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1 KISEP Original Article 대한간질학회지 2006;10(1):46-50 전형적인중심 - 측두부극서파와전두부혹은후두부극서파가동반된중심 - 측두부극서파를보인간질의임상적, 전기생리학적특징에대한비교 김민아 1 김성은 1 황태규 2 인제대학교의과대학부산백병원신경과학교실, 1 소아과학교실 2 The Comparison of Clinical and Electrophysiological Characteristics of Epilepsy with Typical Rolandic Spikes and Concomitantly Additional Frontal or Occipital Spikes with Rolandic Spikes Min Ah Kim, M.D. 1, Sung Eun Kim, M.D., PhD. 1 and Tae Gyu Hwang, M.D., Ph.D. 2 Department of Neurology 1 and Pediatrics, 2 Busan Paik Hospital, Inje University College of Medicine, Busan, Korea Purpose: Recently have there been a few reports that raised the question that Benign Rolandic Epilepsy (BRE) could be a spectrum. This study was conducted to identify whether or not the clinical and electrophysiological characteristics of typical Rolandic Spikes (RS) are different from those of concomitantly additional frontal or occipital spikes with RS. Methods: The consecutive 39 patients who showed centro-temporal spikes were divided into typical RS and RS+ groups. We defined RS+ groups as having concomitantly additional frontal or occipital spikes with RS. The independent variables included clinical data 0(age of onset, a significant antecedent event as part of their etiology of epilepsy, nocturnal seizure, abnormal development, abnormal neurologic examination, pattern of seizure, response to medication for at least 1 year and epilepsy syndrome) and electrophysiological data (dipoles, spikes accentuated during sleep). Results: Eighty two percents (32/39) of patients were RS, whereas 18% (7/39) were RS+. The median age of onset was 7 years old and only 10% showed significant antecedent events. Eighty six percents (34/39) of patients had BRE as epilepsy syndrome. Neither clinical factors nor electrophysiological characteristics were different between both groups. Conclusions: Although RS+ showed additional spikes more than centro-temporal area, the clinical and electrophysiological characteristics of RS+ were not different from those of RS. Centro-temporal with or without additional spikes could be a homogeneous condition rather than a spectrum. (J Korean Epilep Soc 2006;10(1):46-50) KEY WORDS: Benign rolandic epilepsy EEG Centrotemporal spikes. 서 론 Benign Rolandic Epilepsy (BRE) 는소아간질의 15% Received 20 April 2006 Accepted 10 June 2006 Corresponding author: Sung-Eun Kim, M.D., Ph.D., Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Gaegeum-dong, Busanjin-gu, Busan , Korea epidoc@inje.ac.kr 를차지하며특히 5세에서 10세사이에흔한것으로알려져있고주로수면중에안면, 구강인두부, 상지의부분발작으로시작하여전신발작으로이행하는경우가흔하다. 특발성간질로써다른신경학적이상이나지능의저하가없고어떤경우에는상염색체우성유전형태를따르는가족력이있으며약물에대한반응이좋고 10대중반에자연관해되는경우가많다. 1,2 뇌파에서는비교적높은진폭의이상성 (diphasic) 혹은삼상성 (triphasic) 의중심-측두부극서파 (centrotemporal spike and slow wave), 46 대한간질학회지 2006;10(1):46-50

2 김민아 김성은 황태규 즉 Rolandic Spike (RS) 를보이는것이특징이고드물게는전두부혹은후두부의극서파가전형적인 RS에부가적으로나타나는경우도있다. 3 최근에는 Landau-Kleffner syndrome이나 Continuous spikes and waves during slow sleep (CSWS) 를포함하여언어나행동장애등의비정상적인임상적, 전기생리학적소견을보이는비전형적 BRE 가보고되어왔다. 4-9 또한 BRE는동질의 (homogeneous) 질환이아니라다양한스펙트럼을가진비동질의 (heterogeneous) 질환군일수도있다는주장이제기되고있다. 3 즉원래의정의에부합되는순수한형태뿐만아니라 BRE와연관된질환, 혹은 BRE로표현되지만구조적뇌병변이나신경학적이상을보이는비전형적인형태도넓은의미의 BRE 스펙트럼으로생각해볼수있다. 지금까지는전형적인 RS에비하여전두부혹은후두부의극서파가 RS에부가적으로나타나는경우의임상적인의미에대해밝혀진바가없고또한이것이전형적인 BRE의스펙트럼으로간주될수있는지에대한언급도없는실정이다. 그래서본저자들은 RS와전두부혹은후두부의극서파가 RS와동반된경우의임상적, 전기생리학적특징을비교하고자한다. 방법 2004년 12월부터 2005년 2월까지 3개월동안인제대학교의과대학부속부산백병원신경과및소아과외래를통해내원한환자들에게시행한뇌파중에서 RS를보인일련의환자를연구의대상으로하였다. 뇌파는 International 10~20 system에근거하여 19개의표면전극 을사용하여수면과각성시의뇌파를최소 30분이상기록하였다. 뇌파소견을바탕으로중심-측두부에서국소적인이상성혹은삼상성극서파를보이는전형적인 RS 군과여기에덧붙여전두부혹은후두부에서별도로극서파가나타난 RS+ 군 (Rolandic Spike plus) 의두군으로분류하였다 (Figure 1). 단, RS+ 는 RS의전신화 (generalization) 가되는양상과는구별이된다. 모든환자의임상정보는후향적으로의무기록조사를통하여이루어졌다. 환자의나이, 성별, 발병연령, 간질과관련있을것으로생각되는선행사건, 발육장애혹은신경학적이상소견, 수면중경련의유무, 발작의양상, 최소 1년동안의항경련제에대한반응, 진단된간질증후군등의임상적지표와이중극 (dipole) 의유무, 수면시강화되는극서파 (spike and slow waves accentuated during sleep) 의전기생리학적지표를정하여각항목에대한조사를두군에서시행하였다. 전형적인 BRE에서반복적인뇌파를시행했을때극서파가중심 -측두부에서전두엽혹은후두엽으로이동하는경우가보고되어있기때문에 10 본연구에서정의한 RS+ 군과혼돈의가능성이있다. 이렇게극서파가이동하면서 RS+ 군처럼보이는경우를배제하기위하여최소두번이상의반복적인뇌파검사가필요하였다. 연구에포함된 39명의환자중 30명에서 6개월혹은그이상의간격으로검사를반복하였는데뇌파소견의변화를보인환자는없었다. 통계분석을함에있어서연속성변수인경우는 Student s t-test 혹은 Mann-Whitney test를이용하였고범주형변수는 Chi-square test 혹은 Fisher s exact test 를사용하였다. Figure 1. Rolandic Spike plus (RS+) on EEG. Scalp EEG recording shows RS+ which displays centro-temporal spikes [*] with concomitantly additional frontal and occipital spikes (RS+)[ ]. * 대한간질학회지 2006;10(1):

3 중심 - 측두부극서파간질의임상적, 전기생리학적비교 결 과 연구기간동안총 39명의환자에서중심 -측두부의극서파를보였는데이중 82% (32/39 명 ) 는 RS군이었고나머지 18% (7/39명) 는 RS+ 군이었다. 두군에대한비교분석은 Table 1에제시되어있다. 환자연령의중앙값은 RS군에서 9.5 세 (95% CI; 8.00~ 10.80), RS+ 군에서는 12세 (95% CI; 6.01~15.99) 로 RS+ 군이약간높은연령을보였으나통계적으로유의한차이는없었다 (Z=1.72, p=0.08 by Mann-Whitney test). 남녀의성비는 RS군에서는 1:1.1 이었고 RS+ 군은 1:2.5 로두군모두에서여아의발생률이조금씩높은경향을보였으나의미있는차이는없었다 (p=0.43 by Fisher s exact test). 발병연령의중앙값은 RS군이 6.5 세 (95% CI; 5.21~7.00) 였고 RS+ 군이 7세 (95% CI; 1.01~11.00) 로 RS+ 군이약간높게나타났지만임상적인의미는없었다 (Z=-0.07, p=0.94 by Mann-Whitney test). 열성경련의경우는 RS군에서 16% (5/32 명 ), RS+ 군에서 29% (2/7 명 ) 으로차이가없었고 (p=0.59 by Fisher s exact test) 출생전후기병력은 RS+ 군에서는특이사항 Table 1. The clinical and electophysiological characteristics of Rolandic Spike (RS) and Rolandic Spike plus (RS+) groups RS RS+ p Number 32 7 Age (yr), median (95% CI) 9.5 ( ) 12 ( ) Z=1.72, p=0.08 Sex (M:F) 15:17 2:5 p=0.43 Onset age (yr), median (95% CI) 6.5 ( ) 7.0 ( ) Z=-0.07, p=0.94 Febrile convulsion 05/32 2/7 p=0.59 Birth history 04/32 0/7 p=1.00*, Delayed 03/32 1/7 p=0.56 development Seizure during sleep 23/32 5/7 p=1.00 Typical rolandic 08/32 3/7 p=0.38 onset BRE as epilepsy 28/32 6/7 p=1.00 syndrome Dipoles on EEG 13/32 2/7 p=0.69 Accentuated during 25/32 3/7 p=0.08 sleep on EEG Recurrence of 08/32 2/7 p=1.00 seizure on AEDs Recurrence at F/U, months (95% CI) 12.5 (5-16.6) 19 (1-24) Z=0.92, p=0.36 *4 had C/Sec due to delayed labor Mann-Whitney test Fisher s exact test 이없었지만 RS군에서는 13% (4/32 명 ) 에서제왕절개분만이되었고그중 3명은발달저하, 나머지 1명은임신자간증이있었으나두군간의비교에서는큰차이가없었다 (p=1.00 by Fisher s exact test). 발육이나지능저하는 RS군에서 9% (3/32 명 ), RS+ 군에서는 14% (1/7 명 ) 에서있었으나두군간의유의한차이는없었다 (p= 0.56 by Fisher s exact test). 발작이수면도중에일어난경우는 RS군에서 72% (23/ 32명 ), RS+ 군에서는 71% (5/7 명 ) 으로두군모두에서대부분이야간발작을보이는것으로나타났으나두군간의차이는없었다 (p=1.00 by Fisher s exact test). 발작의형태가얼굴이나인후부, 상지의부분발작으로나타나는경우는 RS 군에서 25% (8/32 명 ), RS+ 군에서는 43% (3/7명 ) 이었으나유의한차이는없었다 (p=0.38 by Fisher s exact test). ILAE 분류에근거하여 BRE 로진단할수있었던경우는 RS와 RS+ 군에서각각 86% (28/ 32명 ), 86% (6/7명) 였다 (p=1.00 by Fisher s exact test). 추적조사기간의중앙값은 RS군에서는 12.5 개월 (95% CI; 5~16.6), RS+ 군에서는 19개월 (95% CI; 1~24) 로두군간의차이는없었으며 (Z=0.92, p=0.36 by Mann- Whitney test) 이기간동안항경련제를복용하는중에발작의재발을보인경우는 RS군에서 26% (8/32 명 ), RS+ 군에서는 29% (2/7 명 ) 으로두군간의차이는없었다 (p=1 by Fisher s exact test). 뇌파검사에서전두부에표면양전극 (surface positivity) 을보인수평이중극 (horizontal dipoles) 을형성한경우는 RS군에서 41% (13/32 명 ), RS+ 군에서는 29% (2/ 7명 ) 로큰차이는없었으며 (p=0.69 by Fisher s exact test), 수면시발작파가증가되는현상은 RS군에서 79% (25/32명), RS+ 군에서 43% (3/7명) 로 RS군에서많이나타나는경향을보였으나통계적유의성은없었다 (p= 0.08 by Fisher s exact test). 고찰 BRE는특발성간질증후군의하나로특징적인발작의형태나뇌파소견을보일뿐만아니라뇌의기질적이상이없고지적, 신경학적기능도정상인것으로알려져왔다. 이전의보고에서와마찬가지로본연구에서도발병연령은거의대부분이 3세에서 13세사이에발병하였고호발연령은 7세였으며발작과연관이있다고생각되는과거력으로열성경련이 18% (7/39명), 분만지연으로인한제왕절개가 10% (4/39명) 를차지하였다. 또한 72% 48 대한간질학회지 2006;10(1):46-50

4 김민아 김성은 황태규 (28/39명) 에서는수면중발작이나타났으며 72% (28/ 39명 ) 에서중심-측두부극서파가수면중활성화되었다. RS군에서는 86% (28/32 명 ), RS+ 군에서는 86% (6/7 명 ) 에서 ILAE 에의한간질분류에따라 BRE로진단할수있었다. 그러나최근에는청각이나시공간장애, 언어장애, 주의력결핍장애, 학습및행동장애, 신경영상학적뇌병변등을가진 BRE가보고되었기때문에 BRE의특징적인뇌파소견이있다하더라도어떤경우에서는특발성이아닌증후성으로나타날수도있음이제시되었다 또한 BRE로시작한환자들중일부에서는 atypical benign focal epilepsy of childhood, Landau-Kleffner syndrome, status of benign epilepsy of centrotemporal spikes, 또는 epilepsy with CSWS 로진화되는경우도있기때문에 BRE가항상양성질환이라할수는없다. 19 이러한사실들은 BRE가동질의양성질환이라는기존의개념에혼란을주고있다. 이런의문점에근거하여저자들은 RS+ 소견이전형적인 RS를가진환자와임상적혹은전기생리학적인면에서구분될수있는 BRE 스펙트럼의아형으로간주될수있는지를알기위하여본연구를시작하였다. 그러나분석결과두군에서의미있는차이점을발견할수없었기때문에 RS+ 를 BRE의스펙트럼으로이해하기는힘들었다. BRE의스펙트럼이아니면서도전형적인중심- 측두부극서파에덧붙여전두부및후두부에서극서파가나타나는이유는다음과같이추론할수있다. 첫번째가능성은 BRE가중심- 측두부에만국한된국소적간질이아니라대뇌피질전체에걸쳐나타나는질환일수있다. Kellway 등 10 은 BRE에서반복적으로뇌파검사를했을때중심-측두부극서파는변화없이그대로있고, 독립적인극서파의초점이동측혹은반대측대뇌반구에나타나는현상을발견하여 BRE의자연경과도중에새로운초점의극서파가나타난다고보고하였는데 RS+ 도이와같이해석될수있을것으로생각이된다. 그러나, 본연구에서는 77% (30/39 명 ) 에서는최소 6개월간격으로두번이상의뇌파검사를시행하였고이들에서검사소견의변화가없었기때문에 RS+ 가 BRE 의자연경과도중에나타났을가능성은배제할수있었다. 두번째가능성은 BRE 의유전적요인에서추론할수있다. 지금까지특발성간질은임상적표현형 (clinical phenotype) 혹은뇌파에서나타나는극서파의유전적소인이공통유전적요인 (shared genetic susceptibility) 인지그렇지않으면개개의유전적요인 (discrete genetic factor) 인지는명확하지않 으나아마도양쪽모두가작용할가능성이있다 최근연구 23 에의하면임상적표현형으로써의 BRE의유전적영향은일반적인특발성간질보다는적은것으로알려졌다. 그러나뇌파에서나타나는중심-측두부극서파는특정한연령에서만나타나는불완전한발현 (incomplete penetrance) 을가진상염색체우성으로유전된다. 24 BRE 의스펙트럼이아니면서도전형적인중심- 측두부극서파에덧붙여전두부및후두부에서극서파가나타나는이유를개개의유전적요인모형으로생각한다면중심- 측두부극서파를나타내는유전자와전두부및후두부극서파를나타내는유전자는따로존재할수있으며만일중심-측두부극서파를나타내는유전자와전두부및후두부극서파를나타내는유전자를모두가지고있을경우는뇌파에서본연구의 RS+ 로나타날수있고만일중심-측두부극서파를나타내는유전자만을가지고있는경우는 RS로나타날수있다. 그러나임상적표현형은뇌파에서나타나는상염색체우성유전방식과는별개인다인성 (multifactorial) 유전양상을따르기때문에 RS+ 군과 RS군에서임상양상의차이가없을수도있다. 실제임상에서는 BRE 에합당한임상적소견이나병력이있고신경학적검사에서이상이없으면서특징적인뇌파소견을보일때굳이 CT나 MRI를시행하지않는경우가많다. 저자들의경우에서는총 39명의환자중에서 13명의환자에서 MRI 가시행되었고그중한환자에서우측전두엽에뇌연화증 (cerebromalacia) 을보였다. 그러나과반수이상의환자에서 MRI 가시행되지않았기때문에 RS군과 RS+ 군에있어서어떤차이와임상적인연관성이있는지비교는어려웠다. 본연구는후향적조사에의해단기간동안에시행되었기때문에표본수의제한점이있었다. 그리고연구에포함된 39명의환자중 30명에서만이 6개월혹은그이상의간격으로검사를반복하였다. 따라서 RS+ 군과 RS 군사이에의미있는임상적, 전기생리학적차이가없는것이위음성의오류일가능성이있다. 즉, RS+ 군과 RS 군은 BRE 의스펙트럼일가능성을완전히배제할수는없다. 향후많은수의피험자를모집하여전향적, 다기관, 임상연구를시행하여 RS+ 군과 RS군이 BRE 스펙트럼의아형인지아닌지를밝히는것이앞으로의과제일것으로생각된다. REFERENCES 1. John SD, Simon DS, David RF. Clinical Epilepsy. 1st ed. Philadelphia: W.B. Saunders, 1996; Bouma P, Bovenkerk AC, Westendorp R, Brouwer OF. The course 대한간질학회지 2006;10(1):

5 중심 - 측두부극서파간질의임상적, 전기생리학적비교 of benign partial epilepsy of childhood with centrotemporal spikes: a meta analysis. Neurology 1997;48: Lundberg S, Eeg-Olofsson O. Rolandic epilepsy: a challenge in terminology and classification. Eur J Pediatr Neurol 2003;7: Wirrel EC, Cmfield PR, Cordon KE, Dooley JM, Camfield CS. Benign rolandic epilepsy: Atypical features are very common. J Child Neurol 1995;10: Scheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Berkovic SF. Autosomal dominant rolandic epilepsy and speech dyspraxia: A new syndrome with anticipation. Ann Neurol 1995;38: Fejerman N, Caraballo R, Tenembaum SN. Atypical evolutions of benign localization-related epilepsies in children: Are they predictable? Epilepsia 2000;41: Doose H, Bayer WK. Benign partial epilepsy and related conditions: multifactorial pathogenesis with hereditary impairment of brain maturation. Eur J Pediatr 1989;149: Roulet E, Donna T, Despland PA. Prolonged intermittent drooling and oromotor dyspraxia in benign childhood epilepsy with centrotemporal spikes. Epilepsia 1989;30: Hirsch E, Marescaux C, Maquet P. Landau-Kleffner syndrome. A clinical and EEG study of five cases. Epilepsia 1990;31: Kellaway P. The Electroencephalographic Features of Benign Centrotemporal (Rolandic) Epilepsy of Childhood. Epilepsia 2000;41: Gelisse P, Corda D, Raybaud C, et al. Abnormal neuroimaging in patients with benign epilepsy with centrotemporal spikes. Epilepsia 2003;44: Croona C, Kihlgren M, Lundbrg S, Eeg-Olofsson O, Edebol Eeg- Olofsson K. Neuropsycholigical findings in children with benign childhood epilepsy with centrotemporal spikes. Dev Med Child Neurol 1999;41: Deonna T, Zesiger P, Davidoff V, Maeder M, Mayor C, Roulet E. Benign partial epilepsy of childhood: a longitudinal neuropsychological and EEG study of cognitive function. Dev Med Child Neurol 2000;42: Gunduz E, Demirbilek V, Korkmaz B. Benign rolandic epilepsy: neuropsychological findings. Seizure 1999;8: Picirilli M, D Alessandro P, Sciarma T, et al. Attension problems in epilepsy: possible significance of the epileptogenic focus. Epilepsia 1994;35: Staden U, Isaacs E, Boyd SG, et al. Language dysfunction in children with rolandic epilepsy. Neuro pediatrics 1998;29: Yung AW, Park YD, Cohen MJ, Garrison TN. Cognitive and behavioral problems in children with centrotemporal spikes. Pediatr Neurol 2000;23: Weglage J, Demsky A, Pietsch M, Kurlemann G. Neuropsychological, intellectual and behavioral findings in patients with centrotemporal spikes with and without seizures. Dev Med Child Neurol 1997;39: Fejerman N, Caraballo R, Tenembaum S. Atypical evolutions of benign localization-related epilepsies in children: are they predictable? Epilepsia 2000;4: Winaver MR, Rabinowitz D, Pedley TA, Hauser WA, Ottman R. Genetic influences on myoclonic and absence seizures. Neurology 2003;61: Winawer MR, Rabinowitz D, Barker-Cummings C, et al. Evidence for distinct genetic influences on generalized and localization-related epilepsy. Epilepsia 2003;44: Winawer MR, Marini C, Grinton BE, et al. Familial clustering of seizure types within the idiopathic generalized epilepsies. Neurology 2005;65: Vadlamudi L, Harvey AS, Connellan MM, et al. Is benign rolandic epilepsy genetically determined? Ann Neurol 2004;56: Neubauer BA. The genitics of rolandic epilepsy. Epileptic Disord 2000;2:S 대한간질학회지 2006;10(1):46-50

Clinical heterogeneity of Epilepsy with Rolandic epileptiform discharges

Clinical heterogeneity of Epilepsy with Rolandic epileptiform discharges 순천향의대논문집 : 제 14 권 1 호 2008 J. Soonchunhyang Med. Coll. 14(1), p385-390, 200 특발성및증후성론란드간질에서뇌파특징비교순천향대학교부천병원신경과학교실 박선아 Comparison of electroencephalographic characteristics between idiopathic and symptomatic