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The central nervous system (CNS)
is the most complex organ in the human body comprising a highly
organized anatomic scaffold of billions of cells and a network of
trillions of connections. Structural brain development proceeds
through an integrated series of often rapid developmental events
from early embryogenesis through fetal life and into early adulthood.
It is therefore not surprising that many common childhood neurologic
and developmental disorders have their origins in genetic or environmental
perturbations of embryonic or fetal brain development.
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Advances in genetics and diagnostic imaging, including prenatal
imaging, have led to earlier and more complete diagnosis and enhanced prognostication
for CNS malformations and the ability to counsel effectively regarding
recurrence. The diagnosis of malformations has been revolutionized
by magnetic resonance imaging (MRI), and the challenge for the pediatrician
is often to translate the imaging diagnosis to effectively counsel
the family and plan further care and management for the child. Modern
neonatal neurologic and neurosurgical intensive care together with
progress in early intervention and pediatric rehabilitation means
children with malformations of the brain or spinal cord may now
survive longer and with improved quality of life.
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Malformations of the CNS are among the most common problems in
child neurology. Brain development is abnormal in an estimated 25% of
conceptions and is responsible for a high percentage of miscarriage
and stillbirth. Brain malformations are, together with congenital
heart disease, the leading cause of neonatal and postneonatal mortality
in the developed world. Brain malformations are after cerebral palsy,
the leading cause of childhood morbidity and mortality related primarily
to consequent neurologic disability and epilepsy. Brain malformations
frequently coexist with other malformations of organ systems, in
particular the eye, heart, kidneys, gut, and skeleton.
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The neuraxis develops following the fate decision of several
early embryonic cells to become neural progenitors and by the second week
of embryogenesis the three primary layers of ectoderm, mesoderm,
and endoderm are formed. It subsequently proceeds through the dorsal
and ventral induction to form the neural tube, lower spinal cord
and eventually the prosencephalon (forebrain), mesencephalon (midbrain),
and rhombencephalon (hindbrain). This is followed by massive cellular
proliferation of both neuronal and glial precursors and later differentiation
into specific neuronal and glial types. Cortical development occurs
with migration of neuronal and glial precursors away from the ventricular
and subventricular zone towards the pial surface to form the neocortex
and major commissures such as the corpus callosum. This is followed
by cortical organization that includes alignment, orientation, and
layering of cortical neurons together with synaptogenesis. From
the end of the second trimester into early childhood late glial
differentiation and myelination, together with programmed and experience-dependent
synaptic formation and pruning predominate.
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The range of known malformations is almost as complex as the
series of developmental events that lead to the formation of the brain.
They are perhaps best understood as the effects of insults—regardless
of type—at key points in the development of the brain. Although
much emphasis has been placed on genetic etiologies—cytogenetic
abnormalities, single gene disorders, and polygenic syndromes—environmental
insults at key points in the developmental program may result in similar
malformations with common clinical findings in the infant or child.
As the developing brain, particularly during the first two trimesters,
is not capable of generating the common glial response to injury,
the etiological cause is frequently difficult to discern. For example
early vascular or infectious events may cause abnormalities of cortical migration such
as polymicrogyria indistinguishable from a primary genetic causation. An
overview of the key developmental events in brain and spinal cord
formation, together with examples of corresponding disorders related
to developmental changes at these steps is given in Table
548-1.
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The clinical sequelae of these malformations are broad and often
location specific, but some general themes emerge. Disorders of
embryonic CNS development (neurulation, prosencephalic development,
and neuronal proliferation) are frequently associated with morphological
findings. These include abnormal head size and shape; facial dysmorphology (in
particular midline abnormalities); facial clefting; and anomalies
of optic globe size, shape, and position. Intra-axial anomalies
frequently lead to major variations in ventricular size and structure
and consequently these lesions are diagnosed on routine obstetric
fetal anomaly scans. Spinal closure abnormalities may be associated with
external stigmata such as fistulae, dimples, nevi or ectopic hair,
or fat. In addition fetal lower limb positioning may be abnormal with
talipes and fixed flexion of the hips of extension of knees detectable
prenatally. In addition to fetal miscarriage and death, other fetal
manifestations of early CNS malformations include polyhydramnios,
decreased fetal movement, and preterm labor. Malformations related
to abnormalities in later fetal stages of CNS formation may present
postnatally, often in late infancy or childhood, frequently without
evident dysmorphic features or neonatal manifestation. Early symptoms
may include hypotonia and motor delay, as well as feeding difficulties.
Later symptoms usually encompass speech and language delay and variable
degrees of cognitive impairment including mental retardation. Epilepsy
is particularly associated with disorders of migration and cortical organization but may not present until
late childhood or adolescence. This chapter covers developmental
disorders up to and including disorders of migration. Conditions
associated with aberrant organization, synaptogenesis, pruning,
and myelination are covered elsewhere in detail.
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Anomalies of Prosencephalic Development
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The developing forebrain and face is contingent on the ventral
induction by the prechordal mesoderm at the rostral end of the neural
tube. The sonic hedgehog signaling pathway is critical to the development
of the prosencephalon, with sonic hedgehog protein (Shh)
secreted from the prechordal mesoderm to activate the Patch receptor
and downstream genes.
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The major events are formation of the prosencephalon at the end
of the first month; cleavage in three planes to give the basic structure
of paired cerebral hemispheres, basal ganglia, and ventricles; separation
from the midbrain; and development of paired optic and olfactory
structures. These events are followed by midline prosencephalic
development with thickening of the commissural, chiasmatic, and hypothalamic
plates necessary for formation of the corpus callosum, septum pellucidum,
optic nerve chiasm, and the hypothalamus. The corpus callosum forms
as developing cortical axons cross the midline under the influence
of chemoattractants and repellents.
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This group of disorders is the result of different degrees of
failure of prosencephalic cleavage and distinguished by the severity
of failed cleavage of the cerebral hemispheres and deep nuclear
structures. The most severe form is alobar holoprosencephaly where
there is a single sphere cerebral structure and monoventricle with
fusion of the thalami and deep nuclei together with absence of the
corpus callosum and olfactory bulbs. Neuronal migration and cortical
organization is severely disordered. In semilobar holoprosencephaly
there is failure of separation of the anterior cerebral cortex and absence
of the anterior corpus callosum. The least severe forms are lobar
holoprosencephaly, in which the cerebral hemispheres are fully separated
and the deep nuclei partially separated, and the middle interhemispheric
variant, in which only the posterior frontal and parietal regions
fail to separate. Hydrocephalus is present in most infants with
alobar holoprosencephaly due to fusion of the thalami and impaired
drainage of cerebrospinal fluid (CSF) through the aqueduct. Infants
with semilobar and lobar forms are usually microcephalic. Facial
anomalies are usual and range from severe cyclopia with proboscis
through to ocular hypotelorism with a flat single nostril nose (cebocephaly)
to mild hypotelorism with or without cleft palate. Malformations
of other organ systems are present in 75% of patients.
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Alobar holoprosencephaly occurs in 1/10,000 live births
but is 100 times more common in conceptuses examined after miscarriage
or abortion. Causes include both genetic and cytogenetic etiologies
as well as teratogens. Over two thirds are related to full or partial
chromosomal aneuploidies, in particular trisomy 13. A list of known etiologic
factors is given in Table 548-2.
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The clinical features relate to the severity of failure of cleavage
of the cerebral hemispheres, basal ganglia, and abnormal hypothalamic
function. Most patients with alobar holoprosencephaly do not survive
infancy. Children with less severe forms do have prolonged survival.
Seizures are common as is profound visuomotor and cognitive impairment.
The failure of basal ganglia and thalamic cleavage leads to dystonia
and motor impairment, as well as early apnea. Hypothalamic dysfunction leads
to often life-threatening endocrinopathies such as diabetes insipidus,
as well as poikilothermia. Management is primarily supportive. Although
shunting is performed, the development of hydrocephalus is often
a sign of unrecognized severe failure of cleavage.
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Agenesis of
the Corpus Callosum and Absent Septum Pellucidum
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This group of disorders is characterized by varying degrees of failure of midline prosencephalic
development. Agenesis of the corpus callosum (ACC) may be complete
or partial and is associated with deformation of the lateral ventricles
to give a parallel ventricular arrangement known as colpocephaly.
This is usually accompanied by longitudinal fibers coursing along
the medial aspect of the hemispheres known as Probst bundles. Partial
ACC usually comprises absence of the posterior callosum. Agenesis
of the corpus callosum (ACC) may be isolated or in up to 40% to
50% of cases associated with other cerebral abnormalities,
specifically cerebellar malformation and cortical migration anomalies.
Agenesis of the corpus callosum is one of the most common anomalies
occurring in up to 7 in 1000 live births and 3% of children
with developmental delay. It is increasingly diagnosed in fetal
life. Agenesis of the corpus callosum may be completely asymptomatic or
have symptoms only detected on very refined testing of interhemispheric
transfer. In association with other anomalies however there is a
strong risk of cognitive and neuromotor impairment. Agenesis of
the corpus callosum is associated with well over 65 known genetic
syndromes and the presence of extra-axial abnormalities or cytogenetic
abnormalities is a risk factor for impaired neurologic development
(Table 548-3). A notable condition is Aicardi syndrome,
an X-linked dominant condition affecting females associated with
neuronal heterotopias, chorioretinal lacunes, early onset infantile
spasms and subsequent refractory epilepsy and profound developmental
delay.
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Absence of the septum pellucidum is another common anomaly and frequently
associated with more diffuse cerebral malformations such as schizencephaly,
septo-optic dysplasia, ACC, holoprosencephaly, and hydrocephalus. Failure
of fusion of the septal leaflets is known as cavum septum pellucidum.
This is a normal finding in fetal life and in premature infants,
but, after the neonatal period, has a weak association with later
cognitive deficits. As with ACC, the outcome of absent septum pellucidum
is related to associated brain malformations. The most common and
important of these is septo-optic dysplasia (SOD, de Morsier syndrome) where
absent septal leaflets are associated with optic nerve hypoplasia
and disturbances of the hypothalamic-pituitary axis. Children with
SOD may have profound panhypopituitarism. Identification of absent
septal leaflets on prenatal imaging should be accompanied by postnatal
magnetic resonance imaging (MRI), ophthalmic examination, and complete
endocrinology evaluation.
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Cerebellar Malformations
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Cerebellar development varies considerably and coincides with prosencephalic
development. As the cerebellum is intimately related to development
of the aqueduct of Sylvius and foramina outflow of the fourth ventricle,
hydrocephalus and posterior fossa fluid collections are frequent accompaniments.
Common malformations are listed in Table 548-4.
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Of these the Dandy-Walker malformation (DWM) is the most frequently
encountered and together with stenosis or atresia of the aqueduct
of Sylvius accounts for over 40% of cases of congenital
hydrocephalus. DWM comprises agenesis of the cerebellar vermis,
enlargement of the posterior fossa with rostral displacement of
the torcula, and cystic dilatation of the fourth ventricle. Hydrocephalus
and supratentorial migrational abnormalities are common accompaniments (70–90%).
It is associated with a range of genetic syndromes including Smith-Lemli-Opitz, Meckel-Gruber,
and Rubinstein-Taybi syndrome. The hydrocephalus may be striking
at birth and the majority of children require shunting. Outcome
is related to the onset of hydrocephalus (early fetal onset being
associated with a high mortality and severely impaired neurologic
outcomes) and the associated cerebral malformations.
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Joubert syndrome is another important pediatric cerebellar malformation.
Characterized by vermian dysplasia, neuronal heterotopias, absent
decussation of the cerebellar peduncles, and multiple brainstem
abnormalities. This group of disorders is identifiable by the “molar tooth” conformation
of the superior cerebellar peduncles on magnetic resonance imaging (MRI).
At least 5 gene loci have been identified. The disorder is characterized
by hypotonia, craniofacial dysmorphisms, nystagmus, and respiratory
dysrhythmia. Associated anomalies include retinal colobomata, renal malformations,
and hepatic fibrosis. Cognitive impairment may be mild and not apparent
until later in schooling.
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Abnormalities
of Neuronal Proliferation and Migration
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Following establishment of the basic pattern of the developing
neuraxis, brain growth proceeds by rapid proliferation of progenitor
neurons and glia and migration from the ventricular surface to the
developing fetal cortex. Neuronal and glial progenitors are formed
by symmetric and asymmetric division of pluripotent stem cells in the
ventricular and subventricular zones. These cells exit the cell
cycle and migrate into the intermediate zone and thence to the cortical
plate at the pial surface.
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Abnormalities of proliferation give rise to disorders of brain
size (primary micrencephaly and megalencephaly) that are covered in
more detail in Chapter 550. These include the autosomal recessive
disorders of micrencephaly vera (primary micrencephaly or microcephaly
with simplified gyri) and radial microbrain (where, despite the
extremely small brain size, gyration, and cortical lamination are
normal). Children with micrencephaly vera often do not have major
neurologic findings and cognitive impairment may be mild. There
is often associate migrational abnormality, in particular simplification
of the gyri, which is usually associated with more profound mental
retardation. By contrast, infants with radial microbrain usually
die in the neonatal period.
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Macrencephaly/megalencephaly is a highly heterogeneous
group of disorders that includes macrocosmic syndromes such as Soto,
fragile X, and Beckwith-Tiedemann syndromes. It is a common finding in
neurocutaneous syndromes such as neurofibromatosis and Sturge-Weber
syndrome. Of interest is autosomal dominant and recessive isolated
familial macrencephaly where the head size is large at birth and
continues to grow rapidly postnatally. Neurologic and cognitive
development is usually normal.
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Migrational disorders are a large and complex group of conditions
characterized by relative impairments in the radial migration of neurons
into the cerebral cortex and tangential migration of interneurons
into the cortex (Fig. 548-1). This process
requires the presence of radial glial guides, a series of fetal
transient zones, and a complex panoply of molecular determinants
including guidance molecules, signaling pathways, surface ligands,
cytoskeletal elements, ion channels, and neurotransmitters, in particular glutamate.
Clinically these disorders are manifested by neonatal hypotonia,
early onset of often refractory seizures, and developmental delay.
MRI is the most useful initial investigational tool when a migrational
disorder is suspected, with the hallmark finding of gyral abnormalities
and occasionally abnormalities of the corpus callosum.
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Lissencephaly-pachygyria represents a spectrum of disorders marked
by underdevelopment or absence of normal gyrification. In type 1
lissencephaly there are absent gyri and an immature cerebral mantle
with disorganized and heterotopic neuronal layering. Type II lissencephaly
is characterized by clustered, whorled arrays of neurons separated
by glia and large heterotopic formations of neurons, often migrating
into the pia giving a characteristic “cobblestone” appearance.
Pachygyria is demonstrated by thickened simple gyri that are underdeveloped
and is a continuum of lissencephaly. Radiologic features are shown
in Chapter 550, Figure 550-1. The
known causes of these types of lissencephalies are listed in Table 548-5 together with salient clinical
features and diagnostic indicators.;
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Clinically type I lissencephaly are characterized by postnatal
deceleration of head growth, profound neonatal hypotonia evolving
to a spastic quadriparesis, severe dysphagia, poor movement, early
seizures often
evolving to infantile spasms, and eventually Lennox-Gastaut syndrome.
Mental retardation is prominent. Type II lissencephalies in addition
to those clinical features seen in type I lissencephaly, differ
by the presence of microcephaly, retinal and anterior chamber malformations,
congenital muscular dystrophy, and cerebellar malformations. Epilepsy
and hypotonia predominant and death in infancy are common.
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Polymicrogyria is characterized by numerous small folds of gyri
that may have a basic four-layered anatomy, or unlayered with a
poorly laminated heterotopic collection of neurons below the cerebral
mantle. Polymicrogyria is associated with a number of primary genetic conditions,
as well as metabolic conditions, in particular disorders of peroxisomal
biogenesis, such as Zellweger syndrome. It frequently accompanies
other dysgenetic brain malformations as well as in utero encephaloclastic
events such as vascular insults or congenital infection (congenital
infection in particular). The neurologic sequelae are very variable
and range from severe mental retardation and refractory epilepsy
to milder disorders of neuromotor function or mild learning disability.
A special note is made of perisylvian polymicrogyria syndromes,
particularly the bilateral form, which is associated with specific
deficits in orolingual impairment and pseudobulbar palsy, with expressive
language delay and feeding problems prominent.
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Neuronal heterotopias and focal cortical dysplasias represent
arrest of migration of neurons. These may be located close to the
ventricular surface in the subependyma following arrest in early
radial migration. These are usually nodular and multiple. Other
heterotopias are seen in the subcortical white matter and may be
small nests of cells or more commonly bands. A list of conditions
associated with heterotopias is given in Table
548-6. The clinical manifestation is usually epilepsy, often
presenting in early adolescence or adulthood. Although heterotopias
may be clinically occult, they elevate the lifetime seizure risk
to 40% to 50%. Focal cortical dysplasias represent
abnormalities of the later stages of migration and are a cause of
intractable epilepsy, which may respond to epilepsy surgery. They may
comprise collections of abnormally laminated normal neurons or large
dysplastic multipotent cells known as balloon cells.
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Schizencephaly is a severe restricted disorder of cortical formation characterized by failure of development
of a portion of the cerebral wall leaving a cleft extending from the
ependymal surface to the pial surface. The cleft is usually lined by
dysplastic heterotopic gray matter in particular polymicrogyria. The
lesion may be unilateral or bilateral, usually frontal or perirolandic.
The edges of the pial surface may be opposed (“closed-lip”)
or more commonly, widely separated (“open-lipped”).
Like polymicrogyria the disorder may have a primarily genetic etiology
(eg, mutation in the EMX2 gene) but vascular disruption
and congenital infection such as congenital infection (CMV) is also
associated with this abnormality.
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Clinically the condition is associated with cognitive deficits
(particular in bilateral clefts), late-onset seizures and motor
deficits (particular in frontal open-lipped lesions). Agenesis of
the corpus callosum or absent septum pellucidum may be frequent
accompaniments. Hydrocephalus of unclear mechanism, complicates
up to half of cases.1-8