Assessment of Sulcation of the Fetal Brain in Cases of Isolated Agenesis of the Corpus Callosum Using In Utero MR Imaging

Discussion

In this paper we have studied sulcation in fetuses with structurally normal brains including a normal corpus callosum and compared that feature with fetuses with ACC and no other obvious brain abnormality. Failed commissuration is not always complete but we have not included any fetuses with hypogenesis of the corpus callosum. We recognize that most authorities have pointed out that ACC is an embryologically incorrect term as the fibers of the corpus callosum have not failed to form, rather they have not crossed the midline, remaining ipsilateral as the bundles of Probst. While acknowledging this embryologic truism we have elected to use the term ACC in this paper for reasons of common usage and brevity.

It is becoming recognized that the diagnosis of isolated ACC is relatively unusual as it is frequently associated with a range of other brain anomalies and is implicated in >50 congenital syndromes.²³ Hetts et al reviewed the postnatal MR imaging of 142 patients with corpus callosum anomalies and showed that 51.4% had associated cortical developmental malformations, with gray matter heterotopia being the most common (present in 29% of their patients with ACC).²³ In the review by Coakley et al, half of the fetuses with ACC studied had additional CNS anomalies including Dandy-Walker syndrome, Chiari II malformation, gray matter heterotopia, and holoprosencephaly.⁸ We attempted to define 20 cases of isolated ACC diagnosed on iuMR for this study, but we must stress that our prenatal diagnosis may be incorrect. This is particularly true for the earlier gestational age cases, as the commonly associated neocortical formation abnormalities may be difficult to diagnose at that stage. We have not been able to follow up all of these cases (either by postmortem studies or by postnatal imaging) to confirm the absence of other brain abnormalities. We do not think, however, that the fundamental diagnosis of ACC would be changed in any of our cases, as the literature points to a high sensitivity and specificity for iuMR to show ACC.

It is well known that there is disruption of the normal sulcal pattern in children and adults with ACC involving the paramedian sulci of the cerebral hemispheres, which show a radial pattern as a direct effect of the absent corpus callosum.^5,17,23 That feature, however, was not the subject of our study, though it can be seen in fetuses with ACC after 32 weeks' gestational age. As described previously, the etiology of cortical sulcation delay could be due to the presence of other brain abnormalities and unrelated to the commissural abnormality per se. Our attempt to include only isolated ACC cases was to try to circumvent that confounding factor.

We must consider why sulcation might be delayed in a fetus with ACC. Numerous hypotheses have been proposed regarding the processes intrinsic to normal gyral/sulcal development, including tailored growth during gyrogenesis,^11,12 competitive mechanical tension along axons in the white matter,^12,13 genetic factors,^14,15 and environmental factors.^10,16 Toro and Burnod¹⁷ described a morphogenetic model for development of cortical convolutions combining a mechanical theory of gyrification and genetic factors. It is likely that a number of factors determine normal gyral development; mechanical factors do however appear central to many theories, specifically the organization of long-range projections and resultant gyral morphology relating specifically to underlying cortical pinning.^12,13,17 The work presented in this paper supports the theory that an integral corpus callosum facilitates optimal gyral development and that ACC may lead to delayed gyral formation.

Apparent delayed sulcation has been described recently by Tang et al in a review of 29 cases of fetal ACC.¹⁸ Those authors found evidence of sulcal delay and/or abnormal sulcal morphology in 23 of 29 cases with a statistically significant delay in sulcation in cases of ACC when compared with a control group (P < .0001); not all of those cases, however, were isolated ACC cases. They found that sulcal delay occurred exclusively in fetuses before 30 weeks' gestational age with no detectable delay in those ≥30 weeks' gestational age or on postnatal assessment. Indeed, they presented a case of delayed sulcation identified at 26.4 weeks, in which sulcation became “normal for age” on repeat iuMR imaging at 32.4 weeks. Our own results are somewhat at variance with that; in our assessment of earlier gestation fetuses (group 1, 21–26 weeks gestation), though there was a trend toward significance, no actual statistically significant difference between the normal and ACC cases was identified. Comparative review of the assessments performed during the most accurate dating period according to Garel and colleagues (group 2, 30–34 weeks gestation) did however reveal a statistically significant difference, suggesting that sulcation is delayed in cases of fetal ACC at this stage (30–34 weeks) of neurodevelopment.^1,4 We demonstrated excellent correlation between consensus assessments of gestation versus actual gestational age with 95% of all cases being accurately dated to within 2 weeks.

It is important for us to review some methodologic considerations at this point. While numerous pathologic studies have documented progressive gyral development with increasing gestation, there is a relative paucity of MR studies depicting normal fetal cortical development patterns in utero. One of the largest series published to date was by Garel et al who reported the findings of 225 normal iuMR fetal studies, between 22 to 38 weeks' gestation; they presented the gestational age at which particular sulci were present in 75% of cases (Table 2).¹ Neuropathologic studies^24,25 assessing sulcal pattern typically demonstrate sulcal formation before its visualization on iuMR.^4,5 Levine and Barnes, for example, reported a mean lag of 1.9 ± 2.2 weeks in MR appearance of sulci when compared with neuropathologic studies, with the greatest lag occurring between 20 and 32 weeks' gestation.⁵ The sections used in neuropathologic studies are significantly thinner than those in MR imaging (15–30 μm vs 3–5 mm), thus allowing detection of subtle surface indentations that may initially be overlooked on MR imaging.^1,3,6 Autopsy specimens also allow true orthogonal sections to be obtained, which can be difficult to achieve with fetal movement during imaging acquisition, with oblique sections limiting accurate sulcal detection. Chi et al²⁵ report left-right hemispheric asymmetry in formation of a number of the secondary sulci and an approximately 2 week sulcal delay in twin fetuses; these various factors confound the difficulty of establishing an accurate gestational age and also make formation of an accurate, reproducible, dating atlas extremely difficult.^3–6,25 It is also possible that the fixation process involved in making histologic sections may make sulcation more prominent.

The reference atlas utilized for this work was that of Garel¹; in assessment of delayed sulcation, the author recommends comparative analysis be made with respect to sulcal presence rather than detectability alone.^1,4 A temporal delay of ∼2 weeks exists between when a sulcus is detectable (seen in 25%–75% cases) and present (seen in >75% cases); definitive, accurate prediction of gestational age is accordingly necessarily limited.^4–6 Our assessment of gestational age was based on sulcal presence. The sulcal depth and shape were not separately examined; however, with progressive cortical maturation the sulci deepen and demonstrate increased complexity. Dating correlation between neuropathology studies and MR imaging improves with increased actual gestation; specifically, the later the normal development of a sulcus the closer is the dating correlation. Optimal time for most precise correlation between MR sulcal pattern and actual gestational age is considered to occur between 28 and 34 weeks' gestation.^1,4 At 34 weeks' gestation, most secondary and all primary sulci are present, and estimation of gestation subsequent to this gestation becomes increasingly difficult to delineate.^1,4

When our data are displayed graphically (Fig 1) it is apparent that there is a relative paucity of fetuses between 27 and 29 weeks actual gestational age. This reflects the referral pathway whereby many of the earlier gestation fetuses are referred via screening in contrast to the later gestations, which are imaged for indications such as reduced fetal movement; there is resultantly a natural dearth of cases in the interim.

In our experience, a paucity of primary sulci in early gestation makes clear determination of delayed gestation difficult if not impossible (Fig 2). With increased gestation (ie, between 28 and 34 weeks) discrimination between normal and delayed fetal gestation was more apparent (Figs 3 and 4). Limited study numbers prohibit us to conclude whether a true delay in sulcation in association with fetal ACC is identified more frequently with increased gestation or whether this reflects that accurate gestational assessment is difficult and the most accurate assessment time period is in later gestation; primary and secondary sulci do eventually form, and thus any delay identified in utero does appear to correct during the postnatal period.¹⁸