is an A ssociate Professor of Radiology and Cardiovascular
Medicine, and Director of Cardiac Radiology and Pediatric
Neuroradiology, at Oregon Health and Science University,
Knowledge of basic brain embryology provides the foundation for
making diagnoses of brain malformations, heritable diseases,
congenital neoplasms and even disorders of postnatal development.
Malformation is defined as defective or abnormal
formation, especially when acquired during development. An anomaly
is a marked deviation from normal, especially as a result of
congenital or hereditary defects. The term syndrome is
defined as a set of symptoms occurring together. A
syndrome may be due to malformation or hereditary defects.
Timing of brain malformations and anomalies can be estimated
through critical assessment of absent or malformed structures.
(Figure 1) Heritable neurological diseases are caused by genetic
errors that cause defects in the normal processes of brain
formation and typically have imaging stigmata that, when learned,
are easily recognizable. Congenital brain neoplasms, malformations
and other neurological diseases may be associated with
hydrocephalus and can develop at almost any time of brain
development. Recognition of the imaging milestones in postnatal
brain maturation, primarily the process of myelination, is
important in differentiating dysmyelination from degenerative
The earliest steps in the development of the brain occur at
about 17 days of gestation when the neural plate, a thickening of
the ectoderm, forms in the dorsal midline of the embryo and begins
to differentiate into neurons. By the 20th day of gestation, the
neural tube is formed and begins to close in the early stages of
neurulation (Figure 2). Neurulation continues through stages of
vesicle formation and the dorsal and ventral stages of
The brain forms at the rostral end of the neural tube. By the
middle of the fourth week of gestation, 3 distinct primary vesicles
have developed. As the primary vesicles mature and are folded, they
differentiate into secondary vesicles during the fifth
week of gestation.
The 3 primary vesicles are the forebrain (prosencephalon),
midbrain (mesencephalon) and hindbrain (rhombencephalon). The
secondary vesicles arise from the primary vesicles: the
prosencephalon divides into the telencephalon anteriorly and the
diencephalon posteriorly; the rhombencephalon divides into the
anterior metencephalon and the posterior myelencephalon. The
mesencephalon remains a single vesicle and retains the name
mesencephalon (Figure 3).
At the same time, cavities that will become the ventricular
system form within each vesicle. The lateral ventricles develop in
the forebrain (prosencephalon). The third ventricle develops from
the cavity in the midbrain (mesencephalon) and the fourth ventricle
from the cavity in the hindbrain (rhombencephalon). The foramina of
Monro connect the lateral and third ventricles; the third ventricle
drains to the fourth ventricle via the aqueduct of Sylvius. As this
process occurs, the choroid plexus develops from blood vessels that
invade the ventricles from the diencephalon and the myelencephalon.
Differentiation of the secondary vesicles occurs rapidly. The
telencephalon expands to commence formation of the cerebral
hemispheres by week 11 of gestation. Importantly, each cerebral
hemisphere is formed individually through the process of neuronal
proliferation. During this time the cerebral cortex, basal ganglia
and anterior commissure are formed. Cortical cells continue to
migrate throughout gestation until about the 35th week. The insular
cortex and early formation of the Sylvian fissure occur
during weeks 11 to 28 of gestation through a process termed
operculization. Definition of the sulci and gyri, which
define the lobes of the cerebral hemispheres, is not
complete until the 35th week. The diencephalon develops into the
epithalamus, thalamus, hypothalamus, globi pallidi, the pineal
gland and the neurohypophysis of the pituitary gland.
The cerebral commissures of the telencephalon begin to form
during the seventh week of gestation when a thickening of the
lamina terminalis arises at the rostral end of the neural tube,
becoming the lamina reuniens and the massa commissuralis.
These cells are the site of origin of the anterior commissure and
the corpus callosum, respectively. The corpus callosum is the
largest of the decussating white matter tracts. Its progression of
development is reported to be in sequence, beginning with the
posterior aspect of the genu, followed by the body, splenium,
anterior genu and the rostrum during weeks 10 to 12 of gestation.
This sequence of events has been challenged, raising controversy.
Structures arising from the mesencephalon are the superior and
inferior colliculi of the tectum, cerebral peduncles, optic lobes,
optic tectum, tegmentum and somatic motor neurons of cranial nerves
III and IV. The cerebellum and pons arise from the metencephalon
portion of the rhombencephalon. Like the cerebral hemispheres, the
cerebellar hemispheres are formed by paired dorsal swellings that
grow individually and are aligned at the midline. The
myelencepahlon portion of the rhombencephalon develops into nerve fibers that form the medulla oblongata. Somatic motor
nerves of cranial nerves VI and XII and the visceral motor neurons
of cranial nerves V, VII, IX, X and XI are developed from the
myelencephalon. The rostral neural tube is contiguous with the
myelencephalon and forms the spinal cord.
As each malformation is described, timing and the basis of the
abnormal embryological process will be referenced. I will not
discuss spinal pathology in this article.
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.
Neurulation (3 to 4 weeks)
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
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.
The Chiari malformations I through IV are not a continuum. The
number designations I, II, III or IV do
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 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,
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
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
Neurulation (5 to 10 weeks)
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.
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
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).
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.
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
Agenesis of the corpus callosum
Agenesis of the corpus callosum is one of the most common
malformations of the brain.
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.
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.
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).
The Dandy-Walker complex
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
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).
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,
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).
Neuronal proliferation, migration and histiogenesis (8 to
During this phase of development neuronal cells undergo
proliferation, differentiation and histiogenesis. Neuronal stem
cells migrate from the germinal matrix to the cerebral cortex with
the goal of producing organized cortical layering. Failure of this
process results in microcephaly, megalencephaly, heterotopia, focal
cortical dysplasia, polymicrogyria, lissencephaly,
hemimegalencephaly, schizencephaly, anomalies of operculization,
and phakomatoses. Phakomatoses and other inheritable neurologic
diseases will be discussed in part 2 of this article. Regulators of
cortical malformation have been identified and associated
with specific malformations of the cerebral cortex
through molecular genetic studies.
Vascular malformations are thought to be formed during this time;
indeed, many malformations of the cerebral cortices are accompanied
by abnormal vasculature.
Vascular anomalies will not be discussed further in this
Microcephaly and megalencephaly
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.
Focal cortical dysplasia
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).
) 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.
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
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).
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).
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
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
Anomalies of operculization
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.
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.
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).
Diagnoses in pediatric neuroradiology encompass a broad range of
brain malformations, anomalies, and inherited and metabolic disease
processes. An understanding of basic brain embryology provides the
basis for a more thorough understanding of these pathologic