder research changed in 2004, when Vanda Lennon and colleagues described a serum autoantibody called neuromyelitis optica immunoglobulin G (NMO-IgG) that helped distinguish the condition from multiple sclerosis (MS).^[2]

In 2005, Lennon and colleagues identified aquaporin-4 (AQP4), a water-channel protein expressed on astrocytes, as the antibody’s target. These antibodies subsequently became known as aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). This discovery provided a biological basis for distinguishing antibody-positive disease from MS.^[3]

Neuromyelitis optica spectrum disorder was more clearly distinguished from MS through the 2006 revision of criteria for classical NMO, which incorporated serum antibody status alongside clinical findings and magnetic resonance imaging (MRI) features.^[6]

In 2015, the International Panel for Neuromyelitis Optica Diagnosis (IPND) published consensus criteria that unified classical NMO and its broader spectrum under NMOSD. The criteria recognized optic nerve, spinal cord, area postrema, other brainstem, diencephalic, and cerebral presentations, with separate requirements according to AQP4-IgG status.^[4]

Neuromyelitis optica spectrum disorder was further differentiated from related inflammatory disorders by the publication of international diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in 2023. These criteria formalized recognition of MOGAD as a separate disease, despite overlapping optic neuritis and myelitis presentations.^[7]

Neuromyelitis optica spectrum disorder relapse prevention initially relied on immunosuppressants and evidence from small studies, before larger trials supported targeted therapies.^[5]

• 2005: Bruce Cree and colleagues published an early open-label study of rituximab, providing preliminary evidence for B-cell depletion as a relapse-prevention strategy.^[8]
• 2019: Randomized trials demonstrated reduced attack risk with eculizumab, a complement inhibitor, and inebilizumab, a B-cell-depleting antibody, in predominantly or exclusively AQP4-IgG-positive study populations.^[5]
• 2019–2020: Trials of satralizumab, an interleukin-6 receptor-blocking antibody, evaluated both addition to existing immunosuppression and monotherapy, establishing relapse-prevention benefits in AQP4-IgG-positive disease.^[5]
• 2023: An open-label trial of ravulizumab, a longer-acting complement inhibitor, used an external placebo comparator and provided additional evidence for relapse prevention in AQP4-IgG-positive NMOSD.^[5]
• 2026: The Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) published consensus guidelines integrating antibody-based diagnosis and modern immunotherapies into regional clinical practice.^[9]