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临床研究
DWI及3D SWAN提高新生儿胆红素脑病病理生理机制的认识
于金红 王静石 苗延巍 刘义勇 孙菲

Cite this article as: Yu JH, Wang JS, Miao YW, et al. DWI and 3D SWAN improve the knowledge of pathophysiological mechanism of neonatal bilirubin encephalopathy. Chin J Magn Reson Imaging, 2020, 11(11): 994-998.本文引用格式:于金红,王静石,苗延巍,等. DWI及3D SWAN提高新生儿胆红素脑病病理生理机制的认识.磁共振成像, 2020, 11(11): 994-998. DOI:10.12015/issn.1674-8034.2020.11.008.


[摘要] 目的 通过分析足月新生儿胆红素脑病的扩散加权成像(diffusion-weighted imaging,DWI)及磁敏感加权成像(susceptibility weighted imaging,SWI)表现,探讨高胆红素血症(hyperbilirubinemia,HB)对新生儿脑组织损伤的病理生理可能机制。材料与方法 回顾性分析75例临床确诊HB新生儿的DWI及三维重T2加权血管成像(three dimensions T2* weighted angiography,3D SWAN)资料。依据苍白球T1WI信号将HB患儿分成两组:正常信号组(HBn组,46例)及信号增高组(HBh组,29例)。同时收集44例健康的新生儿作为健康对照组(HC组)。测量ADC值并计算双侧苍白球与额叶白质比值(rADC值),计数脑内3D SWAN低信号灶(微出血)例数。分析MR各参数的组间差异及其与血清总胆红素(total serum bilirubin,TSB)的相关性。结果 HC组、HBn组、HBh组苍白球的rADC值依次减低(P<0.05),而HC组与HBh组间差异明显(P<0.05)。与HC组相比,HB组的脑内微出血数量明显增加(P<0.05)。HB组rADC值与TSB水平正相关(r=0.202,P=0.013),但是,脑内微出血数量与TSB水平无相关性(P=0.278)。结论 HB患儿苍白球水分子扩散受限,并与总胆红素水平相关;HB患儿易伴发脑内微出血,需要在治疗过程予以重视。
[Abstract] Objective: To investigate the possible pathophysiological mechanism of hyperbilirubinemia (HB) on neonatal brain tissue injury by analyzing the diffusion-weighted imaging (DWI) and susceptibility weighted imaging (SWI) manifestations of bilirubin encephalopathy in full-term neonates.Materials and Methods: The DWI and (three dimensions T2* weighted angiography (3D SWAN) data of 75 neonates with HB clinically confirmed were analyzed retrospectively. Children with HB were divided into two groups according to the T1WI signal of globus pallidus: normal signal (HBn group, 46 cases) and high-intensity signal group (HBh group, 29 cases). While 44 cases of healthy neonates were collected as the healthy control group (HC group). The ADC values were measured, and the ADC ratios (rADC value) were calculated in bilateral GPs and frontal white matter (FWM), and the number of low-signal foci (microbleeds) of 3D-SWAN were counted. The differences of MRI parameters between groups and their correlation with total serum bilirubin (TSB) were analyzed.Results: The rADC value of GP in HC group, HBn group and HBh group decreased successively (P<0.05), while the difference between HC and HBh groups was significant (P<0.05). Compared with HC group, the number of intrcerebral microbleeds (CMBs) in HB group was significantly increased (P<0.05). The rADC value of HB group had a positive correlation with TSB (r=0.202, P=0.013). However, no correlation was found between the number of CMBs in HB group and TSB (P=0.278).Conclusions: The limited diffusion of water molecules is present in GP and related to the level of total bilirubin in children with HB. CMBs more likely occur in children with HB and need to attach importance to it during treatment.
[关键词] 胆红素脑病;新生儿;弥散加权成像;磁敏感加权成像
[Keywords] bilirubin encephalopathy;neonates;diffusion weighted imaging;suseeptibility weighted imaging

于金红 大连医科大学附属第一医院放射科,大连 116011;大连市妇女儿童医疗中心放射科,大连 116033

王静石 大连市妇女儿童医疗中心放射科,大连 116033

苗延巍* 大连医科大学附属第一医院放射科,大连 116011

刘义勇 大连市妇女儿童医疗中心放射科,大连 116033

孙菲 大连市妇女儿童医疗中心放射科,大连 116033

通信作者:苗延巍,E-mail:ywmiao716@163. com

利益冲突:无。


收稿日期:2020-05-12
接受日期:2020-09-16
中图分类号:R445.2; R722.17 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2020.11.008
本文引用格式:于金红,王静石,苗延巍,等. DWI及3D SWAN提高新生儿胆红素脑病病理生理机制的认识.磁共振成像, 2020, 11(11): 994-998. DOI:10.12015/issn.1674-8034.2020.11.008.

       新生儿高胆红素血症(hyperbilirubinemia,HB)是新生儿期常见的临床疾病,严重且持续的可以发展成急性胆红素脑病(acute bilirubin encephalopathy,ABE),它是一种潜在破坏性疾病,可导致终生神经发育障碍,甚至死亡[1]。目前普遍公认MRI上双侧苍白球(globus pallidus,GP)对称性T1WI高信号是ABE特征性的影像表现[2],但对其形成机制尚缺乏有力证据,尚待深入研究。DWI对细胞水平水分子扩散具有较高敏感性,通过测量苍白球ADC值可以量化分子扩散状态,评价其微观结构变化。3D SWAN系SWI,对脑组织微量出血很敏感,而目前鲜有新生儿HB的SWI研究。基于此,本研究拟对患有HB的新生儿脑DWI及3D SWAN进行半定量分析,来进一步揭示HB对新生儿脑组织损伤的病理生理可能机制。

1 材料与方法

1.1 研究对象

       回顾性收集大连市妇女儿童医疗中心2014年10月至2019年3月经临床确诊的HB患儿75例(HB组),所有新生儿入院后均行常规MRI、DWI、3D-SWAN扫描并检测静脉血血清总胆红素(total serum bilirubin,TSB)水平。然后依据GP T1信号将HB组分为信号正常组(HBn)和信号增高组(HBh)。纳入标准:(1)单胎,出生孕周≥37周的足月新生儿;(2)发现病情至行MRI检查间隔≤10 d;(3) TSB> 220.6 μmol/L。排除标准:(1)围生期窒息缺氧、宫内感染、低血糖等造成脑内异常;(2) MRI序列不全或存在明显伪影而影响观察、测量。同期收集44例与病例组年龄、性别及体重相匹配的健康足月新生儿作为健康对照(healthy control,HC)组。纳入标准:(1) TSB<205 μmol/L;(2)颅脑(GP) MRI表现未见异常。

1.2 检查方法

       采用美国GE Signa HDXT 1.5 T MRI仪器,8通道头颈联合线圈。检查前30 min经肛门给予10%水合氯醛(1.0 ml/kg)灌肠镇静,患儿熟睡后呈仰卧位,中心线定位眉心进行颅脑MR扫描。具体序列及参数见表1

表1  MRI扫描序列及参数
Tab. 1  MRI scan sequences and parameters

1.3 MR图像分析

       T1W图像:由2名副高以上MR医生对HB组的图像进行双盲阅片、分组,GP信号增高判定通过与内囊后肢进行对比,当GP T1WI信号强度值高于内囊后肢信号时即为T1WI信号增高,对判定存在异议的进行讨论取得一致意见。利用GE ADW4.6后处理工作站的Functool 9.4.05软件对DWI序列进行后处理,获得ADC图。在GP、FWM最大层面手动设置ROI,ROI约20~30 mm2,同一部位测量三处获取同区域的ADC平均值(×10-3 mm2/s),计算GP/FWM的ADC比值,简称rADC值。ROI设置见图1

       3D SWAN图像:将3D SWAN原始图像在GE ADW 4.6工作站进行后处理,重建成轴位SWANMinIP图像(层厚2 mm,层间距1 mm)进行分析。将SWANMinIP图像上传PACS工作站,经2名副高以上MRI医生结合常规MRI来判定各组有无颅内微出血灶。参照Niwa等[3]SWI上出血的诊断标准:排除与常规MRI上相关的血管、骨或伪影结构一致的低信号,其余SWI上显示的低信号认为是出血灶。分别计数各组出血的数量并计算出血发生率。

图1  分别是GP、FWM测量层面的ADC (A、B)示意图,同一部位放置3个ROI
图2  HC组、HBn组及HBh组的rADC值(ADC比值)差异的箱式图。独立样本Kruskal-Wallis检验
图3  各组脑内微出血的数量的柱形图
Fig. 1  A, B: Schematic diagrams of ADC (A、B) of GP and FWM measurement layers,respectively. Three ROIs were placed at the same location.
Fig. 2  Box plot of rADC values (ADC ratio) in HC, HBn and HBh groups. Kruskal Wallis test for independent samples.
Fig. 3  Bar graphs of the number of CMBs in the brain of each groups.

1.4 统计学分析

       采用SPSS 25.0统计分析软件。符合正态分布计量资料以±s表示,不符合正态分布的以M (QR)表示。首先对临床资料性别(χ2检验)年龄(Krukal-Wallis H检验)及体重(one-way ANOVA F检验)差异性进行比较。rADC值三组间差异采用Krukal-Wallis H检验,Bonferroni校正针对多个检验调整显著性值。颅内微出血发生率的组间差异采用Fisher精确检验分析。rADC值、微出血发生率与TSB水平的关系采用Spearman及点二列相关分析。均以P<0.05为差异有统计学意义。

2 结果

2.1 临床资料对比分析

       性别(χ2=1.748,P=0.409)、年龄(H=2.445,P=0.294)及体重(F=0.052,P=0.949)均无显著性差异(P>0.05),见表2

表2  临床资料组间比较
Tab. 2  Comparison of clinical data between groups

2.2 rADC值组间比较

       HBh组的rADC中位值0.710 (0.072),HBn组为0.738(0.060),HC组为0.760 (0.085),三组rADC值存在差异(H=14.387,P=0.001;图2)。两两比较显示,HBh、HC组间存在显著性差异(调整后P=0.000),而HBn-HC组、HBh-HBn组之间rADC值差异无统计学意义(调整后P=0.127、0.135)。

2.3 颅内微出血病例数组间比较

       HB组(43/75)的颅内微出血例数高于HC组(6/44),两组差异具有统计学意义(调整后P=0.000);同时,HC-HBn组、HC-HBh组间微出血也有差异(调整后P<0.05),而HBn-HBh组间无显著差异(调整后P=0.339;图3图4图5)。

图4  胎龄39周,女,出生体质量2950 g;出生后7 d,TSB:348 μmol/L。A:横断面T1WI示双侧苍白球信号增高(HBh组);B~D:横断面T2WI、DWI (ADC图)示双侧苍白球未见异常信号;E:SWANMinIP序列显示左枕叶深部点状低信号,提示微出血
图5  胎龄38周+5,女,出生体质量3050 g,出生后7 d,TSB:288 μmol/L。A~D:横断面T1WI、T2WI、DWI (ADC图)示双侧苍白球未见明确异常信号(HBn组);E:SWANMinIP显示脑内未见异常低信号
Fig. 4  Gestational age 39 W, female, birth weight 2950 g, 7 days after birth, TSB: 348 μmol/L. A: Transverse T1WI showed high signal of bilateral globus pallidus (HBh group). B—D: Transverse T2WI, DWI (ADC map) showed that no abnormal signal were found in bilateral globus pallidus. E: SWANMinIP showed spot-like low signal in the left occipital lobe which indicated microbleeds.
Fig. 5  Gestational age 38 W+5, female, birth weight 3050 g, 7 days after birth, TSB: 288 μmol/L. A—D: Transverse T1WI, T2WI and DWI (ADC map) showed no clear abnormal signals in bilateral pallidum (HBn group). E: SWANMinIP showed no abnormally low signal in the brain.

2.4 MRI各参数与TSB值关系

       Spearmen相关分析显示,HB组的rADC值与TSB水平存在正向弱相关性(r=0.202,P=0.013);但是,HB组颅内出血发生率与TSB水平无关系(P=0.278)。

3 讨论

       胆红素脑病是高胆红素血症最严重的并发症,当过多的游离未结合胆红素(unconjugated bilirubin,USB)超出血清白蛋白的结合能力或血脑屏障破坏时,USB进入颅脑导致的脑功能损伤[4,5],USB主要选择性沉积在苍白球、海马、底丘脑、小脑核、听神经核等部位,尤其最易累及苍白球后部[6,7,8,9],因此,本研究对ADC值测量集中于苍白球。

       本研究利用DWI中ADC值能定量测量细胞水平分子扩散状态,来评估苍白球的水分子扩散的微观变化。近年来,对ABE发生时是否存在弥散受限一直存在争议。以往研究发现,ABE患儿苍白球DWI未见明确异常信号[9,10,11],ADC值对ABE早期诊断意义不大[12],但最新的研究[13]发现亚急性期苍白球附近存在ADC值增高,且ADC值与患儿的TSB水平有一定的相关性。本研究中,发现GP的rADC值于HC组、HBn组、HBh组中依次减低,且HC-HBh组间差异具有统计学意义,提示GP受损区域限制细胞内、外水分子的布朗运动状态改变,水分子弥散受限。Watchko等[14]和Falcao等[15]研究认为胆红素脑病发生时钙离子内流增多激发蛋白水解酶的活性增高可导致细胞凋亡,进而引发水分子布朗运动细微变化,但这种DWI信号变化通过肉眼尚无法分辨,而可通过ADC值量化这种细微差异,来反映出苍白球区域微观结构变化,扩宽了人们以往对ABE发病机制的认识,为临床更好评估及治疗胆红素脑病提供理论依据。

       本研究通过3D SWAN序列进一步发现HB新生儿易发生脑内微出血,分析原因可能是游离胆红素引起血小板活化率较正常健康儿明显升高、血液处于高凝状态,血小板数量增多、粘滞率升高[16,17];过量USB还可以导致细胞膜脆性增加,易出现溶血。USB引发溶血可能会形成恶性循环,进一步加重黄疸,所以临床应时刻警惕脑出血的发生。本结果与闫瑞芳等[2]研究结果不一致,可能与MRI检查时间及样本量差异有关。研究结果也表明虽然HB患儿较健康儿易伴发脑内微出血,但出血发生率与TSB水平无明显关联性,提示TSB水平高低不能准确判断出血发生率的高低。

       综上所述,通过对HB患儿进行DWI及SWI半定量分析,发现患儿苍白球区域微观结构变化存在水分子扩散受限,可为临床进一步治疗及评估胆红素脑病提供科学依据。同时,对HB患儿治疗过程中,应警惕脑内出血的发生,并给与足够重视。

       局限性:本研究不足之处,首先根据DWI解剖手动绘制ROI获取同区域的ADC值,难免有一定主观性,可能影响测量精准性;其次,样本量偏少,待日后继续收集整理。

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