Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder in which the body’s immune system attacks and causes inflammation of the myelin surrounding nerve cells, particularly in the optic nerves and the spinal cord. Around two-thirds of individuals with NMOSD have immunoglobulin G (IgG) autoantibodies to aquaporin-4 (AQP4) water channel proteins, which proliferate astrocytic membranes and are involved closely with the blood-brain barrier.1 

Autoimmune Risk Factors

In one study conducted in 2020, 24.5% (13/53) of patients with NMOSD had accompanying autoimmune diseases, such as Sjögren’s syndrome.2 Another study confirmed this risk factor in 2021, indicating that individuals with highly active NMOSD had a higher proportion of antinuclear antibody-positivity than the control group.3 Another study that implemented whole genome sequencing and Mendelian Randomization analysis indicated that there was a significant causal effect of systemic lupus erythematosus, while multiple sclerosis was not associated.4

Inflammatory Risk Factors

Some cases of NMOSD are potentially triggered by underlying malignancy, as was seen in the 2020 study where 15.1% (8/53) of patients with NMOSD also had cancer. In this same study, 43.4% (23/53) of patients with NMOSD also had recently recorded non-neurological episodes that may have played a role in triggering the NMOSD autoimmune response. These included surgical operations, systemic infections, traumatic injuries, and systemic allergic reactions.2 

Potential triggering infections include Mycoplasma pneumoniae, Mycobacterium tuberculosis, Treponema pallidum, Helicobacter pylori, and Chlamydia pneumoiae.5 One case study suggested a link between NMOSD and autoimmunity triggered by Epstein-Barr virus (EBV).6

Another study showed an association between head trauma and NMOSD, as well as a correlation between intentional abortion and NMOSD in women.7 

Environmental Risk Factors

Investigators of a case-controlled study published in 2018 reported that individuals with NMOSD had dietary and behavioral environmental risk factors, including low dairy consumption, seafood intake, fruit and vegetable consumption, and physical activity levels.7 Other environmental risk factors for NMOSD included smoking and vitamin D insufficiency, along with dietary habits and contracting infections.8

Genetic Risk Factors

The prevalence of comorbid connective tissue disease is higher in individuals with NMOSD than in control groups.3 Although some connective tissue diseases are caused by environmental triggers, some have an underlying familial genetic mutation that has been identified; these are called heritable connective tissue disorders.9

Several HLA-DRB1 alleles and single nucleotide polymorphisms in the major histocompatibility complex (MHC) region confer NMOSD susceptibility, while a single nucleotide polymorphism in the KCNMA1 gene is related to transverse myelitis and disability in NMOSD.10 Evidence from a whole genome sequencing study revealed that NMOSD was associated with C4A copy number with a nonsignificant trend toward affiliation with C4B. This study also confirmed 2 independent signals within the MHC region, one of which may lead to the structural variation within the C4 genes.4

Hematological Risk Factors

Laboratory tests demonstrated elevated leukocyte counts in both the blood and cerebrospinal fluid, protein concentrations, IgG indexes, and 24-hour IgG synthesis rates in individuals with highly active NMOSD.3 More than 70% of patients with NMOSD are seropositive for autoantibodies that target AQP4 water channels (NMO-IgG+).4 

Overall, many disease experts believe that a combination of risk factors, such as a genetic predisposition activated by environmental triggers, contributes to the cause of NMOSD.5 


  1. Dahl AA. Adult optic neuritis: etiology. Medscape. Updated January 22, 2021. Accessed October 21, 2021.
  2. Akaishi T, Takahashi T, Fujihara K, et al. Risk factors of attacks in neuromyelitis optica spectrum disorders. J Neuroimmunol. 2020;343:577236. doi:10.1016/j.jneuroim.2020.577236
  3. Li Y, Zhang J, Zhou Y, et al. Analysis of predictive risk factors in aquaporin-4-IgG positive highly active neuromyelitis optica spectrum disorders. Front Neurol. 2021;12:731835. doi:10.3389/fneur.2021.731835
  4. Estrada K, Whelan CW, Zhao F, et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nat Commun. 2018;9(1):1929. doi:10.1038/s41467-018-04332-3
  5. Christiansen S. Causes and risk factors of neuromyelitis optica spectrum disorder. Verywell Health. Updated July 25, 2021. Accessed October 21, 2021.
  6. Levinson JB, Alvarez MR, Koci K, Feoktistov A, McFarlane IM. Epstein – Barr virus infection in a patient with neuromyelitis optica spectrum disorder and Sjögren’s syndrome: a case report and review of literature. Clin Case Rep Rev. 2018;4(5):10.15761/CCRR.1000411. doi:10.15761/CCRR.1000411
  7. Eskandarieh S, Nedjat S, Abdollahpour I, et al. Environmental risk factors in neuromyelitis optica spectrum disorder: a case-control study. Acta Neurol Belg. 2018;118(2):277-287. doi:10.1007/s13760-018-0900-5
  8. Naser Moghadasi A. Environmental and genetic risk factors in the development of neuromyelitis optica. Expert Rev Ophthalmol. 2020;15(1):1-9. doi:10.1080/17469899.2020.1723416
  9. Dunkin MA. Connective tissue disease. WebMD. Accessed October 21, 2021.
  10. Matsushita T, Masaki K, Isobe N, et al.; Japan Multiple Sclerosis Genetic Consortium. Genetic factors for susceptibility to and manifestations of neuromyelitis optica. Ann Clin Transl Neurol. 2020;7(11):2082-2093. doi:10.1002/acn3.51147

Reviewed by Kyle Habet, MD, on 10/26/2021.

Reviewed by Kyle Habet, MD, on 10/26/2021.