Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic disease involving the brain and spinal cord, characterized by optic neuritis and myelitis.1 NMOSD was formerly thought to be a variant of multiple sclerosis (MS); however, since the identification of highly specific NMO immunoglobulin G (NMO-IgG), which is an autoantibody against the most abundant astrocytic water channel, aquaporin-4 (AQP4), NMOSD is now considered to be separate from MS.2

NMO-IgG/AQP4 antibodies are found in up to 80% of patients with NMOSD.3 The AQP4 protein is found on the foot processes of astrocytes. Astrocyte depletion and blood-brain barrier breakdown may develop when the IgG antibody binds to the AQP4 antigen, initiating complement-mediated inflammatory processes.4

NMOSD Genetic Factors

NMOSD is usually a sporadic disorder. The identification of a minimum of 3% of familial cases is important because of the rarity of the disease. Recent data on familial segregation are most compatible with non-mendelian polygenic inheritance.5

It is plausible that NMOSD is triggered by a number of genes. The human leukocyte antigen (HLA) gene complex has been linked in a few studies. Following identification of the anti-AQP4 antibody, the DPB1*0501 allele was shown to be linked to NMOSD in Japanese and southern Han Chinese, whereas the DRB1*03 allele was found to be linked to NMOSD in Caucasians, implying genetic differences. In addition, the DPB1*0501 allele is associated with anti-AQP4-positive cases of NMOSD. Specific genetic determinants of anti-AQP4–negative NMOSD have not been discovered to date.2

Studies of non-HLA genes, including the cholesterol 7-hydroxylase (CYP7A1) gene, the interleukin 17 receptor gene, and the CD226 gene, have yielded heterogeneous results across various studies and various populations.4

Studies of AQP4 polymorphisms and their relation to NMOSD have also shown mixed results. In a small Chinese cohort, a single nucleotide polymorphism (rs151244) in the AQP4 gene promoter area was recently found to be linked to NMOSD.4

Autoimmunity in NMOSD 

A link has been found between a personal or family history of autoimmune disease and NMOSD, observed in approximately half of cases. Although the actual etiology of autoimmunity in NMOSD is not known, NMOSD is considered to be an autoimmune disorder.1 It is frequently associated with other systemic autoimmune conditions, such as autoimmune thyroid disease, systemic lupus erythematosus (SLE), and Sjögren syndrome (SS), and with a related profile of non–organ-specific autoantibodies. However, in individuals with systemic autoimmunity, elevated levels of autoantibodies, notably AQP4-IgG, cannot explain the association of NMOSD with SS and SLE. Patients who have SS and SLE without optic neuritis or myelitis are routinely found to be AQP4-IgG seronegative.5,6

Tumors and Paraneoplastic syndromes

It is unclear what causes the development of AQP4-IgG antibodies in patients with cancer, but it has been hypothesized that antibody formation represents an immune reaction against cancer. As a result, in individuals with NMOSD, particularly elderly patients, the possibility of underlying cancer should be investigated.7 In rare cases, NMOSD may manifest as a paraneoplastic syndrome. AQP4-IgG antibodies have been implicated in the pathogenesis of paraneoplastic NMOSD, although the clinical value of this finding and the specific mechanisms involved are yet to be established. Therefore, the possibility of a paraneoplastic etiology in cases of NMOSD in elderly persons should be kept in mind.7 


  1. Neuromyelitis optica spectrum disorder. National Organization for Rare Disorders (NORD). Accessed October 13, 2021. 
  2. Liu QB, Li ZX, Zhao GX, Yu H, Wu ZY. No association between identified multiple sclerosis non-MHC risk loci and neuromyelitis optica. Neurosci Bull. 2014;30(6):1036-1044. doi:10.1007/s12264-013-1457-1
  3. Jarius S, Wildemann B, Paul F. Neuromyelitis optica: clinical features, immunopathogenesis and treatment. Clin Exp Immunol. 2014;176(2):149-164. doi:10.1111/cei.12271
  4. Wei Q, Yanyu C, Rui L, et al. Human aquaporin 4 gene polymorphisms in Chinese patients with neuromyelitis optica. J Neuroimmunol. 2014;274(1-2):192-196. doi:10.1016/j.jneuroim.2014.07.003​​
  5. Weinshenker BG, Wingerchuk DM. Neuromyelitis spectrum disorders. Mayo Clin Proc. 2017;92(4):663-679. doi:10.1016/j.mayocp.2016.12.014
  6. Pittock SJ, Lennon VA, de Seze J, et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol. 2008;65(1):78-83. doi:10.1001/archneurol.2007.17
  7. Yuan J, Jia Z, Qin W, Hu W. Paraneoplastic neuromyelitis optica spectrum disorder associated with breast cancer. Clin Interv Aging. 2019;14:1039-1044. doi:10.2147/CIA.S202102

Reviewed by Kyle Habet, MD, on 10/18/2021.