원저 08-054 급성기뇌경색환자에서뇌자기공명영상의확산 - 관류불일치가임상적예후를예측할수있는가? -rcbv 를중심으로 - 동아대학교의과대학신경과학교실, 영상의학과학교실 a 전형원강지혜이수윤이유실강명진 a 차재관 Can Diffusion-Perfusion Mismatch on Brain MRI in Acute Ischemic Stroke Patients Predict Clinical Outcome? -Preliminary Study Focused on rcbv- Hyung Won Jeon, MD, Ji Hye Kang, MD, Su Yun Lee, MD, Yu Sil Lee, NS, Myong Jin Kang, MD a, Jae-Kwan Cha, MD Department of Neurology and Radiology a, College of Medicine, Dong-A University Background: Diffusion-perfusion mismatch (DPM) on MRI has been considered an ischemic penumbra. However, several reports have demonstrated limitation of DPM on MRI as a predictable marker of the ischemic penumbra. In this study, we investigated the relationship between DPM and the clinical progression in acute ischemic stroke patients. Methods: We consecutively recruited fifty-seven patients showing acute ischemic stroke (within 24 hours) in the middle cerebral artery (MCA) territory. The clinical outcomes were determined by serial measurement of National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mrs) during 30 days after their ischemic event. We also evaluated the relationship among the parameters of perfusion MRI and the clinical worsening in patients with DPM on initial MRI. Results: Nineteen (33.3%) patients had DPM on MRI within 24 hours after stroke onset. Even though the frequency of clinical worsening for 30 days after stroke onset was higher in DPM group (26%) than in non-dpm group (11%), it did not reach statistical significance (p=0.143). However, extent of MCA stenosis (p<0.001) and time to peak (TTP) delay on MRI (p<0.001) were significantly greater in patients with DPM than in those without DPM. Among several parameters of the perfusion MRI, only relative cerebral blood volume (rcbv) was significantly related to the clinical worsening (62.9±24.7% vs 96.1±19.2%, p=0.007) in patients with DPM. Conclusions: This study shows that DPM on MRI does not always predict the clinical worsening in acute ischemic stroke. To overcome this problem, we should analyze rcbv map based DPM as well as TTP map based DPM. J Korean Neurol Assoc 26(4):295-300, 2008 Key Words: Stroke, Magnetic resonance imaging, Diffusion, Perfusion Received April 29, 2008 Revised September 1, 2008 Accepted June 23, 2008 *Cha Jae-Kwan, MD Department of Neurology, College of Medicine, Dong-A University, 3ga, Dongdaeshin-dong, Seo-gu, Busan, 602-715, Korea Tel: +82-51-240-5266 Fax: +82-51-244-8338 E-mail: nrcjk@unitel.co.kr *This study was supported by a grant (A060171) of the Korean Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. 서론 급성기뇌경색환자에서정맥을통한 t-pa 의사용은뇌허혈에의한뇌손상을복원시킬수있는유일한치료방법으로공인받고있다. 1,2 그러나증상발현후 3시간이내라는짧은치료가능시간때문에전체뇌경색환자들중단지 7% 정도만이그혜택을받는다고알려져있다. J Korean Neurol Assoc Volume 26 No. 4, 2008 295
전형원강지혜이수윤이유실강명진차재관 최근들어여러가지뇌영상촬영기법의향상은허혈조직의해부학적위치뿐아니라허혈조직상태에대한분석을가능하게하고있다. 그중자기공명영상의확산강조영상과관류영상은각각뇌허혈로인한손상을받은부분과뇌허혈로인한손상이진행되는부위를보여주게된다. 확산강조영상과관류영상과의차이즉확산관류불일치 (diffusion-perfusion mismatch) 라는개념이도입되었고, 이부분이정맥 t-pa 에의해치료가가능한허혈성경계영역과일치한다는여러연구들이보고되었다. 3-6 이전까지이루어진급성뇌경색환자들에서정맥 t-pa 사용에대한메타분석에서는그효과가일반적으로알려진 3시간이내를넘어서 4시간 30 분까지지속된다는결과가나왔고이는허혈성경계영역이시간적제한에의해구분되기보다는여러가지요소에의해다양하게나타날것이라는추측을가능하게한다. 7-10 즉, 급성기뇌경색환자들에서의정맥 t-pa 의사용은이전의 3시간이내라는단순한시간적개념보다는실제허혈성경계영역의존재여부에따라야할것이라는것을말해준다. 그러나최근에보고된한메타연구에서는 MRI 상의확산관류불일치가있는환자들이없는환자들에비해뇌경색의크기가의미있게증가하지않았다고하였다. 11 이는 MRI 상에나타나는확산관류불일치가실제허혈성경계영역과일치하지않음을뜻한다. 이는 MRI 상의여러가지확산강조영상중비교적많이사용되는최고점시간 (time to peak, TTP) 을이용하는경우비교적쉽게영상을얻을수는있으나, 12,13 혈관협착 (vascular stenosis) 이동반되는경우위양성, 즉 benign oligemia 상태를허혈성경계영역으로판단할가능성이있다는보고와도일치한다. 14 이런경우실제로정맥 t-pa 사용에있어판단과정에혼선을줄가능성이있다. 그러나최근들어 MRI 의관류영상기법중상대적대뇌혈액양 (relative cerebral blood volume, rcbv) 을이용한영상의경우허혈부분에들어오는혈액의양을건측과비교하여상대적으로알게해주므로 TTP 와는다른의미의관류영상을제공해주며, 실제일부연구에서는 rcbv 가다른관류영상방법들에비해보다병측의허혈상태를잘반영하여뇌경색의크기증가를예측하게한다고하였다. 15,16 이에저자들은본연구에서급성기중간대뇌동맥뇌경색환자들에서 MRI 상확산관류불일치를보이는경우환자의실제신경학적증상의악화와연관이있는지를알고자하였고, 또한 MRI 상확산관류불일치를보이는환자들중임상적인악화를보이는경우와그렇지않은경우 rcbv 값은어떠한차이를보이는지알고자하였다. 대상과방법 1. 대상 2006 년 11월부터 2007 년 8월사이에동아대병원으로내원한 24 시간이내의급성기뇌경색환자중뇌경색의영역이중간대뇌동맥이면서건측의혈관에폐색소견이없는환자들을대상으로하였다. 이들중치료전확산강조관류자기공명영상을시행한환자는 67명이었고, 그중 t-pa 정맥주사나동맥내혈관조영술을통한재관류시술을행한 10 명을제외한 57 명을대상으로하였다. 뇌경색의발병시각은환자가신경학적결손이없었던마지막시간으로정하였으며, 기상시신경학적결손이발견된경우에는취침시간으로그시간을정하였다. 대상환자들의연령분포는 25세에서 83세 ( 평균 63세 ) 였으며, 남자가 34명 (59.6%) 이었다. 뇌경색의위험인자는고혈압이 36예 (63.2%), 당뇨 10예 (17.5%), 흡연 18예 (31.6%), 심근경색 2예 (3.5%), 심방세동 7예 (12.3%) 이었다. 뇌경색의분류는 TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification 에따라분류하였다. 17 2. MRI영상획득 1.5 tesla 자기공명영상기기 (GE Signa EXCITE HD; GE Healthcare, Milwaukee, WI, USA) 를이용하여 fluid attenuated inversion recovery (FLAIR) 영상, T1 강조영상, 조영증강후 T1 강조영상, 확산강조영상, time of flight (TOF) 자기공명혈관영상 (MRA) 을시행하였다. 조영증강후 T1 강조영상은가돌리늄 (Gadolinium) 조영제 (Omniscan; Amersham Health-care, Norway) 10 ml를정맥으로주입한후즉시촬영을시행하여영상을얻었다. 자기공명관류검사는가돌리늄 20 ml 를초당 2-3 ml 의속도로조영제주입기를이용하여정맥내로주입후평균순환시간 (mean transit time, MTT), TTP, rcbv 영상을구하였다. 3. 영상의분석이상에서획득한자기공명영상을환자들의임상정보를모르는 1명의신경방사선과의사가분석하였다. 확산관류불일치는 TTP 가건측에비해 4초이상의차이를보이는경우에, 관류영상의결손부분이확산강조영상에비해 20% 이상큰경우로정의하였다. 또한 rcbv 는병측의관류이상을보이는국소부위의뇌혈용적을이에상응하는정상뇌조직의뇌혈용적으로나누어 296 대한신경과학회지제 26 권제 4 호, 2008
급성기뇌경색환자에서뇌자기공명영상의확산 - 관류불일치가임상적예후를예측할수있는가? A B A B C D C D Figure 1. MR findings of patient who showed diffusion-perfusion mismatch but no clinical progression. A. DWI; small perforating artery infarction, B. TTP graph; 6 seconds time delay, C. TTP map; diffusion-perfusion mismatch, D. CBV map; No deficit. CBV; cerebral blood volume, DWI; diffusion weighted images, TTP; time to peak. A B Figure 3. MR findings of no diffusion-perfusion mismatch patient. A. DWI; small perforating artery infarction, B. TTP graph; No delay, C. TTP map; No deficit, D. CBV map; No deficit. CBV; cerebral blood volume, DWI; diffusion weighted images, TTP; time to peak. 그비율을 % 로표기하였다. 확산관류불일치와혈관의폐색과의관계를알기위해서 MRA 로중간대뇌동맥협착정도를 4단계로 (Grade I-50% 미만협착, Grade II-50% 이상협착, Grade III-혈관의영상이끊겼다가다시보이는경우, Grade IV-완전폐색 ) 분류하였다. 4. 신경학적결손및임상예후평가 C D 모든환자는내원당시와 2일째그리고 5일째에 National Institute of Health Stroke Scale (NIHSS) 점수를, 그리고내원당일과 30일째에 modified Rankin Scale (mrs) 점수를측정하고이를분석하였다. 임상증상악화는내원후 5일동안 NIHSS 점수가 4점이상높아지거나, 내원후 30일동안 mrs 점수가 1점이상증가한경우로정의하였다. Figure 2. MR findings of patient who showed diffusion-perfusion mismatch and clinical progression. A. DWI; territorial infarction, B. TTP graph; 4 seconds time delay, C. TTP map; diffusionperfusion mismatch, D. CBV map; decreased CBV. CBV; cerebral blood volume, DWI; diffusion weighted images, TTP; time to peak. 5. 통계처리모든수치는평균 ± 표준편차로표시하였으며, 통계는 SPSS 를통하여연속변수는 student t-test 로백분율은 chi-square 로처리하였으며 p값이 0.05 이하인경우통계적의의가있다고정의하였다. J Korean Neurol Assoc Volume 26 No. 4, 2008 297
전형원강지혜이수윤이유실강명진차재관 결과 대상이되었던총 57명의환자중 19명의환자 (33.3%) 에서증상발현후 24시간이내에촬영한뇌자기공명영상에서확산관류불일치가관찰되었다. 확산관류불일치가있는환자들 (Fig. 1, 2) 과그렇지않은환자들 (Fig. 3) 사이의임상적소견과자기공명영상에서관찰되는소견들을비교해보면, 확산관류불일치가있는군에서그렇지않은군에비해흡연의빈도가높았으며 (p=0.032), 건측과의 TTP의차이가크고 (p<0.001) Grade III 이상의중대뇌동맥의폐색을보이는빈도가의미있게높았다 (p<0.001)(table 1). 확산관류불일치가있는군에서심근경색과심방세동의빈도가높았으나통계적의의는없었다. 또한확산관류불일치가있는군에서 rcbv 값이상대적으로적었고, territorial infarction 과대동맥병 (large artery disease)( 동측의중간대뇌동맥협착 or 내경동맥협착 ) 의빈도가높았으나역시통계적의의는없었다. 그러나자기공명영상을촬영한시간이나임상적진행의정도는양군에서유의한차이가없었다. 확산관류불일치가없는군에서는 38명중 4명 (11%) 이, 확산관류불일치가있는군에서는 19명중 5명 (26%) 이임상적으로악화를보여, 불일치군에서그빈도가더높았으나통계적의의는없었다 (p=0.143). 불일치가있음에도진행되지않은군과진행된군을비교해본결과임상적으로진행한군에서는 5예모두에서고혈압이있었으며 (p=0.047), rcbv 의값이 62.9±24.7% 로그렇지않은군에비해의미있게감소하였다 (p=0.007). 그러나 TTP 지연정도와중간대뇌동맥협착의정도는두군간에의미있는차이를보이지않았다 (Table 2). 고찰 급성기뇌경색에서허혈성경계영역의존재는일반적으로시간의존적이다. 이전의보고들에의하면뇌경색발생후 9시간까지는 50% 의환자에서, 5-18 시간까지도 1/3 의환자에서허혈성경계영역의존재가확인되었다. 18-20 본연구에서도급성기중간대뇌동맥경색환자의 33.3% 에서그존재를확인할수있어상당수의환자들은일반적인중재시술의가능시간인 6시간이후에도치료가가능할것으로생각된다. 그러나일반적으로허혈성경계영역으로생각되는자기공명영상의확산관류불일치의문제점들이최근들어몇몇연구들에서보고되고있다. 11,14 그중에서도일반적으로중재적시술로재생될수없는허혈조직으로인지되던 MRI 상의확산강조영상의병변도적극적인혈관의재관류를통해정상화가가능하다는보고들은, 21-22 이병변이꼭치료가불가능한 (ischemic core) 것만은아니며, 허혈성경계영역이일부포함되어있을것이라는추론을가능하게한다. TTP 혹은 MTT 등의시간의존적인관류결손영상은치료를긴급하게요하는허혈성경계영역뿐아니라단순한혈류부족에의한 benign oligemia 를포함하는경우도많을것이다. 특히이러한문제는경동맥혈관폐색이있는환자들에서자기공명영상상의확산관류불일치를나타내는빈도가그렇지않은환자 Table 1. Comparison of clinical and radiological characteristics between DPM group and non-dpm group. Non-DPM (n=38) DPM (n=19) p-value Male (%) 21 (55%) 13 (68%) 0.401 Age, years 62.8±12.4 63.6±12.9 0.823 HT (%) 24 (63%) 12 (63%) 1 DM (%) 7 (18%) 3 (16%) 0.83 Smoking (%) 8 (21%) 10 (53%) 0.032 MI (%) 1 (3%) 1 (5%) 1 AF (%) 4 (11%) 3 (16%) 0.675 MR time, min 848.7±538.8 933±517.6 0.575 TTP-D, sec 3.1±3.7 6.9±1.9 <0.001 rcbv (%) 97±29.9 87.4±25 0.232 Territorial (%) 11 (29%) 7 (37%) 0.56 LAD (%) 26 (68%) 15 (79%) 0.537 MCA stenosis, n (%) 14 (37%) 8 (42%) 0.700 Severe stenosis (%) 5 (36%) 8 (100%) <0.001 Progression (%) 4 (11%) 5 (26%) 0.143 DPM; diffusion-perfusion mismatch, HT; hypertension, DM; diabetes mellitus, MI; myocardial infarction, AF; atrial fibrillation, MR time; time to MR imaging after stroke onset, TTP-d; time to peak delay, Territorial; territorial infarction, LAD; large arterial disease (ICA, MCA), Severe stenosis; grade of stenosis in MCA Ⅲ or Ⅳ, Progression; 4 points increase of NIHSS score in 5 days or 1 point increase of mrs score in 30 days. 298 대한신경과학회지제 26 권제 4 호, 2008
급성기뇌경색환자에서뇌자기공명영상의확산 - 관류불일치가임상적예후를예측할수있는가? 들에비해월등히높으나, 이경우실제허혈성병변의악화로연결되는빈도는의미있는차이를보이지않아위양성의경향을보이는경우가많다고알려져있다. 23 본연구결과에서도증상발현후 24 시간이내의급성기중간대뇌동맥경색환자들중허혈성경계영역으로간주되는 MRI 상확산관류불일치를보이는군에서는 TTP 지연은의미있게차이가났으나, 그렇지않은군에비해관찰기간 30일이내에임상적악화를보이는빈도는통계적의의가없었다. 이는이전에제시된현재의 MRI 관류영상의문제점, 즉실제보다과장해서허혈성경계영역을나타낼가능성이있다는보고와도일치한다. 14 본연구에서는확산관류불일치를보이는환자중임상적으로악화를보이는군 (clinical progression group) 과그렇지않은군 (non-progression group) 사이에건측과의 rcbv 값을비교해본결과임상적으로악화를보이는군에서의미있는감소를보였다. TTP 가혈류가목표지점에도착하는시간적개념임에비해, rcbv 는목표에들어오는전체적인혈액량을측정하는개념으로일반적으로측부순환정도에따라영향을많이받으며, 최종뇌경색크기의예측에가장좋은방법이다. 15,16,24 그러므로급성기뇌경색환자들에서자기공명영상의관류영상중단순히혈액의도달시간을기준으로잡는 TTP 의경우혈관폐색의정도가민감하게반영되나, 20 임상적악화나혹은뇌경색의확대와밀접하게연관된측부순환에대한정보를반영하지못하므로실제환자의상태보다과장해서나오는것으로알려져있다. 14 그래서본연구에서처럼관류영상의분석에있어시간개념인 TTP 뿐만아니라, 양적개념인 rcbv 를같이분석한다면진단의정확도를높일수있으리라고생각된다. 특히최근들어자기공명영상의관류영상분석방법들중 rcbv 에기초한분석이뇌경색의크기와임상적예후에대한가장정확한정보 를제공한다는이전의보고들은저자들의주장을뒷받침한다. 15,16 자기공명영상의확산관류불일치는이제까지급성기뇌경색환자들에서의예후의변화와정맥내 t-pa 사용에있어중요한시금석으로사용되어졌다. 그러나최근보고된확산관류불일치에대한메타분석의부정적인결과와증상발현후 3시간이지난환자에서자기공명영상의확산관류불일치를이용한정맥내재개통을전향적으로연구한 DIAS-II 의실패는아직까지확산관류불일치, 특히 TTP 를기준으로한영상들에서그진단적가치를높이기위해서는방법적개선이요구되며이에대한방법중의하나가 TTP 뿐만아니라 rcbv 를같이분석하는방법이라고생각한다. 본연구의결과들은다음과같이정리할수있다. 첫째, 증상발현후 24시간이내의급성기중간대뇌동맥경색환자의 33.3% 에서허혈성경계영역으로생각되는자기공명영상의확산관류불일치가발견되었다. 둘째, 24시간이내의급성기뇌경색환자들에서확산관류불일치를보이는경우고도의중간대뇌동맥협착을보이는빈도가불일치가없는환자들에비해높았으나내원후 30일동안의임상적악화를보이는빈도에서는유의한차이가없었다. 마지막으로불일치가있는환자들에서임상적으로진행된군에서는그렇지않은군에비해서뚜렷한 rcbv 의감소를보였다. 본연구는의미있는결과를몇가지보여주었지만그와동시에향후개선이필요한부분도있었다. 첫째로연구가후향적이며급성기환자를대상으로하였기에관류영상을얻지못하는경우가많아서대상환자가적다는것이고, 둘째로임상적예후의변화만보았을뿐자기공명영상의뇌경색의변화를보지못했다는것이다. 향후이를개선하는전향적연구를통해 Table 2. Comparison of clinical and radiological characteristics between clinical progression group and non-progression group Non-progression group (n=14) Progression group (n=5) p-value Male (%) 11 (79%) 2 (40%) 0.262 Age, years 61.5±13.9 69.6±7.4 0.237 HT (%) 7 (50%) 5 (100%) 0.047 DM (%) 1 (7%) 2 (40%) 0.155 Smoking, n (%) 9 (64%) 1 (20%) 0.141 MI (%) 1 (7%) 0 (0%) 1 AF (%) 2 (14%) 1 (20%) 0.764 MR time, min 977.9±504.7 807.2±592.4 0.542 TTP-D, sec 6.6±1.6 7.9±2.6 0.183 rcbv (%) 96.1±19.2 62.9±24.7 0.007 Territorial (%) 4 (29%) 3 (60%) 0.305 LAD (%) 11 (79%) 4 (80%) 0.946 MCA stenosis (%) 6 (43%) 2 (40%) 0.912 Severe stenosis (%) 6 (100%) 2 (100%) 1 Abbreviations as in table 1. J Korean Neurol Assoc Volume 26 No. 4, 2008 299
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Diffusion- and perfusion-weighted MRI: influence of severe carotid artery stenosis on the DWI/PWI mismatch in acute stroke. Stroke 2000;31:1311-1317. 24. Richard E. The roles of diffusion and perfusion MR imaging in acute stroke management. Am J Neuroradiol 1999;20:957-959. 300 대한신경과학회지제 26 권제 4 호, 2008