Embryology and Congenital

Anomalies of CNS

Dr. TUMUSIIME GERALD

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 SESSION OBJECTIVES
By the end of the session each participant
should be able to:
1.Describe the embryology of the nervous
system
2.Outline the congenital anomalies of the CNS
3.Appreciate the origin of the different
congenital anomalies and plan to prevent
them in “real life”
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 Terminology

• Congenital means exist since birth, whether

clinical evidences are obvious or not obvious.

• Anomaly means a deviation from the

normal.

• Malformation means faulty development of

a structure
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 Subdivisions of the PNS

Peripheral nervous system (PNS)

a) Somatic (voluntary) nervous system
(SNS)
b) Autonomic (involuntary) nervous
systems (ANS)
c) Enteric nervous system (ENS)
 Organization
Sensory Integration Motor

SNS SNS
(Sensory) (Motor)

ANS Brain
(Sensory)
Spinal
ANS
cord
(Motor)
ENS
(Sensory)
 Formation of Neural Tube
• Three primordial tissues
– endoderm
– mesoderm
– ectoderm
• Which tissue does
nervous system
develop from?
– ectoderm
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Neural
crest

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Neural
crest

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 • Neural crest becomes
peripheral nervous
system (PNS)

• Neural tube becomes

central nervous system
(CNS)

• Somites become spinal

Somites
vertebrae.

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• The nervous system develops from the
neural plate.
– The neural plate is a thickened area of the
embryonic ectoderm
• The neural plate then differentiates to form
the neural tube, neural folds and neural
crest.
– The neural tube differentiate into the CNS
(brain + spinal cord)
– The neural crest will give rise to cells that
form the peripheral and autonomic nervous
system
• Neurulation is the formation of the neural tube
– Begins in the region of the 4th-6th somites
– The cranial 2/3 of the neural plate  the future
brain

– The caudal 1/3 of the neural plate  spinal cord

– Neural canal “the lumen of the neural tube

communicates with the amniotic fluid
– the walls of the neural tube thickens to form the
brain and the spinal cord
– The neural canal is converted into the ventricular
system of the brain and the central canal of the
spinal cord
P 426 “Before we are born”
 Development of the spinal
cord
• The lateral walls of the neural tube thickens
gradually  reduce the size of the neural canal
 central canal of the spinal cord is formed

• The wall of the neural tube is composed of the

neuroepithelium  constitute the ventricular
zone  gives rise to all neurons and microglial
cells in the spinal cord.
Pg 429 “Before we are born”
• Proliferation and differentiation of the
neuroeithelial cells produce thick walls and thin
roof and floor plates

• Differential thickening of the lateral walls of the

spinal cord  shallow groove on each side 
sulcus limitans
– This groove separate the alar plate “ the dorsal
side” from the basal plate “ the ventral part”
– Cell bodies in the alar plates forms the dorsal
gray columns
– Cell bodies in the basal plate form the ventral
and lateral gray horns
Pg 428 “Before we are born”
 Development of spinal ganglia
• The axons of cells in the spinal ganglia are at first
bipolar  the 2 processes unite in a T-shape
fashion unipolar

• The unipolar neurons in the spinal ganglia “dorsal root

ganglia” are derived from neural crest cells

• The peripheral processes of spinal ganglion cells pass

in the spinal cord nerves to sensory endings in
somatic or visceral structures

• The central processes enter the spinal cord  dorsal

roots of spinal nerves
 Positional changes of spinal
cord
• In the embryo: the spinal cord extends the entire
length of the vertebral canal.

• Because the vertebral column and dura mater

grow more rapidly than the spinal cord  the
caudal end of the spinal cord gradually comes
to lie at relatively higher levels.

• The spinal cord in a newborn terminates at L2 or L3

• The spinal cord in the adult terminates at the

inferior border of L1.
 Myelination of nerve fibers

• The myelin sheaths surrounding

nerve fibers within the spinal
cord are formed by
oligodendrocytes.

• The myelin sheaths around the

axons of peripheral nerve fibers
are formed by the plasma
membranes of neurolemmal
(Schwann) cells.
Congenital anomalies of spinal
cord
 Development of brain
• Fusion of the neural folds in the cranial region forms 3
primary brain vesicles
– Forebrain “prosencephalon”
– Midbrain “mesencephalon”
– Hindbrain “rhombencephalon”
• During development,
– the forebrain divides into  telencephalon and
diencephalon
– the hindbrain divides into  metencephalon and
myelencephalon
– The midbrain does not divide
• Consequently, there are 5 secondary brain vesicles
Pg 438 “Before we are born”
 Brain flexures
• During development, the embryonic brain grows
rapidly and bends ventrally with the head fold 
this produces the
– Midbrain flexure in the midbrain
– Cervical flexure at the junction of the hindbrain
and spinal cord

• Later, unequal growth of the brain between these

flexures produces the pontine flexure.
– This flexure results in thinning of the roof of the
hindbrain
 Hindbrain
• The cervical flexure demarcates the hindbrain from
the spinal cord
– Later this junction will be defined as the level of the
superior rootlet of the cervical nerve.

• The pontine flexure divides the hindbrain into

– Myelencephalon “caudal”  develops into medulla
oblongata
– Metencephalon “rostral-toward the front”  develops into
the pons and cerebellum.

• The cavity of the hindbrain becomes the 4th

ventricle and the central canal in the caudal part of
the medulla
 Myelencephalon1
• Neuroblasts from the alar plates in the
mylencephalon migrate into the marginal zone
and form isolated areas of the grey matter 
gracile nuclei “medial” and cuneate nuclei “laterally
• The ventral area of the medulla contains the
pyramids ( pair of fiber bundles)
• During development, as the walls of the medulla
move laterally, the alar plates lie lateral to the
basal plates  motor nuclei medial to sensory
nuclei
• Neuroblasts from the basal plate form nuclei:
– General somatic efferent: neurons of hypoglossal
nerve
– Special visceral efferent: neurons innervating
muscles derived from pharyngeal arches
– General visceral efferent: neurons of the vagus and
glossopharyngeal nerves
• Neuroblasts of the alar plate form nuclei:
– General visceral efferent: receive impulses from
viscera
– Special visceral afferent: receive taste fibers
– General somatic afferent: receive impulses from the
surface of the head
– Special somatic afferent: receiving impulses from
ear
– Olivary nuclei
cerebellum
Pg 439 “Before we are born”
 Metencephalon
• The cerebellum develops from thickenings of
dorsal parts of the alar plates
• Neuroblasts in the intermediate zoon of the
alar plates migrate and differentiate into the
neurons of the cerebellar cortex
• Cells from the alar plate give rise to the dentate
nucleus “largest nucleus”, pontine nuclei, the
cochlear & vestibular nuclei and the sensory
nuclei of the trigeminal nerve.
• Bands of nerve fibers cross the median plane
and from a bulky ridge  pons
Pg 440 “Before we are born”
 Midbrain
• The neural canal that passes through the midbrain
narrows  cerebral aqueduct “ a canal that connect
the 3rd and the 4th ventricles”
• Neuroblasts migrate from the alar plates of the
midbrain into the tectum “roof” and aggregate to form
 superior and inferior collicluli  concerned with
the visual and auditory reflexes
• Neuroblasts from the basal plates give rise to 
neurons in the tegmentum "red nuclei, 3rd and 4th
cranial nerve nuclei, and the reticular nuclei” and the
substantia nigra
• Cerebral peduncles “fibers from the cerebrum” pass
through the midbrain  brain stem  spinal cord
Pg 441 “Before we are born”
 Forebrain
• Optic vesicles are 2 lateral outgrowths that
appear on each side of the forebrain 
primordia of the retinae and optic nerves
• Cerebral vesicles is the second pair of
outgrowths  primordia of cerebral
hemispheres and lateral ventricles
• Telencephalon “anterior part of the forebrain”
and diencephalon “posterior part of the
midbrain” contribute to the formation of 3rd
ventricle.
 Diencephalon
• Swellings develop in the lateral wall of the 3rd
ventricle  epithalamus, thalamus and
hypothalamus.
– The thalamus develops rapidly and bulges into the
cavity of the 3rd ventricle
– The hypothalamus arises by proliferation of
neuroblasts in the intermediate zone of the
diencephalon
– The epithalamus develops form the roof and dorsal
portion of the lateral walls of the diencephalon
Pg 443 “Before we are born”
 Telencephalon
• The telencephalon consist of
– Cerebral vesicles:”2 lateral diverticula” primordia of the cerebral
hemispheres
– The median portion of telencephalon forms the anterior part of
3rd ventricle
• At first, the cerebral vesicles are in communication with
cavity of 3rd ventricle through the interventricular
foramina as the cerebral hemispheres expand, they
meet in the midline.
– The mesenchyme trapped between them gives rise to the falx
cerebri “fold of dura mater”
• Later, corpus striatum develops as a swelling in the floor
of each cerebral hemisphere
Congenital anomalies of the
brain
Anencephaly Encephalocele
Embryonic Development of the Brain

Figure 13.7a–e
 Embryonic Development of the Brain

• Brain grows rapidly, and changes occur in the

relative position of its parts
– cerebral hemispheres envelop the diencephalon and
midbrain
– wrinkling of the cerebral hemispheres, more neurons
fit within limited space
Brain Development - Week 5 to Birth

Figure 13.8a–d
 Basic Parts of the Brain

• Divided into four regions

– Cerebral hemispheres
– Diencephalon
– Brain stem includes the midbrain, pons, and
medulla
– Cerebellum
Figure 13.9
 Embryonic Development of Nervous
System
• Neural plate to
neural tube
• Neural crest–PNS
• Anterior forms brain
– Forebrain
– Midbrain
– Hindbrain
• Hollow ventricles
• Spinal cord 45

Figure 9-2: The embryonic nervous system develops into a hollow tube
 Differentiation
• Specialization of structures
• 3 primary vesicles
– rostral end of tube
– develops into brain
• Prosencephalon  forebrain
• Mesencephalon  midbrain
• Rhombencephalon  hindbrain ~

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 Prosencephalon
• Secondary vesicles
form & separate
– optic  retinas
• retina & optic nerve CNS
• not PNS
– telencephalic  telencephalon
– remainder  diencephalon ~

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 Other Primary Vesicles
• Mesencephalic  mesencephalon
– dorsal - tectum
– ventral - tegmentum
– tube - cerebral aqueduct
• Rhombencephalic
– rostral - metencephalon
– caudal - myelencephalon
– tube - 4th ventricle ~
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 Neural Tube Defects: Rostral
• Neural tube fails to close
• anencephaly
– skull & brain partially or totally absent
– perinatal mortality
• Encephalocele
– parts of brain protrude outside skull
– mental disability depends on extent ~

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 Neural Tube Defects: Caudal
• Spina Bifida
– Cleft spine
– neural tube fails to close
• Incidence
– Spina bifida occulta
• 40% of Americans
– Spina Bifida Manifesta
• 1 in a 1000 births ~

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 Spina Bifida
Manifesta
• Meningocele (4%)
– fluid-filled meningeal cyst
– protrudes through unfused
vertebral arches
– SC/nerves not in sac
– repaired surgically
– less severe disability than
myelomeningocele ~
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 Spina Bifida
Manifesta
• Myelomeningocele (96%)
– protruding cyst as with meningocele
– spinal cord / nerves in protruding sac
• Effects
– paralysis, incontinence, learning disabilities
– 70-90% also hydrocephalus
• can cause severe brain damage
– Repaired surgically ~
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Neural Tube Defects: Prevention
• Possible genetic component
– reoccurrence in families
– ethnic/racial relationship
• Folic Acid (Folate) Deficiency
– 50-70% of cases preventable
– CDC guidelines
not planning pregnancy: 400 mg/day
planned pregnancy: 4000 mg/day
• under direction of health care provider ~
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Neural Tube Related Birth Defects

Anterior failure to close =

neural anencephaly
pore

Posterior failure to close =

neural spina bifida
pore
23/03/1440 Dr. Mostafa Kandil 55
23/03/1440 Dr. Mostafa Kandil 56
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Differentiation of Forebrain

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Eye Cyclopia

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 A lot can go wrong.
• Rate of neurogenesis incredibly rapid.

• Failure to form appropriate connections may

be basis of many neurological and
psychiatric disorders.

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 Neurulation
• Neurulation is the formation of the vertebrate
nervous system in embryos.

• The notochord induces the formation of the

CNS by signaling the ectoderm above it to form
the thick and flat neural plate.

• The neural plate then folds in on itself to form

the neural tube, which will then later
differentiate into the spinal cord and brain.
• Different portions of the neural tube then
form by 2 different processes in different
species:

1. Primary Neurulation – the neural plate

creases inward until the edges come into
contact and then fuse.

2. Secondary Neurulation – the tube forms by

hollowing out of the interior of a solid precursor
 Formation of the Neural Tube

• Secondary Neurulation

1. Occurs beyond the caudal neuropore

2. lumbar and tail region

3. Starts with formation of medullary cord

4. Cavitation of cord to form hollow tube

 Differentiation of Neural Tube

• Major morphological changes:

differentiation of brain vesicles and spinal
cord

• Differentiation of neural tube cells

• Development of peripheral nervous

system
 Neural Crest Cells
• Induced by organizing cells of notochord
• Main functional groups:
– Cranial neural crest:
• Bones and connective tissue of face
• Tooth primordia
• Thymus, parathyroid, thyroid glands
• Sensory cranial neurons
• Parasympathetic ganglia and nerves
• Parts of the heart (cardiac neural crest)
 Neural Crest Cells
A group of cells, which breaks away from the
closing neural tube and populate the periphery
(as opposed to the CNS, which will develop
from the tube).
• Neural crest will supply all neurons of the PNS and a
variety of other peripheral structures, ranging from
melanocytes to craniofacial bones to cells of the
adrenals.
• This population of cells separates from the neural
plate shortly after the fusion of the neural folds, and
streams of dividing cells begin their journey through
the embryo.
• The expression of which genes are turned off during
this migratory stage?
• And, this occurs for individual cells as well as for
groups of cells
 Neural Crest Cells
• For neural crest cells, migratory pathway is
particularly important in cellular determination,
as location (or path) controls the availability of
inducing factors for particular cell fates.
Making Cells
The use of chimeras has been invaluable in the
study of individual cell fates.
What is a chimera?
Cells with a different genome; e.g., chick/quail mix
– heterochromatin marker not found in chick.
[3H] thymidine labeling has helped in the
delineation of migratory pathways and
development potential of neural crest cells.
 Neural Crest Cells
Interaction:
Neural crest migration/movement is rigid and
occurs in a ventral (1st cells give rise to ventral
structures) - to- dorsal order in the head.
Migratory pathways are linked to neuronal fate.
What is the mostly likely result of transplant
experiments when early cells will switch their
fate?
Extrinsic cues  ?
Whether these come from the pathway itself or the
final destination (target-derived cues) is not
clear.
As in the CNS, the earlier the cell is, the more
 Neural Crest Cells
• Main functional groups:
• The stream of neural crest cells migrates via
a ventral route to form:
– Trunk neural crest:
• Melanocytes (via the dorsal route)
• Sensory neurons (DRG)
• Sympathetic ganglia and nerves (ANS)
• Medulla of adrenal glands (chromaffin cells)
Note that they migrate segmentally (sclerotome) –
only in the rostral compartment.
 Neural Crest Cells
• Migration:
– Epithelial to mesenchyme transition
– Migrational pathways are established by juxtacrine
signals:
• Fibronection, laminin in ECM + integrins
• Ephrin proteins: Restrict movement
• Contact inhibition
• Use of existing structures
– Migration ceases when these signals are reversed
 Migration of Neural Crest Cells
Unlike cells in the CNS, which migrate radially
along glial fibers, neural crest cells “crawl along”
independently (like fibroblasts).
Motility is promoted by integrins – bind cell surface
to ECM (how does this contrast with cadherins?)
Prominent ECM components along neural crest
cell pathway: fibronectin, laminin, collagen.
The ECM provides attractive (permissive) cues for
movements, as well as a substrate on which to
bind.
A set of repulsive cues in neighboring structures
keeps cells in their precise migratory pathway
 Migration of Neural Crest Cells
As the cells reach their destination, the expression
of cadherins is once again activated (had been
repressed during free movement)  cells
aggregate into ganglia when they undergo
terminal neuronal and glial differentiation.
Side bar: retroviral labeling:
A cell can be labelled permanently and heritably by
injection with a retrovirus carrying a gene (e.g.,
β-galactosidase)  incorporated into cells’ DNA
and then expressed.
A substance, which will turn blue from the action of
the enzyme, can then be introduced in a
histochemical test.
CNS dev’t begins in the 3rd wk as a flat plate of
thickened ectoderm called the neural plate.

Its lat edges soon elevate to form the neural

folds. These folds later approach @ other in the
midline & fuse forming the neural tube.

Fusion of the neural tube begins in the cervical

region & proceeds in the cephalic & caudal
directions.

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• Closure of the cranial neuropore occurs about
day 25, while the caudal neuropore close at about
2 days later.

• The cephalic end of the neural tube shows 3

dilations called the primary brain vesicles.

Prosencephalon (forebrain)
Mesencephalon (midbrain)
Rhombencephalon (hindbrain)
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 The Brain: embryonic development
• Develops from neural tube
• Brain subdivides into
– Forebrain
– Midbrain
– Hindbrain
• These further divide, each with a fluid filled
region: ventricle, aqueduct or canal
– Spinal cord also has a canal
• Two major bends, or flexures, occur (midbrain
and cervical)
 Brain development

• Encephalos means brain

• At about week 5, the prosencephalon
divides into:
a) the telencephalon, which consists of a
midportion & 2 lateral out pocketings called
the primitive cerebral hemispheres.
b) the diencephalon.

• The rhombencephalic isthmus is a

furrow which separates the mesencephalon
from the rhombencephalon.

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• Space restrictions force cerebral
hemispheres to grow posteriorly
over rest of brain, enveloping it

• Cerebral hemispheres grow into

horseshoe shape (b and c)

• Continued growth causes creases,

folds and wrinkles
• Gyri (plural of gyrus)
– Elevated ridges
– Entire surface
• Grooves separate gyri
– A sulcus is a shallow groove (plural, sulci)
– Deeper grooves are fissures
• The rhombencephalon also consists
of 2 parts:
a) the metencephalon, which later
forms the pons & cerebellum.
b) the myelencephalon.

• The boundary between these 2

portions is marked by the pontine
flexure.
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• The lumen of the spinal cord called the
central canal is continuous with that of the
brain vesicles.

• The cavity of the cerebral hemispheres are

the lat ventricles, that of the diencephalon is
the 3rd ventricle & that of the
rhombencephalon is the 4th ventricle.

• The lumen of the mesencephalon becomes

narrow & connects the 3rd & 4th ventricles. Its
called the aqueduct of Sylvius.
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• The lateral ventricles

communicate with the 3rd

ventricle through the

interventricular foramina of

Monro.
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 Anatomical classification of CNS
• Cerebral
hemispheres
• Diencephalon
– Thalamus
– Hypothalamus
• Brain stem
– Midbrain
– Pons
– Medulla
• Cerebellum

• Spinal cord
 Parts of Brain

Cerebrum
Diencephalon
Brainstem
Cerebellum
• Prenatal life: genes are responsible for creating
the architecture of the brain
– Cortex is the last to develop and very
immature at birth
• Birth: excess of neurons but not inter-connected
– 1st month of life: a million synapses/sec are
made; this is genetic
• First 3 years of life: synaptic overgrowth
(connections)
– After this the density remains constant though
some grow, some die
• Preadolescence: another increase in synaptic
formation
adapted from Dr. Daniel Siegel, UCLA
• Adolescence until 25: brain becomes a
reconstruction site
– Connections important for self-regulation (in
prefrontal cortex) are being remodeled: important
for a sense of wholeness
– Causes personal turbulence
– Susceptible to stress and toxins (like alcohol and
drugs) during these years; affects the rest of one’s
life
• The mind changes the brain (throughout life)
– Where brain activation occurs, synapses happen
– When pay attention & focus mind, neural firing
occurs and brain structure changes (synapses are
formed)
– Human connections impact neural connections
(ongoing experiences and learning include the
interpersonal ones) 144
 FUNCTIONS OF THE BRAIN:
simplified…

• Back of brain: perception

• Top of brain: movement

• Front of brain: thinking

CNS protection

1.Meninges
2. Cerebrospinal fluid
3. Blood brain barrier
Spinal cord:
The inside of a neural tube consists of a thick
pseudostratified epi of neuroepithelial cells which
divide more rapidly immediately after the closure of
the tube during the neural groove stage.

These cells divide repeatedly to form a

neuroepithelial layer or neuroepithelium.

With further dev’t, the neuroepithelial cells give rise to

primitive nerve cells or neuroblasts xterised by large
round nucleus with pale nucleoplasm & dark staining
nucleolus.
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Neuroblasts segregate into a mantle layer, around the
neuroepi layer. This layer later forms the grey matter
of the spinal cord.

The outermost layer of the spinal cord, the marginal

layer, contains nerve fibres emerging from the
neuroblasts in the mantle layer. Bse of myelination,
these fibres appear white hence called the white
matter of the spinal cord.

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With further dev’t, @ side of the neural tube wth
continuos addition of neuroblasts,shows ventral &
dorsal thickenings of the mantle layer.

The ventral thickenings called basal plates form the

motor areas of the spinal cord, while the dorsal
thickenings called alar plates form the sensory areas.

The longitudinal tube,i.e,the sulcus limitans marks the

boundary btn the two plates.

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Roof & floor plates are dorsal & ventral midline
portions of the neural tube which don’t contain
neuroblasts. They serve primarily as pathways for
nerve fibres crossing from one side to the other.

Positional changes of the cord:

In the 3rd mth, the cord extends the entire length of the
embryo, with spinal nerves passing thru the
intervertebral foramina at their level of origin.

151
With increasing age, the vtbral column & dura
lengthen rapidly, hence the terminal end of the cord
gradually shifts to a higher level.

At birth, this end is at the level of L3.

The spinal nerves run obliquely from their segment of

origin in the spinal cord to the corresponding level of
the vtbral column.

The Dura remains attached to the vertebral column at

the coccygeal level.

152
In the adult, the cord terminates at the level of
L2 to L3, while the dural sac & subarachnoid
space extend to S2.

Below L2 / L3, a thread-like extension of the pia

mater forms the filum terminale, which marks the
tract of regression of the spinal cord. Its attached
to the 1st coccygeal vtbra.

Nerve fibres below the terminal end of the cord

collectively constitute the cauda equina.

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 Skeletal defects affecting the
nervous system:
• Spina Bifida

• Spina Bifida Occulta

• Meningocoele

• Meningomyelocoele

• Hydrocephalus
 Neural tube defects:
Most of these result from abnormal closure of
the neural folds. The resulting abnormalities
(Neural tube defects, NTDs), may involve the
meninges, vtbrae, mm & skin.

Spina bifida are defects affecting the spinal

region.
 Spina bifida occulta, is a defect in the vertebral
arches that is covered by skin & does not involve
the underlying neural tissue.

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 Spina bifida cystica, is when neural tissue &
meninges protrude thru defects in the vertebral
arches to form a cyst-like sac.
Fluid may fill the protruding meninges hence
called spina bifida with meningocele, or neural
tissue may protrude in the sac hence called spina
bifida with meningomyelocele.

Causes of NTDs is multifactorial eg, hyperthermia,

hyper-vitaminosis A, folate deficiency and other
teratogens.

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Hydrocephalus
 END

THANK YOU

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