Download OCULAR HEMORRHAGE IN CHILDREN

CNS MALFORMATIONS
EARLY BRAIN DEVELOPMENT
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About the 15th day of life, ectodermal cells on the surface of the
embryo proliferate to form a plate of tissue, the “primitive streak”.
Rapidly proliferating group of cells, the “Hensen’s node” form at
one end (cephalic end).
From Hensen’s node, cells that form the notochord migrate
rostrally and induce differentiation of the dorsal midline ectoderm
into “neuroectoderm”.
The plate like condensation of the neuroectoderm is the “neural
plate”.
At 17 days, lateral aspects of the neural plate thicken and neural
folds bend medially, meeting in the midline around 20 days.
As the neural tube closes, the neuroectoderm which will form the
CNS separates from the overlying ectoderm, which will become
the skin.
EARLY BRAIN DEVELOPMENT
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At the time of closure of the anterior neuropore, three dilatations or
vesicles develop in the rostral cavity of the neural tube: prosencephalon
(forebrain), mesencephalon (midbrain), and rhombencephalon
(hindbrain).
Rhombencephalon separated from the mesencephalon by the cephalic
flexure and from the cervical cord by the cervical flexure.
Prosencephalon is divided into the diencephalon (thalamus,
hypothalamus, globus pallidus) and telencephalon (which will form the
cerebral hemispheres, putamen, caudate).
Diencephalon - cells originate in the germinal matrix of 3rd ventricle;
telencephalon - cells originate in the germinal matrix in the walls of the
future lateral ventricles
Rhombencephalon will divide into myelencephalon (pons and medulla)
and metencephalon (cerebellar hemispheres and vermis)
CNS DEVELOPMENT
Primary
neurulation: 3-4 gw
Prosencephalic development: 2-3 mo
Neuronal proliferation: 3-4mo
Neuronal migration: 3-5 mo
Organization: 5mo-yrs postnatal
Myelination: IU-years postnatal
NORMAL DEVELOPMENT
 Primary
neurulation (Dorsal induction) inductive events in the dorsal aspect of the
embryo resulting in the formation of brain and
spinal cord, excluding segments caudal to
lumbar region.
 Secondary neurulation - exclusive to lower
sacral segments of the cord (caudal neural tube
formation) - occurs later
PRIMARY NEURULATION
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CNS begins on dorsal aspect of embryo as a plate of
tissue in the middle of the ectoderm; underlying
notochord and chordal mesoderm induce formation of
neural plate at 18 days.
Neural tube - first folds neural folds occurs at lower
medulla at 22 days; closure proceeds rostrally and
caudally, but it is not a simple zipper like process
Anterior end of NT closes at 24 days, posterior end at
26 days; posterior site of closure at lumbosacral level;
more caudal segments formed by different process
SECONDARY NEURULATION
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Formation of caudal NT (lower sacral and coccygeal
segments) occurs by sequential canalization (4-7gw)
and retrogressive differentiation (7wks - birth+)
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At 28-32 days, aggregate of undifferentiated cells at
caudal end (caudal cell mass) develop vacuoles enlarge - coalesce - make contact with central canal;
accessory lumina may remain
Remaining structures are ventriculus terminalis (in the
conus) and filum terminale
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DISORDERS OF INDUCTIVE EVENTS
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ORDER OF DECREASING SEVERITY:
 Craniorachischisis totalis
 Anencephaly
 Myeloschisis
 Encephalocele
 Myelomeningocele/Chiari malformation
CRANIORACHISCHISIS TOTALIS
There
may be a neural plate like
structure, but no axial skeleton or
dermal covering
Onset no later than 20-22 days
Most aborted; some to early fetal
stages
ANENCEPHALY
 Defect
is failure of anterior neural tube
closure
 Most severe case - defect from level of
lamina terminalis to foramen magnum
(holocrania/holoanencephaly); if defect
does not extend to foramen magnum meroacrania/meroanencephaly
ANENCEPHALY
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Most commonly - forebrain, variable amount of upper
brainstem involved; exposed neural tissue represented
by hemorrhagic, fibrotic, mass of neuroglial tissue area cerebrovasculosa; anterior pituitary present,
posterior pituitary usually absent
Frontal bones above superciliary ridge, parietal bones,
squamous part of occipital absent
Onset no later than 24 days; polyhydramnios
75% SB; others can have brainstem function.
ENCEPHALOCELE
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Restricted disorder of neurulation, involving anterior
neural tube closure
70-80% are occipital; frontal encephaloceles may
protrude into nasal cavity (more common in SE Asia)
Low occipital encephaloceles may have deformities of
brainstem, cerebellum in the encephalocele, and
abnormalities of skull base and cervical vertebrae
(Chiari III)
Timing around 26 days (time of closure of anterior
neural tube)
MECKEL’S SYNDROME
Constellation
of occipital
encephalocele, microcephaly,
microphthalmia, cleft lip and palate,
polydactyly, polycystic kidney,
ambiguous genitalia
MYELOMENINGOCELE
Restricted
failure of posterior neural
tube closure; 80% in lumbar area
(last area of neural tube to close)
Chiari II, hydrocephalus
Chiari malformation
In 1891, Chiari described 3 malformations of the
hindbrain associated with hydrocephalus.
 Chiari I: caudal cerebellar tonsillar ectopia, below
the foramen magnum; association of chronic
tonsillar herniation with syringomyelia
 Chiari II: complex malformation myelomeningocele, hydrocephalus, hindbrain,
spine abnormalities
 Chiari III: cervical spina bifida with cerebellar
encephalocele
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Chiari malformation
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Squamous bones of the vault have patches of irregular
thickness - craniolacunia; shape does not correspond to
gyri, not secondary to >ICP, can disappear.
Falx is short and fenestrated
Shallow posterior fossa, low position of torcular, low
insertion of tentorium, tightly crowded brainstem and
cerebellum displaced caudally and impacted into the
foramen magnum
Herniated cerebellar tissue protrudes into the cervical
spinal canal and overrides the dorsal surface of the cord
as a peg. Herniation originates from caudal vermis - tissue
firm, sclerotic. In others, tonsils may herniate with vermis.
Chiari malformation
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Deformation of the brainstem- caudal shift of dorsal
medulla, the 4th ventricle, choroid plexus - dorsal nuclear
groups thus much more caudal to the ventral surface. The
tissue caudal to the ventricle containing the gracile and
cuneate nuclei form a hump which overrides and
compresses the cervical cord.
Beaking of the tectum
Cervical spinal roots project cranially instead of taking
their usual lateral or descending course
Hydromyelia common in the cord
Hydrocephalus with redundant cortical gyri (polygyria,
microgyria, stenogyria), but normal lamination
Development of the cerebellum
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During the 5gw, a thickening occurs bilaterally in the alar plate of the
rhombencephalon, forming the rhombic lips, containing the primordia
of the cerebellar hemispheres and the germinal zones for the precursors
of the granule cells.
The neurons that form the deep cerebellar nuclei and Purkinje cells
migrate radially outward from the germinal matrix in the wall of the 4th
ventricle.
Granule cells have a complex origin: at 11-13gw, precursor cells
migrate tangentially from the germinal zone in the lateral portion of the
rhombic lips, to form the external granular layer (EGL) over the surface
of the cerebellum. From here, cells migrate inward past the Purkinje
cells to form the granular layer. EGL attains maximum cell number in
the first few postnatal months, then diminishes in size as the granule
cells migrate inward. EGL disappears by about 13 months.
Cerebellar vermis forms at the site of fusion of the developing
hemispheres, begins superiorly at 9gw and continues inferiorly; entire
vermis formed by end of 15gw - the cerebellar vermis cannot form in the
absence of hemispheres.
DANDY-WALKER MALFORMATION
 Dandy-Walker
malformation - enlarged
posterior fossa, high position of the
tentorium, hypogenesis or agenesis of the
cerebellar vermis, cystic dilatation of the
4th ventricle that fills the posterior fossa,
hydrocephalus
 Most common anomaly associated is
callosal hypogenesis
 There may be dysplasias of the brainstem,
especially abnormal inferior olives.
Malformations of the cerebellum
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Joubert syndrome Agenesis/hypogenesis of the cerebellar
vermis with midline clefting, abnormal eye movements,
periodic hyperpnea, ataxia, mental retardation
Rhombencephalosynapsis - small cerebellar hemispheres
fused in midline with sulci running across, agenesis of
vermis
Lhermitte Duclos syndrome (dysplastic cerebellar
gangliocytoma): Mass effect, focal area of enlarged
cortex, abnormal neurons in granule cell layer,
hypermyelinated marginal layer; can be associated with
Cowden disease (multiple hamartoma syndrome, other
malignancies)
Occult dysraphic states
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Disorders of caudal neural tube formation (secondary neurulation, lower
sacral and coccygeal segments); intact skin but dimples, abnormal hair
tuft, sinus tract, cutaneous abnormalities
Since the process results in formation of the conus and filum, common to
find abnormalities of these structures: thickened filum
Neural lesions: myelocystocele, diastematomyelia-diplomyelia,
meningocele, lipomyelomeningocele, lipoma, dermal sinus with
dermoid/epidermoid, tethered cord
Lipomyelomeningocele may reflect focal premature dysjunction: focal
separation of neuroectoderm from cutaneous ectoderm allows migration of
periaxial mesoderm into the developing neural tube: mesoderm matures
primarily into fat.
PROSENCEPHALIC DEVELOPMENT
 Peak
period 2-3 months of gestation
 Prosencephalic development occurs by
inductive interactions between the
notochord/prechordal mesoderm and
forebrain. This occurs ventrally at the rostral
end of the embryo (ventral induction)
 This affects formation of the face as well as the
brain.
PROSENCEPHALIC FORMATION
Begins
at the rostral end of the
neural tube after anterior neuropore
closes, at the end of the 1st month
and beginning of 2nd month
PROSENCEPHALIC DEVELOPMENT
Three
sequential events:
Prosencephalic formation
Prosencephalic cleavage
midline prosencephalic development
PROSENCEPHALIC
CLEAVAGE
 5-6
gw, includes 3 basic cleavages:
 Horizontally to form paired optic vesicles,
olfactory bulbs and tracts
 Transversely to separate telencephalon from
diencephalon (thalamus, hypothalamus)
 Sagittally to form from the telencephalon the
paired cerebral hemispheres, lateral ventricles
Disorders of prosencephalic
development
 Prosencephalic
formation
(aprosencephaly/atelencephaly)
 Prosencephalic cleavage
(holoprosencephaly)
 Midline prosencephalic development
(agenesis of corpus callosum, agenesis of
septum pellucidum, septo-optic
dysplasia)
APROSENCEPHALY/ATELENCEPHALY
 Most
severe disorder of telencephalic
development - 2nd month
 Aprosencephaly - lethal - absence of both
telencephalon/diencephalon, with rudimentary
brainstem (distinguished from anencephaly by
intact skull, scalp)
 Atelencephaly - diencephalon may be relatively
preserved (can survive for even a year with
little neurological function except breathing)
HOLOPROSENCEPHALY
 Disorder
of prosencephalic cleavage (5-6 wks)
 alobar, semilobar, lobar
 alobar - most severe form, univentricle,
membranous roof over 3rd ventricle (dorsal
cyst), absence of olfactory bulbs/tracts,
hypoplasia of optic nerve/single optic nerve,
absent corpus callosum, falx cerebri,
interhemispheric fissure; azygous anterior
cerebral artery with single trunk supplying
branches to the ACA territories in both
hemispheres
HOLOPROSENCEPHALY
 Facial
anomaly: single median eye (cyclops), no
eye with rudimentary nasal structure
(proboscis), marked ocular hypotelorism with
or without a proboscis (ethmocephaly), and
ocular hypotelorism with a flat single nostril
nose (cebocephaly), cleft lip/palate, absent
philtrum
 Eye abnormalities: cataract, retinal dysplasia,
colobomas
Semilobar holoprosencephaly
Brain less dysmorphic than alobar form
 Interhemispheric fissure and falx cerebri partially
formed in the posterior portions of the brain;
anterior frontal region may be fused and
underdeveloped
 Corpus callosum may be present with posterior
part in the absence of anterior callosal formation
(exception to anteroposterior rule)
 Thalami partially separated, but may be fused
into a single mass
 Syntelencephaly - variant of semilobar type
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CEREBRAL COMMISSURES
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At 7gw, dorsal part of lamina terminalis (the rostral
most end of the neural tube) undergoes a generalized
thickening - called lamina reuniens or commissural
plate.
Lamina reuniens develops a groove which is filled with
material originating in the meninx primitiva - this
material probably in conjunction with glial cells in the
developing hemispheres secrete molecules that guide
axons across the midline (cell adhesion molecules,
axonin 1 involved)
These bundles of axons form the cerebral commissures:
the anterior commissure, the hippocampal commissure,
and the corpus callosum.
MIDLINE PROSENCEPHALIC
DEVELOPMENT
 2-3
months
 Important in formation of corpus callosum and
septum pellucidum, the optic nerve-chiasm,
and hypothalamic structures
 Corpus callosum - earliest appearance at 9
wks, by 12 wks definable as a commissural
plate, completed by approximately 20 weeks of
gestation
CORPUS CALLOSUM
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Corpus callosum composed of 4 sections - rostrum, genu,
body, splenium
If normal development disturbed, corpus callosum may be
completely absent or partially formed.
In hypogenesis of CC, the anterior portion of CC will be
formed (anterior body, posterior genu), but the posterior
part (posterior body, splenium) will be absent.
This anterior to posterior rule helps to differentiate a
hypogenetic CC from one that is secondarily destroyed.
Exceptions to this rule are seen in holoprosencephaly,
where splenium may be present without a normal genu or
body, or body and splenium may be present without genu,
or in interhemispheric fusion cases, genu and splenium
may be present without the body.
CALLOSAL ANOMALIES
Corpus callosum formed around 8-20 gw.
 Anomalies of corpus callosum may be isolated or
associated with other anomalies.
 Aicardi syndrome - X-linked dominant disorder
with infantile spasms, callosal hypo or agenesis,
chorioretinopathy. Almost exclusively in females
(need 2 X), but can be in Klinefelter’s (47XXY).
 Intracranial anomalies include callosal
hypo/agenesis, interhemispheric cysts,
polymicrogyria, heterotopia, cerebellar
hypoplasia, choroid plexus cysts/papillomas,
retinal dysplasia, chorioretinal colobomas.
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AGENESIS OF CORPUS CALLOSUM
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Axons that would normally cross to opposite hemisphere through the CC
turn at the interhemispheric fissure and run parallel to that fissure
forming the longitudinal bundle of Probst.
Probst bundles invaginate the medial borders of the lateral ventricles,
giving the ventricles a crescentic shape (batwing), more so frontally.
When the callosal body is absent, the bodies of the lateral ventricles are
straight and parallel.
Interhemispheric surface shows gyri perpendicular to roof of 3rd ventricle
(radial pattern)
Corpus callosum is the most tightly packed bundle of axons in the brain;
this compactness gives the lateral ventricles their shape. In callosal
agenesis, posterior portions of ventricles expand, resulting in dilatation of
the trigones and occipital horns of lateral ventricles (colpocephaly).
Colpocephaly refers to massive dilatation of occipital horns with normal
size of frontal horns. Nature not well understood, and used loosely in the
literature
INTRACRANIAL LIPOMAS
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Malformations resulting from abnormal differentiation of
the meninx primitiva, the undifferentiated mesenchyme
that surrounds the developing brain.
Meninx differentiates into fat.
As they are formed from the meninx, intracranial lipomas
almost always in the subarachnoid space and blood
vessels and cranial nerves may course through them.
Most common site: deep interhemispheric fissure 40-50%
Interhemispheric lipomas almost always associated with
hypogenesis of corpus callosum; calcification in lipoma
Septo-optic dysplasia
Syndrome
named by De Morsier hypoplasia of optic nerves, hypoplasia
or absence of septum pellucidum,
2/3rds with hypothalamic/pituitary
dysfunction
Development of the cortex
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At 7 gw, proliferation of young neurons occurs in the subependymal
layer of the walls of the lateral ventricles (germinal matrix). Here stem
cells undergo mitoses to produce neurons and glia. After mitoses, some
of the newly generated cells will remain in the germinal zone and
undergo further divisions, while others will migrate outward to their
final destinations.
At 8 gw, the first young neurons begin to migrate outward.
Initially, simple process - cells in the germinal zones elongate, with
nucleus moving to end of the cell farthest from the ventricular surface.
Contact with the ventricular surface is terminated, and remainder of
the cell joins the nucleus.
As cerebral hemispheres enlarge and distance to be traveled increases,
specialized radial glia guide the migrating neurons.
In the cortex, “inside out” sequence, with deeper layers formed before
superficial layers. An exception is the neurons of the molecular layer
which arrive first.
Cortical malformations
Any event that inhibits neuronal or glial
proliferation, neuronal migration, or subsequent
organization can cause a cortical malformation.
 Abnormal proliferation: micrencephaly,
hemimegalencephaly
 Abnormal migration and organization: classical
lissencephaly, cobblestone lissencephaly,
heterotopias, agyria/pachygyria, polymicrogyria,
schizencephaly
 Tuberous sclerosis and focal cortical dysplasia also
show cortical malformation
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Microcephaly and Micrencephaly
 Microcephaly
- smallness of the cranial vault; may
be induced either by hypoplasia of brain tissue, or
by a variety of lesions (infarcts, atrophy etc)
 Micrencephaly - subnormal size of the brain,
thickened scalp, thickened bones of cranial vault,
severe intellectual impairment, delayed motor
function, autosomal recessive, hypoplasia of cortex
and white matter, cerebellum may be spared
 Small brain may be part of other malformations
SCHIZENCEPHALY
 Gray
matter lined clefts extending from the
ependymal lining of the lateral ventricles to the
pial covering of cortex
 Both genetic and acquired causes
 Gray matter lining the clefts is dysplastic
LISSENCEPHALY
 Lissencephaly/agyria
- “smooth brain”
 Pachygyria - focal broad gyri
 Classical lissencephaly - arrest of migration
of neurons, eg, Miller Dieker syndrome
 Cobblestone lissencephaly - eg, Walker
Warburg syndrome, muscle eye brain
disease - overmigration of neurons,
polymicrogyria, muscle/eye disease,
abnormal myelination, hydrocephalus
Agyria/Pachygyria
 Cortex
much thicker than normal, volume
of white matter reduced, large ventricles
 Abnormal cortex with 4 layers:
1. molecular layer, 2. thin superficial layer
of nerve cells, 3. tangential plexus of
myelinated fibers, 4. thick cellular layer of
neurons in disorganized arrangement
 Agyria dates much earlier (11-13gw) than
polymicrogyria which dates near 20-24gw.
Walker Warburg syndrome
 Cobblestone
lissencephaly, polymicrogyria,
congenital hydrocephalus, severe eye
malformations (retinal dysplasia, persistent
primary hyperplastic vitreous, retinal
nonattachment, optic nerve hypoplasia),
hypomyelination, callosal hypogenesis,
cerebellar polymicrogyria, dysplasia, other
associated anomalies (eg, Dandy Walker,
encephalocele), muscular dystrophy
 Neuroglial heterotopias in the subarachnoid
space
Neuronal heterotopia
Collections
of gray matter in
abnormal locations: subependymal,
subcortical, band heterotopia (double
cortex - homogeneous band of gray
matter between cortex and ventricle,
complete or partial, female
preponderance)
TORCH INFECTIONS
CMV
- transplacental congenital
infection - IUGR
Microcephaly, meningoencephalitis,
periventricular calcification,
disturbances of neuronal migration
chorioretinitis, hepatosplenomegaly,
petechia, anemia