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대한임상검사학회지 : 38 권제 2 호, 141-146, 2006 소아와성인의난치성간질환자에서미주신경자극술의효과 서울아산병원신경과 1, 동남보건대학임상병리과 2 김천식 1 노영주 1 최상용 2 김대식 2 Effects of Vagus Nerve Stimulation on Adults and Children with Refractory Epilepsy Cheon-Sik Kim 1, Yeong-Joo Ro 1, Sang-Yong Choi 2, and Dae-Sik Kim 2 Department of Clinical Neurosciences, Asan Medical Center, Seoul 138-736, Korea 1 Department of Clinical Pathology, Dongnam Health College, Suwon 440-714, Korea 2 Vagal nerve stimulation () has been proposed as a possible way to improve the control of refractory epilepsy. We report the effects following treatment in patients with refractory epilepsy. Seventeen patients with a mean age of 12.8 years, ranging from 5 to 29 years, underwent the implantation of vagal nerve stimulation (Cyberonics, Houston, TX). We reviewed the clinical findings before and after in seizure frequency, number of antiepileptic drugs (AED), and quality of life (QOL). All of the patients had intractable seizures, eleven of the patients had additional medical complications, three had hippocampus atrophy, one had encephalomalacia, five had encephalitis, one had pachygyria, and one had schizencephaly. Thirteen patients had symptomatic partial epilepsies, three patients had Lennox-Gastaut syndrome and one had cryptogenic partial epilepsy. The mean follow up duration was 35 months. The mean reduction of seizure frequency compared with baseline before was 26.1% after 3 months (p<0.005), 41.9% after 6 months (p<0.001), 46.9% after 1 year (p<0.001), and 53% at the latest follow-up (p<0.001). Twelve patients showed an improvement of QOL such as mood, language, alertness, expression, and motor function. The most common side effects were transient hoarseness or voice change or cough, which was detected in six patients (35%) and wound infection in one patient (5%). This study has shown a good anti-seizure effect of, decrease in seizure frequency and improvements in QOL. We concluded that is a beneficial therapy in refractory epilepsy with a non-resectable epileptic focus. Further studies should be focused on the prediction of unresponsiveness and the adjustment of parameters for maximum efficacy in patients with various medical histories. Key Words : Vagal nerve stimulation, Refractory epilepsy, Quality of life, Seizure frequency 1) 교신저자 : 김천식, ( 우 ) 138-736 서울특별시송파구풍납동 388-2, 서울아산병원뇌신경센터 Tel : 02-3010-4831, HP : 010-2282-5492 E-mail : dpel-kcs@hanmail.net * 본연구는 2006 년도동남보건대학연구비지원에의해서시행되었음. I. 서론 간질은비교적흔한질환이며전체간질환자의약 20 ~30% 는적절한약물치료를받았음에도불구하고경련이재발하는난치성간질환자로분류된다 (Begley 등, 1994; Duchowny 등, 1997). 141

난치성간질환자의치료방법에는새로운항경련제의투여, 케톤생성식이요법, 간질수술, 심부자극술 (deep brain stimulation) 및미주신경자극술등이있다. 약물로조절이되지않을경우발작초점을찾아수술로제거하는것이가능하나, 간질유발범위가너무광범위하거나양측성인경우, 간질유발부위를발견할수없거나수술로제거가불가능한경우, 수술로제거한후심각한신경학적손상이우려되는경우수술을할수없다. 이러한경우미주신경자극술을고려해볼수있다. 미주신경자극술에의한전기적자극은조직에손상을주지않으면서과흥분만억제할수있고, 증상에따라강도를수시로조절할수있다는장점이있다. 1997년미국식약청 (FDA) 의공인을받은미주신경자극술은현재까지 17,000여건이상의시술이이루어졌으나 (Schachter, 2002) 국내에서는치료비용과홍보부족으로인해지금까지약 50여명에게시행되었으며, 그중서울아산병원에서시행한성인 4명과소아 13명에대한치료결과를알아보았다. 국내에서는 2005년부터미주신경자극술에대한시술이의료보험적용이시행됨에따라시술을시행할환자가늘어날것으로사료되며, 이에저자들은소아와성인에서난치성간질환자들에게미주신경자극기를이용하여미주신경자극술을시행한초기의치료경험과결과를보고하고자한다. II. 대상및방법 불리는작은발전기에연결하여좌측가슴부위피하에이식하는시술을시행하였다. 약 2주간의회복기를거친후외래방문을통하여자극값을프로그래밍하였다. 초기자극값의입력은모두동일하게자극강도 0.25 ma, 자극빈도 30 Hz, 펄스폭 500 μs으로하였고, 30초간자극후 5분간의무자극이 24시간내내반복되도록프로그래밍하였다. 이후 2주간격으로부작용, 발작빈도의변화를관찰하면서자극강도를 0.25 ma씩증가시켰고최대자극강도는 3.5 ma 이하로하였다. 3. 자료수집및분석연구대상의성별, 나이, 첫경련발작당시의나이, 간질분류, 과거력에서간질의원인유무, 수술당시의연령, 과거간질과관련된수술의유무및항경련제의개수를의무기록를통하여후향적으로조사하였다. 미주신경자극후의발작빈도는 3개월, 6개월, 12개월및최종추적관찰로나누어조사하였고, 가장최근외래를통한추적에서항경련제복용개수와삶의질변화를관찰하였다. 미주신경자극후의부작용에대하여조사하였으며, 미주신경자극효과는자극전과비교해서경련빈도의감소가 50% 이상감소하였을때효과가있다고판정하였다. 통계학적분석은 SPSS 12.0을이용하였고, 미주신경자극술전경련발작회수를 100으로간주하고, 미주신경자극술후 3개월, 6개월, 12개월및최종추적결과의경련감소회수를각각비교하였다. 1. 대상 III. 결 과 본연구는 1999년 9월부터 2006년 2월까지서울아산병원신경과와소아과에서난치성간질로진단되어본원신경외과에서미국 Cyberonics 사의 NeuroCybernetic Prosthesis(NCP) 를사용하여미주신경자극치료를받은 17명의환자의의무기록을후향적으로조사하였다. 2. 수술방법및미주신경자극술미주신경자극치료는뇌수술이아니라, 치료장치를몸속에이식하는수술로 2시간내외의시간이소요된다. 전신마취하에좌측경부에있는미주신경에적극을부착시킨후전극리드 (bipolar lead) 를 NCP(Houston, TX) 라 17명의환자중남자가 10명, 여자가 7명이었으며첫경련발작당시의평균연령은 4.9세 ( 생후 1년 ~11년 ), 미주신경자극술직전의평균나이는 12.8세 (5년 ~29년 ), 추적관찰기간은평균 31개월이었다. 모든환자는난치성간질환자이었고, 과거력에서간질의원인을알수있었던환자는 6명, 나머지 11명은특별한원인이없었다. 뇌자기공명영상에서정상소견이 6명, 해마위축 (hippocampus atrophy) 3명, 뇌연화증 (encephalomalacia) 1명, 뇌염 5명, 큰뇌이랑증 (pachygyria) 1명및뇌갈림증 (schizencephaly) 1명이었다. 17명의난치성간질환자를간질분류로구분해보면증상성부분간질 (symptomatic partial epilepsy) 13 명, 레녹스- 가스토증후군 3명, 반사적간질 (reflex 142

epilepsy) 1명이었다. 미주신경자극술을시행하기전 3명의환자에서는뇌량절제술을시행한적이있었고, 1명의환자는측두엽절제술을시행하였으나경련발작조절에실패하였고, 1 명은뇌량절제술과미주신경자극술을동시에시행하였다. 미주신경자극술시행전환자들의항경련제의복용개수는 2개에서 6개사이로평균 4개를복용하고있었음에도하루에 3회이상부터한달에 50회이상의간질이발생하였다 (Table 1). 미주신경자극술시행후의간질발작빈도의감소율은 3개월이지난후 26.1% 나타내었고, 6개월과 1년후에는각각 41.9%, 46.9% 이였다. 환자들의최종관찰에서는 53% 의간질발작빈도감소율을보였다 (p<0.001). 미주신경자극술을시행하기전뇌량절제술을시행하였던 3명의환자들은미주신경자극술시행후최종추적관찰에서 50% 이상의간질발작감소율을보였고, 미주신경자극술과뇌량절제술을동시에시행한소아환자에서 95% 의간질발작빈도감소율을보였다 (Table 2). 미주신경자극술전대비 3명의환자는 1개에서 2개의항경련제복용개수가줄었으나, 2명에서는 1개의항경련제가추가되었고, 나머지는수술전과동일한항경련제를복용하였다. 미주신경자극술이후삶의질평가는보호자의주관적인보고이기는하나전체환자 17명중 12명이향상되었다 (Table 2). 미주신경자극술과관련된부작용은 6명이일시적으로쉰목소리가나타났고, 그중 1명에서는수술부위감염으로수술후목부위전극선고정장치가피하표면에돌출되어교정술을시행하였고, 1명은미주신경자극술 2달후일시적으로기침을하였다 (Table 2). IV. 고찰 미주신경자극술은 1997년미국식품의약청 (FDA) 의공식승인을허가받았고, 시상, 미상핵, 시상하핵등의심부흑질에대한심부자극술이발작을줄이는효과가있다는보고가있다 (The Vagus Nerve Stimulation Study Group, 1995; Helmers 등, 2001). 미주신경자극술의기전연구를위한양전자단층촬영 (positron emission tomography, PET) 에서미주신경자극시시상, 시상하부, 소뇌의뇌혈류등이증가되었고, 양측해마, 편도 (amygdale), 후측띠이랑 (cingulated gyri) 에서는 Table 1. Clinical characteristics of vagus nerve stimulation group* case sex Age at onset (y) Sz type Epilepsy classification Background problem Previous surgery Drug before 1 M 11 1 CPS/GTC SPE hippocampus atrophy 3 2 F 12 5 Atonia LGS encephalitis 5 3 M 8 1 Multiple LGS None total callosotomy 5 4 F 10 5 CPS/GTC SPE None 5 5 M 17 11 Atonia/GTC SPE None 3 6 M 11 3 GTC SPE hippocampus atrophy 3 7 F 6 2 Atonia/GTC SPE None total callosotomy 5 8 M 8 1 CPS/GTC SPE None 6 9 M 9 6 Multiple SPE meningoencephalitis 3 10 M 9 4 PS SPE encephalitis 3 11 M 5 5 PS SPE meningoencephalitis 4 12 F 11 1 CPS LGS pachygyria + callosotomy 3 16 F 12 8 CPS/GTC SPE None 2 14 M 19 6 Reflex Sz UE encephalo-malacis 6 15 M 19 4 CPS SPE hippocampus atrophy 4 16 F 21 11 CPS SPE Encephalitis Temporal lobectomy 5 17 F 29 10 Multiple SPE Schizencephaly total callosotomy 3 * Abbreviation : Sz, Seizure; CPS, Complex partial seizure; GTC, Generalized tonic clonic; PS, Partial seizure; SPE, Symptomatic partial epilepsy; LGS, Lennox-gastaut syndrome; UE, Unclassified epilepsy. 143

Table 2. Seizure reduction rate (%), post- change of medication, side effect, and change of a quality of life* case sz frequency 3mo 6mo 1yr last f/u drug after side effect QOL improvement 1 3/d 0 0 30 20 0 N No 15 2 7-8/d 80 90 90 90 0 N Yes 12 3 3-4/d 0 50 0 60 1 N Yes 13 4 2-4/d, 2-3/2w 0 30 0 30 0 N No 11 5 5/d 80 20 80 90 0 N Yes 13 6 7-8/d 0 20 30 30 0 N No 39 7 15/d 0 60 70 85 0 N Yes 38 8 4/d 50 70 70 60 0 hoarseness Yes 48 9 15/d 0 20 20 30-1 hoarseness Yes 39 10 3/d 50 70 90 90 0 hoarseness Yes 51 11 3-4/d 0 0 40 30 0 hoarseness, remove, Yes 41 wound revison 12 5-6/d 70 85 90 95 1 hoarseness Yes 41 13 8-10/m 10 50 30 10 0 N Yes 13 14 10/d 0 0 0 0-2 N No 45 15 3/d 40 50 50 50 0 N Yes 40 16 5/M 0 20 30 20-1 cough No 48 17 4/d 0 33 66 75 0 hoarseness Yes 20 * Abbreviation : d, day; w, week; mo, month; yr, year; f/u, follow up; other abbreviation are the same as Table 1. total f/u (mo) 뇌혈류가감소되었다. 미주신경자극에의한뇌혈류의증가와감소중시상의뇌혈류증가가경련감소와연관성이있었다 (Henry 등, 1998; Henry 등, 1999; Henry 등, 2004). 동물실험에서미주신경자극시뇌파의비동기화 (desynchronization) 와극파 (spike) 가감소되어미주신경자극시경련발작빈도를줄이는데효과가있는것으로나타났다 (Bailey 등, 1938; McLachlan, 1993). 시상과소뇌자극이간질을조절하는역할을한다고알려져있는데 PET 연구에서밝혀진시상과소뇌의활성하는미주신경의해부학적구심성경로를반영할뿐아니라간질억제기전도반영한다 (Ko 등, 1996). 즉, 목부위에서약 80% 의신경섬유가구심성섬유로이루어진미주신경을자극하게되면연수에서여러구조물과시냅스한뒤다음과같은이론적인작용으로향경련효과를가져오게된다. 첫째, 시상과시상-피질투사로에서시냅스의활성도를증가시켜각성효과를증가시키고피질부위의시냅스활성도의동기화를감소시킨다. 둘째, 섬엽 (insula), 시상하부, 그리고다른중추자율신경계의시냅 스를증가시킨다. 셋째, 편도, 해마와다른변연계의구조물들의시냅스를감소시킨다. 넷째, 광범위한대뇌부위로항경련효과를가지는노르에피네프린, 세로토닌의분비를증가시킨다 (Schachter, 2002). Amar 등 (2004) 에의하면미주신경자극술전에간질과관련하여뇌수술을시행했던환자에서미주신경자극술후의간질발작감소율을 3개월, 6개월, 1년및 2년으로나누어연구해본결과 42.5%, 42.9%, 45% 및 52% 의간질발작감소율을나타낸반면, 미주신경자극술전에간질과관련한뇌수술을시행하지않았던환자들은 47%, 52.9%, 60% 및 66.7% 로미주신경자극술을단독으로시행한환자들의간질발작감소율이훨씬높게나타났다. Koszewski 등 (2003) 에의하면미주신경자극술을시행하기전에뇌량절제술을시행하였던환자들의간질발작빈도감소율이 90%, 그렇지않은환자들의간질발작감소율이 60% 을나타내어미주신경자극술시행전에뇌량절제술을시행했던환자들의간질발작감소율이훨씬높았다고보고하였다. 144

본연구에서 4명이미주신경자극술전에간질과관련되어진수술을시행하였고, 이중 3명은뇌량절제술을시행하였고, 1명은측두엽절제술 (temporal lobectomy) 을시행하였다. 미주신경자극술전에간질과관련되어진수술을시행한환자의간질발작감소율은 60%, 미주신경자극술만시행한환자들은 48% 의간질발작감소율을나타내었고, 1명은미주신경자극술과뇌량절제술을동시에시행하였으며간질발작감소율은 95% 로나타났다. 이에저자들의연구에서뇌량절제술후미주신경자극술을시행하거나뇌량절제술과미주신경자극술을동시에시행할경우간질발작빈도가훨씬감소함을알수있었다. 발작형태에따라 17명의난치성간질환자의간질발작감소율을조사하였더니증상성부분간질 (symptomatic partial epilepsy) 13명, 레녹스- 가스토증후군 3명, 반사적간질 (reflex epilepsy) 1명이었다. 레녹스-가스토증후군에서미주신경자극술의효과는 Murphy 등 (2003) 에의하면환자의 66% 에서 75% 의간질발작감소율을나타냈고, Hosain 등 (2000) 은레녹스-가스토증후군환자 13명중 5 명이 75% 이상의간질발작감소율을보였다고보고하고있다. 본연구에서증상성부분간질의경우 45% 의간질발작감소율을보였고, 레녹스- 가스토증후군에서는 82% 감소율을보였으나, 반사적간질환자에서는간질발작감소율이전혀나타나지않았다. 우리의연구에서레녹스 -가스토증후군에서미주신경자극술은간질발작빈도를감소시키는데효과적인보조적치료수단으로나타났다. Handforth 등 (1998) 에의하면성인에서미주신경자극술의부작용으로쉰목소리, 성대마비, 하안면마비및감염이되어기구를제거한경우가있었고, Helmers 등 (2001) 의보고에서소아에서시행한연구에서부작용은 1% 미만으로특징적으로침흘림, 과잉행동이관찰되었다. 본연구에서는 17명중 7명이미주신경자극술에의한부작용이나타났고, 그중 6명 ( 소아 5명, 성인 1명 ) 이미주신경자극술시행 3개월안에쉰목소리를나타내었고, 6명중 1명은수술부위감염으로인해수술후목부위전극선고정장치가피하표면에돌출되어교정술을받았으며, 1명은기침이일시적으로나타났으나발생후 1달안에모두치료없이호전되었다. 미주신경자극술은간질발작감소뿐아니라삶의질적향상에도효과가있다고보고하고있다. Carmer(2001) 에의하면미주신경자극술을시행한모든환자에서삶 의질이향상되었다고보고하고있으며, Clark 등 (1999) 에의하면간질발작빈도가 50% 이상감소한환자에서각성상태, 기억력, 감정등의호전에의하여환자들의삶의질이향상되었다고보고하였고, Hassert 등 (2004) 의보고에서는미주신경자극술이후 norepinephrine이미주신경자극술시행전보다 98% 이상증가하였고이는 norepinephrine이뇌전체적으로영향을줌으로인해환자의각성상태가미주신경자극술시행전보다더명확하여졌다는보고가있으며, Aldenkamp 등 (2002) 은레녹스- 가스토증후군을가지고있는환자에서미주신경자극술이후과잉행동을보인것으로보고하였다. 저자들의연구에서 12명의환자에서삶의질이향상된것으로나타났다. 6명은미주신경자극술시행전보다훨씬의식상태가훨씬명료해졌고, 2명은눈맞춤이가능해졌으며, 2명은감정의변화, 언어향상및과잉행동을보인환자가각각 1명이었다. 본연구에서경련빈도가 50% 이상감소한환자는소아 13명중 7명, 성인 4명중 2명으로미주신경자극술은난치성간질환자에있어보조적치료수단으로효과적이며, 삶의질을호전시키는비교적안전하고효과적인치료방법중의하나이다. 그러나그결과가반응이없는환자부터탁월한효과를보이는환자까지다양하다. 향후다양한요인들을가진환자들에게적용하여최대의치료효과를나타낼수있는적응증확립이중요하리라생각되어진다. 참고문헌 1. Aldenkamp AP, Majoie HJM, Berfelo MW, Everse SMAA, Kesselsf AGH, Renierg WO, Wilminkd J. Long-term effects of 24-month treatment with vagus nerve stimulation on behaviour in children with Lennox-Gastaut syndrome. Epilepsy Behav 3:475-479, 2002. 2. Amar AP, Apuzzo ML, Liu CY. Vagus nerve stimulation therapy failed cranial surgery for intractable epilepsy: result from the vagus nerve stimulation therapy patient outcome registry. J. Neurosursery 55:1086-1093, 2004. 3. Bailey P, Bremer F. A sensory cortical representation of the vagus nerve with a note on the effects of low 145

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