BCNatal: Fetal Medicine Research Center, Hospital Clínic and Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Ultrasound Obstet Gynecol. 2023 Jun;61(6):749-757. doi: 10.1002/uog.26173.
To evaluate the correlation of periventricular echogenic halo (halo sign) with histopathological findings and its association with other brain imaging abnormalities in fetuses with cytomegalovirus (CMV) infection.
This was a retrospective study of fetuses diagnosed with severe CMV infection based on central nervous system (CNS) abnormalities seen on ultrasound, which had termination of pregnancy (TOP) or fetal demise at a single center from 2006 to 2021. All included cases had been evaluated by conventional complete fetal autopsy. A maternal-fetal medicine expert reanalyzed the images from the transabdominal and transvaginal neurosonography scans, blinded to the histological findings. The halo sign was defined as the presence of homogeneous periventricular echogenicity observed in all three fetal brain orthogonal planes (axial, parasagittal and coronal). Cases were classified according to whether the halo sign was the only CNS finding (isolated halo sign) or concomitant CNS anomalies were present (non-isolated halo sign). An expert fetal radiologist reanalyzed magnetic resonance imaging (MRI) examinations when available, blinded to the ultrasound and histological results. Hematoxylin-eosin-stained histologic slides were reviewed independently by two experienced pathologists blinded to the neuroimaging results. Ventriculitis was classified into four grades (Grades 0-3) according to the presence and extent of inflammation. Brain damage was categorized into two stages (Stage I, mild; Stage II, severe) according to the histopathological severity and progression of brain lesions.
Thirty-five CMV-infected fetuses were included in the study, of which 25 were diagnosed in the second and 10 in the third trimester. One fetus underwent intrauterine demise and TOP was carried out in 34 cases. The halo sign was detected on ultrasound in 32 (91%) fetuses (23 in the second trimester and nine in the third), and it was an isolated sonographic finding in six of these cases, all in the second trimester. The median gestational age at ultrasound diagnosis of the halo sign was similar between fetuses in which this was an isolated and those in which it was a non-isolated CNS finding (22.6 vs 24.4 weeks; P = 0.10). In fetuses with a non-isolated halo sign, the severity of additional ultrasound findings was not associated with the trimester at diagnosis, except for microencephaly, which was more frequent in the second compared with the third trimester (10/18 (56%) vs 1/8 (13%); P = 0.04). With respect to histopathological findings, ventriculitis was observed in all fetuses with an isolated halo sign, but this was mild (Grade 1) in the majority of cases (4/6 (67%)). Extensive ventriculitis (Grade 2 or 3) was more frequent in fetuses with a non-isolated halo sign (21/26 (81%)) and those without a periventricular echogenic halo (2/3 (67%); P = 0.032). All fetuses with an isolated halo sign were classified as histopathological Stage I with no signs of brain calcifications, white-matter necrosis or cortical injury. On the other hand, 25/26 fetuses with a non-isolated halo sign and all three fetuses without a periventricular echogenic halo showed severe brain lesions and were categorized as histopathological Stage II. Among fetuses with a non-isolated halo, histological brain lesions did not progress with gestational age, although white-matter necrosis was more frequent, albeit non-significantly, in fetuses diagnosed in the second vs the third trimester (10/15 (67%) vs 3/11 (27%); P = 0.06).
In CMV-infected fetuses, an isolated periventricular echogenic halo was observed only in the second trimester and was associated with mild ventriculitis without signs of white-matter calcifications or necrosis. When considering pregnancy continuation, detailed neurosonographic follow-up complemented by MRI examination in the early third trimester is indicated. The prognostic significance of the halo sign as an isolated finding is still to be determined. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
评估脑室内回声晕环（ halo 征）与组织病理学发现的相关性及其与巨细胞病毒（CMV）感染胎儿其他脑影像学异常的关系。
这是一项回顾性研究，纳入了 2006 年至 2021 年在单一中心因超声检查发现中枢神经系统（CNS）异常而终止妊娠（TOP）或胎儿死亡的严重 CMV 感染胎儿。所有纳入的病例均经常规完全胎儿尸检评估。一名母胎医学专家对经腹和经阴道神经超声扫描的图像进行重新分析，对组织病理学发现不知情。 halo 征定义为在所有三个胎儿脑正交平面（轴位、矢状位和冠状位）中观察到均匀的脑室周围回声增强。根据 halo 征是否为唯一的 CNS 发现（孤立性 halo 征）或是否存在同时存在的 CNS 异常（非孤立性 halo 征）对病例进行分类。当有磁共振成像（MRI）检查时，一名胎儿放射科专家对其进行重新分析，对超声和组织学结果不知情。苏木精-伊红染色的组织学切片由两名经验丰富的病理学家独立审阅，对神经影像学结果不知情。根据炎症的存在和程度将脑室炎分为四级（0-3 级）。根据脑损伤的严重程度和病变进展，将脑损伤分为两个阶段（Stage I，轻度；Stage II，重度）。
本研究纳入了 35 例 CMV 感染胎儿，其中 25 例在孕中期，10 例在孕晚期诊断。1 例胎儿宫内死亡，34 例进行了 TOP。32 例（91%）胎儿的超声检查发现 halo 征（孕中期 23 例，孕晚期 9 例），其中 6 例为孤立性 sonographic 发现，均在孕中期。孤立性 halo 征胎儿的超声诊断中位孕周与非孤立性 CNS 发现的胎儿相似（22.6 周 vs 24.4 周；P=0.10）。在非孤立性 halo 征胎儿中，除微脑畸形外，其他超声发现的严重程度与诊断时的孕龄无关，微脑畸形在孕中期比孕晚期更常见（10/18（56%）vs 1/8（13%）；P=0.04）。在孤立性 halo 征胎儿中，所有病例均观察到脑室炎，但大多数病例为轻度（Grade 1）（4/6（67%））。非孤立性 halo 征胎儿（21/26（81%））和无脑室周围回声增强的胎儿（2/3（67%））更常发生广泛脑室炎（Grade 2 或 3）（P=0.032）。所有孤立性 halo 征胎儿均被归类为组织病理学 Stage I，无脑钙化、白质坏死或皮质损伤的迹象。另一方面，26 例非孤立性 halo 征胎儿和 3 例无脑室周围回声增强的胎儿均显示严重的脑损伤，并被归类为组织病理学 Stage II。在非孤立性 halo 征胎儿中，尽管白质坏死的发生率更高（尽管无统计学意义），但脑病变的组织学进展与孕龄无关，在孕中期诊断的胎儿（10/15（67%））vs 孕晚期诊断的胎儿（3/11（27%））（P=0.06）。
在 CMV 感染胎儿中，孤立性脑室周围回声晕环仅在孕中期观察到，与无白质钙化或坏死迹象的轻度脑室炎相关。当考虑继续妊娠时，需要详细的神经超声随访，并在孕早期进行 MRI 检查。 halo 征作为孤立性发现的预后意义仍有待确定。
