대한임상검사학회지 : 39권제1호, 56-62, 2007 ISSN 1738-3544 난치성간질환자에서미주신경자극술치료결과분석 ( 레녹스- 가스토증후군환자 ) 동남보건대학임상병리과 1, 서울아산병원신경과 2 김대식 1 김천식 2 Vagus Nerve Stimulation Treatment for Children with Refractory Epilepsy (Lennox-Gastaut Syndrome) Dae-Sik Kim 1 and Cheon-Sik Kim 2 Department of Clinical Laboratory Sciences, Dongnam Health College, Suwon 440-714, Korea 1 Department of Clinical Neurosciences, Asan Medical Center, Seoul 138-736, Korea 2 Lennox-Gastaut syndrome(lgs) is a severe age-specific epilepsy syndrome that causes medication-resistant seizures in childhood. Vagal nerve stimulation (VNS) has been proposed as a possible way to improve the treatment of refractory epilepsy. We treated 9 patients with Lennox-Gastaut syndrome between the ages of 2 and 11 years (mean 5.8 years), by using the vagus nerve stimulation. The mean follow-up duration was 35 months. The mean reduction of seizure frequency compared with baseline before VNS was 52% after 6 months (range, 0% to 89%; P<0.011), and 58% after 1 year (range 0% to 89%; P<0.012). Seven patients showed improvements of quality of life (QOL) such as alertness, mood, and language skills. The most common side effects were transient hoarseness (6 patients) and drooling (1 patient). Our results suggest that the vagus nerve stimulation could be an effective and safe adjunct therapy for the treatment of Lennox-Gastaut syndrome. Key words : LGS, VNS, QOL 1) Ⅰ. 서론 간질은소아의신경계질환중가장흔한질병으로전체의약 70% 가소아기에발병한다. 대부분의간질은기 교신저자 : 김천식, ( 우 )138-736 서울특별시송파구풍납동 388-2, 서울아산병원뇌신경센터 Tel : 02-3010-4831, 010-2282-5492 E-mail : dpel-kcs@hanmail.net 존의항간질약제로잘치료되고있지만간질환자의약 20~30% 는적절한약물치료를받았음에도불구하고경련이재발하는약물불응성간질환자로분류되고있다 (Begley CE 등, 1994; Duchowny 등, 1997). 특히소아간질중레녹스-가스토증후군 (Lennox-Gastaut Syndreome) 은가장심각한간질로분류되며, 대부분의환자들이약물불응성이고잦은경련으로인해정신지연을 56
Korean Soc. Clin. Lab. Sci. 39(1):56-62, 2007 나타내는경우가많다. 레녹스- 가스토증후군은전체소아간질환자중 3~10% 를차지하고 (Gastaut와 Tassinari, 1975; Aliving, 1979; Beaumanoir, 1982; Genton 등, 2000), 여자보다는남자에서많은것으로보고되어있다 (Beaumanoir와 Dravet, 1992; Genton 등, 2000). 레녹스- 가스토증후군환자의일반적인특징은첫째로뇌파검사에서각성시 1.5~2.5 Hz 의전반적서극파 (slow spike wave, SSW) 를보이고수면시 10~20 Hz의폭발적인속파를나타낸다. 둘째로다양한형태의경련양상을보이는데주로근육의강직 (tonic seizure), 비정형적결여 (atypical absences), 떨굼 (drop attack) 등의양상을보인다. 떨굼종류는머리떨굼 (head drop) 과몸전체떨굼 (whole body drop) 증상이주로나타나며이로인해신체적상해를입는경우도많다. 셋째로인지능력의저하와행동의혼란 (behavior disturbance) 을보이는경우가많다 (Niedermeyer E, 1969; Chevrie와 Aicardi, 1972; Markand, 1977). 이와같은특징으로인해대부분환자의장기간예후는매우좋지않기때문에전문기관에서치료를받아야하는실정이다. 레녹스-가스토증후군을포함한난치성간질환자의치료방법에는새로운항경련제의투여, 케톤생성식이요법, 간질수술, 심부자극술 (deep brain stimulation) 및미주신경자극술등이시도되고있다. 항경련제등의약물로조절이되지않을경우발작초점을찾아수술로제거하는것이가능하나, 간질유발범위가너무광범위하거나양측성인경우, 간질유발부위를발견할수없거나수술로제거가불가능한경우, 수술로제거한후심각한신경학적손상이우려되는경우수술을할수없다. 이러한경우미주신경자극술을고려해볼수있다 ( 김등, 2006). 미주신경자극술에의한전기적자극은조직에손상을주지않으면서과흥분만억제할수있고, 증상에따라강도를수시로조절할수있다는장점이있다. 저자들은성인과소아의난치성간질환자의미주신경자극술의효과에서소아난치성간질환자중레녹스- 가스토증후군환자들의미주신경자극술의효과가두드러지는것을확인하였기에향후레녹스-가스토증후군연구분야에있어서기초자료로제시하고자본연구를시행하였다. Ⅱ. 대상및방법 1. 대상본연구는1999년 8월부터 2006년 3월까지서울아산병원소아과에서난치성간질로진단되어본원신경외과에서미국 Cyberonics사의 NeuroCybernetic Prosthesis(NCP) 를사용하여미주신경자극치료를받은 9명환자의의무기록을후향적으로조사하였다. 2. 미주신경자극술방법미주신경자극치료는뇌수술이아니라, 치료장치를몸속에이식하는수술로 2시간내외의시간이소요된다. 전신마취하에좌측경부에있는미주신경에전극을부착시킨후전극리드 (bipolar lead) 를 NCP(Houston, TX) 라불리는작은발전기에연결하여좌측가슴부위피하에이식하는시술을시행하였다. 약 2주간의회복기를거친후외래방문을통하여자극값을프로그래밍하였다. 초기자극값의입력은모두동일하게자극강도 0.25 ma, 자극빈도 30Hz, 펄스폭 500 μs로하였고, 30초간자극후 5분간의무자극이 24시간내내반복되도록프로그래밍하였다. 이후 2주간격으로부작용, 발작빈도의변화를관찰하면서자극강도를 0.25 ma 씩증가시켰고최대자극강도는 3.5 ma 이하로하였다. 3. 자료수집및분석연구대상의성별, 나이, 첫경련발작당시의나이, 간질분류, 과거력상의간질의원인유무, 수술당시의연령, 과거간질과관련된수술의유무등을의무기록를통하여후향적으로조사하였다. 미주신경자극후의발작빈도는 6개월, 12개월로나누어조사하였고, 가장최근외래를통한추적에서삶의질변화를관찰하였다. 미주신경자극후의부작용에대하여조사하였으며, 미주신경자극효과는자극전과비교해서경련빈도의감소가 50% 이상감소하였을때효과가있다고판정하였다. 모든환자들은 24시간비디오모니터링검사를시행하였고이를통해경련의형태를구분하였다. 각환자의임 57
대한임상검사과학회지 39(1):56-62, 2007 Table 1. Patient characteristics Age at implant, years Sex Sz type Etiology EEG findings Neuroimaging 11 F Head drop, atypical absence Myoclonoc tonic Encephalitis Diffuse slow spike waves CC section 4 F Head drop, atypical absence Cryptogenic Focal spike wave discharges with generalization CC section 6 M Atypical absence, falling attack Cryptogenic Diffuse slow spike waves CC section 6 M Head drop, atonia Encephalitis Focal spike wave discharge CC section 5 M Staring Encephalitis Generalization discharges Diffuse atrophy 10 F Head drop, myoclonic Cryptogenic Diffuse slow spike waves Normal 3 M Head drop Cryptogenic Focal spike wave discharge Normal 2 M Hypomotor, head nodding Tuberous sclerosis Cryptog 5 M Myoclonic jerk enic CC section : Corpus Callosum section; EEG : Electroencephalogram Generalization discharges Diffuse slow spike waves Tuberous sclerosis Normal 상데이터와발작과발작전뇌파결과를확인하였고, 경련의분류는강직 (tonic), 무강직 (atonic), 비정형적결여 (atypical absence), 근간대성강직 (myoclonic tonic), 전반적강직-떨림 (generalized tonic-clonic), 복합부분경련으로분류하였다. 4명의환자는전반적인뇌량절제술을시행하였고 3명의환자는케토제닉식이요법를시행했었다. 모든환자는수술전뇌파와수술후뇌파를확인하였다. 베이스라인평균경련횟수는미주신경자극기삽입전 2 달동안경련한횟수를 2로나누었고, 미주신경자극술후평균경련횟수는미주신경자극기삽입후 6개월과 12 개월로나누어조사하였다. 본연구에서는미주신경자극술치료후경련횟수의변화를다음과같은공식을이용하여조사하였다. 미주신경자극후평균경련횟수 베이스라인경련횟수 x 100 베이스라인경련횟수베이스라인경련횟수와미주신경자극술후경련감소를 Wilcoxon matched pairs test로분석하였다. Ⅲ. 결과 본연구결과에서레녹스-가스토증후군을가지고있는환자들에게미주신경자극술치료를시행한결과경련빈도의감소와함께삶의질이향상되는것을볼수있었다. 9명의환자중남자 6명과여자 3명이었고이중 4명은뇌량절제술 (corpus callosum section) 과미주신경자극기를동시에시행하였거나예전에뇌량절제술를시행하였던경험이있는환자들이었다. 미주신경자극기를심었던나이는 2세에서 11세로평균 5.8세였다. 병인의원인은뇌염 (encephalitis) 3명, 결절성경화증 (tuberous sclerosis) 1명, 특발성 (cryptogenic) 5명으로분류되었다. 경련의형태는머리떨굼 (head drop), 비정형적결여 (atypical absence), 근간대성강직 (myoclonic tonic), 응시 (staring) 현상을보였다 (Table 1). 미주신경자극기를심은후 6개월과 12개월의경련감소율을비교한결과 6개월후에는전체환자에서 52%( 범위 0%~89%, P<0.011) 의경련감소를나타내었고, 12개월후에는 59%( 범위0%~91%, P<0.012) 의경련감소가나타났다. 특히미주신경자극술과뇌량절제술을동시에시 58
Korean Soc. Clin. Lab. Sci. 39(1):56-62, 2007 Table 2. Changes in rates of reizures with vagus nerve stimulation Patient NO. Baseline seizures /month Median seizures over 6 months on VNS Median seizures over 12 months on VNS % Reduction in deizures 6 months Post VNS % Reduction in deizures 12 months post VNS 1 75 25 16 66 78 2 95 10 8 89 91 3 130 70 50 46 61 4 78 20 17 74 78 5 197 170 165 13 16 6 168 67 67 60 60 7 87 90 87 0 0 8 67 25 17 62 74 9 96 40 25 58 73 행한환자의경우 6개월후에는 69%, 12개월후에는 77% 의경련감소를나타냈다 (Table 2). 미주신경자극술이후삶의질평가는보호자의주관적인보고이기는하나 5명의환자는시술전보다의식이훨씬명료해졌고, 1명은언어향상, 1명은감정조절능력이향상되어전체환자 9명중 7명의환자에서삶의질이향상되었다. 미주신경자극술과관련된부작용은 6명이일시적으로쉰목소리가나타났고, 1명은침흘림증상그외다른부작용은나타나지않았다. 9명의미주신경자극기시술전뇌파를보면 4명은산재성서극파를보였고 (diffuse slow spike waves), 1명은전반적극파와동시에부분극파 (focal spike wave discharges with generalization), 2명은부분극파 (focal spike wave discharge), 2명은전반적극파 (generalization discharges) 를나타냈다 (Table 1). Ⅳ. 고찰 Lennox-Gastaut syndrome(lgs) 은 Gibbs 등 (1939) 에의해뇌파에서소발작보다서극서파복합 (slow spike and wave complex) 을보여 petit mal variant 로보고되었고, 정신지체의발생률이높고서극파복합을보이면서항경련제에잘반응하지않는난치성간질로분류되고있다. Gastaut 등 (1966) 이산재성서극서파복합을나타내는간질성뇌증에대해기술한후 Lennox 또는 Lennox- Gastaut syndrome 으로명명한많은예가보고되고있다. 본연구에서레녹스-가스토증후군에서미주신경자극술은경련을감소시키는데효과가있고대부분의환자들이미주신경자극기에잘견디는것으로나타났다. 9명의환자에서경련감소율이 0%~89% 로개개인의경련감소차이는있었으나모든환자에서미주신경자극술시행전보다경련빈도가감소하는것으로나타났다. 레녹스- 가스토증후군환자중 10% 내외만이약물에의해경련빈도가 90% 이상감소하고, 나머지 90% 는경련과동시에정신지연현상을보이는것으로보고된다 (Genton 등, 2000). 장기간치료에서나쁜예후를보이는경우는다음과같다. 첫째, 웨스트증후군 (West s syndrome) 처럼 asymptomatic type를보이는경우 (Ohtahara 등, 1976), 둘째, 3세이전에경련이처음발생했을시 (Chevrie와 Aicardi, 1972), 셋째, 경련빈도가증가되거나반복적으로중첩성경련으로빠지는경우 (Doos와 Volzke, 1979; Hoffmann-Riem 등, 2000), 넷째, 뇌파검사시지속적인산재성서파와함께전반적서극파를보이는경우는 (Ohtsuka 등, 1991) 레녹스-가스토증후군을가지고있는환자중에서도특히예후가나쁜것으로보고되고있다. Ohtsuka 등 (1991) 과 Ohtahara 등 (1995) 이발표한 10-29 59
대한임상검사과학회지 39(1):56-62, 2007 년간의장기간에걸친레녹스-가스토증후군환자의뇌파를분석한결과몇가지특징을발견하게되었다. 첫째, 전체환자의 1/3에서는산재성서극파 (diffuse slow spike waves) 를보였고둘째, 1/3에서는부분극파 (focal spike wave) 를나타내었지만전반적서극파는보이지않았고, 부분극파를보인대부분의환자들은한군데또는두군데에서독립적인복합극파를나타냈다. 셋째, 약물에불응성을보이고경련형태도다양한레녹스-가스토증후군을보였던아이들이학동기가되면서극파에서복합극파 (multifocal independent spike foci) 를보이는것으로보고하였다. 본연구에서도산재성서극파 (diffuse slow spike waves) 와부분극파 (focal spike wave discharge) 를보인 6명의환자들이전반적극파와동시에부분극파 (focal spike wave discharges with generalization), 전반적극파 (generalization discharges) 를보인환자들보다미주신경자극기삽입후경련감소가훨씬좋아진것으로나타났다. 레녹스-가스토증후군을가지고있는환자를대상으로미주신경자극술을시행한환자들의관찰보고를보면 Hornig 등 (1997) 은 6명의환자를대상으로평균 26개월간관찰한결과경련감소가베이스라인과비교하여 90% 이상이라고보고하였고, Hosain (2000) 은 13명을대상으로 8개월간추적관찰한결과 52%, Ben-Menachem 등 (1999) 은 8명의환자에서 60% 의경련감소를나타낸것으로보고하였다. 본연구에서미주신경자극술후 6개월후전체환자에서 52% 의경련빈도가감소하였고, 12개월후에는 59% 의경련감소로자극전과비교시미주신경자극술이레녹스- 가스토증후군환자에게효과가있음이증명되었다. 특히미주신경자극술과뇌량절제술을동시에시행한환자의경우 6개월후에는 69% 경련감소와 12개월후에는 77% 의경련감소를나타내어레녹스-가스토증후군환자에있어두시술을동시에시행하는것이경련을감소시키는데효과가있는것으로나타났다 (Table 2). Handforth 등 (1998) 에의하면성인에서미주신경자극술의부작용으로쉰목소리, 성대마비, 하안면마비및감염이되어기구를제거한경우가있었고, Helmers 등 (2001) 의보고에서소아에시행한연구에서부작용은 1% 미만으로특징적으로침흘림 (drooling), 과잉행동이관찰 되었다. 본연구에서는 9명중 7명이미주신경자극술에의한부작용이나타났고, 그중 6명이미주신경자극술시행 3 개월안에쉰목소리를나타내었고, 1명은침흘림증상이나타났으나발생후 1달안에모든환자들에서치료없이호전되었다. 미주신경자극술은간질발작감소뿐아니라삶의질적향상에도효과가있다고보고하고있다. Carmer (2001) 에의하면미주신경자극술후삶의질이향상되었다고보고하고있으며, Clark 등 (1999) 에의하면간질발작빈도가 50% 이상감소한환자에서각성상태, 기억력, 감정등의호전에의하여환자들의삶의질이향상되었다고보고하였고, Hassert 등 (2004) 의보고에서는미주신경자극술이후 norepinephrine이미주신경자극술시행전보다 98% 이상증가하였고이는 norepinephrine이뇌전체적으로영향을줌으로인해환자의각성상태가미주신경자극술시행전보다더명확하여졌다는보고가있으며, Aldenkamp 등 (2002) 에의하면레녹스-가스토증후군을가지고있는환자에서미주신경자극술이후과잉행동을보인것으로보고하였다. 본연구에서 7명이미주신경자극술이후언어, 행동, 감정전달등이향상된것으로나타났다. 5명의환자는시술전보다의식이훨씬명료해졌고, 1명은언어향상, 1 명은감정의조절능력이좋아져다른여러연구에서나타났던것처럼본연구에서의미주신경시술후전반적으로환자들의생활의질이향상된것으로나타났다. 본연구에서미주신경자극술 12개월후경련빈도가 50% 이상감소한환자는전체 9명중 7명이였고특히뇌량절제술과미주신경자극술을동시에시행한환자의경련감소는 77% 로미주신경자극술만시행한환자의경련감소 45% 보다훨씬효과가있는것으로나타났다. 이에저자들은미주신경자극술은약물불응성간질환자에있어보조적치료수단으로효과적이며, 삶의질을호전시키는비교적안전하고효과적인치료방법중의하나라고생각되어진다. 그러나, 그결과가반응이없는환자부터탁월한효과를보이는환자까지다양하다. 향후다양한요인들을가진환자들에게적용하여최대의치료효과를나타낼수있는적응증확립과 LGS 환아에대한임상적고찰이필요하리라사료된다. 60
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