In our study on 3D volume data sets of second- and third-trimester fetuses, we were able to demonstrate the potential of a standardized semiautomated approach of anatomic reconstruction of diagnostic CNS planes in the presence of congenital brain anomalies. Given the nonsatisfactory detection rates of CNS lesions in utero in an unselected population on the one hand and the diagnostic value of 3D ultrasound with simultaneous analysis in three orthogonal planes for advanced assessments of the fetal CNS (as presented herein) on the other hand, the question arises why most of the available data still rely on conventional two-dimensional ultrasound (2DUS). Following the recently revised ISUOG practice guidelines for sonographic examination of the fetal central nervous system, further assessment of additional diagnostic planes is mandatory in cases of a positive family history, congenital heart disease, suspected intrauterine infection, monochorionic twin gestation, abnormal genetic testing, or when an anatomic abnormality is suspected during routine or nuchal translucency scans.15 As exemplified by an apparent enlargement of the ventricular system, a careful assessment of the entire intracranial anatomy is arbitrative, including the lateral, third, and fourth ventricles; (peri-)callosal region; thalami; germinal matrix region; and cerebellum, to rule out additional CNS anomalies (and extracranial defects). However, this, in turn, implicates attainment of numerous additional planes and views that primarily constitute a complete neurosonogram. Developing and maintaining the skills to perform a targeted anatomic survey in general, but fetal neurosonography in particular, requires an investment and an organized approach.16,17 In addition to the capability to detect and localize CNS lesions precisely, it further necessitates an in-depth knowledge of the natural course across gestation and the outcome of the different cerebral malformations.
A collaborative study analyzing the results from 11 international prenatal centers emphasized that 3D US of the fetal CNS constitutes an accurate and reliable method for the diagnosis of fetal brain malformations.8 Assessment of prospective data from the Neurosofe-3D study demonstrated that acquisition of brain volumes following evidence-based guidelines is able to improve the quality of the volumes and visualization rates of the intracranial structures (satisfying evaluation of 91.5% structures in the axial plane, 81.8% in the coronal plane, and 89.9% in the sagittal plane).18 In light of very recent data from a complementary analysis of the INTERGROWTH-21 project cohort that investigated and measured fetal brain structures on ultrasound images extracted from 3D volumes of the fetal head, the importance of obtaining standardized planes using a volumetric approach has been underscored.19
In the last fifteen years, several three-dimensional US protocols have been applied to examine fetal central nervous structures in detail. Substantial efforts have been made toward a thorough volumetric assessment of fetal midbrain and hindbrain structures and their defects in utero (e.g., corpus callosum including pericallosal blood supply, 3rd ventricle and adjacent structures, posterior fossa and cerebellum, Sylvian fissure).9,20−26 Spinelli et al. provided data on how the exact biometry of posterior fossa structures (vermian crest angle) can be obtained in a feasible and reproducible manner using 3D US.27 Rodriguez-Sibaja and colleagues published international standards for fetal cerebellar growth and Sylvian fissure maturation using 3D ultrasound volumes from the same population-based project.28 Qualitative and quantitative studies of cortical development evaluation using volume data sets clearly showed the potential of multiplanar assessment and confirmed 3D US as a robust diagnostic method.14,29,30 Detailed prenatal judgment of even subtle changes in terms of cortical grading and sulci shape and depth is feasible31–34, but it necessitates exact image alignment and, more strikingly, an awareness of the adequacy of planar image adjustment based on anatomical landmarks, as described in the current literature.29,35
In fact, quite a number of the studies analyzed volume information derived from transvaginally acquired 3D datasets, as these showed a higher image resolution (through US propagation via the sagittal suture and subsequent volume postprocessing).36–38 Three-dimensional TVS has been reported to have higher success rates than the 2D approach and is capable of multiplanar volume manipulation along the x-, y-, and z-axes to achieve high-quality images without requiring acquisition in the exact mid-sagittal plane.39,40 However, due to technical obstacles, such as the inability to manipulate the fetal head to an optimal scanning position or due to physical constraints that may limit the number of degrees of freedom of the US probe, transvaginal access to capture fetal CNS anatomy might be challenging or even impossible. Taking this into account, it becomes obvious that despite the somewhat lower resolution, an abdominal (rather than a transvaginal) approach using an axial acquisition plane is much more appropriate in a screening setting. Nevertheless, manual navigation through brain volume datasets to retrieve differently oriented diagnostic planes along the x-, y-, and z-axes necessitates a comprehensive understanding of fetal CNS architecture and a spatial sense of anatomic relations and hence is highly operator dependent, especially when CNS abnormalities are suspected. It has recently been shown that automated volumetric approaches efficiently enable rapid and standardized evaluation of the fetal brain in terms of basic examination41–43 or reconstruction of an entire neurosonogram.12–14 By simplifying the evaluation process of basic and/or advanced CNS examination, these algorithms might aid in earlier detection of abnormal CNS anatomy in utero. However, it remains widely unclear how these automatic techniques are of clinical use in delineating different CNS lesions by means of proper plane reconstruction and visualization of structural defects in detail.
In all cases of our cohort affected by anomalies designated to the posterior fossa, including cerebellar lesions (Fig. 4), the diagnostic planes depicting the particular lesion were correctly reconstructed, which is in line with previous findings using the 5DCNS + algorithm.13 The added value of orthogonally oriented sections displayed in a single template is exemplary and was demonstrated in both fetuses with rhombencephalosynapsis (RES) and cerebellar hypoplasia (Fig. 3). The common features of abnormal rhombencephalic differentiation as described previously can be tracked in a step-by-step manner.44− 47 While summarizing the abnormal anatomic hints of the fetus in Fig. 3, a Goméz-López-Hernandéz syndrome might be likewise suggested. Subtle anatomical measures that might point to concomitant mid- and hindbrain lesions such as tectum length/thickness and tegmental thickness or the absence of the sonolucent appearance of the aqueduct (best visualized in longitudinal and transcerebellar cutting sections) can also be quantified in detail as very recently reported.48 Accordingly, occlusive lesions caused by obstruction of cerebrospinal fluid (CSF) pathways either to aqueductal stenosis or secondary to Chiari-II malformation were present in 7 cases and 21 cases, respectively, and were effectively displayed using 5DCNS+™ (Fig. 2). Depicting axial, coronal, and longitudinal views of these abnormal conditions simultaneously in a single template allows for a more comprehensive anatomic evaluation of the most likely underlying cause of the intracranial pathology. In Fig. 3, indirect signs of internal obstruction that were highly suggestive of AS and commonly seen on comparative MR imaging studies could be readily observed.49,50 Notably, in > 90% of cases with open spina bifida, there were no sonographic hints of discontinuation of CSF circulation downstream of the third ventricle. Birnbaum et al. introduced objective measures of the 3rd ventricle and its surrounding landmarks that have proven to be useful in diagnosing primary obstruction with high accuracy.20 Prerequisites for assessment of the interthalamic adhesion diameter as the strongest proxy are precise midsagittal views through the mid- and hindbrain.
A detailed description of intracranial signs of neural tube defects (NTDs) from the first trimester onwards other than a small posterior fossa and the infratentorial descent of the brainstem and cerebellar tonsils (Chiari II malformation) has been proposed by several groups 51–54. Very recently, the interpeduncular angle (IPA) was reported to be reduced in MR tomography in second- and third-trimester fetuses with dorsal dysraphism corresponding to a complete collapse of the interpeduncular cistern following severe hypotension in hindbrain herniation.55 In our study cohort, a wide range of anatomical severities of intracranial pathology were encountered, encompassing different degrees of ventriculomegaly and hydrocephaly secondary to the observed changes within the Chiari II malformation spectrum.
As the correct plane for the calculation of the IPA is rather confined to an oblique cutting section traversing the eyes toward the occiput above the dislocated cerebellum, this measure could not be obtained accordingly.
In spite of the higher need for manual adjustment and numbers of volumes for proper semiautomatic reconstruction, 5DCNS + is an efficient and valuable method, but it must, however, be considered that similar to conventional 2D US, volume US has several technical limitations, particularly in advanced gestation (e.g., hardly defined edges, multiplicative speckle noise, and the only partially solved issue of estimating missing information in occluded areas caused by acoustic shadows, as seen in the analysis of the proximal parasagittal plane). Moreover, extraction of appropriate cutting sections from the fetal brain volumes depends on acoustic beam penetration and tissue impedance and is further influenced by the fact that most of the brain tissue has similar acoustic properties and impedance values.56 A further limitation of our study is that the initial volume acquisition was made by operators with expertise in fetal US, which may introduce a certain bias on the success rates of 5DCNS + volume reconstruction. Another (methodologically) relevant fact has been stressed by Quarello et al., who stated that the choice of CSP instead of fornices as the anterior most structure (or pivotal point for automatic plane reconstruction) for cortical maturation assessment may lead to misinterpretation of the modification of the SF shape and is prone to a certain variation in cutting Sect. 35 Although we generally agree, we believe that adherence to workflow-based volumetric approaches might considerably limit the extent of variation, imprecise diagnostic planes, and the need for manual plane adjustments.
The advent of newer imaging technologies, as discussed and illustrated herein, might further nourish the controversial debate regarding the role of fetal MRI in the diagnostic work-up of fetal brain anomalies (Fig. 5). There is general acceptance that additional MRI is deemed to act as an adjunct to prenatal US as the primary diagnostic modality. Recent data from the European Neurosonography (ENSO) Working Group indicate that the incidence of an associated fetal anomaly in fetuses with a sonographic diagnosis of isolated mild or moderate ventriculomegaly (VM) or corpus callosum agenesis that was missed on ultrasound and detected only on fetal magnetic resonance imaging (MRI) is lower than that previously reported. These anomalies merely involve migration disorders and hemorrhage.57,58 Notably, no statistically significant differences were noted between the diagnostic accuracy of fetal neurosonography and fetal MRI for CC and CSP anomalies, NTDs, PFA, and PVM.59–61 Accordingly, van der Knoop and colleagues stated that fetal MRI did not demonstrate any anomalies that were not seen on multiplanar neurosonography.62 The complementary information of MR imaging in the evaluation of CNS pathologies might be of value when clarification of a US-identified lesion may advise pre- and postnatal management (including parental decision to terminate the pregnancy) or when feto-maternal conditions hamper detailed US examination.63,64
In conclusion, although the assessment of fetal CNS anomalies continues to improve, the diagnostic potential of 3D ultrasound as a valuable tool in detailed structural analysis of the fetal brain has not been fully utilized. Despite the clinical value and advantages of 3D US over conventional 2D US that have become increasingly obvious and the fact that volume ultrasound has been widely available on multiple ultrasound platforms, it is still underused, and its diagnostic potential remains underestimated, as many centers have not embraced this modality. The main reason for this dilemma and the limited uptake of 3D US might be attributed to the lack of standardization in the acquisition and postprocessing of volume data sets, constituting a major limiting step for the effective performance of 3D US. A workflow-based three-dimensional ultrasound approach, as reviewed herein, has been shown to reproducibly improve the assessment of both the normal and abnormal fetal CNS architecture and can be considered as an easy-to-apply screening and diagnostic tool in a clinical setting, since it enables a more refined diagnosis of most congenital malformations of the brain. Moreover, storage of 3D volume data sets enables offline review of the data volumes and facilitates, if needed, remote second opinions of specialists in the field. However, inexperienced examiners need to become familiar with the anatomy, rendered views, and spatial relationships of the fetal CNS and implement volume acquisition of fetal targets, giving them the opportunity to improve their daily routine in a convenient and time-saving manner.
In contrast to this rapid semiautomatic US technique, MRI consumes vast amounts of time (during which the main questions asked by parents could be addressed in detail by neuropediatricians) and resources and may overlook subtle anatomic anomalies such as a faulty cortical migration or intracranial hemorrhage (Fig. 5).