摘要
背景与目的
脑室扩张是指脑脊液过多地积聚于脑室系统内,多表现为侧脑室扩张,其发生率为1‰-2‰。临床上将侧脑室体部后脚宽度大于10mm定义为侧脑室扩张,根据侧脑室扩张程度区分为重度侧脑室扩张(一侧或双侧侧脑室宽度≥15mm)和轻度侧脑室扩张(侧脑室宽度为10-14.9mm)；部分研究将轻度侧脑室扩张进一步分为轻度侧脑室扩张(10-12.0mm)和中度侧脑室扩张(12.1-14.9mm)。根据侧脑室扩张是否合并其他异常,分为孤立性侧脑室扩张和非孤立性侧脑室扩张。
脑室扩张机制主要包括脑脊液循环障碍,脑室周围损伤及其他疾病造成的损伤。脑脊液循环障碍中,多见于导水管分叉,隔膜形成,继发感染和血栓形成的继发性出血、ChiariⅡ发育异常、脉络丛乳头状瘤等。脑室周围的发育异常多见于胼胝体发育不全、神经元移行障碍和增生异常、胎儿组织器官发育异常等。其他疾病损伤多见于肿瘤、囊肿,血管损伤及感染等基础疾病。
在进行胎儿侧脑室病因探讨时首先需要明确侧脑室扩张是否合并神经系统或非神经系统的畸形,目前超声诊断技术作为胎儿畸形筛查的常规技术在临床广泛应用,但当出现微小结构异常或发生转位,旋转等异常时,B超容易出现漏诊；相对超声诊断技术,MRI技术具图像分辨率高,多方位平面成像,不受孕妇肥胖,羊水,胎儿骨骼等回声衰减影响等优点,针对侧脑室扩张合并的颅脑病理改变,MRI技术对神经元迁移障碍,沟回发育延迟、脑实质出血等异常能够确诊,但目前MRI技术在产前诊断,特别是侧脑室扩张胎儿病因查找方面还尚未广泛推广和应用。
胎儿染色体异常是造成胎儿侧脑室扩张的另一病因。针对侧脑室扩张与染色体相关性的多项研究中表明,约2.8%的孤立性侧脑室扩张与染色体异常相关,其中主要以21三体为主。近期研究显示,0.15%的二倍体胎儿和1.4%的21三体胎儿存在特发性轻度侧脑室扩张,非整倍体的似然比为9。随着细胞生物学技术的发展,学者们采用基因芯片等技术对存在胼胝体发育不全的胎儿进行微缺失、微重复综合征检测,发现了8p23、1p36、1q42-43、6qter等染色体结构异常。目前,染色体核型分析仍是金标准,基因芯片等细胞生物学技术尚未作为常规检查在临床应用,因此在探讨侧脑室扩张与染色体关系中需加入分子生物技术协助染色体核型分析诊断,避免漏诊。
先天性感染也是胎儿侧脑室扩张的病因之一,常见病原体包括弓形虫、巨细胞病毒和风疹病毒,由于感染因素造成神经胶质增生,白质周围导水管阻塞而造成侧脑室扩张。巨细胞病毒感染导致轻度侧脑室扩张的发生率为0-5%,其预后不佳。
侧脑室扩张预后与侧脑室扩张程度,侧脑室宽度在宫内的发展情况,是否合并发育异常以及是否合并染色体异常等相关。侧脑室宽度在宫内的发展情况是影响预后的一个重要因素：侧脑室宽度为10-12.0mm的轻度侧脑室扩张胎儿出生后合并神经发育迟滞的发生率为11.8%,侧脑室宽度为12.1-14.9mm的胎儿出现神经系统发育迟滞的发生率为17.1%。胎儿侧脑室轻度扩张随着孕周的增大,侧脑室扩张程度有三种不同的变化：胎儿侧脑室宽度消退,多在孤立性侧脑室中出现,其预后良好；胎儿侧脑室宽度稳定,与初次诊断相比为宽度波动范围小于2cm,在出生后随访中,预后较好；胎儿侧脑室宽度进展,与胎儿侧脑室扩张原发疾病相关,部分患儿由于初诊时孕周较小,颅内微小结构不易辨认,随着原发疾病的发展,侧脑室宽度增加,研究发现产前胎儿侧脑室宽度呈进展情况的病例约15.7%呈现出不良预后。对于非孤立性侧脑室扩张预后,与其合并中枢神经系统或中枢神经系统以外的畸形的严重程度相关,合并孤立性胼胝体发育不全预后良好。对于孤立性侧脑室扩张预后存在争议,部分研究认为轻度孤立性侧脑室扩张胎儿绝大多数预后良好,生存率达85%,且85%无神经系统后遗症。而部分研究者指出轻度孤立性侧脑室扩张胎儿约11.5%出现神经系统后遗症。
因此,本研究拟通过超声联合MRI技术明确产前胎儿侧脑室扩张病例的诊断,同时对其病因进行探讨；利用实验室常规染色体核型分析及染色体微缺失、微重复检测技术探讨染色体与侧脑室扩张的关系；通过宫内侧脑室宽度监测及出生后随访,对孕妇年龄、胎儿初次诊断时间、胎儿性别、胎儿侧脑室扩张的程度、胎儿侧脑室扩张的对称性等因素进行综合分析,探讨多因素情况下(侧脑室宽度、单侧或双侧侧脑室扩张或孤立性或非孤立性侧脑室扩张等)对胎儿侧脑室扩张宫内预后及患儿出生后神经系统发育的影响。
材料与方法研究对象
本部分的研究对象为2010年3月至2012年12月到南方医院妇产科、广州军区总医院、深圳市妇幼保健院因“胎儿侧脑室扩张”就诊的单胎妊娠的孕妇,在同意并签署知情同意书后将符合纳入标准的孕妇列为研究对象中的实验组。本研究实验组共收集病例数234例进行探讨。同时收集30例胎儿正常发育的单胎妊娠孕妇纳入对照组与实验组同时进行婴幼儿神经发育评估。
研究方法
采用流行病学的队列研究方法进行设计,主要通过临床超声及磁共振技术检测,实验室染色体分析及孕妇血清学TORCH检测以及结合量表、问谈等随访方式进行研究。根据胎儿初诊时侧脑室宽度分为3组：侧脑室宽度为10-12.0mm的轻度侧脑室扩张组、侧脑室宽度为12.1-14.9mm的轻度侧脑室扩张组及重度侧脑室扩张组(≥15mm)。收集孕妇年龄,初次诊断孕周,合并异常等临床资料,分析不同因素影响下的异常发生率及分布情况,分析遗传学因素及感染因素与侧脑室扩张的关系,对于继续妊娠妇女跟踪随访至其分娩,记录宫内胎儿侧脑室转归情况并收集分娩结局的相关信息,继续随访新生儿神经发育状况,收集其一岁内生长发育资料,分析侧脑室扩张程度及侧脑室扩张伴随的相关临床表现(如：是否合并发育异常或超声软标志异常；侧脑室扩张分布：单侧侧脑室扩张或双侧侧脑室扩张；侧脑室扩张宫内转归情况：消退、稳定、进展等)与婴儿生长发育的关系。研究采用实验室检测、临床检测及量表等方式获取资料。
所有数据使用SPSS13.0统计软件进行管理和分析；连续性资料使用均数、标准差、等进行描述；分类或等级变量使用频率、构成比、交叉表等描述；连续性变量两独立样本采用t检验、多组样本比较采用方差分析；分类资料采用卡方检验。单因素分析使用Pearson/Spearman相关系数、t检验、卡方检验；等级资料采用Mann-Whitney(两组)和Kruskal-Wallis检验(多组)。所有的统计检验均采用双侧检验,显著性检验水准取α=0.05,即P<0.05将被认为差别有统计学意义。
结果与讨论
本研究通过超声诊断技术结合磁共振技术检测发现男性胎儿侧脑室扩张发生率为女性胎儿的1.5倍。侧脑室扩张病例中,非孤立性侧脑室扩张发生率为63.2%(148/234),轻度侧脑室扩张(10-12.0mm)胎儿非孤立性侧脑室扩张及双侧侧脑室扩张发生率低,分别为55.1%(65/118)(χ2=8.605,P=0.014),38.1%(45/118)(P=0.001)。
234例孕妇中,62例接受胎儿MRI检查,MRI技术对颅内囊肿、部分性胼胝体发育不全、颅内出血、脑白质发育不良等诊断存在优势,为19.4%(12/62)的病例提供了重要的补充信息。综合超声诊断结果,发现51例胎儿合并两项或两项以上异常,累计异常数目为220例,中枢神经系统异常最常见,占37.7%(83/220),其中颅内囊肿和胼胝体发育不良发生率高,分别是19.2%(16/83),16.9%(14/83)。神经系统外合并的异常中,超声软标志异常(11.8%)、后颅窝轻度扩张(23.6%)、心血管系统异常(5.9%)发生率较高。重度侧脑室扩张组中69.6%(32/46)胎儿合并中枢神经系统发育异常,较轻度组(10-12；12.1-14.9mm)合并中枢神经系统异常发生率高,(χ2=41.420,P=0.000)。轻度组(10-12mm)中以合并超声软标志异常多见,其发生率为73.1%(38/52)(χ2=38.226,P=0.000)。
通过染色体核型分析(G显带)发现侧脑室扩张胎儿中染色体异常12例(5.1%),染色体数目异常10例(83.3%),其中21三体发生率最高,50%(5/10)。采用MLPA技术和基因芯片技术对88例染色体正常胎儿进行检测,发现1p36微缺失综合征1例,可提高约1.1%(1/88)的诊断率。在可能影响染色体异常的因素中发现高龄、胎儿双侧侧脑室扩张及血清学筛查高风险的胎儿发生染色体异常机率较高。
选择继续妊娠的173例孕妇中,轻度侧脑室扩张(10-12mm)组胎儿宫内转归较12.1-14.9mm组良好,72.9%(78/107)胎儿侧脑室扩张消退,(χ2=15.769,P=0.000)；孤立性侧脑室扩张胎儿较非孤立性胎儿宫内预后好,好转率分别为74.6%(59/79),52.1%(49/94)(χ2=10.222,P=0.006)；侧脑室对称性扩张胎儿较非对称侧脑室扩张胎儿宫内转归良好,好转率分别为66.7%(44/66),1/9(11.1%)(P=0.001)。说明孤立性轻度侧脑室扩张(10-12mm)胎儿宫内预后良好。
实验组中新生儿NBNA评分低于对照组(P=0.016)。出生后6月随访,失访27例,失访率为16.5%(27/164),对继续随访的病例和对照组进行BSID神经发育评估,实验组和对照组PDI评分存在差异(P=0.0148),MDI无显著差异(P=0.076)。实验组组内非孤立性/孤立性侧脑室扩张组间PDI评分差异有显著性差异(Z=-2.835,P=0.005),婴儿宫内不同转归结局的PDI及MDI评分差异有显著性差异(P=0.000；P=0.018)。
结论
1、63.2%的胎儿合并中枢神经系统或神经系统外的异常,侧脑室宽度为12-14.9mm的胎儿和重度侧脑室扩张胎儿多合并中枢神经系统异常。
2、MRI诊断技术具有分辨率高、不受羊水量或胎儿骨骼回声等影响,可对中枢神经系统内的细微结构进行直接诊断,可为19.4%(12/62)的病例提供重要的补充信息。
3、侧脑室扩张胎儿中,染色体异常发生率为5.6%(13/234),其中21三体最常见,孕妇高龄,胎儿双侧侧脑室扩张可增加胎儿染色体异常风险。采用MLPA、基因芯片等细胞分子生物学技术进行染色体微小结构变异检测,可提高1.1%的诊断率。
4、孤立性轻度侧脑室扩张(10-12mm)胎儿宫内预后良好。产前侧脑室扩张胎儿新生儿期NBNA评分低于产前正常胎儿；产前侧脑室扩张胎儿是否合并异常及宫内转归情况影响其神经发育特别是心理运动发育。
Background and objectives
Ventriculomegaly (VM) is a descriptive term, indicating the presence of an excess of fluid, usually cerebrospinal fluid (CSF), in the lateral ventricles of the developing brain. It is defined as the width of one or both ventricles, measured at the level of the glomus of the choroid plexus (atrium), is≥10mm. Some authors define VM as mild when the width of one or both ventricles is10-14.9mm and severe when>15mm (the 'true'hydrocephalus), whereas others define mild VM as between10-12mm and moderate VM as between12.1-14.9mm. Based on the evidence of additional abnormalities, VM is defined as isolated and non-isolated.
VM can result from different processes including the abnormal turnover of CSF, anomalies of the periventricular brain structures and other disorders. An abnormal turnover of CSF may be a consequence of forking formation, septum, gliosis secondary to infections and blood clots secondary to intraventricular haemorrhage, Chiari Ⅱ malformation and cerebello-medullary cistern. Anomalies of the periventricular brain structures include corpus callosum agenesis, neuronal migration and proliferation disorders and disorders of fetal development. Other disorders include tumors and vascular anomalies.
The first step of etiologic analysis of fetal ventriculomegaly is to make sure whether there are associated neural or extraneural malformations. Ultrasound imaging is widely used as a routine referral examination in prenatal screening, however the sensitivity of ultrasound in screening of VM is controversial, especially when there are subtle malformations and abnormalities in gyration. Many studies have indicated that magnetic resonance imaging (MRI) adds important information to that obtained by ultrasound imaging with a higher resolution and a possibility of multi-plane imaging. MRI image is least affected by obesity of the mother, amniotic fluid, low position of fetal head or calcification of fetal cranium. Fetal CNS anomalies that were better seen on MRI compared to ultrasound include:porenceohaly, cortical gyral abnormalities, partial or complete hypoplasia, vermian cysts, hemorrhage, cortical cleft, mid-brain dysgenesis, partial or complete agenesis of the septi pellucid, and subependymal and cortical tubers. However, MRI hasn't been widely used in prenatal diagnosis, especially in the etiological analysis of fetal ventriculomegaly.
Chromosomal anomalies can also cause fetal ventriculomegaly. It has been shown that about2.8%isolated VM is associated with chromosomal abnormalities-mainly trisomy21-in a large number of studies. Recent studies addressing the issue of the risk of trisomy21in idiopathic mild VM highlighted that this finding is present in0.15%of euploid fetuses and in1.4%of trisomy21fetuses, providing a likelihood ratio of9for the risk aneuploidy. Along with the development of biochemistry and molecular biology, several research groups have been using microarray to detect microdeletions and microduplications in corpus callosum agenesis patients, and abnormalities locate at8q23,1p36,1q42-43and6qter have been identified. Although karyotyping is still the standard method in prenatal diagnosis of fetal ventroculomegaly, molecular biological methods are necessarily used in addition to routine cytogenetic analysis.
Congenital infection may cause VM as a consequence of gliosis of the white matter surrounding the aqueduct and subsequent obliteration. Possible pathogens include Toxoplasma, cytomegalovirus (CMV) and rubella. The incidence of CMV as a cause of mild VM varies from0-5%with a poor prognosis.
Factors that influence the prognosis of fetuses with ventriculomegaly include the size of ventricles, the in-utero progression of ventricular dilatation, the association with other abnormalities and the presence of chromosomal anomalies. A measurement of10-12mm is generally associated with a lower incidence of neurodevelopmental delay (11.8%) than12.1-14.9mm (17.1%). The in-utero variation of ventricular dilatation is one of the most important prognostic factors in fetal VM and the possible variations include regression and progression of the ventricular dilatation. Stable and regressive ventriculomegaly is with a good prognosis, while progressive ventricular dilatation often gives a poor prognosis. The prognosis of isolated VM (IVM) is controversial. Some authors pointed out that85%IVM (10-15.0mm) fetuses could be lively born without neurological abnormalities, while others found11.5%IVM fetuses will suffer from neurological disorders.
Here in our study, an MRI test was performed after the routine ultrasound imaging, and a standard karyotype examination combined with of microdeletion microduplication detection was conducted to find out the correlations between chromosomal abnormalities and fetal VM. Once VM had been diagnosed, monthly ultrasound scans were performed and parents were contacted and invited to participate in postnatal follow-up. Maternal age, gestational age at initial diagnosis, fetal sex, size of ventricles and symmetry of the ventricular system was analyzed to identify factors correlated with the outcome of VM on postnatal neurological development.
Methods and Materials Patients
234pregnancies confirmed of ventriculomegaly, from Nanfang Hospital, General Hospital of Guangzhou Military Command of PLA and Shenzhen Maternal and Child Hospital during March2010to December2012, were recruited after the medical informed consent.30normal fetuses were recruited as the control.
Methods
A cohort study was conducted on ventriculomegaly fetuses diagnosed by ultrasound imaging and MRI. The etiological analysis was conducted by standard karyotype examination and maternal serologic investigation (TORCH). The postnatal neurological development was evaluated by assessment of infants' general cognitive and motor skills. Based on the ventricular size of the initial diagnosis, patients were divided into3groups:mild ventriculomegaly group with ventricular dilatation to10-12mm; moderate ventriculomegaly group with ventricular dilatation to12.1-14.9mm and severe ventriculomegaly group with ventricular dilatation to more than15mm. Informations including maternal age, gestational age at initial diagnosis and associated abnormalities were collected and analyzed. The correlation of genetic anomalies and congenital infection to ventriculomagaly was studied. On-going pregnancies were followed up till childbirth. The in-utero alteration of ventricular dilatation was recorded and followed up till1year after birth.
Summary statistics was performed using SPSS statistical software version13.0for Windows. Statistics for continuous variables were presented using the mean and standard deviation. Categorical and class variables were described by frequency, constituent ratio and crosstab. Two samples were detected by t-test and categorical variable were examined by x2test. Single-factor used Pearson/Spearman correlation coefficient, t-test and x2test. Two class variables were examined by Mann-Whitney and multi-samples detected by Kruskal-Wallis test. All the statistical tests were double-side test and data were deemed to be significantly different when P^0.05.
Results and discussion
In our study, the affected males were1.5times more than females diagnosed by ultrasound imaging and MRI examination. Among all the ventriculomegaly cases,63.2%(148/234) were non-isolated VM. A lower incidence of non-isolated VM and bilateral VM was seen in mild ventriculomegaly (10-12mm) cases, which was55.1%(65/118)(X2=8.605, P=0.014<0.05) and38.1%(45/118) respectively (P=0.001<0.05).
62/234fetuses underwent MRI examination, which is better at detecting partial agenesis of corpus callosum and hemorrhage etc, added important information to19.4%(12/62) ultrasound imaging results. Ultrasound results showed that51fetuses were with two or more additional abnormalities and the total number of abnormal cases was220. CNS abnormalities were with the highest incidence (37.3%,83/220), and intracranial cysts (19.2%,16/83) as well as corpus callosum agenesis (16.9%,14/83) were mostly seen. Extraneural abnormalities included abnormalities in ultrasound soft markers (11.8%), mild dilatation of posterior fossa (23.6%) and cardiovascular anomalies (5.9%).69.6%of severe VM (≥15mm) fetuses were complicated with neurodevelopmental delay, which is higher than mild and moderate VM (x2=41.420, P=0.000). However, the incidence of abnormalities in ultrasound soft markers is higher in mild VM fetuses (73.1%,38/52, x2=8.226, P=0.000).
Karyotype examination showed12(5.1%) chromosomal abnormalities in VM fetuses, including10(83.3%) numerical abnormalities, and trisomy21was the most common prenatally detected chromosomal anomaly (50%,5/10). Multiplex ligation-dependent probe amplification (MLPA) was performed in88fetuses with normal karyotype and a Ip36microdeletion was identified in one case, which increased the diagnostic rate by1.1%. The factors that may be correlated to chromosomal abnormalities are advanced maternal age, bilateral VM and high risk of congenital infection.
Among the173on-going pregnancies, the in-utero outcomes of mild VM (10-12mm) were better than moderate VM (12.1-14.9mm). About72.9%(78/109) mild VM spontaneously regressed (x2=15.769, P=0.000). IVM fetuses had better prognosis than VM ones, and the regression rate was74.6%(59/79) vs.52.1%(49/94)(X2=10.222, P=0.006). The in-utero outcomes of symmetrical VM were better than asymmetrical VM, and the regression rate was66.7%(44/66) vs.1/9(11.1%)(P=0.001). These indicated that the in-utero outcomes of mild (10-12mm) IVM fetuses were better.
NBNA score of VM infants was lower than the normal ones (P=0.016). A follow-up visit was paid6months after birth.27cases lost to follow-up (16.5%,27/164). Neurodevelopmental assessment was by BSID Scales at the follow-up visit. There was a significant difference in PDI score between VM infants and normal ones (P=0.0148), and between IVM and VM (Z=-2.835, P=0.005). Infants with different in-utero outcomes had a significant difference in PDI and MDI score (P=0.000; P=0.018).
Conclusion
1.63.2%VM fetuses were complicated with neural or extraneural abnormalities. Fetuses with ventricular dilatation to12.1-14.9mm or more were with a higher incidence of CNS anomalies.
2. MRI image is least affected by obesity of the mother, amniotic fluid, low position of fetal head or calcification of fetal cranium. Subtle abnormalities can be detected by MRI which added important information to19.4%(12/62) VM cases.
3. Chromosomal abnormalities were detected in5.2%(12/234) VM fetuses, and Trisomy21was most common (38.5%,5/13). Advanced maternal age, bilateral VM were prone to a higher risk of chromosomal abnormalities. MLPA, microarray combined with standard cytogenetic technology can increase the diagnostic rate of microdeletion and microduplication by1.1%.
4. Mild IVM (10-12mm) fetuses have better in-utero outcomes. Infant NBNA score of prenatal VM fetuses was lower than normal ones. Additional abnormalities and the in-utero outcomes were associated with neurodevelopment and psychomotor development.
引文
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