伴右向左分流的偏头痛患者左房前后径与脑白质病变的相关研究

Association between Left Atrial Anterior-Posterior Diameter and White Matter Hyperintensities in Migraineurs with Right-to-Left-Shunt

目的:脑白质病变(White Matter Hyperintensities, WMHs)在偏头痛中很常见,可能与右向左分流(Right- to-Left-shunt, RLS)有关。近年来,有研究表明RLS对左心房扩大(left atrium enlargement, LAE)有影响。然而,关于LAE与伴有RLS偏头痛患者的WMHs发病机制相关性的研究甚少。我们旨在探讨LAE对伴RLS偏头痛患者的WMHs的影响,并进一步评估偏头痛患者WMHs的独立危险因素。方法:本研究选入自2016年1月至2021年8月在青岛大学附属医院神经内科病房住院及门诊就诊的偏头痛患者共计206名。选入研究对象均符合《国际头痛疾病分类》(第3版)的诊断标准(International Classification of Headache Disorders (3rd edition beta version))。所有入选的受试者均接受了经颅多普勒造影(C-TCD)、经胸超声心动图(TEE)、MRI检查。入选标准:(1) 年龄在18~65岁之间;(2) 声窗良好,能有效执行Valsalva手法(VM)。排除具有以下特征的患者:(1) 急性脑卒中。(2) 合并严重心肺疾病。(3) 创伤、手术和妊娠。(4) 严重肝肾功能不全、癌变、严重感染、癫痫等精神病。(5) 不能配合Valsalva动作。(6) 颅内或颅外动脉狭窄。由于合并心功能不全、Valsalva动作无法完成、严重的颅内动脉狭窄以及声窗不良而排除18人,最终纳入本研究共188人。入选的受试者均参与有关脑血管疾病的主要危险因素的标准化问卷调查,包括性别、年龄、高血压病史、糖尿病史、高脂血症病史、缺血性脑卒中病史,偏头痛既往史以及家族史、酒精状况(每月至少一次饮酒5年以上)和吸烟情况(连续或累计吸烟6个月以上,包括研究前6个月戒烟的前吸烟者)。此外,所纳入对象均完成颅脑MRI的T2加权序列(T2WI)和液体衰减反转恢复序列(Flare-image)扫描以确定WMHs。在Flare和T2WI图像上,脑白质病变被定义为侧脑室周围区域(通常是额部、后角或放射冠区、脑室旁)和深部白质的高强度病灶,可散发或融合成斑片状。通过经胸超声心动图(transthoracic echocardiography, TTE)确定左心房前后径、左心房长径、左心房短径、左室舒张末期内径、左室收缩末期内径、室间隔厚度、左室后壁厚度、肺动脉压以及心脏射血分数。所有研究对象完成对比增强经颅多普勒检查(Contrastenhanced Transcranial Doppler, c-TCD),通过c-TCD在双侧颞窗和枕窗探及到的微气泡信号证明RLS的存在。根据探测到的微栓子信号(MB)分级及划分流量大小:0级(未探测到微栓子信号)、I级(1~10 MB)、II级(11~25 MB)、III级(>25 MB,未形成雨帘)、IV级(形成雨帘);小流量(25 MB或形成雨帘)。通过颅脑MRI分为有WMHs组和无WMHs组并进行各心脏径线、年龄等相关危险因素的组间差异比较。此外,根据c-TCD分为有RLS和无RLS组以及大小不同流量亚组,比较组间各心脏径线、脑白质病变及相关危险因素有无差异。针对上述资料进行单因素分析并将具有统计学意义的变量(p < 0.05)进行多因素Logistic回归分析,讨论关于伴有RLS偏头痛患者脑白质病变的独立危险因素。所用资料的统计分析均通过软件SPSS 24.0完成。结果:本研究最终纳入188名偏头痛患者,平均年龄43.3岁(18至65岁),其中男性64例(34%)、女性124例(66%),伴有脑白质病变的偏头痛患者97例(51.6%),不伴有脑白质病变的患者91例(48.4%)。与无脑白质病变组相比,伴有脑白质病变的偏头痛患者的左心房前后径更大(LAAPD 3.59 ± 0.43 VS. 3.27 ± 0.34, p = 0.000)。此外,伴WMHs的偏头痛组的左房长径(LA major axis)、左室舒张末期内径(LVDd)、左室收缩末期内径(LVDs)均大于不伴有WMHs组(LA major axis 4.79 ± 0.57 VS. 4.50 ± 0.47, p = 0.000;LVDd 4.53 ± 0.30 VS. 4.43 ± 0.28, p = 0.012;LVDs 2.89 ± 0.30 VS. 2.80 ± 0.28, p = 0.041)。而且,伴有WMHs偏头痛患者的左心室射血分数(LVEF)小于无WMHs的偏头痛患者(63.98 ± 3.07 VS. 65.02 ± 3.52;p = 0.031)。在年龄、高血压、高脂血症以及缺血性脑血管病史方面,有无WMHs偏头痛组间样存在明显差异。此外,伴有RLS的偏头痛患者(占纳入对象的69.14%)被进一步分为大分流量亚组79名和小分流量亚组51名。与包含58名不伴RLS的偏头痛患者组比较,RLS (+)组偏头痛患者更易出现脑白质病变(%)(75 (57.5) VS. 22 (38.6), p = 0.018),而且RLS (+)组中偏头痛病史更常见(%) (104 (80) VS. 37 (63.8), p = 0.028),组间比较显示RLS与脑白质病变及偏头痛关系密切。但在大、小分流量亚组之间脑白质病变、各心脏径线均无统计学差异。Logistic回归分析显示,左心房前后径增大是偏头痛患者脑白质病变发生的独立危险因素(OR = 9.352;95% CI = 2.081~42.027;p = 0.004)。结论:在偏头痛患者中,伴有WMHs组的LAAPD明显大于无WMHs组,此外,WMHs组的LA major axis、LVDd及LVDs也显著大于无WMHs组。而在有无RLS组间以及RLS大小分流亚组之间LAAPD无差异。研究表明,在伴RLS的偏头痛患者中LAAPD与WMHs有关,而且LAAPD增大是偏头痛患者发生WMHs的独立危险因素。

Background and Purpose: White Matter Hyperintensities (WMHs) are common in migraine and might be related to right-to-left-shunt (RLS). Recently, several studies indicated the effect of RLS on left atrium enlargement (LAE). Nevertheless, there is few literature on the association between LAE and the pathogenesis of WMHs in migraineurs with RLS. We aim to explore the effect of LAE on WMHs in migraineurs with RLS, and further evaluate independent risk factor of WMHs in migraine patients. Methods: A total of 206 enrolled participants were diagnosed with migraine by Interna-tional Classification of Headache Disorders, (3rd edition beta version) at the Affiliated Hospital of Qingdao University from January 2016 to August 2021. All selected subjects underwent Contrast Enhancement Transcranial Doppler (C-TCD), Transthoracic echocardiography (TEE), MRI, Inclusion criteria was as follows: (1) age between 18 to 65 years;(2) with well acoustic window and effective execution of Valsalva maneuver (VM). Patients with following characteristic were excluded: (1) acute stroke;(2) complicated with severe cardiopulmonary disease;(3) trauma, surgery and preg-nancy;(4) severe liver and renal dysfunction, cancer, serious infection, epilepsy and other psycho-sis;(5) ineffective execution of VM;(6) intracranial or extracranial arterial stenosis. 18 migraineurs were excluded due to cardiac insufficiency, inability to complete Valsalva movements, severe intra-cranial artery stenosis, and poor acoustic window, a total of 188 patients were finally included in this study. The enrolled subjects participated a standardized, structured questionnaire to obtain information of main risk factor to cerebral vascular disease, including age, hypertension, diabetes, hyperlipidemia, alcohol status (alcohol intake at least once a month for more than 5 years) and cig-arette smoking (continuous or cumulative smoking for 6 months or more and include former smoker who had quitted smoking up to 6 months before the study). In addition, all subjects under-went brain MRI T2-weighted sequence (T2WI) and fluid-attenuated inversion recovery sequence (Flare-image) scans to determine WMHs. On Flare and T2WI images, leukodystrophy is defined as high-intensity lesions in the periventricular area (usually the frontal, posterior horn, or radio-crown area, paravulicular) and deep white matter that can be sporadic or fused into patchy patches. Transthoracic echocardiography (TTE) was used to determine the anteroposterior diameter of the left atrium, the long diameter of the left atrium, the short diameter of the left atrium, the end dias-tolic diameter of the left ventricle, the end systolic diameter of the left ventricle, the thickness of the ventricular septum, the posterior wall of the left ventricle, the pulmonary artery pressure, and the ejection fraction. All enrolled migraineurs underwent Contrastenhanced Transcranial Doppler (c-TCD), and the presence of RLS was confirmed by microbubble signals detected by TCD in bilateral temporal and occipital Windows. According to detected microembolus signal (MB) classification and flow size: Level 0 (no microembolus signal detected), Level I (1~10 MB), Level II (11~25 MB), Level III (>25 MB, no rain curtain formed), Level IV (rain curtain formed);Small traffic (25 MB). Brain MRI was used to divide WMHs group into WMHs group and WMHS group without WMHS group. In addition, according to c-TCD, they were di-vided into groups with RLS and without RLS as well as different flow subgroups. The differences in cardiac diameters, leukoencephalopathy and related risk factors were compared between groups. Based on the above data, univariate analysis and multivariate Logistic regression analysis were performed for statistically significant variables (p < 0.05) to discuss the independent risk factors for WMHs in migraineurs with RLS. Statistical analysis of the data used was completed by SPSS 24.0 software. Results: A total of 188 migraine patients with a mean age of 43.3 years (18~65 years) were enrolled in this study, including 64 males (34%) and 124 females (66%), 97 migraineurs (51.6%) with WMHs and 91 patients (48.4%) without WMHs. The LAAPD of the left atrium was larger in migraineurs with WMHs compared with those without WMHs (LAAPD 3.59 ± 0.43 VS. 3.27 ± 0.34, p = 0.000). In addition, the left atrial long diameter (LA major axis), left ventricular end-diastolic internal diameter (LVDd), and left ventricular end-systolic internal diameter (LVDs) in WMHs group were greater than in non- WMHs group (LA major axis 4.79 ± 0.57 VS. 4.50 ± 0.47, p = 0.000;LVDd 4.53 ± 0.30 VS. 4.43 ± 0.28, p = 0.012;LVDs 2.89 ± 0.30 VS. 2.80 ± 0.28, p = 0.041). Moreover, the left ventricular ejection fraction (LVEF) in WMHs group was lower than that in non-WMHs group (63.98 ± 3.07 VS. 65.02 ± 3.52;p = 0.031). There were also significant differences in age, cardiovascular disease risk factors, and ischemic cerebrovascular history between the groups with and without WMHs. In addition, migraineurs with RLS (69.14% of the enrolled sub-jects) were further divided into the large shunt subgroup of 79 patients and the small flow sub-group of 51 patients. Comparing with 58 subjects without RLS, 130 migraineurs with RLS were more likely to suffer WMHs (%) (75 (57.5) VS. 22 (38.6), p = 0.018). Furthermore, the history of mi-graine was more common in the RLS positive group (%) (104 (80) VS 37 (63.8), p = 0.028), and comparison among groups showed that RLS was closely associated with WMHs and migraine. How-ever, there was no significant difference in WMHs and cardiac diameter between large and small flow subgroups. Logistic regression analysis showed that the enlarged LAAPD of left atrium was an independent risk factor for WMHs in migraineurs (OR = 9.352;95% CI = 2.081 42.027;p = 0.004). Conclusions: In migraine patients, LAAPD in the group with WMHs was significantly larger than that in group without WMHs. In addition, LA major axis, LVDd and LVDs in the group with WMHs were also obviously higher than those without WMHs. There was no difference in LAAPD between groups with and without RLS or between subgroups with different shunts. Our studies showed that LAAPD is associated with WMHs in migraineurs, and increased LAAPD is an independent risk factor for WMHs in migraine patients.