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1 원저접수번호 : 분당서울대학교병원뇌졸중센터신경과, 신경외과 a, 영상의학과 b, 재활의학과 c 고영채박정현김욱주양미화권오기 a 오창완 a 정철규 b 백남종 c 한문구배희준 The Long-term Incidence of Recurrent Stroke: Single Hospital-based Cohort Study Youngchai Ko, MD, Jung-Hyun Park, MD, Wook-Joo Kim, MD, Mi Hwa Yang, O-Ki Kwon, MD a, Chang Wan Oh, MD a, Cheolkyu Jung, MD b, Nam-Jong Paik, MD c, Moon-Ku Han, MD, Hee-Joon Bae, MD Departments of Neurology, Neurosurgery a, Radiology b, and Rehabilitation Medicine c, Seoul National University College of Medicine, Stroke center, Seoul National University Bundang Hospital, Seoul, Korea Background: Recurrent stroke is a major cause of morbidity and mortality among stroke survivors. However, studies of the long-term prognosis after acute stroke are very rare, especially in Asia. This study aimed to provide estimates of recurrent stroke rates by age, gender, and subtype of stroke in an unselected cohort of patients hospitalized to a community-based general hospital due to acute stroke. Methods: Based on a prospective stroke registry, acute stroke patients were enrolled within 7 days of symptom onset and followed retrospectively or prospectively for up to 3 years. Information was gathered about stroke recurrence and other vascular events. The cumulative risk of recurrent stroke was calculated using the Kaplan-Meier method. Results: Two-thousand and sixty-eight patients were enrolled in this study. The cumulative risks of stroke recurrence were 2.3%, 5.5%, 8.6%, and 10.0% at 90 days and 1, 2, and 3 years, respectively. The prevalence of stroke recurrence increased with age and the presence of previous stroke history (p<0.001), but not with gender or stroke subtype. Conclusions: To the best of our knowledge, this is the first cohort study of stroke recurrence in Korea. Its limitation of being a single hospital-based study warrants community- or multicenter-based cohort studies to identify high-risk groups for stroke recurrence. J Korean Neurol Assoc 27(2): , 2009 Key Words: Cerebrovascular disorders, Epidemiology, Recurrence, Stroke outcome 서론 뇌졸중의재발은뇌졸중으로인한이환율 (morbidity) 과사망률 (mortality) 증가의주된원인이며, 1 과거보다높아진생존율 Received November 17, 2008 Revised December 29, 2008 Accepted December 29, 2008 *Hee-Joon Bae, MD Department of Neurology, Seoul National University College of Medicine, Stroke center, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, , Korea Tel: Fax: braindoc@snu.ac.kr * 본연구는보건복지가족부보건의료기술진흥사업의지원에의하여이루어진것임 ( 과제고유번호 : A060171) 에도불구하고, 환자개인과가족나아가국가적으로도뇌졸중으로인한질병부담이높아지는주된이유이기도하다. 2 그럼에도불구하고뇌졸중재발에관한연구는의외로적으며, 특히아시아에서는거의찾아보기힘들다. 국내에서도일부뇌졸중아형에따른허혈뇌졸중의재발률에대한연구 3 나재발된뇌졸중의위험인자에관한단면연구 (Cross sectional study) 4 들이보고되고있을뿐, 미국의 NOMAS study 2 나영국의 Oxfordshire Community Stroke Project 5 와같은형태의뇌졸중환자기반의장기간코호트연구결과는아직보고된적이없다. 과거대규모의전향적연구들의보고에서뇌졸중의재발위험은 1개월이내에 1.7~4%, 1년이내에 6~13%, 그리고이후 2~5 년까지는매년 5~8% 씩증가하여결과적으로 5년이후재 110 대한신경과학회지제 27 권제 2 호, 2009

2 발률은 19~42% 에이른다고하였다. 2,6 연구디자인, 연구집단의사회인구학적요소, 뇌졸중재발의정의그리고재발을막기위한항혈전제의복용여부등의차이로인하여연구간에재발률의차이가있겠으나, 1 대부분에서발병 1년이내뇌졸중의재발위험은이후 4년간평균재발률의두배정도로높았다. 2,5,7 따라서, 환자뿐아니라의사의입장에서도자신들이진료하는환자의연간뇌졸중재발률을파악하고, 발병초기부터재발에관여하는위험인자를평가하고관리하는것은매우중요할것이다. 이에저자들은본병원에입원하여등록된뇌졸중환자코호트를기반으로하여발병후 1년동안의뇌졸중재발률및성별, 연령별, 입원시중요한임상적특성에따른재발률의차이를알아보고자하였다. 대상과방법 전향적으로일관되게수집한분당서울대학병원뇌졸중등록 Table 1. Baseline characteristics of study population Demographics N=2086 Age, years (mean±sd) 66.50± (40.2) 65~ (32.2) 75~ (22.2) (5.4) Male 1236 (59.3) Onset to arrival time, hours, 10 (2 to 41) median (interquartile range) NIH stroke scale at admission, 4 (2 to 8) median (interquartile range) Systolic blood pressure (mmhg, mean±sd) ±28.61 Diastolic blood pressure (mmhg, mean±sd) 87±17.42 Hypertension 1281 (61.4) Diabetes mellitus 579 (27.8) Hyperlipidemia 335 (16.1) Smoking (current or quit <5 years) 593 (28.4) Previous stroke history Yes 382 (18.3) No 1704 (81.7) Hemorrhagic stroke 237 (11.4) Ischemic stroke 1849 (88.6) TOAST classification (Ischemic stroke only) Large artery disease 730 (39.5) Small vessel occlusion 414 (22.4) Cardioembolism 361 (19.5) Other determined 36 (1.9) Undetermined 308 (16.7) Thrombolysis (Ischemic stroke only) Intravenous rt-pa 77 (4.2) Intra-arterial thrombolysis 69 (3.7) Combined 61 (3.3) Data are expressed as number (%), if not indicated. SD; standard deviation 체계자료를기반으로, 2004 년 5월부터 2008 년 6월까지분당서울대학교병원신경과에입원한발병 7일이내의급성뇌졸중환자를대상으로하였다. 뇌졸중은세계보건기구 (WHO) 의정의에따라 혈관성원인에의한 24 시간이상지속하거나사망을초래하는갑자기발생하는국소또는전반적뇌기능의장애를보이는임상적징후 라하였으며, 8 뇌영상에서관련된병변이확인된경우로국한하였다. 뇌졸중의재발은기존의연구에따라 지표뇌졸중발병 21일이후에새롭게발생된혈관성원인에의해발생한신경학적증상 2,5,6 또는 21일이후뇌졸중으로사망한경우로정의하였다. 뇌졸중은뇌출혈과뇌경색을포함하였으며, 뇌경색의경우 TOAST 분류체계에따라큰동맥죽상경화증 (Large artery atherosclerosis), 심인성색전증 (Cardioembolism), 소동맥폐쇄 (Small artery occlusion), 기타원인 (Other determined cause), 그리고원인불명 (Undetermined cause) 으로분류하였다. 9 연구선정의지표가되는뇌졸중 ( 지표뇌졸중, Index stroke) 발병때의무기록을통하여나이, 성별, 고혈압, 당뇨병, 고지혈증, 심방세동, 흡연, 음주등의뇌졸중재발위험인자에대한정보와과거뇌졸중병력, 신경학적상태의심한정도평가를위한 NIH stroke scale 점수를수집하였다. 환자가급성뇌졸중으로 2회이상중복입원한경우는제일빠른입원을지표뇌졸중으로정의하였다. 환자들의추적관찰은 2006 년 11월 1일이후입원한환자에대해서는전향적인 (prospective) 방법으로한명의뇌졸중전문간호사 ( 양미화 ) 가발병 3개월과 1년째두차례전화설문을통해미리구성된뇌졸중재발여부, 재발날짜, 재발된뇌졸중의종류, 관상동맥질환의발생여부, 사망여부, 사망날짜, 그리고사망원인등에관한질문사항을기록하는방식으로조사하였고, 2004 년 5월 1일부터 2006 년 10월 31일까지입원한환자들은 2007 년 10월 1월부터 2008 년 10월 31일까지역시전화설문을통하여후향적인 (retrospective) 방법으로조사하였다. 본원외래를통해추적관찰하고있거나환자가본원에뇌졸중재발로재입원한경우는의무기록조회를동시에병행하였다. 또한등록된모든환자에대하여사망여부및사망원인을통계청사망원인원시자료를이용하여확인하였다. 통계분석으로 Kaplan-Meier 법을이용하여뇌졸중재발률을평가하였으며, log-rank test 를통하여성별, 연령, 뇌졸중의종류, TOAST 분류에따른재발률을비교하였다. 뇌졸중재발의정의에따라관찰기간이증상발생으로부터 21일이내인환자는분석에서제외하였고, 3개월과이후 1년단위로재발률을관찰하였다. 모든통계적분석은 SPSS for Windows (version J Korean Neurol Assoc Volume 27 No. 2,

3 고영채박정현김욱주양미화권오기오창완정철규백남종한문구배희준 Table 2. Cumulative risks (%) of fatal or nonfatal stroke recurrence after index stroke 90 days 1-year 2-year 3-year p, log-rank test All patients Gender Male Female Age (years) < ~ ~ TOAST classification 9 Large artery disease Small vessel occlusion Cardioembolism Other determined Undetermined Type of Stroke Ischemic Hemorrhagic Previous Stroke Yes <0.001 No , Chicago, US) 를사용하였으며 p<0.05일때통계적유의성이있는것으로판정하였다. 결과 연구기간동안 7일이내급성뇌졸중으로입원한환자는 2,246 명이었으며, MRI 또는 CT상상응하는병변 (relevant lesion) 이있는환자는 2,232 명 (99.4%) 이었다. 이중에서중복입원을다시제외한 2,139 명이의도된연구대상이었으며, 이중추적소실 (N=9), 21 일이내뇌졸중재발또는사망 (N=44) 을제외한총 2,086 명 (97.5%, 2086/2139) 이최종분석대상이되었다. 환자의연령은 66.50±12.65 세 ( 평균 ± 표준편차 ) 였고, 65세이상의비율이높았다 (59.8%). 남성이 1,236 명 (59.3%) 으로여성보다많았으며, 허혈뇌졸중의비율이높았다 (88.6%). TOAST 분류 9 중큰동맥죽상경화증이가장많았으며 (39.5%) 혈전용해시술을받은환자는전체허혈뇌졸중환자의 9.9% 였다 (Table 1). 추적관찰기간의중앙값은 741 일, 사분위범위 (interquartile range) 는 208 일에서 1039 일이었다. 관찰기간중 152 건의치명적 (fatal) 혹은비치명적 (nonfatal) 뇌졸중재발이있었으며, Kaplan-Meier 법으로예측한뇌졸중재발의누적발생률은 3개월 2.3%, 1년 5.5%, 2년 8.6%, 3년 10.0% 였다 (Table 2). 성별과 64세미만, 65~74, 75~84, 85세이상의 4개연령군, 뇌졸중의유형, TOAST 분류, 9 과거뇌졸중병력의유무에따라뇌졸중재발률을비교하였다 (Table 2, Fig.). 성별과뇌졸중의 유형에따라서는통계적으로유의한뇌졸중재발률의차이는없었다. TOAST 분류에서는심인성색전증과원인불명에서 3년누적재발률이각각 13.7% 와 13.8% 로전반적인뇌졸중재발률 10.0% 보다높은경향이었고, 소동맥폐색은 6.3% 로재발률이낮았으나통계적유의성은없었다 (p=0.087). 과거뇌졸중병력의유무에따른 3년누적재발률은 17.9% 와 7.8% 로뇌졸중병력이있는환자에서현저하게재발률이높았고, 4개의연령군으로비교하였을때에도연령이높을수록재발률이높았다 (p<0.001). 고찰 일개지역사회기반병원에급성뇌졸중으로입원하여치료를받은뇌졸중환자 2,086 명의 1년과 3년뇌졸중재발률은각각 5.5% 와 10% 였으며, The Oxfordshire Community Stroke Project (OCSP) 5 의 13.2% 와 24.9%, Perth Community Stroke Study (PCSS) 10 의 12.9% 와 18.8%, South London Stroke Register 7 의 8% 와 14.1%, Northern Manhattan Study (NO- MAS) 11 의 7.7% 와 15% 등과거지역사회기반의연구들과보고와비교할때재발률이낮았다 (Table 3). 이러한이유는다음몇가지로설명할수있을것이다. 첫째, 본연구는과거지역사회기반의연구와달리단일병원에등록되어있는환자기반의코호트이기때문에추적소실률이낮았으며환자나보호자들이이차예방에적극적이었던점을들수있겠다. 실제로전화설문혹은의무기록조회를통하여, 사망 112 대한신경과학회지제 27 권제 2 호, 2009

4 A B C D E Figure. Kaplan-Meier survival curves comparing risk of nonfatal or fatal recurrent stroke. Cumulative analysis of the primary endpoints shows fatal or nonfatal recurrent stroke rate according to gender (A), age groups (B), previous stroke history (C), type of stroke (D), and TOAST classification (E). LAA; large artery atherosclerosis, SVO; small vessel occlusion, CE; cardioembolism, OD; other determined cause, UD; undetermined cause 환자 (N=128) 를제외한 1,958 명중약 75% 가항혈전제를복용하고있다는결과를얻을수있었다 (OCSP 의경우항혈소판제복용률은 6%, 항응고제복용률은 1% 였다 5 ). 뿐만아니라, 저자들이인용한문헌중에서 1980 년대이루어진연구보다최근연구일수록뇌졸중의재발빈도가낮은것을알수있는데 (Table 3), 세대가변하면서과거보다이차예방에대한적절한치료와함께위험인자관리가잘되고있는것으로추정할수있을것이다. 둘째, 뇌졸중재발의정의가각연구마다조금씩다른점이다. 대부분의연구 5,7,10 에서분석의편의성을위해 21 일이후발생한뇌졸중 이란정의와 21 일이내발생한뇌졸중가운데지표뇌졸중과명백하게구분되는신경학적증상을보이는뇌졸중 이란정의를같이사용하였다. 하지만, 뇌졸중이재발된환자가본원에내원하지않는경우신경학적증상에대해정확한정보수집이어려워 21일이후의시간적정의만가져오게되었다. 따라서, 본연구에서는사망등으로인해관찰기간이 21 일이내인환자를제외하였고, 21일이내에재발한경우는뇌졸 중재발로포함하지않았으므로실제보다재발률이낮게평가되었을것이다. 셋째, 연구대상의구성이다른점을들수있다. 앞서기술한과거 4개연구대상의평균연령이 70 대였으며 (Table 3), 본연구에등록된환자의평균연령이 66세인점을고려하면상대적으로고령환자의비율이낮다. 그리고, 인종간의차이와그에따른고위험인자유병률의차이를들수있겠다. 저자들이인용한외국의연구중가장뇌졸중재발률이낮았던 NOMAS 의고혈압 (78.2%) 과당뇨병 (43.4%) 유병률 11 을비교해도, 각각 61.4% 와 27.8% 로빈도가낮았다 (Table 1). 이러한요인들로인하여본연구의뇌졸중재발률이과거연구보다낮았을것으로생각하였다. TOAST 분류에따른뇌졸중재발률을분석하여보고한과거연구는많지않으며, 본연구에서비록통계적으로유의하지는않았지만심인성색전이나원인불명으로분류된뇌경색에서재발률이높은경향이있었다 (Fig. E). 보편적으로색전에의한뇌경색이의심되나심인성원인을찾지못할때원인불명으로 J Korean Neurol Assoc Volume 27 No. 2,

5 고영채박정현김욱주양미화권오기오창완정철규백남종한문구배희준 Table 3. Comparisons of cumulative risks (%) of stroke recurrence within defined time interval between the previous studies and ours 30 days 0-3 month 0-6 month 6-12 month 0-1 year 1-2 year 2-3 year 0-3 year A B C D E A Oxfordshire 5 Community (105,000) based 1st-stroke patient (n=675) Male; 47%, Mean age; 72 Follow-up period; 2~6.5 years Ischemic stroke; 80%, Hemorrhagic stroke; 20% B Perth Community 10 Community (138,708) based 1st-stroke patient (n=370) Male; 53%, Mean age; 73±13 Follow-period; 5 years (median) Ischemic stroke; 73%, Hemorrhagic stroke; 14.3%, Unknown; 12.7% C South London Stroke Register 7 Population (234,533) based 1st-stroke (n=1,626) Male; 48.7%, Mean age; 71.4±14.2 Follow-up period; 432 days, 32 to 1090 (median, interquartile range) Ischemic stroke; 71.8%, Hemorrhagic stroke; 14.6%, Unknown; 13.6% D NOMAS (2006) 11 NOMAS cohort, >40 year-old, 1st- ischemic stroke (n=655) Male; 44.6%, Mean age; 69.7±12.7 Follow-up period; 4 years (median) Ischemic stroke; 100% E SNUBH Cohort Seoul National Univ. Bundang Hospital Cohort Single hospital based cohort, acute stroke (n=2,086) Male; 59.3%, Mean age; 66.5±12.65 Follow-up period; 741 days, 208 to 1039 (median, interquartile range) Ischemic stroke; 88.6%, Hemorrhagic stroke; 11.4% 분류되는경우가많다는것을고려하면, 원인불명의뇌경색에서재발률이높은것은색전뇌경색의재발률이반영된것으로추정된다. 독일의연구 12 에서심인성색전에의한 2년뇌졸중재발률이 22% 로가장높았으며소동맥폐색은 11% 로재발률이낮았다. 뇌출혈과뇌경색의재발률의차이는통계적의미를부여하기어려운데, 이는뇌경색보다뇌출혈환자의수가적고, 신경과에입원한뇌출혈환자만을대상으로하여상대적으로증상이심한뇌출혈환자들이배제되었을우려가높기때문이다. 연령에따른재발률은확실한차이가있었는데이러한양상들은과거외국연구들과유사한결과이다. 5,7,10,11 본연구의제한점으로단일기관 (single center) 기반의연구라는점과뇌졸중재발률을조사하는방식에서후향적방법과전향적방법이섞여있는점을들수있겠다. 이를보완하기위하여의무기록을같이조회하였으며, 통계청사망원인원시자료를이용하여추적소실을최소화하려고노력하였으나, 외래에서통원치료를받지않아의무기록이없고입원날짜가오래전인경우전적으로전화응답자의기억에의존해야하는등정보수집의제한에따른바이어스가있을가능성은인정해야할것이다. 뇌졸중에이환된환자와보호자는뇌졸중재발을항상두려워하며, 담당의사로부터예방에대한조언과정보를얻기원한다. 5 그러므로, 자신이진료하는환자들의뇌졸중재발률을파 악하고, 환자에게이차예방을하도록하였을때얼마나재발률을낮출수있는가에대한정보를환자에게제공하는것은뇌졸중환자를진료하는의사들에게있어서매우중요한일일것이다. 하지만, 실제아시아권에서는이에대한연구가발표되지못하고있다. 본연구의고찰을준비하는과정에서 2008 년 10월부터 11월사이에 PubMed, KoreaMed, MEDLIS, 국회도서관의인터넷검색을통해체계적인문헌검색을하였는데, 주제어는한국어검색의경우뇌졸중, 재발등 2개의단어로조합하여검색하였고, 영문검색의경우 Stroke, Recurrence, Outcome 을각각조합하여검색하였으나국내는물론아시아권에서조차뇌졸중환자코호트의뇌졸중재발률을조사한연구를찾지못하였다. 따라서, 향후국내에서도재발을포함한뇌졸중환자의장기예후에관하여다기관 (multicenter) 혹은지역사회기반의대규모코호트연구가시급한것으로판단하였다. REFERENCES 1. Mohr JP CD, Grotta JC, Weir B, Wolf PA. Stroke: Pathophysiology, Diagnosis, and Management. 4 ed. Philadelphia: Churchill Livingstone, 2004; Sacco RL, Shi T, Zamanillo MC, Kargman DE. Predictors of mortality and recurrence after hospitalized cerebral infarction in an urban community: the Northern Manhattan Stroke Study. Neurology 1994;44: 대한신경과학회지제 27 권제 2 호, 2009

6 3. Shin DH, OY Bang. Mechanisms of Recurrence in Subtypes of Ischemic Stroke: A Hospital-based Follow-up Study. J Korean Neurol Assoc 2005; 23: Shin DS, Song MK, Lee SM, Choi SM, Kim BC, Kim MK, et al. Factors Determining the Severity of Recurrent Stroke. Korean J Stroke 2002; 4: Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Long-term risk of recurrent stroke after a first-ever stroke. The Oxfordshire Community Stroke Project. Stroke 1994;25: Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O Fallon WM, Wiebers DO. Survival and recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 1975 through Neurology 1998;50: Hillen T, Coshall C, Tilling K, Rudd AG, McGovern R, Wolfe CD, et al. Cause of stroke recurrence is multifactorial: patterns, risk factors, and outcomes of stroke recurrence in the South London Stroke Register. Stroke 2003;34: Stroke Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke 1989;20: 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 in Acute Stroke Treatment. Stroke 1993;24: Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, et al. Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998;29: Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology 2006;66: Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001;32: J Korean Neurol Assoc Volume 27 No. 2,

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical