Commissural and Cortical Maldevelopment

Main Text

Preamble

Corpus callosum dysgenesis and malformations of cortical development are two of the most important congenital brain anomalies. Anomalies of the cerebral commissures are the most common of all congenital brain malformations, and corpus callosum dysgenesis is the single most common malformation that accompanies other developmental brain anomalies.

Cortical malformations arise when migrating precursor cells fail to reach their target destinations. Malformations of cortical development (MCDs) are intrinsically epileptogenic and may be responsible for 25-40% of all medically refractory childhood epilepsies.

Commissural Anomalies

Callosal Dysgenesis Spectrum

Terminology

The corpus callosum (CC) can be completely absent (agenesis) (42-1) or partially formed (dysgenesis). Complete CC agenesis is almost always accompanied by the absence of the hippocampal commissure (HC). The anterior commissure (AC) is usually present and normal. If the CC is dysgenetic, the splenium and rostrum are most frequently affected.

Pathology

In complete CC agenesis, all five segments are missing. The cingulate gyrus is absent on sagittal images and in its place is a radiating spoke-wheel gyral pattern extending perpendicularly to the roof of the third ventricle (42-4).

On coronal sections, the “high-riding” third ventricle looks as if it opens directly into the interhemispheric fissure. It is actually covered by a thin membranous roof that bulges into the interhemispheric fissure, displacing the fornices laterally. The lateral ventricles have upturned, pointed corners (42-1).

A prominent longitudinal white matter (WM) tract called the Probst bundle is situated just medial to the apex of each ventricle (42-1). These bundles consist of the misdirected commissural fibers, which should have crossed the midline but instead course from front to back, indenting the medial walls of the lateral ventricles.

Axial sections show that the lateral ventricles are parallel and nonconverging. The occipital horns are often disproportionately enlarged, a condition termed “colpocephaly.”

Clinical Issues

CC dysgenesis is the most common of all CNS malformations and is present in 3-5% of individuals with neurodevelopmental disorders.

Minor CC dysgenesis/hypogenesis is often discovered incidentally on imaging studies or at autopsy. Major commissural malformations are associated with seizures, developmental delay, and symptoms secondary to disruptions of the hypothalamic-pituitary axis.

Imaging

MR Findings

Sagittal T1 and T2 scans best demonstrate complete CC absence or partial dysgenesis.

Complete Corpus Callosum Agenesis

With complete agenesis, the third ventricle appears continuous with the interhemispheric fissure and is surrounded dorsally by fingers of radiating gyri that “point” toward the third ventricle on sagittal images (42-4) (42-5). Associated findings include a variable midline interhemispheric cyst and azygous anterior cerebral artery.

Axial scans demonstrate the parallel lateral ventricles especially well. The myelinated tracts of the Probst bundles can appear quite prominent (42-3B).

Coronal scans show a Viking helmet or moose head appearance caused by the curved, upwardly pointed lateral ventricles and “high-riding” third ventricle that expands into the interhemispheric fissure (42-3A). The Probst bundles are seen as densely myelinated tracts lying just lateral to the lateral ventricle bodies. The hippocampi appear abnormally rounded and vertically oriented. Moderately enlarged temporal horns are common. Look for malformations, such as heterotopic gray matter (GM) (42-3A).

DTI allows depiction of the abnormal WM tracts in CC agenesis. The normal red (right-to-left encoded) color of the CC is absent. Instead, prominent front-to-back (green) tracts of the Probst bundles are seen.

Corpus Callosum Dysgenesis

In partial agenesis, the rostrum and splenium are most often affected being either absent or hypoplastic (42-6). The remaining genu and body often have a blocky, thickened appearance. The HC is typically absent, but the AC is generally preserved and often appears quite normal or even larger than usual.

Associated Anomalies and Syndromes

Although CC dysgenesis can occur as an isolated phenomenon, CC anomalies are the single most common malformation associated with other CNS anomalies and syndromes. Chiari 2 malformation, Dandy-Walker spectrum, syndromic craniosynostoses, hypothalamic-pituitary anomalies, and MCDs all have an increased prevalence of CC anomalies.

Anomalies of the cerebral commissures have been described in nearly 200 different syndromes and many are linked to mutations in tubulin isotypes. Striking examples include Aicardi syndrome, where callosal agenesis is the most common anatomic abnormality.

Malformations of Cortical Development

Focal Cortical Dysplasias

Focal cortical dysplasias (FCDs) are a common cause of medically refractory epilepsy in both children and adults. Surgical resection is an increasingly important treatment option, so recognition and accurate delineation of FCD on imaging studies are key to successful patient management.

Terminology and International League Against Epilepsy Classification

FCD type Iis an isolated malformation with abnormal cortical layering that demonstrates either abundant developmental microcolumns (FCD type Ia) or abnormal layering (FCD type Ib) in one or multiple lobes. FCD type Ic is characterized by both vertical and horizontal abnormalities of cortical organization.

FCD type II is an isolated lesion characterized by altered cortical layering and dysmorphic neurons either without (type IIa) or with balloon (type IIb) cells. Type II is the most common type of FCD in surgical epilepsy specimens.

The third type of FCD, FCD type III,  is a postmigrational disorder associated with principal pathologies, such as ischemia, infection, trauma, etc. In such cases, cytoarchitectural abnormalities occur together with hippocampal sclerosis (FCD type IIIa), epilepsy-associated tumors (FCD type IIIb), vascular malformations (FCD type IIIc), or—in the case of FCD type IIId—other epileptogenic lesions acquired in early life.

Etiology

The most convincing data implicate mammalian target of rapamycin (mTOR) cascade abnormalities as the cause of FCD. FCD type IIb is considered an “mTORopathy” as is tuberous sclerosis complex (TSC) and the rare hemimegalencephaly syndrome. FCD IIb resembles the cortical tubers seen in TSC.

Pathology

Mildly thickened, slightly firm cortex with poor demarcation from the underlying WM is characteristic (42-7). The histopathologic hallmarks of FCD are disorganized cytoarchitecture and neurons with abnormal shape, size, and orientation. Prominent balloon cells are typical of type IIb. These balloon cells are histologically identical to giant cells in the tubers from TSC patients.

Clinical Issues

FCDs are the single most common cause of severe early-onset drug-resistant epilepsy in children and young adults. This is a critical diagnosis to make because successful surgical resection of FCD results in a very high chance of seizure freedom.

Imaging

MR of FCD type IIb shows a localized area of increased cortical thickness and a funnel-shaped area of blurred GM-WM interface at the bottom of a sulcus extending towards the ventricular margin, the transmantle MR sign (42-8). Signal intensity varies with age. In older patients, FCD most often appears as a wedge-shaped area of T2/FLAIR hyperintensity extending from the bottom of a sulcus into the subcortical and deep WM (42-9) (42-10). In the first few months of life prior to myelination, FCD is typically T1 hyperintense and T2 hypointense compared to adjacent unmyelinated WM. Any nonenhancing signal involving both cortex and subcortical WM should prompt consideration of FCD. FCD type IIb does not enhance on T1 C+.

FCD type I is not typically visible on MR.

Differential Diagnosis

The major differential diagnosis of FCD (especially type IIb) includes epilepsy-associated neoplasm (e.g., dysembryoplastic neuroepithelial tumor, ganglioglioma, diffuse astrocytoma) and TSC. Cortical lesions in TSC can look very similar to FCD type IIb. TSC usually shows multifocal dysplasias (“tubers”) and usually demonstrates other imaging stigmata, such as subependymal nodules.

Abnormalities of Neuronal Migration

Preamble

The most common abnormalities of neuronal migration are GM heterotopias and lissencephaly (LIS) spectrum disorders.

Heterotopias

Arrest of normal neuronal migration along the radial glial cells can result in grossly visible masses of “heterotopic” GM. These collections come in many shapes and sizes and can be found virtually anywhere between the ventricles and the pia. They can be solitary or multifocal and exist either as an isolated phenomenon or in association with other malformations.

Periventricular Nodular Heterotopia

Periventricular nodular heterotopia (PVNH) is the most common form of cortical malformation in adults. Here, one or more subependymal nodules of GM line the lateral walls of the ventricles (42-11). PVNH can be unilateral or bilateral, focal or diffuse. Collections of round or ovoid nodules indent the lateral walls of the ventricles, giving them a distinctive lumpy-bumpy appearance (42-12).

PVNH follows GM in density/signal intensity and does not enhance following contrast administration. The overlying cortex may be dysplastic (42-13), but sulcation and gyration of overlying brain are most often grossly normal.

The major differential diagnosis of PVNH is the subependymal nodules of TSC.

Subcortical Heterotopias

Subcortical heterotopias are malformations in which large, focal, mass-like collections of neurons are found in the cerebral WM anywhere from the ependyma to the cortex (42-14). The involved portion of the affected hemisphere is abnormally small, and the overlying cortex appears thin and sometimes dysplastic (42-15).

In other forms of heterotopia, focal masses of ectopic GM occur in linear or swirling curved columns of neurons that extend through normal-appearing WM from the ependyma to the pia. The overlying cortex is thin, and the underlying ventricle often appears distorted (42-16). The masses follow GM on all sequences, do not demonstrate edema, and do not enhance.

Occasionally, ribbon-like bands of heterotopic GM (subcortical band heterotopia) form partway between the lateral ventricles and cortex (42-18). Although these have been described with megalencephaly and polymicrogyria (PMG), most are probably part of the “double cortex” form of LIS.

Lissencephaly Spectrum

Malformations due to widespread abnormal transmantle migration include agyria, pachygyria, and band heterotopia. All are part of the LIS spectrum.

Terminology

The term LIS literally means “smooth brain.” The spectrum of LISs ranges from severe (agyria) to milder forms, including abnormally broad folds (pachygyria) or a heterotopic layer of GM embedded in the WM below the cortex (subcortical band heterotopia).

In classic LIS (cLIS), the brain surface lacks normal sulcation and gyration. cLIS is also called type 1 LIS or four-layer LIS to differentiate it from cobblestone cortical malformation. Agyria is defined as a thick cortex with absence of surface gyri (“complete” LIS).

True agyria with complete loss of all gyri is relatively uncommon. Many cases of LIS spectrum show areas of broad, flat gyri (“pachygyria”) and shallow sulci (“incomplete” LIS). Subcortical band heterotopia is also called “double cortex” syndrome.

Etiology

cLIS is caused by mutation in genes that regulate the outward migration of neuroblasts from the subependymal ventricular zone. Guided by radial glial fibers, postmitotic neuroblasts normally migrate outward to populate the cortical plate.

Pathology

In cLIS, the external surface of the brain shows a marked lack of gyri and sulci. In the most severe forms, the cerebral hemispheres are smooth with poor opercularization and underdeveloped sylvian fissures. In cLIS, the normal six-layer cortex is replaced by a thick four-layer cortex. Coronal sections demonstrate a markedly thickened cerebral cortex with absent or broad gyri (42-19)and reduced volume of the underlying WM (42-18).

Clinical Issues

Patients with cLIS typically exhibit moderate to severe developmental delay, impaired neuromotor functions, variable intellectual disability, and seizures. Patients with band heterotopia are almost always female.

Imaging

General Features

Imaging in patients with complete cLIS (agyria) shows a smooth, featureless brain surface with shallow sylvian fissures and mildly enlarged ventricles. The cortex is thickened, and the WM is diminished in volume. The normal finger-like interdigitations between the cortical GM and subcortical WM are absent. In some cases, the cerebellum appears hypoplastic.

CT Findings

Axial NECT scans in cLIS show an hourglass or figure-eight appearance caused by the flat brain surface and shallow, wide sylvian fissures. A thick band of relatively well-delineated dense cortex surrounds a thinner, smooth band of WM.

CECT scans show prominent primitive-appearing veins running in the shallow sylvian fissures and coursing over the thickened cortices.

MR Findings

Classic Lissencephaly

In cLIS, T1 scans show a smooth cortical surface, a thick band of deep GM that is sharply demarcated from the underlying WM, and large ventricles (42-23). T2 sequences are best to distinguish the separate cortical layers. A thin outer cellular layer that is isointense with GM covers a hyperintense “cell-sparse” layer (42-20). The WM layer is smooth and reduced in volume (42-20). A deeper, thick layer of arrested migrating neurons is common and may mimic band heterotopia (42-23). Callosal hypogenesis is common in cLIS.

Variant Lissencephaly

In variant LIS (vLIS), sulcation is reduced, and the cortex appears thick (although not as thick as in cLIS).

Band Heterotopia or “Double Cortex” Syndrome

In band heterotopia, a band of smooth GM is separated from a relatively thicker, more gyriform cortex by a layer of normal-appearing WM.

MR scans show a more normal gyral pattern with relatively thicker cortex. The distinguishing feature of band heterotopia is its “double cortex,” a homogeneous layer of GM separated from the ventricles and cerebral cortex by layers of normal-appearing WM.

Differential Diagnosis

Extremely premature brain is smooth at 24-26 gestational weeks and normally has a “lissencephalic” appearance. Full sulcation and gyration do not develop completely until term gestation. Pachygyria is more localized, often multifocal, and usually asymmetric. In contrast to cLIS, the GM-WM junction along the thickened cortex is indistinct. Cytomegalovirus-associated LIS demonstrates periventricular calcifications.

Malformations Secondary to Abnormal Postmigrational Development

Preamble

The third major group of cortical malformations is secondary to abnormal postmigrational development and often reflects infectious or ischemic insults. This group was formerly designated “abnormalities of cortical organization.” It is currently divided into several subtypes of polymicrogyria (PMG) according to whether clefts (schizencephaly) are present and whether they occur as part of a recognized multiple malformation syndrome, inherited metabolic disease, or genetic disorder.

Polymicrogyria

The signature feature of PMG is an irregular cortex with numerous small convolutions and shallow or obliterated sulci. The appearance is that of tiny miniature gyri piled on top of other disorganized gyri (42-24).

Etiology

Both genetic and nongenetic causes of PMG have been identified. Encephaloclastic insults, such as infection (e.g., TORCH, Zika virus infection), intrauterine vascular accident (e.g., middle cerebral artery occlusion), trauma, and metabolic disorders, have been implicated in the development of PMG.

Mutations in > 30 genes are associated with PMG, especially mutations in the tubulin family. The phenotypic spectrum of TUBA1A mutations includes bilateral perisylvian PMG with dysmorphic basal ganglia (42-27), cerebellar vermis dysplasia, and pontine hypoplasia.

Pathology

PMG is characterized by overfolding of the cerebral cortex and abnormal cortical layering. PMG can involve a single gyrus or most of an entire cerebral hemisphere. It can be uni- or bilateral, symmetric or asymmetric, and focal or diffuse. Multiple small, shallow, and abnormally oriented gyri with an undulating surface and complex sulcal branching are typical findings (42-25).

Bilateral perisylvian PMG is the most common location (61% of cases). Generalized (13%), frontal (5%), and parasagittal parietooccipital (3%) sites are less common. Associated periventricular GM heterotopias are found in 11% of cases, and other anomalies, such as schizencephaly, are common.

Clinical Issues

PMG can present at any age, but many do not present until late in childhood, and some mild cases may remain asymptomatic. PMG is the most common imaging abnormality seen in infants with congenital cytomegalovirus infection. Symptoms depend on the location and extent of PMG, ranging from global developmental delay to focal neurologic deficit(s) and seizures.

Imaging

Multiplanar MR with high-resolution thin sections is required for complete delineation and detection of subtle lesions. 3D acquisitions with MPRs are ideal. Thickened or overfolded cortex with nodular surfaces and irregular “stippled” GM-WM interfaces are the most characteristic findings (42-26). Detection of PMG is more difficult prior to completion of myelination. Prior to myelination, T2-weighted imaging tends to be the most sensitive sequence for detecting PMG (42-26). Early or asymmetric sulcation in the fetus is a sign of PMG on fetal MR.

Differential Diagnosis

The major differential diagnosis of PMG is type 2 LIS (cobblestone malformation) (42-27) (42-28). The absence of congenital muscular dystrophy and Z-shaped brainstem is a helpful clinical distinction.

Sometimes, pachygyria can be confused with PMG. In pachygyria, the cortex and GM-WM junction are smooth. In contrast, the cortex in PMG is nodular and excessively folded with an irregular GM-WM junction. In FCD, the GM is focally thickened with subtle cortical and subcortical T2/FLAIR hyperintensity, and the GM-WM interface is blurred.

In schizencephaly, the dysplastic cortex lining the cleft may appear “pebbled,” but the cleft distinguishes it from PMG.

Schizencephaly

Schizencephaly (literally meaning “split brain”) is a GM-lined cleft that extends from the ventricular ependyma to the pial surface of the cortex. The cleft spans the full thickness of the affected hemisphere (42-29). Encephaloclastic in utero insults, including vascular disruptions and infections (e.g., TORCH) occurring before 28 fetal weeks, are the primary etiologies. Schizencephaly can be considered on the severe spectrum of PMG with similar causes and associations (e.g., septo-optic dysplasia).

A schizencephalic brain exhibits a deep cleft that extends from its surface to the ventricle. The cleft is surrounded and lined by disorganized, dysmorphic-appearing GM (42-30). The “lips” of the cleft can be fused or closely apposed (“closed-lip” schizencephaly) (42-31)or appear widely separated (“open-lip” schizencephaly) (42-33). Clefts may be associated with a range of other macroscopic abnormalities involving the septi pellucidi, CC, optic chiasm, and hippocampus.

The key imaging features of schizencephaly are (1) a CSF-filled defect extending from the ventricle wall to the pial surface and (2) dysplastic GM lining the cleft.

Imaging studies show a focal V-shaped outpouching or “dimple” of CSF extending outward from the lateral ventricle (42-30). The clefts can be uni- (60%) or bilateral (40%) with prominent (“open”) or barely visible (“closed”) lips (42-32).

MR is more sensitive than CT in delineating associated abnormalities, such as cortical dysplasia (PMG, pachygyria) and heterotopic GM. The cleft follows CSF signal intensity on all sequences (42-34).

The differential diagnosis includes both developmental and destructive lesions. The major differential diagnosis of schizencephaly is porencephaly. In porencephaly, the cleft is lined by gliotic WM, not dysplastic GM. Transmantle heterotopia or deeply infolded PMG may be difficult to distinguish from schizencephaly with closed, nearly fused “lips.” An arachnoid cyst displaces the adjacent cortex, which is otherwise normal in appearance.

POSTMIGRATION DISORDERS

Polymicrogyria

• Etiology

 Acquired [infection (e.g., cytomegalovirus), intrauterine vascular accident]

 Inherited (tubulin gene mutations)

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