【作者】 宋婷婷；

【导师】 陈蕾；

【作者基本信息】 四川大学 ， 神经病学（专业学位）， 2022， 硕士

【摘要】 背景及目的:癫痫(epilepsy,EP)是最常见的慢性中枢神经系统疾病之一,具有较高的致残率、致死率与疾病负担,明确癫痫发作类型、危险因素及癫痫病因是进行癫痫诊疗的重要条件。先天性心脏病(congenital heart disease,CHD)是最常见的先天性异常之一,近年来由于医疗技术的进步,成年先天性心脏病(adult congenital heart disease,ACHD)患者的数量逐渐增加,研究者逐渐发现CHD患者偏头痛、卒中、癫痫等中枢神经系统疾病发生的高风险,大量观察性研究及随机对照试验已经证实了卵圆孔未闭(patent foramen ovale,PFO)同偏头痛、隐源性卒中(cryptogenic stroke,CS)等中枢神经系统疾病相关,癫痫作为神经科的常见疾病,与偏头痛、卒中等疾病之间关系密切,但癫痫与PFO之间的相关性未知。虽然既往研究已经发现了CHD患者癫痫发生风险较健康对照组高,但在临床诊治中神经科医生及心脏内科医生普遍对其重视程度不高,目前的研究纳入所有类型的CHD,未进行分类讨论,尚无文献报道包括PFO在内占比较高的简单型CHD与癫痫的相关性,且缺乏中国西部人群的数据。基于此,本研究主要研究目的包括:(1)探究PFO、房间隔缺损(atrial septal defect,ASD)、室间隔缺损(ventricular septal defect,VSD)、动脉导管未闭(patent ductus arteriosus,PDA)这四种中国西部地区占比较高的简单型CHD中癫痫患病率的差异;(2)探究癫痫人群与自然队列人群PFO阳性率的差异;通过建立以上双向的研究样本人群,探究PFO与癫痫之间的相关性。材料和方法:纳入华西医院住院部CHD患者连续登记系统2010年1月至2020年12月间所有诊断为简单型CHD(PFO、ASD、VSD、PDA)的患者,通过电话随访以及门诊复诊的方式对简单型CHD人群进行随访,了解癫痫发作情况。本研究采集的信息主要包括:年龄、性别、BMI、长期居住地海拔等人口学信息;吸烟、饮酒、熬夜等行为和生活习惯因素;早产、出生缺氧、先天性异常、高热惊厥、头颅外伤等既往病史;高血压、糖尿病、偏头痛等合并症;是否患有癫痫等临床信息。同时,连续登记2019年7月至2021年9月华西医院癫痫中心的癫痫患者,并招募同期成都龙泉驿社区无癫痫的自然队列人群作为对照组。纳入的癫痫患者要求通过病史询问及辅助检查未发现明确的导致癫痫发作的病因,并能接受经胸超声心动图(transthoracic echocardiography,TTE)和经胸超声心动图声学造影(contrast transthoracic echocardiography,c-TTE)检查。采集的信息包括:年龄、性别、BMI、居住地等人口学信息;吸烟、饮酒、饮咖啡、熬夜等生活行为习惯;早产、出生缺氧、先天性异常、高热惊厥、共患偏头痛等既往病史,对于癫痫患者还会收集癫痫家族史、发病年龄、发作频率与发作持续时间、发作类型、抗癫痫药物(anti-seizure medication,ASM)的使用、是否为难治性癫痫、是否存在癫痫持续状态等癫痫疾病特征。本研究首先建立多因素logistic回归模型分析简单型CHD人群癫痫发生的危险因素;同时通过逆概率处理加权法(the inverse probability of treatment weighting,IPTW)校正癫痫人群与自然队列人群中的混杂因素,在此基础上采用加权卡方检验比较两组人群PFO阳性率差异;通过上述方法,从两个方面探讨PFO与癫痫的相关性。结果:本研究纳入10914例简单型CHD患者,总体癫痫患病率为0.99%,其中PFO、ASD、VSD、PDA患者中癫痫的患病率依次为2.15%、0.6%,0.89%,0.77%,在调整了既往病史、行为生活习惯等因素的条件下,发现PFO患者癫痫患病率是非PFO患者癫痫患病率的3.671倍(OR值[Odds ratio]:3.671,95%CI[95%Confidence interval]:2.412～5.541)。同时,纳入癫痫患者723例,其中141例(19.50%)癫痫患者年龄<18岁,582例(80.50%)年龄在18～55岁之间,同期纳入了2760例自然队列人群为对照组,年龄在18～55岁之间。PFO在癫痫组中的阳性率为38.45%,在年龄<18岁的癫痫组中为42.55%,在18～55岁癫痫组中为37.46%,难治性癫痫组的PFO阳性率更是高达53.78%,对照组的PFO阳性率仅为24.46%,在平衡其他影响因素的条件下,18～55岁癫痫组中PFO阳性率是对照组的1.435倍(OR值1.435,95%CI:1.288～1.599)。在癫痫组中,随着右向左分流(Right to left shunt,RLS)分级的提高,癫痫发作频率、发作持续时间增高,癫痫持续状态、难治性癫痫患者增多。结论:本研究从两个角度证实了PFO与癫痫之间存在相关性,PFO是癫痫的一项独立的危险因素,结果表明,在简单型CHD人群中,PFO组癫痫患病率高于其他三种CHD(ASD、VSD、PDA);同时,癫痫组PFO阳性率高于对照组,且癫痫的严重程度与RLS分级呈正相关。更多还原

【Abstract】 Background and Objective:Epilepsy(EP)is one of the most common chronic central nervous system diseases,with the higher disability rate,mortality rate and disease burden.It is essential to identify the type,risk factors and etiology of epilepsy in order to conduct more appropriate diagnosis and treatment of epilepsy.Congenital heart disease(CHD)is one of the most common congenital abnormalities.In recent years,the number of adult congenital heart disease(ACHD)increased.Researchers have found that patients with CHD have an increased risk of migraine,stroke,epilepsy and other diseases.A large amount of observational and randomized controlled studies had confirmed that patent foramen ovale(PFO)is associated with migraine,cryptogenic stroke(CS),and other central nervous system diseases.As a common ailment in neurology,epilepsy is related to migraine and stroke,but the correlation between epilepsy and PFO is unknown.Although previous studies have found that the risk of epilepsy in patients with CHD is higher than those without CHD,neurologists and cardiologists do not pay much attention to it in clinical practice.The current research focused on all types of CHD.The correlation between simple CHD and epilepsy is deficient,and there is a lack of data in western China.On account of above background,the main purposes of this study include:(1)studying the different risks of epilepsy in simple CHDs: PFO,atrial septal defect(ASD),ventricular septal defect(VSD)and patent ductus arteriosus(PDA),which account for a relatively high proportion in Western China;(2)comparing the different prevalence of PFO in patients with epilepsy and natural cohort population.We explored the correlation between PFO and epilepsy by the above study.Materials and Methods:We included patients with simple CHD(PFO 、 ASD 、 VSD 、 PDA)in the continuous registration system of patients with CHD in the inpatient department of West China Hospital from January 2010 to December 2020.The patients were followed up by telephone or in the outpatient department in order to know the seizure.The information collected in this study includes demographic information such as age,gender,BMI,and altitude of residence;behavioral and lifestyle factors such as smoking,drinking,and staying up late;previous medical history such as premature delivery,birth hypoxia,congenital abnormality,febrile convulsion,and head trauma;complications such as hypertension,diabetes,and migraine;and clinical information such as whether suffering from epilepsy.Meanwhile,we continuously registered patients with epilepsy in West China Hospital from July 2019 to September 2021,and we also recruited natural cohort population without epilepsy in community as the control group.The patients with epilepsy included in our study were required to find no etiology and accept transthoracic echocardiography(TTE)and contrast transthoracic echocardiography(c-TTE).We collect demographic information: age,gender,BMI,and place of residence;behavioral factors: smoking,drinking,drinking coffee,and staying up late;past medical history: premature birth,birth hypoxia,congenital abnormalities,febrile seizures,and migraine.For patients with epilepsy,the family history of epilepsy,the onset age of epilepsy,the frequency and duration of seizures,the type of seizures,the use of antiepileptic drugs(ASMs),whether it is intractable epilepsy and other characteristics of epilepsy were also collected.Multiple logistic regression model was used to analyze the risk factors of epilepsy in population with simple CHD.At the same time,the inverse probability of treatment weighting(IPTW)was used to correct the confounding factors in patients with epilepsy and natural cohort population.Then,the prevalence of PFO between the two groups was compared by weighted chi square test.Through the above steps,the correlation between PFO and epilepsy was discussed from two aspects.Results:10914 patients with simple CHD were included in this study.The prevalence of epilepsy in patients with PFO,ASD,VSD and PDA was 2.15%,0.6%,0.89% and0.77%,respectively,and the overall prevalence was 0.99%.After adjusting for the previous medical history,behavior and living habits and other factors,we found that the risk of epilepsy in patients with PFO was 3.671 times as high as that in patients without PFO(OR: 3.671,95% CI: 2.412 ～ 5.541).At the same time,723 patients with epilepsy were included,of which 141(19.50%)were younger than 18 years old and582(80.50%)were between 18 and 55 years old.The number of natural cohort population was 2760,and it was regarded as controls aged 18～55.The positive rate of PFO in patients with epilepsy was 38.45%,of which 42.55% in patients with epilepsy younger than 18 years old and 37.46% aged 18～55.The prevalence of PFO was 53.78% in patients with refractory epilepsy and only 24.46% in the control group.After adjusting for confounding factors,the prevalence of PFO in patients with epilepsy was 1.435 times higher than that in natural cohort population(OR: 1.435,95%CI: 1.288 ～ 1.599).With the improvement of RLS grade,the frequency and duration of seizures,the number of patients with status epilepticus and intractable epilepsy increased.Conclusion:This study confirmed that PFO is related to epilepsy and PFO is an independent risk of epilepsy from two aspects.The results showed that the prevalence of epilepsy in patients with PFO was higher than in other simple CHDs(ASD,VSD,PDA).At the same time,the positive rate of PFO in patients with epilepsy was higher than in natural cohort population,and the severity of epilepsy was positively correlated with RLS grade.更多还原