Pediatric neuroradiology, part 1: Embryologic basis for brain malformation

Dorsal induction and ventral induction are 2 processes of neurulation in brain embryology that occur subsequent to the early formation of the primaryand secondary vesicles.

Dorsal induction occurs at 3 to 4 weeks gestation and is the process by which the neural tube closes, forming the spinal cord. There are 3 phases of dorsal induction; neurulation, canalization and retrogressive differentiation. Failed closure of the rostral end of the neural tube can result in anencephaly, a defect in which brain tissue is completely absent, a malformation that is incompatible with postnatal life. Other major malformations of abnormal dorsal induction are cephalocele and the Chiari II malformation.¹¹

Cephalocele is an extension of intracranial contents (e.g. meninges, CSF and/or brain) through a dural and calvarial defect. The type of malformation is named for its anatomic location and the contents included in the herniated tissue. The defect is usually midline and is typically occipital in those of European descent (Figure 4) and frontoethmoidal in those with Asian heritage (Figure 5). Chiari III malformation is an occipital, C1-to-C2 encephalocele that may contain cerebellar tissue and CSF. ¹²

The Chiari malformations I through IV are not a continuum. The number designations I, II, III or IV do not imply a progression of severity of a single brain malformation. They are numerous malformations that can occur during neurulation of the hindbrain and commonly are associated with hydrocephalus. Some of the Chiari malformations are controversial, such as Chiari IV: hypoplasia of the cerebellum alone or in association with Chiari II.¹³ Chiari zero is also a controversial designation: indicating normal position of the cerebellar tonsils on imaging studies, but clinical presentation of headache, which is reminiscent of the experiences of patients with Chiari I (personal communication, David M. Frim, MD, Chairman of Neurosurgery, The University of Chicago, Chicago, IL).

Chiari I malformation is characterized by low-lying cerebellar tonsils (Figure 6). The posterior fossa may be small because of shortening of the clivus. The foramen magnum is defined on sagittal magnetic resonance (MR) images by the ventral and dorsal margins of the occipital bone, i.e. the clivus (basion) and occiput (opisthion). Horizontal orientation of the clivus and cupping of the occiput is seen in many patients, contributing to smallness of the posterior fossa (Figure 7). Normal cerebellar tonsils are oval in shape and should lie <5 mm below a line drawn between the ventral and dorsal borders of the foramen magnum (Figure 8).¹⁴

Chiari II malformation and meningomyelocele are nearly always associated. The posterior fossa is small and the tentorium is low lying, resulting in crowding of the cerebellum and brainstem into the cervical medullary junction and upper cervical spinal canal. This crowding results in kinking of the medullary cervical junction and elongation of the fourth ventricle (Figure 9). Although many patients are developmentally normal, agenesis of the corpus callosum and cortical migration anomalies may accompany Chiari II malformation.¹⁵

Ventral induction takes place during weeks 5 to 10 of neurulation. The brain segments, neuronal proliferation occurs and the face is formed. The primary and secondary vesicles (prosencephalon, mesencephalon and rhombencephalon) form the cerebrum, midbrain, cerebellum and lower brainstem. The cerebrum and cerebellum each form 2 distinct hemispheres.

Failure of these neural proliferation processes results in midline supratentorial anomalies such as holoprosencephaly, agenesis of the corpus callosum, pituitary maldevelopment and posterior fossa malformations such as Dandy-Walker malformation, cerebellar hypoplasia and rhombencephalosynapsis. Hydrocephalus due to aqueductal stenosis can also occur during this time.¹¹

Hydrocephalus is an enlargement of the ventricular system in the brain and implies there is elevated intracranial pressure. Almost all of the malformations, diseases and syndromes mentioned in this article can be associated with hydrocephalus.

The cavities that become the ventricles, and the foramina and aqueducts connecting them, form during weeks 4 to 12 of gestation. Obstruction at any point of the ventricular system due to failure in the formation of these cavities can occur at any time. Other sources of ventricular obstruction are canalization of the foramina and aqueducts, overproduction of CSF by the choroid plexus, or diminished reabsorption through the arachnoid villi. Obstruction can occur prenatally, from the time of formation, to birth, or postnatally and result in hydrocephalus.

When severe, hydrocephalus may be difficult to differentiate from hydranencephaly, which is an extreme form of cerebral encephalomalacia, probably the result of occlusion of both internal carotid arteries and infarction of all cerebral tissue (Figure 10).^9,16

Congenital stenosis of the aqueduct of Sylvius can be due to intrinsic or extrinsic narrowing or malformation of the aqueduct. Abnormal histiogenesis and proliferation of periaqueductal grey matter in the midbrain can result in primary stenosis or formation of numerous minute channels through the aqueduct. Mass effect on the quadrigeminal plate from supratentorial hydrocephalus, or a mass, can cause secondary narrowing of the aqueduct. Pre- and postnatal infection, inflammatory disease or intraventricular hemorrhage can lead to acquired aqueductal stenosis due to fibrosis or gliosis, leading to stenosis. X-linked forms of aqueductal stenosis are also described. Stenosis results in lateral and third ventricle hydrocephalus; the fourth ventricle remains normal in volume (Figure 11).¹⁷

Holoprosencephaly occurs due to failure of proliferation of cerebral tissue to form 2 separate cerebral hemispheres. Normally, the right and left cerebral hemispheres form independently in a unified process of neuronal proliferation. Although prosencephalon formation abnormalities are programmed for failure earlier in gestation, even before the neural tube closes, it is during the proliferative phase of ventral induction that holoprosencephaly manifests. When the hemispheres fail to develop into 2 separate hemispheres but rather form a single, midline mass of cerebral tissue, the result is holoprosencephaly.

The most severe form of holoprosencephaly is termed alobar, because the cerebral tissue bears no resemblance to normally defined cerebral lobes (Figure 12). The lateral ventricles are also abnormal, forming a midline monoventricle. Septo-optic dysplasia is the mildest form of the holoprosencephaly spectrum: the septum pellucidum and the optic nerves are atrophic (Figure 13). Pituitary gland malfunction is part of the syndrome of septo-optic dysplasia (Figure 14). Semilobar and lobar forms of holoprosencephaly describe the degree to which the frontal, temporal, parietal and occipital lobes are defined. The degree of cerebral malformation is less severe than in the alobar form. Other midline structures, the falx and septum pellucidum are dysplastic. Schizencephaly is associated in 50% of cases.^9,17,18

Because there is a temporal relationship between facial formation and neuronal proliferation, facial malformation is usually seen in patients with holoprosencephaly. Facial malformations are due to abnormal development of the premaxillary segments of the face and result in arrhinia and midline facial clefts.¹⁹

Agenesis of the corpus callosum is one of the most common malformations of the brain.²⁰ The corpus callosum begins to form in the seventh week of gestation and is complete by 18 to 20 weeks. There has been controversy regarding the definitive order in which segments of the corpus callosum are formed, but its absence is known to be associated with a range of findings including normal development, Dandy-Walker complex, Chiari II malformation, numerous syndromes, and the absence may be accompanied by seizure disorders and mental retardation.^{6, 7}

Radiographic findings of dysgenesis or agenesis of the corpus callosum include absence of, or a malformed corpus callosum (Figure 15), and parallel orientation of the lateral ventricles; normally the frontal horns lie closer together than the occipital horns of the lateral ventricles. The occipital horns and atria of the lateral ventricles may be dilated, a finding termed colpocephaly (Figure 15). When the corpus callosum is completely or partially absent the cingulate gyrus does not form normally, allowing interhemispheric gyri to radiate toward the roof of the lateral ventricles. The neurons that normally cross the midline to form the corpus callosum course along the interhemispheric fissure, in groups of white matter called Probst bundles (Figure 15). These bundles lie along the superior medial surface of the lateral ventricles, indenting the ventricle which causes a bull’s horn configuration.²⁰

The roof of the third ventricle can be displaced upward because the corpus callosum is not limiting its superior expansion; an interhemispheric cyst or lipoma may be associated (Figure 15).²⁰

The Dandy-Walker complex is the result of malformation of the metencephalon portion of the rhombencephalon leading to atresia of the cerebellar outlet foramina. As a result, the roof of the fourth ventricle does not develop normally and there is hypogenesis or agenesis of the cerebellar vermis. The fourth ventricle therefore communicates freely with extra-axial fluid in the posterior fossa (Figure 16). The tentorium and position of the torcular Herophili are elevated; i.e. the posterior fossa is enlarged (Figure 16). The Dandy-Walker complex encompasses a range of hypoplasia or dysplasia of the cerebellar hemispheres and/or vermis which can be found in patients with numerous diagnoses of chromosomal anomalies and syndromes.^11,21

Cerebellar hypoplasia may be diffuse or can be limited to a single hemisphere and may involve the vermis. Differentiating hypoplasia from other cerebellar malformations, dysplasia and atrophy requires determining that the posterior fossa is normal volume and determining the absence of an associated cyst in communication with the fourth ventrice (Figure 17).²¹

Although rhombencephalosynapsis is usually described as a “fusion” anomaly, or dysplasia of the cerebellar hemispheres and vermis, and has been described in a patient with holoprosencephaly,^9,21 I believe this malformation is probably the result of failed neuronal proliferation of the cerebellar hemispheres, much like holoprosencephaly of the cerebral hemispheres.

Imaging studies reveal an absence of the normal formation of midline structures of the posterior fossa including the vermis and mesencephalic structures. The cerebellar hemispheres are continuous across the midline (Figure 18).⁹

Microcephaly and megalencephaly are due to disorders of neuronal and glial proliferation or excess or reduced apoptosis. Microcephaly is a malformation secondary to abnormal stem-cell proliferation or apoptosis after normal proliferation of stem cells. By definition, the head circumference in these children is ≥3 standard deviations below the norm. There are fewer gyri, the depth of the sulci is shallow and the volume of white matter is diminished (Figure 19).

Megalencephaly is the result of a generalized increase in neuronal and glial proliferation or diminished apoptosis.⁹

Focal cortical dysplasia is the result of abnormal migration of neurons to the cerebral cortical cell layers. Histologically, the cortical cells are also abnormal. Some forms of cortical dysplasia contain balloon cells, and may show abnormal signal and architecture extending from the germinal matrix through the deep and subcortical white matter. Imaging findings are variable, depending on the involvement of white matter and may show focal blurring of the grey-white junction, or thinning or thickening of the affected cerebral cortex, which usually has high T2 signal on MR (Figure 20).⁹

Heterotopia (singular: heterotopion) are abnormal anatomic locations of cortical grey matter which are due to premature arrest of neuronal migration. Typical locations of heterotopia are subependymal, where they are usually asymmetric, at the trigones of the lateral ventricles and subcortical, where they may be focal (Figure 21) or generalized, forming a band or double cortex underlying the normal-appearing cerebral cortices.⁹

In the later stages of neuronal migration, the 6 layers of the cerebral cortex are organized. When the deep layers of the cerebral cortex form numerous small gyri instead of organized cortical layers, the imaging result appears to be thickening or thinning of the cerebral cortex, which is usually associated with abnormal sulcal formation. MR may also show a nodular appearance of the cortex and normal-to-increased signal in the cortical tissue. There are numerous syndromes and patterns of polymicrogyria, and many have been shown to correspond with chromosomal abnormalities (Figure 22).^9,22

Lissencephaly (smooth brain) describes the malformation with lack of gyral and sulcal development such that the surface of the cerebral hemispheres is smooth, due to arrested neuronal migration. Agyria (complete lissencephaly) or pachygyria (incomplete lissencephaly) as well as a thickened cerebral cortex are seen on imaging studies, differentiating lissencephaly from malformations of neuronal proliferation (Figure 23).^9,22

Hemimegalencephaly is unilateral megalencephaly that is isolated, part of a hemihypertrophy syndrome or the result of hamartomatous overgrowth of one cerebral hemisphere. The malformation occurs because of defective neuronal proliferation, migration and cortical organization. The unilateral enlargement of the cerebral hemisphere includes proportionate ventriculomegaly and unilateral enlargement of CN I and CN II which of course are really glial tracts rather than true cranial nerves (Figure 24).^9,22

Schizencephaly may be the result of abnormal cellular proliferation, migration and/or cortical organization. The malformation could be the result of a focal injury at the germinal matrix as neurons begin to migrate — a transmantle injury later in gestation may be familial or caused by chromosomal mutation. The germinal matrix, located at the caudal thalamic groove is at the margin of the lateral ventricles. A cleft is formed in the cerebral mantle when neurons fail to migrate from a focal area of the germinal matrix.

Characteristic imaging findings may be unilateral or bilateral; when bilateral, the clefts are typically symmetric. The cleft, lined by dysplastic grey matter, extends from the margin of the lateral ventricle to the cerebral cortex and is in communication with the ventricle and the subarachnoid space overlying the cerebral hemisphere. The margins of the cleft may be splayed (open lip) or lie in close apposition (closed lip, Figure 25).^9,22

Formation of the Sylvian fissure and insula begins during the 14th week of gestation, between the orbitofrontal and temporal lobes. The insula is defined by infolding of the structures by the 19th week of gestation.¹² The process of formation of the Sylvian fissures is called operculization. Disorders of neuronal proliferation and neuronal migration which are limited to the operculum result in abnormal gyration and/or cortical dysplasia which is manifested as abnormalities in the processes managed by these areas, namely speech, language and pseudobulbar palsy.^22,23

The imaging appearance can vary from wide Sylvian fissures, thickening of the cortex, localized polymicrogyria of the insula, and thickened or shallow gyri and they may be accompanied by anomalous vessels. When symmetric malformation is found, the brain has a “figure 8” shape on axial images (Figure 26).^9,23