414 오현식 최유덕 김현중외 5 인 라각각 NF-H (200 kd), NF-M (160 kd), NF-L (70 kd) 의세가지아형으로나뉜다. NF-M과 L은신경세사의중심을이루어주로축삭과수상돌기에분포되어있고, NF-H는심하게인산화되어있어다른세사와교차결합을하고주로축삭에

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1 대한병리학회지 : 제 37 권제 6 호 2003 The Korean Journal of Pathology. 2003; 37: 신경세포이주장애질환에서신경세사단백아형의발현 오현식 최유덕 김현중 이경화김명규 우영종 김재휴 이민철 전남대학교의과대학병리학교실 1 신경과학교실, 2 소아과학교실 3 신경외과학교실 접수 : 2003년 10월 24일게재승인 : 2003년 11월 28일 책임저자 : 이민철우 광주광역시동구학동 5 전남대학교의과대학병리학교실전화 : Fax: mclee@chonnam.ac.kr * 이연구는 2002년도보건의료기술연구개발사업 (02-PJ1-PG ) 의연구비지원에의하여수행되었음. Neurofilament Protein Subtype Expression in Neuronal Migration Disorders Hyun-Sik Oh, Yoo-Duk Choi, Hyun-Joong Kim, Kyung-Hwa Lee, Myoung-Kyu Kim 1, Young- Jong Woo 2, Jae-Hyu Kim 3 and Min-Cheol Lee Departments of Pathology, 1 Neurology, 2 Pediatrics, and 3 Neurosurgery, Chonnam University Medical School, Gwangju, Korea Background : Neuronal migration disorder (NMD) is one of the causes of medically intractable epilepsy. As neurosurgical treatments for medically intractable epilepsy have expanded recently, precise histopathologic diagnosis is required. Histopathologic grading of NMD is important due to its association with neocortical development and expectation of prognosis. Many studies revealed abnormalities of neuronal cytoskeletal protein in abnormal neuronal cells of NMD. Methods : We performed immunohistochemical staining for neurofilament protein (NF) subtypes, one of the neuronal cytoskeletal proteins, and investigated the staining pattern of specific cells in each grade of NMD. Results : NF-L was more intensely labeled in perikarya, dendrites, and axons of normal or small sized dysplastic neurons, cytomegalic neurons, and balloon cells than of normal-looking neurons. Furthermore, positive reaction was more intense in high-grade lesion. NF-H and NF-M were mainly positive in the axons of gray and white matter and weakly positive in a few cytomegalic neurons and some balloon cells. Conclusion : NF-L is a better marker than NF-H and NF-M for the detection of normal or small sized dysplastic neurons, cytomegalic neurons, and balloon cells and for grading of NMD. Key Words : Cerebral Cortex-Nervous System Malformations-Neurofilament Proteins 신경세포이주장애질환은대뇌피질의발생과정의장애로인해발생하는질환으로약물난치성간질을일으키는원인중의하나이다. 최근이러한약물난치성간질에대한치료로외과적절제술이증가하고있는데이에따라정확한병리조직학적인진단이요구된다. 대뇌피질의기형에는전통적으로형태학적소견에의해 Friede 1 에의한분류, Rorke 2 에의한분류, Barth 3 에의한분류가있었고, 대뇌피질기형중의하나인대뇌피질이형성증에대해서는 Palmini 등 4-6 에의한분류, Mischel 등 7 에의한병리조직학적인기술, 대뇌의미세발생장애에대한 Meenke 등 8 의기술등이있었다. 이상의소견들중에서상당부분이중복되므로과거에서로분리되어사용되었던대뇌피질의기형에대한분류들을신경세포이주장애질환이라는단일질환에포함시킬수있다. 3,7,9-13 또한최근에는신경세포이주장애질환이대뇌피질의발생장애와연관성이있기때문에 Lee 등 14,15 에의한 4등급체계가제안 되었다. 이와같이신경세포이주장애질환에대한분류가중요한이유는, 본질환의발생시기를대뇌의발생과관련지을수있고예후측정에대한기준으로삼을수있기때문이다. 16 Lee 등 14 과 Farrell 등 17 은신경세포이주장애질환에서은염색상비정상거대신경세포의핵주위세포질과수상돌기가정상신경세포에비해강하게염색이된다는것을확인하였고, Mischel 등 7 과 Duong 등 18 은그양상이알츠하이머병에서관찰되는신경섬유농축체와유사하다고보고하였다. 이는신경세포이주장애질환에서관찰되는비정상신경세포에서세포골격을이루는신경세사의이상을시사해주는것이다. 그리고 Lee 등 19 과 Spreafico 등 20 은신경세사단백 (neurofilament protein, NF), MAP2, tau, ubiquitin 등의신경세포골격단백구성물질에대한면역조직화학염색을통하여비정상신경세포를관찰함으로써신경세포이주장애질환을진단하는데도움이된다고하였다. 신경세사단백은신경세포골격단백중의하나로분자량에따 413

2 414 오현식 최유덕 김현중외 5 인 라각각 NF-H (200 kd), NF-M (160 kd), NF-L (70 kd) 의세가지아형으로나뉜다. NF-M과 L은신경세사의중심을이루어주로축삭과수상돌기에분포되어있고, NF-H는심하게인산화되어있어다른세사와교차결합을하고주로축삭에분포하며, 인산화되지않은 NF-H는수상돌기에도분포되어있다. 21 저자는신경세포이주장애질환에서각등급별특징을나타내는세포에서신경세포골격단백중의하나인 NF의각아형에대한면역조직화학염색정도를확인하여, 신경세포이주장애질환을진단하고등급을결정하는데도움을얻고자본연구를시행하였다. 재료 재료와방법 2000년 1월부터 2002년 12월까지최근 3년동안약물치료에반응하지않은난치성측두엽간질로인하여외과적절제술이시행된환자중에서, 병리조직검사결과신경세포이주장애질환으로진단된환자를대상으로하였다. 병리조직학적으로 2등급부터 4등급까지각등급별로 5예씩 15예를선택하였고, 비교를위해서비신경계질환으로사망한환자의병리부검조직을대조군으로하였다. 모든예의헤마톡실린과에오신염색표본을재검토하고가장대표적인파라핀포매블록하나를선택하여면역조직화학염색을시행하였다. Table 1. Histopathologic grading of neuronal migration disorders Grade Pathology Defect in Neural Development Ia Four layered polymicrogyria Post migratory event Ib Microdysgenesis Neuronal migration II Small and oval dysplastic Neuronal migration and neurons with or without differentiation columnar arrangement III Cytomegalic neurons Neuronal differentiation and migration IVa Balloon cells Neuronal and glial differentiation IVb Tubers in tuberous sclerosis TSC 1&2 genes TSC: Tuberous sclerosis complex. Table 2. Primary antibodies used in this study Antibody Source Specificity Clone Optimal dilution NF-H NeoMarkers 200 kda NF :100 NF-M NeoMarkers kda NF :100 NF-L NeoMarkers 68 kda NF :100 NF-H: high molecular weight neurofilament protein, NF-M: medium molecular weight neurofilament protein, NF-L: low molecular weight neurofilament protein. 조직병리학적등급및면역조직화학염색 조직병리학적등급은신경세포이주장애질환의병인론과연관하여제안된 4등급체계로하였다 (Table 1). 14,15 면역조직화학염색은파라핀포매조직편을 4 m 두께로박절하여 ProbeOn Plus Microscopic Slide (Fischer scientific, Pittsburg, PA, U.S.A.) 에부착시키고, 충분히건조한다음염색을시행하였다. 염색의전과정은유리슬라이드를맞대어생기는 capillary gap action을응용하여개발한 Microprobe System (Fisher scientific, Pittsburg, PA, U.S.A.) 을이용해서 avidinbiotin complex 방법으로하였다. 파라핀절편은탈파라핀과함수과정을거친후 Autoblocker (Research Genetics, Huntsville, AL, U.S.A.) 로내재성과산화효소를억제시켰다. 일차항체로는신경세사단백 (Neurofilament protein, NF-H, M, L, NeoMarkers, Fremont, PA, U.S.A.) 을사용하였다 (Table 2). NF-H, M, L은 45 에서 30분간반응시킨후, 일차항체의검출을위한이차항체는 biotin이부착된 anti-mouse IgG (Shandon, Pittsburg, PA, U.S.A.) 를이용하여 45 에서 7분간반응시켰다. 이후 avidin-alkaline phosphatase를 45 에서 7분간반응시킨후, 발색제로 fast red TR salt (Research Genetics, Huntsville, AL, U.S.A.) 를이용하였다. 양성반응은헤마톡실린으로대조염색을시행한후 Universal mount (Research Genetics, Huntsville, AL, U.S.A.) 로봉입하여관찰하였다. 병리조직학적소견 결과 신경세포이주장애질환의등급에따라대뇌피질의병변은정도가다양하였으나, 대뇌피질의층상배열형성장애는 15예모두에서공통적으로관찰되었다. 신경세포의배열이불규칙하고, 정 Table 3. Summary of immunohistochemical findings Control Normal or small Cytomegalic Balloon sized dysplastic neuron cell neuron NF-H neuron (-) - (+/-) (-) - (+/-) (+/-) (+) axon GM (+/-) (+/-) (+/-) (+/-) WM (+) (+) (+) (+) NF-M neuron (-) - (+/-) (-) - (+/-) (+/-) (+) axon GM (+/-) (+/-) (+/-) (+/-) WM (+) (+) (+) (+) NF-L neuron (+) (++) (++) - (+++) (+++) axon GM (+) (++) (++) (+++) WM (+) (++) (++) (+++) GM: gray matter, WM: white matter. -~+++: negative, weak, moderate, strong immunoreactivity.

3 신경세포이주장애질환과신경세사단백 415 A B C Fig. 1. (A) Normal or small sized dysplastic neurons (arrows) are noted among relatively normaly looking neurons. (B) Immunohistochemical stain for NF-L disclosed strong immunoreactivity in perikarya and dendrites of dysplastic neurons (arrows) and abnormally thickened, haphazardly oriented axons. (C) Immunohistochemical stain for NF-M disclosed weak immunoreactivity in abnormally thickened, haphazardly oriented axons. 상층상구조가소실되어있었으며, 비정상신경세포의군집이관찰되었다. 신경세포이주장애질환 2등급으로진단된예에서는크기는피라미드세포와유사하거나작지만다각형또는원형으로변형되어있는비정상신경세포가관찰되었다 (Fig. 1A). 신경세포이주장애질환 3등급으로진단된예에서는수상돌기의방향성이일정하지않고, 세포체로부터여러개의수상돌기가돌출되어있고핵의크기가정상신경세포보다최대 4배까지커져있는호염기성인거대신경세포를관찰할수있었다. 이들은소수의세포가산재되어존재하거나또는군집을형성하고있었다 (Fig. 2A). 4등급으로진단된예에서는타원형또는원형의거대세포 로서, 편재된핵과호산성의풍부한세포질을갖는풍선세포가관찰되었다. 이들은거대신경세포또는비정상신경세포들과혼재되어나타나거나때로는군집을이루고있었다 (Fig. 3A). 면역조직화학염색소견 (Table 3) 정상대조군에서 NF-L은핵주위질과수상돌기그리고축삭에서약하게양성반응을보였고, NF-H와 NF-M은거의양성반응을보이지않고, 일부회백질과백질의축삭에서만약하게양성반응을보였다 (Fig. 4).

4 416 오현식 최유덕 김현중외 5 인 A B C Fig. 2. (A) Cytomegalic neurons (arrows) are noted among normal or small sized dysplastic neurons and relatively normal-looking neurons. (B) Immunohistochemical stain for NF-L disclosed strong immunoreactivity in cytomegalic neurons (arrows) with complex arborizing perikarya and dendrites, abnormally thickened, haphazardly oriented axons, and normal or small sized dysplastic neurons. (C) Immunohistochemical stain for NF-M disclosed weak immunoreactivity in abnormally thickened, haphazardly oriented axons. 신경세포이주장애질환에서 NF-L은정상또는작은크기의비정상신경세포가관찰되었고, 거대신경세포와풍선세포에서정상신경세포에비해강한양성반응이관찰되었다. 양성반응은주로핵주위질과수상돌기그리고축삭에서발현되었고, 등급이높아질수록양성반응의정도가더강했다 (Fig. 1B, 2B, 3B). 또한일부거대신경세포의핵주위질과수상돌기에서신경섬유농축체와비슷한구조를관찰할수있었다. 비교적정상으로보이는병변주위피질에서는주로신경세포의축삭에서양성반응이나타났고, 핵주위질에서도양성반응이나타났으나그정도는약해서대조군의염색소견과유사하였다. NF-H와 NF-M은주로 회백질과백질의축삭에서양성반응이나타났고, 일부회백질의핵주위질과수상돌기도양성반응을보였지만 NF-L에의한양성반응의정도보다는약했다 (Fig. 1C, 2C, 3C). 고찰신경세포이주장애질환은대뇌피질의발생과정의장애로인해생기는질환으로전통적으로형태학적인소견에의해기술된것이대부분이었다. Friede 1 은대뇌피질의기형을 (1) 무회뇌증 /

5 신경세포이주장애질환과신경세사단백 417 A B C Fig. 3. (A) Balloon cells with eccentrically located nucleus and eosinophilic cytoplasm (arrows) are noted. (B) Immunohistochemical stain for NF-L disclosed strong immunoreactivity in balloon cells (arrow), cytomegalic neurons, normal or small sized dysplastic neurons, and abnormally thickened, haphazardly oriented axons. (C) Immunohistochemical stain for NF-M disclosed immunoreactivity in balloon cells and abnormally thickened, haphazardly oriented axons. 활택뇌 / 단후두뇌 (agyria/lissencephaly/pachycephaly), (2) 층상또는결절성이소성병변 (laminar or nodular heterotopia), (3) 백질내단일이소성신경세포 (single heterotopic white matter neurons), (4) 결절성대뇌피질이형성증 (nodular cortical dysplasia), (5) 사마귀모양이형성증 (verrucous dysplasia), (6) 이소성신경교 -신경세포(glioneuronal heterotopia), (7) 연막하과립성신경세포의잔존 (persistent subpial granule cell layer), (8) 국소대뇌피질이형성증 (focal cortical dysplasia) 으로분류하였다. Barth 3 은이질환의원인적분류에대한의견을제시하면서주로형태학적소견만기술하였다. Rorke 등 2 은무회 뇌증 / 활택뇌 / 단후두뇌, 소회뇌증 (microgyria), 이소성병변과대뇌피질이형성증간에때로는형태학적인구분이어렵다는점을기술하였다. Palmini 등 6 은병변의중등도에따라세가지로분류하였다. 1등급은가장경한형태로서대뇌피질부신경원의층상배열의장애가있는경우, 2등급은 1등급소견이외에비정상적인거대신경세포가관찰되는경우, 3등급은이상의소견외에풍선세포가관찰되는경우이며, 등급이높을수록예후가나쁘다고하였다. Mischel 등 7 은병리조직소견을 9가지로구분하여기술하였으며, 이들의소견에따라병변을경도, 중등도, 고도의세등급으로구분하였다. 경도는피질층모양배열의이상 (corti-

6 418 오현식 최유덕 김현중외 5 인 A B Fig. 4. (A) Immunohistochemical stain for NF-L disclosed weak immunoreactivity in perikarya and dendrites of neurons and axon in control brain. (B) Immunohistochemical stain for NF-M disclosed weak immunoreactivity in axon and no immunoreactivity in perikarya and dendrites of neurons in control brain. cal laminar disorganization), 백질내단일이소성신경세포, 피질분자층내이소신경원 (neurons in the molecular layer), 연막하과립성신경세포의잔존및변연부이소신경교-신경세포 (marginal glioneuronal heterotopia) 등이관찰될때로보았고, 중등도는소다뇌회증 (polymicrogyria), 백질내이소성신경세포가관찰될때로보았다. 그리고고도는거대신경세포및풍선세포가관찰될경우라고하였다. 이상의소견들중에서상당부분이 Meenke 등 8 이기술한바와중복된다. Meenke 등은대뇌의미세발생장애의형태학적인소견인연막또는연막하부분자층의이소성신경원, 분자층과외과립층의불분명한경계, 대뇌피질의잔존하는열상구조, 회백질내다수의이소신경원, 해마의구조이상, 소뇌의이소성퓰킨예세포의존재등에대하여기술하였다. 따라서, 과거에서로분리되어사용되었던대뇌피질의기형에대한분류를신경세포이주장애질환이라는단일질환에포함시킬수있다. 3,7,9,11-13 또한, 최근에는신경세포이주장애질환이대뇌피질의발생장애와연관성이있기때문에, Lee 등 14,15 에의한 4등급체계가이용되고있다. 이때무회뇌증, 소회뇌증등과거부터흔히사용되어오던특징적인육안또는방사선소견이있으면같이기술해주고있다. 신경세포이주장애질환의조직학적소견및그정도에따른분류가이처럼중요한이유는, 본질환의발생시기를대뇌의발생과관련지을수있고, 예후측정에대한기준으로삼을수있기때문이다. 16 신경세포이주장애질환에서대뇌피질의층상배열장애는거의모든병변에서관찰할수있고, 정상또는작은크기의비정상신경세포가관찰될수있다. 그러나이들세포에대해서는기술 이많이되어있지않기때문에정확한진단과병소부위를판단하는데어려움이있다. 19 따라서거대신경세포와풍선세포가이질환의진단에서중요한소견이된다. 풍선세포는타원형또는원형의거대세포로편재된핵과호산성의풍부한세포질을가지고있다. 세포질이호산성으로나타나는이유는전자현미경상세포질에길이 nm, 두께 30 nm정도의막을갖지않는세사들이전자밀도가높은나선형으로분포하고있기때문이다. 그외전자현미경상세포질은조면내형질세망이소실되고중간세사로채워져있으며, 정상신경세포에서관찰되는사립체및골지체도드물게관찰할수있다. 이러한중간세사는별아교세포에서관찰할수있는것으로원시신경모세포에서별아교세포로의분화흔적을보여주고있다. 그리고면역조직화학염색을볼때 vimentin, Neuron specific enolase, NF-H/M, GFAP 등에서강하게염색되므로, 대뇌발생초기에뇌실하부에존재하여신경모세포와아교모세포로분화하는원시신경모세포의손상때문에나타나는가장초기의병변이라판단된다. 16 본연구에서도 NF-L이풍선세포의핵주위질에강한양성반응을보였고, 주위의비정상신경세포와수상돌기, 축삭에서도강한양성반응을관찰할수있었으며, 백질의축삭에서도강한양성반응을보였다. NF-H와 NF-M은소수의풍선세포의핵주위질과축삭돌기, 풍선세포주위와백질의축삭에서양성반응을보였지만, NF- L보다는약한양성반응을보였다. 거대신경세포는핵이정상신경세포보다 4배까지증가해있고, 첨부수상돌기의방향성이일정하지않다. 그리고세포체로부터여러개의수상돌기가돌출되어있으며세포체주위의연접이증가되어있지만, 실제기능을하는축삭-세포간연접은상실

7 신경세포이주장애질환과신경세사단백 419 되어있다. 18,22,23 이세포크기의증가는 DNA와 RNA 함량증가와관련이있다. 24,25 이런소견은전자현미경에서도관찰할수있으며, 이로인한비정상적인신경전도과정이간질발작에관여하리라고생각된다. 그외전자현미경상핵막이불규칙하고, 세포질의조면내형질세망의두께가불규칙적으로비후되어있다. 그리고사립체의수가증가되어있으며, 이들사이에서미세세사가풍부하게관찰되고, 리보소체가소실되어있으며, 신경연접낭사이에완전한신경연접구조가관찰되지않는다. 이러한비후된조면내형질세망의증가로호염기성으로나타난다. 16 거대신경세포의세포질에서중간크기의미세세사로구성된은친화성또는크리스탈모양물질이관찰되는데, 이는 Taylor 등 26 에의해서처음보고된비정상세포골격단백이다. 이후여러연구에서 Bielschowsky 은염색을통해서비정상신경세포의세포질내에서신경세사의봉입체를발견하였고, 이는알츠하이머병에서보이는신경섬유농축체와유사한소견을보였다. 19,23 Duong 등 18 도 NF, ubiquitin, tau 등을이용해서위와같은소견을관찰하였는데, 이들은신경섬유농축체 (neurofilamentous tangle, NFLT) 라명명하였다. 그리고이는세포골격단백의비정상적인인산화로인하여세포질내에축적되었거나축삭으로의운송장애로인해세포질과첨부수상돌기에서인산화된결과라고하였다. 이런소견의기전은아직확실하게밝혀지지않았고, 신경세포이주장애질환에대한이차반응으로서신경세포성장인자나그수용체가과발현됨으로써거대신경세포가나타난다는보고도있다. 2 한편 Mizoguchi 등 27 은 Bodian silver 염색과 NF, tau 등의면역화학염색에서 NFLT를발견하지못했다. Barth 등, 3 Mischel 등, 7 Meenke 등 8 의연구에의하면임신중기의대뇌손상이나, 신경모세포의이주통로인방사상신경교섬유의장애, 대뇌피질의발육장애등대뇌발생과정중중기의손상으로신경세포이주장애질환이발생하는것으로보인다. 본연구에서도 NF-L에서거대신경세포의핵주위질에강한양성반응을보였고, 주위의비정상신경세포와수상돌기, 축삭에서도강한양성반응을관찰할수있었다. 또한핵주위질에서는신경섬유농축체와유사한염색양상이관찰되었고, 백질의축삭에도강한양성반응을보였다. 그러나 NF-H와 NF-M은소수의거대신경세포의핵주위질과축삭돌기, 거대신경세포주위와백질의축삭에서는약한양성반응을보였다. 정상또는작은크기의다각형또는원형으로변형되어있는비정상신경세포에대해서는기술이많이되어있지않지만, NF- H/M, MAP2, tau, ubiquitin 등신경세포골격단백구성물질에대한면역조직화학염색을통하여신경세포이주장애질환을관찰하는데도움이된다는보고가있다. 19,20 Lee 등 19 은 Palmini 등 6 의분류를이용한연구에서 NF-H/M 은거대신경세포와정상크기의비정상신경세포의세포질과수상돌기에정상신경세포에비해강한양성반응을보이고, MAP2 는수상돌기의모양을잘관찰할수있어정상크기의비정상신경세포를관찰하기에용이하다고했다. 또한 tau, ubiquitin은모 양은정상이지만세포골격에이상이있는신경세포를발견하여신경세포이주장애질환을진단하는데도움이된다고하였다. 본연구에서는 NF-H와 NF-M도소수의거대신경세포와정상크기의비정상신경세포에서양성소견을보였지만 NF-L보다양성반응의정도가약하였다. 그뿐만아니라 NF-L 에서는수상돌기의모양을잘관찰할수있었고, 정상또는작은크기의비정상신경세포를발견할수있었으므로, MAP2, tau, ubiquitin 에대한추가적인면역조직화학염색없이도신경세포이주장애질환을진단하는데도움이되었다. 본연구의결과로신경세사단백을이용한면역조직화학염색에의해병리조직학적으로는구별이어려운정상또는작은크기의비정상신경세포를발견하여신경세포이주장애질환을진단하고등급을결정하는데도움이된다는사실을확인할수있었다. 그리고 NF-H, M, L의분포는정상신경세포에서보이는분포와유사하였지만, 주로 NF-L의분포가많았고등급이높을수록그정도가심한소견을보였기때문에, NF-L이더도움이되는사실도알수있었다. 참고문헌 1. Friede RL. Developmental Neuropathology. 2nd ed. Berlin: Springer- Verlag, 1989; Rorke LB. A perspective: The role of disordered genetic control of neurogenesis in the pathogenesis of migration disorders. J Neuropath Exp Neurol 1994; 53: Barth PG. Disorders of cerebral migration. Can J Neurol Sci 1987; 14: Palmini A, Andermann F, Oliver A, et al. Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neurol 1991; 30: Palmini A, Andermann F, Oliver A, et al. Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 1991; 30: Palmini A, Gambardella A, Andermann F, et al. Operative strategies for patients with cortical dysplastic lesions and intractable epilepsy. Epilepsia 1994; 35: Mischel PS, Nguyen LP, Vinters HV. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 1995; 54: Meenke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: a study of eight cases. Epilepsia 1984; 25: Andermann F, Oliver A, Melanson D, et al. Epilepsy due to focal cortical dysplasia with macrogyria and the forme fruste of tuberous sclerosis: a study of 15 patients. In: Wolf P, Dam M, Janz D, Dreifuss E,

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고태성 Table 1. Classification of malformations of cortical development I. Malformations due to abnormal neuronal and glial proflieration A. Generalized

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