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1 ISSN Journal of Multiple Sclerosis 7(2):29-39, 2016 REVIEW ARTICLE 국립암센터신경과학교실 1, 영남대학교의과대학영남대학교병원신경과학교실 2, 제주대학교의과대학제주대학교병원신경과학교실 3, 동국대학교의과대학동국대학교일산병원신경과학교실 4, 울산대학교의과대학울산대학교병원신경과학교실 5, 서울대학교의과대학서울대학교병원신경과학교실 6, 명지병원신경과학교실 7, 전남대학교의과대학전남대학교병원신경과학교실 8, 성균관대학교의과대학삼성서울병원신경과학교실 9, 연세대학교의과대학세브란스병원신경과학교실 10, 건국대학교의학전문대학원건국대학교병원신경과학교실 11, 국민건강보험일산병원신경과학교실 12, 인제대학교의과대학일산백병원신경과학교실 13, 고신대학교의과대학고신대학교복음병원신경과학교실 14, 가톨릭대학교의과대학서울성모병원신경과학교실 15, 을지대학교의과대학을지대학교을지병원신경과학교실 16 김수현 1* 박민수 2* 강사윤 3 김남희 4 김선영 5 김성민 6 김지영 7 남태승 8 민주홍 9 신하영 10 오지영 11 조정희 12 조중양 13 허소영 14 김우준 15 권오현 16 Clinical Practice Guideline of Clinically Isolated Syndrome: Part I. Evaluation and Diagnosis Su-Hyun Kim 1*, Min Su Park 2*, Sa Yoon Kang 3, Nam-Hee Kim 4, Sun-Young Kim 5, Sung-Min Kim 6, Jee Young Kim 7, Tai-seung Nam 8, Ju-Hong Min 9, Ha Young Shin 10, Jeeyoung Oh 11, Jung Hee Cho 12, Joong-Yang Cho 13, So-Young Huh 14, Woojun Kim 15, Ohyun Kwon 16 1 Department of Neurology, Research Institute and Hospital of National Cancer Center, 2 Department of Neurology, Yeungnam Medical Center, Yeungnam University College of Medicine, 3 Department of Neurology, Jeju National University Hospital, Jeju University College of Medicine, 4 Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, 5 Department of Neurology, Ulsan University Hospital, Ulsan University College of Medicine, 6 Department of Neurology, Seoul National University Hospital, Seoul University College of Medicine, 7 Department of Neurology, Myongji Hospital, 8 Department of Neurology, Chonman National Univeristy Hospital, Chonnam National University Medical School, 9 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of medicine, 10 Department of Neurology, Severance Hospital, Yonsei University College of Medicine, 11 Department of Neurology, Kunkuk University Hospital, Kunkuk University School of Medicine, 12 Department of Neurology, National Health Insurance Service Ilsan Hospital, 13 Department of Neurology, Ilsan Paik Hospital, Inje University College of Medicine, 14 Department of Neurology, Kosin University Gospel Hospital, Kosin University College of Medicine, 15 Department of Neurology, Seoul St. Mary Hospital, College of Medicine, The Catholic University of Korea, 16 Department of Neurology, Eulji University Eulji Hospital, Eulji University College of Medicine Received September 7, 2016 / Revised / Accepted September 12, 2016 Address for correspondence: Ohyun Kwon Department of Neurology, Eulji University Eulji Hospital, Eulji University College of Medicine, 68 Hangeulbisuk-ro, Nowon-gu, Seoul 01830, Korea Tel: , Fax: , koh1407@eulji.ac.kr Woojun Kim Department of Neurology, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea wjkim@catholic.ac.kr *These authors contributed equally to this work.

2 김수현박민수강사윤김남희김선영김성민김지영남태승민주홍신하영오지영조정희조중양허소영김우준권오현 ABSTRACT Clinically isolated syndrome (CIS) is the typical first clinical episode that is highly suggestive of multiple sclerosis (MS). Without diagnostic marker, diagnosing CIS is exactly alike diagnosing MS with even less evidences and requires careful and integrative interpretation of clinical, radiological and immunological findings. In the aspect of management, numerous clinical trials and cohort studies strongly support prompt start of disease modifying therapies even in the stage of CIS to prevent disability accumulation with disease activity. This guideline covers sequential stages of clinical practice - encounter, assessment, diagnosis, and management - and addresses their principal evidences to help clinicians make correct diagnosis and proper management. Though it cannot be emphasized too much to consider every possible differential diagnosis other than MS thoroughly when we encounter patients with CIS, the details regarding differential diagnosis are out of the scope of this guideline. The guideline would be regularly updated and revised every a few years to serve its role. Journal of Multiple Sclerosis 7(2):29-39, 2016 Key Words: Clinically isolated syndrome, Evaluation, Diagnosis, Guideline Charcot이 1868년 la sclérose en plaques 라는이름으로체계적으로기술한이후 1870년대부터하나의독립적질환으로인식되기시작한다발성경화증 (multiple sclerosis, MS) 은중추신경계의대표적자가면역질환으로다른질환에비할바없이임상신경의사, 신경병리학자, 신경면역학자등의지대한관심을끌어왔다. 1,2 1930년대 MS의동물모델로받아들여지는 experimental autoimmune encephalomyelitis (EAE) 이소개되고, 1980년대자기공명영상 (magnetic resonance imaging, MRI) 이도입되면서 MS에대한체계적인연구와이해가가능하게되었다. 이와같은병리생리적이해는 1990년대부터오늘날에이르기까지다양한질병완화요법 (disease-modifying therapies, DMTs) 이개발되는데결정적인역할을하였다. 그러나, 이미 MS에의해발생한비가역적인신경학적손상은회복할수없기에, 조기에 MS를진단하고적절히관리하는것이무엇보다중요해졌다. 이러한인식에따라, MS의최초임상발현으로간주되는임상적단독증후군 (clinically isolated syndrome, CIS) 단계부터적극적으로감시하고, 관리하여 MS로의전환을예방의필요성이강조되고있다. 하지만 MS 유병률이상대적으로높은서구에비해국내에서는발병율이낮아질환에대한인식및 CIS에대한개념적이해가부족하다또한서구에비해우리나라를비롯한아시아에는 MS 와비교하여시신경척수염범주질환 (neuromyelitis optica spectrum disorder, NMOSD) 유병율의상대적비율이높아중추신경계질환의발병시 NMOSD의감별이더욱중요하다. 따라서 CIS에대한올바른이해와관리는한국의신경과전문의들에게미뤄서는안될중요한과제의하나라할수있다. 이에대한다발성경화증학회에서는근거중심의진료의일환으로임상현장에서의 CIS의진단과정및치료관리계획수립에근거가되도록본한글임상진료지 침을개발하였다. 2015년 8월 CIS 진료지침작성을위한개발그룹이결성되었고, 환자를처음대면해진단에접근해나가고치료를결정하는임상흐름에맞추어지침을개발하기로하였다. 이에따라네개의소위원회 ( 역학, 진단, 관리, 감시 ) 가결성되어각위원회별로핵심질문을도출하였고, 문헌검색을통하여근거수준을평가하여종합하였다. 작성된권고안은대한다발성경화증학회임원진의합의를도출하여 2016년 8월연례학술대회에서발표되었다. 향후주기적인진료지침개발위원회의를통하여새로운근거를확인하고갱신해나갈계획이다. 본고는 CIS의관리와감시에관한것으로, 급성기치료와 MS로의이환을억제하기위한치료에대한지침을다루고있다. 1. 임상적단독증후군의정의는? 답 : 임상적단독증후군은다발성경화증을시사하는소견의첫임상삽화이다. 시신경, 뇌줄기, 척수, 혹은대뇌를침범한임상소견으로나타나며, 향후다발성경화증, 즉, 재발완화형다발성경화증으로전환할수있다. 과거에특별한신경학적증상을보인적없는환자들이시신경염 (optic neuritis, ON), 뇌줄기증상 (brainstem presentations), 척수염 (myelitis) 과같은전형적인 MS 증상이단독혹은그조합의처음삽화로발현한경우를 CIS라한다. 전체 MS 환자의 90% 가 CIS를경험하며, 재발완화형다발성경화증 (relapsing remitting multiple sclerosis, RRMS) 으로전환한다. CIS는향후 MS로전환될수있음을시사하는증후군으로, 기본적으로다른중추신경계를침범하는질환들과의감별을요한다. 그래서, 임상소견뿐만아니라, 30 대한다발성경화증학회지제 7 권제 2 호, 2016

3 영상의학적, 혹은혈청학적소견등이적어도 MS에반하지는않고, 다른질환으로설명할수없다는기준, 즉, 다른더나은다른설명이없음 (no other better explanation) 을만족해야한다. CIS라는단어자체의모호함과배제질환의고려등의이유로, 신경과의사간에 CIS에대한다른, 일부에서는그른, 시각을가질수있다. 3 본지침에서언급되는 CIS는다른감별진단이배제되고, 아직 임상적으로확진된다발성경화증 (clinically definite multiple sclerosis, CDMS) 이나, MRI 소견을포함한 McDonald 기준을만족하는 McDonald MS로도전환되지않은상태로정의한다. 4-7 CIS는최초의단상성 (monophasic) 임상발현으로정의되기에임상으로만평가한다면, MS 진단에필수적인시간적산재 (dissemination in time, DIT) 기준을만족시키지는못한다. 일부 CIS 환자에서는다초점성발현 (multifocal presentation), 예를들어, 시신경염과척수염, 또는시신경염과뇌줄기증상등의조합으로공간적산재 (dissemination in space, DIS) 기준을만족할수는있으나여전히 DIT 를충족할수없다. 그러나 2010년 McDonald 기준을적용할경우, CIS 로발현한경우에도뇌 MRI에서조영증강병터와조영증강되지않는병터가함께있는경우엔 DIT 를만족한다고할수있다. 또한임상적으로단초점 (monofocal) 발현을하더라도뇌 MRI에서 MS의특징적인침범영역인피질연접 (juxtacortical), 뇌실주위 (periventricular), 천막아래 (infratentorial), 그리고척수중 2군데이상에서 1개이상의무증상의 T2 병터가있는경우에는 DIS를만족한다고할수있다. 그러므로, 이젠 CIS 발현당시라도 MRI 소견을고려하여 DIS나 DIT의기준을충족할수있으며, 두기준을모두충족할경우는 CIS 단계에서 MS 로진단할수있다. 실제로 2010년 McDonald 기준을적용 할경우, DIT 기준을만족하는경우가전체 CIS 의 30% 에 달하며, 8 또한, CIS는 1/4에서임상적으로다초점성발현 (multifocal presentation) 을보이고, 1/2에서Swanton 의 DIS 진단기준을만족하는것으로보고된다 년제안되어두차례의개정을거친 McDonald 기준은임상재발이없어도조기에 MS를진단하고자하는노력의산물인까닭에과거 Poser 기준에의거한 CIS 군의상당수가적절한 MRI 평가를통해 McDonald MS로진단될수있고, 또한 MS로전환한 CIS의대다수가 CDMS 에앞서조기에 McDonald MS로전환한다 (Fig.). 11 한국의 CIS 환자를대상으로 2010 McDonald 기준을적용하여도서구의 CIS 환자대상연구와마찬가지로민감도 (76%) 와특이도 (60%) 가높았다. 12 그러므로국내에서도 2010 McDonald 기준은타당하게적용될수있다. 2. 임상적단독증후군의임상적정의는? 답 : 발열이나감염의증거없이중추신경계의염증성탈수초병터에합당한증상이나징후가 24시간이상지속하는경우를임상적단독증후군이라한다. 일반적으로환자가호소하는증상혹은객관적으로확인된징후들이중추신경계의급성염증성탈수초병증에전형적이며 24시간이상지속된경우를 CIS의기본요건으로한다. 단, 발열이나감염의증거가없어야한다. 환자가호소하는증상들은증상이있을당시신경학적진찰로확인되어야하지만과거에지나간증상이객관적인신경학적진찰로확인되지않는다고하더라도그정황이 CIS 에전형적이고적절하다면발병으로인정할수있다. 중추신경계의탈수초병터는간헐적증상을유발하기도하지만, 간헐적증상이 CIS로인정되려면그증상이적어도 24 시간이상에걸쳐발생하여야한다. 현재의 MRI검사와시신경유발전위검사의결과가대응되는과거의증상에합당할경우, CIS에의한발현일가능성이더욱높아진다. CIS의임상발현은부위에따라몇가지특징적인소견을가지며, 비전형적일경우, 다른감별진단의가능성을고려해야한다 (Table 1) 임상적단독증후군의역학은? Figure. Kaplan-Meier survival curve showing time to diagnosis of multiple sclerosis (MS) using Poser and McDonald criteria among patients with clinically isolated syndrome who developed clinically definite MS. From Brownlee, et al. 11 답 : 임상적단독증후군은여성에서 배더많이발생하고, 평균적으로 30대초반에발생한다. CIS 는남성보다여성에서 배더많이발생하고 Journal of Multiple Sclerosis Vol. 7, No. 2,

4 김수현박민수강사윤김남희김선영김성민김지영남태승민주홍신하영오지영조정희조중양허소영김우준권오현 Table 1. Clinically isolated syndrome characteristics which are typical and atypical for multiple sclerosis Site Typical Atypical Optic nerve Optic neuritis in one eye Optic neuritis in both eyes at the same time Mild pain on eye movement Painless or very severe pain Reduced visual acuity and reduced color vision No perception of light Normal disc or mild disc swelling Severe hemorrhages and exudates Improvement begins within 3 weeks from onset Extended loss of vision Afferent pupil defect Vitritis and neuroretinitis Photophobia Brainstem or Bilateral internuclear ophthalmoplegia Complete external ophthalmoplegia cerebellum Ataxia and gaze-evoked nystagmus Vascular territory signs Sixth nerve palsy (in patients aged years) Isolated trigeminal neuralgia Paroxysmal phenomena (occurring for at least 24 h) Progressive trigeminal sensory neuropathy Multifocal signs (eg, facial sensory loss and vertigo) Movement disorders Fluctuating ocular or bulbar weakness, or both Spinal cord Incomplete transverse myelitis Complete transverse myelitis Lhermitte s syndrome Complete Brown-Séquard syndrome Sphincter symptoms Cauda equina syndrome Asymmetric limb weakness Anterior spinal artery territory lesion Deafferented hand Localized or radicular spinal pain Progression to nadir between 4 h and 21 days Progressive and symmetrical spastic paraparesis or progressive sensory ataxia (from involvement of posterior columns) Sharp level to all sensory modalities Areflexia Cerebral Hemiparesis Encephalopathy hemispheres Hemisensory disturbance Epilepsy Cortical blindness 발병연령은평균 세이며, 26-54% 가 ON, 16-33% 가뇌줄기병터, 28-53% 가척수염으로발병한다 임상적단독증후군을평가하기위한자기공명영상의표준프로토콜은? 답 : 자기공명영상은최소1.5T 자기장세기이상그리고평면상 1X1 mm 의해상도이상의기기를이용하여최대 3mm 이하의절편두께로틈 (gap) 없이촬영되어야한다. 뇌자기공명영상은횡단면 proton density 강조혹은 T2강조 /T2-FLAIR 영상, 시상면 T2-FLAIR 영상, 그리고조영증강 T1강조영상이, 척수자기공명영상은횡단면및시상면 proton density, T2 강조, 지방포화 (fat suppression) T1 강조영상 (short tau inversion recovery, STIR), 조영증강 T1강조 spin-echo 영상이필수적으로요구된다 (Strong recommendation; moderate quality-evidence). MRI는 CIS의평가에가장중요한도구로, 임상증상을뒷받침하는객관적인병터를확인하고, 다른질환을감별하는데이용된다. 20 일반적으로 T2강조영상 (T2 weighted image, T2WI) 의질환부하 (burden of disease, BOD), T2WI병터, T1강조영상 (T1 weighted image, T1WI) 의조영증강병 터가대부분의 MS 임상시험에서일차또는이차결과측정치 (primary and secondary outcome measure) 로사용되어왔다. MRI 는임상척도보다더민감하게무증상질환 (subclinical disease) 을확인할수있으며, 새로운병터를임상척도보다 5-10배민감하게반영하며 DIS, DIT의근거를제시한다. 21 그러나, 표준화되지않는 MRI protocol을이용하는경우에는pulse sequence, 영상절편두께의차이, 환자자세등에따라 CIS 상태에서평가한 MRI와추적 MRI의비교를통해새로이발생하거나커진병터의유무를평가하기에어려울수있다. 잘확립된 CIS환자에서지름이 3mm이상인 T2병터가두개이상이며이들중적어도하나는뇌실주변부 (periventricular area) 에있거나혹은타원형이어서 MS에전형적인경우는 MS로의전환위험이더욱높기에, 이소견에근거하여질병완화치료 (disease-modifying therapy, DMT) 개시하는경우도많다. 22 MS와 CIS의진단과추적을위한뇌와척수 MRI의제안된프로토콜은 Table 2, 3과같다. 23 MRI는최소1.5T 이상그리고최소 1X1 mm의해상도를갖는 MRI 기기를이용하여최대 3mm 이하의절편두께로촬영되어야한다. 24 뇌 MRI검사는횡단면 (axial) 영상으로 proton density-weighted image (PDWI) 나 T2WI/T2WI-FLAIR 영상둘모두혹은하나, 시상면 (sagittal) T2WI-FLAIR 영상, 그리고조영증강 T1WI 가필수적이다. T2-FLAIR 영상은천막아래병터를관찰하는데는덜민감 32 대한다발성경화증학회지제 7 권제 2 호, 2016

5 Table 2. Recommended brain MRI protocol Sequence Diagnostic scan for MS baseline of CIS follow-up scan Comment 1 3 plane (or other) Recommended Recommended Set up axial sections through subcollasal line 1 scout 2 Sagittal fast FLAIR Recommended Optional Sagittal FLAIR sensitive to early MS pathology, such as corpus callosum 3 Axial FSE PD 2 /T2 Recommended Recommended TE1 minimum (eg. 30ms) TE2 (usually 80ms) PD series sensitive to infratentorial lesions that may be missed by FLAIR series 4 Axial fast FLAIR Recommended Recommended Sensitive to white matter lesions and especially juxtacortical-cortical lesions 5 Axial precontrast T1 Optional Optional Considered routine for most neuroimaging studies 6 3D T1 Optional Optional Some centers use this atrophy measures 7 Axial contrast-enhanced T1 Recommended Optional Standard dose of 0.1mmmol/kg injected over 30 s; scan starting minimum 5 min after start of injection FSE, fast-spin echo (or turbo spin-echo); PD, proton density-weighted (long TR, short TE sequence); T2, T2-weighted (long TR, long TE sequence); T1, T1-weighted (short TR, short TE sequence). Section thickness for sequences 3-6 is < 3mm with no intersection gaps when feasible. Partition thickness for 3D sequences 6 is 1.5mm. In-plane resolution is approximately 1X1mm. 1 The subcallosal line joints the undersurface of the front (rostrum) and back (splenium) of the corpus callosum. 2 PD series can be replaced by T2-FLAIR in some situations. Table 3. Recommended spinal cord MRI protocol 1 When acquired immediately following an enhanced brain MRI Sequence Recommendation 1 3 plane (or other scout) Recommended 2 Postcontrast sagittal T1 Recommended 3 Postcontrast sagittal FSE PD/T2 2 Recommended 4 Postcontrast axial T1 Through suspicious lesions 5 Postcontrast axial FSE PD/T2 3 Through suspicious lesions 6 Postcontrast 3D T1 4 Optional When acquired without a preceding enhanced Brain MRI Sequence Recommendation 1 3 plane (or other scaout) Recommended 2 Postcontrast sagittal T1 Recommended 3 Postcontrast sagittal FSE PD/T2 2 Recommended 4 Precontrast axial FSE PD/T2 3 Through suspicious lesions 5 3D T1 4 Optional 6 Postcontrast-enhanced sagittal T1 5 Recommended 7 Postcontrast-enhanced axial T1 Through suspicious lesion(s) FSE, fast spin-echo (or turbo spin-echo); PD, proton density-weighted (long TR, short TE sequence); T2, T2-weighted (long TR, long TE sequence); T1, T1-weighted (short TR, short TE sequence). 1 Indications are (1) main presenting symptoms are at the level of the spinal cord, and these have not resolved (2) if the brain MRI results are equivocal. No additional intravenous contrast is required if the spinal cord study immediately follows the contrast-enhanced brain MRI, as gain is very limited. The segment to be studied (cervical and/or thoracic) is based on clinical findings. Sagittal section thickness is 3-mm (no gap). 2 PD series may depict lesions less apparent on heavily T2-weighted series. 3 Increases confidence in the findings of sagittal series; may provide classic lesion characteristics. 4 For volumetric analysis if desired. 5 Standard dose of 0.1 mmol/kg injected over 30 s; scan starting 5 min after start of injection. 하나, 피질연접및뇌실주위병터를보다민감하게보여주는장점이있어상황에따라 PDWI 를대신할수있다. 뒤오목 (posterior fossa) 이나앞관자엽 (anterior temporal lobe) 같이흐름에연관한결함 (flow-related artifact) 에취약한부위에서는 DIT를증명하는새로운 T2병터는 PDWI/T2-FL- AIR 영상과 T2WI 모두에서반드시보여야한다. 뇌량의병터유무를확인하기위해서는횡단면 T2WI 와 PDWI/T2-FL- AIR영상을시상면 FLAIR 영상과함께비교하는것이가장좋은방법이다. 24 그외피질혹은피질연접병터를보다민감하게찾기위한 double inversion recovery 영상, 급성허혈성병터와의감별을위한확산강조영상 (diffusion-weighted image) 검사는선택적으로시행할수있다. 조영되지않는 T1저신호음영병터 (T1-hypointense lesion) 는이전의심한신경축삭의손상을시사하는근거로서, CIS 환자에서 MS로의전환을높이는위험인자이며 25 이러한병터를찾기위한비조영증강 T1WI 도선택적으로고려할수있다. 24 또한, 시신경을평가하기위한안와 (orbit) MRI 영상은필요한뇌 MRI 영상영상을같이얻는경우가많으며, 안와영상으로 3 mm 이하절편두께의횡단면 T1WI, 지방포화 (fat-saturated) 횡단면및관상면 (coronal) T2WI, 지방포화조영증강횡단면및관상면 T1WI 로구성한다. 26 관상면영상은적어도안와에서뇌줄기직전까지얻어야하며, 사면시상면 (oblique sagittal) 영상을추가할수있다. 척수 MRI는최소 1.5T 이상의해상도를갖는기기를이용하여최대 3mm 이하절편두께로틈없이촬영하여야하며, 횡단면및시상면 PDWI, T2WI, STIR, 조영증강 T1WI 가필요하다. 가돌리늄 (gadolinium chelate) 조영제는 0.1 mmol/kg ( 최 Journal of Multiple Sclerosis Vol. 7, No. 2,

6 김수현박민수강사윤김남희김선영김성민김지영남태승민주홍신하영오지영조정희조중양허소영김우준권오현 대 20 ml) 의용량을주사하며주사후적어도 5분은대기후조영증강 T1WI 를얻는다. 더많은용량이나지연영상이병터의선명도와병터개수를증가시킬것이라는보고가있었지만, 일반적으로고용량을지지하는증거는뚜렷하지않다. 27 조영증강병터는염증과관련된혈관- 뇌장벽 (blood-brain barrier) 의손상의표지자며, 병터발생약 1주후부터선명해고길게는 16주까지지속될수있으나대개는 4주미만에사라진다. 28 그러므로조영증강된병터는활동성병터로서추후임상적인재발의강한독립적예측인자이며, 무증상의조영증강되지않는병터와함께관찰되면 DIT의근거로고려할수있다. 19,22,29 CIS의발현이척수병터에의해생긴경우, 척수 MRI뿐만아니라, 뇌 MRI도함께시행하여야한다. 또한, 척수염의임상발현이없더라도뇌 MRI결과가모호하고 MS진단을여전히고려하는상태라면척수영상을시행해볼수있다. 척수에무증상 MS 병터가있다면, MS로의전환가능성이높고, 척수병터는 DIS의기준에포함되어있으며, 조영증강병터는 DIT 기준에적용될수있다. 더구나, 척수의 T2 병터는정상적인노화로나타나지않으며혈압, 당뇨, 동맥경화의위험인자와연관된소혈관질환 (small vessel diseases) 에서관찰되는경우는매우드물어특이도가높다. 30 CDMS 환자의 50-90% 는척수에 MRI로확인할수있는병터를가진다. 31 MS의척수병터는흉수보다경수에서더흔하고, 대개 2척추분절 (vertebral segments) 이하의길이를가지며, 횡단면상비대칭적으로침범한다 임상적단독증후군환자에서추적자기공명영상검사는언제, 어떻게시행되어야하는가? 답 : 최초의뇌자기공명영상에이상이있으나, Mc- Donald 기준에부합하지않는임상적단독증후군환자에서추적뇌자기공명영상은임상증상이없어도처음검사로부터 3-6개월간격으로시행하도록권고한다. 두번째뇌자기공명영상으로진단이불분명하다면 3번째추적뇌자기공명영상은두번째검사로부터 6-12개월후에시행한다. (Strong recommendation; moderate-quality evidence) CIS 환자에서추적 MRI의시기는아직논쟁이있지만, 처음뇌 MRI에이상이있으나, McDonald 기준에부합하지않는 CIS 환자에서추적뇌 MRI는임상증상이없어도처음 MRI로부터 3-6개월간격으로시행하도록권고된다. 32 두번째뇌 MRI로도진단이불분명하다면 3번째추적뇌 MRI는두번째 MRI로부터 6-12개월후에시행한다. 32 CIS 환자에서 DIS, DIT 근거를얻기위해임상증상이없 어도척수 MRI 를추적해서검사하는것은권고되지않는다. 33 이상적으로는추적 MRI 는같은기기를이용하여같은프로토콜로시행하도록권고된다. 처음검사때와같은해부학적기준을이용하여가급적머리위치도똑같이하도록한다. 추적 MRI검사시에는횡단면 PDWI, T2WI, T2-FLAIR 영상및 2D 혹은 3D 조영증강 T1WI 가필수적이다. 24 MRI는 CIS의감별진단에매우중요한역할을하며, 환자의임상발현이탈수초질환이외의질환으로인한것은아닌지감별할수있게한다. T2WI 의고신호음영 (high signal intensity) 병터는소혈관질환 (small vessel disease) 과비특이적인백질변성 (non-specific white matter disease) 등에의해흔히유발된다. 탈수초질환으로인한 MRI상이상은뇌어느곳에서도일어날수있으나일반적으로뇌실주변부및피질연접부 (juxtacortical area) 에서잘관찰된다. 19,34 특히피질아래 (subcortical) U-fiber는일반적으로혈액의공급이충분하여이부위에는소혈관질환이잘발생하지않으므로해당부위에병터가있는환자의경우탈수초질환을가지고있을확률이높다. 19 천막아래병터의경우위치에따라탈수초질환과혈관질환의감별의단서가된다. 탈수초질환으로인한병터의경우등쪽뇌다리 (dorsal pons) 및중간소뇌다리 (middle cerebellar peduncle) 에주로관찰되나혈관질환으로인한병터는주로소뇌의회색질이나뇌다리의중앙에주로관찰되기때문이다. 이외에 CIS환자에서척수의병터는탈수초질환을가지고있을가능성을시사하는강력한근거이다. 30,35 이외에도일부 MRI소견들은 CIS로의심되는환자들의병터가탈수초질환으로인한것인지혹은기타의질환으로인한것인지를알수있는주요단서를제공한다 (Table 4). 2010년 McDonald 기준에따라 MRI상 DIS ( 뇌실주변 / 피질연접 / 천막아래 / 척수중 2곳이상에병터가있을경우 ) 와 MRI상 DIT ( 추적 MRI상새로운 T2 병터나조영증강병터가관찰되거나, 첫 MRI에서증상이없는조영증강이되는병터가조영증강이없는병터와함께있는경우 ) 기준에따라 MS로진단을할수있다. 7 영상기술발전에더불어 MRI 검사의접근성이증가함에따라기대하지않았던 MRI의이상을발견하는경우가증가하고있다. 특히전형적인 MS나 CIS의임상증상이나증후가없는사람의 MRI에서 MS을시사하는병터가발견되는경우를영상적단독증후군 (radiologically isolated syndrome, RIS) 이라한다 (Table 5). 36 RIS의약 1/3에서 2-5 년의추적동안임상증상이발현되어 CIS 또는 MS로진행한다 세미만의나이, 남성, 척수병터가임상증상발생의주요예측인자로보고되었다.36 RIS는 MS의임상발병이전에중추신경계에서활동성염증이진행되고 34 대한다발성경화증학회지제 7 권제 2 호, 2016

7 Table 4. MRI features suggesting other than MS and possible differential diagnoses Site MRI lesion features Differential diagnoses to be considered Brain Hemorrhages/ microhemorrhages Amyloid angiopathy; Moyamoya disease; CADASIL; vasculitis Calcifications Cysticercosis; toxoplasmosis, mitochondrial disorders Selective involvement of the anterior temporal and inferior frontal CADASIL lobe Persistent Gd enhancement and continued enlargement of lesions Lymphoma; glioma; vasculitis; sarcoidosis Simultaneous enhancement of all lesions Vasculitis; lymphoma; sarcoidosis T2-hyperintensity in the dentate nuclei Cerebrotendinous xanthomatosis T1-hyperintensity of the pulvinar Fabry disease; hepatic encephalopathy; manganese toxicity Large and infiltrating brainstem lesions Behçet s disease; pontine glioma Predominance of lesions at the cortical/subcortical junction Embolic infarction; vasculitis; progressive multifocal leukoencephalopathy Vascular territory syndrome, e.g., lateral medullary lesion Cerebral infarct Large lesion (> 1-2cm), diffuse bilateral lesion and involvement of the ADEM basal ganglia Spinal cord Anterior spinal artery territory lesion Spinal infarct Progressive sensory ataxia (posterior columns) Vitamin B 12 deficiency Complete transverse myelitis, longitudinally extensive transverse Neuromyelitis optica, Behcet, lymphoma, ADEM myelitis Table 5. Proposed definition for the radiologically isolated syndrome according to Okuda and colleagues (D. T. Okuda et al., 2009) A. The presence of incidentally identified CNS white matter anomalies meeting the following MRI criteria: 1. Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the corpus callosum 2. T2 hyperintensities measuring >3mmand fulfilling Barkhof 7 criteria (at least 3 out of 4) for dissemination in space 3. CNS white matter anomalies not consistent with a vascular pattern B. No historical accounts of remitting clinical symptoms consistent with neurologic dysfunction C. The MRI anomalies do not account for clinically apparent impairments in social, occupational, or generalized areas of functioning D. The MRI anomalies are not due to the direct physiologic effects of substances (recreational drug abuse, toxic exposure) or a medical condition E. Exclusion of individuals with MRI phenotypes suggestive of leukoaraiosis or extensive white matter pathology lacking involvement of the corpus callosum F. The CNS MRI anomalies are not better accounted for by another disease process 있음을시사할뿐만아니라, MS 발생의주요위험인자로서중요한의미를가진다. 그러나, 장기적인관점에서 RIS 의 DMT 적용이이득이있을지는확립되지않았다. 7,37 수동적으로는환자에게임상증상발생시병원을방문하도록교육할수있겠으나, 적극적인관점에서는정기적인신경학적검사와 MRI 검사의추적이권고된다 임상적단독증후군의진단에필요한혈액이나체액검사는? 답 : 혈액검사는임상과부임상적소견들이비특이적이거나비전형적일경우시행한다. 특히, 한국에서는시신경척수염범주질환의배제를위해항 aquaporin-4 항체검사를고려한다. (Strong recommendation; low quality-evidence) CIS의정확한진단과감별을위해여러가지면역학적혈액검사가필요하다. 하지만 MS 유사질환의가능성을배제하기위한감별진단과이에따른검사들은임상과부 임상적 (paraclinical) 소견들을바탕으로시행하는것을권고한다. 13,42-44 한국을포함한아시아지역에서는 NMOSD 가상대적으로더흔하고, MS의치료약물은 NMOSD 를악화시킬수있으므로두질환의감별이중요하다. CIS를의심하는환자에서 MS에비전형적인소견이있고 NMOSD 에합당한임상및영상소견이있다면혈중 aquaporin-4 (AQP-4) 항체검사를시행해야한다. 7,12 일부 NMOSD 환자에서척수염이척추 3분절이내의길이로발생할수있으므로척추 3분절이상의 위아래로광범위한횡단성척수염 (longitudinally extensive transverse myelitis, LETM) 이아니더라도 AQP-4 항체검사는시행할수있다. 45 그외자가항체검사들은임상적그리고부임상적소견들을종합해서 MS를시사하는 CIS (CIS suggestive of MS) 에전형적이지않을때선별적으로시행한다. 뇌척수액 (cerebrospinal fluid, CSF) 검사는진단에필수적인것은아니지만다른질환과의감별을위해권고되며, 7 CIS 환자에서 CSF내올리고클론띠 (oligoclonal band, OCB) 의존재는 MS로의전환의독립적인위험인자이다. 46,47 Journal of Multiple Sclerosis Vol. 7, No. 2,

8 김수현박민수강사윤김남희김선영김성민김지영남태승민주홍신하영오지영조정희조중양허소영김우준권오현 7. 임상적단독증후군의감별진단은? 답 : 매우다양한질환들이 CIS 와유사한임상혹은영상의학적소견으로발현할수있다. 감별에특히유의해야할질환들은다음과같다. 1) 시신경척수염범주질환 (neuromyelitis optica spectrum disorder, NMOSD) 2010년 McDonald 기준을적용할때, 아시아와라틴아메리카인들은 MS에대한 NMOSD 의상대적비율이높기때문에주의가필요하며, AQP4 항체검사를권고한다. 7 한쪽또는양쪽눈의심한시신경염, LETM, 등쪽연수또는제4 뇌질주위병터에의한지속적인딸꾹질, 구역과구토 (area postrema syndrome), 기면증을동반한시상하부병터또는증상을동반하는 3cm 이상의큰피질아래또는깊은백질병터를보이는환자의경우반드시 NMOSD와감별되어야한다. 48 2) 급성파종성뇌척수염 (acute disseminated encephalomyelitis, ADEM) 사춘기이전소아 MS는성인과달리비전형적인임상과 MRI 소견을보여 McDonald 기준을그대로적용하는데는제한이있다. 49 소아의경우, 남녀성비가비슷하고, 종종 ADEM 과유사한임상양상을가진다. 성인에비해, 뇌줄기와소뇌를잘침범하고, 척수는덜침범한다. 또한 T2 병터가시간이지남에따라사라지기도한다. CSF 에서 50개 /ml 이상의세포증다증 (pleocytosis) 이흔하고, 호중구가검출될수있는반면 OCBs가성인에비해낮은빈도로관찰된다. 50 ADEM 은전형적으로동시에여러구역을침범하여다초점성증상으로발현하며, 의식저하등의뇌병증 (encephalopathy) 이흔하다. CIS 와 ADEM은임상적으로는중첩되며, 두질환을구분할수있는생체표지자나 MRI 기준은아직제시되지않았다 년 McDonald 기준을소아에게적용하면, 11세미만의 15-20% 의 CIS 환자는뇌병증을동반하고, 다초점성신경학적결손이발생하여 ADEM 과구분하기어렵다. 52,53 그러므로, 첫번째증상후약 3-6 개월후에 MRI 검사를하도록추천한다. 54 3) 소혈관질환 (small vessel disease) McDonald 기준은또한 50세이상의고령의환자에서는아직유효성이검증되지않았다. 고령환자들은소혈관허혈성병터가백질에서관찰되며, CIS 와의감별이어려울수있다. 건강한성인을대상으로 50세이하에서는약 5%, 50대에서는 30%, 60세이상에서는절반에서다초점성백질병터가 MRI에서관찰되며, 이병터들은대체로허혈성이의심되는비특이적인병터로기술된다. 55,56 이런백질병터들은어느정도 CIS/MS 병터들과구별될수있는데, 좀더작고, 뇌실에서좀떨어진피질하백질에위치하며, 기저핵을잘침범하고, 뇌실주변부에위치한경우에는부드러운윤곽 (smooth contour) 과좀더대칭적인분포를한다. 55 반대로뇌량 (corpus callosum) 이나척수의병터는종종병적인탈수초질환에서나타나지만노령화에따른혈관변성에의해서는잘보이지않는다. 31,57 4) 그외드문탈수초질환들그밖에감별해야할질환으로는 tumefactive MS (Marburg variant, Balo concentric sclerosis, Schilder disease), 급성출혈백질뇌염 (acute hemorrhagic leukoencephalitis, AHL), Bickerstaff 뇌줄기뇌염 (brainstem encephalitis) 와만성재발특발시신경병 (chronic relapsing idiopathic optic neuropathy, CRION) 등이있다. Tumefactive MS는적어도한개의큰 (>2 cm) 급성탈수초병터로나타나며종종부종, 용적효과 (mass effect), 반지모양조영증강 (ring enhancement) 을동반한다. 58,59 임상양상은크기와병터의위치에따라다양하지만두통과혼동, 실어증, 실행증을동반할수있고, 드물게경련이있다. 59 Tumefactive lesions 은종양이나농양과감별해야한다. Marburg형과 Balo concentric sclerosis가 tumefactive MS의아형 (variant) 으로받아들여진다. 이들은급격히진행하며, 비전형적인신경병리및영상의학적소견등의차이가있다. Schilder disease는 myelinoclastic diffuse sclerosis 로알려져있으며, 적어도 2-3 cm 정도의한두개의대칭적인병터가반란원중심 (centrum semiovale) 에서관찰되며, OCBs 가 CSF에서관찰되지않는다. 부신백질형성장애 (adrenoleukodystrophy) 가검사에서감별되어야하며, 증상전에고열과감염, 예방접종의병력이없어야한다. 60 약 5-41 세연령에서발견되며여성에서약간더잘발생한다. MRI 와 MRS로조직검사없이진단가능하다. 그밖에 ADEM 아형으로급성출혈백질뇌염 (acute hemorrhagic leukoencephalitis), 혹은급성출혈백질뇌척수염 (acute hemorrhagic leukoencephalomyelitis), 그리고급성괴사출혈백질뇌염 (Hurst acute necrotizing hemorrhagic leukoencephalitis) 등이있다. 이들은드물고급격하게염증과출혈이동반된탈수초병터를보인다. 상기도감염이흔히선행하는경우가많다. MRI 에서보이는백질병터는크고광범위하고부종과용적효과가동반되며침범된뇌영역에서제한된확산 (restricted diffusion) 이관찰된다. 61 CSF에서백 36 대한다발성경화증학회지제 7 권제 2 호, 2016

9 혈구, 적혈구, 단백이상승한다. 초기의적극적인치료가생존율을높일수있다. Bickerstaff뇌염은감염후발생하는면역질환이며, 외안근장애, 파행, 의식장애, 양측안면신경마비등이동반된다. 선행된기도감염이나위장관감염이있고, 병리적으로혈관부위에림프구침윤과뇌줄기부종을보이는것은 ADEM과유사하다. CRION 는면역관련시신경병증이며 CIS나 MS와는다른질환으로여겨진다. CRION는종종일측성또는양측성시력상실로나타난다. 이러한질환은 MS와관련된시신경병증과는차이가있는데, 종종심한시력상실이있고, 시력상실후지속적인통증이있으며, 잘재발하고스테로이드의존성경과를보인다. 뇌 MRI에는시신경염증이외에는다른병터가보이지는않는다. 장기간면역억제요법이필요하며, 치료하지않으면회복은좋지않다. CRION 의일부는결국 NMO나 MS으로진행하는경우도있으며, 특히, 양측성 ON, 재발성 ON에잘동반되는 anti-myelin oligodendrocyte glycoprotein (anti-mog) 항체유무를확인해야한다. 62,63 그외에도매우다양한질환이 CIS와유사한발현을할수있지만, 이를구체적으로언급하는것은본지침의영역을벗어난다. 13,64 Acknowledgements 1. 본지침의원고는대한다발성경화증학회임원진들의감수를거쳐수정, 승인되었음. 2. 본연구는한국바이엘 (Bayer Korea) 의재정적인지원을받았음. 한국바이엘은본연구의재정적인지원외에자료의수집, 원고의작성및검토, 발간에영향을미치지않았음. REFERENCES 1. Lassmann H. Multiple Sclerosis Pathology: Evolution of Pathogenetic Concepts. Brain Pathol 2005;15: Rolak LA. MS: The Basic Facts. Clin Med Res 2003;1: Montalban X, Sastre-Garriga J. Diagnosis and trials of clinically isolated syndrome. Lancet Neurol 2014;13: Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Ann Neurol 2005;58: McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50: Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann Neurol 1983;13: Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69: Runia TF, Jafari N, Hintzen RQ. Application of the 2010 revised criteria for the diagnosis of multiple sclerosis to patients with clinically isolated syndromes. Eur J Neurol 2013;20: Swanton JK, Rovira A, Tintore M, Altmann DR, Barkhof F, Filippi M, et al. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study. Lancet Neurol 2007;6: Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343: Brownlee WJ, Swanton JK, Altmann DR, Ciccarelli O, Miller DH. Earlier and more frequent diagnosis of multiple sclerosis using the McDonald criteria. J Neurol Neurosurg Psychiatry 2015;86: Huh SY, Kim SH, Kim W, Lee SH, Park MS, Ahn SW, et al. Evaluation of McDonald MRI criteria for dissemination in space in Korean patients with clinically isolated syndromes. Mult Scler 2014;20: 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: Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003;9: Mowry EM, Pesic M, Grimes B, Deen SR, Bacchetti P, Waubant E. Clinical predictors of early second event in patients with clinically isolated syndrome. J Neurol 2009;256: Tintore M, Rovira A, Arrambide G, Mitjana R, Rio J, Auger C, et al. Brainstem lesions in clinically isolated syndromes. Neurology 2010;75: Fisniku LK, Brex PA, Altmann DR, Miszkiel KA, Benton CE, Lanyon R, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131: Kuhle J, Disanto G, Dobson R, Adiutori R, Bianchi L, Topping J, et al. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Multiple Sclerosis Journal 2015;21: Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120 ( Pt 11): Miller DH, Thompson AJ, Filippi M. Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol 2003;250: McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50: Group CS. MRI predictors of early conversion to clinically definite MS in the CHAMPS placebo group. Neurology 2002;59: Simon JH, Li D, Traboulsee A, Coyle PK, Arnold DL, Barkhof F, Journal of Multiple Sclerosis Vol. 7, No. 2,

10 김수현박민수강사윤김남희김선영김성민김지영남태승민주홍신하영오지영조정희조중양허소영김우준권오현 et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol 2006;27: Rovira A, Wattjes MP, Tintore M, Tur C, Yousry TA, Sormani MP, et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol 2015;11: Mitjana R, Tintoré M, Rocca MA, Auger C, Barkhof F, Filippi M, et al. Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes. Multiple Sclerosis Journal 2014;20: Moon WJ KS, Kim ST, Kim JH, Shon CH, Ahn GJ, Lee SG. Proposal of Standard MRI Protocol for Multiple Sclerosis and Neuromyelitis Optica. Journal of Multiple Sclerosis 2011;2: Silver NC, Good CD, Sormani MP, MacManus DG, Thompson AJ, Filippi M, et al. A modified protocol to improve the detection of enhancing brain and spinal cord lesions in multiple sclerosis. J Neurol 2001;248: Cotton F, Weiner HL, Jolesz FA, Guttmann CR. MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly intervals. Neurology 2003;60: Tas MW, Barkhol F, van Walderveen MA, Polman CH, Hommes OR, Valk J. The effect of gadolinium on the sensitivity and specificity of MR in the initial diagnosis of multiple sclerosis. AJNR Am J Neuroradiol 1995;16: Lycklama G, Thompson A, Filippi M, Miller D, Polman C, Fazekas F, et al. Spinal-cord MRI in multiple sclerosis. Lancet Neurol 2003;2: Bot JC, Barkhof F, Lycklama a Nijeholt G, van Schaardenburg D, Voskuyl AE, Ader HJ, et al. Differentiation of multiple sclerosis from other inflammatory disorders and cerebrovascular disease: value of spinal MR imaging. Radiology 2002;223: Pestalozza IF, Pozzilli C, Di Legge S, Piattella MC, Pantano P, Caramia F, et al. Monthly brain magnetic resonance imaging scans in patients with clinically isolated syndrome. Mult Scler 2005;11: Jacobi C, Hahnel S, Martinez-Torres F, Rieger S, Juttler E, Heiland S, et al. Prospective combined brain and spinal cord MRI in clinically isolated syndromes and possible early multiple sclerosis: impact on dissemination in space and time. Eur J Neurol 2008;15: Montalban X, Tintoré M, Swanton J, Barkhof F, Fazekas F, Filippi M, et al. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010;74: Sombekke M, Wattjes M, Balk L, Nielsen J, Vrenken H, Uitdehaag B, et al. Spinal cord lesions in patients with clinically isolated syndrome: a powerful tool in diagnosis and prognosis. Neurology 2013;80: Okuda DT, Siva A, Kantarci O, Inglese M, Katz I, Tutuncu M, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One 2014;9:e Granberg T, Martola J, Kristoffersen-Wiberg M, Aspelin P, Fredrikson S. Radiologically isolated syndrome--incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler 2013;19: Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, et al. Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. J Neurol Neurosurg Psychiatry 2008;79: Lebrun C, Bensa C, Debouverie M, Wiertlevski S, Brassat D, de Seze J, et al. Association between clinical conversion to multiple sclerosis in radiologically isolated syndrome and magnetic resonance imaging, cerebrospinal fluid, and visual evoked potential: follow-up of 70 patients. Arch Neurol 2009;66: Sierra-Marcos A, Mitjana R, Castillo J, Edo MC, Horga-Hernandez A, Tintore M, et al. [Demyelinating lesions as incidental findings in magnetic resonance imaging: a study of 11 cases with clinico-radiological follow-up and a review of the literature]. Rev Neurol 2010;51: Sellner J, Schirmer L, Hemmer B, Muhlau M. The radiologically isolated syndrome: take action when the unexpected is uncovered? J Neurol 2010;257: Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4: Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation". Lancet Neurol 2006;5: Katz Sand I. Classification, diagnosis, and differential diagnosis of multiple sclerosis. Curr Opin Neurol 2015;28: Flanagan EP, Weinshenker BG, Krecke KN, Lennon VA, Lucchinetti CF, McKeon A, et al. Short myelitis lesions in aquaporin-4-igg-positive neuromyelitis optica spectrum disorders. JAMA Neurol 2015;72: Tintore M, Rovira A, Rio J, Otero-Romero S, Arrambide G, Tur C, et al. Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain 2015;138: Kuhle J, Disanto G, Dobson R, Adiutori R, Bianchi L, Topping J, et al. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. Mult Scler 2015;21: 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: Waubant E, Chabas D. Pediatric multiple sclerosis. Curr Treat Options Neurol 2009;11: Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002;59: Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain : a journal of neurology 2000;123 Pt 12: Banwell B, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol 2007;6: Mikaeloff Y, Adamsbaum C, Husson B, Vallee L, Ponsot G, Confavreux C, et al. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain 2004;127: Pohl D, Waubant E, Banwell B, Chabas D, Chitnis T, Weinstock-Guttman B, et al. Treatment of pediatric multiple sclerosis and variants. Neurology 2007;68:S Miller D KJ, McDonald WI, Paty DW, Thompson AJ. Magnetic 38 대한다발성경화증학회지제 7 권제 2 호, 2016

11 Resonance in Multiple Sclerosis. Cambridge, UK: Cambridge University Press, Kirkpatrick JB, Hayman LA. White-matter lesions in MR imaging of clinically healthy brains of elderly subjects: possible pathologic basis. Radiology 1987;162: Gean-Marton AD, Vezina LG, Marton KI, Stimac GK, Peyster RG, Taveras JM, et al. Abnormal corpus callosum: a sensitive and specific indicator of multiple sclerosis. Radiology 1991;180: Kepes JJ. Large focal tumor-like demyelinating lesions of the brain: intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients. Ann Neurol 1993;33: Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain : 2008;131: Poser CM, Goutieres F, Carpentier MA, Aicardi J. Schilder's myelinoclastic diffuse sclerosis. Pediatrics 1986;77: Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute hemorrhagic leukoencephalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology 2003;60: Ramanathan S, Reddel SW, Henderson A, Parratt JDE, Barnett M, Gatt PN, et al. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm 2014;1:e Chalmoukou K, Alexopoulos H, Akrivou S, Stathopoulos P, Reindl M, Dalakas MC. Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm 2015;2:e Solomon AJ, Klein EP, Bourdette D. Undiagnosing multiple sclerosis: the challenge of misdiagnosis in MS. Neurology 2012;78: Journal of Multiple Sclerosis Vol. 7, No. 2,