Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorders (NMOSDs) are rare neuro-inflammatory demyelinating disorders of the central nervous system that primarily affect the optic nerves, spinal cord, and brainstem. The clinical features, magnetic resonance imaging findings, and presence of water channel aquaporin 4 auto-antibodies (AQP4-Abs) are used to make the diagnosis.1 Consensus criteria are difficult to formulate because the disease is relatively rare.2 Therapies to prevent recurrent attacks and associated long-term disability are classified as follows: (1) traditional immunosuppressive treatment, (2) interleukin 6 (IL-6) pathway inhibitors, (3) complement-blocking therapy, and (4) B cell-depleting therapy. Because of the relapsing and remitting course of NMOSD, frequently incomplete recovery after attacks, and associated disability, it is important to initiate therapy as soon as possible.3 A short course of immunosuppressive therapy (typically a corticosteroid), followed by some form of long-term immunosuppressive therapy, is recommended in most of the case series. Long-term immunosuppressive therapy is initiated with azathioprine or rituximab. Mycophenolate and methotrexate are examples of second-line agents. These second-line agents may be useful because less-frequent dosing is requred.2 

Prevention of Relapse and Long-term Treatment 

At the time of the initial attack, long-term immunosuppressive therapy is initiated for all patients who have AQP4-Abs. Mycophenolate mofetil and azathioprine are the drugs most often used as first-line immunosuppressants in NMOSD.1,4

Conventional Immunosuppressants 


One study that assessed the effectiveness of oral prednisolone monotherapy in NMOSD found a reduction in the annualized relapse rate (ARR). However, prolonged corticosteroid therapy can cause hypertension, diabetes, osteoporosis, Cushing syndrome, and an increased susceptibility to infection. Euphoria and psychosis are rare adverse effects.5


Azathioprine (AZA) is a purine analogue that acts as an antimetabolite and suppresses lymphocyte differentiation. As a result, it inhibits cell proliferation and possesses immunosuppressive properties. AZA is administered at a daily dose of 2 to 3 mg per kilogram of body weight and must be taken for 3 to 6 months before maximum effectiveness is attained. Additional oral prednisone (1 mg/kg daily) is required during the early phase of treatment, although this can be gradually tapered if AZA is fully effective.6 Combination treatment with AZA and low-dose corticosteroids reduces the ARR by 72.1% but has a high failure rate (>50%) as a consequence of adverse events.7 The most significant adverse effect is bone marrow depression associated with anemia, leukopenia, and/or thrombocytopenia. An increased risk for bacterial, viral, or fungal infections has been noted.6 

Mycophenolate Mofetil

Mycophenolate mofetil (MMF) is a reversible inhibitor of inosine monophosphate dehydrogenase, which is involved in the synthesis of guanosine nucleotides. Limiting the synthesis of guanosine nucleotides reversibly inhibits the proliferation of T and B lymphocytes. MMF is generally more effective than AZA in preventing relapse and is better tolerated; however, it may be less efficacious than rituximab, particularly in preventing severe relapse. MMF reduces the ARR by 87.4% with a 36% rate of treatment failure.7 The main issue with this drug is its teratogenic potential. The long-term probability of cancer is still unknown. Therapy with MMF also increases the risk for infection with herpesvirus and Mycobacterium tuberculosis.8


Methotrexate (MTX) is a folate analogue that inhibits dihydrofolate reductase and functions as a folate antagonist. It acts as an immunosuppressive and anti-inflammatory agent by inhibiting DNA and RNA synthesis. Nausea, diarrhea, bone marrow depression, and a rise in liver enzymes are all possible side effects.Various retrospective studies of MTX in NMOSD have revealed a reduction in the ARR between 64% and 87%.6

Cyclosporin A 

Cyclosporin A inhibits calcineurin by binding to cyclophilins. Calcineurin inhibition in turn inhibits translocation of the transcription factor nuclear factor of activated T cells (NFAT); decreases transcriptional activation of IL-2, tumor necrosis factor alpha (TNF-α), IL-3, IL-4, CD40, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon gamma (IFN-γ); and finally decreases the proliferation of T cells. In a retrospective study, the drug was found to be useful in preventing NMOSD relapse.8 


Tacrolimus is a macrolide calcineurin inhibitor. Its mode of action is similar to that of cyclosporin A. It inhibits T-lymphocyte signal transduction and IL-2 transcription by reducing peptidyl-prolyl isomerase activity via binding to immunophilin FKBP-12. Tacrolimus was found to be effective in preventing NMOSD relapse in a recent study.9 


Mitoxantrone has a potent immunosuppressive effect, strongly inhibiting the proliferation of T and B cells, as well as macrophages. Studies have reported the therapeutic effectiveness of mitoxantrone in relapse prevention, along with durable improvement in the Expanded Disability Status Scale (EDSS) score in patients with NMOSD and seropositivity for AQP4 immunoglobulin G.8 


  1. Held F, Klein AK, Berthele A. Drug treatment of neuromyelitis optica spectrum disorders: out with the old, in with the new?. ImmunoTargets Ther. 2021;10:87-101. doi:10.2147/ITT.S2876542
  2. Shumway CL, Patel BC, De Jesus O. Neuromyelitis optica (NMO, Devics disease). StatPearls [Internet]. Updated November 2, 2021. Accessed March 11, 2021.
  3. Trebst C, Jarius S, Berthele A, et al; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014;261(1):1-16. doi:10.1007/s00415-013-7169-7
  4. Huda S, Whittam D, Bhojak M, et al. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19(2):169-176. doi:10.7861/clinmedicine.19-2-169
  5. Watanabe S, Misu T, Miyazawa I, et al. Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler. 2007;13:968-974. doi:10.1177/1352458507077189
  6. Borisow N, Mori M, Kuwabara S, Scheel M, Paul F. Diagnosis and treatment of NMO spectrum disorder and MOG-encephalomyelitis. Front Neurol. 2018;9:888. doi:10:3389/fneur.201800888
  7. Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M. Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol. 2014;71(3):324-330. doi:10.1001/jamaneurol.2013.5699
  8. Chan KH, Lee CY. Treatment of neuromyelitis optica spectrum disorders. Int J Mol Sci. 2021;22(16):8638. doi:10.3390/ijms22168638
  9. Chen B, Wu Q, Ke G, Bu G. Efficacy and safety of tacrolimus treatment for neuromyelitis optica spectrum disorder. Sci Rep. 2017;7(1):831. doi:10.1038/s41598-017-00860-y

Reviewed by Kyle Habet, MD, on 3/30/2022.