2. Out line
• Overview of the first three weeks of development
and Neurulation.
• Spinal cord development
• The brain development
• Some clinical correlations
Dr. Girum M.
3. Objective
• To understand the basic embryogenesis of Nervous
system
• To Clinical correlate this basic embryogenesis to
some congenital anomalies
Dr. Girum M.
4. Overview of events in the first week
• Ovulation
• Fertilization
• Multiple cell divisions
• Blastocyst formation
– With inner and outer cell mass
Dr. Girum M.
6. Overview of events in the second week
• Blastocyst Partially embedded in the Endometrium
• the trophoblast has differentiated into two layers
• the cytotrophoblast, and
• the syncytiotrophoblast
• Formation of Bilaminar disk
• Epiblast and
• Hypoblast
Dr. Girum M.
8. Third week of development
• Gastrulation
• the process that establishes all three germ layers
(a Trilaminar Disk)
»ectoderm,
»mesoderm, and
»Endoderm
• Formation of the body axis
• Formation of the nothochord
Dr. Girum M.
10. Formation of the Notochord
• Prenotochordal cells invaginating in the primitive
node move forward cranially in the midline until they
reach the prechordal plate.
Dr. Girum M.
12. Neurulation
• Neurulation is the process whereby the neural plate
forms the neural tube.
• By the end of the third week, the lateral edges of the
neural plate become elevated to form neural folds,
and the depressed midregion forms the
neural groove.
• Gradually, the neural folds approach each
other in the midline, where they fuse .
Dr. Girum M.
14. • The lumen of the neural tube becomes the neural canal,
which communicates freely with the amniotic cavity.
• The cranial Neuropore will close at the 25th day
• The caudal Neuropore will close at the 27th day.
Dr. Girum M.
16. Development of the spinal cord
• The primordial spinal cord develops from the caudal
part of the neural tube.
• There are three layer
– Neuroepithelial layer(ventricular layer)-has the pleuripotent
pseudostratified neuroepithelium
– Mantel layer- later forms the gray matter of the spinal cord
– Marginal layer-later forms the white matter of the spinal
cord
Dr. Girum M.
17. • Some of the neuroblasts in mantel layer proliferates
posteriorly and anteriorly respectively to give
– The Alar plate is predominantly sensory in function.
– The Basal plate is predominantly motor in function.
• Sulcus Limitans :
– It is a longitudinal groove along the inner surface of the
lateral walls of the developing spinal cord.
– It differentiates the grouping of cells into dorsal (Alar) plate
and a ventral (Basal) plate.
• The neural canal becomes the central canal of the spinal
cord exists at 9 to 10 weeks.
Dr. Girum M.
20. • The spinal cord and the vertebral column are the same length up until the 3rd
month.
• As each vertebral body grows thicker, the overall length of the vertebral
column begins to exceed that of the spinal cord such that , in the adult the
spinal cord terminates at L1 or 2.
• At the end of the cord, a threadlike extension of pia mater passes
caudally, called the filum terminale.
“Regression” of the spinal cord
Dr. Girum M.
21. Derivatives of Neural Crest cells
• Melanocytes
• Leptomeninges
• Adrenal medulla
• Sensory, sympathetic & enteric Ganglia
• Schwann cells
• Para-follicular cells
• odontoblasts
• mesenchyme of the
pharyngeal arches
Dr. Girum M.
22. Meninges
• Derived from mesoderm and neural crest cells
• Form two layers
External layer give rise to dura mater…Mesoderm
Internal layer give rise to leptomeninges…NCC
Dr. Girum M.
23. Development of The Brain
• Primary brain vesicles………3
• Secondary brain vesicles…..5
Dr. Girum M.
25. Brain flexures
– Cephalic ( Mid brain) flexure: at the junction of
the fore and mid brains.
– Pontine flexure: B/n the mylencephalon and
metencephalon
– Cervical flexure: Between the brain and spinal
cord.
Dr. Girum M.
28. Myelencephalon
– Give rise to Medulla oblongata
– Basal plate contain three groups of motor nuclei
– Alar plate contain three groups of sensory nuclei
Dr. Girum M.
29. Metencephalon
• Has similar organization as myelencephalon
• The basal plate consists three groups of motor nuclei
• Alar plates consists three groups of sensory nuclei
• Give rise to pons and cerebellum
Dr. Girum M.
33. Prosencephalon: Forebrain
• The prosencephalon consists of the
– Telencephalon, which forms the cerebral hemispheres and
– Diencephalon, which forms the
• optic cup and stalk,
• pituitary,
• thalamus,
• hypothalamus, and
• Epiphysis(pineal gland).
Dr. Girum M.
34. Telencephalon
• Most rostral brain vesicle consists of two lateral out
pocketing the cerebral hemispheres, cavities of the
hemispheres; lateral ventricles and foramen of
Monro and medial portion Lamina Terminalis.
• Continuous growth of the cerebral hemispheres in
anterior, dorsal, and inferior directions results in the
formation of frontal, parietal, temporal and occipital
lobes, respectively.
Dr. Girum M.
35. Diencephalon
• Which develops from the median portion of the
prosencephalon.
• is thought to consist of a
– a roof plate
• Choroid Plexus of 3rd ventricle
• Pineal body(epiphysis)
– two alar plates
• hypothalamus
• Thalamus
• Mammillary body
• Hypophysis or Pituitary Gland
• but No floor and basal plates
Dr. Girum M.
36. • The pituitary gland (hypophysis), develops from two
completely different parts:
– (1) an ectodermal outpocketing of the stomodeum (primitive
oral cavity) immediately in front of oropharyngeal
membrane known as Rhathke’s pouch.
– (2) down ward extension of diencephalon, the infidibulum
Development of Pituitary Gland
Dr. Girum M.
37. Clinical Correlates
Neural Tube Defects
• Is due to an abnormal closure of neural fold at 3rd -4th
weeks
• Classification
– There is no universally accepted classification system
Lemire classification
1. Neurulation defects
2. postneurulation defects
Dr. Girum M.
38. 1, Neurulation defects:
non-closure of the neural tube results in open lesions
a) craniorachischisis:
total dysraphism
Many die as spontaneous abortion
Dr. Girum M.
39. b) Anencephaly: AKA exencephaly
– Due to failure of fusion of the anterior neuropore.
– is characterized by an open defect in the calvaria and
skin, such that the cranial neural tube is exposed.
– Neither cranial vault nor scalp covers the partially
destroyed brain
– Uniformly fatal.
– Risk of recurrence in future pregnancies 3%
Dr. Girum M.
42. 2, Postneurulation defects:
– produces skin-covered (AKA closed) lesions.
– also be considered “migration abnormalities”.
a) cranial
– Microcephaly:
• head circumference more than 2 SD below the mean
for sex and gestational age.
Dr. Girum M.
43. ⁻ Holoprosencephaly: AKA arhinencephaly
• Failure of the telencephalic vesicle to cleave into two
cerebral hemispheres.
• It is a spectrum of abnormalities in which a loss of
midline structure results in malformation of the brain
and face
Dr. Girum M.
44. ⁻ Schizencephaly:
⁻ is an uncommon disorder of
neuronal migration characterized
by a cerebrospinal fluid–filled cleft,
which is lined by gray matter.
- Hydranencephaly:
– loss of most of cerebral hemispheres, replaced by CSF.
– Total or near-total absence of the cerebrum
– small bands of cerebrum may be consistent with the
diagnosis
Dr. Girum M.
45. b) spinal
– diplomyelia: Split cord
malformation
– Hydromyelia / syringomyelia:
• AKA syrinx
• Cystic cavitation of the spinal
cord
• 70% are associated with Chiari I
malformation
Dr. Girum M.
46. Spinal dysraphism (spina bifida)
▶ Spina bifida occulta: Congenital absence of a spinous
process and variable amounts of lamina. No visible
exposure of meninges or neural tissue.
▶ spina bifida aperta (spina bifida cystica):
▶ Meningocele- Congenital defect in vertebral arches with cystic
distension of meninges, but no abnormality of neural tissue. One
third have some neurologic deficit.
▶ Myelomeningocele- Congenital defect in vertebral arches with
cystic dilatation of meninges and structural or functional
abnormality of spinal cord or cauda equina.
Dr. Girum M.
48. • Closed spinal dysraphism (aka spina
bifida occulta)
o is characterized by failure of fusion
of the vertebral bodies due to
abnormal fusion of the posterior
vertebral arches, with unexposed
neural tissue; the skin overlying the
defect is intact.
o prevalence range of SBO: 5–30%
Dr. Girum M.
49. The Chiari Malformations
• Chiari malformation is a structural defect of
the cerebellum.
• It is characterized by a tongue-like projection of the
medulla and inferior displacement of the cerebral tonsil
through the foramen magnum into the vertebral canal.
• The condition may lead to a type of noncommunicating
hydrocephalus that obstructs the absorption and flow of
CSF; as a result, the entire ventricular system is
distended.
Dr. Girum M.
50. • Several types of Chiari malformations have
been described.
– In type I, the inferior part of the cerebellum herniates through
the foramen magnum. This is the most common form. It is
usually asymptomatic and detected in adolescence.
– In type II, also known as Arnold-Chiari malformation, cerebellar
tissue and the brainstem herniate through the foramen
magnum, often accompanied by occipital encephalocele and
lumbar myelomeningocele.
– In type III, the most severe form, there is herniation of the
cerebellum and brainstem through the foramen magnum into
the vertebral canal, which has serious neurologic consequences.
– In type IV, the cerebellum is absent or underdeveloped; these
infants do not survive.
Dr. Girum M.
a Zygote which is a diploid cell .
Zygote continues to divide to form Blastula a 2-4 cell in number which continues to divide to form Morula 8-12 cell size which starts to migrate to the endometrium of Uterus
At the endometrium Blastocyst reach with inner cell mass and outer cell mass
Blastula a 2-4 cell
Embryoblast
the trophoblast has differentiated into two layers:
(1) an inner layer of mononucleated cells, the cytotrophoblast, and (2) an outer multinucleated zone without distinct cell boundaries, the syncytiotrophoblast
4 major events in the 3rd week of life
The most characteristic event occurring during the third week of gestation is gastrulation, the process that establishes all three germ layers (ectoderm,mesoderm, and endoderm) in the embryo.
Establishment of the body axes, anteroposterior, dorsoventral, and left–right, takes place before and during the period of gastrulation
Gastrulation begins with formation of the primitive streak on the surface of the epiblast.
This inward movement is known as invagination i.e migration of Epiblast into the primitive streak . Cell migration and specification are controlled by fibroblast growth factor 8 (FGF8), which is synthesized by streak cells themselves.
An adult derivative of Notochord is Nucleus pulposis
The notochord and prenotochordal cells extend cranially to the prechordal plate (an area just caudal to the oropharyngeal membrane) and caudally to the primitive pit.
At the point where the pit forms an indentation in the epiblast, the neurenteric canal temporarily connects the amniotic and yolk sac cavities.
Neurulation is a process in which the neural plate bends up and later fuses to form the hollow tube that will eventually differentiate into the brain and the spinal cord of the central nervous system.
Folding and closure of the neural tube occurs first in the cervical region.
The neural tube then “zips” up toward the head and toward the tail, leaving two openings which are the anterior and posterior neuropores.
The anterior neuropore closes around day 25.
The posterior neuropore closes around day 27.
The lumen of the neural tube becomes the neural canal, which communicates freely with the amniotic cavity. The cranial opening (rostral neuropore) closes at approximately the 25th day, and the caudal neuropore closes at approximately the 27th day.
Derivatives of Neural Crest cells
1 Melanocytes
2 Leptomeninges NB dura matter is a derivative of Mesoderm
3 adrenal medulla
4 spinal ganglia
5 Schwann cells
6 Para follicular cells
7 odontoblasts
8 Aoroto pulmonary septum
Meninges
Derived from mesoderm and neural crest cells
Form two layers
External layer give rise to dura mater
Internal layer give rise to leptomeninges
The primordial spinal cord develops from the caudal part of the neural plate and caudal eminence. The neural tube caudal to the fourth pair of somites develops into the spinal cord . The lateral walls of the neural tube thicken, gradually reducing the size of the neural canal until only a minute central canal of the spinal cord exists at 9 to 10 weeks.
The neural tube has 03 layers
1 neuroepithelial layer….has the pleuri potent neuroepithelium…AkA ventricular Zone
2 matel layer…..Gray matter
3 marginal layer……white matter
During the neural groove stage and immediately after closure of the tube, they divide rapidly, producing more and more neuroepithelial cells. Collectively, they constitute the neuroepithelial layer or neuroepithelium. Once the neural tube closes, neuroepithelial cells begin to give rise to another cell type characterized by a large round nucleus with pale nucleoplasm and a dark-staining nucleolus. These are the primitive nerve cells, or neuroblasts . They form the mantle layer, a zone around the neuroepithelial layer (Fig. 18.8). The mantle layer later forms the gray matter of the spinal cord. The outermost layer of the spinal cord, the marginal layer, contains nerve fibers emerging from neuroblasts in the mantle layer. As a result of myelination of nerve fibers, this layer takes on a white appearance and therefore is called the white matter of the spinal cord.
Sacrum at 3rd month of fetal life …..the entire length of vertebrae
L3 at birth
L1 at adult
By the fifth week, the forebrain and hindbrain vesicles divide into two secondary vesicles.
With in 4 days secondary vesicles will develop from primary vesicles
The most caudal vesicle
As development proceeds, the lateral walls are moved laterally (like an opening clamshell) at higher levels by the expanding fourth ventricle.
As a result, the alar plates come to lie lateral to the basal plates.
The neurons of the basal plate form the motor nuclei of cranial nerves (CNs) IX, X, XI, and XII and are situated in the floor of the fourth ventricle medial to the sulcus limitans.
The neurons of the alar plate form the sensory nuclei of CNs V, VIIl, IX, and X and the gracile and cuneate nuclei. Other cells of the alar plate migrate ventrolaterally and form the olivary nuclei.
Between the fourth and fifth months, local resorptions of the roof plate occur; forming paired lateral foramina, the foramina of Luschka, and a median foramen, the foramen of Magendie. These Important foramina allow the escape of the CSF, which is produced in the ventricles, into the subarachnoid space
The neurons of the basal plates form the motor nuclei of CNs V. VI, and VII. The neurons of the ventromedial part of each alar plate form the main sensory nucleus of CN V. a sensory nucleus of CN VII, and the vestibular and cochlear nuclei of CN VIII; they also form the pontine nuclei.
The neuroblasts in the basal plates will differentiate Into the neurons forming the nuclei of CNIII and IV and possibly the red nuclei, the substantia nigra and the reticular formation.
The hypothalamus, forming the lower portion of the alar plate, differentiates into a number of nuclear areas that regulate the visceral functions, including sleep, digestion, body temperature, and emotional behavior.
The ruminant of anterior neuropore is Lamina Terminalis.
Telencephalon is the lateral growth from prosencephalon
is thought to consist of a roof plate and two alar plates but to lack floor and basal plates (interestingly, SHH, a ventral midline marker, is expressed in the floor of the diencephalon, suggesting that a floor plate does exist).
The roof plate of the diencephalon consists of a single layer of ependymal cells covered by vascular mesenchyme. Together, these layers give rise to the choroid plexus of the third ventricle . The most caudal part of the roof plate develops into the pineal body, or epiphysis. This body initially appears as an epithelial thickening in the midline, but by the seventh week, it begins to evaginate . Eventually, it becomes a solid organ on the roof of the mesencephalon (Fig. 18.30) that serves as a channel through which light and darkness affect endocrine and behavioral rhythms
. In the adult, calcium is frequently deposited in the epiphysis and then serves as a landmark on radiographs of the skull.
Anencephaly is characterized by an open defect in the calvaria and skin, such that the cranial neural tube is exposed. It is a severe defect and is not compatible with survival. Infants that are alive at birth generally die within hours, but occasionally survive for a few days or weeks.
Anencephaly is one of the three major neural tube defects (NTDs). The others are encephalocele and myelomeningocele, which are discussed in separate topic reviews:
●Encephalocele is a herniation of the brain and/or meninges through a defect in the skull (cranium bifidum) that is "closed" or covered with skin.
●Myelomeningocele is characterized by a cleft in the vertebral column, with a corresponding defect in the skin so that the meninges and spinal cord are exposed.
AKA arhinencephaly. Failure of the telencephalic vesicle to cleave into two cerebral hemispheres. The degree of cleavage failure ranges from the severe alobar (single ventricle, no interhemispheric fissure) to semilobar and lobar (less severe malformations). The olfactory bulbs are usually small and the cingulate gyrus remains fused. Median faciocerebral dysplasia is common, and the degree of severity parallels the extent of the cleavage failure Table 17.9). 80% are associated with trisomy (primarily trisomy 13, and to a lesser extent trisomy 18). Survival beyond infancy is uncommon, most survivors are severely retarded, a minority are able to function in society. Some develop shunt dependent hydrocephalus. The risk of holoprosencephaly is increased in subsequent pregnancies of the same couple.
MustR/O maxim al hydrocephalus (see below)
Dierentiation from hydrocephalus Progressive enlargement of CSF spaces m ay occur which can mimic severe (“maxim al”) hydrocephalus (HCP). It is critical to differentiate the two since true HCP m ay be treated by shunting which may produce some re-expansion of the cortical mantle. Many means to distinguish hydranencephaly and HCP have been described, including: 1. EEG: show s no cortical activity in hydranencephaly (maxim al HCP typically produces an abnormal EEG, but background activity will be present throughout the brain and is one of the best ways to differentiate the two 2. CT, MRI or ultrasound: majority of intracranial space is occupied by CSF. Usually do not see frontal lobes or frontal horns of lateral ventricles (there m ay be remnants of temporal, occipital or subfrontal cortex). A structure consisting of brainstem nodule (rounded thalamic m asses,hypothalam us) and m edial occipital lobes sitting on the tentorium occupies a midline position surrounded by CSF. Posterior fossa structures are grossly intact. The falx is usually intact (unlike alobar holoprosencephaly), and is not thickened, but m ay be displaced laterally. In HCP, some cortical mantle is usually identifiable 3. transillumination of the skull: in a darkened room , a bright light is placed against the surface of the skull. To transilluminate, the patient must be < 9 mos old and the cortical mantle under the light source must be < 1 cm thick,33 can also occur if fluid displaces th e cortex inward (e.g. subdural eusions). Too insensitive to be very helpful 4. angiography: in “classic” cases resulting from bilateral ICA occlusion, no flow through supraclinoid carotids and a norm al posterior circulation is expected
SPINA BIFIDA OCCULTA Spina bifida occulta is an NTD resulting from failure of the halves of one or more neural arches to fuse in the median plane. This NTD occurs in the L5 or S1 vertebra in approximately 10% of otherwise normal people. In the minor form, the only evidence of its presence may be a small dimple with a tuft of hair arising from it. An overlying lipoma, dermal sinus or other birthmark may also occur. Spina bifida occulta usually produces no symptoms. A few affected infants have functionally significant defects of the underlying spinal cord and dorsal roots.
The posterior cranial fossa is usually abnormally small, causing pressure on the cerebellum and brainstem.
Magnetic resonance imaging is now used to diagnose Chiari malformation, and as a result, more cases have been detected than before.
