Diffusion Imaging of the Congenitally Thickened Corpus Callosum

Discussion

Nonprogressive pervasive global developmental delay is relatively common, affecting 1%–3% of children.⁹ Along with routine cytogenetics and testing for Fragile X syndrome, MR imaging is suggested in the evaluation of developmental delay because MR imaging may show congenital malformations, brain injury, and unsuspected phakomatoses or metabolic disorders.⁹ DTI is a fairly recent addition to conventional MR imaging, which may provide additional information when cerebral malformations associated with the developmental delay involve larger white matter fibers. DTI can be acquired in routine clinical practice; a single acquisition that provides adequate SNR at 3T adds approximately 4 minutes to the imaging time. Tensor data can be viewed as directionally encoded color maps or as 3D renderings by using a variety of readily available software tools.¹⁰ As the largest white matter bundle in the brain and by virtue of having a highly parallel structure, the corpus callosum is readily assessed with diffusion imaging.⁵

The normal corpus callosum is composed of transversely oriented red fibers that connect mirror-image regions of the cerebral hemispheres.^4,5 In the normal brain, there are no midline longitudinal supracallosal fibers seen by diffusion imaging because all longitudinal fibers are, by definition, association fibers that connect heterotopic regions within the same hemisphere. The patients reported here are ones who underwent referral for variable developmental delay, in whom conventional MR imaging showed focal callosal thickening; additional insight into the malformed corpus callosum was provided by DTI, which showed that the callosal thickening was due to the presence of longitudinal midline supracallosal fibers. These fibers may represent the heterotopic cingulum, indusium griseum, or aberrantly oriented callosal axons.

The cingulum has longitudinally oriented parasagittal association fibers that form the outer limbic arch.¹¹ Reports of anomalies of the cingulum are uncommon. Hori and Stan¹² described 2 deceased adults with thick midline longitudinal midline fibers attributed to an aberrant cingulum on the basis of the attachment of the fibers to the cingulated gyrus. Friede and Briner¹³ described similar findings in a deceased patient who had undergone closure of a lumbar myelomeningocele at birth, but they speculated that the abnormal supracallosal tract was a malformation of the forniceal system rather than the cingulum. The cingulum is visually indistinguishable from regional white matter by conventional MR imaging but is readily identifiable by diffusion tractography as green fibers arching over the corpus callosum from the prefrontal to the retrosplenial region and extending into the temporal lobes. Diffusion tractography has been used to show anomalies of the cingulum and aberrant midline supracallosal fibers connected to the cingulum in patients with Chiari II malformations and in lobar holoprosencephaly.^8,14

The IG is a supracallosal midline structure containing cells that produce the axonal guidance and repellant molecules critical to normal callosal formation.¹⁵ The IG is a small anatomic structure that may be visible in healthy adults by using high-resolution MR imaging as symmetric pairs of narrow gray matter strips, which may be centrally fused, or a single lateralized strip of neural tissue.¹⁶ The IG is presumed to be vestigial and nonfunctional in humans, though it may have some role in hippocampal seizure disorders because the IG is thought to have connections with hippocampal-amygdaloid pathways, the entorhinal cortex, dentate gyrus, medial septum, and piriform cortex.¹⁷ A small structure in the human brain, the IG is not commonly discussed in the imaging literature or noted in clinical practice. In knockout mice models, loss or significant reduction in the size of the IG is associated with failure of formation of the corpus callosum.¹⁷ Whether hypertrophy of the IG is associated with overgrowth of the corpus callosum is unknown.

The anomalous fibers that explain the segmental thickening of the corpus callosum may represent commissural axons that went astray during axonal migration. Aberrant migration of callosal axons have been reported in partial callosal agenesis; the longitudinal fiber bundle has been termed the “sigmoid aberrant bundle” by Wahl et al.⁴ They used high angular resolution diffusion imaging to study callosal connectivity in adults with partial callosal agenesis and described asymmetric aberrant bundles connecting the frontal lobe with the contralateral occipitoparietal cortex.⁴ The Probst bundles seen in callosal agenesis are also examples of misdirected callosal axons, though Probst bundles do not cross the midline.^1,2

The longitudinal fibers reported herein do not appear to represent the medially displaced superior occipitofrontal longitudinal fasciculus because this fiber bundle was identifiable in a normal location in all of the subjects. I do not believe the finding is artifacts because one would expect to have seen the artifacts in other cases during the past decade during which we have been doing diffusion tensor imaging, and we have not seen them. We have seen subjects with mild thickening of the rostral callosal body who did not demonstrate the anomalous supracallosal fibers; this finding suggests other explanations for congenital callosal thickening.

Congenital nonsyndromic thickening of the corpus callosum is rare. Lerman-Sagie et al⁷ reported 9 cases in which a thick corpus callosum was diagnosed on prenatal sonography; the malformation was associated with developmental delay and seizures in early childhood. Syndromic conditions associated with enlargement of the corpus callosum include NF type 1, Cohen syndrome, and M-CMTC.^18⇓–20 In NF type 1, the large commissural tracts may result from a lack of the normal postnatal apoptotic cell pruning documented in the young rhesus monkey and in mice.^21,22 Cohen syndrome is characterized by failure to thrive, early-onset hypotonia, microcephaly, moderate-to-profound psychomotor retardation, and typical facial features.¹⁹ M-CMTC is a rare congenital syndrome of unknown etiology associated with enlargement of a portion or the entire corpus callosum.²⁰ Neuroimaging in this rare disorder has shown cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy along with focal cortical dysplasia, polymicrogyria primarily involving the peri-Sylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth.²⁰ None of the 4 cases reported herein had other clinical or imaging stigmata of NF type 1, microcephaly, or evidence of M-CMTC, though 1 subject did have bifrontal and peri-Sylvian polymicrogyria.

Diffusion imaging can be used to quantify white matter differences in healthy and disease states and can provide information about fiber orientation and connectivity.¹⁰ The directional information about white matter fibers was used to create the color-coded FA maps and 3D mathematic depictions of the corpus callosum and supracallosal fibers. However, the use of diffusion tensor imaging precludes assessment of axonal connectivity due to the insensitivity of tensor imaging to intravoxel crossing fibers, and which regions of gray matter were connected by the anomalous supracallosal fibers or whether these fibers connected with the normally positioned cingulum could not be determined. The use of high-angular-diffusion imaging with multiple b-values would have been preferable for purposes of determining connectivity. However, because patient throughput limits the time allotted for imaging, we routinely limit diffusion imaging to diffusion tensor, notwithstanding the inherent limitations of DTI.