Neuromyelitis optica spectrum disorder risk factors
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Julinka Auta Fernandes
Overview
- Risk factors for developing neuromyelitis optica spectrum disorder (NMOSD) remain incompletely established. The most reproducible associations are female sex, higher population-level occurrence among people of Black/African ancestry and in some East Asian populations, selected immunogenetic variants, and coexisting autoimmune disease.[1]
- These are susceptibility associations, not sufficient or necessary causes. They cannot predict whether an individual will develop NMOSD, and their absence does not exclude the disease.
- No validated NMOSD risk score, population screening test, or confirmed modifiable risk factor is currently available. Proposed environmental factors remain unconfirmed because the evidence is predominantly observational, heterogeneous, and vulnerable to confounding and reverse causation.[2]
Common Risk Factors
| Factor | Evidence | Clinical interpretation |
|---|---|---|
| Female sex | Female predominance is greatest in aquaporin-4 immunoglobulin G (AQP4-IgG)-positive NMOSD. The female-to-male ratio has been reported as high as 10:1 in AQP4-IgG-positive cohorts, compared with up to approximately 3:1 in AQP4-IgG-negative cohorts; the imbalance is particularly marked during reproductive age.[1] | Female sex is the most consistent demographic association, especially for AQP4-IgG-positive disease. It is not diagnostic, and NMOSD may occur in males. |
| Ancestry and population group | Incidence and prevalence are generally higher in Black populations and in some Asian populations than in White populations. In a Canadian national case-control study restricted to AQP4-IgG-positive NMOSD, self-identified Black and East Asian participants each had at least eightfold higher odds than White participants.[3] A contemporary multiethnic United States cohort also found the highest population rates among Black individuals.[4] | These are population-level associations and are not deterministic. Race and ethnicity are not biological tests; observed differences may reflect genetic ancestry, environmental exposures, social determinants of health, access to care, and ascertainment. |
| Immunogenetic susceptibility | Associations with human leukocyte antigen (HLA) class I and class II alleles differ according to ancestry and AQP4-IgG status. HLA-DRB1*03:01 is a repeatedly observed susceptibility allele in AQP4-IgG-positive disease. A 2026 genome-wide association study identified independent signals within the major histocompatibility complex and the signal transducer and activator of transcription 4 (STAT4) locus.[5] A 2026 multiethnic study confirmed ethnicity- and serostatus-specific HLA associations, including the HLA-DRB1*03:01–HLA-DQA1*05:01–HLA-DQB1*02:01 haplotype in White AQP4-IgG-positive patients and HLA-DRB1*08:04 in Black AQP4-IgG-positive patients.[6] | Genetic findings support susceptibility rather than Mendelian inheritance. Effect sizes and associated alleles vary across populations. Routine HLA typing or genetic screening is not recommended for predicting NMOSD in clinical practice.[1] |
| Coexisting autoimmunity | Other autoimmune diseases or autoantibodies are reported in approximately 25%–40% of AQP4-IgG-positive cohorts. Associated conditions include systemic lupus erythematosus, Sjögren syndrome, myasthenia gravis, celiac disease, and autoimmune thyroid disease.[1] In the Canadian case-control study, a history of another autoimmune disease was associated with higher odds of NMOSD (odds ratio 2.7; 95% confidence interval 1.4–5.0).[3] | Coexisting autoimmunity is a marker of shared immune susceptibility, not proof that one autoimmune disease causes NMOSD. It should not be used alone to diagnose or screen for NMOSD. |
Less Common or Unconfirmed Risk Factors
| Proposed factor | Current evidence | Interpretation |
|---|---|---|
| Vitamin D deficiency or low sunlight exposure | Several observational studies have reported lower vitamin D concentrations or less sunlight exposure in NMOSD, but results are inconsistent and the vitamin D studies summarized in the 2025 systematic review were geographically limited.[2] The Neuromyelitis Optica Study Group considers vitamin D deficiency a less well-established association.[1] | A causal effect has not been established. Low vitamin D may reflect disease-related behavior, disability, geography, diet, or other confounding factors. Vitamin D measurement or supplementation should not be presented as a proven NMOSD-prevention strategy. |
| Smoking | Studies have produced conflicting findings, including differing directions of association across populations.[2] Smoking is therefore considered a less well-established NMOSD association.[1] | Smoking is not an established causal risk factor for NMOSD, and no apparent inverse association should be interpreted as protective or used to justify tobacco exposure. |
| Prior infection or microbial seroreactivity | Small studies have reported associations with selected infectious exposures or antibodies, including seroreactivity to Mycobacterium avium subspecies paratuberculosis. Evidence is heterogeneous and is largely derived from cross-sectional or case-control observations.[2] | No specific infection has been proven to cause NMOSD. Temporal proximity between an infection and first attack does not establish causality. |
| Dietary patterns | Limited observational and genetic-instrument studies have reported associations with particular foods or dietary patterns, but findings have not been consistently replicated.[2] | No diet has been established to cause or prevent NMOSD, and no disease-specific preventive diet is recommended. |
| Migration or place of birth | In the Canadian study, birth outside Canada was associated with higher odds of AQP4-IgG-positive NMOSD (odds ratio 5.5; 95% confidence interval 3.6–8.3).[3] | This is a study-specific association that may reflect ancestry, migration patterns, environmental exposures, or ascertainment. It should not be generalized as an independent causal risk factor. |
Factors Not Established as Risk Factors
- Neuromyelitis optica spectrum disorder has no convincing latitude gradient, and latitude should not be regarded as an established risk factor.[1]
- Reproductive history and age at menarche were not associated with NMOSD in the Canadian case-control study.[3] Pregnancy and the postpartum period may influence disease activity after NMOSD has developed, but they are not established risk factors for initially developing the disease.
- Published temporal reports following infection or vaccination do not demonstrate causation; current evidence does not establish vaccination as an NMOSD risk factor.[2]
- AQP4-IgG is a disease-associated biomarker, not an exposure or demographic risk factor. Testing asymptomatic people solely because of demographic or environmental associations is not supported.
- Factors associated with relapse, disability, treatment response, or treatment complications are prognostic or management factors and are outside the scope of this risk-factor page.
Clinical Interpretation
- Neuromyelitis optica spectrum disorder risk factors must not be used to confirm or exclude the diagnosis.
- Routine HLA typing, population genetic screening, environmental-exposure testing, or a clinical risk calculator is not recommended for predicting NMOSD.
- No evidence-based primary-prevention intervention has been shown to prevent NMOSD in an otherwise asymptomatic person.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Mohammadi Lapevandani M, Bazmi E, Jahani S, Asgari N, Sahraian MA. Environmental risk factors of neuromyelitis optica spectrum disorder: a systematic review. Therapeutic Advances in Neurological Disorders. 2025;18:17562864251363293. doi:10.1177/17562864251363293. PMID: 41080217; PMCID: PMC12511702.
- ↑ 3.0 3.1 3.2 3.3 Rotstein DL, Wolfson C, Carruthers R, et al. A national case-control study investigating demographic and environmental factors associated with NMOSD. Multiple Sclerosis Journal. 2023;29(4-5):521-529. doi:10.1177/13524585231151953. PMID: 36803237; PMCID: PMC10152218.
- ↑ Lee A, Iordanova RT, Smith JB, et al. Incidence and prevalence of neuromyelitis optica spectrum disorder in a contemporary, multi-ethnic cohort. Multiple Sclerosis Journal. 2025;31(6):642-657. doi:10.1177/13524585251328554. PMID: 40156304.
- ↑ 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.
- ↑ Niederschweiberer M, Panagiotaropoulou G, Fernandez-Viña MA, et al. HLA associations differ by ethnicity and aquaporin-4 antibody status in patients with neuromyelitis optica spectrum disorders. Neurology: Neuroimmunology & Neuroinflammation. 2026;13(3):e200562. doi:10.1212/NXI.0000000000200562. PMID: 41990286; PMCID: PMC13088193.