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1 원저접수번호 :09-029(2 차 -0710) 급성허혈뇌경색에서액체감쇠역전회복영상변화에소혈관질환의세가지징후가미치는영향에대한환자 - 대조군연구 서울대학교의과대학분당서울대병원뇌졸중센터신경과, 영상의학과 a 김도형강지훈김나영노원영장민욱김범준한문구정철규 a 최병세 a 김재형 a 배희준 Influence of 3 Stigmas of Small Vessel Disease on FLAIR Change in Acute Ischemic Stroke: Case-Control Study Dohoung Kim, MD, Jihoon Kang, MD, Nayoung Kim, MD, Won-Young Noh, MD, Min Uk Jang, MD, Beom Joon Kim, MD, Moon-Ku Han, MD, Cheolkyu Jung, MD a, Byung Se Choi, MD a, Jae Hyoung Kim, MD a, Hee-Joon Bae, MD Department of Neurology, Seoul National University Bundang Hospital Stroke Center, Seoul National University College of Medicine, Seongnam, Korea Department of Radiology a, Seoul National University Bundang Hospital Stroke Center, Seoul National University College of Medicine, Seongnam, Korea Background: Attempts have been made to use the signal changes of fluid-attenuated inversion recovery (FLAIR) MRI as "a tissue clock," defined as a surrogate marker of the tissue damage resulting from acute ischemic stroke. The evolution of FLAIR signals after stroke onset has never been fully explained solely by time. The aim of this study was to determine whether cerebral small-vessel disease (SVD) affects FLAIR changes following acute ischemic stroke. Methods: Based on data from a prospective stroke registry, consecutive patients who were hospitalized to the stroke center within 12 hours of stroke onset between January 2004 and May 2011 and had occlusion of the major cerebral arteries in the anterior circulation, as evidenced by MR angiography, were enrolled. Cases with FLAIR changes and controls without FLAIR changes were matched according to the time elapsed from stroke onset to MR study. Results: Among the 130 patients who met the eligibility criteria, 62 (47.7%) had FLAIR changes. The time interval between stroke onset and MR study differed significantly between those with and without FLAIR changes (5.2 hours vs. 3.0 hours). FLAIR changes were more common among males and smokers. Comparisons between cases and controls matched on a one-to-one basis did not reveal any difference in the three signs of cerebral SVD: white-matter hyperintensities, lacunae, and cerebral microbleeds. Conclusions: This study failed to find any data supporting the hypothesis that cerebral SVD affects FLAIR changes after acute ischemic stroke. J Korean Neurol Assoc 31(3): , 2013 Key Words: Acute stroke, Fluid attenuated inversion recovery, Small-vessel disease Received March 4, 2013 Revised May 28, 2013 Accepted May 28, 2013 *Hee-Joon Bae, MD Department of Neurology, Seoul National University Bundang Hospital Stroke Center, Seoul National University College of Medicine, 82 Gumi-ro 173 beon-gil, Bundang-gu, Seongnam , Korea Tel: Fax: braindoc@snu.ac.kr 서론 재조합조직플라스미노겐활성제 (recombinant tissue plasminogen activator) 를이용한정맥내혈전용해요법은급성뇌경색환자의기본치료로인정받고있다. 1 그러나치료적응증이증상발생으로부터경과한시간을기반으로하고있어서소수의환자에게제한적으로사용되고있다. 2 특히뇌졸중환자의 25% J Korean Neurol Assoc Volume 31 No. 3,

2 김도형강지훈김나영노원영장민욱김범준한문구정철규최병세김재형배희준 에해당하는, 자고일어나서증상이발견되어정확한증상발생시각을알수없는환자의경우정맥내혈전용해치료를받지못한다. 3 이를극복하기위해액체감쇠역전회복 (fluid attenuated inversion recovery, FLAIR) 영상을이용하여뇌졸중발생으로부터경과한시간을예측하는조직시계 (tissue clock) 로 FLAIR 변화를확인하려는노력이있었다. 4-7 뇌경색부위에서발생하는 FLAIR 변화는혈관부종을반영하는표지자로허혈뇌손상의정도를평가하는데사용할수있다. 8 그러나 FLAIR 변화가나타나기시작하는시점이비교적넓은시간대에분포하여개개인의편차가크고시간하나만으로 FLAIR 변화를설명하기에도한계가있다. 따라서발생시각이명확하지않은뇌경색환자에서 FLAIR 변화를조직시계로사용하기위하여는, FLAIR 변화에관여하는변인을추가로밝히는것이중요하다고할수있다. 소혈관질환 (small vessel disease) 은일반적으로뇌의백질에발생하는불완전한허혈병변으로생각한다. 9,10 소혈관질환은뇌의관류상태와깊은관련이있으며 11,12 관류예비능이떨어져있음이알려져있다. 13,14 따라서소혈관질환이있는조직에뇌경색이발생한경우, 신경세포손상속도가더욱빠를가능성이있다. 본연구는발병 12시간이내의급성뇌경색에서뇌졸중발생부터경과한시간을짝지은상태에서 FLAIR 변화가있는환자군과없는대조군사이에소혈관질환을비교함으로써시간이외에소혈관질환이 FLAIR 변화에관여하는지를알아보려한다. 뇌병변내에위치하여 FLAIR 변화유무를확인할수없는경우, 영상화질이불량하여판독할수없는경우는연구에서제외하였다. 2. 방법 MRI는 1.5 테슬라 (tesla) 강도이상의장비 (Intera, Philips Medical Systems) 를사용하여 DWI, FLAIR, 기울기에코영상 (gradient echo imaging, GRE), 조영증강 T1 강조영상, 관류강조영상 (perfusion-weighted imaging, PWI) 과삼차원시간지연측정 (3D time-of-flight) MRA를촬영하였다. 상술한기준을만족하는환자에게내원후첫번째얻은 MRI를검토하여 FLAIR 변화의유무를판정하였다 (Fig. 1). 5,7,15 이를위해두명의신경과의사 ( 김도형, 강지훈 ) 가임상정보를모르는상태에서판정하였다. 판독을위하여창너비 (window width) 와창수준 (window level) 은자유롭게조절할수있도록하였으며예비분석을통해판독과정에숙달된후에연구를진행하였다. 4 DWI에서보이는급성허혈뇌병변영역내에서 FLAIR 변화유무를판정하였고두명의의견이일치하지않는경우에는다른연구자 ( 배희준 ) 와같이영상을판독하여변화유무를결정하였다. 소혈관질환의세가지징후 ( 백질변성, 미세출혈, 열공뇌경 A B 대상과방법 1. 대상 2004년 1월부터 2011년 5월 31일까지분당서울대학교병원신경과에입원하여분당서울대학교병원뇌졸중등록체계에등록된환자중 1) 최종진단이뇌경색이고 2) 발생시각이명확하며 3) 증상발생시간 12시간이내에뇌자기공명영상 (magnetic resonance imaging, MRI) 검사를하였고 4) 뇌자기공명혈관촬영 (magnetic resonance angiography, MRA) 에서내경동맥혹은중대뇌동맥부위에폐색이있으며 5) 동일한영역에확산강조영상 (diffusion-weighted imaging, DWI) 에서급성병변이발견된환자를대상으로하였다. DWI, FLAIR, 혹은 MRA 영상이없는경우, 뇌경색의크기가작아 (<1.5 cm) 열공뇌졸중에해당되는경우, FLAIR나 DWI 신호강도가달라발생시각이다를것으로추정되는병변이동시에보이는경우, DWI에서보이는뇌경색영역이백질변성또는과거의 Figure 1. Representative image of FLAIR change over time. Upper row: diffusion-weighted imaging, lower row: FLAIR imaging. (A) No FLAIR change is seen in the first hour of stroke onset. (B) Follow-up MRI shows obvious FLAIR change in the diffusion restriction area. 166 대한신경과학회지제 31 권제 3 호, 2013

3 급성뇌경색의액체감쇠역전회복영상변화에소혈관질환이미치는영향 색 ) 9,16 에대해서한명의연구자 ( 김도형 ) 가임상적인정보와 FLAIR 변화유무에대해서는모르는상태를유지하면서평가를시행하였다. 백질변성에대해서는 Fazekas 등 17 이제시한방법을따라정상 (absent, 등급 [grade] 0), 점병터 (punctate foci, 등급 1), 초기융합병터 (beginning confluence of foci, 등급 2), 큰융합병터 (large confluent areas, 등급 3) 로구분하고등급 2 이상인경우양성으로판정하였다. 미세출혈은 GRE에서 5 mm 이하크기의신호가소실된병변으로정의하였고이것의유무와개수를조사하였다. 18,19 열공뇌경색은 FLAIR 혹은 T1 강조영상에서뇌척수액과같은신호강도를보이는 3 mm 이 상의병변으로정의하여유무와개수를측정하였다. 20 관류결손영역은 DWI에서보이는병변을포함하는영역중최고농도시간 (time to peak, TTP) 의지연을보이는영역으로정의하였으며 21 가로면에서가장넓은결손영역을보이는절편에서결손영역의가장큰직경을측정하고이와직교하는직경을구한후결손영역의사진수를구하여수직직경을계산하고구한세직경을모두곱한다음 2로나누어결손영역의부피를구하였다. 22 혈관폐색여부는 MRA를확인하여총경동맥, 두개외내경동맥, 두개내내경동맥, 중대뇌동맥, 전대뇌동맥, 후대뇌동맥, 뇌 Table 1. Comparisons of clinical and neuroradiological characteristics according to FLAIR change All FLAIR negative FLAIR positive n=130 n=68 n=62 p value Age (yr) 67.5± ± ± Male sex 76 (58.5) 32 (47.1) 44 (71.0) <0.01 Admission NIHSS 14.9± ± ± Time to MRI (hr) 4.0± ± ±2.5 <0.01 Risk factors History of prior TIA 3 (2.3) 0 (0) 3 (4.8) 0.11 History of prior stroke 21 (16.2) 11 (16.2) 10 (16.1) 0.99 Hypertension 65 (50.0) 38 (55.9) 27 (43.5) 0.16 Diabetes 33 (25.4) 16 (23.5) 17 (27.4) 0.61 Dyslipidemia 17 (13.1) 8 (11.8) 9 (14.5) 0.64 Smoking 45 (34.6) 17 (25.0) 28 (45.2) 0.02 Atrial fibrillation 72 (58.1) 46 (69.7) 26 (44.8) <0.01 TOAST Classification 0.02 Large artery atherosclerosis 37 (28.5) 16 (23.5) 21 (33.9) Cardioembolism 67 (51.5) 43 (63.2) 24 (38.7) Other determined 1 (0.8) 0 (0) 1 (1.6) Undetermined 25 (19.2) 9 (13.2) 16 (25.8) Small vessel disease Presence of lacunes 21 (16.2) 8 (11.8) 13 (21.0) 0.15 No. of lacunes 0.37± ± ± Presence of microbleeds 19 (15.1) 11 (16.4) 8 (13.6) 0.66 No. of microbleeds 0.56± ± ± Leukoaraiosis 0.26 Grade I 50 (39.7) 27 (40.03) 23 (39.0) Grade II 19 (15.1) 9 (13.4) 10 (16.9) Grade III 14 (11.1) 6 (9.0) 8 (13.6) Vessel status Proximal ICA occlusion 40 (30.8) 19 (27.9) 21 (33.9) 0.46 Distal ICA occlusion 3 (2.3) 2 (2.9) 1 (1.6) 1.00 M1 occlusion 58 (44.6) 35 (51.5) 23 (37.1) 0.10 M2 occlusion 29 (22.3) 12 (17.6) 17 (27.4) 0.18 Treatment Thrombolysis 76 (58.9) 50 (73.5) 26 (42.6) <0.01 Outcome Discharge mrs 4 (2 5) 4 (1 5) 5 (3 5) 0.05 Values are means±sd, median (IQR) or Nos. of patients (percentage). p values were obtained using the Pearson s χ 2 test or Mantel-Haenszel χ 2 for trends for categorical data and Student's t-test for continuous data. FLAIR; fluid attenuated inversion recovery, NIHSS; National Institutes of Health Stroke Scale, MRI; magnetic resonance imaging, TIA; transient ischemic attack, TOAST; Trial of ORG in Acute Stroke Treatment, ICA; internal carotid artery, mrs; modified Rankin scale. J Korean Neurol Assoc Volume 31 No. 3,

4 김도형강지훈김나영노원영장민욱김범준한문구정철규최병세김재형배희준 기저동맥, 척추동맥으로구분하여기록하였다. 뇌졸중등록체계 23 와의무기록검토로나이, 성별, 고혈압, 당뇨병, 고지혈증, 흡연, 뇌졸중의과거력, 심장성색전증의원인질환, 입원시혈압과 NIH뇌졸중척도 (National Institute of Health Stroke Scale, NIHSS) 와혈전용해술, 항혈소판제, 항응고제투약여부, 뇌경색의아형 (TOAST 분류 ) 24 등임상정보를수집하였다. 3. 통계분석연구포함과제외기준에맞는환자에대해 FLAIR 변화유무 로구분하여양군사이에임상적인특성과소혈관질환을포함하는뇌영상관련변수의차이를분석하였다 (Table 1). 범주형변수에대해서는 Pearson s χ 2 test나 Mantel-Haenszel χ 2 for trends를사용하였고연속변수에대해서는 Student's t test를적용하였다. 소혈관질환이 FLAIR 변화에미치는영향을조사하는데있어발병부터경과한시간이미치는영향을통제하기위해서환자군 (FLAIR 변화가관찰되는경우 ) 과대조군 (FLAIR 변화가관찰되지않는경우 ) 으로구분한다음, 증상발생으로부터 MRI 촬영까지소요된시간을조사하여환자군과대조군짝사이의시차가한시간미만이되도록 1:1로짝을지었다. 이후양군간의임상적특징과뇌영상변수의차이의비교를 Table 2. Comparisons of clinical and neuroradiological characteristics between the case and control groups (matched) All Controls Cases n=74 n=37 n=37 p value Age (yr) 65.2± ± ± Male sex 46 (62.2) 19 (51.4) 27 (73.0) 0.15 Admission NIHSS 14.3± ± ± Risk factors History of prior TIA 3 (4.1) 0 (0) 3 (8.1) NA History of prior stroke 11 (14.9) 6 (16.7) 5 (13.9) 1.00 Hypertension 34 (45.9) 21 (58.3) 13 (36.1) 0.13 Diabetes 14 (18.9) 6 (16.7) 8 (22.2) 0.79 Dyslipidemia 11 (14.9) 5 (13.9) 6 (16.7) 1.00 Smoking 31 (41.9) 11 (30.6) 19 (52.8) 0.09 Atrial fibrillation 18 (24.3) 14 (38.9) 4 (11.1) 0.02 TOAST classification Large artery atherosclerosis 21 (28.4) 10 (27.0) 11 (29.7) 1.00 Cardioembolism 34 (45.9) 23 (62.2) 11 (29.7) 0.01 Other determined 1 (1.4) 0 (0) 1 (1.4) Undetermined 18 (24.3) 4 (10.8) 14 (37.8) Small vessel disease Presence of lacunes 13 (18.1) 5 (13.5) 8 (21.6) 0.55 No. of lacunes 0.38± ± ± Microbleeds 9 (12.2) 7 (18.9) 2 (5.4) 0.18 No. of microbleeds 0.52± ± ± Leukoaraiosis ( Grade II) 14 (18.9) 19 (51.4) 24 (64.9) 0.36 Perfusion status Perfusion defect 58 (84.0) 30 (93.8) 28 (87.5) 0.69 Perfusion defect size 99.1± ± ± Vessel status Proximal ICA occlusion 24 (32.4) 12 (32.4) 12 (32.4) 1.00 Distal ICA occlusion 2 (2.7) 1 (2.7) 1 (2.7) 1.00 M1 occlusion 31 (41.9) 14 (37.8) 17 (45.9) 0.63 M2 occlusion 17 (23.0) 7 (18.9) 10 (27.0) 0.58 Treatment Thrombolysis 47 (63.5) 24 (64.9) 23 (62.2) 1.00 Outcome Discharge mrs 4.0 ( ) 4.0 ( ) 4.0 ( ) 0.54 Values are means±sd or Nos. of patients (percentage). p values were obtained using the McNemar test for categorical data and paired t-test for continuous data. NIHSS; National Institutes of Health Stroke Scale, TIA; transient ischemic attack, TOAST; Trial of ORG in Acute Stroke Treatment, ICA; internal carotid artery, mrs; modified Rankin scale. 168 대한신경과학회지제 31 권제 3 호, 2013

급성뇌경색의액체감쇠역전회복영상변화에소혈관질환이미치는영향 위하여분석대상변수의특성에따라연속변수인경우 paired t-test, 범주형인경우 McNemar test를하였다 (Table 2). 양군간차이를보이는특성중교란요인으로파악되는변수의효과를통제하기위하여다변량분석방법인 conditional logistic regression을하였다. 이때단변량분석에서 p<0.

5 급성뇌경색의액체감쇠역전회복영상변화에소혈관질환이미치는영향 위하여분석대상변수의특성에따라연속변수인경우 paired t-test, 범주형인경우 McNemar test를하였다 (Table 2). 양군간차이를보이는특성중교란요인으로파악되는변수의효과를통제하기위하여다변량분석방법인 conditional logistic regression을하였다. 이때단변량분석에서 p<0.1인인자와임상적으로의미있는인자를선택하였고이들인자와소혈관질환의세가지징후중하나를포함하는회귀모형을만들어교란변수를통제한상태에서소혈관질환의각징후가 FLAIR 변화에미치는영향을검증하였다. 첫번째와두번째모델은소혈관질환의징후와단변량분석에서 p<0.1인인자를순서대로추가하였으며세번째모델은앞모델에서투입된인자에뇌졸중의악화에기여하는인자를추가하였다. 25,26 모든통계학적분석은 SPSS 18.0 (SPSS Inc., Chicago, USA) 을사용하였으며모든검정은양측성으로유의수준은 0.05 미만인경우로정의하였다. 연구에필요한표본수를추정하기위하여 G*Power (Universität Kiel, Germany) 를사용하였다. 이전뇌졸중환자를대상으로한연구에서백질변성은 44%, 27 열공뇌경색은 8.8%, 미세출혈은 24% 에서보였다. 28 그러나이전소혈관질환과 FLAIR 변화유무의관계에관한연구가없어 FLAIR 변화에미치는소혈관질환의교차비 (odds ratio, OR) 를 3으로가정하였다. 비일치쌍 (discordant pair) 의비율은 0.5, 유의수준 0.05 인 McNemar 검정에서 80% 의검정력확보를위해필요한대상수는 60명이었다. Figure 2. Patient screening and enrollment. 결 과 연구기간동안연구포함기준에맞는내경동맥혹은중대뇌동맥폐색환자는모두 246명이었다. 이중뇌경색병변이 1.5 cm 이하로열공뇌경색에해당하는경우 (n=85), 다른시기의다발성병변이있는경우 (n=22), 이전뇌병변부위에뇌경색이발생한경우 (n=7), 영상의질이좋지않은경우 (n=2) 를제외한 130명을최종분석하였다 (Fig. 2). 두판독자간의일치도는 94% 이었다 (κ=0.88). 이중 FLAIR 변화가보이지않은환자는 68명 (52.3%), FLAIR 변화가있는환자는 62명 (47.7%) 이었다. 증상발생으로부터시간이경과할수록 FLAIR 변화양성인환자의비율이증가하였으며 (Fig. 3), MRI 촬영까지의시간은 FLAIR 변화가없는경우평균 2.6시간, 있는경우 4.8시간으로유의한차이가있었다 (Table 1). FLAIR 변화양성인군에서남성의비율이더높았으며 (47.1% 대 71.0%), 흡연자의비율도높았다 (25.0% 대 45.2%). 입원시 NIH뇌졸중척도에는유의한차이 Figure 3. FLAIR change according to MR time from initial onset. 가없었으며, 고혈압, 당뇨병, 고지혈증, 뇌졸중의과거력도양군간에차이가없었다. 짝짓기전소혈관질환의세가지징후중백질변성의정도가 FLAIR 변화양성인군에서유의하게많았다. 짝짓기후환자 74명과대조군을비교하였을때심장성색전증의위험인자가대조군에서더많았던것을제외하고임상요인에유의한차이는없었다 (Table 2). 소혈관질환의세가지징후인백질변성유무나정도, 미세동맥출혈의유무와개수나열공뇌경색또한양군간에차이가없었고기타뇌영상관련변수도의미있는차이가없었다 (Table 2). 소혈관질환의세가지징후각각에대해잠재적교란변수를 J Korean Neurol Assoc Volume 31 No. 3,

6 김도형강지훈김나영노원영장민욱김범준한문구정철규최병세김재형배희준 Table 3. Multivariate conditional logistic regression analysis for small vessel disease Unadjusted OR Model 1 Model 2 Model 3 Leukoaraiosis 1.20 ( ) 1.10 ( ) 1.08 ( ) 1.96 ( ) Cardioembolism 0.29 ( ) 0.40 ( ) 0.32 ( ) Smoking 1.55 ( ) 1.81 ( ) Age 1.01 ( ) Perfusion defect size 1.00 ( ) Admission NIHSS 0.89 ( ) Lacunes 1.75 ( ) 1.79 ( ) 1.75 ( ) 1.97 ( ) Cardioembolism 0.25 ( ) 0.27 ( ) 0.18 ( ) Smoking 1.13 ( ) 1.18 ( ) Age 1.01 ( ) Perfusion defect size 1.01 ( ) Admission NIHSS 0.92 ( ) Cerebral microbleeds 0.40 ( ) 0.49 ( ) 0.49 ( ) 0.33 ( ) Cardioembolism 0.30 ( ) 0.42 ( ) 0.33 ( ) Smoking 1.54 ( ) 1.63 ( ) Age 1.03 ( ) Perfusion defect size 1.00 ( ) Admission NIHSS 0.89 ( ) The ORs for lacunar infarcts and cerebral microbleeds (0 = subjects with no infarct or microbleeds; 1 = subjects with infarcts or microbleeds more than one) were calculated using a multiple conditional logistic regression analysis. The ORs for moderate leukoaraiosis (0 = grades 0 and 1 on Fazekas scale; 1 = grades 2 and 3 on Fazekas scale) were also examined. Model 1: adjusted for cardioembolic stroke subtype. Model 2: adjusted for cardioembolic stroke subtype and smoking. Model 3: adjusted for cardioembolic stroke subtype, smoking, age, perfusion defect size, and admission NIHSS. OR; odds ratio, NIHSS; National Institutes of Health Stroke Scale. 통제한다변량분석에서도유의한결과는보이지않았으나 model 1에서는심장성색전증위험인자가유의하게 FLAIR 변화의보호인자로나왔으나다른임상요인을추가투입한 model 2, 3에서는의미가없었다 (Table 3). 고찰 환자- 대조군연구를통하여소혈관질환이 FLAIR 변화에관여하는지를알아보고자하였다. 즉뇌경색발생직후시간의경과에따라 FLAIR 변화가나타나는속도가소혈관질환의유무에따라차이가있는지를알아본결과유의한차이가없었다. 이는나이, NIH뇌졸중척도의중증도, 관류결손영역같은다양한교란변수를통제하기전과후모두같은결과를보였다. 따라서소혈관질환은급성뇌경색초기에발생하는 FLAIR 변화와는관련이없다는결론을내릴수있다. 그러나표본수가적어서통계검정력이낮아유의한결과가나오지않았을가능성도있다. 뇌졸중환자에서 FLAIR 신호강도가뇌졸중발생후수시간에걸쳐서서히변하는특성을이용하여뇌졸중발생시간을역으로유추하고자하는노력이있어왔다. Thomalla 등 7 은급성뇌졸중환자에서 DWI 양성이면서 FLAIR가음성인환자가발생 3시간이내에 93% 의특이도와 94% 의양성예측도 를보임을보고하였다. 이후연구에서도 DWI이양성이고 FLAIR가음성인경우 4.5시간내에서특이도가 96% 임을보고하였다. 5 그러나 Ebinger 등 6 은 4.5시간내의 FLAIR가음성인환자의민감도가 46%, 특이도가 79% 로 FLAIR 변화만으로발생시각을정확히예측하기에는부족하다는결론을내렸다. 이와같은결과를볼때아직까지 FLAIR가정확한뇌졸중발생시간에대한정보를제공하기에는불충분하다. 이번연구에서도 FLAIR 변화가없는환자는대부분발생시간이 6시간이내에분포하였으며 FLAIR 변화가뇌졸중이발생한지 2 시간안에있는환자도있었다. 이연구의장점은 FLAIR 변화에가장큰영향을미치는시간변수를통제하기위하여환자군과대조군간에증상부터 MRI를촬영까지걸린시간이일치하도록짝짓기를하였다는점이다. Fig. 3에서보듯이증상발생 1.5시간이내에 MRI 검사를한경우에는 FLAIR 변화가전혀없었고그이후에는 FLAIR 변화가있는비율이점점증가하다가 7.5시간이후에는대부분에서 FLAIR 변화를보였다. 즉, 시간이 FLAIR 변화에가장중요한변수이므로그외에영향을미치는변수를찾아내기위해서는시간의영향을통제할필요가있으며추후 FLAIR 변화를이용하여뇌경색발생시각을정확하게추정하기위해서는이러한요인을밝혀내는것이필요하다. 이전연구에서 FLAIR 변화가있는군과없는군을비교하는경우가있었으나시간을통제하여분석한 170 대한신경과학회지제 31 권제 3 호, 2013

7 급성뇌경색의액체감쇠역전회복영상변화에소혈관질환이미치는영향 연구는없었으며시간이외의다른변수에관한연구도없었다. 4-7 다른장점으로는관류상태나뇌경색크기같은차이를최소화하기위하여내경동맥혹은중대뇌동맥폐색이있고동일부위에뇌경색이발생한환자만을대상으로하여연구를하였다는점이다. 대부분의기존연구에서는뇌경색의원인이나위치, 크기를구분하지않고 FLAIR 변화의유무를분석하였다. 저자들이이러한방식을적용하여 FLAIR 변화의유무를판단하였을때뇌경색위치가피질또는피질하에있는지에따라크기나 DWI에서병변강도에따라판독의기준이달라질수가있어판정에어려움이있었다. 15 따라서이러한요인에따른판독의혼란을최소화하기위하여저자들은비교적동일한부위에뇌경색이발생하였고혈관폐색에의하여뇌관류상태가유사한환자만을분석대상으로한정하였다. 그리고후순환계는전순환계에비하여백질이상대적으로많고곁순환이풍부하여뇌허혈에대한반응이다를가능성이있어이부위에서발생한뇌경색은제외하였다. 29 또한경증열공뇌경색환자보다는큰동맥폐쇄로인한중증뇌경색환자에서정맥내혹은동맥내혈전용해요법을고려하는경우가많고이때 FLAIR 변화유무가치료여부를결정하는데영향을미칠수있으므로 30,31 연구대상을이와같이제한하였다. 이연구에는몇가지문제점이있다. 첫째, 표본수가가설을증명하기에부족하다. 2004년부터 2011년까지비교적긴시간동안환자를모집하였지만이중증상발생이 12시간이내이면서발생시점이명확하고전순환계폐색이있는경우로제한을하였을때 246명만이대상에포함되었다. 통계검정력이약화되었을가능성이있다. 둘째, 소혈관질환이 FLAIR 변화의판정에도영향을미쳤을가능성이있다. 소혈관질환이심한경우 FLAIR 변화가있더라도신호를발견하지못하여대조군으로배정되고반대로소혈관질환이없는경우에는 FLAIR 변화를알아내기가더쉬워서환자군으로배정될수있다. 이는소동맥질환이있는경우 FLAIR 변화가빨리올것이라는가설에반대되는결과를가져올수있다. 저자들은이러한상호작용을최소화하기위하여소혈관질환이심한경우는연구대상에서제외하였으나이렇게제외된환자에서 FLAIR 변화가더심하였기때문에의미있는결과를얻지못하였을수도있다. 셋째, FLAIR 변화의역치를정하여이분법으로구분하는방법자체에한계가있을수있다. 기존의연구는 FLAIR 변화정도를두, 세명의연구자가의견일치를보이는것으로평가하거나 4,7,30 FLAIR 변화를연속변수로측정하였다. 6,15 후자의방법은수기로뇌경색영역을표시해야하는임상적용의어 려움이있고전자에비하여민감도가떨어진다는연구결과가있어 32 본연구에서는전문가의판단에따라 FLAIR 변화의유무를결정하였다. 그러나뇌허혈상태에서 FLAIR 신호강도는시간이지나면증가한다. 15 따라서실제로는역치사이에서강도차이가크지않아도이를환자군과대조군으로이분하여짝짓기함에따라원하는결론을얻지못할수있다. 넷째, 뇌허혈과관계된모든인자를고려하지않았다. 전순환계폐색이있는환자만포함하여관류상태가비교적동일한군을모으고, 관류결손영역의크기도다변량분석에서통제를하였으나시각평가에의한분석을하였기때문에한계가있다. 또한 DWI에서뇌경색의크기나현성확산계수 (apparent diffusion coefficient) 가 FLAIR 신호강도에도영향을미칠가능성이있으며뇌조직생존에필요한포도당, 혈압, 혈색소, 산소포화도같은인자도고려했어야한다. 이연구에서는이러한인자를모두포함하기에는표본수가충분하지않았기때문에분석에포함하지못했다. 결론적으로본연구에서는급성뇌경색환자에서소혈관질환의유무와 FLAIR 변화와는관계가없었다. 추후 FLAIR 변화에영향을주는요인을규명하는연구를통하여뇌졸중의발생시각을더정확하게추정할수있다면임상적으로뇌경색발생시각을알지못하더라도안전하게혈전용해요법으로치료할수있을것이다. REFERENCES 1. Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-pa Stroke Study Group. N Engl J Med 1995;333: Fink JN, Kumar S, Horkan C, Linfante I, Selim MH, Caplan LR, et al. The stroke patient who woke up: Clinical and radiological features, including diffusion and perfusion MRI. Stroke 2002;33: Chaturvedi S, Adams HP Jr, Woolson RF. Circadian variation in ischemic stroke subtypes. Stroke 1999;30: Thomalla G, Rossbach P, Rosenkranz M, Siemonsen S, Krutzelmann A, Fiehler J, et al. Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less. Ann Neurol 2009;65: Aoki J, Kimura K, Iguchi Y, Shibazaki K, Sakai K, Iwanaga T. FLAIR can estimate the onset time in acute ischemic stroke patients. J Neurol Sci 2010;293: Ebinger M, Galinovic I, Rozanski M, Brunecker P, Endres M, Fiebach JB. Fluid-attenuated inversion recovery evolution within 12 hours from stroke onset: a reliable tissue clock? Stroke 2010;41: Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, Wu O, et al. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4.5 h of symptom onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol 2011;10: Qiao M, Malisza KL, Del Bigio MR, Tuor UI. Correlation of cere- J Korean Neurol Assoc Volume 31 No. 3,

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Homocysteine

Homocysteine cardioembolic stroke : how is it different? 강동화서울아산병원울산의대신경과 talk outline 뇌 는 심장 과다르다 Cardioembolic stroke 은다른 stroke subtypes 과어떻게다른가? Ischemic stroke mechanism 추정의어려움 뇌졸중은? 腦卒中 Lumper 中風 Splitter Ischemic