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1 Original Articles Journal of Korean Epilepsy Society Journal of Korean Epilepsy Society 13(2):52-57, 2009 ISSN Received November 26, 2009 Accepted December 22, 2009 서울대학교의과대학소아청소년과학교실 황희 임병찬 최지은 최창원 김병일 채종희 김기중 황용승 EEG Characteristics of Full-Term Neonatal Seizures Confirmed by Electrical Seizure Hee Hwang, MD, Byung Chan Lim, MD, Ji Eun Choi, MD, Chang Won Choi, MD, Beyong Il Kim, MD, Jong Hee Chae, MD, Ki Joong Kim, MD, and Yong Seung Hwang, MD Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea Purpose: Neonatal seizure is the most significant parameter of neurological insult, however its pathophysiology and diagnostic consensus is still controversial. We performed this study to investigate the characteristics of electroencephalogram (EEG) in neonatal seizures,to validate the efficacy of radiological studies, and to estimate the occurrence of further subsequent epileptic seizures. Methods: Seventeen patients with full-term neonatal seizure confirmed by electrical seizure were enrolled. Mean birth weight is 3.29 kg, and mean duration of follow-up is 22.7 months. Medical records and EEG were retrospectively reviewed. Results: Subtle seizure is the most common seizure type: subtle seizure in 6 (35%), subtle seizure with focal clonic seizure in 2(12%). In 12 patients (71%), abnormal background activities were observed, and trace discontinua is the most common abnormal finding. Ictal EEGs were mostly localized into unilateral posterior quadrant in 11 (64%), however, the remained were localized into the frontal area. Brain USG did not reveal any abnormal finding in 9 patients (53%), whereas brain MRI didn t in 4 patients (25%). Brain MRI found abnormal findings in 5 out of 9 patients with negative brain USG result. Subsequent epileptic seizures followed in 7 patients (44%). Conclusion: Background activity is still useful as an indirect marker of neonatal seizure. Different generation or propagation mechanism can be suggested in that ictal EEGs were often localized into the frontal area in minor portion. Brain MRI is more sensitive than brain USG, especially in case of cerebral infarct or hypoxic-ischemic encephalopathy. Keywords: Neonatal seizure, Electroencephalogram (EEG), Ictal EEG 서론 신생아발작은신생아기신경학적손상의가장확실한지표이며, 신생아기신경학적손상의비특이적증상들을고려할때, 예후예측에중요한인자로서임상적의미를가진다. 1 대개만삭출생아에서 0.7~2.7% 정도의발생빈도를보이며, 미숙아의경우그빈도가훨씬높은것으로알려져있는데, 2 신생아시기는일생을통틀어다양한신경학적손상에가장흔히노출되는시기이며, 이에따라당연히발작의발생빈도또한가장높은시기로알려져있다. 3 최근이러한외부적요인외에도신생아시기는신경전달물질의역할이성숙한신경계와는다른형태로작용하며, 이에따라발작이보다쉽게유발될수있으며, 병태생리도영아기이후의경련과는다르며, 결과적으로치료적접근도차이가있을수있음을 Address for correspondence: Ki Joong Kim, MD Division of Pediatric Neurology, Department of Pediatrics, Seoul National University Children s Hospital, 28 Yongon-dong, Jongno-gu, Seoul , Korea Tel: , Fax: , pednr@plaza.snu.ac.kr 52 대한간질학회지제 13 권제 2 호, 2009
2 A B C Figure 1. Abnormal background of interictal EEG, examples. (A) Trace discontinua pattern. (B) Pathological frontal sharp transients. (C) Burst-suppression pattern. 시사하는보고가알려져있다. 4 다른경련과마찬가지로뇌파검사는신생아발작에서도진단적검사로서가장신뢰할수있는검사방법이지만, 그이용에는제한점이많은것도사실이다. 5,6 장시간비디오뇌파감시를시행할수없는경우뇌파상확실한발작의표지자가없으며, 생리적인 sharp transient 와극파혹은예파를구분하기어려운경우가많아빈번하게판독의곤란을겪게된다. 배경파의이상유무를간접적인표지자로언급하기도하나이는엄밀히중추신경계의기능적미성숙을의미하는것이지이자체가발작의표지자라고하기는어렵다. 7 본연구를통해저자들은뇌파상전기적발작이확인된만삭신생아발작환자에서발작간기및발작기뇌파의특성을알아보고, 기타영상학적검사의유용성에대해살펴보며, 추후간질성발작의발생과의연관성을살펴보고자하였다. 대상과방법 2004년 3월부터 2007년 12월까지분당서울대학교병원신생아실및신생아중환자실에서신생아발작으로진단받은 131명을대상으로후향적의무기록분석및뇌파검토를시행하였다. 진단적모호함을피하고연구의목적에적합한환자만을포함하기위하여뇌파상전기적발작이확인되지않은환자 95명을제외하였고, 유사한병태생리적특성을가진환자만을대상으로연구를진행하기위하여 38주이상의만삭출생재태주령환자만을대상으로하였다. 총 17명의환자가연구에포함되었으며, 남자 9명, 여자 8명으로성비의차이는없었다. 평균출생재태주령은 39.5주였으며, 평균출생체중은 3.29 kg (2.75~4.02 kg) 이었고, 평균 apgar 점수는 1분 5.82 (1-8), 5분 7.06 (1-9) 이었다. 17명중 6명 (36%) 에서신생아호흡곤란증후군 (respiratory distress syndrome: RDS) 을보였으며, 환자들의평균추적기간은생후 3일에사망한 1명을제외하면 22.7개월 (14~32 개월 ) 이었다. 발작의분류는 Volpe 에의한임상적분류 8 에따라구분하였으며, 예외적으로특별한동반증상없이움직임이떨어지며, 자극에반응이없어진환자를저운동성발작 (hypomotor seizure) 으로기술하였다. 모든환자에서 11채널신생아뇌파몽타쥬를기준으로 Grass Telefactor 사의 Twin ver. 3.0을이용하여디지털뇌파검사를시행하였고, 이들에대한뇌파소견을분석하였다. Journal of Korean Epilepsy Society Vol. 13 No. 2,
3 황희 임병찬 최지은 최창원 김병일 채종희 김기중 황용승 결과 발작의형태적분류상비전형적발작 (subtle seizure) 6명 (35%), 국소간대발작 (focal clonic seizure) 4명 (23%), 국소강직발작 (focal tonic seizure) 2명 (12%), 비전형적발작과동반된국소간대발작 2명 (12%), 근간대발작 (myoclonic seizure) 1명 (6%), 전반성강직발작 (generalized tonic seizure) 1명 (6%), 저운동성발작 1명 (6%) 의분포를보였다. 발작간기뇌파를분석했을때, 배경파의이상을보인경우는 12명 (71%) 으로비연속성뇌파 (trace discontinua) 6명을비롯하여, 비연속성뇌파와국소성서파 (focal slowing), 비연속성뇌파와 positive vertex sharp transient, 비대칭성 (asymmetric) frontal sharp transient, 반구성억제 (hemispheric suppression), 비정상 (pathological) frontal sharp transient, 군발- 억제성뇌파 (burst-suppression Table 1. Interictal EEG findings (N=17) EEG features Number Background activity Normal 5 Trace discontinua 6 Trace discontinua + focal slowing 1 Trace discontinua + positive vertex sharp transient 1 Asymmetric frontal sharp transient 1 Pathological frontal sharp transient 1 Hemispheric suppression 1 Burst-suppression 1 Interictal epileptiform discharges (IED) Absent 12 Focal 4 Multifocal 1 pattern) 이각각 1명씩이었다 (Figure 1). 12명 (71%) 의환자에서발작간기발작파 (Interictal epileptiform discharge: IED) 가관찰되지않았고, 관찰된환자중군발-억제성뇌파의다초점성 (multifocal) IED를제외하면, 4명모두국소성 (focal) IED 였다 (Table 1). 발작기뇌파를분석했을때발작의기시부가측두및후두부를포함하는편측후방 (posterior quadrant) 에위치하는경우가 11명 (64%), 편측전두부가 3명 (18%), 양쪽전두부가 3명 (18%) 로분포하고있었으며, 발작뇌파의형태는 rhythmic delta 7명 (41%), spike and wave 6명 (35%), repetitive spike 혹은 fast activities 가 4명 (24%) 으로비교적고른분포를보이고있었다 (Figure 2, Table 2). 환자중 12명 (71%) 에서는전기적발작이있을때, 임상적발작소견을보였으나, 5명 (29%) 에서는전기적발작이관찰될때임상적발작소견은관찰되지않는임상-전기적해리현상 (clinicoelectrical dissociation) 을보였는데, 이중 2명에서는추후간질성발작이발생하였다. 대부분의환자에서뇌초음파검사 (brain ultrasonogram: brain USG) 및뇌자기공명영상 (brain magnetic resonance image: brain MRI) 을시행하였다. 뇌초음파검사상 9명 (53%) 에서는 Table 2. Ictal EEG findings (N=17) EEG features Number Ictal onset rhythm Rhythmic delta 7 Spike and wave running 6 Repetitive spikes or fast activities 4 Ictal onset zone Unilateral posterior quadrant 11 Unilateral frontal 3 Bifrontal 3 A B Figure 2. Ictal EEG finding, examples. (A) repetitive fast activities on the left frontal area. (B) rhythmic spike and wave discharges from the left frontal area. 54 대한간질학회지제 13 권제 2 호, 2009
4 Table 3. Results of radiological studies Radiological study Number Brain USG 17 Normal 9 IVH 4 PVL 2 HIE 2 Brain MRI 16 Normal 4 HIE 4 ICH 3 Infarct 3 PVL 2 Brain MRI in case of negative brain USG 9 Normal 5 Infarct 3 HIE 2 HIE, hypoxic-ischemic encephalopathy; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; MRI, magnetic resonance image; PVL, periventricular leukomalacia; USG, ultrasonogram. 이상소견이발견되지않았으며, 4명 (23%) 에서뇌실내출혈 (Intraventricular hemorrhage: IVH) 이발견되었고, 각각 2명 ( 각 12%) 에서는뇌실주위백질연화증 (periventricular leukomalacia: PVL) 과저산소성- 허혈성뇌증 (hypoxic-ischemic encephalopathy: HIE) 에합당한소견이관찰되었다. 뇌자기공명영상은생후 3 일에사망한 1명을제외한 16명에서시행하였고, 4명 (25%) 에서정상소견을보였으며, 4명 (25%) 에서는 HIE에합당한소견을, 대뇌출혈 (intracerebral hemorrhage: ICH) 이 3명 (19%), 편측뇌경색 (cerebral infarct) 이 3명 (19%), PVL이 2명 (12%) 에서관찰되었다. 뇌초음파상정상소견이었던 9명중 5명에서뇌자기공명영상에서이상소견이관찰되었으며, 각각편측뇌경색 3명과, HIE 2명이었다 (Table 3). 조기사망한 1명을제외하고평균 22.7개월의추적기간중추후간질성발작이발생한환자는 16명중 7명 (44%) 으로, 5명에서부분복합발작 (complex partial seizure), 1명에서탈력발작 (atonic seizure), 1명에서영아연축 (infantile spasm) 이발생하였다. 고찰 신생아발작은임상적중요성에도불구하고, 여전히발생기전이모호하며진단이나분류에대한합의도부족한상태로, 9,10 최근비디오-뇌파검사를통하여보다정확한진단및예후예측에도움을받을수있다는보고가있으나, 11 대부분의임상환경에서는여전히적절한진단이나치료가어려운 질환이다. 일반적으로신생아발작의진단은의사및간호사의임상경험에따라, 또한적용하는질환의정의, 특히발작간기뇌파의이상소견을어디까지진단에적용하느냐의문제에따라차이를보일수있다. 12 뇌파상 IED나전기적경련이관찰되지않는경우배경파의이상이발작의진단에의미를가질수있는지, 역으로, 임상적인발작이없는데, 전기적발작이관찰되는임상-전기적해리현상 (clinicoelectrical dissociation) 을신생아발작으로진단하고치료해야하는지에관한논란은아직도뚜렷한결론은얻지못한상태다. 13,14 본연구에서는비디오-뇌파검사를시행하지못하는경우에이러한논란을배제하고신생아발작의발작간기뇌파소견을분석하여진단적의의를갖는지표들을알아보고자대상환자를발작간기뇌파상전기적발작이있는경우로한정하였는데, 대상환자중 5명 (21%) 은임상-전기적해리현상을보인경우로, 이 5명중 2명에서는추적관찰중부분복합발작이관찰되었고, 이는논란이되는임상-전기적해리현상도장기적예후의관점에서볼때적절한치료가이루어져야함을시사하는소견으로생각된다. 비전형적발작 (subtle seizure) 을의심하게되는안구고정이나, 자전거를타는양상의하지움직임, 팔의비정형적인움직임등의증상들은경련이아닌생리적혹은뇌손상으로초래되는뇌간해체현상 (brain stem release phenomenon) 의일종으로보일수있는것으로알려져있어, 감별이쉽지않다. 15,16 그러나, 이러한사실을염두에두더라도전체신생아경련에서비전형적발작은가장많은부분을차지하는것으로알려져있다. 17 본연구에서도비전형적발작은전체발작의 47% 를차지하여가장많은발작의형태로나타났으며, 이중일부환자는비전형적발작과다른형태의발작을동반하는것으로진단되었다. 연구의대상이발작간기뇌파상전기적경련이있는환자로제한하였음에도, 이전의연구결과 17,18 와큰차이가없는점에서비전형적발작의진단에있어기존에알려진뇌파의배경파이상, 자율신경계증상변화등의보조적지표들이의미가있다고할수있다. 발작간기뇌파의배경파는중추신경계손상에따르는기능이상의가장정확한예측지표로알려져있다. 19 그러나, 이는비특이적소견으로그자체가특정질환을시사하지는못하는것으로알려져있는데, 신생아발작의경우전기적발작외에발작을시사하는정확한뇌파상의지표가없는데반해, 발작현상자체는진행하는혹은심대한신경학적손상의결과로나타난다는점에서배경파의이상을간접적인신생아경련의지표로인정해왔다. 3,20 본연구에서도 71% 의환자에서배경파의이상을보였으며, 만삭신생아에서비정상으로간주되는비연속성뇌파가가장많이관찰되어배경파의이상출현빈도는높으나그임상적의미는중추신경계 Journal of Korean Epilepsy Society Vol. 13 No. 2,
5 황희 임병찬 최지은 최창원 김병일 채종희 김기중 황용승 손상을반영하는간접적지표라는기존의연구와같은결과를보여주었다. 그러나일부환자에서대뇌의국소적병변과관련하여국소성혹은비대칭성이상소견을보인경우가있었고, 이는빌작의기시지점에대해다른지표에비해편측화능력을가진다고할수있다. 한편발작간기뇌파상 IED 는전체환자의 29% 에서만관찰되었는데, 이는발작간기뇌파가가지는신생아발작진단에있어서의약점을보여주는소견이라하겠다. 발작기뇌파의경우 64% 의환자에서발작기시부가편측후방 (posterior quadrant) 에위치하고있었는데, 이는신생아기의신경연접의완성관정과수초화과정을고려한기존의개념 3,21 과일치하는소견이다. 그러나, 본연구에서양측전두엽에서기시하는발작이확인되었으며, 발작의형태에서도 1명의환자에서전반성강직발작을보인점은일반적인개체의신경연접성숙에따른발작의표현외에다른종류의발작의생성및전파과정이관련될수있음을시사한다. 기존의연구에서 21 발작기리듬은 rhythmic alpha파가가장흔한것으로알려져있으나, rhythmic theta 혹은 delta파, spike wave complex, 반복적인극파혹은 fast activity 등의여러가지소견이모두흔히관찰되며그임상적의미는아직뚜렷이밝혀진바없다. 본연구대상환자에서도 rhythmic delta파, spike and wave, 반복적 fast activity 등의소견이큰차이없이고르게분포하고있었으며, 발작의형태나뇌자기공명영상의이상소견과의연관성은없었다. 최근신생아기중추신경계손상의원인및정도의평가에뇌자기공명영상이활용되면서뇌초음파검사와의유용성의차이에대한관심이높아졌다. 이전연구에서뇌자기공명영상은뇌초음파검사에비해민감도가높은검사로보고되었으며, 특히저산소성-허혈성뇌증의경우뇌자기공명영상의민감도는더욱높은것으로알려져있다. 22,23 본연구에서는환자중 53% 가뇌초음파검사상에서이상소견을발견하지못한데비해, 뇌자기공명영상에서는 25% 만이정상소견으로보여뇌자기공명영상이뇌초음파검사보다중추신경계손상의원인을밝히는데예민한검사임을증명하였다. 특히뇌초음파검사에서정상이었던환자 9명중 5명이뇌자기공명영상에서는이상소견을보였으며, 편측뇌경색 3명은모두뇌자기공명영상에서만이상소견을보였고, 저산소성- 허혈성뇌증환자도 2명이추가로뇌자기공명영상에서발견된점은임상적의미가있는데, 뇌경색의경우장기적관점에서기저질환을밝히기위한여러가지대사적, 유전학적검사들이필요하며, 이를통해환자의장기예후를향상시킬수있다는점에서뇌자기공명영상은신생아경련의진단및치료적전략수립에기여할여지가크다고할수있다. 생후 3일에사망한환자 1명을제외한 16명의환자들을평균 22.7개월의기간동안외래추적하였을때, 44% 에서간 질성발작이발생하였는데, 이는임상적기준에따른신생아경련의진단시약 20%, 뇌파상의이상소견까지고려한진단시는약 25~50% 정도의발생빈도로신생아발작이후간질성발작이발생함을제시한기존연구들 에잘부합하는결과다. 대상환자에서간질성발작이발생한환자는모두뇌자기공명영상에서이상소견이보였던환자로일종의증상성간질 (symptomatic epilepsy) 라고할수있다. 그러나, 아직은간질성발작이발생하는환자와발생하지않는환자사이의임상적으로의미있는뇌파및영상학적검사의지표는확실하지않은상태로보다많은환자를대상으로장기간의추적연구가필요한상태이다. 본연구는기존의다수의연구와달리전기적경련이확인된환자를대상으로경련의형태적분류, 뇌파특성, 영상학적검사소견등을살펴본것으로비록대상환자의수가적은점을충분히고려하여향후보다대규모의전향적연구가필요하다는제한점이있으나, 이를통해신생아경련의임상적특징과병태생리적기전의이해, 원인질환의진단및장기예후에관련된치료적접근에이해를도왔을것으로생각한다. 결론 임상적으로신생아발작을의심하는환자에서전기적발작이확인된환자 17명을대상으로의무기록분석및뇌파검토를시행하였다. 발작의형태적분류상비전형적발작이가장많았으며, 발작간기뇌파분석시 71% 에서배경파의이상을보였다. 발작기뇌파를분석시발작의기시부는 64% 에서편측후방 (posterior quadrant) 에위치하고있었으나, 일부에서는편측전두부및양쪽전두부에위치하였는데, 이는일반적인개체의신경연접성숙에따른경련의표현외에다른종류의경련의생성및전파과정이관련될수있음을시사한다. 뇌초음파검사에서는 53% 에서정상소견을보였으나, 뇌자기공명영상에서는 25% 만정상소견을보여서더나은민감도를보였다. 특히뇌경색의경우뇌자기공명영상에서만이상소견을보여, 임상적의미를가질수있다. 추적기간중간질성발작이발생한환자는 16명중 7명 (44%) 이었다. 임상- 전기적해리현상을보이는환자중일부에서추적관찰중부분복합발작이관찰되었고, 이는논란이되는임상-전기적해리현상도장기적예후의관점에서볼때적절한치료가이루어져야함을시사하는소견으로생각된다. 결론적으로, 뇌파는아직까지신생아발작의진단에있어필수적인검사방법이며, 일부소견을통해기존의개념과다른신생아발작의병태생리를추론하는데도움을받을수있고, 정확한진단및치료적전략수립을위해뇌자기공명 56 대한간질학회지제 13 권제 2 호, 2009
6 영상을적극적으로시행하는것이좋을것으로생각되며, 향후, 더많은환자에서추적연구가이루어지면보다명확한이해에다가설수있을것으로기대한다. REFERENCES 1 Hill A, Volpe JJ. Seizures, hypoxic-ischemic brain injury, and intraventricular hemorrhage in the newborn. Ann Neurol 1981;10: Evans D, Levene M. Neonatal seizures. Arch Dis Child. Fetal Neonatal Ed 1998;78:F70-F5. 3. Volpe JJ. Neonatal seizures. In: Volpe JJ, ed. Neurology of the newborn. 4th ed. Philadelphia: W. B. Saunders, 2001; Silverstein FS, Jensen FE. Neonatal seizures. Ann Neurol 2007;62: Doose H. Neonatal seizures: relationship to epilepsy. In: Doose H, ed. EEG in childnood epilepsy. Montrouge: John Libbey Eurotext, 2003; Patrizi S, Holmes GL, Orzalesi M, Allemand F. Neonatal seizures: Characteristics of EEG ictal activity in preterm and fullterm infants. Brain Dev 2003;25: Morgan JD, Painter MJ. Neonatal seizures. In: Swaiman KF, Ashwal S, ed. Pediatric Neurology. Principles and practice, 3rd ed. St. Louis: Mosby, 1999; Volpe JJ. Management of neonatal seizures. Crit Care Med 1977;5: Mizrahi EM, Plouin P, Kellaway P. Neonatal seizures. In: Engel J, Pedley TA, ed. Epilepsy. Philadelphia: Lippincott-Raven, 1998; Panayiotopoulos CP. Neonatal seizures and neonatal syndromes. In: Panayiotopoulos CP, ed. A clinical guide to epileptic syndromes and their treatment. Oxfordshire, UK: Bladon, 2002; Pisani F, Copioli C, Di Gioia C, Turco E, Sisti L. Neonatal seizures: relation of ictal video-electroencephalography (EEG) findings with neurodevelopmental outcome. J Child Neurol 2008;23: Laroia N. Current controversies in diagnosis and management of neonatal Seizures. Indian Pediatr 2000;37: Biagioni E, Ferrari F, Boldrini A, Roversi MF, Cioni G. Electroclinical correlation in neonatal seizures. Eur J Paediatr Neurol 1998;2: Pinto LC, Giliberti P. Neonatal seizures: background EEG activity and the electroclinical correlation in full-term neonates with hypoxic-ischemic encephalopathy. Analysis by computer- synchronized long-term polygraphic video-eeg monitoring. Epileptic Disord 2001;3: Radvanyi-Bouvet MF, Vallecalle MH, Morel-Kahn F, Relier JP, Dreyfus-Brisac C. Seizures and electrical discharges in premature infants. Neuropediatr 1985;16: Mizrahi EM. Neonatal seizures: problems in diagnosis and classification. Epilepsia 1987;28:S46-S Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics 1989;84: Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37: Westas LH, Rosen I. Electroencephalography and brain damage in preterm infants. Early Hum Dev 2005;81: Caroline C. Menache MD, Blaise F, Bourgeois FD, Volpe JJ. Prognostic value of neonatal discontinuous EEG. Pediatr Neurol 2002;27: Watanabe K, Hara K, Miyazaki S, Hakamada S, Kuroyanagi M. Apneic seizures in the newborn. Am J Dis Child 1982;136: Belet N, Belet U, Incesu L, Uysal S, Ozinal S, Keskin T, et al. Hypoxic-ischemic encephalopathy: correlation of serial MRI and outcome. Pediatr Neurol 2004;31: Glass HC, Bonifacio SL, Sullivan J, Rogers E, Ferriero DM, Goldstein R, et al. Magnetic resonance imaging and ultrasound injury in preterm infants with seizures. J Child Neurol 2009;24: Holden KR, Mellitis ED, Freeman JM. Neonatal seizures: correlation of prenatal and perinatal events with outcome. Pediatrics 1982; 70: Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia 1991;32: Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology 2007;69: Journal of Korean Epilepsy Society Vol. 13 No. 2,
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