J Clin Neurol.  2011 Sep;7(3):115-127. 10.3988/jcn.2011.7.3.115.

New Insights into Neuromyelitis Optica

• Kim W
• Kim SH
• Kim HJ

• KMID: 2287626
• DOI: http://doi.org/10.3988/jcn.2011.7.3.115

Abstract

Neuromyelitis optica (NMO) is an idiopathic inflammatory disorder of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. In Asia, NMO has long been considered a subtype of multiple sclerosis (MS). However, recent clinical, pathological, immunological, and imaging studies have suggested that NMO is distinct from MS. This reconsideration of NMO was initially prompted by the discovery of a specific antibody for NMO (NMO-IgG) in 2004. NMO-IgG is an autoantibody that targets aquaporin-4 (AQP4), the most abundant water channel in the CNS; hence, it was named anti-AQP4 antibody. Since it demonstrated reasonable sensitivity and high specificity, anti-AQP4 antibody was incorporated into new diagnostic criteria for NMO.The spectrum of NMO is now known to be wider than was previously recognized and includes a proportion of patients with recurrent, isolated, longitudinally extensive myelitis or optic neuritis, and longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease or with brain lesions typical of NMO. In this context, a new concept of "NMO spectrum disorders" was recently introduced. Furthermore, seropositivity for NMO-IgG predicts future relapses and is recognized as a prognostic marker for NMO spectrum disorders. Humoral immune mechanisms, including the activation of B-cells and the complement pathway, are considered to play important roles in NMO pathogenesis. This notion is supported by recent studies showing the potential pathogenic role of NMO-IgG as an initiator of NMO lesions. However, a demonstration of the involvement of NMO-IgG by the development of active immunization and passive transfer in animal models is still needed. This review focuses on the new concepts of NMO based on its pathophysiology and clinical characteristics. Potential management strategies for NMO in light of its pathomechanism are also discussed.

Keyword

neuromyelitis optica; Devic's disease; neuromyelitis optica spectrum disorder; pathogenesis; diagnosis; management

MeSH Terms

Asia
Autoimmune Diseases
B-Lymphocytes
Brain
Central Nervous System
Complement System Proteins
Humans
Light
Models, Animal
Multiple Sclerosis
Myelitis
Neuromyelitis Optica
Optic Nerve
Optic Neuritis
Recurrence
Sensitivity and Specificity
Spinal Cord
Vaccination
Water
Complement System Proteins
Water

Reference

1. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007. 6:805–815.

2. Allbutt T. On the ophthalmoscopic signs of spinal disease. Lancet. 1870. 1:76–78.

3. Devic E. Myelite subaigue compliquee de nevrite optique. Bull Med (Paris). 1894. 8:1033–1034.

4. 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. 364:2106–2112.

5. 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. 202:473–477.

6. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006. 66:1485–1489.

7. Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Opin Neurol. 2007. 20:255–260.

8. Cabrera-Gómez JA, Kurtzke JF, González-Quevedo A, Lara-Rodríguez R. An epidemiological study of neuromyelitis optica in Cuba. J Neurol. 2009. 256:35–44.

9. Cabre P. Environmental changes and epidemiology of multiple sclerosis in the French West Indies. J Neurol Sci. 2009. 286:58–61.

10. Bizzoco E, Lolli F, Repice AM, Hakiki B, Falcini M, Barilaro A, et al. Prevalence of neuromyelitis optica spectrum disorder and phenotype distribution. J Neurol. 2009. 256:1891–1898.

11. Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol. 2003. 2:117–127.

12. Cree BA, Khan O, Bourdette D, Goodin DS, Cohen JA, Marrie RA, et al. Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology. 2004. 63:2039–2045.

13. Papais-Alvarenga RM, Miranda-Santos CM, Puccioni-Sohler M, de Almeida AM, Oliveira S, Basilio De Oliveira CA, et al. Optic neuromyelitis syndrome in Brazilian patients. J Neurol Neurosurg Psychiatry. 2002. 73:429–435.

14. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology. 1999. 53:1107–1114.

15. de Seze J, Lebrun C, Stojkovic T, Ferriby D, Chatel M, Vermersch P. Is Devic's neuromyelitis optica a separate disease? A comparative study with multiple sclerosis. Mult Scler. 2003. 9:521–525.

16. Davis R, Thiele E, Barnes P, Riviello JJ Jr. Neuromyelitis optica in childhood: case report with sequential MRI findings. J Child Neurol. 1996. 11:164–167.

17. Banwell B, Tenembaum S, Lennon VA, Ursell E, Kennedy J, Bar-Or A, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology. 2008. 70:344–352.

18. McKeon A, Lennon VA, Lotze T, Tenenbaum S, Ness JM, Rensel M, et al. CNS aquaporin-4 autoimmunity in children. Neurology. 2008. 71:93–100.

19. Filley CM, Sternberg PE, Norenberg MD. Neuromyelitis optica in the elderly. Arch Neurol. 1984. 41:670–672.

20. McAlpine D. Familial neuromyelitis optica: its occurrence in identical twins. Brain. 1938. 61:430–438.

21. Ch'ien LT, Medeiros MO, Belluomini JJ, Lemmi H, Whitaker JN. Neuromyelitis optica (Devic's syndrome) in two sisters. Clin Electroencephalogr. 1982. 13:36–39.

22. Yamakawa K, Kuroda H, Fujihara K, Sato S, Nakashima I, Takeda A, et al. Familial neuromyelitis optica (Devic's syndrome) with late onset in Japan. Neurology. 2000. 55:318–320.

23. Keegan M, Weinshenker B. Familial Devic's disease. Can J Neurol Sci. 2000. 27:557–558.

24. Cabrera-Gómez JA, Ramón-Pérez L, Saiz A, Llerena-Fernández P, Fernández-Fernández L, Ercilla G, et al. Neuromyelitis optica and multiple sclerosis in sisters. Mult Scler. 2009. 15:269–271.

25. Matiello M, Kim HJ, Kim W, Brum DG, Barreira AA, Kingsbury DJ, et al. Familial neuromyelitis optica. Neurology. 2010. 75:310–315.

26. Yamasaki K, Horiuchi I, Minohara M, Kawano Y, Ohyagi Y, Yamada T, et al. HLA-DPB1^*0501-associated opticospinal multiple sclerosis: clinical, neuroimaging and immunogenetic studies. Brain. 1999. 122:1689–1696.

27. Ito H, Yamasaki K, Kawano Y, Horiuchi I, Yun C, Nishimura Y, et al. HLA-DP-associated susceptibility to the optico-spinal form of multiple sclerosis in the Japanese. Tissue Antigens. 1998. 52:179–182.

28. Misu T, Fujihara K, Nakashima I, Miyazawa I, Okita N, Takase S, et al. Pure optic-spinal form of multiple sclerosis in Japan. Brain. 2002. 125:2460–2468.

29. Wang H, Dai Y, Qiu W, Zhong X, Wu A, Wang Y, et al. HLA-DPB1 0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in southern Han Chinese. J Neuroimmunol. 2011. 233:181–184.

30. 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. 125:1450–1461.

31. Itoh T, Rai T, Kuwahara M, Ko SB, Uchida S, Sasaki S, et al. Identification of a novel aquaporin, AQP12, expressed in pancreatic acinar cells. Biochem Biophys Res Commun. 2005. 330:832–838.

32. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol. 2006. 63:964–968.

33. Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci. 2003. 4:991–1001.

34. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997. 17:171–180.

35. Crane JM, Tajima M, Verkman AS. Live-cell imaging of aquaporin-4 diffusion and interactions in orthogonal arrays of particles. Neuroscience. 2010. 168:892–902.

36. Marnetto F, Hellias B, Granieri L, Frau J, Patanella AK, Nytrova P, et al. Western blot analysis for the detection of serum antibodies recognizing linear Aquaporin-4 epitopes in patients with Neuromyelitis Optica. J Neuroimmunol. 2009. 217:74–79.

37. Mader S, Lutterotti A, Di Pauli F, Kuenz B, Schanda K, Aboul-Enein F, et al. Patterns of antibody binding to aquaporin-4 isoforms in neuromyelitis optica. PLoS One. 2010. 5:e10455.

38. Weinshenker BG, Wingerchuk DM, Vukusic S, Linbo L, Pittock SJ, Lucchinetti CF, et al. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann Neurol. 2006. 59:566–569.

39. Matiello M, Lennon VA, Jacob A, Pittock SJ, Lucchinetti CF, Wingerchuk DM, et al. NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology. 2008. 70:2197–2200.

40. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain. 2007. 130:1235–1243.

41. 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. 131:3072–3080.

42. Kim HJ, Li XF, Kim W, Kim SH, Choi K, Lee JE, et al. Quantitative measurement of anti-aquaporin-4 antibody by enzyme-linked immunosorbent assay using purified human aquaporin-4 [abstract P60]. Proceedings of 4th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis. 2010. Singapore. 1290.

43. 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. 130:1224–1234.

44. 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. 69:2221–2231.

45. Waters P, Jarius S, Littleton E, Leite MI, Jacob S, Gray B, et al. Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis. Arch Neurol. 2008. 65:913–919.

46. Kinoshita M, Nakatsuji Y, Moriya M, Okuno T, Kumanogoh A, Nakano M, et al. Astrocytic necrosis is induced by anti-aquaporin-4 antibody-positive serum. Neuroreport. 2009. 20:508–512.

47. 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. 181:5730–5737.

48. Takano R, Misu T, Takahashi T, Sato S, Fujihara K, Itoyama Y. Astrocytic damage is far more severe than demyelination in NMO: a clinical CSF biomarker study. Neurology. 2010. 75:208–216.

49. 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. 205:2473–2481.

50. Marignier R, Giraudon P, Vukusic S, Confavreux C, Honnorat J. Anti-aquaporin-4 antibodies in Devic's neuromyelitis optica: therapeutic implications. Ther Adv Neurol Disord. 2010. 3:311–321.

51. Kinoshita M, Nakatsuji Y, Kimura T, Moriya M, Takata K, Okuno T, et al. Neuromyelitis optica: Passive transfer to rats by human immunoglobulin. Biochem Biophys Res Commun. 2009. 386:623–627.

52. 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. 133:349–361.

53. 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. 66:630–643.

54. Bennett JL, Lam C, Kalluri SR, Saikali P, Bautista K, Dupree C, et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol. 2009. 66:617–629.

55. Sharma R, Fischer MT, Bauer J, Felts PA, Smith KJ, Misu T, et al. Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination. Acta Neuropathol. 2010. 120:223–236.

56. Kalluri SR, Rothhammer V, Staszewski O, Srivastava R, Petermann F, Prinz M, et al. Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica. PLoS One. 2011. 6:e16083.

57. Jarius S, Franciotta D, Bergamaschi R, Wildemann B, Wandinger KP. Immunoglobulin M antibodies to aquaporin-4 in neuromyelitis optica and related disorders. Clin Chem Lab Med. 2010. 48:659–663.

58. Pittock SJ, Lennon VA, de Seze J, Vermersch P, Homburger HA, Wingerchuk DM, et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch Neurol. 2008. 65:78–83.

59. Pittock SJ, Weinshenker BG, Wingerchuk D, Lucchinetti CF, Lennon VA. Autoimmune neurological accompaniments of neuromyelitis optica (NMO). Ann Neurol. 2006. 60:S41.

60. Furukawa Y, Yoshikawa H, Yachie A, Yamada M. Neuromyelitis optica associated with myasthenia gravis: characteristic phenotype in Japanese population. Eur J Neurol. 2006. 13:655–658.

61. Kister I, Gulati S, Boz C, Bergamaschi R, Piccolo G, Oger J, et al. Neuromyelitis optica in patients with myasthenia gravis who underwent thymectomy. Arch Neurol. 2006. 63:851–856.

62. Antoine JC, Camdessanché JP, Absi L, Lassablière F, Féasson L. Devic disease and thymoma with anti-central nervous system and antithymus antibodies. Neurology. 2004. 62:978–980.

63. Magaña SM, Pittock SJ, Lennon VA, Keegan BM, Weinshenker BG, Lucchinetti CF. NMO-IgG status in fulminant CNS inflammatory demyelinating disorders (IDD). Neurology. 2007. 68:A160. Abstract.

64. Mandler RN. Neuromyelitis optica - Devic's syndrome, update. Autoimmun Rev. 2006. 5:537–543.

65. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival. Neurology. 2003. 60:848–853.

66. Kim W, Kim SH, Lee SH, Li XF, Kim HJ. Brain abnormalities as an initial manifestation of neuromyelitis optica spectrum disorder. Mult Scler. 2011. 17:1107–1112.

67. Lotze TE, Northrop JL, Hutton GJ, Ross B, Schiffman JS, Hunter JV. Spectrum of pediatric neuromyelitis optica. Pediatrics. 2008. 122:e1039–e1047.

68. Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y. Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology. 2005. 65:1479–1482.

69. Riphagen J, Modderman P, Verrips A. Hiccups, nausea, and vomiting: water channels under attack! Lancet. 2010. 375:954.

70. Pittock SJ, Lennon VA, Krecke K, Wingerchuk DM, Lucchinetti CF, Weinshenker BG. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006. 63:390–396.

71. Li Y, Xie P, Lv F, Mu J, Li Q, Yang Q, et al. Brain magnetic resonance imaging abnormalities in neuromyelitis optica. Acta Neurol Scand. 2008. 118:218–225.

72. Cabrera-Gómez J, Saiz-Hinarejos A, Graus F, González-Quevedo A, Rodríguez-Rojas R, Quevedo-Sotolongo L, et al. Brain magnetic resonance imaging findings in acute relapses of neuromyelitis optica spectrum disorders. Mult Scler. 2008. 14:248–251.

73. Kim W, Park MS, Lee SH, Kim SH, Jung IJ, Takahashi T, et al. Characteristic brain magnetic resonance imaging abnormalities in central nervous system aquaporin-4 autoimmunity. Mult Scler. 2010. 16:1229–1236.

74. Ito S, Mori M, Makino T, Hayakawa S, Kuwabara S. "Cloud-like enhancement" is a magnetic resonance imaging abnormality specific to neuromyelitis optica. Ann Neurol. 2009. 66:425–428.

75. Kim JE, Kim SM, Ahn SW, Lim BC, Chae JH, Hong YH, et al. Brain abnormalities in neuromyelitis optica. J Neurol Sci. 2011. 302:43–48.

76. Saiki S, Ueno Y, Moritani T, Sato T, Sekine T, Kawajiri S, et al. Extensive hemispheric lesions with radiological evidence of blood-brain barrier integrity in a patient with neuromyelitis optica. J Neurol Sci. 2009. 284:217–219.

77. Magaña SM, Matiello M, Pittock SJ, McKeon A, Lennon VA, Rabinstein AA, et al. Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology. 2009. 72:712–717.

78. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica. Tohoku J Exp Med. 2006. 210:307–313.

79. Tanaka Y, Kimura K, Kawachi I, Inuzuka T. No relapse of neuromyelitis optica during drug-induced B-lymphopenia with hypogammaglobulinemia. Neurology. 2010. 75:1745–1747.

80. Matsuoka T, Matsushita T, Kawano Y, Osoegawa M, Ochi H, Ishizu T, et al. Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese. Brain. 2007. 130:1206–1223.

81. Paul F, Jarius S, Aktas O, Bluthner M, Bauer O, Appelhans H, et al. Antibody to aquaporin 4 in the diagnosis of neuromyelitis optica. PLoS Med. 2007. 4:e133.

82. Hayakawa S, Mori M, Okuta A, Kamegawa A, Fujiyoshi Y, Yoshiyama Y, et al. Neuromyelitis optica and anti-aquaporin-4 antibodies measured by an enzyme-linked immunosorbent assay. J Neuroimmunol. 2008. 196:181–187.

83. Fazio R, Malosio ML, Lampasona V, De Feo D, Privitera D, Marnetto F, et al. Antiacquaporin 4 antibodies detection by different techniques in neuromyelitis optica patients. Mult Scler. 2009. 15:1153–1163.

84. Bergamaschi R, Tonietti S, Franciotta D, Candeloro E, Tavazzi E, Piccolo G, et al. Oligoclonal bands in Devic's neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations. Mult Scler. 2004. 10:2–4.

85. Zaffaroni M. Italian Devic's Study Group. Cerebrospinal fluid findings in Devic's neuromyelitis optica. Neurol Sci. 2004. 25:S368–S370.

86. Argyriou AA, Makris N. Neuromyelitis optica: a distinct demyelinating disease of the central nervous system. Acta Neurol Scand. 2008. 118:209–217.

87. Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008. 14:1157–1174.

88. Chan KH, Tsang KL, Fong GC, Cheung RT, Ho SL. Idiopathic severe recurrent transverse myelitis: a restricted variant of neuromyelitis optica. Clin Neurol Neurosurg. 2005. 107:132–135.

89. Kidd D, Burton B, Plant GT, Graham EM. Chronic relapsing inflammatory optic neuropathy (CRION). Brain. 2003. 126:276–284.

90. Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, et al. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010. 17:1019–1032.

91. Bennetto L, Totham A, Healy P, Massey E, Scolding N. Plasma exchange in episodes of severe inflammatory demyelination of the central nervous system. A report of six cases. J Neurol. 2004. 251:1515–1521.

92. Lehmann HC, Hartung HP, Hetzel GR, Stüve O, Kieseier BC. Plasma exchange in neuroimmunological disorders: Part 1: Rationale and treatment of inflammatory central nervous system disorders. Arch Neurol. 2006. 63:930–935.

93. Narita YM, Hirahara K, Mizukawa Y, Kano Y, Shiohara T. Efficacy of plasmapheresis for the treatment of severe toxic epidermal necrolysis: is cytokine expression analysis useful in predicting its therapeutic efficacy? J Dermatol. 2011. 38:236–245.

94. Weinshenker BG, O'Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Dodick DW, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol. 1999. 46:878–886.

95. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker BG. Plasma exchange for severe attacks of CNS demyelination: predictors of response. Neurology. 2002. 58:143–146.

96. Ruprecht K, Klinker E, Dintelmann T, Rieckmann P, Gold R. Plasma exchange for severe optic neuritis: treatment of 10 patients. Neurology. 2004. 63:1081–1083.

97. Watanabe S, Nakashima I, Misu T, Miyazawa I, Shiga Y, Fujihara K, et al. Therapeutic efficacy of plasma exchange in NMO-IgG-positive patients with neuromyelitis optica. Mult Scler. 2007. 13:128–132.

98. Bonnan M, Valentino R, Olindo S, Mehdaoui H, Smadja D, Cabre P. Plasma exchange in severe spinal attacks associated with neuromyelitis optica spectrum disorder. Mult Scler. 2009. 15:487–492.

99. Llufriu S, Castillo J, Blanco Y, Ramió-Torrentà L, Río J, Vallès M, et al. Plasma exchange for acute attacks of CNS demyelination: Predictors of improvement at 6 months. Neurology. 2009. 73:949–953.

100. Wang KC, Wang SJ, Lee CL, Chen SY, Tsai CP. The rescue effect of plasma exchange for neuromyelitis optica. J Clin Neurosci. 2011. 18:43–46.

101. Munemoto M, Otaki Y, Kasama S, Nanami M, Tokuyama M, Yahiro M, et al. Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis. J Clin Neurosci. 2011. 18:478–480.

102. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010. CD002063.

103. Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile. Pharmacol Ther. 2004. 102:177–193.

104. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options Neurol. 2008. 10:55–66.

105. Warabi Y, Matsumoto Y, Hayashi H. Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J Neurol Sci. 2007. 252:57–61.

106. Shimizu J, Hatanaka Y, Hasegawa M, Iwata A, Sugimoto I, Date H, et al. IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology. 2010. 75:1423–1427.

107. Palace J, Leite MI, Nairne A, Vincent A. Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol. 2010. 67:1016–1017.

108. Invernizzi P, Benedetti MD, Poli S, Monaco S. Azathioprine in multiple sclerosis. Mini Rev Med Chem. 2008. 8:919–926.

109. Hommes OR, Weiner HL. Clinical practice of immunosuppressive treatments in multiple sclerosis: results of a second international questionnaire. J Neurol Sci. 2004. 223:65–67.

110. Mandler RN, Ahmed W, Dencoff JE. Devic's neuromyelitis optica: a prospective study of seven patients treated with prednisone and azathioprine. Neurology. 1998. 51:1219–1220.

111. La Mantia L, Mascoli N, Milanese C. Azathioprine. Safety profile in multiple sclerosis patients. Neurol Sci. 2007. 28:299–303.

112. Watanabe S, Misu T, Miyazawa I, Nakashima I, Shiga Y, Fujihara K, et al. Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis. Mult Scler. 2007. 13:968–974.

113. Ginzler EM, Aranow C, Merrill JT, Orloff K, Henry D. Toxicity and tolerability of mycophenolate mofetil (MMF) vs intravenous cyclophosphamide (IVC) in a multicenter trial as induction therapy for lupus nephritis (LN). Arthritis Rheum. 2003. 48:S647.

114. Falcini F, Trapani S, Ricci L, Resti M, Simonini G, de Martino M. Sustained improvement of a girl affected with Devic's disease over 2 years of mycophenolate mofetil treatment. Rheumatology (Oxford). 2006. 45:913–915.

115. 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. 66:1128–1133.

116. Zwerner J, Fiorentino D. Mycophenolate mofetil. Dermatol Ther. 2007. 20:229–238.

117. Fidler JM, DeJoy SQ, Smith FR 3rd, Gibbons JJ Jr. Selective immunomodulation by the antineoplastic agent mitoxantrone. II. Nonspecific adherent suppressor cells derived from mitoxantrone-treated mice. J Immunol. 1986. 136:2747–2754.

118. 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. 63:957–963.

119. Kim SH, Kim W, Park MS, Sohn EH, Li XF, Kim HJ. Efficacy and safety of mitoxantrone in patients with highly relapsing neuromyelitis optica. Arch Neurol. 2011. 68:473–479.

120. Cohen BA, Mikol DD. Mitoxantrone treatment of multiple sclerosis: safety considerations. Neurology. 2004. 63:S28–S32.

121. Ellis R, Boggild M. Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it? Mult Scler. 2009. 15:505–508.

122. Bakker J, Metz L. Devic's neuromyelitis optica treated with intravenous gamma globulin (IVIG). Can J Neurol Sci. 2004. 31:265–267.

123. Okada K, Tsuji S, Tanaka K. Intermittent intravenous immunoglobulin successfully prevents relapses of neuromyelitis optica. Intern Med. 2007. 46:1671–1672.

124. 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. 64:1270–1272.

125. 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. 65:1443–1448.

126. 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. [Epub ahead of print].

127. Ibrahim H, Dimachkie MM, Shaibani A. A review: the use of rituximab in neuromuscular diseases. J Clin Neuromuscul Dis. 2010. 12:91–102.

128. Tyler KL. Progressive multifocal leukoencephalopathy: can we reduce risk in patients receiving biological immunomodulatory therapies? Ann Neurol. 2010. 68:271–274.

129. Miyamoto K, Kusunoki S. Intermittent plasmapheresis prevents recurrence in neuromyelitis optica. Ther Apher Dial. 2009. 13:505–508.