| Summary: | 博士 === 國立臺灣大學 === 流行病學研究所 === 93 === Cerebrovascular disease (CVD) was the 1st leading cause of death from 1963-1981, the 2nd leading cause of death from 1982-2003 in Taiwan. Although CVD became the 3rd cause of death in 2004, it still will prevail in the future decades for the ageing population, unchanged age-specific stroke incidence and low case-fatality of stroke in Taiwan.
Past Taiwan epidemiological studies on CVD were reviewed extensively. The review was divided into several parts, including vital statistic data of CVD, population-based incidence and prevalence study of stroke, hospital-based stroke registry studies, risk factor studies of stroke and carotid atherosclerosis, stroke clinical trials, genetic epidemiological stroke studies, and survival analytic studies of CVD. The past studies emphasized on conventional risk factors of CVD. Therefore, the present study focus on unconventional risk factors of CVD, including pregnancy related stroke, and post-irradiation carotid atherosclerotic disease. For increasing prevalence of carotid stenosis in Taiwan, long-term outcome and survival analysis of patients with cervical carotid artery stenosis was studied.
This study’s method mainly stemmed from “The Stroke and Cerebral Atherosclerosis Study in National Taiwan University Hospital” (SCAN) The objectives of SCAN are: (1) to study the risk factors, pathophysiological characteristics and prognosis in different types of stroke; (2) to study specific types of CVD, such as stroke related to pregnancy and puerperium, cerebral venous thrombosis (CVT), and post-irradiation vasculopathy, etc.; (3) to investigate the extent and severity of carotid atherosclerosis and its risk factors and the long-term outcome and survival of patients with cervical carotid artery stenosis. Both stroke registry and carotid stenosis registry were set up. The stroke registry in the SCAN project was closed to the standard of an optimal stroke data bank. There was good validity in stroke subtyping and carotid atherosclerotic quantification. Based on the SCAN structure, three substudies were present in this doctoral thesis: substudy-1, pregnancy-related stroke study; substudy-2, cervical radiation therapy (RT) as a significant risk factor of carotid atherosclerosis study; substudy-3, long-term outcome and survival analysis of patients with cervical carotid artery stenosis.
Pregnancy is a known risk factor for stroke, but relatively few studies have been conducted in Asian populations to document the risk. The substudy-1 aimed to analyze the incidence and etiologies of stroke occurring during pregnancy and puerperium, and to assess risk factors and etiologies of stroke in women of reproductive age based on relationship to pregnancy. From 1984 to 2002, all female patients 15 through 40 years of age with a first-ever stroke at National Taiwan University Hospital were included in this study. Pregnancy-related stroke (PRS) was defined as patients who had stroke occurrence during pregnancy or within 6 weeks postpartum. Stroke was classified as cerebral infarct (CI, including arterial infarct [AI] and CVT), cerebral hemorrhage (CH), and subarachnoid hemorrhage (SAH). Of 402 young female stroke patients, 49 had stroke during pregnancy and puerperium, including 16 with AI, 11 with CVT, 19 with CH and 3 with SAH. After excluding referral patients, the incidences of pregnancy-related stroke were 46.2 (95% confidence interval [CI], 30.7-69.5) per 105 pregnancies. CVT was more common in PRS than stroke unrelated to pregnancy (39% vs. 7%, P<0.001), and 73% of these cases occurred postpartum. Preeclampsia-eclampsia was an important cause of peripartum CH (37%), but not CI (4%). Eclampsia (37%) and arteriovenous malformation (26%) were the most important etiologies of CH. The incidence of stroke occurrence during pregnancy and puerperium in Taiwanese women is higher than that of Caucasian populations; the majority of strokes occurred in the third trimester and puerperium, particularly CVT. Among PRS cases, postpartum cerebral venous thrombosis and preeclampsia-eclampsia were the major causes of CI and CH, respectively.
Cervical carotid artery disease following cervical irradiation has been well documented. In Taiwan, the incidences of head and neck malignancies, especially nasopharyngeal carcinoma, are quite high and accounted for one of the leading causes of cancer. Therapeutic RT to the affected area has successfully increased survival time for afflicted patients and has created a pool of potential RT-induced vasculopathy. The substudy-2 aimed to analyze whether cervical irradiation therapy as an important risk factor for cervical carotid stenosis in patients with ischemic stroke. From 1995 to 2004, there were 4,862 adult patients with first-ever ischemic stroke, including 70 (1.4%, male were 69%, mean age was 62.2+10.3 years). The average duration from patients receiving RT to the onset of stroke was 12.3+9.0 years. Total anterior circulation infarct was higher in RT patientsthan non-RT patients (27.1% vs. 14.9%). RT patients had higher incidences than non-RT patients in carotid atherosclerosis (91.4% vs. 78.3%, P=0.009), carotid stenosis (44.3% vs. 11.1%, P<0.001) and bilateral carotid stenosis (14.3% vs. 1.9%, P<0.001). By multivariate logistic regression analysis, RT was a significant risk factor for carotid stenosis >50% (odds ratio [OR]: 9.16, 95% confidence interval [CI]: 5.51-15.22, P<0.001) and carotid plaque score >6 (OR: 11.89, 95% CI: 6.57-21.51, P<0.001). Of 70 ischemic stroke patient with RT, only male gender (OR: 3.196, P=0.05) and the duration from RT to stroke more than 10 years (OR: 6.06, P=0.016) were significant independent rrisk factors. For patients ever received cervical RT, periodical screening of cervical arteries is required.
There were several large clinical trials documenting the efficacy of interventional therapies (carotid endarterectomy [CEA] and carotid artery stenting [CAS]) in cervical carotid artery stenosis. However, all these studies were undergone in Caucasian countries, and no large studies was ever reported from Asian countries. The substudy-3 aimed to analyze the long-term outcome in patients with cervical carotid artery stenosis receiving different methods of treatment. From 1995 to 2004, a total of 1,269 patients (male, 71%; mean age, 69.6+11.0 years, asymptomatic patients, 58.3%) included. There were 76 patients receiving CEA, 292 receiving CAS, and 901 patients with medical therapy. The average duration of follow-up was 3.3+2.5 years. Major peri-procedural complications (including death, stroke, and acute myocardial infarction within 30days) were acceptable for both CEA (symptomatic, 7.1%, asymptomatic, 5%) and CAS (symptomatic, 7.1%, asymptomatic, 3%). The annual recurrent severe carotid stenosis for both CEA (2.0%) and CAS (1.4%) was low. There were significantly lower death rates for long-term follow-up of patients with interventional therapies than those with medical treatment (p<0.001). For symptomatic patients, the major cause of death during long-term follow-up was stroke, followed by infection, cancer and myocardial infarction. However, stroke was not the major cause of death in asymptomatic patients. By Cox proportional hazard model, age>65 years, diabetes, ischemic heart disease, renal disease and malignancy were unfoavorable long-term survival factors. CEA and CAS had lower stroke recurrence and had better long-term survival than medical therapy for symptomatic carotid stenosis patients. The treatment strategies for different types of carotid stenosis patients with different severity of carotid stenosis should be defined.
Single-hospital based registry study has potential limitations, including patient selction bias, more complicated cases in medical center, and inability to delineate causal- relationship as population-based study. However, it has advantages of low study cost, large-scaled clinical informations and data, particularly helpful for study on specific forms of CVD. The SCAN project will continue and highlight on intracranial atherosclerosis, posterior circulation stroke, and cerebral hemorrhage in the future. In the genetic era, genetic study on CVD, esp. gene therapy (such as stem cell therapy) in stroke will be emphasized.
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