원저 뇌미세혈관병증 3 가지표식과열공뇌경색초기신경학적악화와의관련성 서울대학교의과대학신경과학교실, 분당서울대학교병원뇌졸중센터신경과 문장섭김나영강지훈양미화장명숙한문구배희준 Association of 3 Stigmas of Cerebral Microangiopathy With Early Neurological Deterioration in Lacunar Infarction Jangsup Moon, MD, Nayoung Kim, MD, Jihoon Kang, MD, Mi Hwa Yang, MD, Myung Sook Jang, MD, Moon-Ku Han, MD, Hee-Joon Bae, MD Department of Neurology, Stroke Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea Background: Neurological deterioration following acute lacunar infarction is not uncommon. Its association with poor clinical outcome is well-known, but little is known about what causes it. This study aimed to elucidate whether 3 stigmas of cerebral microangiopathy, a pathogenesis of lacunar infarction, are associated with neurological deterioration in patients with acute lacunar infarction. Methods: Patients with acute lacunar infarction who were admitted within 24 hours of onset were identified using a prospective stroke registry. Patients who presented neurological deterioration within 7 days of hospitalization (progressive lacune group) were matched to 4 controls (non-progressive lacune group) for onset to arrival time. Three stigmas of cerebral microangiopathy (leukoaraiosis, cerebral microbleeds, and silent lacunes) were measured using initial brain MRI, and their associations with neurological deterioration were analyzed. Results: During 45 months, a total of 23 patients were identified and matched to 80 controls. Simple comparison of 2 groups showed that those 3 stigmas of cerebral microangiopathy were not significantly associated with neurological deterioration. Hyperlipidemia (p=0.18), history of transient ischemic attack or stroke (p=0.01), initial NIH stroke scale (p=0.07), white blood cell counts (p=0.16), and lesion volume (p=0.03) were possibly different (p s<0.2) between 2 groups. Multivariable logistic regression analysis did not reveal any significant association of those 3 stigmas with neurological deterioration, too (all p values>0.5). Conclusions: This study did not find a relationship between cerebral microangiopathy and neurological deterioration following acute lacunar infarction. The possibility of inadequate power should be noted. J Korean Neurol Assoc 30(4):267-273, 2012 Key Words: Cerebral microangiopathy, Cerebral small vessel disease, Lacunar infarction, Neurological deterioration, Progressive stroke 서 론 Received September 10, 2012 Revised September 20, 2012 Accepted September 20, 2012 *Hee-Joon Bae, MD Department of Neurology, Stroke Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 463-707, Korea Tel: +82-31-787-7467 Fax: +82-31-787-4059 E-mail: braindoc@snu.ac.kr * 본연구는보건복지부보건의료연구개발사업의지원에의하여이루어진것임 ( 과제고유번호 : A102065). 전체뇌경색환자의약 25% 는열공뇌경색 (lacunar infarction) 에해당하며, 1 이들중 12-36% 는입원기간동안증상의악화를경험한다. 2 진행성뇌경색은그렇지않은경우에비해높은치명률과이환율을보이며, 신경학적인장애의비율도높다. 3,4 그러나아직까지진행성뇌경색을예측하거나예방할수있는효과적인방법은발견되지않았다. 과거열공뇌경색에서흔히발생하는신경학적악화 (neurological deterioration) 와관련이있는요 J Korean Neurol Assoc Volume 30 No. 4, 2012 267
문장섭김나영강지훈양미화장명숙한문구배희준 인들을밝히기위한시도들이있었다. 5-12 연령, 성별, 초기 NIHSS score, 당뇨병의병력, 병변크기등이관련있다고하였으나, 결과의재현성이떨어지고통계적검정력도높지않다는문제점이있다. 열공뇌경색의발병기전으로미세죽종 (microatheroma) 과지방유리질증 (lipohyalinosis) 이제시되고있다. 13,14 미세죽종의존재여부는현재의영상기술로확인할수없으나, 지방유리질증의심한정도는뇌영상에서뇌미세혈관병증 (cerebral microangiopathy, cerebral small vessel disease) 의징후 (stigma) 가있는지, 있다면얼마나심한지에따라확인이가능하다. 뇌미세혈관병증의징후로백질변성 (leukoaraiosis), 뇌미세출혈 (cerebral microbleeds), 무증상열공뇌경색 (silent lacunar infarction) 이있으며, 15 이들이존재할때뇌경색의발생이증가한다. 16,17 열공뇌경색에서발생하는신경학적악화의발생기전은아직밝혀져있지않으나, 열공뇌경색의발병과동일하게미세죽종과지방유리질증이관련되어있을가능성이높다. 그러나아직이런각도에서접근한연구는없었다. 저자들은열공뇌경색환자에서뇌미세혈관병증의중증도가신경학적악화의발생과관련이있는지를규명하고자하였다. 대상과방법 뇌졸중군 (non-progressive lacune group) 으로구분하였다. 신경학적악화가능성에발병후내원할때까지소요된시간이관여하는것을최소화하기위해소요시간을기준으로진행성뇌졸중군과비진행성뇌졸중군을 1:4 비율로짝짓기를시행하였다. 짝짓기가완벽하게이루어지지는않아본연구에최종적으로포함된환자는환자군 23명과대조군 80명이었다 (Fig.). 2. 자료의수집환자들의성별, 연령, 위험인자 ( 고혈압, 당뇨병, 고지혈증, 흡연, 뇌졸중의과거력, 심장성색전증위험인자 ), 기타임상적인특성 ( 첫증상발견후내원시까지소요된시간, 내원시 NIHSS 에대한정보는전향적으로구축중인뇌졸중등록체계 (prospective stroke registry) 데이터베이스를이용하거나직접의무기록검토를통해얻었다. 뇌졸중위험인자및기타임상변수에대한정의는한국뇌졸중자료은행의정의를이용하였다. 21 혈액검사의결과는내원후처음시행한검사의결과이며, 분당서울대학교병원에서전자의무기록의임상적활용을위해별도로구축한임상데이터웨어하우스 (clinical data warehouse) 를이용하여얻었다. 뇌경색의병인분류는 Trial of Org 10172 in Acute Stroke Treatment (TOAST) 분류를사용하였다. 22 1. 대상 2007년 7월부터 2011년 3월까지분당서울대학교병원에서급성뇌졸중으로입원치료를받은환자들중뇌자기공명영상 (Magnetic resonance Image, MRI) 검사를받았고, 검사에서관찰되는급성뇌경색병변의최대직경이 20 mm 이하이며, 증상발생시각으로부터 24시간이내에내원한경우를후향적으로모집하였다. 증상발생시각은첫증상발견시각 (first abnormal time) 을기준으로하였다. 기존연구결과에따르면, 열공뇌경색환자에서신경학적악화의상당수는입원후 2-5일내에발생하는것으로알려져있다. 18-20 이미신경학적악화가발생하고난뒤에내원한환자가비진행성뇌졸중군에잘못분류되는것을최소화하기위해증상발생 24시간이내에내원한환자들만을연구에포함시켰다. 자기공명뇌혈관조영술 (MR angiography), 전산화단층촬영뇌혈관조영술 (CT angiography) 혹은대퇴동맥경유뇌혈관조영술 (transfemoral cerebral angiography) 중어느한가지도시행하지않은경우는제외하였다. 상술한포함및제외조건을만족시키면서입원 1주일이내에신경학적악화를보인환자들을진행성뇌졸중군 (progressive lacune group), 신경학적악화를보이지않은환자들을비진행성 Figure. Patients selection. SNUBH: Seoul National University Bundang Hospital, FAT: first abnormal time, MRA: magnetic resonance angiography, CTA: computed tomography angiography, TFCA: transfemoral cerebral angiography. 268 대한신경과학회지제 30 권제 4 호, 2012
뇌미세혈관병증 3 가지표식과열공뇌경색초기신경학적악화와의관련성 2007년 7월이후분당서울대학교병원신경과에서는입원한뇌졸중환자진료의질관리를위해전향적으로입원중발생하는모든신경학적악화를수집하고있다. 사전에정의된기준에따라숙련된뇌졸중전문간호사 1인 (Yang MH) 에의해수집되어, 발생유무나기전분류의정확도에대해뇌졸중전임의에의해검토후, 매주정례회의보고를거쳐의무기록및뇌졸중등록체계데이터베이스에입력되고있다. 신경학적악화는입원중발생한 (1) NIHSS 총점 2점이상악화, (2) NIHSS 중의식과관련된항목의 1점이상악화, (3) NIHSS 중사지근력과관련된항목의 1점이상악화, (4) 새로운신경학적증상의발생, 이네가지중에하나이상에해당되며, 그것이뇌경색의재발이나출혈변환혹은내과적인합병증에의한것이아닐때로정의하였다. 본연구에서는내원일주일이내의신경학적악화만을진행성뇌졸중군의선택기준으로사용하였으며, 일주일이후에신경학적악화가발생한경우는연구에서제외하기로하였다. 뇌경색의재발은증상악화후시행한확산강조영상 (diffusion-weighted MRI) 에서기존병변과구별되는새로운병변이관찰되고이것이증상의악화를설명할수있는경우로정의하였다. 입원중뇌졸중의악화가발생하지않는경우를비진행성뇌졸중군으로분류하였다. 3. 뇌영상획득및분석모든환자에서 1.5 Tesla 이상의해상도로뇌자기공명영상이시행되었는데, 뇌영상의분석은짝지은후양군을대상으로임상경과에대한정보가없는상태에서한명의신경과의사 (Moon J) 에의해수행되었다. 뇌미세혈관병증의중증도를평가하였고, 급성뇌경색의크기를측정하였는데, 판단이어려운경우는다른신경과의사 (Kim N) 와의협의를통해결정하였다. 뇌백질변성의정도는액체감쇠역전회복영상 (fluid-attenuated inversion recovery, FLAIR) 에서 Fazeka척도를이용하여평가하였다. 23 무증상열공뇌경색은뇌피질을침범하지않는뇌실질의병변중, FLAIR영상에서뇌척수액과같은신호강도를보이는직경 3 mm 이상의병변으로정의하여개수를확인하였다. 24 뇌미세출혈은기울기에코영상 (gradient echo imaging) 에서신호소실을보이는직경 5 mm 이하의원형병변으로정의하여개수를확인하였다. 25 급성뇌경색병변의크기측정은 MIPAV (Johns Hopkins MedIC, http://mipav.cit.nih.gov/) 프로그램을이용하였다. 4. 통계분석및검정력산정포함및제외기준을만족하는모든열공뇌경색환자들을진 행성뇌졸중군과비진행성뇌졸중군으로분류하여짝짓기전과후에각각임상적인특성을비교분석하였다. 연속형변수의분석에는독립적 T검정 (independent t-test) 과 Mann-Whitney U test를이용하였으며, 범주형변수분석에는카이제곱검정 (chisquare test) 을이용하였다. 뇌백질변성은 Fazeka척도 0, 1점을 경증, 2, 3점을 중증 으로, 뇌미세출혈은유무에따라이분하여분석하였다. 무증상열공뇌경색은 0개, 1개, 2개이상 의세군으로구분하였다. 뇌백질변성이중증이상, 대뇌미세출혈이나무증상열공뇌경색이관찰되는경우를 진행된뇌미세혈관병증이있는경우 로조작적으로정의하여신경학적악화와의연관성을분석하였다. 다변량분석은짝지은두군을대상으로시행하였고뇌미세혈관병증의유무및세가지징후를각각주요폭로변수로하여모델을구축하였다. 보정을위한교란변수로는조사한임상적인특성중짝지은후양군을대상으로수행한단변량분석에서 p<0.2인변수를선정하였다. 다변량회귀분석은작은표본수로모델에포함된공변량이많을경우우려되는 overfitting의가능성을줄이기위해최소한의보정변수를사용하는것을원칙으로하였다. 단변량분석의결과선정된잠재적교란변수만으로회귀모델을만들고단계적후향소거법 (backward elimination and stepwise regression) 으로왈드통계량 (Wald statistics) 를이용하여상관성이가장낮은변수부터모델에서제거한뒤, 통계적으로유의한변수들만포함하는다변량회귀분석모델을구축하였다. 이모델에뇌미세혈관병증의유무및세가지징후변수들을주폭로변수로하나씩포함시켜다변량로지스틱회귀분석 (multivariate logistic regression) 을시행하였으며, 교란변수가보정된상태에서뇌미세혈관병증유무및세가지징후의교차비와 95% 신뢰구간, p값을계산하였다. 통계분석을위한프로그램으로는 SPSS (version 18.0, SPSS Inc, Chicago, IL) 를사용하였으며, 유의수준은 0.05 미만으로하였다. 연구계획의수립단계에서확보가능한표본수가연구가설이입증하기에충분한지를검증하고자하였다. 국내일개병원에입원한열공뇌경색을대상으로조사였을때뇌백질변성이 52.0%, 뇌미세출혈이 29.2%, 무증상열공뇌경색이 54.2% 관찰된다는최근보고가있다. 24 열공뇌경색에서뇌미세혈관병증과뇌졸중의진행과의상관성에대한기존연구가없어, 무증상열공뇌경색과뇌졸중발생위험에대한연구에서교차비 (odds ratio, 3.6) 을차용하였다. 16 상술한자료에근거하여진행성열공뇌경색에서무증상열공뇌경색의유병률을 50% 로가정하고 1:4 짝짓기를하여 23명의진행성뇌졸중군과 92명의비진행성뇌졸중군을확보하였을때통계적검정력은 61% 가되었다. 통계적검증력의계산에는 nquery advisor (version 7.0, Statistical J Korean Neurol Assoc Volume 30 No. 4, 2012 269
문장섭김나영강지훈양미화장명숙한문구배희준 Solutions Ltd., Cork, Ireland) 를사용하였다. 결과 연구기간동안본원에서급성뇌졸중으로입원치료를받은 2841명중열공뇌경색의정의에부합되는환자는 417명으로전체의 14.7% 에해당하였다. 이들중증상발생 24시간이후에내원하거나뇌동맥에대한평가를시행하지않은경우를제외하고총 222명이본연구의포함및제외기준을만족하는환자에해당하였다 (Fig.). 222명중 23명 (10.4%) 에서입원첫 1주일동안신경학적악화가발생하였다. 모든신경학적악화는진행성뇌졸중의정의에부합되었으며, 재발이나다른이유로인한신경학적악화가발생하거나일주일이후에발생한경우는없었다. 짝짓기를시 행하기전과후에진행성뇌졸중군과비진행성뇌졸중군을비교하여 Table 1에정리하였다. 짝짓기전비진행성뇌졸중군에서고혈압의유병률이높았으나, 짯짓기후에는양군사이에나이, 성별등의인구학적특성과, 뇌경색의위험인자로알려진고혈압, 당뇨병, 고지혈증, 흡연등에서통계적으로유의한차이가없었다. 다만, 짝짓기전과후에모두진행성뇌졸중군의 뇌졸중혹은일과성허혈발작의병력 이많았다. 뇌자기공명영상과관련된변수는짝짓기이후에만측정하였고진행성뇌졸중군에서비진행성뇌졸중군에서비해급성뇌경색병변이더컸다. 짝짓기를시행한 103명의환자를대상으로, 뇌미세혈관병증의세가지징후 ( 뇌백질변성, 뇌미세출혈, 무증상열공뇌경색 ) 및진행된뇌미세혈관병증 ( 방법에서기술한바와같이세징후중어느하나라도있으면있다고정의함 ) 과신경학적악화와의 Table 1. Comparison of demographics and clinical characteristics between progressive lacune and non-progressive lacune groups Progressive lacune Non-Progressive lacune (unmatched) Non-Progressive lacune (matched) n=23 n=199 p value n=80 p value Age a 63.9±13.3 65.0±12.0 0.66 63.1±11.6 0.79 Sex, male b 11 (47.8%) 120 (63.3%) 0.25 43 (53.8%) 0.64 Hypertension b 9 (39.1%) 126 (63.3%) 0.02 36 (45%) 0.64 Diabetes b 3 (13.0%) 57 (28.8%) 0.11 20 (25%) 0.27 Hyperlipidemia b 9 (39.1%) 42 (21.1%) 0.05 19 (23.8%) 0.18 Smoking b 11 (47.8%) 92 (46.2%) 0.89 32 (40%) 0.63 Previous history of TIA or stroke b 10 (43.5%) 43 (21.6%) 0.02 13 (16.3%) 0.01 Prestroke MRS 2 b 2 (8.7%) 18 (9%) 0.96 4 (5%) 0.61 Onset to admission, c min 165 (86-433) * 354 (112-758) * 0.11 153 (64-408) * 0.58 Onset to MRI, c min 196 (128-574) * - - 196 (114-452) * 0.58 NIHSS at admission c 4 (2-5) * 3 (1-4) * 0.07 2 (1-5) * 0.07 lesion volume, c cc 589 (422-870) * - - 427 (194-822) * 0.03 WBC a /μl 7818.7±2107.4 7477.4±2446.1 0.52 7146.0±1986.7 0.16 Hb a g/dl 14.0±1.7 14.2±1.7 0.59 14.0±1.9 0.99 Hct, a % 41.1±4.7 41.3±6.7 0.89 40.9±5.2 0.85 Platelet, a 10 3 /μl 236.1±67.7 246.9±77.1 0.52 253.3±84.0 0.37 FBS, a mg/dl 120.4±50.2 118.6±50.8 0.87 112.3±41.4 0.43 HbA1c, a % 6.3±1.0 6.2±1.2 0.94 6.1±1.1 0.48 Total cholesterol, a mg/dl 199.0±42.0 191.4±37.0 0.37 193.9±39.5 0.59 HDL-cholesterol, a mg/dl 47.0±11.9 45.8±11.8 0.66 47.7±12.1 0.79 LDL-cholesterol, a mg/dl 108.4±33.6 106.1±32.0 0.75 106.8±34.4 0.84 Triglyceride, a mg/dl 155.4±88.7 132.7±76.8 0.19 141.5±89.7 0.51 BUN, a mg/dl 16.5±4.9 15.3±7.1 0.42 15.3±7.1 0.46 Cr, a mg/dl 0.99±0.37 1.02±0.95 0.85 1.06±1.45 0.81 aptt, a sec 35.4±4.9 35.5±4.2 0.90 35.7±4.8 0.76 PT INR a 0.99±0.06 0.99±0.16 0.92 0.98±0.06 0.70 AST, a U/L 24.0±11.7 23.2±10.3 0.73 22.2±7.7 0.36 ALT, a U/L 26.4±25.3 23.1±12.8 0.31 21.4±10.7 0.37 Categorical variables are expressed as number (percentage) whereas continuous variables are expressed as mean ± SD or * median (interquartile range). a Independent t-test was performed. b Chi-square test was performed. c Mann-Whitney U test was performed. TIA; transient ischemic attack, MRS; modified Rankin scale, MRI; magnetic resonance image, NIHSS; National Institutes of Health Stroke Scale, WBC; white blood cell, Hb; hemoglobin, Hct; hematocrit, FBS; fasting blood sugar, HbA1c; glycosylated hemoglobin, BUN; blood urea nitrogen, Cr; creatinine, aptt; activated partial thromboplastin time, PT; prothrombin time, AST; aspartate aminotransferase, ALT; alanine aminotransferase. 270 대한신경과학회지제 30 권제 4 호, 2012
뇌미세혈관병증 3 가지표식과열공뇌경색초기신경학적악화와의관련성 연관성을보기위해카이제곱검정을시행하였다. 진행성뇌졸중군과비진행성뇌졸중군사이에통계적으로유의한차이를발견할수없었다 (Table 2). 다변량모델을위한교란변수를찾기위해짝짓기후진행성뇌졸중군과비진행성뇌졸중군의비교분석에서 p<0.2이었던고지혈증, 뇌졸중혹은일과성허혈발작의과거력, 내원시 NIHSS, 병변의크기, 백혈구수치를독립변수하여다변량로지스틱회귀분석을시행하였다. 후향소거법으로상관성이가장낮은변수부터제거한결과, 뇌졸중혹은일과성허혈발작의과거력, 병변의크기, 백혈구수치가신경학적악화에독립적인영향을미치는변수로확인되었다 (Table 3). 이세변수를교란변수로다변량모델을구축하고뇌미세혈관병증의세가지징후및조작적으로정의된진행된뇌미세혈관병증의유무에대해분석을시행하였고, 단변량분석과마찬가지로신경학적악화와통계적으로의미있는상관성을발견하지못하였다 (all p values>0.50). 고찰 본연구는열공뇌경색에서나타나는신경학적악화의발생기 전이열공뇌경색의발병기전인뇌미세혈관병증과관련있는지확인해보고자하였고, 열공뇌경색에서뇌경색의진행과뇌미세혈관병증의세가지징후및진행된뇌미세혈관병증의유무에유의한차이를발견할수없었다. 이런결과는뇌졸중혹은일과성허혈발작의과거력, 병변의크기, 백혈구수치등세가지교란변수를통제하기전이나후에모두일관되었다. 따라서열공뇌경색에서신경학적악화발생은뇌미세혈관병증의중증도와는관련이없고, 다른발병기전이있다고유추해볼수있다. 그러나실제로는뇌미세혈관병증중증도가신경학적악화발생과관련이있으나검정력부족으로이를본연구에서통계적으로입증하지못했을가능성도배제할수는없다. 본연구의큰장점은열공뇌경색에서발생하는신경학적악화가사전에정의된기준에의해일관되게전향적으로수집되었다는점이다. 뇌경색의초기신경학적악화에대해많은연구들은있었으나, 대부분이후향적으로신경학적악화를평가한것들이다. 5-12 후향적으로신경학적악화를평가할때증상의악화가실제로뇌경색의진행에의한것인지, 뇌경색의재발혹은다른내과적인원인에의한것인지판단하기어려운경우가많다. 본연구에서는연구기간동안모든뇌경색입원환자의증상 Table 2. Comparison of cerebral microangiopathy between progressive and non-progressive groups after matching Progressive n=23 Non-Progressive n=80 p value a OR 95% CI Adjusted b OR 95% CI p value Leukoaraiosis 0.68 1.22 0.48-3.11 0.65 0.77 0.25-2.41 Mild (Fazeka's grade 0, 1) 13 (56.5%) 49 (61.3%) Severe (Fazeka's grade 3, 4) 10 (43.5%) 31 (38.8%) Cerebral microbleeds 0.44 1.53 0.52-4.54 0.86 0.91 0.30-2.73 None 17 (73.9%) 65 (81.3%) 1 6 (26.1%) 15 (18.8%) Silent lacunar infarction 0.76 - - 0.62 0.84 0.43-1.65 None 14 (60.9%) 55 (68.8%) 1 4 (17.4%) 10 (12.5%) 2 5 (21.7%) 15 (18.8%) Advanced cerebral microangiopathy * 0.55 1.34 0.52-3.45 0.94 1.04 0.36-2.99 None or negligible 9 (39.1%) 37 (46.2%) Present 14 (60.9%) 43 (53.8%) * Advanced cerebral microangiopathy = leukoaraiosis or cerebral microbleeds or silent lacunar infarction. a Chi-square test was performed. b Multivariable logistic regression was performed. Adjusted variables were previous history of TIA or stroke, WBC count, and lesion volume. OR; odds ratio, CI; confidence interval. Table 3. Covariate selection process for multivariable models: Backward elimination approach with Wald statistics Step 1 (p value) Step 2 (p value) Step 3 (p value) OR 95% CI NIHSS at admission 0.46 Eliminated Hyperlipidemia 0.22 0.26 Eliminated Lesion volume 0.07 0.03 0.04 6.113 1.78-20.99 WBC 0.02 0.02 0.01 1.001 1.00-1.002 Previous history of TIA or stroke 0.01 0.01 0.004 1.000 1.00-1.001 J Korean Neurol Assoc Volume 30 No. 4, 2012 271
문장섭김나영강지훈양미화장명숙한문구배희준 변화를감시하여변화가생긴경우, 숙련된뇌졸중전문간호사가사전에정의된기준을바탕으로평가하여신경학적악화를수집하였고, 그결과는뇌졸중전임의의검토와매주정례회의보고를거쳐최종입력되어자료의신뢰도가높다. 본연구의또다른장점은증상발생시각으로부터병원에내원할때까지소요된시간을기준으로진행성뇌졸중군과비진행성뇌졸중군사이에짝짓기를시행하였다는점이다. 저자들은열공뇌경색에서발생하는신경학적악화의대부분이입원수일내에발생한다는점에주목하여, 증상발생후부터내원시까지걸린시간이신경학적악화의발생에중요한변수가될것이라고판단하였다. 기존의뇌경색에서신경학적악화에대한연구들중, 증상발생에서내원시까지의시간을기준으로짝짓기를시행한연구는없었다. 짝짓기를통해내원전진행유무가연구결과에영향을줄가능성은효과적으로통제되었다고판단되나, 역으로이런방법이연구의검정력을약화시키는방향으로작용했을가능성도적지않다. 발병후내원까지소요시간을 24시간이내로제한하여내원전진행의가능성을최소화하려고하였으나뇌경색의진행을결정하는요인이심할수록내원전진행이많고이런영향이고려되지않아연구의검정력약화로연결되었을가능성이있다. 향후연구에서내원전진행에대한정보를수집하여이를극복할수있을것으로판단되나이를위해서는전향적인연구디자인이필수일것이다. 본연구를통하여열공뇌경색에서신경학적악화와관련된기타요인몇가지를확인할수있었다. 뇌졸중혹은일과성뇌허혈발작의병력, 뇌경색병변의크기, 백혈수수치가의미있는요인이었고이는과거연구와부합되는결과이다 6,10-12 (Table 4). 단변량분석에서 p<0.2으로잠재적교란변수로여겨졌던내원시 NIHSS 및고지혈증은다변량모델을통한교란변수선택과정에서소거되었다. 내원시 NIHSS의경우 5점이상이신경학적악화의발생과연관된다는과거연구가있었으나, 12 뇌경색의크기또한내원시 NIHSS와같이뇌경색에의한신경세포 손상의정도를반영하는변수로둘사이의경쟁결과좀더뇌손상의크기를잘반영할수있는뇌경색의크기가선택된것으로보인다. 고지혈증의경우과거연구에서관련성에대한보고가없고관련성의병태생리에대해고려해볼때, 우연에의해 p<0.02인단변량분석결과가나왔을가능성이높다. 본연구는몇가지제한점을가지고있다. 첫째, 표본수가많지않은점을지적해야할것이다. 3년 9개월의연구기간동안입원한거의 3000명에가까운환자들을초기코호트로대상선정을시작했음에도불구하고, 증상발생 24시간이내내원하고뇌동맥에대한평가를시행한열공뇌경색환자는 222명이었고, 이중입원 1주일이내에신경학적악화를경험한경우는 23명에지나지않았다. 비록결과분석전에시행한검정력계산에서 61% 로나오긴하였으나, 검정력계산에필요한뇌미세혈관병증이뇌경색의진행을초래할위험성크기를건강인에서무증상열공뇌경색의뇌졸중발생증가기여도인교차비 3.6을차용하여, 뇌미세혈관병증이뇌경색의악화에기여하는효과크기가과대평가되었을가능성이있다. 그리고이런과대평가가주어진표본수에따른검정력과대평가로이어져실제로는크지않은뇌미세혈관병증의악화에미치는효과를평가하기에는표본수가부족했을지도모른다. 그러나분석결과 (Table 2) 는뇌미세혈관병증의세가지징후나조작적으로정의한진행된뇌미세혈관병증의유무중어느하나에서도통계적의미와관계없이뇌경색의악화와관련있을가능성을보여주지못하여, 검정력부족만으로연구결과를설명하기는부족하다할것이다. 둘째, 기존의연구에서열공뇌경색의신경학적악화와관련이있다고보고된요인들을모두통제하지못했다. C-반응단백질 (C-reactive protein), 섬유소원 (fibrinogen) 6, 병변의해부학적인형태 ( 원형혹은길쭉한형태 ) 9 등이신경학적악화의발생과연관이있었다는보고가있었으나, 본연구에서는이들을분석에포함시키지않았다. 그러나 C-반응단백질이나 fibrinogen 등은염증과관계가있어백혈구수치에어느정도반영되어있 Table 4. Predictors of neurological progression in lacunar stroke on previous studies OR 95% CI p value Age>75 8 7.55 1.73-44.48 0.006 Female 8 4.41 1.13-20.42 0.03 Lesion located in the posterior part of corona radiate 8 14.83 3.54-87.21 <0.001 Initial NIHSS>5 12 in LSA territory group 5.28 2.63-10.59 <0.0001 in APA territory group 3.03 1.32-6.95 0.0088 DM in APA territory group 12 3.28 1.36-7.92 0.0079 Infarct volume>0.5 (cm 3 ) 10 18.0 1.4-270 0.027 Infarct area on DWI>0.98 (cm 2 ) 11 10.57 2.24-68.32 0.006 LSA; lenticulostriate arteries, APA; anterior pontine arteries. 272 대한신경과학회지제 30 권제 4 호, 2012
뇌미세혈관병증 3 가지표식과열공뇌경색초기신경학적악화와의관련성 고, 병변의해부학적형태의경우주관적인요소가많고반복되어보고된것은아니다. 더구나본연구의경우표본수가많은교란변수를다변량모델에포함하기에는부족하였던것도이들변수를포함하지않은이유중하나이다. 마지막으로, 열공뇌경색은전순환계 (anterior circulation) 과후순환계 (posterior circulation) 에서진행혹은악화의기전이서로다를가능성이있다. 두영역에위치한신경학적구조물이다르고, 곁순환등의특성이다를수있다는점등을고려하면, 두영역을구분하여분석해볼필요가있고, 과거연구에서는두영역을구분하여진행한경우가있었다. 7,8,11,12,26 본연구에서는이런하위집단분석을하기에는표본수가부족하여시행하지못하였다. 결론적으로, 본연구에서뇌미세혈관병증은열공뇌경색의발병후뇌경색의진행혹은악화와는관련이없었다. 향후좀더많은환자를대상으로, 내원전진행, 뇌경색의발생위치, 열공뇌경색의두가지발병기전인지방유리질증 (lipohyalinosis) 및미세죽종 (microatheroam) 의구분등을고려한후속연구가필요할것이다. REFERENCES 1. Wardlaw J. What causes lacunar stroke? J Neurol Neurosurg Psychiatry 2005;76:617. 2. Roden-Jullig A. Progressing stroke: epidemiology. Cerebrovas Dis 1997;7:2-5. 3. Davalos A, Cendra E, Teruel J, Martinez M, Genis D. Deteriorating ischemic stroke. Neurology 1990;40:1865. 4. Castillo J. Deteriorating stroke: diagnostic criteria, predictors, mechanisms and treatment. Cerebrovas Dis 2000;9:1-8. 5. Vila N, Castillo J, Davalos A, Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 2000;31: 2325. 6. Audebert HJ, Pellkofer TS, Wimmer ML, Haberl RL. Progression in lacunar stroke is related to elevated acute phase parameters. Eur Neurol 2004;51:125-131. 7. Nagakane Y, Naritomi H, Oe H, Nagatsuka K, Yamawaki T. Neurological and MRI findings as predictors of progressive-type lacunar infarction. Eur Neurol 2008;60:137-141. 8. Ohara T, Yamamoto Y, Tamura A, Ishii R, Murai T. The infarct location predicts progressive motor deficits in patients with acute lacunar infarction in the lenticulostriate artery territory. J Neurol Sci 2010;293:87-91. 9. Kim JT, Yoon GJ, Park MS, Nam TS, Choi SM, Lee SH, et al. Lesion patterns of small deep infarcts have different clinical and imaging characteristics. Eur Neurol 2010;63:343-349. 10. Terasawa Y, Iguchi Y, Kimura K, Kobayashi K, Aoki J, Matsumoto N, et al. Neurological deterioration in small vessel disease may be associated with increase of infarct volume. J Neurol Sci 2008;269:35-40. 11. Takase K, Murai H, Tasaki R, Miyahara S, Kaneto S, Shibata M, et al. Initial MRI findings predict progressive lacunar infarction in the territory of the lenticulostriate artery. Eur Neurol 2011;65:355-360. 12. Yamamoto Y, Ohara T, Hamanaka M, Hosomi A, Tamura A, Akiguchi I, et al. Predictive factors for progressive motor deficits in penetrating artery infarctions in two different arterial territories. J Neurol Sci 2010;288:170-174. 13. Horowitz DR, Tuhrim S, Weinberger JM, Rudolph SH. Mechanisms in lacunar infarction. Stroke 1992;23:325. 14. Han J, Bae HJ, Wong LK. Pathophysiology and mechanisms whereby hypertension may cause stroke. Hypertension and Stroke V Aiyagari and P. B. Gorelick, Humana Press: 77-94. 15. Potter GM, Roman G. Cerebral small-vessel disease: what lies beyond the early years? Neurology 2011;76:684-685. 16. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler M. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003;34:1126. 17. Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007;130:1988. 18. Steinke W, Ley SC. Lacunar stroke is the major cause of progressive motor deficits. Stroke 2002;33:1510. 19. Nakamura K, Saku Y, Ibayashi S, Fujishima M. Progressive motor deficits in lacunar infarction. Neurology 1999;52:29. 20. Serena J, Leira R, Castillo J, Pumar JM, Castellanos M, Davalos A. Neurological deterioration in acute lacunar infarctions: the role of excitatory and inhibitory neurotransmitters. Stroke 2001;32:1154. 21. Yu KH, Bae HJ, Kwon SU, Kang DW, Hong KS, Lee YS, et al. Analysis of 10,811 cases with acute ischemic stroke from Korean Stroke Registry: hospital-based multicenter prospective registration study. J Korean Neurol Assoc 2006;24:535-543. 22. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. 23. Fazekas F, Chawluk J, Alavi A, Hurtig H, Zimmerman R. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol 1987;149:351. 24. Kim YS, Park SS, Lee SH, Yoon BW. Reduced severity of strokes in patients with silent brain infarctions. Eur J Neurol 2011;18:962-971. 25. Lee SH, Bae HJ, Kwon SJ, Kim H, Kim YH, Yoon BW, et al. Cerebral microbleeds are regionally associated with intracerebral hemorrhage. Neurology 2004;62:72. 26. Kim SK, Song P, Hong JM, Pak CY, Chung CS, Lee KH, et al. Prediction of progressive motor deficits in patients with deep subcortical infarction. Cerebrovas Dis 2008;25:297-303. J Korean Neurol Assoc Volume 30 No. 4, 2012 273