Neuromyelitis optica spectrum disorder causes
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Julinka Auta Fernandes
Overview
Neuromyelitis optica spectrum disorder (NMOSD) is an acquired autoimmune disease of the central nervous system, but its initiating cause has not been identified. Most patients have pathogenic aquaporin-4 immunoglobulin G (AQP4-IgG); this autoantibody is an established disease-driving mediator, but its presence does not explain why immune tolerance to aquaporin-4 is lost.[1][2] Current evidence supports a multifactorial autoimmune etiology involving immune dysregulation and host susceptibility; no single environmental exposure or inherited mutation has been established as a universal cause of NMOSD.[3] AQP4-IgG-negative NMOSD is etiologically heterogeneous, and patients who fulfill contemporary criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) should be classified as having MOGAD rather than NMOSD.[4][5] To review factors associated with susceptibility or attack timing, see neuromyelitis optica spectrum disorder risk factors.
Causes
AQP4-IgG-positive NMOSD
- The initiating cause of AQP4-IgG-positive NMOSD remains unknown.[1][3]
- AQP4-IgG is an established pathogenic autoantibody directed against aquaporin-4 on astrocyte end-feet. Once present, it mediates astrocytic injury and downstream inflammation; it should therefore be described as a pathogenic mediator rather than as the identified initiating cause of the disease.[1][2]
- Loss of immune tolerance is likely multifactorial. Current genetic and immunologic findings identify susceptibility pathways but do not establish a single necessary or sufficient cause.[3][6]
AQP4-IgG-negative NMOSD
- AQP4-IgG-negative NMOSD is not known to represent one uniform etiologic disease; the cause remains unknown, and alternative diagnoses must be carefully excluded.[4][2]
- Patients with serum myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) who fulfill the international MOGAD diagnostic criteria should be classified as having MOGAD, a pathogenetically distinct disorder, rather than as having MOG-IgG-caused NMOSD.[2][5]
- Patients who remain negative for both AQP4-IgG and MOG-IgG and fulfill the stricter NMOSD diagnostic requirements constitute a heterogeneous group; no single cause has been established.[2]
Rare possible paraneoplastic NMOSD
- Rare cases of AQP4-IgG-positive NMOSD occur in temporal association with malignancy, and aquaporin-4 expression has been demonstrated in some tumors. A paraneoplastic cause is therefore possible in exceptional cases, but NMOSD is not tumor-associated in the vast majority of patients.[2][7]
- The coexistence of cancer and NMOSD does not by itself prove a causal relationship. Evaluation for malignancy should be individualized according to age, symptoms, examination findings, and conventional cancer risk factors; routine invasive cancer screening solely because NMOSD is diagnosed is not recommended.[2]
Distinguishing causes from associations and possible triggers
| Finding or exposure | Current interpretation |
|---|---|
| AQP4-IgG | An established pathogenic mediator and disease-defining biomarker in seropositive NMOSD; it does not identify the event that initiated the autoimmune response.[1][2] |
| Genetic susceptibility | Human leukocyte antigen (HLA) alleles and other immune-related loci are associated with susceptibility to AQP4-IgG-positive NMOSD, but NMOSD is not established as a single-gene inherited disorder, and these variants are not sufficient to cause the disease.[2][6] |
| Coexisting systemic autoimmunity | Sjögren syndrome, systemic lupus erythematosus, antiphospholipid syndrome, myasthenia gravis, celiac disease, and autoimmune thyroid disease may coexist with AQP4-IgG-positive NMOSD. Current consensus interprets this mainly as shared autoimmune predisposition rather than proof that one disorder causes the other.[4][2] |
| Infection | A common infection may precede a first attack or relapse. It remains uncertain whether infection initiates new autoimmunity or nonspecifically unmasks or exacerbates pre-existing disease; infection is therefore not an established cause of NMOSD.[2] |
| Vaccination | First onset after vaccination has been reported very rarely, but a temporal association does not establish causation. Current consensus does not identify vaccination as a proven cause of NMOSD.[2] |
| MOG-IgG | MOG-IgG positivity with fulfillment of international MOGAD criteria indicates MOGAD, not a cause or subtype of NMOSD.[2][5] |
| Malignancy | A possible paraneoplastic cause exists in a small minority of AQP4-IgG-positive cases, but most NMOSD is not cancer-associated and coincidence must be distinguished from causation.[2][7] |
References
- ↑ 1.0 1.1 1.2 1.3 Jarius S, Paul F, Weinshenker BG, Levy M, Kim HJ, Wildemann B. Neuromyelitis optica. Nature Reviews Disease Primers. 2020;6(1):85. doi:10.1038/s41572-020-0214-9. PMID: 33093467.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 Jarius S, Aktas O, Ayzenberg I, et al. Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders—revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis. Journal of Neurology. 2023;270(7):3341-3368. doi:10.1007/s00415-023-11634-0. PMID: 37022481.
- ↑ 3.0 3.1 3.2 Bradl M, Yu Q, Takai Y. The immunological processes behind aquaporin 4-antibody seropositive neuromyelitis optica spectrum disorders. Seminars in Immunology. 2025;78:101945. doi:10.1016/j.smim.2025.101945. PMID: 40154151.
- ↑ 4.0 4.1 4.2 Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729. PMID: 26092914.
- ↑ 5.0 5.1 5.2 Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. The Lancet Neurology. 2023;22(3):268-282. doi:10.1016/S1474-4422(22)00431-8. PMID: 36706773.
- ↑ 6.0 6.1 Attfield KE, Armen AP, Kuttikkatte SB, et al. Identification of genetic risk loci associated with aquaporin 4-positive neuromyelitis optica spectrum disorder: a genome-wide association study. The Lancet Neurology. 2026;25(5):482-491. doi:10.1016/S1474-4422(26)00084-0. PMID: 42009010.
- ↑ 7.0 7.1 Dinoto A, Borin GU, Campana G, Carta S, Ferrari S, Mariotto S. Investigating paraneoplastic aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorder through a data-driven approach. European Journal of Neurology. 2022;29(11):3466-3472. doi:10.1111/ene.15479. PMID: 35767391.