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1 ISSN Journal of Multiple Sclerosis 1(2):38-43, 2010 REVIEW ARTICLE 인제대학교의과대학일산백병원신경과 조중양 Recent Update of Neuromyelitis Optica Joong-Yang Cho, MD Department of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea ABSTRACT Neuromyelitis optica (NMO) is a relapsing inflammatory disorder of the central nervous system that closely resembles multiple sclerosis (MS). It is originally described as a monophasic disorder, but most of patients with NMO experience recurrent attacks with severe attack-related disability. The recently identified serum immunoglobulin marker, NMO-IgG binds selectively to the aquaporin-4 (AQP4) water channel and appears to be specific for NMO. Anti-AQP4 antibody has a pathogenetic role in the development of NMO and serves as a useful diagnostic and prognostic marker. Detection of this autoantibody has led to the categorization of NMO as an autoimmune channelopathy. Because this highly specific autoantibody marker is also found in patients with a limited form of NMO such as recurrent optic neuritis, longitudinally extensive transverse myelitis, and optic neuritis or myelitis associated with brain lesions typical of NMO, the concept of NMO has been broadened to NMO spectrum disorders. Acute attacks usually result in moderate to severe functional impairment without the absence of a secondary progressive course. Prevention of relapse is of crucial importance in the management of the disease. Journal of Multiple Sclerosis 1(2):38-43, 2010 Key Words: Neuromyelitis optica, NMO-IgG 서론 시신경척수염 (neuromyelitis optica, NMO) 은중추신경계의특발성염증성탈수초성질환으로시신경과척수를주로침범하며, 중증도의시신경염과척수염이동시에또는수주의간격을두고연속적으로발생하는단상성질환으로알려져왔다. 그러나대부분의환자에서시신경과척수증상이재발함이밝혀지면서, 1 NMO가다발성경화증 (multiple sclerosis, MS) 의한아형인지아니면독립된질환인지에대한논란이계속되어왔다. 최근에 NMO에특이적인 NMO-IgG/AQP-4 항체가발견되면서 NMO에대한비약적인발전이이루어졌다. 재발성 시신경염이나 longitudinal extensive myelitis (LEM) 질환에서도 NMO-IgG 가발견되는경우가있어, NMO 와관련한개념이 NMO 범주질환 (NMO spectrum disorders, NMOSD) 으로확장되었으며, 임상양상과기존에알려져있던 MRI 침범양상을바탕으로정한진단기준 1 이새롭게정립되었다. 2 본론 1. 역학 NMO 는서양인보다는동양인에서흔하며, 여성의빈도 Received July 26, 2010 / Accepted August 10, 2010 Address for correspondence: Joong-Yang Cho Department of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, 2240 Daewha-dong, Ilsan-gu, Goyang , Korea Tel: , Fax: , joongyangcho@gmail.com 38 대한다발성경화증학회지제 1 권제 2 호, 2010

2 가높은것으로알려져있다. 인구비례표본추출법에의한연구 (population-based study) 는 NMO에서매우제한적인데, 3,4 2003~2004년에쿠바에서시행된인구비례표본추출법에의한연구에서유병율은 10만명당 0.51이었으며, 평균연발생율은 10만명당 0.053이었고, 인종간의차이는없으며, 여성의유병율 (0.91) 이남성 (0.12) 보다높았다. 4 반면동양인에서의결과는여성이남성보다약 9배많으며, 평균시작연령은 39세로 MS보다약 10년정도차이가났다. 1 대부분기존의연구들은 2006년도에 NMO의진단기준이수정되기전연구였으며, 새로운진단기준 2 을근거로프랑스에서진행된관찰적후향적다기관연구가 2010년도에발표되었다 (Table 1) 임상양상및영상소견 MS 환자와마찬가지로대부분의 NMO 환자들은재발을한다. 시신경염과척수염이동시에발생할수도있고, 수주또는수년간격을두고발생하기도있다. 하지만 MS 와다르게 NMO 환자는중증도의발병을자주경험하고재발로부터불완전한회복으로인한장애를조기에가지는경우가많지만, 1,6 이차진행형경과를갖는경우는매우 Table 1. Demographic and disease-related characteristics of 125 patients with NMO 5 NMO Gender, n (%) Female 94 (75.2) Male 31 (24.8) Ethnicity, n (%) White 74 (87) Nonwhite 11 (13) Initial topography, n (%) Spinal 57 (45.6) Optic 46 (36.8) Optic and spinal 22 (17.6) Age at onset, yr Mean±SD 34.5±13.2 Median 34.7 Range 4-66 Opticospinal interval, mon Mean±SD 35.6±48 Median 15 Range First-second attack interval, mon Mean±SD 30.8±43.1 Median 12 Range Mean number of attacks after onset 0-1 y y 2.3 Mean annualized rate of attacks 0.99 드물다. 7 MS 환자에서보이는시신경염과는달리 NMO 환자에서의시신경염은망막의혈관성변화와함께더심하고광범한축삭손상을보인다. 8 이러한축삭손상으로인해, optical coherence tomography (OCT) 로측정된 retinal peripapillary nerve fiber layer의감소소견이관찰되며, visual acuity, visual field, disability score와어느정도상관관계를가진다. 9,10 MRI상병변은척수의중심부에위치하며길이는척수분절 3개이상인척수병변 (longitudinally extensive myelitis, LEM) 을보이고급성기에척수부종및조영증강이흔히관찰되며, 병의후반기에는척수위축과중심공동 (cavitation) 으로진행하기도한다. 11 경부척수염병변은뇌줄기 (brainstem) 까지진행하여딸꾹질, 구역또는신경성호흡부전을일으키기도한다. 1,12 그러나, 전형적인 MS의척수염병변은비대칭적이고주로주변부를침범하며, 척수분절 1개또는 2개를넘지않는다. 13 NMO에서는치명적인자율신경장애가나타나기도하는데, 흉부척수염내의자율신경계유출로 (autonomic outflow) 가침범되기때문으로사료된다 뇌척수액 급성기 CSF 검사에서는대개 50 cells/mm 3 또는 5 neutrophils/mm 3 을보인다. MS에서는약 90% 에서 oligoclonal band 가양성이지만, NMO 에서는 10~30% 에서만 oligoclonal band가양성이거나 IgG index 가증가한다. 1,6,15 Astrocyte 지표인 glial fibrillary acidic protein (GFAP) 과 S100B이상승해있어, 급성기에 astrocyte의손상이있었다는간접적인증거가되며, 16 MMP9의농도는 NMO보다 MS에서높게나타난다 NMO-IgG 21세기에들어와서 NMO-IgG라는높은질병특이도를가진항체가발견되었다. 18 간접면역형광염색을통해 NMO-IgG 항체여부를살펴본결과 NMO 및일본의 optico-spinal MS 환자의혈청에서는양성을보인반면, 전형적인 MS 환자및기타질환에서는음성을보였으며, 높은특이성을보이는자가항체의존재는그후다른연구들에서도입증되었다. 19,20 NMO-IgG 는 NMO 환자뿐아니라 LEM의첫번째발병인경우에도 40% 에서양성을보였고, 항체가양성인경우 1년이내에반수이상의환자가재발을경험해항체의존재유무가 LEM 환자의향후재발방지를위한면역치료의필요성여부를결정지을수있는한지표로사용될가능성을제시하였다. 21 또한재발성시 Journal of Multiple Sclerosis Vol. 1, No. 2,

3 조중양 신경염에서도 NMO-IgG 가시력예후와추가적인척수염재발을예측할수있다고보고되었다 Anti-aquaporin-4 (AQP4) 항체 NMO-IgG 의면역학적표적은 aquaporin-4(aqp4) 라고불리는 water channel로 astrocyte의 foot process에위치해있으며, 23 이곳은혈관뇌장벽을구성하는뇌의미세혈관들이풍부하다. Anti-AQP4 항체의특이도가높고 NMO 병변에서 AQP4 의선택적소실이관찰되어보체활성 anti-aqp4 항체가 NMO 병변의발생에중요한역할을할것이라고제시되고있다. 24 Anti-AQP4 항체가혈액뇌장벽을통과하면 AQP4 분자는 astrocyte의 foot process에부착하고보체를활성화하며, 활성화된보체는 neutrophil과 eosinophil을동원하여조직손상을유발한다. 지금까지관찰된 anti-aqp4 항체는대부분 IgG1 subclass이며보체를효율적으로고정시키는기능을한다. 이러한 astrocyte의파괴에의한이차적인탈수초화는 myelin antigen-specific T cells 과 anti-myelin autoantibodies에의한일차적탈수초화의기전과는차이를보인다. Anti-AQP4 항체는환자의말초혈액에서순환하며중추신경계에서는생성이되지않기때문에 MS와달리뇌척수액에서 IgG의클론성증가가결여되어 oligoclonal bands 가대부분관찰되지않는다. 기준이제시되었다. 또한 NMO와유사한증상을보이는환자들에서 NMO-IgG 가확인됨에따라 NMO의범위는기존에알려진것보다확장되었다. 1999년에제시된진단기준 1 이가장널리사용되어왔으나진단기준의특이도, NMO-IgG 의발견, MS와구별되는 LEM의높은특이도, 전형적인 NMO에서대뇌침범이드물지않은문제점등이있어개선이필요하였다. 새로운진단기준은 NMO 진단시시신경염과척수염이있어야하고 3가지의보조기준즉, 1) 3개이상의척추분절을침범하는광범위한척수 MRI 병변, 2) 뇌 MRI소견이 MS의진단기준을만족하지않을것, 3) NMO-IgG 혈청양성의조건중최소 2가지가필요하다 (Table 2). 2 예전과크게달라진기준중에강조할점은더이상뇌 MRI 병변의존재가제외기준이아니라는것이다. 뇌병변은발병시에는보통없거나비특이적인피질하병변이일부관찰되어이전까지 NMO 진단의제외기준으로사용되어왔었다. 하지만뇌병변은비교적흔히발견되며대부분은작고비특이적이지만약 10% 환자의경우 MS의 Barkhof MRI 기준을만족시키기도하며, 26 증상을동반한뇌병변도드물지않게관찰된다. 또한 NMO의특징적인시상하부와뇌줄기수도관주위 (periaqueductal brainstem) 의병변은높은 AQP4 발현을보이는부위와일치한다 NMO spectrum disorders (NMOSD) 6. Anti-AQP4 항체음성 NMO 재발성 NMO에서 anti-aqp4 항체양성군과음성군의임상적큰차이는없는것으로알려져있으나, 18 일본에서발표된연구에서는재발의빈도와강도가항체음성군에서약하게나타나는경향이있다고하였다. 25 단독 NMO 보다는재발성 NMO 에서양성율을높게나타나는경향이있다. 7. 시신경척수염의진단기준최근 NMO에좀더특이적이고간단하게개선된진단 시신경염과척수염이각각독립적으로발생하거나, 단독또는재발성 LEM을보이거나한쪽또는양쪽시신경염만을보이는형태는 NMO와다른질환인지아니면결국 NMO로진행될질환인지에대해여러논란이있어왔다. Table 2. Proposed diagnostic criteria for neuromyelitis optica 2 Optic neuritis Acute myelitis And at least two of three supportive criteria 1. Contiguous spinal cord MRI lesion extending over 3 vertebral segments 2. Brain MRI not meeting diagnostic criteria for multiple sclerosis 3. NMO-IgG seropositive status Table 3. The Neuromyelitis optica spectrum disorders 28 Neuromyelitis optica Limited forms of neuromyelitis optica Idiopathic single or recurrent events of longitudinally extensive myelitis ( 3 vertebral segment spinal cord lesion seen on MRI) Optic neuritis (often severe): recurrent or simultaneous bilateral Asian optic-spinal multiple sclerosis Optic neuritis or longitudinally extensive myelitis associated with systemic autoimmune disease Optic neuritis or myelitis associated with brain lesions typical of neuromyelitis optica (hypothalamic, corpus callosal, periventricular, or brainstem) 40 대한다발성경화증학회지제 1 권제 2 호, 2010

4 그러나 NMO-IgG 의존재를통해이러한제한된형태의질환들이 NMO와관련이있다고밝혀졌으며 NMOSD 로정립되었다 (Table 3). 28 Anti-AQP4 항체는중추신경계염증성탈수초성질환에서특정표적항원에대해발견된첫번째항체로, 중추신경계물분자의이동에관여하기때문에여러질환과의관련성에대해주목받고있으며, 증상성뇌침범으로인한내분비이상 (endocrinopathy) 29 이나뇌병증 (posterior reversible encephalopathy syndrome, PRES) 30, 전신적자가면역질환과동반등이언급되고있다. Mayo Clinic 의보고에의하면 NMO 환자 5명에서 PRES를경험하였고, 모두 NMO-IgG 항체양성이었으나, NMO 가아닌 14명의 PRES 를환자에서는 NMO-IgG가음성이었다. 30 NMO 환자나 LETM 환자중에서중증도의침샘염증이종종발견되어, 쇼그렌증후과 NMOSD 와의관련성이제시되었다. 침샘에서는 AQP4 보다는 AQP5 의발현이높은것으로알려져있으나, AQP5 는 AQP4와약 50% protein sequence를공유하므로 NMOSD 환자는 AQP4 와 AQP5의 homologous portion을인지하는 autoreactive cells에의해중추신경계와침샘에염증을동반한다고사료된다. 31 그밖에 NMO-IgG 와부종양현상 (paraneoplastic phenomenon) 의관련성도제시되고있다 Anti-AQP4 자가면역에근거한 NMO 병인의제한점 NMO 병인을전적으로 anti-aqp4 항체의자가면역에의한것이라고정의하기에는몇가지제한점이있다. 첫째, NMO와 anti-aqp4 항체와의직접적인상관관계인데, anti-aqp4 항체의역가가높은데도불구하고완화 (remission) 상태에있는경우도있고, 33 반대로 anti-aqp4 항체를가지고있으면서 NMO의임상양상을보이지않는경우도있다. 32 또한 AQP4 는혈액뇌장벽뒤의 astrocyte의 foot process에위치하기때문에, 재발을유발하기위해서는혈액뇌장벽을파괴하여항체를중추신경계로통과할수있게하는추가적인요소들이필요하다. 실제로동물모델에서 anti-aqp4 항체가중추신경계안에서작동하기위해서는 myelin antigen-specific T-cells이필요하다. 34,35 따라서, anti-aqp4 항체역가와지금까지밝혀진임상지표들과의연관성에논쟁이있는것은다른추가적인요소들이재발을유발하기위해필요하다는것을뒷받침해준다. 둘째, AQP4는망막, 원위부 collecting tubules, gastric mucosa, 근육과폐에존재하며, NMO-IgG 와잘결합하지만, 28 지금까지이러한조직의손상이밝혀지지않았다. 또한 Müller 세포의 foot process에서 AQP4 발현이풍부하지만 anti-aqp4 항체양성인 NMO 환자에서중증도 의염증소견이발견되지않았다는것은보체고정 (complementfixing) anti-aqp4 항체만으로조직손상을유발하기에는충분하지않다는것을시사한다. 셋째, NMO 병변의부검소견은주로 IgM의침착이지만, anti-aqp4 항체는 90% 이상이 IgG라는사실과, 36 마지막으로 MS plaque에서 AQP4 의소실이관찰되는경우고있으며, 반대로 NMO 병변에서 AQP4의보존이관찰되기도하는결과는 37 아마도 AQP4 의소실이 NMO 병변형성의전부는아니라는것을시사한다 Anti-AQP4 검사의임상적유용성 시신경염이나횡단성척수염또는탈수초질환을시사하는비전형적인뇌 MRI 병변을가진모든환자를다검사하면좋겠으나, 고가의검사비등으로인해실용적이지는못하다. 임상적으로전형적인 NMO 환자에서는 anti-aqp4 항체의양성유무와관계없이치료방법은동일하기때문에, 반드시 NMO-IgG 검사가필요한것은아니다. 그러나척수 MRI 병변이척수 3분절은넘지않지만긴탈수초성을보이는경우, 중증도의시신경염이나 LEM이처음발생한경우등진단이명확하지않을때는 NMO-IgG 검사가중요하다. 이러한경우, anti-aqp4 항체가양성이라면 NMOSD 가능성이높으며, 향후재발가능성과예방적면역요법을고려해야하기때문이다. 그러나임상적으로전형적인 NMO이거나척수염이짧은분절을침범하거나오직척수의주변부를침범한경우, 예후가매우좋은시신경만을보이는경우, 임상적으로나신경학적소견이전형적인 MS인경우에는필요성이감소한다. 39 Anti-AQP4 항체역가와재발의상관관계에대해서는논란의여지가있다. 최근연구에의하면 anti-aqp4 항체역가와 CD19 cells 은재발하기전에상승하고치료하면서감소한다고보고하였으나, 40 재발이항상항체역가가높았을경우에발생하는것은아니어서항체만으로재발을유도한다고하기에는불충분하다. 11. NMO 치료 NMO의급성발병이나재발방지를위한치료는이에관한대규모임상시험이이루어지지않아대부분증례보고나전문가의의견을바탕으로하여이루어지고있다. NMO 급성발병시고용량의 methylprednisolone 정주요법이흔히사용된다. Methylprednisolone으로호전을보이는않는환자에게는혈장교환술이효과적이다. 41 재발성 NMO 환자의경우 MS 재발방지를위해사용 Journal of Multiple Sclerosis Vol. 1, No. 2,

5 조중양 되는 interferon 등은효과가없는것으로알려져있고면역억제요법이주로사용된다. Azathioprine과 prednisone 단독혹은병용요법이 NMO 환자의장기치료로흔히이용된다. 42 Mitoxantrone은조기에매우강력한면역억제및조정효과를보여임상적및영상의학적으로효과가있으며대개이치료에대해무난한적응을보이지만심장독성으로인한심박출량의감소가발생할수있어주의를요하며일정용량이상은사용할수없다. 43 Mycophenolate mofetil 은 azathioprine에반응하지않는경우관해유도와유지에사용한다. 44,45 CD20 양성 B 세포들에특이적인단클론항체인 rituximab 또한 NMO 치료에이용되고있으나, 진행성다초점백색질뇌증 (progressive multifocal leukoencephalopathy) 의주의를요한다. 46 결론 최근특이생물학적표지자 (specific biomarker) 와표적항원의발견, 그리고면역병리학적연구들의발전으로 NMO 에대한개념이새롭게정립되었다. 그러나환자의치료결과는아직도초기진단과재발에대한적극적치료, 초기의효과적인면역억제요법에따라장애정도가결정되기때문에 NMOSD 를조기에진단하는것이중요하다. 향후여러연구들을통해원인병인론, 유전적감수성, NMO-IgG의병인, NMO 의자연사와최선의치료에대해발전이있을것으로기대된다. REFERENCES 1. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999;53: Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66: Cabre P, Heinzlef O, Merle H, Buisson GG, Bera O, Bellance R, et al. MS and neuromyelitis optica in Martinique (French West Indies). Neurology 2001;56: Cabrera-Gomez JA, Kurtzke JF, Gonzalez-Quevedo A, Lara- Rodriguez R. An epidemiological study of neuromyelitis optica in Cuba. J Neurol 2009;256: 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: 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: Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA, Weinshenker BG. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007;68: Green AJ, Cree BA. Distinctive retinal nerve fibre layer and vascular changes in neuromyelitis optica following optic neuritis. J Neurol Neurosurg Psychiatry 2009;80: de Seze J, Blanc F, Jeanjean L, Zephir H, Labauge P, Bouyon M, et al. Optical coherence tomography in neuromyelitis optica. Arch Neurol 2008;65: Merle H, Olindo S, Donnio A, Richer R, Smadja D, Cabre P. Retinal peripapillary nerve fiber layer thickness in neuromyelitis optica. Invest Ophthalmol Vis Sci 2008;49: Filippi M, Rocca MA. MR imaging of Devic's neuromyelitis optica. Neurol Sci 2004;25 Suppl 4:S Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y. Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology 2005;65: Bot JC, Barkhof F, Polman CH, Lycklama a Nijeholt GJ, de Groot V, Bergers E, et al. Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination. Neurology 2004;62: Baudoin D, Gambarelli D, Gayraud D, Bensa P, Nicoli F, Sudan N, et al. Devic's neuromyelitis optica: a clinicopathological review of the literature in connection with a case showing fatal dysautonomia. Clin Neuropathol 1998;17: 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: Miyazawa I, Nakashima I, Petzold A, Fujihara K, Sato S, Itoyama Y. High CSF neurofilament heavy chain levels in neuromyelitis optica. Neurology 2007;68: Mandler RN, Dencoff JD, Midani F, Ford CC, Ahmed W, Rosenberg GA. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in cerebrospinal fluid differ in multiple sclerosis and Devic's neuromyelitis optica. Brain 2001;124: 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: Zuliani L, Lopez de Munain A, Ruiz Martinez J, Olascoaga J, Graus F, Saiz A. [NMO-IgG antibodies in neuromyelitis optica: a report of 2 cases]. Neurologia 2006;21: Jarius S, Franciotta D, Bergamaschi R, Wright H, Littleton E, Palace J, et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007;68: 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: 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: 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: Minohara M, Ochi H, Matsushita S, Irie A, Nishimura Y, Kira J. Differences between T-cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls. Tissue Antigens 2001;57: 대한다발성경화증학회지제 1 권제 2 호, 2010

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The Window of Multiple Sclerosis

THE WINDOW OF MULTIPLE SCLEROSIS Vol.2 No.1 MAR 2009 Topic Review Article Review 01. 02. 03. 04. Case Review The Window of Multiple Sclerosis THE WINDOW OF MULTIPLE SCLEROSIS The Window of Multiple Sclerosis