, Volume 79, Issue 2, pp 125–142 | Cite as

Pharmacotherapy for Neuromyelitis Optica Spectrum Disorders: Current Management and Future Options

  • Nicolas CollonguesEmail author
  • Estelle Ayme-Dietrich
  • Laurent Monassier
  • Jérôme de Seze
Review Article


Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease of the central nervous system. Although the prevalence of NMO is low, the rapid and severe impairment observed in patients has led to extensive development of research in the fields of diagnostic criteria and therapy in the past 15 years. With improved understanding of the pathophysiology of NMO and the role of aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein antibodies, numerous therapeutic approaches have been proposed and are currently undergoing evaluation. In this review, we describe the rationale for existing therapeutics and their benefit/risk ratio. We also discuss the pharmacological and clinical interest of future approaches targeting, among others, B or T cells, the blood–central nervous system barrier, complement, polynuclear cells, AQP4-antibody linkage and AQP4 activity. The numerous agents under development are the result of a major collaborative effort all over the world. After the considerable progress on diagnosis, we are now close to class I evidence for a therapeutic effect of several drugs in NMO spectrum disorders, most notably with the anti-interleukin-6 receptor antibody (satralizumab) and anti-complement-5 antibody (eculizumab).


Compliance with ethical standards



Conflict of interest

N. Collongues has received honoraria for consulting or presentation from Biogen Idec, Almirall, Novartis, Merck Serono, LFB, Teva Pharma, Sanofi-Genzyme, and Roche, and is a member of the Editorial Board of the Journal de la Ligue Française contre la Sclérose en plaques. E. Aylme-Dietrich has no conflict of interest to declare. L. Monassier has no conflict of interest to declare. J. de Seze has received honoraria for consulting or presentation from Biogen Idec, Novartis, Chugai, Merck Serono, LFB, CSL Behring, Teva Pharma, Sanofi-Genzyme, and Roche.


  1. 1.
    Kim HJ, Paul F, Lana-Peixoto MA, Tenembaum S, Asgari N, Palace J, et al. MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology. 2015;84(11):1165–73.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Pittock SJ, Lennon VA, Krecke K, Wingerchuk DM, Lucchinetti CF, Weinshenker BG. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390–6.PubMedGoogle Scholar
  3. 3.
    Collongues N, Cabre P, Marignier R, Zephir H, Papeix C, Audoin B, et al. A benign form of neuromyelitis optica: does it exist? Arch Neurol. 2011;68(7):918–24.PubMedGoogle Scholar
  4. 4.
    Collongues N, Marignier R, Zephir H, Papeix C, Blanc F, Ritleng C, et al. Neuromyelitis optica in France: a multicenter study of 125 patients. Neurology. 2010;74(9):736–42.PubMedGoogle Scholar
  5. 5.
    Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12.PubMedGoogle Scholar
  6. 6.
    Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473–7.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ, et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology. 2007;69(24):2221–31.PubMedGoogle Scholar
  8. 8.
    Hinson SR, Roemer SF, Lucchinetti CF, Fryer JP, Kryzer TJ, Chamberlain JL, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473–81.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Hinson SR, Romero MF, Popescu BF, Lucchinetti CF, Fryer JP, Wolburg H, et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci USA. 2012;109(4):1245–50.PubMedGoogle Scholar
  10. 10.
    Zeng XN, Sun XL, Gao L, Fan Y, Ding JH, Hu G. Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes. Mol Cell Neurosci. 2007;34(1):34–9.PubMedGoogle Scholar
  11. 11.
    Howe CL, Kaptzan T, Magana SM, Ayers-Ringler JR, LaFrance-Corey RG, Lucchinetti CF. Neuromyelitis optica IgG stimulates an immunological response in rat astrocyte cultures. Glia. 2014;62(5):692–708.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125(Pt 7):1450–61.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Misu T, Fujihara K, Kakita A, Konno H, Nakamura M, Watanabe S, et al. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain. 2007;130(Pt 5):1224–34.PubMedGoogle Scholar
  14. 14.
    Marignier R, Nicolle A, Watrin C, Touret M, Cavagna S, Varrin-Doyer M, et al. Oligodendrocytes are damaged by neuromyelitis optica immunoglobulin G via astrocyte injury. Brain. 2010;133(9):2578–91.PubMedGoogle Scholar
  15. 15.
    Alves Do Rego C, Collongues N. Neuromyelitis optica spectrum disorders: features of aquaporin-4, myelin oligodendrocyte glycoprotein and double-seronegative-mediated subtypes. Rev Neurol (Paris). 2018;174(6):458–70.Google Scholar
  16. 16.
    Collongues N, Chanson JB, Blanc F, Steibel J, Lam CD, Shabbir A, et al. The Brown Norway opticospinal model of demyelination: does it mimic multiple sclerosis or neuromyelitis optica? Int J Dev Neurosci. 2012;30(6):487–97.PubMedGoogle Scholar
  17. 17.
    Storch MK, Stefferl A, Brehm U, Weissert R, Wallstrom E, Kerschensteiner M, et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol. 1998;8(4):681–94.PubMedGoogle Scholar
  18. 18.
    Peschl P, Schanda K, Zeka B, Given K, Bohm D, Ruprecht K, et al. Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflamm. 2017;14(1):208.Google Scholar
  19. 19.
    Saadoun S, Waters P, Owens GP, Bennett JL, Vincent A, Papadopoulos MC. Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol Commun. 2014;31(2):35.Google Scholar
  20. 20.
    Ikeda K, Kiyota N, Kuroda H, Sato DK, Nishiyama S, Takahashi T, et al. Severe demyelination but no astrocytopathy in clinically definite neuromyelitis optica with anti-myelin-oligodendrocyte glycoprotein antibody. Mult Scler. 2015;21(5):656–9.PubMedGoogle Scholar
  21. 21.
    Zhou L, Huang Y, Li H, Fan J, Zhangbao J, Yu H, et al. MOG-antibody associated demyelinating disease of the CNS: a clinical and pathological study in Chinese Han patients. J Neuroimmunol. 2017;15(305):19–28.Google Scholar
  22. 22.
    Sabater L, Giralt A, Boronat A, Hankiewicz K, Blanco Y, Llufriu S, et al. Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: an in vitro study. J Neuroimmunol. 2009;215(1–2):31–5.PubMedGoogle Scholar
  23. 23.
    Bradl M, Misu T, Takahashi T, Watanabe M, Mader S, Reindl M, et al. Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol. 2009;66(5):630–43.PubMedGoogle Scholar
  24. 24.
    Bernard-Valnet R, Liblau RS, Vukusic S, Marignier R. Neuromyelitis optica: a positive appraisal of seronegative cases. Eur J Neurol. 2015;22(12):1511–1518, e82–3.PubMedGoogle Scholar
  25. 25.
    Vaknin-Dembinsky A, Brill L, Kassis I, Petrou P, Ovadia H, Ben-Hur T, et al. T-cell reactivity against AQP4 in neuromyelitis optica. Neurology. 2012;79(9):945–6.PubMedGoogle Scholar
  26. 26.
    Hamid SHM, Whittam D, Mutch K, Linaker S, Solomon T, Das K, et al. What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients. J Neurol. 2017;264:2088–94.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Hoftberger R, Sepulveda M, Armangue T, Blanco Y, Rostasy K, Calvo AC, et al. Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult Scler. 2015;21(7):866–74.PubMedGoogle Scholar
  28. 28.
    Hyun JW, Woodhall MR, Kim SH, Jeong IH, Kong B, Kim G, et al. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases. J Neurol Neurosurg Psychiatry. 2017;88(10):811–7.PubMedGoogle Scholar
  29. 29.
    Jurynczyk M, Geraldes R, Probert F, Woodhall MR, Waters P, Tackley G, et al. Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis. Brain. 2017;140(3):617–27.PubMedGoogle Scholar
  30. 30.
    Collongues N, Marignier R, Jacob A, Leite MI, Siva A, Paul F, et al. Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset. Mult Scler. 2014;20(8):1086–94.PubMedGoogle Scholar
  31. 31.
    Kitley J, Woodhall M, Waters P, Leite MI, Devenney E, Craig J, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology. 2012;79(12):1273–7.PubMedGoogle Scholar
  32. 32.
    Ramanathan S, Reddel SW, Henderson A, Parratt JD, Barnett M, Gatt PN, et al. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm. 2014;1(4):e40.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Sato DK, Callegaro D, de Haidar Jorge FM, Nakashima I, Nishiyama S, Takahashi T, et al. Cerebrospinal fluid aquaporin-4 antibody levels in neuromyelitis optica attacks. Ann Neurol. 2014;76(2):305–9.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Sepulveda M, Armangue T, Sola-Valls N, Arrambide G, Meca-Lallana JE, Oreja-Guevara C, et al. Neuromyelitis optica spectrum disorders: comparison according to the phenotype and serostatus. Neurol Neuroimmunol Neuroinflamm. 2016;3(3):e225.PubMedPubMedCentralGoogle Scholar
  35. 35.
    van Pelt ED, Wong YY, Ketelslegers IA, Hamann D, Hintzen RQ. Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in the Netherlands. Eur J Neurol. 2016;23(3):580–7.PubMedGoogle Scholar
  36. 36.
    Cobo-Calvo A, Ruiz A, Maillart E, Audoin B, Zephir H, Bourre B, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study. Neurology. 2018;90(21):e1858–69.PubMedGoogle Scholar
  37. 37.
    Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–89.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Probstel AK, Dornmair K, Bittner R, Sperl P, Jenne D, Magalhaes S, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology. 2011;77(6):580–8.PubMedGoogle Scholar
  39. 39.
    Collongues N, de Seze J. Current and future treatment approaches for neuromyelitis optica. Ther Adv Neurol Disord. 2011;4(2):111–21.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Wegner B, et al. Neuromyelitis optica: evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. 2016;79(2):206–16.PubMedGoogle Scholar
  41. 41.
    Bonnan M, Valentino R, Debeugny S, Merle H, Ferge JL, Mehdaoui H, et al. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg Psychiatry. 2018;89(4):346–51.PubMedGoogle Scholar
  42. 42.
    Montcuquet A, Collongues N, Papeix C, Zephir H, Audoin B, Laplaud D, et al. Effectiveness of mycophenolate mofetil as first-line therapy in AQP4-IgG, MOG-IgG, and seronegative neuromyelitis optica spectrum disorders. Mult Scler. 2017;23(10):1377–84.PubMedGoogle Scholar
  43. 43.
    Elsone L, Panicker J, Mutch K, Boggild M, Appleton R, Jacob A. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler. 2014;20(4):501–4.PubMedGoogle Scholar
  44. 44.
    Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflamm. 2016;13(1):280.Google Scholar
  45. 45.
    Walshe CA, Beers SA, French RR, Chan CH, Johnson PW, Packham GK, et al. Induction of cytosolic calcium flux by CD20 is dependent upon B cell antigen receptor signaling. J Biol Chem. 2008;283(25):16971–84.PubMedGoogle Scholar
  46. 46.
    Hultin LE, Hausner MA, Hultin PM, Giorgi JV. CD20 (pan-B cell) antigen is expressed at a low level on a subpopulation of human T lymphocytes. Cytometry. 1993;14(2):196–204.PubMedGoogle Scholar
  47. 47.
    Illidge T, Klein C, Sehn LH, Davies A, Salles G, Cartron G. Obinutuzumab in hematologic malignancies: lessons learned to date. Cancer Treat Rev. 2015;41(9):784–92.PubMedGoogle Scholar
  48. 48.
    Golay J, Semenzato G, Rambaldi A, Foa R, Gaidano G, Gamba E, et al. Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics. mAbs. 2013;5(6):826–37.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kim SH, Jeong IH, Hyun JW, Joung A, Jo HJ, Hwang SH, et al. Treatment outcomes with rituximab in 100 patients with neuromyelitis optica: influence of FCGR3A polymorphisms on the therapeutic response to rituximab. JAMA Neurol. 2015;72(9):989–95.PubMedGoogle Scholar
  50. 50.
    Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol. 2003;14(4):520–35.PubMedGoogle Scholar
  51. 51.
    Harjunpaa A, Wiklund T, Collan J, Janes R, Rosenberg J, Lee D, et al. Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma. Leuk Lymphoma. 2001;42(4):731–8.PubMedGoogle Scholar
  52. 52.
    Lampson LA. Monoclonal antibodies in neuro-oncology: getting past the blood–brain barrier. mAbs. 2011;3(2):153–60.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Collongues N, Brassat D, Maillart E, Labauge P, Ouallet JC, Carra-Dalliere C, et al. Efficacy of rituximab in refractory neuromyelitis optica. Mult Scler. 2016;22(7):955–9.PubMedGoogle Scholar
  54. 54.
    Yang CS, Yang L, Li T, Zhang DQ, Jin WN, Li MS, et al. Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica. Neurology. 2013;81(8):710–3.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lin J, Li X, Xue B, Tong Q, Chen Z, Zhu W, et al. Low-dosage of rituximab in Chinese patients with neuromyelitis optica spectrum disorder. J Neuroimmunol. 2018;15(317):1–4.Google Scholar
  56. 56.
    Dass S, Rawstron AC, Vital EM, Henshaw K, McGonagle D, Emery P. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum. 2008;58(10):2993–9.PubMedGoogle Scholar
  57. 57.
    Batchelor TT, Grossman SA, Mikkelsen T, Ye X, Desideri S, Lesser GJ. Rituximab monotherapy for patients with recurrent primary CNS lymphoma. Neurology. 2011;76(10):929–30.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Damato V, Evoli A, Iorio R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis. JAMA Neurol. 2016;73(11):1342–8.PubMedGoogle Scholar
  59. 59.
    Bedi GS, Brown AD, Delgado SR, Usmani N, Lam BL, Sheremata WA. Impact of rituximab on relapse rate and disability in neuromyelitis optica. Mult Scler. 2011;17(10):1225–30.PubMedGoogle Scholar
  60. 60.
    Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64(7):1270–2.PubMedGoogle Scholar
  61. 61.
    Ip VH, Lau AY, Au LW, Fan FS, Chan AY, Mok VC, et al. Rituximab reduces attacks in Chinese patients with neuromyelitis optica spectrum disorders. J Neurol Sci. 2013;324(1–2):38–9.PubMedGoogle Scholar
  62. 62.
    Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol. 2008;65(11):1443–8.PubMedGoogle Scholar
  63. 63.
    Lindsey JW, Meulmester KM, Brod SA, Nelson F, Wolinsky JS. Variable results after rituximab in neuromyelitis optica. J Neurol Sci. 2012;317(1–2):103–5.PubMedGoogle Scholar
  64. 64.
    Pellkofer HL, Krumbholz M, Berthele A, Hemmer B, Gerdes LA, Havla J, et al. Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology. 2011;76(15):1310–5.PubMedGoogle Scholar
  65. 65.
    Radaelli M, Moiola L, Sangalli F, Esposito F, Barcella V, Ferre L, et al. Neuromyelitis optica spectrum disorders: long-term safety and efficacy of rituximab in Caucasian patients. Mult Scler. 2016;22(4):511–9.PubMedGoogle Scholar
  66. 66.
    Zephir H, Bernard-Valnet R, Lebrun C, Outteryck O, Audoin B, Bourre B, et al. Rituximab as first-line therapy in neuromyelitis optica: efficiency and tolerability. J Neurol. 2015;262(10):2329–35.PubMedGoogle Scholar
  67. 67.
    Longoni G, Banwell B, Filippi M, Yeh EA. Rituximab as a first-line preventive treatment in pediatric NMOSDs: preliminary results in 5 children. Neurol Neuroimmunol Neuroinflamm. 2014;1(4):e46.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Olivieri G, Nociti V, Iorio R, Stefanini MC, Losavio FA, Mirabella M, et al. Rituximab as a first-line treatment in pediatric neuromyelitis optica spectrum disorder. Neurol Sci. 2015;36(12):2301–2.PubMedGoogle Scholar
  69. 69.
    Miljkovic D, Samardzic T, Drakulic D, Stosic-Grujicic S, Trajkovic V. Immunosuppressants leflunomide and mycophenolic acid inhibit fibroblast IL-6 production by distinct mechanisms. Cytokine. 2002;19(4):181–6.PubMedGoogle Scholar
  70. 70.
    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47(2–3):85–118.PubMedGoogle Scholar
  71. 71.
    Jiao Y, Cui L, Zhang W, Zhang C, Zhang Y, Zhang X, et al. Dose effects of mycophenolate mofetil in Chinese patients with neuromyelitis optica spectrum disorders: a case series study. BMC Neurol. 2018;18(1):47.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Mealy MA, Kim SH, Schmidt F, Lopez R, Jimenez Arango JA, Paul F, et al. Aquaporin-4 serostatus does not predict response to immunotherapy in neuromyelitis optica spectrum disorders. Mult Scler. 2017;1:1352458517730131.Google Scholar
  73. 73.
    Huh SY, Kim SH, Hyun JW, Joung AR, Park MS, Kim BJ, et al. Mycophenolate mofetil in the treatment of neuromyelitis optica spectrum disorder. JAMA Neurol. 2014;71(11):1372–8.PubMedGoogle Scholar
  74. 74.
    Jacob A, Matiello M, Weinshenker BG, Wingerchuk DM, Lucchinetti C, Shuster E, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol. 2009;66(9):1128–33.PubMedGoogle Scholar
  75. 75.
    Jeong IH, Park B, Kim SH, Hyun JW, Joo J, Kim HJ. Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints. Mult Scler. 2016;22(3):329–39.PubMedGoogle Scholar
  76. 76.
    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):324–30.PubMedGoogle Scholar
  77. 77.
    Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther. 2001;15(11):1699–708.PubMedGoogle Scholar
  78. 78.
    Mandler RN, Ahmed W, Dencoff JE. Devic’s neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology. 1998;51(4):1219–20.PubMedGoogle Scholar
  79. 79.
    Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, et al. Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain. 2008;131(Pt 11):3072–80.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, Mandrekar J, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011;77(7):659–66.PubMedGoogle Scholar
  81. 81.
    Elsone L, Kitley J, Luppe S, Lythgoe D, Mutch K, Jacob S, et al. Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK. Mult Scler. 2014;20(11):1533–40.PubMedGoogle Scholar
  82. 82.
    Bichuetti DB, Perin MMM, Souza NA, Oliveira EML. Treating neuromyelitis optica with azathioprine: 20-year clinical practice. Mult Scler. 2018;1:1352458518776584.Google Scholar
  83. 83.
    Nikoo Z, Badihian S, Shaygannejad V, Asgari N, Ashtari F. Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial. J Neurol. 2017;264(9):2003–9.PubMedGoogle Scholar
  84. 84.
    Neuhaus O, Kieseier BC, Hartung HP. Mechanisms of mitoxantrone in multiple sclerosis—what is known? J Neurol Sci. 2004;223(1):25–7.PubMedGoogle Scholar
  85. 85.
    Weinstock-Guttman B, Ramanathan M, Lincoff N, Napoli SQ, Sharma J, Feichter J, et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease). Arch Neurol. 2006;63(7):957–63.PubMedGoogle Scholar
  86. 86.
    Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler. 2002;8(2):142–54.PubMedGoogle Scholar
  87. 87.
    de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005;44(11):1135–64.PubMedGoogle Scholar
  88. 88.
    Birnbaum J, Kerr D. Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus. Nat Clin Pract Rheumatol. 2008;4(7):381–6.PubMedGoogle Scholar
  89. 89.
    Bonnet F, Mercie P, Morlat P, Hocke C, Vergnes C, Ellie E, et al. Devic’s neuromyelitis optica during pregnancy in a patient with systemic lupus erythematosus. Lupus. 1999;8(3):244–7.PubMedGoogle Scholar
  90. 90.
    Mok CC, To CH, Mak A, Poon WL. Immunoablative cyclophosphamide for refractory lupus-related neuromyelitis optica. J Rheumatol. 2008;35(1):172–4.PubMedGoogle Scholar
  91. 91.
    Arabshahi B, Pollock AN, Sherry DD, Albert DA, Kreiger PA, Pessler F. Devic disease in a child with primary Sjogren syndrome. J Child Neurol. 2006;21(4):285–6.PubMedGoogle Scholar
  92. 92.
    Chen D, Gallagher S, Monson NL, Herbst R, Wang Y. Inebilizumab, a B cell-depleting anti-CD19 antibody for the treatment of autoimmune neurological diseases: insights from preclinical studies. J Clin Med. 2016;5(12):107.PubMedCentralGoogle Scholar
  93. 93.
    Agius MA, Klodowska-Duda G, Maciejowski M, Potemkowski A, Li J, Patra K, et al. Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study. Mult Scler. 2017;1:1352458517740641.Google Scholar
  94. 94.
    Araki M, Matsuoka T, Miyamoto K, Kusunoki S, Okamoto T, Murata M, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology. 2014;82(15):1302–6.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Ringelstein M, Ayzenberg I, Harmel J, Lauenstein AS, Lensch E, Stogbauer F, et al. Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol. 2015;72(7):756–63.PubMedGoogle Scholar
  96. 96.
    Yamamura T, Araki M. Use of tocilizumab, an antibody against interleukin-6 receptor, for the treatment of neuromyelitis optica. Brain Nerve. 2014;66(10):1159–65.PubMedGoogle Scholar
  97. 97.
    Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol. 2010;28(11):1203–7.PubMedGoogle Scholar
  98. 98.
    Yamamura T, Kleiter I, Fujihara K, Palace J, Greenberg BM, Zakrzewska-Pniewska B, et al. A double-blind placebo-controlled study of satralizumab (SA237), a recycling anti-IL-6 receptor monoclonal antibody, as add-on therapy for neuromyelitis optica spectrum disorders (NMOSD). ECTRIMS Congress. 2018;2018:abstract 323.Google Scholar
  99. 99.
    Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013;12(6):554–62.PubMedGoogle Scholar
  100. 100.
    Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, et al. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci Rep. 2017;7(1):1080.PubMedPubMedCentralGoogle Scholar
  101. 101.
    de Romeuf C, Dutertre CA, Le Garff-Tavernier M, Fournier N, Gaucher C, Glacet A, et al. Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. Br J Haematol. 2008;140(6):635–43.PubMedGoogle Scholar
  102. 102.
    Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, et al. Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Investig. 2016;126(8):3036–52.PubMedGoogle Scholar
  103. 103.
    Verkman AS, Phuan PW, Asavapanumas N, Tradtrantip L. Biology of AQP4 and anti-AQP4 antibody: therapeutic implications for NMO. Brain Pathol. 2013;23(6):684–95.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Tradtrantip L, Zhang H, Saadoun S, Phuan PW, Lam C, Papadopoulos MC, et al. Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol. 2012;71(3):314–22.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Tradtrantip L, Zhang H, Anderson MO, Saadoun S, Phuan PW, Papadopoulos MC, et al. Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J. 2012;26(5):2197–208.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Vincent T, Saikali P, Cayrol R, Roth AD, Bar-Or A, Prat A, et al. Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood–brain barrier permeability and granulocyte recruitment. J Immunol. 2008;181(8):5730–7.PubMedGoogle Scholar
  107. 107.
    Shimizu F, Sano Y, Takahashi T, Haruki H, Saito K, Koga M, et al. Sera from neuromyelitis optica patients disrupt the blood–brain barrier. J Neurol Neurosurg Psychiatry. 2012;83(3):288–97.PubMedGoogle Scholar
  108. 108.
    Mealy MA, Shin K, John G, Levy M. Bevacizumab is safe in acute relapses of neuromyelitis optica. Clin Exp Neuroimmunol. 2015;6(4):413–8.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Takeshita Y, Obermeier B, Cotleur AC, Spampinato SF, Shimizu F, Yamamoto E, et al. Effects of neuromyelitis optica-IgG at the blood–brain barrier in vitro. Neurol Neuroimmunol Neuroinflamm. 2017;4(1):e311.PubMedGoogle Scholar
  110. 110.
    Uchida T, Mori M, Uzawa A, Masuda H, Muto M, Ohtani R, et al. Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: their possible role on blood–brain barrier disruption. Mult Scler. 2017;23(8):1072–84.PubMedGoogle Scholar
  111. 111.
    Tasaki A, Shimizu F, Sano Y, Fujisawa M, Takahashi T, Haruki H, et al. Autocrine MMP-2/9 secretion increases the BBB permeability in neuromyelitis optica. J Neurol Neurosurg Psychiatry. 2014;85(4):419–30.PubMedGoogle Scholar
  112. 112.
    Zhang H, Bennett JL, Verkman AS. Ex vivo spinal cord slice model of neuromyelitis optica reveals novel immunopathogenic mechanisms. Ann Neurol. 2011;70(6):943–54.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Saadoun S, Waters P, Bell BA, Vincent A, Verkman AS, Papadopoulos MC. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain. 2010;133(Pt 2):349–61.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet. 2009;373(9665):759–67.PubMedGoogle Scholar
  115. 115.
    Phuan PW, Zhang H, Asavapanumas N, Leviten M, Rosenthal A, Tradtrantip L, et al. C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica. Acta Neuropathol. 2013;125(6):829–40.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE. C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev. 2000;52(1):91–112.PubMedGoogle Scholar
  117. 117.
    Levy M, Mealy MA. Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm. 2014;1(1):e5.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Tradtrantip L, Asavapanumas N, Phuan PW, Verkman AS. Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model. PLoS One. 2014;9(9):e106824.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Hertwig L, Pache F, Romero-Suarez S, Sturner KH, Borisow N, Behrens J, et al. Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica. Mult Scler. 2016;22(2):160–73.PubMedGoogle Scholar
  120. 120.
    Jarius S, Paul F, Franciotta D, Ruprecht K, Ringelstein M, Bergamaschi R, et al. Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci. 2011;306(1–2):82–90.PubMedGoogle Scholar
  121. 121.
    Jacob A, Saadoun S, Kitley J, Leite M, Palace J, Schon F, et al. Detrimental role of granulocyte-colony stimulating factor in neuromyelitis optica: clinical case and histological evidence. Mult Scler. 2012;18(12):1801–3.PubMedGoogle Scholar
  122. 122.
    Saadoun S, Waters P, MacDonald C, Bell BA, Vincent A, Verkman AS, et al. Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain. Ann Neurol. 2012;71(3):323–33.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Aikawa N, Kawasaki Y. Clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of acute respiratory distress syndrome. Ther Clin Risk Manag. 2014;10:621–9.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Masood A, Yi M, Belcastro R, Li J, Lopez L, Kantores C, et al. Neutrophil elastase-induced elastin degradation mediates macrophage influx and lung injury in 60% O2-exposed neonatal rats. Am J Physiol Lung Cell Mol Physiol. 2015;309(1):L53–62.PubMedGoogle Scholar
  125. 125.
    Herges K, de Jong BA, Kolkowitz I, Dunn C, Mandelbaum G, Ko RM, et al. Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein. Mult Scler. 2012;18(4):398–408.PubMedPubMedCentralGoogle Scholar
  126. 126.
    von Nussbaum F, Li VM. Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores. Bioorg Med Chem Lett. 2015;25(20):4370–81.Google Scholar
  127. 127.
    Zhang H, Verkman AS. Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica. J Clin Investig. 2013;123(5):2306–16.PubMedGoogle Scholar
  128. 128.
    Zhang C, Tian DC, Yang CS, Han B, Wang J, Yang L, et al. Safety and efficacy of bortezomib in patients with highly relapsing neuromyelitis optica spectrum disorder. JAMA Neurol. 2017;74(8):1010–2.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol. 2011;68(11):1412–20.PubMedGoogle Scholar
  130. 130.
    Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013;70(9):1110–7.PubMedGoogle Scholar
  131. 131.
    Cohen M, Romero G, Bas J, Ticchioni M, Rosenthal M, Lacroix R, et al. Monitoring CD27+ memory B-cells in neuromyelitis optica spectrum disorders patients treated with rituximab: results from a bicentric study. J Neurol Sci. 2017;15(373):335–8.Google Scholar
  132. 132.
    Opelz G, Dohler B. Critical threshold of azathioprine dosage for maintenance immunosuppression in kidney graft recipients. Collaborative Transplant Study. Transplantation. 2000;69(5):818–21.PubMedGoogle Scholar
  133. 133.
    Valentino P, Marnetto F, Granieri L, Capobianco M, Bertolotto A. Aquaporin-4 antibody titration in NMO patients treated with rituximab: a retrospective study. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e317.PubMedGoogle Scholar
  134. 134.
    Chanson JB, de Seze J, Eliaou JF, Vincent T. Immunological follow-up of patients with neuromyelitis optica: is there a good biomarker? Lupus. 2013;22(3):229–32.PubMedGoogle Scholar
  135. 135.
    Chanson JB, Alame M, Collongues N, Blanc F, Fleury M, Rudolf G, et al. Evaluation of clinical interest of anti-aquaporin-4 autoantibody followup in neuromyelitis optica. Clin Dev Immunol. 2013;2013:146219.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Peschl P, Bradl M, Hoftberger R, Berger T, Reindl M. Myelin oligodendrocyte glycoprotein: deciphering a target in inflammatory demyelinating diseases. Front Immunol. 2017;8:529.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Tradtrantip L, Jin BJ, Yao X, Anderson MO, Verkman AS. Aquaporin-targeted therapeutics: state-of-the-field. Adv Exp Med Biol. 2017;969:239–50.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Wang C, Yan M, Jiang H, Wang Q, He S, Chen J, et al. Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin. Life Sci. 2018;15(193):270–81.Google Scholar
  139. 139.
    Salman MM, Kitchen P, Woodroofe MN, Brown JE, Bill RM, Conner AC, et al. Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)- and calmodulin-mediated mechanism. Eur J Neurosci. 2017;46(9):2542–7.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Harraz OF, Longden TA, Hill-Eubanks D, Nelson MT. PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells. Elife. 2018;7:7.Google Scholar
  141. 141.
    Lucchinetti CF, Guo Y, Popescu BF, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol. 2014;24(1):83–97.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6(2):159–63.PubMedGoogle Scholar
  143. 143.
    Ribeiro Mde C, Hirt L, Bogousslavsky J, Regli L, Badaut J. Time course of aquaporin expression after transient focal cerebral ischemia in mice. J Neurosci Res. 2006;83(7):1231–40.PubMedGoogle Scholar
  144. 144.
    Bargiotas P, Krenz A, Hormuzdi SG, Ridder DA, Herb A, Barakat W, et al. Pannexins in ischemia-induced neurodegeneration. Proc Natl Acad Sci USA. 2011;108(51):20772–7.PubMedGoogle Scholar
  145. 145.
    Xiong XX, Gu LJ, Shen J, Kang XH, Zheng YY, Yue SB, et al. Probenecid protects against transient focal cerebral ischemic injury by inhibiting HMGB1 release and attenuating AQP4 expression in mice. Neurochem Res. 2014;39(1):216–24.PubMedGoogle Scholar
  146. 146.
    Wang Y, Huang J, Ma Y, Tang G, Liu Y, Chen X, et al. MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4. J Cereb Blood Flow Metab. 2015;35(12):1977–84.PubMedPubMedCentralGoogle Scholar
  147. 147.
    He L, Zhang X, Wei X, Li Y. Progesterone attenuates aquaporin-4 expression in an astrocyte model of ischemia/reperfusion. Neurochem Res. 2014;39(11):2251–61.PubMedGoogle Scholar
  148. 148.
    Karasu A, Aras Y, Sabanci PA, Saglam G, Izgi N, Biltekin B, et al. The effects of protein kinase C activator phorbol dibutyrate on traumatic brain edema and aquaporin-4 expression. Ulus Travma Acil Cerrahi Derg. 2010;16(5):390–4.PubMedGoogle Scholar
  149. 149.
    Nakano T, Nishigami C, Irie K, Shigemori Y, Sano K, Yamashita Y, et al. Goreisan prevents brain edema after cerebral ischemic stroke by inhibiting aquaporin 4 upregulation in mice. J Stroke Cerebrovasc Dis. 2018;27(3):758–63.PubMedGoogle Scholar
  150. 150.
    Penton-Rol G, Cervantes-Llanos M, Martinez-Sanchez G, Cabrera-Gomez JA, Valenzuela-Silva CM, Ramirez-Nunez O, et al. TNF-alpha and IL-10 downregulation and marked oxidative stress in neuromyelitis optica. J Inflamm (Lond). 2009;2(6):18.Google Scholar
  151. 151.
    Li W, Tan C, Liu Y, Liu X, Wang X, Gui Y, et al. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia–reperfusion injury. Mol Med Rep. 2015;12(5):7756–62.PubMedGoogle Scholar
  152. 152.
    Mazumder MK, Borah A. Piroxicam confer neuroprotection in cerebral ischemia by inhibiting cyclooxygenases, acid- sensing ion channel-1a and aquaporin-4: an in silico comparison with aspirin and nimesulide. Bioinformation. 2015;11(4):217–22.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Bhattacharya P, Pandey AK, Paul S, Patnaik R, Yavagal DR. Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents. PLoS One. 2013;8(9):e73481.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Chen JH, Yang LK, Chen L, Wang YH, Wu Y, Jiang BJ, et al. Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of AQP4 expression in rabbits. Int J Mol Med. 2016;37(4):1059–66.PubMedGoogle Scholar
  155. 155.
    Zhang M, Cui Z, Cui H, Cao Y, Zhong C, Wang Y. Astaxanthin alleviates cerebral edema by modulating NKCC1 and AQP4 expression after traumatic brain injury in mice. BMC Neurosci. 2016;17(1):60.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Duan L, Di Q. Acetazolamide suppresses multi-drug resistance-related protein 1 and P-glycoprotein expression by inhibiting aquaporins expression in a mesial temporal epilepsy rat model. Med Sci Monit. 2017;8(23):5818–25.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nicolas Collongues
    • 1
    • 2
    • 3
    Email author
  • Estelle Ayme-Dietrich
    • 4
  • Laurent Monassier
    • 4
  • Jérôme de Seze
    • 1
    • 2
    • 3
  1. 1.Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS)Université de Strasbourg, Bâtiment 3 de la Faculté de MédecineStrasbourgFrance
  2. 2.Département de NeurologieCentre Hospitalier Universitaire de StrasbourgStrasbourgFrance
  3. 3.Centre d’investigation Clinique, INSERM U1434Centre Hospitalier Universitaire de StrasbourgStrasbourgFrance
  4. 4.Laboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, Fédération de Médecine Translationnelle, Faculté de MédecineUniversité de StrasbourgStrasbourgFrance

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