Agenesis of the fetal corpus callosum: sonographic signs change with advancing gestational age

Authors


ABSTRACT

Objectives

To assess the presence and degree of indirect signs of agenesis of the corpus callosum (ACC) according to gestational age and determine the percentage of cases in which each sign is present by 24 gestational weeks.

Methods

We analyzed retrospectively 54 cases of ACC which underwent three-dimensional neurosonography at our unit between January 2005 and December 2012. A single examination was available in 48 cases and six cases were followed up longitudinally, giving a total of 69 examinations. The following variables were assessed: indication for referral, karyotype, width of the atrium and presence/absence of colpocephaly, the cavum septi pellucidi, dorsal cyst and additional central nervous system (CNS) and non-CNS anomalies.

Results

Overall, there were 31 cases of complete ACC (cACC, 42 examinations) and 23 cases of partial ACC (pACC, 27 examinations). The mean gestational age was lower in the cases referred because of anomalies other than ACC than it was in those referred because of ventriculomegaly and/or suspicion of ACC (P < 0.05). Atrial width showed a positive linear correlation with advancing gestational age (P < 0.0001); it was < 10.0 mm in 25/34 (73.5%) examinations < 24 gestational weeks and in 9/35 (25.7%) ≥ 24 weeks (P < 0.001). Colpocephaly was present in 20.6% (7/34) of examinations < 24 weeks and in 68.6% (24/35) of those after 23 weeks (P < 0.05). The cavum septi pellucidi was present and visible at least in part in 17 (63%) of the 27 pACC examinations. In nine of the 27 (33.3%) pACC examinations, there was neither ventriculomegaly nor absence of the cavum septi pellucidi. Associated anomalies were present in 25/54 (46.3%) cases, and in 11 these included or consisted of CNS abnormalities. Karyotype was abnormal in seven of the 40 (17.5%) cases in which it was available.

Conclusions

In a significant proportion of cases, most of the indirect signs of ACC are either absent or barely visible at the time of the midtrimester screening ultrasound examination. Therefore, ACC may escape diagnosis at midtrimester screening ultrasound. In particular, a third of examinations in fetuses with pACC may not show any abnormality in the transventricular screening view < 24 weeks. The medicolegal implications of such findings are important and should be considered. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

INTRODUCTION

The prenatal diagnosis of agenesis of the corpus callosum (ACC) is based upon the midsagittal view of the fetal brain, in which the corpus callosum, or its absence, is detected[1], but suspicion of such malformation is raised at midtrimester screening ultrasound on the basis of indirect sonographic findings visible on the transventricular view: absence of the cavum septi pellucidi, ventriculomegaly and colpocephaly (teardrop-shaped dilatation of the occipital horn of the ventricle)[1-3]. However, these signs may be missing or rather subtle, which explains why ACC may go unrecognized, particularly if the transventricular view of the fetal head is not assessed properly. In a significant number of cases it is recognized only in the late second trimester, when these signs become more evident. This increase in anatomical distortion as gestation progresses is well known, but until now there have been few studies analyzing this problem[3, 4].

In this study, we analyzed retrospectively the three-dimensional (3D) volumes of all fetuses with ACC seen at our unit over the last 8 years. Our objectives were to assess the presence and degree of indirect signs of ACC according to gestational age and determine the percentage of cases in which each sign is already present at gestational age < 24 weeks.

METHODS

All cases of ACC seen at our unit from January 2005 to December 2012 were retrieved from our database. All cases had undergone expert neurosonography with high-end ultrasound systems equipped with transabdominal and transvaginal volumetric transducers (E8 and Voluson 730, GE Healthcare Ultrasound, Milwaukee, WI, USA). Criteria for inclusion in the study were: presence of one or more 3D volume datasets available for offline assessment and confirmed final diagnosis of ACC. Fifty-four of the original 72 cases met these criteria and represent the study population. A single examination was available in 48 cases, while six cases were followed up at 2–3-week intervals until delivery. Hence, a total of 69 examinations was available for analysis. ACC was defined as complete (cACC) if no part of the corpus callosum was recognizable, and partial (pACC) if at least one of the four anatomical segments (rostrum, genu, body, splenium) of the corpus callosum could be recognized. In all cases, the following variables were assessed retrospectively: indication for referral, karyotype, width of the atrium and presence/absence of colpocephaly, cavum septi pellucidi, dorsal cyst and additional central nervous system (CNS) and non-CNS anomalies.

In particular, atrial width was considered abnormal if > 9.9 mm, measured according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines[5]. Colpocephaly was defined as a teardrop-shaped dilatation of the occipital horn, with the horn measuring > 9.9 mm; if the width was ≤ 9.9 mm, but the lateral ventricle was spear-shaped, due to a pointed aspect of the frontal horns (Figure 1), this was defined as ‘spear-shaped lateral ventricle’. Magnetic resonance imaging (MRI) was carried out in all cases of isolated ACC, either at diagnosis or, in those cases in which the parents elected to continue the pregnancy, at 28–30 weeks. We evaluated the sonographic variables offline with dedicated software (4D View, version 10.5, GE Healthcare Ultrasound). Measurements of atrial width and assessment of the cavum septi pellucidi and colpocephaly were carried out on volumes acquired axially, if available; alternatively, volumes acquired sagittally were used, and the atrial width was measured on the reconstructed coronal view of the occipital horns. Sonographic variables were assessed in the entire group of 69 ultrasound examinations, regardless of the fact that some of these consisted of follow-up examinations in the same fetus, whereas the case series of 54 fetuses was considered to derive clinical data.

Figure 1.

Transventricular plane of fetal head in two cases of complete agenesis of the corpus callosum, illustrating difference between colpocephaly and ‘spear-shaped’ lateral ventricles. (a) In this 22 + 4-week fetus, teardrop-shaped dilatation of occipital horn is clearly visible, with atrial width > 9.9 mm (10.3 mm, calipers); note pointed aspect of frontal horn (arrowhead) and absence of cavum septi pellucidi (arrow). (b) In this 20 + 3-week fetus, with atrial width < 9.9-mm cut-off (8.7 mm, calipers), ventricle appears ‘spear-shaped’ due to pointed aspect of frontal horn (arrowhead) and cavum septi pellucidi was absent (arrow).

Statistical analysis was carried out with the SPSS 17.0 package (SPSS Inc., Chicago, IL, USA). We performed correlation analysis and comparison of numerical variables using the Mann–Whitney U-test for independent samples and of categorical data using the chi-square test. Statistical significance was accepted as P < 0.05.

RESULTS

The mean gestational age at diagnosis was 24 (range, 18–37) weeks (Figure 2), with no difference between pACC (n = 23) and cACC (n = 31) groups (23 vs 24 gestational weeks). Indications for referral were: malformations other than ACC in 22 (40.7%) cases, suspicion of ACC or non-visualization of the cavum septi pellucidi in 21 (38.9%) cases, ventriculomegaly in eight (14.8%) cases; three cases (5.6%) were diagnosed incidentally by the authors during routine ultrasound. The mean gestational age was statistically different between the group of 22 cases referred because of malformations other than ACC and the group of 32 cases referred because of suspicion or incidental diagnosis of ACC or ventriculomegaly (22.4 vs 25.4 weeks; P < 0.05). Taking into consideration all examinations (n = 69, including 27 pACC and 42 cACC), the width of the atrium showed a positive linear correlation with advancing gestational age (P < 0.0001, Figures 3 and 4, Table 1); the six cases followed longitudinally showed a similar trend (Figure 4). In particular, the atrial width was normal in 25/34 (73.5%) examinations < 24 gestational weeks and in 9/35 (25.7%) beyond 23 weeks (P < 0.001). There was no difference in atrial width between cACC and pACC groups across gestation. Colpocephaly was present in 20.6% (7/34) of examinations < 24 weeks of gestation and in 68.6% (24/35) after 23 weeks (P < 0.05), with four of the seven cases of spear-shaped ventricles converting to clear colpocephaly in the second half of gestation. The cavum septi pellucidi was present at least in part and visible in 17 of 27 (63%) pACC examinations. A large midline dorsal cyst was present in four, while a smaller cyst or remnants of the cavum septi pellucidi were present in 21/42 (50.0%) cACC examinations. In 9/27 (33.3%) pACC examinations, there was neither ventriculomegaly nor absence of the cavum septi pellucidi.

Figure 2.

Histogram showing gestational age distribution of the case series of 54 fetuses with corpus callosal agenesis. For the six cases evaluated longitudinally, only the initial diagnostic scan was considered.

Figure 3.

Scatterplot showing positive linear correlation between atrial width and advancing gestational age (P < 0.0001) in 54 cases of corpus callosal agenesis (image, complete; image, partial) with a total of 69 examinations. Regression line from equation and 9.9-mm cut-off are indicated.

Figure 4.

Graph showing increase in atrial width with advancing gestational age in six cases of corpus callosal agenesis (five complete, one partial (image)) followed longitudinally.

Table 1. Sonographic signs of fetal partial/total agenesis of the corpus callosum (ACC) according to gestational age
Sonographic sign< 24 weeks (n = 34)≥ 24 weeks (n = 35)
  1. Data are presented as n (%).

  2. a

    Non-visualization of cavum septi pellucidi (CSP) evaluated only in fetuses with partial ACC.

Atrial width > 9.9 mm9/34 (26.5)26/35 (74.3)
Colpocephaly7/34 (20.6)24/35 (68.6)
Spear-shaped ventricles7/34 (20.6)3/35 (8.6)
Non-visualization of CSPa6/17 (35.3)2/10 (20.0)

Associated anomalies were present in 25/54 (46.3%) fetuses, and in 11 these included or consisted of CNS abnormalities: Dandy–Walker malformation (n = 4), gyration abnormalities (n = 4), Blake's pouch cyst (n = 2) or open spina bifida (n = 1). Among these, atrial width was increased in three: the case associated with spina bifida, measured at 23 weeks, one case associated with Dandy–Walker malformation (20 weeks) and one case associated with gyration abnormality (33 weeks). The karyotype was available in 40/54 cases, and it was abnormal in seven (17.5%) of these: three cases of trisomy 13, two cases of trisomy 18 and two rarer chromosomal anomalies, including one case of Pallister–Killian syndrome (tetra 12p) and one case of unbalanced translocation [46XY t(4;6) (p16;q14)] of maternal origin. Finally, there was a case of L1 syndrome.

DISCUSSION

Direct ultrasound diagnosis of ACC is made on the midsagittal view of the fetal head[1]. However, suspicion of such malformation is usually raised at the midtrimester anomaly scan on the basis of an abnormal transventricular view, due to colpocephaly, absent cavum septi pellucidi and/or ventricular dilatation. These sonographic signs have always been considered as clear clues for diagnosis of ACC in the fetus[2, 3, 6, 7] and, until now, it was believed but not fully demonstrated that these signs become more evident with advancing gestational age[3, 4]. The present study shows that most of these indirect signs are either absent or barely visible at the time of the midtrimester screening ultrasound in a significant proportion of cases. In particular, before 24 weeks, ventriculomegaly (atrial width > 9.9 mm) was present in 26.5% of cases and colpocephaly in 20.6% of cases. In agreement with other series[7, 8], the cavum septi pellucidi was almost normal in 15/23 (65.2%) fetuses. In addition, a midline cystic structure, which may create a false impression of a cavum septi pellucidi, was present in 18/31 fetuses with cACC (Figure 5). Hence, in these 33/54 (61.1%) cases, ACC could be potentially missed (as the cavum septi pellucidi was either present (pACC cases) or its absence could be missed (cACC cases)). Along the same lines, normal cavum septi pellucidi and normal atrial width were present in 33.3% (9/27) of examinations, in which, therefore, a diagnosis of pACC could only be made if the midsagittal view of the fetal head were obtained; however, this plane is not included in the checklist for the second-trimester anomaly scan[5, 7, 8]. The concept that ACC is missed relatively often at the time of the midtrimester anomaly scan is further supported by the finding that mean gestational age differed significantly between cases referred because of other malformations, in which ACC was then found on neurosonography, and those referred because of ventriculomegaly and/or suspicion of ACC (22.4 vs 25.4 weeks, P < 0.05).

Figure 5.

Three-dimensional multiplanar image comparing midsagittal (a) with reconstructed axial (b) views of fetal brain in a case of corpus callosal agenesis. Reference dot (arrow) is positioned at level of elevated third ventricle in (a), and corresponds to sonolucent midline structure in (b). This structure can be mistaken for a cavum septi pellucidi. cp, choroid plexus; V, cerebellar vermis.

The diagnostic issue is made even more challenging because, as recently reported, the cavum septi pellucidi may sometimes be ill-defined or difficult to visualize[9]. This obviously adds to the diagnostic difficulties because these cases need to be referred for expert opinion and neurosonography[5] even though the corpus callosum is present and unremarkable in a significant percentage of them.

In the second half of gestation, all these sonographic features of ACC become much more evident; ventriculomegaly was present in 74.3% of cases (Figure 3 and Table 1) and colpocephaly in 68.6%. At the same time, in relation to the dimensions of the fetal brain, the midline cysts that could be mistaken for a pseudocavum in the second trimester then become too small to continue resembling a cavum septi pellucidi.

MRI is of little help, because it is usually employed as a second-level test to diagnose possible associated cerebral malformation, such as gyration abnormalities; it is not expected to replace ultrasound in the screening setting, especially before 24 weeks of gestation[5, 10].

In conclusion, we have demonstrated that indirect sonographic signs leading to diagnosis of ACC become more evident > 24 weeks of gestation, and that ACC may escape recognition at the time of the midtrimester anomaly scan. In particular, pACC did not show any abnormality of the transventricular screening view before 24 gestational weeks in 33.3% of cases. The medicolegal implications of such findings are important and should be considered.

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