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1 ISSN Journal of Multiple Sclerosis 9(1):1-6, 2018 REVIEW ARTICLE 수초희소돌기아교세포당단백질항체연관중추신경염증질환 영남대학교의과대학신경과학교실 류성근박민수 Myelin Oligodendrocyte Glycoprotein Immunoglobulin-G Associated Central Nervous System Inflammatory Disorder Seong Geun Ryu, MD, Min Su Park, MD Department of Neurology, Yeungnam University College of Medicine, Daegu, Korea ABSTRACT Autoantibody against myelin oligodendrocyte glycoprotein (MOG) has been recently recognized as a new inflammatory disease entity distinct from multiple sclerosis (MS) and aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD). MOG autoantibody may cause oligodendrocyte damage and myelin dysfunction without astrocytopathy. MOG-immunoglobulin G (IgG) is detected in 4-10% of central nervous system (CNS) inflammatory demyelinating disorders that include MS, NMOSD, acute disseminated encephalomyelitis (ADEM), idiopathic optic neuritis and idiopathic acute transverse myelitis. MOG-IgG disease affects female slightly more than male. The most common clinical phenotype is optic neuritis followed by myelitis, brainstem symptoms, ADEM like presentation and multifocal involvement. About 50-80% of MOG-IgG disease have relapsing disease course and relapsing optic neuritis is the most common clinical syndrome. Acute treatment and long term maintenance therapy are needed in MOG-IgG disease. Prognosis in MOG-IgG disease has more favorable outcome than AQP4 antibody positive NMOSD. Journal of Multiple Sclerosis 9(1):1-6, 2018 Key Words: Myelin oligodendrocyte glycoprotein, Neuromyelitis optica spectrum disorder, Aquaporin 4 서론 수초희소돌기아교세포당단백질 (myelin oligodendrocyte glycoprotein, MOG) 은중추신경계말이집 (myelin sheath) 의표면과희소돌기아교세포의형질막에분포하는단백질이다. 1 세포분석기법이발달함에따라시신경척수염범주질환 (neuromyelitis optica spectrum disorder, NMOSD), 급성파종성뇌척수염 (acute disseminated encephalomyelitis, ADEM), 특발성시신경염, 특발성척수염그리고드물게다발성경화증 (multiple sclerosis, MS) 과같은중추신경염증성질환에서 MOG-면역글로불린 G (immunoglobulin G antibody, IgG) 가중요한 항체로발견되었다. 2-8 MOG-IgG 중추신경염증질환은경한증상과단상성경과를가진다고보고되었다. 4,9 하지만 MOG-IgG 질환에대한연구가많아지면서특징적인증상과영상학적소견그리고잦은재발을보이는보고가늘어났다. 7,8,10-12 별아교세포가아닌희소돌기아교세포의손상과직접적인탈수초현상이라는새로운병리기전을가지고있고, NMO나 MS와다른임상적특징으로 MOG- IgG 중추신경염증질환은새로운독립적임상적질환군으로생각되고있다. 4,5,9 MOG-IgG 중추신경염증질환환자들의임상적특징과질병의경과, 영상학적소견, 치료그리고예후에대하여정리하였다. Received February 20, 2018 / Revised February 28, 2018 / Accepted February 28, 2018 Address for correspondence: Min Su Park, MD Department of Neurology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: , Fax: , minsupark@ynu.ac.kr Journal of Multiple Sclerosis Vol. 9, No. 1,

2 류성근박민수 본론 MOG는중추신경계말이집의표면과희소돌기아교세포의형질막에분포한다. MOG 항체가최근몇년사이에보고되어서병리기전은명확하게밝혀지지는않았다. MOG-IgG 중추신경염증질환환자의뇌척수액검사에서수초염기성단백질 (myelin basic protein) 과별아교세포의손상을시사하는신경교섬유질산성단백질 (glial fibrillary acidic protein) 을검사하였고말이집손상을시사하는수초염기성단백질은상승하였으나신경교섬유질산성단백질의상승은없었다. 13 즉 MOG-IgG 중추신경염증질환은별아교세포손상의병리기전을가지는아쿠아포린 4 (aquaporin-4, AQP4) 와는다르게별아교세포의손상없이말이집손상을야기한다고생각할수있다. MOG-IgG 는말이집을직접적으로손상시키고희소돌기세포의기능저하를야기하고보체와연관된염증반응을통하여중추신경계에염증성병변을유발할수있다고보고되었다. 1,13-16 그래서 MOG-IgG 중추신경염증질환은 AQP4-IgG 양성질환과는다른독립적인질환군으로최근에생각되고있다. 1. 빈도및항체역가 MOG-IgG 는혈청에서세포기반분석 (cell based assay) 으로검사하였다. MOG-IgG는시신경염, 척수염또는급성뇌줄기증상이나급성파종성뇌척수염과같은중추신경염증질환에서약 4-10% 에서검출되었다. 7,10,17 그리고 AQP4- IgG 음성 NMOSD 환자의약 20-40% 에서검출되었다. 4,5,10,18 MOG-IgG는급성기뿐만아니라질병완화시기에도역가는감소하지만혈청에서검출될수있다. 그리고척수염보다시신경염을보인환자에서 MOG-IgG 항체가더많이발견되었다. 4,10 AQP4-IgG 와 MOG-IgG가같이검출되는경우는거의없으며, 2,10 MS에서도거의발견되지않는다. 7,10, 년국내에서발표된연구에서 505명의중추신경염증질환환자에서 MOG-IgG 항체를검사하고분석하였다. 22명 (4.4%) 의환자에서 MOG-IgG 항체가검출되었으며, MOG-IgG 항체가검출된환자들은 NMOSD 로진단된경우가 45.5% 로가장많았고이어서특발성 AQP4-IgG 음성시신경염, 특발성 AQP4-IgG 음성척수염이었다. 그리고 1명은 MS로진단되었다. 7 MOG-IgG 항체역가는질병활성도, 임상양상그리고병의경과에따라다르게나타날수있다. 항체역가는급성발병시기에질병완화 (remission) 시기보다높게측정되었으나치료방법에따른차이는없었다. 임상적으로척수염이있는환자에서척수염이없는환자보다역가가높게측정되고척수염과시신경염이동시에발병할때더높은역가를보인다. MOG-IgG 항체역가는환자들마다개인차가있어서명확한결정수치 (cut off value) 를정하기는어렵다. 10 하지만혈청에서 MOG-IgG 항체음성전환이될경우, 재발을잘하지않는다고보고되었다. 7 혈정에서 MOG-IgG 항체역가변화를통하여질병활성도와재발가능성을판단하는데도움을얻을수있다. A B Figure 1. The clinical phenotype in myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G central nervous system inflammatory disorder. (A) Illustration of the clinical phenotype at initial presentation of patients with a breakdown reflecting the distribution of each clinical phenotype in pediatric age and adult group. (B) Illustration of clinical phenotype at all presentations (initial presentation plus relapses) with a breakdown the distribution of each clinical phenotype in pediatric age and adult group. Adapted from Ramanathan et al. 11. BON, bilateral optic neuritis; UON, unilateral optic neuritis; TM, transverse myelitis; LETM, longitudinally extensive transverse myelitis. 2 대한다발성경화증학회지제 9 권제 1 호, 2018

3 MOG-IgG Associated CNS Inflammatory Disorder 2. 임상양상 MOG-IgG 중추신경염증질환환자들은여자에서많이발생하며호발연령은 30대초반이다. 하지만어린이나노인에게서도발병할수있다. 특히어린이들은 ADEM 증상을보이는경우가성인에비해서많다. 성별은여성이남성보다약 1.5-2배많이발병한다. AQP4-IgG 양성 NMOSD 에서는여성이남성보다 10배정도많이발병하는것에비하면 MOG-IgG 중추신경염증질환은상대적으로남성의발병률이높다. 증상은급성또는아급성으로발병하며점차적인악화를보이는경우는드물다. 7,11,12,20,21 MOG-IgG 중추신경염증질환에서시신경염이가장흔한임상증상이다. 그리고척수염, 뇌줄기증상, ADEM 증상이뒤를따른다. 그리고두가지이상의증상이동시에나타나는경우도 15-40% 정도로비교적흔하게관찰된다. 7,8,11,12,21 특히 ADEM 증상은성인보다어린이에서흔하게관찰된다 (Fig. 1). 11 MOG-IgG 중추신경염증질환에서시신경염은중요한증상이다. 특징적으로고대비시력 (high contrast visual acuity) 저하가흔하며색지각장애, 구후부통증과안구운동통증그리고안저검사에서유두부종이관찰된다. MOG-IgG 중추신경염증질환의시신경염은빛간섭단층촬영기 (optical coherence tomography) 에서유두주위망막신경섬유총 (peripapillary retinal nerve fiber layer) 과신경절세포-내망상층 (ganglion cell and inner plexiform layer) 두께가현저히감소된다. MOG-IgG 양성시신경염은 AQP4 양성 NMOSD 보다첫번째발병시경한손상을주지만재발이많아서시신경에축적되는손상을준다. 21,22 척수염은심한운동마비와감각이상, 이상감각통증 (dysesthetic pain), 배뇨와배변장애, 발기기능부전그리고레미떼징후 (Lhermitte s sign) 가나타날수있다. MOG-IgG 중추신경염증질환에서뇌줄기증상과소뇌증상은 AQP4-IgG 양성 NMOSD 환자들보다드물게발생한다. 4 하지만약 15-30% 에서난치성딸꾹질, 구역, 구토, 심한호흡부전과같은뇌줄기증상이나타난다. 6,8,21 MOG-IgG 중추신경염증질환에서뇌줄기단독으로침범하는경우는드물며대부분시신경염이나척수염과동반된다. 그리고 magnetic resonance imaging (MRI) 에서뇌줄기병변이있어도약 30% 에서는무증상을나타낼수있다. 6 뇌줄기병변이있는환자에서는높은확장장애상태척도 (expanded disability status scale) 점수를보이며나쁜예후를보이는경우가많다. 6,21 MOG-IgG 중추신경염증질한은초기에는단상성경과를가지는경한질환으로생각되었다. 4,9 하지만연구가많 아지면서약 50-80% 환자가재발을하며시신경염이가장흔한임상증상으로보고되었다. 8,12,21 약 25% 의환자는 5개월이내에재발을하였고, 젊은나이와시신경염증상이있는경우재발이많았다. 8 그리고재발방지치료를하지않거나재발방지치료기간이 3개월미만으로짧아도재발이많았다. 11 최근에는혈청에서 MOG-IgG 항체의음성전환이재발을예측할수있는표시로보고되었다. 7 MOG-IgG 중추신경염증질환에서도항핵항체 (antinuclear antibody), 항카디오리핀항체 (anti-cardiolipin antibody), 류마티스인자 (rheumatoid factor) 와같은자가항체들이발견될수있다. 하지만자가면역질환은 10% 미만에서동반되었다. 11,21 뇌척수액검사에서는대개중성구가포함된뇌척수액세포증가증을보이고단백질이증가된다. 올리고클론띠는약 15% 에서검출된다. 알부민뇌척수액 / 혈청비율은증가되어서혈액 -뇌척수액장벽기능저하를시사하는소견을보인다. 11,21 MOG-IgG 중추신경염증질환은선행되는감염, 백신, 임신이나출산에의하여증상이발생되는경우도있으니주의가필요하다. MOG-IgG 중추신경염증질환환자들은약 20-40% 에서 2015년 International Panel for NMO Diagnosis의 NMOSD 진단기준 23 에부합되었으며가장많은환자들이 AQP4-IgG 음성 NMOSD로진단되었다. 특발성 AQP4-IgG 음성시신경염, 특발성 AQP4-IgG 음성척수염, ADEM 이뒤를이었다. 그리고 1-5% 에서 MS로진단되었다. 7,8,10 3. 영상학적소견 MOG-IgG 중추신경염증질환은시신경염이가장흔한증상이다. 안와 MRI에서양측또는일측의길게확장된시신경염이흔히관찰된다. MOG-IgG 양성시신경염은시신경유두부의부종이특징적으로관찰되며안구뒤쪽의병변이흔하게관찰된다. AQP4-IgG 양성시신경염이시신경의두개내부분에서병변이많이관찰되는것과는다르다. AQP4-IgG 양성시신경염은시신경교차 (optic chiasm) 와양측시각로 (optic tract) 에병변이관찰되나 MOG-IgG 양성시신경염에서는잘침범하지않는다. 24 MOG-IgG 양성시신경염은시신경에국한되는조영증강이아니라시신경과주변조직까지조영증강되는특징적인소견이관찰된다. 17 뇌 MRI에서는 30-45% 에서정상을보인다. 11,25 MOG- IgG 중추신경염증질환에서는전형적으로 3개미만의적은개수의병변이관찰되며크고경계가불명확한병변들이 Journal of Multiple Sclerosis Vol. 9, No. 1,

류성근 박민수 A B C D E F G H I Figure 2. Radiological characteristics in optic neuritis with myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G central nervous system inflammatory disorder.

4 류성근 박민수 A B C D E F G H I Figure 2. Radiological characteristics in optic neuritis with myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G central nervous system inflammatory disorder. (A) Bilateral retrobulbar optic nerve enhancement and swelling (arrows) is noted. (B) Bilateral optic nerve head swelling (black arrows) is visible in axial T2 image. (C) Bilateral longitudinally extensive optic nerve involvement is noted in axial T1 image. (D) Extensive enhancement patterns that were no confined to the optic nerve but extended to the soft tissue around the optic nerve (perineural enhancement) is noted. (E, F) Midbrain, pons, cerebellar peduncles, cerebellum and adjacent to fourth ventricle bilateral large and poorly demarcated. (G, H) Fluffy large and 17 bilateral lesions in pons, cerebellar peduncles and adjacent to fourth ventricle and thalamus. Adapted and modified from references Kim et al., Wingerchuk et al., and Jurynczyk et al.. 천막하부와 4번뇌실 주변 뇌줄기와 소뇌다리에 나타난다. AQP4-IgG 양성 NMOSD에서 흔히 발생하는 3번 뇌실 주 변, 맨아래구역(area postrema)에서는 잘 관찰되지 않았다. 11,26 그리고 질병완화 때 다시 촬영한 뇌 MRI의 약 75%에 서 병변이 소실되거나 희미해졌다.26 MOG-IgG 중추신경 염증질환의 MRI 소견은 MS와 비교할 때, 측뇌실 주변에 병변이 드물며, Dawson s fingers가 없는 점으로 구별이 4 대한다발성경화증학회지 제9권 제1호, 2018 잘 되었다. 하지만 AQP4-IgG 양성 NMOSD와는 비슷한 26,27 소견이 많았다(Fig. 2). 척수 MRI에서는 50-60%에서 병변이 관찰된다. 병변은 경추와 흉추 부위에서 흔하게 관찰된다. 척수염은 longitudinally extensive transverse myelitis뿐만 아니라 short segment transverse myelitis 병변도 다수에서 관찰될 수 있다.21,26,28

5 MOG-IgG Associated CNS Inflammatory Disorder 4. 치료 이많으므로적절한재발방지치료가필요하다. MOG-IgG 중추신경염증질환의치료는급성기치료와장기적인재발치료로나눌수있다. 1) 급성기치료급성기치료는정맥을통하여고용량스테로이드를투여한다. 고용량스테로이드치료에충분한반응을보이지않는경우에는혈장교환술을시행할수있다. 11,21 2) 재발방지치료 MOG-IgG 중추신경염증질환은잦은재발을하는질환군으로재발은신경학적후유증에큰영향을준다. 그래서장기적인재발방지치료가필요하다. 하지만 MOG-IgG 중추신경염증질환은다양한질환군이며충분한연구결과가있지않아명확한치료방침이아직없다. 경구프레드니솔론 (prednisolone) 이재발방지치료에효과적이다. 프레드니솔론을하루 10 mg 이상사용하였을때연간재발률을감소시키고치료실패는 5% 에서관찰되었다. 하지만하루 10 mg 이하의용량, 3개월미만사용그리고빠른용량감소를하였을때는재발이자주발생하였다. 11 Mycophenolate mofetil, azathioprine, rituximab 등의면역억제제도재발방지치료로사용할수있다. 11,21 한연구에서 MOG-IgG 중추신경염증질환으로진단받은어린이들에서 MS 질병조절치료약제를사용하였지만임상적인호전을보이지않았다. 하지만 NMOSD에서재발방지치료를위해사용하는 mycophenolate mofetil, azathioprine 그리고 rituximab을사용하였더니연간재발률이감소하였다고보고하였다. 29 하지만 MOG-IgG 중추신경염증질환중재발 -완화 MS로진단된환자에서는 interferon-beta가재발방지에효과를보였다. 7 아직충분한연구가되어있지않지만일반적으로경구용스테로이드나 NMOSD 에서재발방지를위하여서사용중인면역억제치료를통해재발방지치료를시행할수있다. 5. 예후 MOG-IgG 중추신경염증질환은일반적으로 AQP4-IgG 양성 NMOSD보다좋은예후를보인다. 8,12,30 MOG-IgG 중추신경염증질환은약 50% 에서신경학적장애가남았다. 특히척수염이나뇌줄기병변이있는경우나쁜예후를시사한다. 8,10 시력저하, 마비증상, 인지장애, 배뇨이상, 배변이상그리고발기기능부전이후유증으로남았다. 장기적인재발방지치료를적절하게하지않을경우재발 결론 중추신경염증질환에서 MOG-IgG 항체가 4-10% 에서발견되었으며새로운병리기전과특징적인임상양상으로최근에새로운질환군으로생각되고있다. MOG-IgG 중추신경염증질환은반복적으로나타나는시신경염이가장흔한임상증상이며척수염, 뇌줄기증상또는급성파종성뇌척수염증상을보일수있다. 영상학적으로특징적인시신경염의소견을관찰할수있다. 다수의환자에서재발을하므로장기적인재발치료가중요하다. 시력저하, 사지마비그리고배변, 배뇨이상및발기부전을보일수있으나일반적으로나쁘지않은예후를보인다. 하지만아직명확한진단과치료방법에대한연구가부족하므로앞으로 MOG-IgG 중추신경염증질환에대한충분한연구가필요하다. REFERENCES 1. Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, Kozubski W. The immunology of neuromyelitis optica-current knowledge, clinical implications, controversies and future perspectives. Int J Mol Sci 2016;17: 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: Dale RC, Tantsis EM, Merheb V, Kumaran RY, Sinmaz N, Pathmanandavel K, et al. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Neurol Neuroimmunol Neuroinflamm 2014;1:e Sato DK, Callegaro D, Lana-Peixoto MA, Waters PJ, de Haidar Jorge FM, Takahashi T, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014;82: Höftberger R, Sepulveda M, Armangue T, Blanco Y, Rostásy K, Cobo Calvo A, et al. Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult Scler 2015;21: Jarius S, Kleiter I, Ruprecht K, Asgari N, Pitarokoili K, Borisow N, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement-frequency, presentation and outcome. J Neuroinflammation 2016;13: 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; Jurynczyk M, Messina S, Woodhall MR, Raza N, Everett R, Roca-Fernandez A, et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain 2017;140: Journal of Multiple Sclerosis Vol. 9, No. 1,

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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