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1 종설 J Korean Neurol Assoc / Volume 24 / June, 2006 파킨슨병에대한시상하핵심부뇌자극술 연세대학교의과대학신경과학교실, 신경외과학교실 a 류철형장진우 a 이명식 Subthalamic Deep Brain Stimulation for Parkinson s Disease Chul Hyoung Lyoo, M.D., Jin Woo Chang, M.D., Ph.D. a, Myung Sik Lee, M.D., Ph.D. Departments of Neurology, Neurosurgery a, Yonsei University College of Medicine, Seoul, Korea The recent progress in the basic knowledge of basal ganglia pathways and advances in the techniques of the neuroimaging studies enabled subthalamic deep brain stimulation (STN DBS). In Korea, more than three hundreds and fifty patients with PD have been treated with STN DBS since the first trial at March STN DBS effectively improves all parkinsonian deficits occurring especially during levodopa off period and decreases the daily off time. The daily requirement of levodopa dosage can be reduced to about half of the preoperative one. The favorable responses to the STN DBS can be maintained even after five years. However, parkinsonian deficits during levodopa on period can not be controlled as effectively as those during the levodopa off period. The axial symptoms including gait disturbance and postural instability during the levodopa on period cannot be improved or even are worsen by STN DBS. Patients aged over 70 frequently show less remarkable improvement of parkinsonian deficits than the younger ones. Therefore, selection of appropriate candidate for STN DBS is the most important factor deciding the outcome of the STN DBS. J Korean Neurol Assoc 24(3): , 2006 Key Words: Parkinson Disease, Deep brain stimulation, Subthalamic nucleus 서 론 20세기초부터파킨슨병증상을치료하기위한수술이시행되었는데, 기저핵에대한수술은치명적인혼수상태를일으킬수있다는우려때문에금기시되었으며운동과직접적으로관련된부위를제거하는운동피질제거술 (motor corticectomy), 척수신경로절단술 (cordotomy) 등이시행되었다 년대에이르러창백시상로 (pallidothalamic pathway) 를포함하는기저핵회로에대한수술로파킨슨병의증상을개선시킬수있다는사실이알려졌으며, 년대이후뇌정위수술법 (stereotaxic brain surgery) 이발전되면서파킨슨병환자에게기저핵회로에대한수술이시행되었다. 2,3 그러나뇌에병변을만드는 *Myung Sik Lee, M.D., Ph.D. Department of Neurology, Youngdong Severance Hospital Yonsei University College of Medicine Dogok-dong, Gangnam-gu, Seoul, , Korea Tel: Fax: mslee@yumc.yonsei.ac.kr 치료법은효과가제한적일뿐아니라심각한후유증을남길수있기때문에 1960 년대에레보도파 (levodopa) 가도입된이후수술적치료법이시행되는경우는급격히감소하였다 년대에도입된심부뇌자극술 (deep brain stimulation; 이하 DBS) 은제거술 (ablative surgery) 의문제점인연하곤란, 언어장애등영구장애를일으키지않으며수술후에도파킨슨병의진행정도에따라치료강도를조절할수있기때문에약물투여만으로는한계에도달한파킨슨병환자의치료에널리이용되고있다. 국내에서는 2000 년 3월운동동요 (motor fluctuation) 와레보도파에의해유발된이상운동증 (levodopa induced dyskinesia; 이하 LID) 을보이던 56세여자환자에게처음으로양측시상하핵 DBS(subthalamic nuclei deep brain stimulation; 이하 STN DBS) 가시행된이래, 년 12월까지전국 16곳의의료기관에서 133 명의파킨슨병환자를대상으로 220 개 (STN 184 개, 내측담창구 31개, 시상 5개 ) 의박동기 (implantable pulse generator; 이하 IPG) 가삽입되었다 년 1월부터파킨슨병에대한 DBS 치료가건강보험급여 J Korean Neurol Assoc Volume 24 No. 3,

2 류철형장진우이명식 대상에포함되면서 2005 년에한해동안 19곳의의료기관에서 220 명의파킨슨병환자가 DBS 수술을받았으며앞으로도많은환자가수술적치료를받게될것으로예상된다. 파킨슨병의병태생리 흑질 -선조체도파민신경세포가소실되면직접경로 (direct pathway) 를통해내측창백핵 (internal globus pallidus; 이하 GPi) 으로전달되는억제성연결의활성이감소하여 GPi 의활성이올라간다. 또한간접경로 (indirect pathway) 를통해외측창백핵 (external globus pallidus; 이하 GPe) 으로부터 STN 으로전달되는억제성연결의활성이감소함에따라 STN 의활성이증가하고 GPi 의활성이증가함으로써시상으로전달되는억제성기저핵출력이증가되어파킨슨증상이생기는것으로생각된다 (Fig. 1). 6,7 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( 이하 MPTP) 로파킨슨병을유발시킨원숭이기저핵의 2-deoxyglucose ( 이하 2-DG) 섭취율을조사한연구 8 에서 GPe 의 2-DG 섭취율은 24-27% 증가하고, 시상의배쪽바깥쪽핵 (ventrolateral nucleus) 과배쪽앞쪽핵 (ventroanterior nucleus) 의 2-DG 섭취율은 14-22% 증가하지만 STN 의 2-DG 섭취율은 17-26% 감소했으며, GPi 의 2-DG 섭취율은변화가없었다. 2-DG 섭취율은주로신경접합부의활성 (synaptic activity) 을나타내기때문에, 이소견들은, 선조체에서 GPe 로보내는억제성신호가증가하고 GPe 에서 STN 으로보내는억제성신호가감소하며 STN 의활성도가증가해 GPi 가활성화되고, GPi 에서시상으로보내는억제성신호는증가하는것으로해석될수있다. 결과적으로시상에서대뇌피질로보내지는흥분성신호가과도하게억제되어파킨슨증상이나타나는것으로해석된다. MPTP 로파킨슨증상이생긴원숭이에게신경세포자체의활성을나타내는 cytochrome oxidase I (COX-I) mrna 의발현을조사한결과 9 STN, GPi, 흑질망상부 (substantia nigra pars reticulata; 이하 SNr) 신경세포의 COX-I mrna 발현이증가했다. 레보도파를투여하면이들신경세포의활성도는부분적으로감소되었으며, 장기적으로레보도파치료를받은환자의기저핵에서는 COX-I mrna 발현이정상인과차이가없어, 비정상적으로증가된기저핵출력이레보도파치료에의해서감소되는것이파킨슨증상의호전과관련이있을것으로생각된다. 9 미세전극 (microelectrode) 을이용하여정상원숭이 STN 신경세포의전기활동을측정하면평균 19 Hz 의자발적전기활동이나타나지만, MPTP 를투여해서파킨슨병을유발시킨원숭이는평균 26 Hz 로나타나고돌발파 (bursting activity) 를보이는신경세포도증가한다. 10 GPi 의전기활동빈도는증가된다는보 Figure 1. Basal ganglia pathways in normal and parkinsonian conditions. In Parkinson s disease, the inhibitory striato-gpe (external globus pallidus) pathway is enhanced and the activity of inhibitory signal from GPe to GPi (internal globus pallidus) is decreased. The subthalamic (STN) activity is increased with the progressive degeneration of nigral dopaminergic neurons. With the pathologically overactive STN and decreased inhibitory signal from GPe, the neurons in the GPi are over activated and consequently thalamic output to the cerebral cortex is inhibited. The activating and inhibitory pathways are represented by black and gray arrows, respectively. The activity of each pathway is expressed as the thickness of the arrow. 192 J Korean Neurol Assoc Volume 24 No. 3, 2006

3 파킨슨병에대한시상하핵심부뇌자극술 고도있지만, 11 일정하지않다는보고도있다. 10 실제파킨슨병환자의 STN 에서도평균 37 Hz (25-75 percentile: Hz) 의자발적전기활동과불규칙하게돌발적으로나타나는전기활동패턴 (irregular bursting activity pattern) 이관찰되고, 사지의수동적움직임이나진전과연관된돌발파가나타난다. 12 MPTP 로파킨슨병을유발시킨영장류에게 apomorphine 을투여하면돌발파를보이는 GPi 신경세포가줄어들면서전기활동빈도도감소하는것으로보아파킨슨증상의호전은기저핵출력부위의전기활동이정상으로돌아오는것과관련이깊다는것이밝혀졌다. 13 STN DBS 수술기법 1. STN 의뇌정위좌표 STN 은전교련-후교련연결선 (anterior commissure-posterior commissure line; 이하 AC-PC line) 을기준으로아래로 0-6 mm 사이, 정중선에서옆으로 mm 사이, AC-PC line 의중간 1/3 위치에서아몬드형태로관찰된다. 적핵 (red nucleus) 의 1-2 mm 앞, SNr 의 2-3 mm 위쪽옆에위치하며, 바깥쪽으로는내포 (internal capsule) 에의해, 뒤쪽으로는유두체 (mammillary body) 에의해경계지워진다 (Fig. 2). 28 일반적으 STN DBS 의작용기전 파킨슨병환자나동물모델에서 STN 에병변을만들면파킨슨증상이호전되는것으로보아파킨슨증상은 STN 활성증가와관계가있는것으로생각된다 STN DBS 도파킨슨증상을호전시키는것으로보아 STN DBS 가 STN 신경세포의활성을억제한다는가설이제시되었다. 실제로파킨슨병환자에게 STN에고주파전기자극 (high frequency stimulation; HFS) 을가하면자극이끝난뒤일정기간동안 STN 신경세포의전기활동이억제된다 또한 6-hydroxydopamine (6-OHDA) 을투여해서만든파킨슨병모델쥐에서 STN 에 HFS 를가하면 STN 신경세포의 COX-I mrna 발현이 10-35% 감소한다. 21,22 그러나일반적으로전기자극을가하면신경세포는억제되기 보다는흥분된다. 23 STN, GPi, 중간배쪽핵 (ventral intermediate nucleus; 이하 Vim) DBS 의부작용으로나타나는증상들은목표주변을지나는구조물이흥분될때나타나는증상인이상감각 (paresthesia), 근긴장이상증, 이상시각 (visual flashes) 인경우가대부분이다. 24 STN DBS 를하면 GPi 세포외액의 cgmp 농도가증가되는것이관찰되어 DBS 는 STN 의활성을증가시킨다는보고가있었다. 25 이런상반된결과들로인해 DBS 의작용기전에대해서아직 논란이있다. 19,24,26 쥐의뇌절편을이용한실험에서 STN 에 HFS 를가하면돌발파를이루는극파 (spike activity) 가유발되나극파와극파사이에서는자연적으로발생하는전기활동이억제되는것으로보아, STN DBS 는신경세포를흥분시키는것과억제하는기전을모두갖고있다는가설이제시되었다. 27 HFS 는 STN 신경세포를단순히흥분혹은억제시키는것이아니라새로운규칙적인외부자극 (HFS) 에따라반응하도록만들기때문에 10,12 비정상적인기저핵활동대신에강제된규칙적인전기활동이시상으로전달되게한다는가설이제시되었다. 26,27 Figure 2. Serial section of coronal magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) sequence visualizing the subthalamic nucleus (STN). The STN can be visualized by T2-weighted and FLAIR MRI as the low signal intensity structure. The red nucleus is located posteromedial to the STN. The substantia nigra constitutes the inferior border of STN. The serial section of coronal MRI around the STN from the point 20mm (top) posterior to the anterior commissure (AC). The arrows indicate outer margin of STN. J Korean Neurol Assoc Volume 24 No. 3,

류철형장진우이명식 로 STN DBS 의최적의표적은 AC-PC line 중앙에서아래로 2-4 mm 사이, 정중선에서옆으로 11-13 mm 사이, AC-PC line 중앙에서후방으로 2-3 mm 사이로알려져있다. 2. STN DBS 수술과정 STN DBS 수술은신경계영상검사와신경생리검사를이용해해부학적및생리학적표적의위치에전극을삽입한뒤, 외부전기자극기 (test stimulator) 를이용하여삽입된전극이그위치에서어떤반응을일으키는지확인하는과정으로진행된다.

4 류철형장진우이명식 로 STN DBS 의최적의표적은 AC-PC line 중앙에서아래로 2-4 mm 사이, 정중선에서옆으로 mm 사이, AC-PC line 중앙에서후방으로 2-3 mm 사이로알려져있다. 2. STN DBS 수술과정 STN DBS 수술은신경계영상검사와신경생리검사를이용해해부학적및생리학적표적의위치에전극을삽입한뒤, 외부전기자극기 (test stimulator) 를이용하여삽입된전극이그위치에서어떤반응을일으키는지확인하는과정으로진행된다. 국소마취하에서정위수술장치 (stereotactic frame) 를환자의두개골에고정시킨후자기공명영상 (magnetic resonance image; MRI) 을얻는다. T1- 강조영상과 T2- 강조영상을이용해 STN 의뇌정위좌표값을얻는다. 양측관상봉합선앞쪽에두개골천공 (burr hole) 을만든다음신경생리검사를시행한다. 미세전극기록 (microelectrode recording; MER) 은 AC-PC line 을지나는여러축을따라미세전극을전진시키며각지점 의신경세포의자발및유발전기활성도 (spontaneous and evoked neuronal electrical activity) 를기록한다. 모든지점에서나타나는전기활성도를, 목표점을지나는시상단면에표시하여 STN 의경계를확인한뒤전극을삽입할목표점을설정하고, 최종적으로외부전기자극기를이용하여목표지점이 STN 위치와일치하는지확인한다. 정해진목표지점에네개의접촉면이있는전극 (tetrapolar electrode) 을삽입하고엑스선조영술 (fluoroscope) 등으로전극의위치를확인한후두개골에고정한다. 전신마취를한후 IPG 를쇄골아래부분에삽입하고, 전극선과연장선을피부밑으로통과시킨다음 IPG 와연장선을연결한다 (Fig. 3). 3. 미세전극기록 (microelectrode recording; MER) 전기생리학적검사인 MER 은 STN DBS 수술의성적향상과합병증예방에도움이된다. 두개골천공위치에서 STN 까지조금씩전극을전진시키면서 MER 을시행하면, 각부위마다신경세포의고유한전기활동이나타난다. STN 은 Hz, SNr Figure 3. Postoperative radiological studies after a subthalamic deep brain stimulation (STN DBS). (A) A plain X-ray shows components of STN DBS. The arrow heads indicate the connector between the electrode lead and extension wire. (B and C) The axial T2 and T1-weighted MRI show the tips of the electrodes which are visualized as the signal void structures located at the midbrain. (D and E) The reconstructed coronal and sagittal T1-weighted MRI studies show electrode leads passing through the brain parenchyme. 194 J Korean Neurol Assoc Volume 24 No. 3, 2006

5 파킨슨병에대한시상하핵심부뇌자극술 은 Hz 로높은주파수를보이기때문에 STN 의위치를확인하기가용이하다는주장이있으나, 12 STN 신경세포의전기주파수가 SNr 보다더높다는보고도있다. 29 이런주파수에관한논란이있지만 STN 에서는 ( 주로등쪽바깥쪽 STN) 진전과연관된활동을하는신경세포, 수동혹은자발적관절운동에반응하는신경세포가다수관찰되기때문에 SNr 이나다른기저핵부위와구분된다. 4. 거시전극을이용한전기자극술 (electrical stimulation using macroelectrode) DBS 효과는일정치않았는데오히려두배로나빠졌다는보고도있었다. 약효작동때의 ADL 점수는호전되었다는보고도있으나, 나빠졌다는보고가더많았으며심지어 92% 악화되었다는보고도있다. 체간증상 (axial signs) 을평가하는보행점수는약효소멸상태에서는수술전과비교했을때약 28-52% 호전을보였지만, 약효작동상태에서는수술전에비해변화가없거나오히려두배이상증가해서환자의 ADL 이수술전에비해나빠지는큰원인이되었다. STN DBS 의부작용 수술중에외부로부터삽입된전극을통해전기자극기로 STN 을자극하면사지의무운동증 (akinesia) 이크게호전되는것을관찰할수있다. 특히손목강직이줄어들면그곳을좋은수술목표로판단한다. 30 STN DBS의효과 1. STN DBS 의장기적인효과 2년이상추적관찰을시행한연구들에서 STN DBS 는레보도파에반응하는대부분의파킨슨증상을크게호전시키며, 장기간레보도파치료에따른합병증인운동동요를감소시키고, 레보도파투여량도줄일수있게해준다는사실이확인되었다 (Table 1) 약물효과가소멸된 ( 약효소멸 ; drug off) 상태에서측정한 UPDRS 운동점수는수술전에비해 28-65% 호전되고하루중약효소멸상태가차지하는비율도 50% 에서 5-17% 로줄어들었으며, 환자의일상생활척도 (activities of daily living score; 이하 ADL 점수 ) 도 17-61% 호전되었다. 수술전에비해레보도파복용량은 30-67% 줄었는데도불구하고진전, 강직, 서동과같은파킨슨병의주요증상이모두호전되었으며, 특히진전은가장큰호전 (60-87%) 을보였다. 뿐만아니라약물효과가지속되는 ( 약효작동 ; drug on) 상태에나타나는이상운동증 (levodopa induced dyskinesia; 이하 LID) 의심한정도도 29-79% 줄어들었다. 약효작동상태에서 STN DBS 를가하면약효소멸상태에서 STN DBS 를가했을때만큼좋은효과를얻을수는없다. UPDRS 운동점수가 36% 호전되었다는연구가있으나, 오히려 48% 나빠졌다는보고도있어약효작동상태에서는 STN DBS 효과가일정치않은것으로생각된다. 진전은약효작동상태에서도 50-98% 호전되어약효소멸상태와유사한효과를얻을수있었고, 강직도 7-63% 호전되었다. 그러나서동에대한 1. 수술과연관된부작용 81명의파킨슨병환자에게 160 개의전극을삽입해 DBS 를시행한결과가발표되었는데, 한명에게서수술중에전극삽입으로인한뇌출혈이생겼지만후유증없이회복되었고, 한명은수술직후에한차례의간질발작을일으켰다. 한명에게는수술 1개월이내전극선에감염이생겨서이를제거했고, 다른한명은수술 9개월뒤에전극선감염이생겼다. IPG 에감염이생긴 3명에게는 IPG 와전극을모두제거한뒤다시삽입했다. 전극을잘못삽입하여효과가없었던 10명은모두재수술을통해좋은효과를보았다 명에대해 316개의전극을삽입한연구에서는수술부작용이조금더높게보고되었는데, 12명 (6.1%) 이뇌출혈이생겼고, 7명 (3.5%) 이감염이생겼으며, 전극을잘못삽입해서위치를교정해야했던경우는 3명 (1.7%) 이었다. 수술직후에 17명 (8.6%) 은혼돈이생겼으며두명 (1%) 은폐색전증이생겼다 기계적인문제로인한부작용파킨슨병으로인해 DBS를받은환자중 20-25% 에서기계및전기시스템장애가생길수있다. 40,42,43 전극선이나연장선 (extension wire) 의이동, 절단, 단락이생길수있으며 IPG 자체에이상이생길수도있다. 42 전극선이나연장선의손상은목에이상운동이심한환자에게잘생긴다. 44 연장선이손상된경우와는달리전극선이손상되면뇌정위수술을다시해야하므로, 전극선이손상되지않도록하는것이중요한데, 연결부를유상돌기위쪽에두면전극선이목움직임의영향을받지않게된다. 45 수술후추적관찰중갑자기 DBS 효과가떨어지거나예상하지못했던자극과연관된증상이나타나는경우에는전극의임피던스를측정하고 X-선촬영을해서전극선과연장선이파손되었는지확인해야한다. 46 J Korean Neurol Assoc Volume 24 No. 3,

6 류철형장진우이명식 196 J Korean Neurol Assoc Volume 24 No. 3, 2006

7 파킨슨병에대한시상하핵심부뇌자극술 3. DBS 자극또는자극목표부위와연관되어생기는부작용 STN 은연결되는신경회로에따라서등쪽바깥쪽 (dorsolateral) 의감각 -운동영역 (sensory-motor part), 가운데의연합영역 (associative part), 배쪽안쪽 (ventromedial) 의변연영역 (limbic part) 으로나뉘어진다. 47 STN DBS 는등쪽바깥쪽 STN 을자극해서파킨슨운동증상에대한개선을목표로하지만, 전기자극이 STN 의연합영역이나변연영역으로도퍼지기때문에인지기능과행동에변화가생길수있다. 48 또한전기자극이 STN 주변으로퍼져서근육수축, 구음장애, 이상감각, 현훈, 안구편위 (ocular deviation), 안검연축 (blepharospasm), 무운동증악화등이생길수있다. 30 STN DBS 후장기간추적관찰한결과약 25% 의환자가인지기능저하가나타났고, 행동및기분장애 (behavioral or mood disorders) 가생겼다. 31 언어유창성 (verbal fluency) 과언어기억력 (verbal memory) 의장애가생기며, 그외에도수행능력 (executive function), 집중력 (attention), 작업기억력 (working memory) 에영향을준다. 48 STN DBS 를받은환자들중 17-76% 에서항우울효과 (antidepressant effect) 가나타났지만, 2-33% 에서는우울증이유발되고, 4-8% 에서는조증이유발 (mania inducing effect) 된다. 49 일부에서는운동증상이개선됨에도불구하고자살을시도한보고도있다 특히수술전에우울증이있었던환자는수술후세심한관찰이필요하다. 49,52,53 4. 주변환경에의해발생되는부작용일상생활에자성을띤물체 ( 예 : 대형스피커 ) 의영향으로갑자기 IPG 가꺼지거나켜질수있어 Access Review 를사용하여환자스스로 IPG 를켜고끄는것을익혀야한다. 일상생활에사용되는전자제품들은 IPG 에간섭을일으키지않지만, 비교적큰전자기장을보내는공항검색대같은경우는 DBS 자극강도가변할수도있기때문에노출되지않도록주의한다. STN DBS 후증상이호전되었으나치과에서양쪽얼굴에고주파투열치료 (high frequency diathermy) 를받은뒤 DBS 전극주변에치명적인뇌손상이생긴경우가있어, 54 DBS 수술을받은환자에게모든종류의투열치료 ( 단파, 초단파, 초음파 ) 는금기사항이다. STN DBS 수술을받은환자에게 MRI 촬영을해도 IPG 의기계적오작동, 전극선위치변동등은생기지않아 DBS 수술후 MRI 촬영은안전한것으로여겨졌다. 55 그러나 1.5T MRI 로요추를촬영한파킨슨병환자에게 DBS 전극선끝주변으로뇌출혈이생긴예가보고되었다. 56 DBS 수술을받은 환자에서는 1.5T 이상의 MRI 를사용하지말도록권고되며코일 (coil) 의선택에서도 receive 전용 head coil, 전신에전달되는 transmit coil, 가슴까지전달되는 head transmit coil 은금기이다. 그외에 MRI 촬영조건에따라서신체로전달되는에너지가변할수있기때문에사용할 SAR(specific absorption rate) 이 0.1 W/kg 이하일때촬영한다. 그밖에시상에 DBS 를받은환자가심율동전환 (cardioversion) 후시상에병변이생기고이로인해 DBS 가더이상작동하지않게된경우도보고되었다. 57 수술목표물의선택 : STN 혹은 GPi 창백핵제거술 (pallidotomy) 을통해파킨슨증상에대한효과가알려져있던 GPi 를목표물로 DBS 가시작되었다. 58 파킨슨병동물모델에서 STN 을수술적으로제거하거나 14,15 전기자극을가하면 59 파킨슨증상이크게호전된다는것이밝혀지고신경계영상기술의발달과 MER 에힘입어 STN 의경계를정확히확인하는것이가능해지면서 STN 을목표로 DBS 가시도되었다. 60,61 STN 은 GPi 에비해부피가작기때문에 (STN= 약 158 mm 3, GPi= 약 478 mm 3 ) GPi DBS 에비해낮은강도의자극을가해도원하는효과를얻을수있다. 62 GPi DBS 는수술후레보도파복용량을줄일수없거나오히려늘려야하지만 STN DBS 은레보도파복용량을줄여도증상을개선시킬수있으며 LID 도 GPi DBS 수준으로감소시킨다는연구도있어 63,66,67 STN 을목표로한 DBS 가널리시행되고있다. 68 그러나 STN 과 GPi DBS 결과를직접비교하여어떤목표물이더좋은효과를보이는지연구된경우는많지않다 (Table 2). 31,63,65-67,69,70 이연구들중에서 STN과 GPi 중에서어느곳을수술할지무작위로선정한두연구를 67,70 제외하고나머지연구들은환자의상태에따라의사가임의로 DBS 목표를정했기때문에선택편견 (selection bias) 이개입되었다. 즉, LID 가심한환자에대해서는 GPi 를목표로선택했을가능성이높다. 이경우 GPi DBS 는 LID 에대한억제효과가크기때문에 GPi DBS 후에 LID 에대한걱정없이레보도파를증량투여했을가능성이있다. 71 최근에 STN 과 GPi DBS 의장기적인효과에대한비교연구 31 와단기효과에대한이중맹검연구 70 에서 GPi DBS 도 STN DBS 에버금갈정도로파킨슨증상에효과가있었다. 소수의연구 63 를제외한대부분의연구에서 STN DBS 는수술전약효소멸상태의 UPDRS 운동점수를 39-54%, GPi DBS 는 33-39% 호전시켜둘사이에는약 4-11% 차이가있다 (Table 2). 그러나 STN DBS 의부작용으로인지기능과언어능력저하가생길수 J Korean Neurol Assoc Volume 24 No. 3,

8 류철형장진우이명식 Table 2. Summary of the results of direct comparison between the efficacy of STN and GPi DBS author (year) study design selection of target duration of follow-up target number of patients OFF UPDRS III (motor) ON UPDRS IV (dyskinesia) ON LED Rodriguez- Oroz (2005) Open label multicenter Clinician Mean 3.8y STN GPi Minguez- Castellanos (2005) Anderson (2005) DBS for PD study group (2001) Krause (2001) Burchiel (1999) Krack (1998) Open label retrospective Clinician 1y STN GPi Double blind Random 1y STN GPi Open label Clinician 6 m STN GPi Open label Clinician 1y STN GPi Open label Random 1y STN GPi Open label Clinician 6 m STN GPi STN; subthalamic nucleus, GPi; globus pallidus pars interna, LED; levodopa equivalent dose, y; years, m; months 있다는것과 LID 에대한효과가불확실하다는것을고려하면 GPi 도 DBS 의목표로다시고려할필요가있다. 68 STN DBS 대상환자 1. 수술시기 : 나이와파킨슨병이환기간 수술받을때의나이와 STN DBS 의효과사이에는상관이없다는일부연구가있지만, 72 대부분의다른연구에서는나이가많을수록 STN DBS 효과가떨어지는것으로나타났다 세이상 13명이포함된 52 명의 50 대이상파킨슨병환자를대상으로 STN DBS 의효과를조사한연구에서 70세이상인환자들도 대환자들처럼약효소멸상태의운동능력이개선되며레보도파투여용량, LID 는감소하는것으로나타났다. 79 그러나 70세이상인환자에게서운동능력개선효과와레보도파감량은 대환자에비해서적었고, 수술후약효작동상태의 UPDRS 운동점수는 26%, ADL 점수는 42% 나빠졌다. 특히 대환자에서약효작동상태때나타나는체간증상은수술후변화가없었지만, 70세이상환자는악화되기때문에 70세이상의고령환자이면서상당한체간증상을보이면수술 대상에서제외시키는것이바람직하다. 파킨슨병환자의적절한수술시점을결정하는것은매우중요하다. 질병이환기간이짧을수록수술효과가좋으며, 질병이진행함에따라비도파민성신경계의손상이동반되어 DBS 효과가떨어지기때문에가급적젊은나이에일찍수술을하는것이좋다. 75,80 그러나질병의초기에는다계통위축증 (multiple system atrophy; MSA) 환자가파킨슨병으로오진될가능성이 25% 에달하는것으로알려져있다. 81 또한증상이경미한경우에 DBS 를시행하면증상개선은미미하고수술에따른부작용이더클수도있다. 그러므로발병하고나서진단에확신이설정도의시간이지난뒤약물치료만으로는일정수준이상의독립적인생활을영위할수없다고판단될때수술을고려한다. CAPSIT-PD (Core Assessment Program for Surgical Interventional Therapies in Parkinson s Disease) 도발병후 5년이상경과된환자를수술대상으로할것을권고하고있다 레보도파에대한반응성수술전레보도파에반응하는정도는파킨슨병진단에중요할뿐만아니라수술후어느정도증상이개선될지예측하는 198 J Korean Neurol Assoc Volume 24 No. 3, 2006

9 파킨슨병에대한시상하핵심부뇌자극술 기준이된다. 72,73,75,76,82 레보도파에대한반응정도를측정하는방법은다양하다. 고용량의레보도파를투여한다음반응정도를보기도하지만, 환자가일상적으로복용하는용량을투여했을때호전되는 UPDRS 운동점수가수술후호전되는정도와상관관계가있기때문에일상용량을투여한다음반응정도를보기도한다. 72 CAPSIT-PD 는밤동안 12시간정도약물을중단한뒤아침에레보도파를투여해 UPDRS 운동점수가 33% 이상호전될때레보도파에반응하는것으로정했다. 77 수술전 apomorphine 에대한반응이클수록 DBS 에대한반응도크기때문에 apomorphine test 도수술대상환자선정에이용된다. 83 LID 의심한정도는수술효과를예측하는데도움이되지않는것으로알려져있다. 75 약효작동기간동안에도호전되지않는보행동결이나자세불안정같은체간증상이있으면 STN DBS 에의해서도호전되지않을가능성이크다는사실을수술전에환자와가족들에게알려주는것이중요하다. 75,82,84 3. 인지기능장애경도일지라도인지기능장애가있는환자는수술후에전반적인운동능력은호전되지만보행장애와자세불안이더심해지는경우가흔하고인지기능도급격히나빠질수있기때문에가볍더라도치매가있으면수술대상에서제외하는것을고려해야한다. 75,85 CAPSIT-PD 는 MDRS(Mattis Dementia Rating Scale) 130 혹은 120 이상을수술대상선정의기준으로제시했다. 77 Benabid 등 76 은 MMSE (Mini Mental State Examination score) 24점미만, MDRS 130 점미만의인지장애가있는환자들은수술대상에서제외했다. 4. 그밖에특별한경우 MSA 환자의 30% 정도는초기에레보도파치료에반응하고, 86 이들중 80% 는 2년후에 LID 가생기기때문에파킨슨병으로오진되기쉽다. 87 파킨슨병으로진단되어 STN DBS 를받은환자들중사망후부검을통해 MSA 로확진되었거나, 88,89 MRI 에전형적인 MSA 소견을보였던환자들이보고되었다. 90 이들은장기간레보도파치료에좋은반응을보였고, 전형적인 LID 와 motor fluctuation 이있었으나 STN DBS 에는반응하지않았다. 부검으로확진된 MSA 환자에게양측 GPi DBS 를시행한경우가있었는데 UPDRS 운동점수가 25% 정도호전되었고 LID 가거의사라져서 STN DBS 와는차이가있었다. 91 PSP 환자는 STN DBS 에전혀반응하지않는다. 92 Parkin 유전자의돌연변이에의한파킨슨증후군환자는 STN DBS 에매우좋은반응 을보였다. 93,94 수술전에편측창백핵제거술, 95,96 편측 Vim 시상제거술, 편측혹은양측 Vim DBS, 97 양측 GPi DBS98 등 STN 이외의다른부위에이미뇌정위수술을받았더라도 STN DBS 의효과에는영향이없는것으로알려져있다. 그러나양측창백핵제거술을받았던환자에게 STN DBS 를했더니효과가없었다는보고가있다. 99 일반적으로심장박동기를장착한환자에게도 DBS 수술은가능하다. 100,101 다만수술전뇌정위좌표를정하기위한 MRI 촬영이심장박동기에영향을미칠염려가있기때문에 CT 를이용해서좌표를정하고 MER 로 STN 의위치를확인하는것이좋다. 101 IPG 와심장박동기사이에심각한간섭은없는것으로알려져있지만 6인치이상거리를두는것이좋다. 101 보통한쪽쇄골아래쪽에심장박동기를삽입하기때문에 Kinetra 처럼양쪽 STN 을한개의 IPG 로자극할수있는시스템을, 심박동기가설치된반대쪽가슴에삽입하는것이이상적이며 Soletra 처럼두개의 IPG 가필요한경우에는심박동기설치반대쪽은흉벽에, 심박동기가설치된쪽은좀더긴연장선을이용해서복벽에 IPG를삽입한다. 결 론 파킨슨병환자에게서 STN DBS 로좋은효과를얻기위해서는지난 10여년동안축적된결과분석을통해 STN DBS 대상환자를선정하는정확한기준이마련되어야한다. STN DBS 는약효소멸기간동안의운동능력및이상운동증개선에는확실한효과가있으나, 약효작동기간동안의운동능력개선에는일정한효과를나타내기어렵다는사실이알려졌다. 따라서 STN DBS 대상환자를선정하기위해서는장기간경과관찰을통해파킨슨병으로확인된환자들이약효작동및약효소멸기간동안어떤운동장애를보이는지세밀히관찰해야한다. 약효소멸기간동안에 STN DBS 에잘반응하는운동증상이주증상인환자를선정하고, 환자와가족들에게수술후기대되는효과를정확히알려준다음에수술을시행하는것이중요하다. REFERENCES 1. Meyers R. Surgical experiments in the therapy of certain 'extrapyramidal' diseases: a current evaluation. Acta Neurol Scand Suppl 1951;67: Cooper IS. Ligation of the anterior choroidal artery for involuntary movements; parkinsonism. Psychiatr Q 1953;27: Hassler R, Riechert T. Indications and localization of stereotactic J Korean Neurol Assoc Volume 24 No. 3,

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12 류철형장진우이명식 advanced Parkinson's disease: results of a randomized, blinded pilot study. Neurosurgery 1999;45: Okun MS, Foote KD. Subthalamic nucleus vs globus pallidus interna deep brain stimulation, the rematch: will pallidal deep brain stimulation make a triumphant return? Arch Neurol 2005;62: Minguez-Castellanos A, Escamilla-Sevilla F. Pallidal vs subthalamic deep brain stimulation for Parkinson disease: winner and loser or a sharing of honors? Arch Neurol 2005;62: ; author reply Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 2005;62: Minguez-Castellanos A, Escamilla-Sevilla F, Katati MJ, Martin- Linares JM, Meersmans M, Ortega-Moreno A, et al. Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson's disease: target related effect or selection bias? J Neurol Neurosurg Psychiatry 2005;76: Pahwa R, Wilkinson SB, Overman J, Lyons KE. 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13 파킨슨병에대한시상하핵심부뇌자극술 subthalamic stimulation in PD. Neurology 2000;55: Samii A, Giroux ML, Slimp JC, Goodkin R. Bilateral subthalamic nucleus stimulation after bilateral pallidotomies in a patient with advanced Parkinson's disease. Parkinsonism Relat Disord 2003;9: Capelle HH, Simpson RK Jr., Kronenbuerger M, Michaelsen J, Tronnier V, Krauss JK. Long-term deep brain stimulation in elderly patients with cardiac pacemakers. J Neurosurg 2005;102: Senatus PB, McClelland S 3rd, Ferris AD, Ford B, Winfield LM, Pullman SL, et al. Implantation of bilateral deep brain stimulators in patients with Parkinson disease and preexisting cardiac pacemakers. Report of two cases. J Neurosurg 2004;101: J Korean Neurol Assoc Volume 24 No. 3,

의학강좌 백선하

의학강좌 백선하 Continuing Education Column Sun Ha Paek, MD Department of Neurosurgery, Seoul National University College of Medicine E mail : paeksh@snu.ac.kr J Korean Med Assoc 2008; 51(2): 158-167 Abstract Parkinson