Download Neuroembryology: CNS Developmental Anomalies

Neuroembryology: CNS Developmental Anomalies
Raymond J. Colello, Ph.D.
*Lecture written by Dr. John Povlishock
Note: Emphasize Dr. Colello’s lecture PPT and developmental anomalies
OBJECTIVES (Revised)
1. Review basic neuroembryology
2. Review the differentiation of the neural tube into the CNS
3. Understand the differentiation of the alar plate into sensory structures (sensory cell columns),
and basal plate into motor structures (motor cell columns), in the brainstem
4. Above the brainstem, trace the differentiation of the alar plate into forebrain structures,
eg. thalamus, basal ganglia, cortex
5. Define causes of major developmental anomalies (eg. spina bifida, meningomyelocele,
encephalocele, hydrocephalus, microgyria, agenesis of the corpus callosum, etc.)
OBJECTIVES
After studying the material presented in this lecture, the student should be capable of:
1.
Discussing the basic developmental plan for the brain stem, appreciating the precise organization of the motor
and sensory columns found within the basal and alar plates.
2. Describing in detail the development of the midbrain, pons, cerebellum and medulla.
3. Describing the basic developmental features of the forebrain.
4. Describing the general development of the telencephalon, appreciating the origin of five anatomical lobes of
the brain as well as the basal ganglia.
5. Discussing the origin of the internal capsule and the major commissural systems.
I.
Introduction
In humans, the nervous system and the neuro-epithelium of special sense organs are derived
from embryonic ectoderm. The CNS (brain and spinal cord) takes origin from an elongated
area of ectoderm, the neural plate, situated dorsally in the embryo, anterior to Hensen's node
and primitive streak. The peripheral nervous system (PNS) arises from a specialized band of
ectoderm, the neural crest, which flanks the lateral margins of the neural plate.
In the development of the CNS, the neural plate assumes a major organizational role. By the
18th day of embryonic life, the edges of the neural plate become elevated forming the neural
folds, with the depressed region intervening between folds constituting the neural grove
(Figure 1). As development proceeds, the neural folds continue to elevate and sweeping
medially, the opposing folds meet and fuse in the midline. This folding, with the resulting
closure of the neural folds, thereby forms the neural tube. This closure of the neural folds
with subsequent formation of the tube continues in a rostral and caudal direction. At the
most rostral and caudal ends of this tube fusion is somewhat delayed. Thus continuity
temporarily exists between the lumen of the neural tube and the surrounding amniotic fluid.
The rostral and caudal poles of the neural tube at which point this continuity is established,
are referred to as the anterior and posterior neuropores. Closure of the anterior neuropore
occurs by the 23rd day, while the closure of the posterior neuropore lags until the 25th day.
With the closure of the anterior and posterior neuropores the fundamental form of the human
CNS is that of a hollow tube. As the result of further differential growth and expansion of its
walls, this tube can now be subdivided into an elongated caudal portion, which will become
the spinal cord and a shorter, broader, cephalic part, the future brain, which early in its
development appears as three dilations on the cephalic portion of the neural tube.
II.
Neural Tube: Caudal Neural Tube/Spinal Cord
* Link to Netter Image 1.67
* Link to Netter Image 1.68
* Link to Netter Image 1.69
* Link to Netter Image 1.70
* Link to Netter Image 1.71
Histologic examination of the developing caudal neural tube reveals several interesting
phenomena. During the neural plate stage and immediately after closure of the neural tube,
the neural wall consists solely of neuroepithelial cells. With closure of the tube, some of
these cells give rise to another cell type called a neuroblast, whose proliferation now causes
distinct zonation within the neural tube. Those neuroepithelial cells from which the
neuroblasts arose now constitute an inner zone, the ependymal layer which borders on the
neural tube lumen. The migrating neuroblasts form an outer zone called the mantle layer
which is destined to form the gray matter of the spinal cord, while proliferating nerve fibers
originating from the neuroblasts constitute an outermost zone called the marginal layer,
which is to become the white matter of the spinal cord.
Figure 1
Due to the continuous development of the neuroblasts and the subsequent formation of the
mantle and marginal layers, several distinct changes are now noted in relation to the once
simple caudal neural tube which is to form the spinal cord. Among these changes are the
appearance of the: (Figure 2)
1. Alar plate - a dorsal thickening - future posterior (dorsal) horn
2. Basal plate - a ventral thickening - future anterior (ventral) horn
3. Sulcus limitans - a longitudinal furrow which marks the boundary between the sensory
(alar) and motor (basal) portions of the central nervous system
4. Roof plate - thin dorsal midline portion of the neural tube - formed by ependymal and
glial cells, it becomes a pathway for crossing or commissural fibers.
5. Floor plate - thin ventral midline portion of the neural tube - also pathway for crossing
fibers
6. Ependymal lining - which has undergone a marked transition from its original stratified
form
7. Neural crest development - these cells of neuroectodermal origin that appeared initially
along the lateral edge of the neural plate now give rise to:
a. Cell bodies of the dorsal root ganglia
b.
c.
d.
e.
f.
g.
Sympathetic ganglia cells
Chromaffin cells (adrenal medulla)
Neurilemmal (Schwann) cells
Melanocytes
Leptomeninges (pia and arachnoid)
Cell bodies of the sensory ganglia of the 5th, 7th, 9th, and 10th cranial nerves - in
relation to the rostral portion of the neural tube which is to become the brain.
Figure 2
III.
Malformations of the Caudal Neural Tube
Spina bifida - This term covers a wide range of defects in which there is a failure of the
dorsal portions of the vertebrae to fuse. (Figure 3)
Figure 3
1. Spinal bifida occulta-- Usually localized in the sacrolumbar region, and though there is
a failure of the dorsal portions of the vertebral column to fuse, there is no protrusion of
intraspinal contents to the surface.
Figure 4
2. Meningocele -- The meninges of the spinal cord, bulge through the defect in the
vertebral column, however, this developmental defect generally does not involve any
neurological abnormalities.
3. Meningomyelocele -- Both the meninges and neural elements bulge through the defect
in the vertebral column.
Figure 5
4. Complete Rachischisis -- The neural tube remains unclosed and the defective spinal
cord lies exposed on the infant's back.
5. Congenital dermal sinus -- Represents the remnants of an incomplete cleavage of the
cutaneous and neural ectoderm during embryonic life. There is usually a narrow opening
appearing as a small dimple in the midline and a tract lined with stratified squamous
epithelium.
IV.
Neural Tube: Rostral Portion/Brain (General Features)
* Link to Netter Image 1.73
* Link to Netter Image 1.74
The rostral portion of the neural tube terminates as the lamina terminalis representing the
closure of the anterior neuropore. This region divides into three primary vesicles which by
the third week of life are termed from rostral to caudal, the prosencephalon, mesencephalon,
and rhombencephalon. By the fifth week of life, these three primary vesicles undergo
dramatic transformation with the rostral prosencephalic bulge differentiating into two
telencephalic bulges, capping a relatively undifferentiated midline bulge termed the
diencephalon (Figure 4). The intermediate bulge, the mesencephalon, remains relatively
undifferentiated, while the caudal bulge, the rhombencephalon further differentiates into the
rostral metencephalon and the more caudally directed myelencephalon which is confluent
with the spinal cord (Figure 4). Although this basic developmental pattern of the rostral
neural tube is relatively straightforward, the actual alignment of these primary brain vesicles
is somewhat difficult to conceptualize. This is due to the fact that, as the rostral portion of
the neural tube develops, it undergoes extreme flexuring, with compensatory infolding.
Thus, in the early gestational period, the ventral surface of the mesencephalon shows an
infolding, termed the mesencephalic or cephalic flexure, while a comparable ventral
infolding forms at the junction of the myelencephalon and spinal cord, termed the cervical
flexure. These ventrally originating flexures are compensated, in part, by the development of
a dorsal infolding between the mesencephalon and myelencephalon termed the pontine
flexure.
Figure 6
In relation to the developing brain and brain stem, the mesencephalon, metencephalon, and
myelencephalon follow a development pattern quite reminiscent of that seen in the spinal
cord, whereas the diencephalic and telencephalic regions deviate from this developmental
plan. Specifically:
A. In relation to the brain stem, the spinal cord patterns of alar and basal plates persist
throughout the myelencephalon, metencephalon and mesencephalon, with a major
distinction involving the expansion or closure of the roof plate. As can be seen in Figure
5, the basal plate, as in the spinal cord, gives rise to motor neurons that are organized in
discrete columns reflecting specific the functional components of the cranial nerves with
which they are associated. For example, the most medial column contains cells
contributing to general somatic efferent functional components of the cranial nerves,
while the intermediate and more lateral basal columns provide for the special visceral
efferent and general visceral efferent functional components respectively.
Figure 7
The alar plate gives rise to sensory neurons which are also organized in distinct columns,
again reflecting the specific functional components of those cranial nerves with which
they are associated. The most medial column of neurons is associated with general
visceral afferents, while the intermediate and lateral columns are associated with special
visceral afferents and general and special somatic afferents respectively. In addition to
providing for these sensory columns, the alar plate of the brain stem also contributes
some migratory cells which give rise to cell groups or clusters scattered throughout the
ventral brain stem. Lastly, in the process neural development, the marginal zone
undergoes significant expansion and modification due to the presence of large numbers
of ascending and descending fiber systems which, in concert with the development of
local nuclear groups, give the brain stem its characteristic shape, particularly in the
ventral region.
B. In relation to the diencephalon and telencephalon, these regions spring exclusively from
the alar plate, and thus, undergo developmental patterns quite dissimilar seen in the brain
stem and spinal cord.
V.
Rostral Neural Tube - Specific Developmental Features of the Brain Stem
A.
Myelencephalon (Figure 8)
1.
Although following the organizational plan seen in the developing spinal
cord, the developing myelencephalon or medulla undergoes a dramatic
thinning of the roof plate so that alar plates migrate laterally and the basal
plates shift to a midline position. The thinned roof plate covers a large fluidfilled chamber which will persist as the fourth ventricle. Further, thinning in
the mid and lateral quadrants of the roof plate will give rise to foramina of
Magendie and Luschka respectively, whereas the ingrowth of pial and
mesenchymal tufts give rise to the choroid plexus of the fourth ventricle.
2.
The basal plate gives rise to all the motor neurons of the medullary region
with the general somatic efferent cell clusters giving rise to the hypoglossal
nucleus, the special visceral efferent cell clusters giving rise to the nucleus
ambiguus, and the general visceral efferent cell clusters giving rise to the
dorsal motor nucleus of the vagus.
3.
As previously noted, the alar plate will differentiate into the sensory
components of the medulla, with the medial and intermediate cell groupings
giving rise to the nucleus solitarius. The more lateral cell groupings give rise
to the vestibular nuclei as well as the gracile and cuneate nuclei.
In addition to forming the sensory columns, the alar plate also gives rise to a
thin, ventrally directed stream of neurons which forms the bulbopontine
extension. These migrating cells form the inferior olivary nucleus and
continue rostrally to contribute to the formation of some of the caudal pontine
nuclei.
4.
The ventrally lying marginal zone which encompasses both the basal and alar
plates initially shows little overt change; however, over time its shape is
altered by the continuing expansion of the inferior olivary nuclei as well as
the presence of large numbers of ascending and descending fiber systems.
This region undergoes further change as these ascending and descending
systems undergo myelination. Typically, by the sixth month, this region
shows myelination within the medial longitudinal fasciculus, soon followed
by myelination of the vestibulospinal, reticulospinal, and tectospinal tracts.
Afferent fibers are not myelinated until the eighth fetal month, when the
corticospinal system also undergoes myelination.
Figure 8
B. Metencephalon (Figure 8)
1. In general, the metencephalon replicates many of the important features seen in
the myelencephalon. Initially, the roof plate of the metencephalon is thin. It is
triangular in shape, with the apex of the triangle situated cranially. The alar plates
of this part of the developing brain approach each other as they are traced
forward, the most dorsal portions of the alar plates undergo thickening to form
the primordium of the cerebellum discussed below. The ventral medial portion of
the alar plate forms the pontine component of the bulbopontine extension which
helps seed the pontine nuclei. A portion of the ventral medial plate not
undergoing migration gives rise to the somatic afferent nuclei. In this regard, the
caudal portion of the alar plate forms the somatic afferents of the vestibular and
cochlear nuclei, whereas the more cranial portion of this mass gives rise to the
general somatic afferents of the chief sensory nucleus of V.
2. Cerebellum
The cerebellum originates from the dorsal portion of the alar plate termed the
rhombic lip. Initially, the rhombic lips from both sides of the metencephalon
grow into the ventricular compartment, merging in the midline, forming a
continuous cerebellar primordium. Once this fusion is complete, the cerebellum
undergoes expansion of its extraventricular portion.
3. In the developing basal plate of the metencephalon, one can find motor columns
comparable to those found in the basal plate of the myelencephalon. Again, these
motor columns are highly organized, with the most medial cell clusters giving
rise to general somatic efferents such as the abducens nucleus, which the more
lateral cell columns give rise to the special visceral efferents of the facial nucleus
and motor nucleus of V. The most lateral cell column gives rise to the general
visceral efferents associated with the superior salivatory nucleus and perhaps
inferior salivatory nucleus.
4. Like the myelencephalon, the metencephalon undergoes further expansion of the
marginal zone due to the ingrowth of afferents and efferents as well as ongoing
myelination. The pontine nuclei contribute to further expansion in that they give
rise to the transverse pontine fibers which stream into the cerebellum,
contributing to the formation of the massive middle cerebellar peduncle.
C. Mesencephalon
1. The mesencephalon closely replicates many of the developmental features seen
in the developing spinal cord. The alar plates differentiate into the sensory
domains of the superior and inferior colliculi involved with the visual and
auditory pathways respectively. The underlying ventricular space becomes
narrowed, much like the central canal, forming the cerebral aqueduct which is the
conduit between the third and fourth ventricle.
2. The developing basal plates, as in the other brain stem regions, give rise to motor
nuclei. Once again, the most medial of the motor columns give rise to the general
somatic efferent components of the oculomotor and trochlear nerves, while the
more lateral of the motor columns gives rise to the Edinger-Westphal nucleus.
3. The origin of the red nucleus and substantia nigra are controversial. Some
contend that both of these nuclear groups derive from the alar plate, while others
argue that these nuclei develop in situ in the basal plate itself.
4. The marginal zone undergoes characteristic expansion due to the presence of
large numbers of descending corticospinal, corticobulbar, and corticopontine
projections which expand marginal zone bilaterally resulting in the development
of the characteristic cerebral peduncles.
VI.
Rostral Neural Tube - Specific Developmental Features of the Forebrain
* Link to Netter Image 1.75A
* Link to Netter Image 1.75B
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* Link to Netter Image 1.75D
* Link to Netter Image 1.75E
* Link to Netter Image 1.75F
* Link to Netter Image 1.76
As was noted, the forebrain is derived from the prosencephalic bulge which further
subdivides into two telencephalic swellings that expand around a centrally directed
diencephalon.
A.
Diencephalon
1.
Early in the development of the alar plate in this region, the hypothalamic
sulcus is formed, separating the thalamus from the hypothalamus. This
sulcus, in turn, is followed by the development of another sulcus, the
epithalamic sulcus, which isolates the dorsal thalamus proper from the
overlying epithalamic domain. Cells within the mantle zone of the
epithalamic region differentiate into the habenular nuclei which lies adjacent
to the pineal stalk. The stria medullaris thalami also develops in this region
which undergoes relatively regressive growth in comparison to the
underlying thalamus. Thus, in the adult man, the epithalamus is
proportionally smaller than the underlying thalamus.
2.
In the hypothalamic region, neuroblasts within the mantle zone differentiate
into various nuclei associated with visceral function. In the thalamic region,
nuclei within the mantle zone and those migrating into the marginal zone
develop into the thalamic nuclei proper in addition to the metathalamic
nuclei, the medial and lateral geniculate bodies. With expansion of these
nuclei, the thalamus swells and projects medially where it compresses the
third ventricular cavity. In some cases, portions of these thalamic swellings
fuse in the midline, giving rise to the mass intermedia or interthalamic
adhesion.
B.
3.
The roof plate of the diencephalon is thin and is invaginated by pial elements
which form the tela choroidea with the subsequent formation of the choroid
plexus of the third ventricle. In the posterior aspect of the roof of the
diencephalon, an outgrowth arises which extends upward and forward as a
hollow mass. Over time, this hollow mass becomes filled with proliferating
cells which transform this projection into the pineal gland.
4.
A medium diverticulum in the floor plate forms the neurohypophysis which
is encompassed by the adenohypophysis that arises from the roof plate.
Telencephalon
1.
General Developmental Features - The telencephalic vesicles arise during the
seventh week of development as outgrowths of the prosencephalic cavity.
Initially, these outgrowths exist as relatively thin bands of tissue surrounding
relatively massive ventricular cavities which are confluent with the third
ventricle through the interventricular foramina. The interventricular foramina
are bounded anteriorally by the lamina terminalis which delineates the
closure of the anterior neuropore. Initially, the telencephalic bulges lie
posterior and lateral to the lamina terminalis; however, over time, both
telencephalic bulges expand, moving rostrally, superiorally, posteriorally and
inferiorally. With rapid telencephalic growth, large numbers of neuroblasts
migrate through the mantle layer to the outer marginal zone, where they form
the cerebral cortex or pallium. The growth pattern of the pallium is planar,
growing rapidly as an expanding two-dimensional sheet. In the ventral
portion of the telencephalon, the basal ganglia arise from the mantle zone. As
a result of differential growth patterns, the pallium expands like the shell of a
balloon. At the same time, the rapidly growing basal ganglia push into the
balloon like an expanded fist. As result of this process, the basal ganglia
expand into the ventricle from the ventral medial aspect of the telencephalon
and the pallium balloons outward, forward, and to the rear, while that portion
of the pallium directly related to the basal ganglia undergoes little expansion.
In fact, it is this process that results in the differential development of the
frontal, parietal, temporal and occipital lobes which will balloon out and
encompass the insular lobe which is held in place by the developing basal
ganglia.
2.
Specific Development of the Pallium (Figure 7)
Over time, the developing pallium becomes organized into archipallium
which is confined to the dorsal midline, the paleopallium, which is located
more ventrally and the neopallium which spans the areas between these two
regions, giving rise to the bulk of the convexity of the cerebral cortex. As the
development proceeds, the neopallium grows at a fast rate, and both the
archipallium and paleopallium are displaced to more medial positions.
(Figure 8)
a.
The archipallium which gives rise to the hippocampal formation is
displaced in a caudal direction into the medial wall of the temporal
lobe, due to the extensive growth of the neopallium in both the frontal
and lateral areas.
b.
The pyriform and entorhinal cortices, which are parts of the
paleopallium, are displaced medially and inferiorally to the basal
portion of the temporal lobe. The neopallium undergoes major
expansion which persists as the bulk of the definitive cerebral cortex.
c.
Initially, all areas of the cerebral cortex appear smooth, showing no
gyri and sulci. With continued development, however, gyri and sulci
develop so that by birth the lissencephalic brain is transformed into a
brain containing the complex gyri and sulci.
Figure 9
3. Commissural Fibers (Figure 10)
With the growth of the cerebral hemispheres, there is a concomitant development
of the major commissural systems, all of which derive from portions of the
lamina terminalis. Although the specific origin of these pathways is somewhat
controversial, it appears that the anterior commissure and hippocampal
commissure are the first to appear, followed in the tenth week of gestation by the
development of the corpus callosum. Lastly, the posterior commissure as well as
the optic chiasm appear.
Figure 10
4. Corpus striatum - Basal Ganglia (Figure 11)
As noted, the basal ganglia are derived from the base of the telencephalon and
protrude into the forming ventricular cavity. Initially, due to marked proliferation
in the mantle zone of this region, the basal ganglia differentiate into medial and
lateral striatal elevations. With expansion of the cerebral hemispheres, these
striatal elevations form longitudinal ridges in the floor of the main part of the
ventricular cavity, and when traced caudally, lie in the anterior wall of the
descending portion of the ventricle and the roof of the inferior horn. These
relationships are attributed to the fact that the striatal development proceeds in
relation to the expanding and turning cerebral hemispheres. In general, ascending
and descending cortical fibers further divide these bulges into a dorsal medial
portion which forms the caudate and a dorsal lateral portion which forms the
putamen and globus pallidus. The descending and ascending cortical fibers
involved in this process form the internal capsule.
Figure 11
VI.
Abnormal Development of the Brain
As one can imagine the complex processes described above suggests the potential for
various forms of congenial abnormality. While the purpose of this lecture is not to provide
detailed insight into the neurobiology of all CNS developmental abnormalities, the
following are provided to give examples of some of the key developmental abnormalities
that can occur.
1.
Marked disorders of neurulation can occur with non-closure of the anterior
neuropore. The common abnormalities related to this include complete dysaphia,
anencephaly, exencephaly, and Meningoencephalocele. These malformations are
recognized as direct failures of neurulation since CNS tissue is directly exposed to
the outside of the body. In anencephaly, most of the frontal and parietal bones are
absent with the forebrain appearing as a hemorrhagic mass. Exencephaly involves a
condition in which the brain is outside of the skull and Meningoencephalocele
involves the herniation of both brain and meningeal tissue out through a defect in the
skull.
Figure 12
Figure 13
2. Developmental Abnormalities Associated with the Forebrain
a. Pachygyria, a condition which the gyri are abnormally broad.
b. Lissencephaly - a condition in which there is a virtual absence of gyri and sulci
Figure 14
c. Microgyri - refers to a reduction in the size of the gyri
d. Hydranencephaly - a condition associated with virtual resorption of all the
telencephalic mass, such that the telencephalon persists as a thin strand of tissue
encompassing grossly enlarged ventricular cavities.
e. Porencephaly - involves the destruction of specific areas of the cortices, resulting
in a direct conduits established between the ventricular and cerebrospinal fluid
fronts.
Figure 15
3. Agenesis
Development can be associated with the absence or agenesis of various parts of the
brain including
a. Agenesis of the corpus callosum
Figure 16
b. Agenesis of the cerebellar hemispheres
c. Agenesis of the cerebellar vermis
* Netter Presenter Image Copyright 2004 Icon Learning Systems. All rights reserved.